WO2024054868A1 - An il-2 fc fusion protein for use in methods for the treatment of plaque psoriasis and atopic dermatitis - Google Patents

An il-2 fc fusion protein for use in methods for the treatment of plaque psoriasis and atopic dermatitis Download PDF

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Publication number
WO2024054868A1
WO2024054868A1 PCT/US2023/073577 US2023073577W WO2024054868A1 WO 2024054868 A1 WO2024054868 A1 WO 2024054868A1 US 2023073577 W US2023073577 W US 2023073577W WO 2024054868 A1 WO2024054868 A1 WO 2024054868A1
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days
fusion protein
subject
weeks
dose
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PCT/US2023/073577
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French (fr)
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Raphael Clynes
Ralph ZITNIK
Shelley BELOUSKI
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Xencor, Inc.
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Publication of WO2024054868A1 publication Critical patent/WO2024054868A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]

Definitions

  • a method of treating plaque psoriasis or atopic dermatitis in a subject in need thereof comprising subcutaneously administering to the subject an interleukin-2 (IL-2) Fc fusion protein, wherein the IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject every 12 to 16 days or every 27 to 31 days at a dose of about 0.003 mg/kg to about 0.100 mg/kg.
  • IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject every 12 to 16 days or every 27 to 31 days at a dose of
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least four cycles. In some aspects, the subject is administered the dose of about 0.007 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose - 1 - NAI-1537985011v1 of about 0.007 mg/kg every 14 days or every 30 days. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least four cycles.
  • the subject is administered the dose of about 0.015 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose of about 0.015 mg/kg every 14 days or every 30 days. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles. In some aspects, the subject is administered the dose of about 0.025 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose of about 0.025 mg/kg every 14 days or every 30 days.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles. In some aspects, the subject is administered the dose of about 0.040 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose of about 0.040 mg/kg every 14 days or every 30 days. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles. In some aspects, the subject is administered the dose of about 0.065 mg/kg every 13 to 15 days or every 28 to 30 days.
  • the subject is administered the dose of about 0.065 mg/kg every 14 days or every 30 days.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles.
  • the subject is administered the dose of about 0.100 mg/kg every 13 to 15 days or every 28 to 30 days.
  • the subject is administered the dose of about 0.100 mg/kg every 14 days or every 30 days.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for at least 3 - 2 - NAI-1537985011v1 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for at least 4 cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 14 days or every 30 days for at least two cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for at least 4 cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL- 2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 14 days or every 30 days for at least two cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose - 3 - NAI-1537985011v1 of about 0.065 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for at least 4 cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 14 days or every 30 days for at least two cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for 4 cycles. [0007] In some aspects, the IL-2 Fc fusion protein is XmAb®27564 (XmAb®564). In some aspects, the IL-2 Fc fusion protein is a biosimilar, biobetter, or bioequivalent of XmAb®27564 (XmAb®564). In some aspects, the subject is a human subject.
  • the human subject is 18 to 75 years of age. In some aspects, the human subject has a body surface area (BSA) of psoriasis of ⁇ 2%. In some aspects, the human subject has an Investigator’s Global Assessment of 2 (mild) to 4 (severe). In some aspects, the subject has not previously been administered a therapy for plaque psoriasis or atopic dermatitis. In some aspects, the subject has previously been administered a therapy for plaque psoriasis or atopic dermatitis. [0008] In some aspects, the subject has not previously been administered an oral treatment for plaque psoriasis or atopic dermatitis in the 4 weeks prior to the administration of the IL-2-Fc fusion protein.
  • BSA body surface area
  • the subject has not previously been administered a biologic treatment for plaque psoriasis or atopic dermatitis for 12 weeks or 5 half-lives, whichever is longer, prior to the administration of the IL-2-Fc fusion protein.
  • the subject has - 4 - NAI-1537985011v1 not previously been administered a phototherapy in the 4 weeks prior to the administration of the IL-2-Fc fusion protein.
  • the subject has not previously been administered a topical treatment for psoriasis or atopic dermatitis in the 2 weeks prior to the administration of the IL-2-Fc fusion protein.
  • the subject does not have any other inflammatory or dermatological condition besides the plaque psoriasis or atopic dermatitis. In some aspects, the subject does not have any other form of psoriasis or atopic dermatitis.
  • the administering of the IL-2 Fc fusion protein results in an increase in the number of CD4+ regulatory T (Treg) cells in the subject as compared to before the administering.
  • the number of CD4+ Treg cells is increased about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-fold, about 12-fold, about 13-fold, about 14-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, about 25-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, or about 100- fold.
  • the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD4+ effector T (Teff) cells in the subject as compared to before the administering.
  • the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of NK cells in the subject as compared to before the administering.
  • the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD4+ conventional T (Tcon) cells in the subject as compared to before the administering.
  • the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD8+ Tcon T cells in the subject as compared to before the administering.
  • the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a Psoriasis Area and Severity Index (PASI) score of about 50% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein.
  • the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a PASI score of about 75% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein.
  • the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a PASI score of about 90% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein.
  • the administering of the IL-2 Fc fusion protein results in the subject having a Static Investigator’s Global Assessment (sIGA) score of 0, 1 or 2.
  • the administering of the IL-2 Fc fusion protein results in the subject having an improvement in a Dermatology Life Quality Index (DLQI) score as compared to the baseline DLQI score in the subject prior to the administering of the IL-2 Fc fusion protein.
  • DLQI Dermatology Life Quality Index
  • the administering of the IL-2 Fc fusion protein results in the subject having a decrease in body surface area (BSA) of psoriasis or atopic dermatitis as compared to the baseline BSA of psoriasis or atopic dermatitis in the subject prior to the administering of the IL-2 Fc fusion protein.
  • BSA of psoriasis is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 60%, about 80%, about 90%, or about 100%.
  • the subject does not have another type of psoriasis besides the plaque psoriasis, or the subject has atopic dermatitis.
  • a method of treating plaque psoriasis or atopic dermatitis in a subject in need thereof comprising subcutaneously administering to the subject a single dose of an interleukin-2 (IL-2) Fc fusion protein, wherein the IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the single dose is an amount of about 0.003 mg/kg to about 0.1 mg/kg.
  • IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the single dose is an amount of about 0.003 mg/kg to about 0.1 mg/kg.
  • the single dose is an amount of 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, 0.065 mg/kg, or 0.1 mg/kg. In some aspects, the single dose is an amount of 0.065 mg/kg.
  • the IL-2 Fc fusion protein is XmAb®27564 (XmAb®564). In some aspects, the IL-2 Fc fusion protein is a biosimilar, biobetter, or bioequivalent of XmAb®27564 (XmAb®564). In some aspects, the subject is a human subject.
  • the administering of the IL-2 Fc fusion protein results in an increase in the number of CD25 bright Treg cells in the subject as compared to baseline. In some aspects, the administering of the IL-2 Fc fusion protein results in an increase in CD25 bright Treg/Tcon ratio in the subject as compared to baseline. In some aspects, the administering of the IL-2 Fc fusion protein results in an increase in the number of total Treg cells in the subject as compared to baseline. In some aspects, the total Treg cells comprises CD25 bright FoxP3+ CD4 Treg cells.
  • the increase is an increase of about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-fold, about 12- - 6 - NAI-1537985011v1 fold, about 13-fold, about 14-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, about 25-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, or about 100-fold.
  • the increase is an increase of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or more than about 100%.
  • FIG.1 depicts an IL-2 Fc fusion protein of the disclosure.
  • FIG.1 shows the structure of an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) engineered for reduced potency plus Treg selectivity.
  • FIGS.2A-2B each depict a study design of XmAb ® 27564 with an ascending dose escalation.
  • FIGS.3A-3C depict a study design using XmAb ® 27564.
  • FIG.3A depicts a dose escalation of XmAb ® 27564 for psoriasis and FIG.3B for atopic dermatitis.
  • the first cohort is administered a dose of 0.007 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the second cohort is administered a dose of 0.015 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the third cohort is administered a dose of 0.025 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the fourth cohort is administered a dose of 0.040 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the fifth cohort is administered a dose of 0.065 mg/kg of XmAb ® 27564 every 14 days for 4 doses; and the sixth cohort is administered a dose of 0.100 mg/kg of XmAb ® 27564 every 14 days for 4 doses (FIG.3A).
  • the first cohort is administered a dose of 0.015 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the second cohort is administered a dose of 0.025 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the third cohort is administered a dose of 0.040 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the fourth cohort is administered a dose of 0.065 mg/kg of XmAb ® 27564 every 14 days for 4 doses; and the fifth - 7 - NAI-1537985011v1 cohort is administered a dose of 0.100 mg/kg of XmAb ® 27564 every 14 days for 4 doses (FIG.
  • FIG.3C depicts an open-label extension phase using XmAb ® 27564.
  • FIG.4 depicts a figure showing Tregs role in homeostasis and autoimmune diseases.
  • FIG.5 depicts XmAb ® 27564 engineered to improve selectivity for Treg.
  • FIGS.6A-6D depict XmAb ® 27564 designed to reduce potency and improve Treg selectivity.
  • FIG.6A In vitro stimulation of human PBMCs with either XmAb ® 27564 (FIG.6A) or Fc- WT-IL-2 (FIG.6B) revealed approximately 400-fold potency reduction for IL-2 signaling in human Tregs (phosphorylated STAT5 induction), with enhanced Treg selectivity over Tcons, gamma delta T cells, or NK cells.
  • the Treg EC50 is 21nM in FIG.6A and 0.06nM in FIG.6B.
  • FIGS.6C-6D depict a comparison of pharmacological half–life in cynomolgus macaques showing prolonged exposure of low-potency XmAb ® 27564 vs. WT Fc-IL-2.
  • FIG.7 depicts XmAb ® 27564 Phase 1a study design in healthy subjects.
  • FIG.7 shows a randomized and double-blinded Phase 1a single-ascending dose (SAD) study.
  • SAD Phase 1a single-ascending dose
  • the outcome measures were: 1) safety and tolerability and 2) pharmacokinetics and activity biomarkers (e.g., T-cell populations).
  • FIGS.8A-8B depict graphs showing that XmAb ® 27564 promotes robust and durable expansion of CD25 bright Tregs.
  • FIG.8B The numeric values in FIG.8B are the mean values. Peak fold change is the peak CD25 bright FoxP3 + CD4 Treg cell absolute count at a post-treatment time point divided by absolute count at baseline. NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test.
  • FIGS.9A-9B depict graphs showing that XmAb ® 27564 promotes robust and durable increase in CD25 bright Tregs/Tcon ratio.
  • the numeric values in FIG.9B are the mean values.
  • the dashed horizontal middle line represents the average of pre-dose values from all 48 subjects with ⁇ 2SD shown in grey lines above and below the middle dashed line.
  • FIGS.10A-10C depict graphs showing Treg responses after a single subcutaneous dose of XmAb ® 27564 in healthy subjects.
  • FIGS.10A-10B show that XmAb ® 27564 promotes robust and durable expansion of total Treg cells.
  • the numeric values in FIGS.10A-10C are the mean values. Peak fold change is the peak CD25+FoxP3+ CD4 Treg cell absolute count at a - 8 - NAI-1537985011v1 post-treatment time point divided by absolute count at baseline.
  • FIG.10C depicts a graph showing CD25 bright Treg cells (functionally highly immunosuppressive Tregs) after a single subcutaneous dose of XmAb ® 27564 in healthy subjects.
  • FIGS.11A-11B depict graphs showing that CD25 bright and total Treg remain elevated for at least three weeks following administration of XmAb ® 27564.
  • the numeric values in FIGS. 11A-11B are the mean values.
  • FIGS.12A-12D depict graphs showing Tcon (CD4 Tcon and CD8 Tcon) and NK cells (CD56+ and CD56bright NK cells) after a single subcutaneous dose of XmAb ® 27564.
  • FIGS.12A-12C depict graphs showing that XmAb ® 27564 induces minimal increases in conventional T cells and NK cells.
  • FIG.12A is directed to CD4 + Tcon cell count;
  • FIG.12B is directed to CD8 + Tcon cell count; and
  • FIG.12C is directed to CD56 + NK cell count.
  • FIG.12D depicts a graph showing CD25 bright NK cells after a single subcutaneous dose of XmAb ® 27564.
  • FIGS.12A-12D included: placebo, 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, and 0.065 mg/kg of XmAb ® 27564. Dashed horizontal middle line represent the average of pre-dose values from all 48 subjects with ⁇ 2SD shown in grey lines above and below the middle horizontal dashed line.
  • FIGS.13A-13B depict graphs showing that peak fold induction of CD25 bright and total Treg cells showed consistent dose response of Treg populations to XmAb ® 27564.
  • FIG. 13A shows Treg peak fold induction
  • FIG.13B shows total Treg peak fold induction.
  • FIGS.13A-13B are the mean values.
  • NS p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test.
  • FIGS.14A-14B depict graphs showing that ratio of CD25 bright /Tcon and total Treg/Tcon peak fold induction showed consistent dose response of Treg populations to - 9 - NAI-1537985011v1 XmAb ® 27564.
  • FIG.14A shows CD25 bright Treg/Tcon peak fold induction (CD25 hi FoxP3 + CD4 + ) and FIG.14B shows total Treg/Tcon peak fold induction (CD25 + FoxP3 + CD4 + ).
  • the numeric values in FIGS.14A-14B are the mean values.
  • NS p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test.
  • FIG.15 depicts a graph showing pharmacokinetics data after cohorts were injected with 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, or 0.065 mg/kg of XmAb ® 27564.
  • FIGS.16A-16B depict pharmacodynamics data.
  • FIG.16B shows selective and durable expansion and activation of Tregs through Day 21. *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 by Wilcoxon test to compare median from 564-treated group to placebo-treated group.
  • FIGS.17A-17F depict Treg (FIGS.17A-17B), Tcon (FIGS.17C-17D), and NK cells (FIGS.17E-17F) responses after a single subcutaneous dose of XmAb ® 27564 in healthy volunteers.
  • FIGS.18A-18H depict graphs characterizing expanded Tregs after a single subcutaneous dose of XmAb ® 27564.
  • FIGS.19A-19B depict graphs showing that serum levels of IL-10 increased in a dose-dependent manner, and at the highest dose level of 0.065 mg/kg there was a 15-fold increase at Day 10 after treatment.
  • FIG.19B shows that a peak mean 16-fold increase was observed in a graph showing serum IL-10/IFN- ⁇ ratio.
  • FIG.20 depicts a graph showing induction of peripheral eosinophilia in adult healthy volunteers after a single subcutaneous dose of XmAb ® 27564.
  • FIG.21 depicts a graph showing that IL5 increased in normal healthy volunteers after a single subcutaneous dose of XmAb ® 27564. 4.
  • a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
  • the conjunctive term “and/or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and/or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the - 11 - NAI-1537985011v1 first. A third option refers to the applicability of the first and second elements together.
  • cycle refers to a specified period of time during which a treatment (e.g., an IL2-Fc fusion protein) is administered to a subject.
  • a treatment e.g., an IL2- Fc fusion protein
  • Fc When a treatment is administered to a subject for multiple cycles, the cycles can occur at regular intervals. For example, a cycle can be immediately followed by one or more additional cycles, or two or more cycles can be separated by a period without treatment.
  • the terms “Fc,” “Fc region,” or “Fc domain” as used herein refer to the polypeptide comprising the CH2-CH3 domains of an IgG molecule, and in some cases, inclusive of the hinge. In EU numbering for human IgG1, the CH2-CH3 domain comprises amino acids 231 to 447, and the hinge is 216 to 230. Thus, the definition of “Fc domain” includes both amino acids 231-447 (CH2-CH3) or 216-447 (hinge-CH2-CH3), or fragments thereof.
  • an “Fc fragment” in this context may contain fewer amino acids from either or both of the N- and C-termini but still retains the ability to form a dimer with another Fc domain or Fc fragment as can be detected using standard methods, generally based on size (e.g., non-denaturing chromatography, size exclusion chromatography, etc.)
  • Exemplary human IgG Fc domains that can be used herein include human IgG1, IgG2, or IgG4.
  • the terms “Fc variant” or “variant Fc” as used herein refer to a protein comprising an amino acid modification in an Fc domain.
  • the Fc variants of the present disclosure are defined according to the amino acid modifications that compose them.
  • N434S or 434S is an Fc variant with the substitution serine at position 434 relative to the parent Fc polypeptide, wherein the numbering is according to the EU index.
  • M428L/N434S defines an Fc variant with the substitutions M428L and N434S relative to the parent Fc polypeptide. It is noted that the order in which substitutions are provided is arbitrary, that is to say that, for example, 428L/434S is the same Fc variant as M428L/N434S, and so on.
  • the EU index or EU index as in Kabat or EU numbering scheme refers to the numbering of the EU antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, hereby entirely incorporated - 12 - NAI-1537985011v1 by reference.)
  • the modification can be an addition, deletion, or substitution. Substitutions can include naturally occurring amino acids and, in some cases, synthetic amino acids. Examples include U.S. Pat. No.6,586,207; WO 98/48032; WO 03/073238; US2004-0214988A1; WO 05/35727A2 WO 05/74524A2; J. W.
  • Fc fusion protein refers to a protein comprising an Fc region, generally linked (optionally through a linker moiety, which can be the hinge region of an IgG, such as IgG1) to a different protein, such as IL-2.
  • an IL-2 Fc fusion protein is a protein comprising an IL-2 (in this case, variant IL-2) and Fc domain. These generally have the structure IL-2-hinge-CH2-CH3.
  • two Fc domains can self- assemble to provide dimeric Fc fusion proteins.
  • nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same, when compared and aligned for maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection.
  • sequence comparison typically one sequence acts as a reference sequence, to which test sequences are compared.
  • sequence comparison algorithm test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated.
  • sequence comparison algorithm calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.
  • Sequence identity between two similar sequences can be measured by algorithms such as that of Smith, T.F. & Waterman, M.S. (1981) “Comparison of Biosequences,” Adv. Appl. Math.2:482 [local homology algorithm]; Needleman, S.B. & Wunsch, CD. (1970) “A General Method Applicable to the Search for Similarities in the Amino Acid Sequence of Two Proteins,” J. Mol. Biol.48:443 [homology alignment algorithm], Pearson, W.R. & Lipman, D.J.
  • BLAST and BLAST 2.0 algorithms are described in Altschul et al. (1990) J. Mol. Biol.215: 403-410 and Altschul et al. (1997) Nucleic Acids Res. 25: 3389-3402, respectively.
  • Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information.
  • This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra).
  • the BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
  • the BLASTP program uses as defaults a word length (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)).
  • the BLAST algorithm In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. Nat’l. Acad. Sci. USA 90:5873-5787 (1993)).
  • One measure of similarity provided - 14 - NAI-1537985011v1 by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance.
  • a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.
  • isolated when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Ordinarily, an isolated polypeptide can be prepared by at least one purification step.
  • “Recombinant,” when used to describe the various polypeptides disclosed herein, means the polypeptides are generated using recombinant nucleic acid techniques in exogeneous host cells, and they can be isolated as well.
  • wild type or WT refer to an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations.
  • a WT protein has an amino acid sequence or a nucleotide sequence that has not been intentionally modified.
  • the terms “peptide,” “polypeptide,” or “protein” can refer to a molecule comprised of amino acids and can be recognized as a protein by those of skill in the art.
  • peptide polypeptide
  • protein protein
  • variant protein refers to a protein that differs from that of a parent protein by virtue of at least one amino acid modification.
  • Protein variant may refer to the protein itself, a composition comprising the protein, or the amino sequence that encodes it.
  • the protein variant has at least one amino acid modification compared to the parent protein, e.g., from about one to about seventy amino acid modifications, or from about one to about five amino add modifications compared to the parent.
  • the parent polypeptide for example an Fc parent - 15 - NAI-1537985011v1 polypeptide, is a human wild type sequence, such as the Fc region from human IgG1, IgG2, IgG3 or IgG4.
  • the parent polypeptide is human IL-2, the mature sequence of which is SEQ ID NO: 1.
  • he protein variant sequence herein can possess at least about 80% identity, at least about 90% identity, or at least about 95%, 98%, or 99% identity with a parent protein sequence.
  • Variant protein can refer to the variant protein itself, compositions comprising the protein variant, or the DNA sequence that encodes it [0059]
  • the term “linker” as used herein refers to a proteinaceous linker that is used to join two other protein domains (e.g., the variant IL-2 domain and the variant Fc domain). In some cases, the linker is a “domain linker”, used to link any two domains.
  • linker While any suitable linker can be used, many embodiments utilize a glycine-serine polymer, including for example (GS)n, (GSGGS)n (SEQ ID NO: 4), (GGGGS)n (SEQ ID NO: 5), and (GGGS)n (SEQ ID NO: 6), where n is an integer of at least one (and generally from 3 to 4 to 5) as well as any peptide sequence that allows for recombinant attachment of the two domains with sufficient length and flexibility to allow each domain to retain its biological function.
  • charged domain linkers can be used.
  • the hinge domain of the human IgG1 protein can also be a domain linker.
  • the terms “regulatory T cells” or “Tregs” as used herein refers to T cells that are CD3+/CD4+/CD8 ⁇ /CD25+/FOXP3+.
  • the terms “treat,” “treatment,” and “treating” refer to the reduction or amelioration or elimination of the progression, severity and/or effect associated with plaque psoriasis or atopic dermatitis, as described herein, or the improvement in the plaque psoriasis or atopic dermatitis, or the improvement in the disease associated with the plaque psoriasis or atopic dermatitis, or the increase in the immune system response of the human subject, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of the plaque psoriasis or atopic dermatitis described herein resulting from the administration of one or more therapies.
  • treating plaque psoriasis or atopic dermatitis involves administering the IL2-Fc fusion protein for a pre-specified period of time, discontinuing administration for another specific period of time, and resuming administration of the IL2-Fc fusion protein for yet another specific period of time.
  • treating plaque psoriasis or atopic dermatitis involves administering the IL2-Fc fusion protein until one of the treatment effects described herein is achieved, pausing administration of the IL2-Fc fusion - 16 - NAI-1537985011v1 protein while this treatment effect continues to be observed, and resuming administration of the IL2-Fc fusion protein if this treatment effect ceases to be observed.
  • plaque-type psoriasis refers to plaque-type psoriasis (or plaque psoriasis).
  • Plaque-type psoriasis (or plaque psoriasis) treatment can be determined by standardized response criteria specific to the disease, e.g., by assessing the Psoriasis Area and Severity Index (PASI) score, Body Surface Area (BSA), Investigator’s Global assessment of improvement (IGA), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI), and/or based on photographs of whole body or specific plaques.
  • Psoriasis Area and Severity Index Psoriasis Area and Severity Index (PASI) score, Body Surface Area (BSA), Investigator’s Global assessment of improvement (IGA),
  • atopic dermatitis refers to eczema, and/or a chronic (long-lasting) disease that causes inflammation, redness, and irritation of the skin.
  • Atopic dermatitis treatment can be determined by standardized response criteria specific to the disease, e.g., by assessing Eczema Area and Severity Index (EASI), Body Surface Area (BSA), validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD), Peak Pruritis Numerical Rating Scale (PP-NRS), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI), and/or based on photographs of body.
  • EASI Eczema Area and Severity Index
  • BSA Body Surface Area
  • vIGA-AD validated Investigator Global Assessment for Atopic Dermatitis
  • Treatment according to the present invention includes a “therapeutically effective amount” of the medicaments used.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • a therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the medicaments to elicit a desired response in the individual. Alternatively, this property of a composition may be evaluated by examining the ability of the compound to inhibit cell growth or to induce apoptosis by in vitro assays known to the skilled practitioner.
  • a therapeutically effective amount can ameliorate at least one symptom in a subject.
  • a “therapeutically effective amount” refers to an amount of an IL-2 Fc fusion protein of the disclosure that is effective, upon single or multiple dose administration to a subject (such as a human patient) at treating, preventing, curing, delaying, reducing the severity of, ameliorating at least one symptom of a disorder (e.g., plaque psoriasis or atopic - 17 - NAI-1537985011v1 dermatitis) or recurring disorder, or prolonging the survival of the subject beyond that expected in the absence of such treatment.
  • a disorder e.g., plaque psoriasis or atopic - 17 - NAI-1537985011v1 dermatitis
  • One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject’s size, the severity of the subject’s symptoms, and the particular composition or route of administration selected.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the IL-2 Fc fusion protein can be incorporated into pharmaceutical compositions suitable for administration to a subject according to a dosage regimen described herein.
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564) and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are physiologically compatible and are suitable for administration to a subject using the methods described herein.
  • Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as any combination thereof.
  • isotonic agents can be included, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffers (such as an organic acid, which as a citrate or an acetate), which enhance the shelf life or effectiveness of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffers (such as an organic acid, which as a citrate or an acetate), which enhance the shelf life or effectiveness of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffer
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564) and histidine. In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564) and sorbitol. In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564), histidine (or a comparable agent), and sorbitol (or a comparable agent).
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564), 20 mM histidine (or a comparable agent), and 250 mM sorbitol (or a comparable agent), and the pH is 6.5.
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564), between about 10 mM and about 40 mM histidine (or a comparable agent), and between about 100 mM and about 400 mM sorbitol (or a comparable agent).
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564), between about 15 mM and about 25 mM histidine (or a comparable agent), and between about 200 mM and about 300 mM sorbitol (or a comparable agent).
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564), between about 17 mM and about 23 mM histidine (or a comparable agent), and between about 240 mM and about 250 mM sorbitol (or a comparable agent).
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 1mL to 10 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 1mL to 30 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 10 mL vial (e.g., glass vial) or syringe.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 5 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 2 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 1 mL vial (e.g., glass vial) or syringe.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a vial in each vial (e.g., glass vial), or in a syringe.
  • between about 15 mg and about 50 mg of an IL-2 Fc fusion protein is in a vial, in each vial (e.g., glass vial), or in a syringe.
  • between about 20 mg and about 40 mg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is in a vial, in each vial (e.g., glass vial), or in a syringe. In some embodiments, between about 25 mg and about 35 mg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is in a vial, in each vial (e.g., glass vial), or in a - 19 - NAI-1537985011v1 syringe.
  • about 30 mg/mL of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is in a vial, in each vial (e.g., glass vial), or in a syringe. In some embodiments, between about 15 mg/mL and about 50 mg/mL of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is in a vial, in each vial (e.g., glass vial), or in a syringe.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • between about 20 mg/mL and about 40 mg/mL of an IL-2 Fc fusion protein is in a vial, in each vial (e.g., glass vial), or in a syringe.
  • between about 25 mg/mL and about 35 mg/mL of an IL-2 Fc fusion protein is in a vial, in each vial (e.g., glass vial), or in a syringe.
  • the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is stored or shipped at a temperature of about 2° to about 8°C.
  • the vial with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is a single use vial.
  • the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is a sterile liquid supplied in a single use vial.
  • the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is supplied as a sterile liquid for injection. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is lyophilized. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is provided as an aqueous solution. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is suitable for subcutaneous administration.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the pharmaceutical composition comprising an IL-2 Fc fusion protein is prepared by mixing an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of a desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (e.g., as outlined in Remington’s Pharmaceutical Sciences, 16th edition, Osol, A. editor [1980]) for storage as a lyophilized formulation or as an aqueous solution.
  • the pharmaceutical compositions can be in a variety of forms. These include, for example, liquid, lyophilized, liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions.
  • compositions are in the form of subcutaneous solutions.
  • Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • Sterile injectable solutions can be prepared by incorporating the IL- - 20 - NAI-1537985011v1 2 Fc fusion protein in the required amount in an appropriate solvent with one or any combination of ingredients enumerated herein, as required, followed by filtered sterilization.
  • An IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the route/mode of administration is subcutaneous injection. The route and/or mode of administration can vary depending upon the desired results.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is administered subcutaneously. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is administered until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated (whether voluntarily or involuntarily) by the human subject. [0073] In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is a front line therapy, second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy.
  • a medical professional can readily determine and prescribe the effective amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) composition required.
  • a physician could start doses of the medicament employed in an IL-2 Fc fusion protein (e.g., XmAb ® 27564) composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • IL2-Fc Fusion Proteins Provided herein is a method of treating plaque psoriasis or atopic dermatitis in a subject with an IL-2 Fc fusion protein of the disclosure.
  • an IL-2 Fc fusion protein of the disclosure has three different domains: a Fc domain, one or more domain linkers, and an IL-2 domain.
  • an IL-2 Fc fusion protein of the disclosure is a heterodimeric monovalent construct, in which a variant IL-2 domain is generally fused to a variant human IgG Fc domain using either the hinge as the domain linker (generally including a C220S variant) or using an additional linker attached to the hinge, with the other Fc domain (including the hinge) remaining “empty”.
  • monovalent IL-2-Fc with linker comprises IL-2 (or variant IL-2) recombinantly fused to the N-terminus of a heterodimeric Fc- region via a domain linker, with the other side of the molecule being “Fc-only” or “empty-Fc”.
  • an IL-2 Fc fusion protein of the disclosure is a homodimeric bivalent construct, in which variant IL-2 domains are generally each fused to a variant human IgG1 Fc domain using either the hinge as the domain linker (generally including a C220S variant) or - 21 - NAI-1537985011v1 using an additional linker attached to the hinge.
  • bivalent IL-2-Fc with linker comprises IL-2 (or a variant IL-2) recombinantly fused to the N-terminus of both sides of a homodimeric Fc-region via a domain linker.
  • the domain linker is the IGG1 hinge, and in others it can include a linker selected from (GS)n, (GSGGS)n (SEQ ID NO: 4), (GGGGS)n (SEQ ID NO: 5), and (GGGS)n (SEQ ID NO: 6), where n is an integer of at least one.
  • an IL-2 Fc fusion protein of the disclosure is a heterodimeric protein complex comprising a first protein monomer comprising an IL-2 protein (e.g., a variant IL-2 protein) covalently linked to a first Fc domain (e.g., a first variant Fc domain) and a second protein monomer comprising a second Fc domain (e.g., a second variant Fc domain).
  • an IL-2 Fc fusion protein of the disclosure comprises an IL-2 protein consisting of an amino acid sequence of SEQ ID NO: 1.
  • an IL-2 Fc fusion protein of the disclosure comprises a variant human IL-2 protein (as compared to SEQ ID NO: 1).
  • an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence that is about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a wild-type IL-2 protein (e.g., SEQ ID NO: 1).
  • an IL-2 Fc fusion protein of the disclosure comprises amino acid substitution(s) as compared to a wild-type IL-2 protein (e.g., SEQ ID NO: 1) selected from T3A, D20N, T37R, N71K, T3A/D20N, T3A/D20N/T37R and T3A/D20N/N71K.
  • a first monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises SEQ ID NO: 2.
  • a second monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises SEQ ID NO: 3.
  • a first monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 2.
  • a first monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 2 and comprises one or more mutation(s) selected from C220S, S267K, L368D, K370S, M428L, and/or N434S (variant Fc domain).
  • a second monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, - 22 - NAI-1537985011v1 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 3.
  • a second monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 3 and comprises one or more mutation(s) selected from C220S, S267K, S364K, E357Q, M428L, and/or N434S (variant Fc domain).
  • a first monomer or chain of an IL-2 Fc fusion protein of the disclosure consists of an amino acid sequence of SEQ ID NO: 2.
  • a second monomer or chain of an IL-2 Fc fusion protein of the disclosure consists of an amino acid sequence of SEQ ID NO: 3.
  • a monomer (e.g., first monomer) or chain of an IL-2 Fc fusion protein of the disclosure comprises at least one of C220S, S267K, L368D, K370S, M428L, and N434S (compared to human IgG1 Fc domain).
  • a monomer (e.g., second monomer) or chain of an IL-2 Fc fusion protein of the disclosure comprises at least one of C220S, S267K, S364K, E357Q, M428L, and N434S (compared to human IgG1 Fc domain).
  • an IL-2 Fc fusion protein of the disclosure consists of: an amino acid sequence of SEQ ID NO: 1, an amino acid sequence of SEQ ID NO: 2, and an amino acid sequence of SEQ ID NO: 3.
  • an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to: SEQ ID NO: 1, SEQ ID NO: 2, and/or SEQ ID NO: 3.
  • N- and/or C-terminal clipping can occur during protein synthesis, whereby the heavy chains depicted herein may have the C-terminal lysine removed, as well as the penultimate glycine, and optionally additional amino acids residues (e.g., from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more C-terminal amino acids can be removed).
  • an IL-2 Fc fusion protein of the disclosure is XmAb ® 27564.
  • an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about, at least about, or at most about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to any amino acid sequence in Table 1.
  • - 23 - NAI-1537985011v1 an IL-2 Fc fusion protein of the disclosure is a biosimilar of an IL-2 Fc fusion protein provided in Table 1.
  • an IL-2 Fc fusion protein of the disclosure is a biobeter of an IL-2 Fc fusion protein provided in Table 1.
  • an IL-2 Fc fusion protein of the disclosure is a bioequivalent of an IL-2 Fc fusion protein provided in Table 1. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a biosimilar of XmAb ® 27564. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a biobeter of XmAb ® 27564. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a bioequivalent of XmAb ® 27564. Table 1.
  • an IL-2 Fc fusion protein of the disclosure comprises an Fc domain that comprises an ablation variant.
  • the normal binding of the Fc domain to one or more or all of the Fc ⁇ receptors is reduced or eliminated to avoid additional mechanisms of action.
  • ablation variants can be independently and optionally included or excluded.
  • an ablation variant includes, but is not limited to, C236R/L328R, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G, and E233P/L234V/L235A/G236del.
  • an IL-2 Fc fusion protein of the disclosure has a variant Fc domain that is a variant human IgG1 Fc domain comprising at least one amino acid substitution from E233P, L234V, L235A, G236del, and S267K (ablation variant).
  • the ablation variants of the disclosure ablate Fc ⁇ R binding but generally not FcRn binding.
  • an IL-2 Fc fusion protein of the disclosure is any IL-2 variant or IL-2 Fc fusion protein disclosed in WO2019125732 (PCT/US2018/063443) (the content of which is herein incorporated by reference in its entirety).
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a method for treating plaque psoriasis or atopic dermatitis in a human subject in need thereof comprising administering to the subject an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure, wherein the subject is first administered a first dose of the an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure on day 1, and subsequently administered a second dose of the an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure about 2 weeks after the first dose and at regular intervals (e.g., every 2 weeks) thereafter.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the first dose and the second dose is the same.
  • a method for treating plaque psoriasis or atopic dermatitis in a human subject in need thereof comprising administering to the subject an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as a single dose administration.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a method of the disclosure is used in a subject who has previously been treated for plaque psoriasis or atopic dermatitis.
  • a method of the disclosure is used in a subject who has not been previously treated for plaque psoriasis or atopic dermatitis (e.g., a na ⁇ ve subject).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein of the disclosure e.g., XmAb ® 27564
  • the subject does not have or has not been diagnosed with another type of psoriasis or atopic dermatitis, does not have or has not been diagnosed with another inflammatory condition (besides plaque psoriasis or atopic dermatitis), and/or does not have or has not been diagnosed with another dermatologic condition (besides plaque psoriasis or atopic dermatitis).
  • provided herein is a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) as a monotherapy treatment.
  • an IL-2 Fc fusion protein of the disclosure e.g., XmAb ® 27564
  • provided herein is a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) as a monotherapy treatment for plaque psoriasis or atopic dermatitis and at least one additional agent to treat or ameliorate at least one side effect of the IL-2 Fc fusion protein (e.g., XmAb ® 27564) administration or injection site in the subject.
  • an IL-2 Fc fusion protein of the disclosure e.g., XmAb ® 27564
  • provided herein is a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) as a monotherapy treatment for plaque psoriasis or atopic dermatitis and at least one additional agent to treat or ameliorate at least one symptom associated with the IL-2 Fc fusion protein (e.g., XmAb ® 27564) treatment.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • provided herein is a method of treating a subject diagnosed with or suspected of having severe plaque psoriasis or severe atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564). In some embodiments, provided herein is a method of treating a subject diagnosed with or suspected of having moderate plaque psoriasis or moderate atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564).
  • provided herein is a method of treating a subject diagnosed with or suspected of having mild plaque psoriasis or mild atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564).
  • an IL-2 Fc fusion protein of the disclosure e.g., XmAb ® 27564.
  • a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • an additional agent to treat at least one side effect or at least one symptom associated with plaque psoriasis and/or atopic dermatitis and/or the IL-2 Fc fusion protein (e.g., XmAb ® 27564) treatment.
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • Plaque psoriasis is an immune-mediated disease that causes raised, scaly patches on the skin due to systemic inflammation. In some embodiments, plaque psoriasis is triggered by at least one environmental factor. [0085] In some embodiments, the plaque psoriasis is chronic plaque psoriasis or chronic plaque-type psoriasis. In some embodiments, the plaque psoriasis is relapsing plaque psoriasis. In some embodiments, the plaque psoriasis is relapsing remitting plaque psoriasis. In some embodiments, the plaque psoriasis is non responsive to other plaque psoriasis treatment.
  • the plaque psoriasis is on the elbow(s) of the subject. In some embodiments, the plaque psoriasis is on the knee(s) of the subject. In some embodiments, the plaque psoriasis is on the scalp of the subject. In some embodiments, the plaque psoriasis is on the torso of the subject. [0086] In some embodiments, symptoms of plaque psoriasis include, but are not limited to, red or purple skin, itchy patches, shiny patches, and/or scaly skin. In some embodiments, symptoms of plaque psoriasis include, but are not limited to, thickening (plaque elevation, induration), and scaling (desquamation).
  • symptoms of plaque psoriasis include, but are not limited to, psoriasis-related itching, flaking, peeling, cracking, pain, scaling, and redness. 4.4.2.
  • Atopic Dermatitis is an immune-mediated skin disease.
  • atopic dermatitis is referred to as eczema.
  • the clinical characteristics of atopic dermatitis vary depending on age, disease stage, race or ethnic group, and/or geographic location. Typical acute lesions are circumscribed patches of eczema and erythema, which is more frequently violaceous or even invisible in patients with darker skin.
  • the lesions are characterized by papules, papulovesicles, edema, crusting, and scaling with hyperpigmentation or hypopigmentation of lesions after healing.
  • Atopic dermatitis may have disease stages.
  • a patient with atopic dermatitis has an eczema-free interval.
  • a patient with atopic dermatitis use emollients.
  • a topical immunosuppressive therapy is used when eczema occurs (e.g., in addition to XmAb ® 27564).
  • a patient has not been previously treated with an atopic dermatitis treatment.
  • a patient has been previously treated with an atopic dermatitis treatment.
  • a patient has been treated with or is being treated with monoclonal anti- - 27 - NAI-1537985011v1 interleukin-4, anti-interleukin-13, and/or anti-interleukin-31 antibodies, phosphodiesterase-4 inhibitors, and/or Janus kinase (JAK) inhibitors.
  • JNK Janus kinase
  • Target Patient Population Provided herein are methods of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject does not have any other type or form of psoriasis. In some embodiments, the subject does not have any other type or form of atopic dermatitis. In some embodiments, the subject does not have any other inflammatory or dermatological condition (besides the plaque psoriasis or atopic dermatitis treated with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the subject has or is suspected of having plaque psoriasis. In some embodiments, the subject has or is suspected of having chronic plaque-type psoriasis.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject has or is suspected of having plaque psoriasis on one or at least one part of the body. In some embodiments, the subject has or is suspected of having atopic dermatitis. In some embodiments, the subject has or is suspected of having chronic atopic dermatitis. In some embodiments, the subject has or is suspected of having atopic dermatitis on one or at least one part of the body. In some embodiments, the subject is a human subject. In some embodiments, the subject is a male human subject. In some embodiments, the subject is a female human subject. In some embodiments, the subject is a juvenile. In some embodiments, the subject is an adult. In some embodiments, the human subject is between 18 to 65 years of age.
  • the subject has been diagnosed with or is suspected of having plaque psoriasis or atopic dermatitis.
  • the subject has at least one symptom (e.g., psoriasis-related itching, atopic dermatitis-related itching, flaking, peeling, cracking, pain, scaling, and redness) related to plaque psoriasis or atopic dermatitis.
  • the subject is experiencing or has experienced at least one symptom associated with plaque psoriasis or atopic dermatitis, such as, red or purple skin, eczema, itchy patches, shiny patches, scaly skin, and/or thickening (plaque elevation, induration) of skin.
  • the subject is not experiencing a symptom related to plaque psoriasis or atopic dermatitis.
  • the subject had at least one episode of plaque psoriasis or atopic dermatitis.
  • the subject has mild plaque psoriasis or previously had mild plaque psoriasis.
  • the subject has moderate plaque psoriasis or previously had moderate plaque - 28 - NAI-1537985011v1 psoriasis. In some embodiments, the subject has severe plaque psoriasis or previously had severe plaque psoriasis. In some embodiments, severity of plaque psoriasis is determined based on the PASI scoring system. In some embodiments, severity of plaque psoriasis is determined based on the body surface area (BSA), Investigator’s Global Assessment (IGA) score, or any suitable assessment, assay, or scoring system (e.g., as disclosed in Section 4.4.8 of the disclosure).
  • BSA body surface area
  • IGA Global Assessment
  • the subject has mild atopic dermatitis or previously had mild atopic dermatitis. In some embodiments, the subject has moderate atopic dermatitis or previously had moderate atopic dermatitis. In some embodiments, the subject has severe atopic dermatitis or previously had severe atopic dermatitis. In some embodiments, severity of atopic dermatitis is determined based on the EASI scoring system. In some embodiments, severity of atopic dermatitis is determined based on the body surface area (BSA), vIGA-AD, or any suitable assessment, assay, or scoring system used for atopic dermatitis.
  • BSA body surface area
  • the subject has a relapse of plaque psoriasis or atopic dermatitis. In some embodiments, the subject has refractory plaque psoriasis. In some embodiments, the subject has chronic relapsing plaque psoriasis. In some embodiments, the subject is unresponsive to at least one treatment for plaque psoriasis. In some embodiments, the subject is unresponsive to several treatments for plaque psoriasis (e.g., unresponsive to several biologics). In some embodiments, the subject has refractory atopic dermatitis. In some embodiments, the subject has chronic relapsing atopic dermatitis.
  • the subject is unresponsive to at least one treatment for atopic dermatitis. In some embodiments, the subject is unresponsive to several treatments for atopic dermatitis (e.g., unresponsive to several biologics). [0091] In some embodiments, the subject has at least one risk factor associated with plaque psoriasis or atopic dermatitis (e.g., smoking, obesity or overweight, elevated body mass index (BMI), use of certain medications, infection, use of alcohol, vitamin D deficiency, stress, skin irritation or any injury to the skin).
  • BMI body mass index
  • the subject has been previously treated with an agent for plaque psoriasis or atopic dermatitis (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment).
  • an agent for plaque psoriasis or atopic dermatitis e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment.
  • the subject has been previously treated with a treatment for plaque psoriasis or atopic dermatitis (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical - 29 - NAI-1537985011v1 treatment) within the last 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days
  • the subject is a na ⁇ ve subject (i.e., has not previously undergone treatment for plaque psoriasis or atopic dermatitis).
  • the subject has been previously treated with only one agent or only one treatment regimen for plaque psoriasis or atopic dermatitis.
  • the subject has been previously treated with at least one agent or with at least one treatment regimen for plaque psoriasis or atopic dermatitis.
  • the subject has been previously treated with two or more agents or two or more treatment regimens for plaque psoriasis or atopic dermatitis.
  • the subject has not been previously treated with a plaque psoriasis or atopic dermatitis agent or treatment (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment) within about or within the last 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days,
  • the subject has not been previously treated with a plaque psoriasis or atopic dermatitis agent or treatment (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment) within about 30 days prior to treatment or first administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure to the subject.
  • a plaque psoriasis or atopic dermatitis agent or treatment e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject has not been previously treated with any agent or any treatment regimen for plaque psoriasis or atopic dermatitis.
  • the subject has not been previously treated with two or more agents or two or more treatment regimens for plaque psoriasis or atopic dermatitis.
  • the subject has not previously been administered an oral treatment for plaque psoriasis or atopic dermatitis in the 4 weeks prior to the administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject has not previously been administered a topical treatment for plaque psoriasis or atopic dermatitis in the 2 weeks prior to the administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject has not previously been administered a phototherapy in the 4 weeks prior to the administration of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL- 2 Fc fusion protein e.g., XmAb ® 27564
  • the subject has not previously been administered a biologic treatment for plaque psoriasis or atopic dermatitis for 12 weeks or 5 half-lives, whichever is longer, prior to the administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. 4.4.4.
  • a dose has a specific amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure that is administered to a subject over a defined time period.
  • the amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure administered to a subject is also known as the dose amount.
  • the time over which the dose amount is administered to a subject is also known as the administration time.
  • the dosage may be determined based upon the weight of the subject, such as by multiplying the weight (in kg, for example) of the subject by a dose amount - 31 - NAI-1537985011v1 (such as those described herein).
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject as a single dose.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject as part of a treatment cycle.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject more than once.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject at predetermined intervals.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is about, at least about, or at most about 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45 mg, 1.5 mg, 1.55 mg, 1.6 mg, 1.65 mg, 1.7 mg, 1.75 mg, 1.8 mg, 1.85 mg, 1.9 mg, 1.95 mg, 2 mg, 2.1 mg, 2.
  • a dose of an IL-2 Fc fusion protein is about, at least about, or at most about 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, - 32 - NAI-1537985011v1 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.010 mg/kg, 0.011 mg/kg, 0.012 mg/kg, 0.013 mg/kg, 0.014 mg/kg, 0.015 mg/kg, 0.016 mg/kg, 0.017 mg/kg, 0.018 mg/kg, 0.019 mg/kg, 0.020 mg/kb, 0.021 mg/kg, 0.022 mg/kg, 0.023 mg/kg, 0.024 mg/kg, 0.025 mg/kg, 0.026 mg/kg, 0.027 mg/kg
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is between about 0.001 mg/kg and about 0.150 mg/kg, between about 0.003 mg/kg and about 0.120 mg/kg, between about 0.005 mg/kg and about 0.02 mg/kg, between about 0.005 mg/kg and about 0.0270 mg/kg, between about 0.005 mg/kg and about 0.025 mg/kg, between about 0.003 mg/kg and about 0.007 mg/kg, between about 0.003 mg/kg and about 0.1 mg/kg, between about 0.002 mg/kg and about 0.008 mg/kg, between about 0.005 mg/kg and about 0.045 mg/kg, between about 0.005 mg/kg and about 0.050 mg/kg, between about 0.005 mg/kg and about 0.070 mg/kg, between about 0.005 mg/kg and about 0.15 mg/kg, between about 0.005 mg/kg and about 0.1 mg/
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is between about 0.003 mg/kg and about 0.12 mg/kg, 0.007 mg/kg and about 0.100 mg/kg, between about 0.006 mg/kg and about 0.020 mg/kg, between about 0.006 mg/kg and about 0.030 mg/kg, between about 0.006 mg/kg and about 0.040 mg/kg, between about 0.006 - 33 - NAI-1537985011v1 mg/kg and about 0.06 mg/kg, between about 0.006 mg/kg and about 0.070 mg/kg, 0.006 mg/kg and about 0.08 mg/kg, 0.006 mg/kg and about 0.090 mg/kg, 0.006 mg/kg and about 0.100 mg/kg, between about 0.006 mg/kg and about 0.120 mg/kg, between about 0.010 mg/kg and about 0.020 mg/kg, between about 0.010 mg/kg and
  • a method of treating plaque psoriasis or atopic dermatitis in a subject comprising subcutaneously administering to the subject a single dose of an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564).
  • a single dose of an IL-2 Fc fusion protein of the disclosure includes any dosage of the disclosure.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of about 0.003 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.003 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.007 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.007 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.015 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.015 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.025 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of 0.025 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.04 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.04 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.065 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.065 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.1 mg/kg. In certain embodiments, an - 35 - NAI-1537985011v1 IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.1 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of between about 0.002 mg/kg to about 0.1 mg/kg, between about 0.003 mg/kg to about 0.07 mg/kg, between about 0.003 mg/kg to about 0.065 mg/kg, between about 0.002 mg/kg to about 0.004 mg/kg, between about 0.006 mg/kg to about 0.008 mg/kg, between about 0.010 mg/kg to about 0.020 mg/kg, between about 0.020 mg/kg to about 0.030 mg/kg, between about 0.030 mg/kg to about 0.050 mg/kg, between about 0.060 mg/kg to about 0.070 mg/kg, between about 0.050 mg/kg to about 0.080 mg/kg, between about 0.040 to about 0.07 mg/kg, or between about 0.060 to about 0.1 mg/kg.
  • XmAb ® 27564 is administered at a single dose of between about 0.002 mg/kg to about 0.1 mg/kg, between about 0.00
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of at least about 0.003 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at most about 0.003 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at least about 0.007 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of at most about 0.007 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at least about 0.015 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at most about 0.015 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of at least about 0.025 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at most about 0.025 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at least about 0.04 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of at most about 0.04 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at least about 0.065 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at most about 0.065 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at least about 0.1 mg/kg. - 36 - NAI-1537985011v1 In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at most about 0.1 mg/kg. [00102] In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject as a single dose.
  • a dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for 1 dose or 1 cycle, 2 doses or 2 cycles, 3 doses or 3 cycles, 4 doses or 4 cycles, 5 doses or 5 cycles, 6 doses or 6 cycles, 7 doses or 7 cycles, 8 doses or 8 cycles, 9 doses or 9 cycles, 10 doses or 10 cycles, 15 doses or 15 cycles, 20 doses or 20 cycles, 25 doses or 25 cycles, 30 doses or 30 cycles, 35 doses or 35 cycles, 40 doses or 40 cycles, 45 doses or 45 cycles, 50 doses or 50 cycles, 100 doses or 100 cycles, or more than 100 doses or 100 cycles.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a dose is administered about every 2 weeks.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered every 12, 13, 14, 15, 16, or 17 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered about or every 12 to 17 days, 13 to 17 days, 14 to 17 days, 15 to 17 days, 16 to 17 days, 12 to 16 days, 13 to 16 days, 14 to 16 days, 15 to 16 days, 12 to 15 days, 13 to 15 days, or 14 to 15 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered about every 25, 26, 27, 28, 29, 30, 31, or 32 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered about or every 22 to 32 days, 25 to 31 days, 26 to 31 days, 27 to 31 days, 28 to 31 days, 29 to 31 days, 30 to 31 days, 25 to 31 days, 26 to 30 days, 27 to 30 days, 28 to 30 days, 29 to 30 days, 28 to 30 days, or 29 to 30 days.
  • a dose of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered monthly (or once per month). In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered twice per month. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered every four weeks. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered every two weeks.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered twice a month or three times a month.
  • a cycle is about 12, 13, 14, 15, 16, or 17 days.
  • a cycle is about 25, 26, 27, 28, 29, 30, 31, or 32 days.
  • a cycle is about two weeks.
  • a cycle is about four weeks.
  • one cycle comprises administration of one dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • a dose is the same as an earlier dose and/or a subsequent dose. In some embodiments, a dose in a cycle is the same from an earlier dose and/or subsequent dose in a different cycle. In some embodiments, the number of cycles or doses varies based on the plaque psoriasis or atopic dermatitis of the subject. In some embodiments, the number of cycles or doses varies based on the treatment regimen for the plaque psoriasis or atopic dermatitis in the subject.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a subject e.g., every two weeks or every four weeks.
  • about, at least about, or at most about 0.007 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks).
  • about, at least about, or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks). In some embodiments, about, at least about, or at most about 0.025 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks).
  • about, at least about, or at most about 0.040 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks). In some embodiments, about, at least about, or at most about 0.065 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a subject e.g., every two weeks, and for about, e.g., four doses; or every four weeks.
  • a dose amount (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for about, at least about, or at most about: one dose, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200 doses or cycles, or more than 200 doses or cycles).
  • the subsequent dose is the same as the first dose or earlier dose.
  • a first dose amount e.g., - 38 - NAI-1537985011v1 between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a second dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a first dose amount (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject
  • a second dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a third dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject.
  • a first dose amount (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject
  • a second dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a third dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a fourth dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject.
  • more than four doses e.g., between about 0.003 mg/kg and about 0.2 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure are administered to a subject.
  • a fifth dose and/or any subsequent dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is/are administered to a subject.
  • a dose or a subsequent dose is administered about 2 weeks after a previous dose (e.g., the second dose is administered about 2 weeks after the administration of the first dose).
  • a dose or a subsequent dose is administered about 4 weeks after a previous dose (e.g., the second dose is administered about 4 weeks after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered about 13-15 days after a previous dose (e.g., the second dose is administered about 13-15 days after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered about 14 days after a previous dose (e.g., the second dose is administered about 14 days after the administration of the first dose).
  • a dose or a subsequent dose is administered about 27-31 days after a previous dose (e.g., the second dose is administered about - 39 - NAI-1537985011v1 24-31 days after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered about 24, 25, 26, 27, 28, 29, 30, or 31 days after a previous dose (e.g., the second dose is administered about 24, 25, 26, 27, 28, 29, 30, or 31 days after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered every four weeks (e.g., 24-31 days; or about 24, 25, 26, 27, 28, 29, 30, or 31 days).
  • a subsequent dose e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200 doses, or more than 200 doses; e.g., between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a dose amount (e.g., between about 0.005 mg/kg and about 0.009 mg/kg, or about 0.007 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a dose amount (e.g., between about 0.010 mg/kg and about 0.020 mg/kg, or about 0.015 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a dose amount (e.g., between about 0.020 mg/kg and about 0.030 mg/kg, or about 0.025 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a dose amount (e.g., between about 0.035 mg/kg and about 0.045 mg/kg, or about 0.40 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a dose amount (e.g., between about 0.06 mg/kg and about 0.07 mg/kg, or about 0.065 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a dose amount (e.g., between about 0.095 mg/kg and about 0.15 mg/kg, or about 0.1 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a subsequent dose (e.g., 5, 6, 7, 8, 9, and/or 10, or - 40 - NAI-1537985011v1 more than 10 doses) (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject (e.g., after about 2 weeks from a previous dose; about 13-16 days after a previous dose; or about 14 days after a previous dose; or every four weeks).
  • a subsequent dose is the same as the previous dose.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for 4 doses (e.g., between about 0.003 mg/kg and about 0.2 mg/kg). In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for more than 4 doses (e.g., between about 0.003 mg/kg and about 0.2 mg/kg).
  • a cycle includes one administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure to a subject (e.g., between about 0.003 mg/kg and about 0.2 mg/kg). In some embodiments, a cycle is about two weeks. In some embodiments, a cycle is about four weeks. [00107] In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 12 and about 17 days.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 13 and about 15 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 13-15 days.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 12 and about 16 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 12-16 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 14-16 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 13 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 13 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 14 days.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 14 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every two weeks.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every two weeks.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 13 and about 17 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 13-17 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 15 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 15 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 16 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 24 and about 32 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 27 and about 31 days.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 28-31 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 28 and about 30 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 24-32 days or 27-31 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 28-30 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 24, 25, 26, 27, 28, 29, 30, or 31 days.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 24, 25, 26, 27, 28, 29, or 30 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 24, 25, 26, 27, 28, 29, or 30 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every four weeks.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every four weeks.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 24 and about 32 days or between about 27 and about 30 days.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 27-30 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 28, 29, 30, or 31 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 28 or 30 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 28, 29, 30, or 31 days.
  • a method of the disclosure comprises administration (e.g., subcutaneous) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure to a subject.
  • administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is via subcutaneous administration.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject for a period of time. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject until plaque psoriasis or atopic dermatitis is treated.
  • the IL- - 43 - NAI-1537985011v1 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject until plaque psoriasis or atopic dermatitis is improved in the subject (e.g., improved based on at least one efficacy assessment or assay for plaque psoriasis or atopic dermatitis (e.g., Section 4.4.8 and Section 5 of the disclosure)).
  • administration of an IL-2 Fc fusion protein stops after a positive therapeutic response (e.g., based on at least one efficacy assessment or assay for plaque psoriasis or atopic dermatitis (e.g., Section 4.4.8 or Section 5 of the disclosure)) is achieved.
  • a positive therapeutic response is a therapeutic response that ameliorates at least one symptom of plaque psoriasis or atopic dermatitis and/or ameliorates the severity (e.g., severe to moderate or mild) of plaque psoriasis or atopic dermatitis in a subject after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure begins again once the positive therapeutic response diminishes or disappears.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject at the start of relapse from a prior plaque psoriasis or atopic dermatitis treatment.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject after the subject has undergone at least one treatment for plaque psoriasis or atopic dermatitis.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject after the subject has been diagnosed with plaque psoriasis or atopic dermatitis. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject in combination with at least one agent that ameliorates at least one symptom associated with plaque psoriaris or atopic dermatitis.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject in combination with at least one agent that ameliorates at least one symptom associated with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject as a single dose administration.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every 2 weeks.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every 4 weeks. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about, at - 44 - NAI-1537985011v1 least about, or at most about once a month, twice a month, three times a month. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about, at least about, or at most about every 12, 13, 14, 15, 16, or 17 days..
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about, at least about, or at most about every 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every 14 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every 24, 25, 26, 27, 28, 29, 30, or 31 days.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject every 12 to 17 days, 12 to 16 days, 12 to 15 days, 12 to 14 days, 13 to 15 days, 13 to 16 days, 13 to 17 days, 14 to 15 days, 14 to 16 days, 14 to 17 days, or any suitable time period.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every two weeks.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject every 24 to 32 days, 24 to 31 days, 24 to 30 days, 25 to 32 days, 26 to 31 days, 27 to 31 days, 27 to 30 days, 28 to 30 days, 29 to 30 days, 28 to 31 days, 28 to 30 days, or any suitable time period.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every four weeks. [00112]
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every 14 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every two weeks. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every four weeks. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject on Day 1, Day 15, Day 19, and/or Day 43.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject on Day 1, Day 15, Day 19, Day 43, and/or every 14 days thereafter or every 14 days until end of treatment.
  • treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure comprises about, at least about, or at most about, 4 doses (or cycles).
  • treatment with an IL-2 Fc fusion protein comprises about, at least about, or at most about, 1 dose (or cycle), 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, - 45 - NAI-1537985011v1 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 350, 400, 450, 500 doses (or cycles), or more than about 500 doses (or cycles).
  • 1 dose or cycle
  • each dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject every 12, 13, 14, 15, 16, or 17 days.
  • each dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject every 24, 25, 26, 27, 28, 29, 30, or 31 days.
  • a cycle is about 12, 13, 14, 15, 16, or 17 days.
  • a cycle is about 24, 25, 26, 27, 28, 29, 30, or 31 days.
  • each dose is administered to a subject every 12 to 17 days.
  • each dose is administered to a subject every 25 to 32 days.
  • each dose is administered to a subject every 14 days. In some embodiments, each dose is administered to a subject every 24, 25, 26, 27, 28, 29, 30, or 31. In some embodiments, each dose is administered to a subject every 13 to 15 days. In some embodiments, each dose is administered to a subject every 24 to 30 days, 24 to 31 days, 25 to 32, 27 to 31, or 28 to 30 days. In some embodiments, each cycle is 12 to 17 days. In some embodiments, each cycle is 14 days. In some embodiments, each cycle is 13 to 15 days. In some embodiments, a dose is administered every 2 weeks. In some embodiments, a cycle is about two weeks. In some embodiments, each cycle is 24 to 31 days or 26 to 31 days. In some embodiments, each cycle is 14 days.
  • each cycle is 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, each cycle is 27 to 30 days. In some embodiments, a dose is administered every 4 weeks. In some embodiments, a cycle is about 4 weeks. 4.4.5.1 Subcutaneous administration [00113] In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject via a subcutaneous administration. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject via a single dose subcutaneous administration. In some embodiments, the term “subcutaneous” infusion or injection is meant to encompass any method of transcutaneous delivery to a subject.
  • a needle device is inserted at a selected site within the body of a subject for subcutaneous delivery of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) to the subject.
  • a pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is administered subcutaneously to the subject.
  • a solution comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564), histidine - 46 - NAI-1537985011v1 (e.g., 20 mM), and sorbitol (e.g., 250 mM) is subcutaneously administered to the subject.
  • the solution is a sterile liquid for injection and practically free of visible particulates.
  • a solution comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) suitable for subcutaneous administration is provided in a vial or ampule.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is subcutaneously administered to a subject about every 2 weeks or every 2 weeks.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is subcutaneously administered to a subject every 12 to 17 days, 12 to 16 days, 12 to 15 days, 12 to 14 days, 13 to 17 days, 13 to 16 days, 13 to 15 days, 13 to 14 days, 14 to 17 days, 14 to 16 days, or 14 to 15 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is subcutaneously administered to a subject about every, at least every, or at most every: 12 days, 13 days, 14 days, 15 days, 16 days, or 17 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is subcutaneously administered to a subject every 22 to 32 days, 24 to 30 days, 25 to 31 days, 27 to 30 days, or 28 to 30 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is subcutaneously administered to a subject about every, at least every, or at most every: 24, 25, 26, 27, 28, 29, 30, 31, or 32 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is subcutaneously administered to a subject about every 14 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is subcutaneously administered to a subject about every 24, 25, 26, 27, 28, 29, or 30 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is subcutaneously administered to a subject once in a month, twice in a month, or three times in a month. [00114] In some embodiments, an autoinjector is used for subcutaneous administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) to the subject.
  • an autoinjector is used for subcutaneous administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) to the subject.
  • a syringe is used for subcutaneous administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) to the subject.
  • a 27 gauge syringe is used to administer an IL-2 Fc fusion protein (e.g., XmAb ® 27564) to the subject.
  • a 25 gauge to 30 gauge syringe is used (e.g., to administer an IL-2 Fc fusion protein to the subject).
  • a 3/8 inches to 5/8 inches needle is used.
  • a prefilled syringe is used to administer an IL-2 Fc fusion protein to the subject.
  • the syringe is a 1 mL - 47 - NAI-1537985011v1 syringe. In some embodiments, a syringe is a 2 mL syringe. In some embodiments, a syringe is a 5 mL syringe. In some embodiments, the syringe is at most a 10 mL syringe. In some embodiments, the syringe is at most a 30 mL syringe. In some embodiments, subcutaneous injection is administered at a 45- to 90-degree angle. In some embodiments, the injection is administered in any suitable body part of a subject.
  • the injection is administered in the left upper lateral arm (deltoid). In some embodiments, the injection is administered in the right upper lateral arm (deltoid).
  • the injection site is marked with a small circle and date of injection to identify injection site and to monitor reaction(s). In some embodiments, the injection site is monitored for pain, tenderness, erythema and/or swelling (e.g., Example 1 and/or by using a Canfield photography system). In some embodiments, a subject is assessed for allergic and non-allergic injection-related reactions after a subcutaneous administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564.
  • a subject is assessed for adverse event (e.g., within about 6 hours) from the start of a subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • an adverse event is a sign and/or symptom associated with hypersensitivity/anaphylactic reaction (e.g., skin, gastrointestinal, respiratory, cardiovascular, and neurologic systems) from a subcutaneous injection.
  • an electrocardiogram (ECG) assessment is performed predose and/or after (e.g., about 4 hours after) a subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected prior to subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected after subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected about 30 minutes after subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected every 60 minutes for 4 hours after subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564). 4.4.6.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564.
  • Previous Treatment For Plaque Psoriasis or Atopic Dermatitis - 48 - NAI-1537985011v1 Provided herein is a method of treating plaque psoriasis or atopic dermatitis in a subject with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure, wherein the subject has been previously treated with a previous therapy or treatment for plaque psoriasis or atopic dermatitis that is not the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the previous therapy or treatment for plaque psoriasis or atopic dermatitis includes one agent for treating plaque psoriasis or atopic dermatitis.
  • the previous therapy or treatment for plaque psoriasis or atopic dermatitis means that the subject has undergone one treatment regimen for plaque psoriasis or atopic dermatitis.
  • the previous therapy or treatment for plaque psoriasis or atopic dermatitis means at least one agent for treating plaque psoriasis or atopic dermatitis.
  • the previous therapy or treatment for plaque psoriasis or atopic dermatitis means that the subject has undergone at least one treatment regimen for plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy or treatment for plaque psoriasis or atopic dermatitis means two or at least two agents for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy or treatment for plaque psoriasis or atopic dermatitis means that the subject has undergone two or at least two treatment regimen for plaque psoriasis or atopic dermatitis.
  • the previous therapy is used to treat the plaque psoriasis or atopic dermatitis that an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is used to treat in the subject.
  • a method of the disclosure further comprises administering an additional agent for treating at least one side effect or symptom associated with IL-2 Fc fusion protein (e.g., XmAb ® 27564) treatment and/or associated with the previous therapy.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is one agent for treating plaque psoriasis or atopic dermatitis.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis are two or more agents for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis are three or more agents for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy is administered prior to the administration with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. [00117] In some embodiments, a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a non-responder.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a responder.
  • a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a relapser.
  • a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a rebounder.
  • a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a partial responder.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a topical therapy.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is phototherapy (UVB, PUVA).
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a biologic, such as efalizumab.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a biologic, such as an antagonist of TNF, IL-12/23, IL-23, and IL-17.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a non-biologic, such as cyclosporine.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a small molecule systemic therapy or small molecule immunomodulators, such as methotrexate, acitretin, apremilast, and cyclosporin.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a systemic agent for plaque psoriasis or atopic dermatitis.
  • Examples of a systemic agent for treating plaque psoriasis or atopic dermatitis include, but are not limited to, methotrexate, cyclosporine, fumaric acid esters, acitretin, alefacept, adalimumab, efalizumab, etanercept, infliximab, golimumab and/or ustekinumab.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is secukinumab.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is adalimumab, alefacept, etanercept, infliximab, and/or ustekinumab.
  • a previous therapy for atopic dermatitis is a monoclonal anti- interleukin-4, -13, and -31 antibodies, phosphodiesterase-4 inhibitors, and Janus kinase (JAK) inhibitors.
  • a previous therapy for atopic dermatitis is a topical immunosuppressive therapy.
  • the previous therapy is an IL-17 binding molecule (e.g., an IL- 17 antibody, such as secukinumab), a topical therapy (over the counter, non-steroidal compounds and steroidal compound), phototherapy, and/or systemic treatment (e.g., with biologics or chemical entities).
  • an IL-17 binding molecule e.g., an IL- 17 antibody, such as secukinumab
  • a topical therapy over the counter, non-steroidal compounds and steroidal compound
  • phototherapy e.g., with biologics or chemical entities.
  • Non-limiting examples of topical agents include salicylic acid, coal tar, Dovonex ® (calcipotriene), Taclonex ® (calcipotriene and betamethasone dipropionate), Tazorec ® (tazarotene), pimecrolimus, castellani’s paint (Castederm), tacrolimus, Vectical ® (calcitriol), - 50 - NAI-1537985011v1 Zithranol-RR ® (anthralin), and topical steroids (e.g., corticosteroids).
  • Non-limiting examples of phototherapy include treatment with psoralen+UVA or treatment with UVB (with or without tar).
  • Non-limiting examples of phototherapy include retionoids such as Acitretin (Soriatane ® ), cyclosporine, methotrexate, Hydrea ® (hydroxyurea), isotretinoin, tildrakizumab, risankizumab, broadalumab, ixekizumab, mycophenolate mofetil, mycophenolic acid, sulfasalazine, 6- thioguanine, fumarates (e.g, dimethylfumarate and fumaric acid esters), azathioprine, corticosteroids, leflunomide, tacrolimus, T-cell blockers (such as Amevive ® (alefacept) and Raptiva ® (efalizumab), tumor necrosis factor-alpha (TNF-alpha) blockers (such as Enbrel ® (etanercept), Humira ® (adalimumab), Remicade ®
  • the previous therapy includes, but it is not limited to, apremilast, mometasome, voclosporin, Ketokonazol, Neuroskin Forte, recombinant human interleukin-10, voclosporin, VX-765, dovonex, MED-I545, fluphenazine decanoate, bimosiamose cream, doxycycline, vancomycin, AbGn168, Vitamin D3, RO5310074, fludarabine Calcipotriol and hydrocortisone (LEO 80190), LE80185 (Taclonex ® Scalp topical suspension/Xamiol ® gel), Focetria (Monovalent MF59-Adjuvanted vaccine, tgAAC94 gene therapy vector, Apremilast, Capsaicin, Psirelax, ABT-874 (anti IL-12), IDEC-114, MEDI-522, INCB018424 phosphate cream, LE29102, B
  • An IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure and at least one additional therapeutic agent (e.g., agent for treating a side effect) can be administered simultaneously, in the same or in separate compositions, or sequentially.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure can be administered first, and the additional agent can be administered second, or vice versa.
  • An IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure can be administered before the other treatment or agent, concurrently with the treatment, post-treatment, or during a positive therapeutic response to the disorder.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure and the one or more additional agents can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each agent used individually.
  • an additional agent is an agent that ameliorates at least one side effect associated with plaque psoriasis or atopic dermatitis or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject.
  • a steroid is administered to a subject.
  • a steroid is administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the steroid is administered in an amount between about 5 mg and about 30 mg.
  • the steroid described herein is administered in an amount between about 5 mg and about 25 mg.
  • the steroid is administered in an amount between about 5 mg and about 15 mg.
  • the steroid is administered in an amount between about 8 mg and about 12 mg.
  • the steroid is administered in an amount between about 10 mg and about 20 mg. In one embodiment, the steroid is administered in an amount of about 10 mg.
  • the steroid is administered in an amount of 10 mg. In one embodiment, the steroid is administered in an amount between about 18 mg and about 22 mg. In one embodiment, the steroid is administered in an amount of about 20 mg. In one embodiment, the steroid is administered in an amount of 20 mg. In one embodiment, the steroid is dexamethasone. In one embodiment, the steroid is dexamethasone and is administered in an amount between about 10 mg and about 20 mg. In one embodiment, the steroid is dexamethasone and is administered in an amount of about 10 mg. In one embodiment, the steroid is dexamethasone. In some embodiments, dexamethasone is administered intravenously.
  • the steroid is dexamethasone and is administered in an amount of about 20 mg. In one embodiment, the steroid is dexamethasone and is administered between about 45 minutes and 75 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the steroid is dexamethasone and is administered about 60 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the steroid is dexamethasone and is administered about 60 minutes before an administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • about 20 mg of dexamethasone is administered about 60 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, about 20 mg of dexamethasone is administered about 60 minutes before an administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, a corticosteroid is administered to a subject. [00126] In some embodiments, an antidiarrheal treatment (e.g., Imodium or an equivalent) is administered to a subject. In some embodiments, electrolytes is administered to a subject.
  • an antidiarrheal treatment e.g., Imodium or an equivalent
  • electrolytes is administered to a subject.
  • acetaminophen e.g., 650 mg orally
  • an antipyretic is administered to a subject.
  • - 53 - NAI-1537985011v1 an analgesic is administered to a subject.
  • diphenhydramine e.g., 25 to 50 mg intravenously or orally
  • an equivalent is administered to a subject for treating rash, pruritus, or other signs and/or symptoms of hypersensitivity (allergic) reaction.
  • tocilizumab e.g., 8 mg/kg IV over 1 hour
  • dexamethasone e.g., 10 to 20 mg IV
  • about 10 mg dexamethasone is administered to a subject.
  • pressors, fluids, oxygen, epinephrine, bronchodilators, ventilatory support, antipyretic, and/or analgesic is administered to a subject.
  • an antihistamine is administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the antihistamine is an H1 antagonist. In one embodiment, the H1 antagonist is a first generation H1 antagonist. In one embodiment, the antihistamine is an ethanolamine. In one embodiment, the ethanolamine is diphenhydramine, carbinoxamine, doxylamine, orphenadrine, bromazine, clemastine, dimenhydrinate, or any combination thereof. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is administered in an amount between about 20 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount between about 20 mg and 30 mg. In one embodiment, the antihistamine is administered in an amount of about 25 mg.
  • the antihistamine is administered in an amount of 25 mg. In one embodiment, the antihistamine is administered in an amount between about 40 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount between about 45 mg and 55 mg. In one embodiment, the antihistamine is administered in an amount of about 50 mg. In one embodiment, the antihistamine is administered in an amount of 50 mg. In one embodiment, the antihistamine is diphenhydramine and the amount between about 20 mg and about 30 mg. In one embodiment, the antihistamine is diphenhydramine and the amount is about 25 mg.
  • the antihistamine is diphenhydramine and is administered between about 20 minutes and 70 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes before an IL- - 54 - NAI-1537985011v1 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • acetaminophen is administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, acetaminophen is administered in an amount between about 100 mg and 1000 mg.
  • acetaminophen is administered in an amount between about 400 mg and 600 mg. In one embodiment, acetaminophen is administered in an amount of about 500 mg. In one embodiment, acetaminophen is administered in an amount of 500 mg. In one embodiment, acetaminophen is administered in an amount between about 500 mg and 800 mg. In one embodiment, acetaminophen is administered in an amount between about 550 mg and 750 mg. In one embodiment, acetaminophen is administered in an amount between about 600 mg and 700 mg. In one embodiment, acetaminophen is administered in an amount of about 650 mg. In one embodiment, acetaminophen is administered in an amount of 650 mg. In one embodiment, acetaminophen is administered in an amount of 650 mg.
  • the acetaminophen is administered between about 15 minutes and about 45 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the acetaminophen is administered about 30 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the acetaminophen is administered between about 60 minutes and about 30 minutes before an administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the acetaminophen is administered between about 60 minutes and about 30 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, about 650 mg of acetaminophen is administered about 30 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • a steroid, an H1 antagonist, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • dexamethasone, an H 1 antagonist, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a - 55 - NAI-1537985011v1 steroid, diphenhydramine, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • dexamethasone, diphenhydramine, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • dexamethasone is administered in an amount of about 10 mg or about 20 mg
  • diphenhydramine is administered in an amount of about 25 mg to 50 mg
  • acetaminophen is administered in an amount of about 650 mg prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. 4.4.8.
  • response to treatment after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject can be determined based on at least one efficacy assessment or assay for plaque psoriasis or atopic dermatitis as disclosed herein.
  • treatment efficacy or assessment is determined for a method of the disclosure.
  • treatment efficacy or assessment is determined before and/or after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • any assay available for determining improvement or used for assessing plaque psoriasis or atopic dermatitis can be used with a method of the disclosure.
  • maximum response, partial response, improvement, lost improvement, start of relapse, etc. may be measured by any available scoring system for plaque psoriasis, e.g., physician’s assessed efficacy measures, such as Psoriasis Area an Severity Index (PASI), Body Surface Measurement (BSA), clinical signs score: Investigator’s Global assessment of improvement (IGA), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), or health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI)).
  • PPSI Psoriasis Area an Severity Index
  • BSA Body Surface Measurement
  • HRQOL health-related quality of life
  • maximum response, partial response, improvement, lost improvement, start of relapse, etc. may be measured by any available scoring system for atopic dermatitis, e.g., physician’s assessed efficacy measures, such as Eczema Area and Severity Index (EASI), Body Surface Measurement (BSA), clinical signs score: validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA-AD), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), or health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI)).
  • EASI Eczema Area and Severity Index
  • BSA Body Surface Measurement
  • HRQOL health-related quality of life
  • DLQI Dermatology Life Quality Index
  • efficacy of treatment after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject - 56 - NAI-1537985011v1 can be determined based on the number of regulatory T cells (e.g., CD4+ regulatory T (Treg) cells), NK cells, and/or conventional T cells (e.g., CD4+ conventional T (Tcon) cells, CD8+ Tcon T cells, or all non-Treg cells).
  • regulatory T cells e.g., CD4+ regulatory T (Treg) cells
  • NK cells e.g., NK cells
  • conventional T cells e.g., CD4+ conventional T (Tcon) cells, CD8+ Tcon T cells, or all non-Treg cells.
  • treatment efficacy or assessment is determined by comparing the score or outcome from at least one of the assessments or assays of the disclosure after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline score or outcome taken before treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564); compared to the score or outcome taken from the subject at an earlier time point; and/or compared to the score or outcome taken from at least one subject with plaque psoriasis or atopic dermatitis).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • treatment efficacy or assessment is determined 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
  • 4.4.8.1 Increase in the number of regulatory T (Treg) cells [00132]
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on the number of Treg cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Treg cells is determined by flow cytometry.
  • a Treg cell is CD4+ Treg cell.
  • a Treg cell is CD4+ CD25high Foxp3+ Tregs.
  • a Treg cell is CD3+/CD4+/CD8 ⁇ /CD25+/FOXP3+.
  • the number of Treg cells can be assessed at any time before or after administration - 57 - NAI-1537985011v1 of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Treg cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Treg cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week. In some embodiments, an increase in the number of Treg cells is observed while no increase or no significant increase in the number of convention T cells is observed after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure In some embodiments, conventional T cells are all non-Treg cells.
  • an increase in the number of Treg cells is observed within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks,
  • administration or treatment with an IL-2 Fc fusion protein results in an increase in the number of Treg cells or the number of Treg cells in a population of cells in the subject as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the increase is an increase of about, at least about, or at most about, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, or more than 300% as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the increase is an increase of about, at least about, or at most about, 0.5 fold, 1 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 5 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, or more than 50 fold as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the increase is an increase of about, at least about, or at most about, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, or more than 100 fold as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the
  • the number of Treg cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks,
  • the number of Treg cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Treg cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 5 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Treg cells is assessed on - 59 - NAI-1537985011v1 Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 12 post administration of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 15 e.g., predose
  • the number of Treg cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 17 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start
  • the number of Treg cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 31 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counte
  • the number of Treg cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on the last day of treatment (e.g., about Day 88).
  • the number of Treg cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Treg cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on the number of effector T (Teff) cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Teff cells is determined by flow cytometry.
  • the number of Teff cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Teff cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Teff cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a reference e.g., compared to the number of Teff cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure used in a method of the disclosure is an amount that does not result in an increase or a significant increase in the number of Teff cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to the number of Teff cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or - 61 - NAI-1537985011v1 standard deviation).
  • little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%.
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the number of Teff cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks
  • the number of Teff cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Teff cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 5 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Teff cells is assessed on - 62 - NAI-1537985011v1 Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 12 post administration of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 15 e.g., predose
  • the number of Teff cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 17 e.g. 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted
  • the number of Teff cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 31 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 33, Day 36, and/or Day 40 (e.g
  • the number of Teff cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on the last day of treatment (e.g., about Day 88).
  • the number of Teff cells is assessed after treatment with an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Teff cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on the number of NK cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells is determined by flow cytometry.
  • the number of NK cells or the total number of NK cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or the total number of NK cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of NK cells or the total number of NK cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week. In some embodiments, the NK cells refers to CD45+CD3-CD56+ NK cells.
  • NK cells or total NK cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to the number of NK cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • an amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure used in a method of the disclosure is an amount that does not result in an increase or a significant increase in the number of NK cells or total NK cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to the number of NK cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., compared to the number of NK cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase - 64 - NAI-1537985011v1 that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or standard deviation).
  • little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%.
  • NK cells or total NK cells are observed within 1 day, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or longer than 24 weeks after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the number of NK cells or the total of NK cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week
  • the number of NK cells or total NK cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed on Day 5 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed on Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 12 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 8 post administration of an IL-2 Fc fusion protein
  • the number of NK cells or total NK cells is assessed on Day 12 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed on Day 15 (e.g., pre
  • the number of NK cells or total NK cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • the number of NK cells or total NK cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • the number of NK cells or total NK cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on the last day of treatment (e.g., about Day 88).
  • Day 45 e.g. 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counte
  • the number of NK cells or total NK cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 - 66 - NAI-1537985011v1 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days,
  • an IL-2 Fc fusion protein
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on the number of CD4+ conventional T (Tcon) cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD4+ Tcon cells is determined by flow cytometry.
  • the number of CD4+ Tcon cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD4+ Tcon cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a reference e.g., compared to the number of CD4+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure used in a method of the disclosure is an amount that does not result in an increase or a significant increase in the number of CD4+ Tcon cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to the number of CD4+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., compared to the number of CD4+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or standard deviation).
  • little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%.
  • little or no increase or no significant increase in the number of CD4+ Tcon cells is observed within 1 day, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or longer than 24 weeks after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the number of CD4+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks,
  • the number of CD4+ Tcon cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 5 post administration of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL- 2 Fc fusion protein e.g., XmAb ® 27564
  • the number of CD4+ Tcon cells is assessed on Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 12 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD4+ Tcon cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 17 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 19, Day 22, and/or Day 26
  • the number of CD4+ Tcon cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 31 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 33, Day 36,
  • the number of CD4+ Tcon cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on the last day of treatment (e.g., about Day 88).
  • Day 45 e.g. 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an
  • the number of CD4+ Tcon cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the - 69 - NAI-1537985011v1 number of CD4+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days,
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on the number of CD8+ conventional T (Tcon) cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD8+ Tcon cells is determined by flow cytometry.
  • the number of CD8+ Tcon cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD8+ Tcon cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a reference e.g., compared to the number of CD8+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure used in a method of the disclosure is an amount that does not result in an increase or a significant increase in the number of CD8+ Tcon cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as - 70 - NAI-1537985011v1 compared to a reference (e.g., compared to the number of CD8+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., compared to the number of CD8+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or standard deviation).
  • little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%.
  • little or no increase or no significant increase in the number of CD8+ Tcon cells is observed within 1 day, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or longer than 24 weeks after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the number of CD8+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks,
  • the number of CD8+ Tcon cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 5 post administration of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL- 2 Fc fusion protein e.g., XmAb ® 27564
  • the number of CD8+ Tcon cells is assessed on Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 12 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD8+ Tcon cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 17 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 19, Day 22, and/or Day 26
  • the number of CD8+ Tcon cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 31 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 33, Day 36,
  • the number of CD8+ Tcon cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on the last day of treatment (e.g., about Day 88).
  • Day 45 e.g. 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an
  • the number of CD8+ Tcon cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the number of CD8+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 days, 5 days
  • Psoriasis Area and Severity Index [00152]
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on a Psoriasis Area and Severity Index (PASI) score.
  • PASI Psoriasis Area and Severity Index
  • 4 main body areas are assessed: the head (h), the trunk (t), the upper extremities (u), and the lower extremities (l), corresponding to 10, 30, 20, and 40% of the total body area, respectively.
  • 3 target symptoms namely erythema (E), infiltration (I), and desquamation (D) are assessed according to a scale 0–4, where 0 means a complete lack of cutaneous involvement and 4 represents the severest possible involvement.
  • the severity rating for the 3 main target symptoms is multiplied with the numerical value of the areas involved and with the various percentages of the 4 body areas.
  • PASI 0.1 ⁇ Ah ⁇ (Eh + Ih + Dh) + 0.3 ⁇ At ⁇ (Et + It + Dt) + 0.2 ⁇ Au ⁇ (Eu + Iu + Du) + 0.4 ⁇ Al ⁇ (El + Il + Dl).
  • the index varies in steps of 0.1 units from 0.0 to - 73 - NAI-1537985011v1 72.0.
  • the PASI 50, 75, and 90 represent the fraction of patients that have improvement of the PASI score of 50%, 75% and 90% over the baseline PASI (Oji V, Luger TA.
  • PASI can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, PASI is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • PASI is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week.
  • the subject achieves an improvement in PASI score of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline PASI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to PASI score of other subjects with plaque psoriasis; and/or compared to PASI score of the same subject taken at an earlier time point).
  • an IL-2 Fc fusion protein e.g.,
  • the subject achieves an improvement in PASI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, -24, -25, -26, -27, -28, -29, or -30, for example, at about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days
  • the subject achieves a PASI 50, 75, 90, or 100 by about, or at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 85 days, 90 days, 95 days, 100 days
  • the subject achieves a PASI 50, 75, or 90 by 70 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50, 75, 90, or 100, by 60 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50, 75, 90, or 100, by 90 days or less (e.g., at 88 days or less) after administration (e.g., first administration, second administrations, or any - 75 - NAI-1537985011v1 administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50, 75, 90, or 100, by 100 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50, 75, 90, or 100, by 200 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50, 75, 90, or 100 before the end of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 75 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 90 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 100 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • PASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60
  • PASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 - 76 - NAI-1537985011v1 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1
  • EASI Eczema Area and Severity Index
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on Eczema Area and Severity Index (EASI) score.
  • EASI is assessed based on the area of involvement, intensity of lesions, region score, and final EASI score.
  • area of involvement includes four body regions, such as head and neck, upper extremities, trunk, and lower extremities.
  • an area score can be: 0 (no involvement), 1 (1%–9%), 2 (10%–29%), 3 (30%–49%), 4 (50%–69%), 5 (70%–89%), and 6 (90%–100%).
  • the intensity of lesions is assessed separately for 4 signs including erythema, edema/papulation, excoriation, and lichenification.
  • each sign is assigned an intensity score from 0 to 3, with 0 being absent; 1, mild; 2, moderate; and 3, severe.
  • each region is assigned based on the relative contribution of that region to the total BSA.
  • a region score is calculated separately for each region by multiplying the sum of the regional intensity score by the regional area score and the region-specific multiplier.
  • the final EASI score is the summation of the 4 regional scores, ranging from 0 to 72. A score of 0 indicates clear or no eczema, 0.1 to 1.0 indicates almost clear, 1.1 to 7 indicates mild disease, 7.1 to 21 indicates moderate disease, 21.1 to 50 indicates severe disease, and greater than 51 indicates very severe disease.
  • EASI can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, EASI is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, EASI is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week.
  • the subject achieves an improvement in EASI score of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline EASI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to EASI score of other subjects with atopic dermatitis; and/or compared to EASI score of the same subject taken at an earlier time point).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject achieves an improvement in EASI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, - 24, -25, -26, -27, -28, -29, or -30, for example, at about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days
  • the subject achieves EASI 50, 75, 90, or 100 by about, or at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days,
  • the subject achieves a EASI 50, 75, or 90 by 70 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50, 75, 90, or 100, by 60 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50, 75, 90, or 100, by 90 days or less (e.g., at 88 days or less) after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50, 75, 90, or 100, by 100 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50, 75, 90, or 100, by 200 days or less after - 79 - NAI-1537985011v1 administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50, 75, 90, or 100 before the end of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 75 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 90 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • EASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60
  • EASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 - 80 - NAI-1537985011v1 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week
  • treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure results in improvement of at least one health-related quality of life (HRQOL) outcome (e.g., Dermatology Life Quality Index (DLQI)).
  • HRQOL health-related quality of life
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on DLQI.
  • DLQI is self-administered with a mean completion time of 2 min.
  • DLQI consists of 10 questions concerning impact of skin diseases on different aspects of subject’s quality of life (QOL) over, for example, the last week (e.g., 1 week after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • the DLQI items include symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the side effects of treatment (Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple practical measure for routine clinical use. Clin Exp Dermatol.1994;19:210–216).
  • the minimal clinically important difference of the DLQI varies from 3 to 5 (Basra MK, Salek MS, Camilleri L, et al. Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data. Dermatology.2015;230(1):27–33).
  • the subject achieves a Dermatology Life Quality Index (DLQI) score of about 0 or 1 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • DLQI Dermatology Life Quality Index
  • the subject achieves a Dermatology Life Quality Index (DLQI) score of about or at most about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the - 81 - NAI-1537985011v1 disclosure.
  • the subject achieves an improvement in DLQI score of about or at least about -1 (i.e., a decrease of 1) after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline DLQI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to DLQI score of other subjects with plaque psoriasis or atopic dermatitis; and/or compared to DLQI score of the same subject taken at an earlier time point).
  • a reference e.g., compared to baseline DLQI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure
  • a reference e.g., compared to
  • the subject achieves an improvement in DLQI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, - 24, -25, -26, -27, -28, -29, or -30 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline DLQI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to DLQI score of other subjects with plaque psoriasis or atopic dermatitis; and/or compared to DLQI score of the same subject taken at an IL-2 F
  • the subject achieves an improvement in DLQI score of about or at least about -5 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference. In some embodiments, the subject achieves an improvement in DLQI score of about or at least about -7 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference. In some embodiments, the subject achieves an improvement in DLQI score of about or at least about -8 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject achieves an improvement in DLQI score of about or at least about -9 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference.
  • the subject achieves a clinically meaningful reduction in Dermatology Life Quality Index (DLQI) score.
  • DLQI Dermatology Life Quality Index
  • a clinically meaningful reduction in DLQI score is a decrease of 5 points or greater than 5 points in DLQI score compared to a reference.
  • a clinically meaningful reduction in DLQI score is a decrease of 3 points or greater than 3 points in DLQI score compared to a reference.
  • a clinically meaningful reduction in DLQI score is a decrease of 4 points or greater than 4 points in DLQI score compared to a reference.
  • the subject achieves an improvement in DLQI score at about or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 - 82 - NAI-1537985011v1 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline DLQI
  • the subject achieves an improvement in DLQI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, - 23, -24, -25, -26, -27, -28, -29, or -30 at about or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after treatment with an IL-2 Fc fusion protein (e.g.,
  • a reference is the baseline DLQI score obtained from the same subject prior to start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • a reference is the DLQI score obtained from the same subject at an earlier time point.
  • a reference is the DLQI score of at least one subject with plaque psoriasis or atopic dermatitis (e.g., an average DLQI score based on the DLQI scores from other subjects with plaque psoriasis or atopic dermatitis).
  • the at least one subject and/or the other subjects have the same plaque psoriasis or atopic dermatitis as the subject. In some embodiments, the at least one subject and/or the other subjects have the same plaque psoriasis or atopic dermatitis with the same level of severity (e.g., mild, moderate, or severe plaque psoriasis or atopic dermatitis) as the subject. In some - 83 - NAI-1537985011v1 embodiments, the at least one subject and/or the other subjects have been diagnosed with a different level of severity of plaque psoriasis or atopic dermatitis as the subject.
  • BSA body surface area
  • efficacy of treatment with an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • BSA Body Surface Area
  • the body surface area of plaque psoriasis is estimated by using the size of the handprint as 1% of the body surface area.
  • the number of handprints across the patient’s body that have activity with plaque psoriasis or atopic dermatitis is counted to determine BSA (Ramsay B, Lawrence CM. Measurement of involved surface area in patients with plaque psoriasis or atopic dermatitis. Br J Dermatol.1991;124(6):565–70).
  • BSA body surface area
  • the subject has a body surface area (BSA) of plaque psoriasis of ⁇ 3%.
  • the subject has a body surface area (BSA) of plaque psoriasis of ⁇ 2%.
  • the BSA is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 days,
  • the BSA of the subject is decreased by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, or more than 300% after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline BSA score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to BSA score of other subjects with - 84 - NAI-1537985011v1 plaque psoriasis or atopic dermatitis; and/or compared to BSA score of the same subject taken at an earlier time point).
  • an IL-2 Fc fusion protein e.g.
  • the BSA of the subject is decreased after about or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline BSA score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to BSA score of other subjects with plaque psoriasis or atopic IL-2 Fc
  • the subject had about, less than about, or at most about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% body surface area (BSA) affected by plaque psoriasis or atopic dermatitis prior to administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • BSA body surface area
  • the subject has about, less than about, or at most about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% body surface area (BSA) affected by plaque psoriasis or atopic dermatitis after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • BSA body surface area
  • efficacy of treatment with an IL-2 Fc fusion protein is assessed based on a Physician’s Global Assessment (PGA) test or an Investigator’s Global Assessment test (IGA) or a Static Investigator Global Assessment (sIGA) (Langley RG, Feldman SR, Nyirady J, et al.
  • the 5-point Investigator's Global Assessment (IGA) Scale A modified tool for evaluating plaque psoriasis severity in clinical trials.
  • efficacy of treatment with an IL-2 Fc fusion protein is assessed using - 85 - NAI-1537985011v1 Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) for atopic dermatitis.
  • the validated Investigator Global Assessment for Atopic Dermatitis is a static 5-point scale that was developed to assess the overall atopic dermatitis severity.
  • a score of 0 (clear) to 4 (severe) is provided based on a morphological description (refer to Table 17).
  • the IGA or sIGA is a 5- point system that measures severity of plaque psoriasis or atopic dermatitis.
  • the PGA is a 5 or 6 point scoring system used to assess severity of plaque psoriasis or atopic dermatitis in a subject.
  • the PGA or IGA or sIGA or vIGA-AD is about or at most about 2 (mild) after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the PGA or IGA or sIGA or vIGA-AD is about or at most about 0 or 1 (clear, almost clear, or mild) after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the PGA or IGA or sIGA or vIGA-AD is about or at most about 0 or 1 or 2 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the PGA or IGA or sIGA or vIGA-AD is about or at most about 0 or 1 by about or by at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days,
  • the PGA or IGA or sIGA or vIGA-AD is about or at most about 0, 1, 2, 3, after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure (e.g., by about or by at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 - 86 - NAI-1537985011v1 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55
  • efficacy of treatment after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on photography of whole body and/or selected plaques or active regions of atopic dermatitis (e.g., utilizing a Canfield photography system (Canfield Scientific, Parsippany, NJ)).
  • photographs e.g., of the whole body, selected plaques, or active regions of atopic dermatitis, or site of injection
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • photographs taken at baseline or before treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is compared with photographs taken after the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • photographs are taken at different time points after the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • photographs taken at a later time point after the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is compared with photographs taken at an earlier time point.
  • photographs are taken prior to the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • photographs are taken at about or by at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 - 87 - NAI-1537985011v1 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60
  • photographs of injection site reactions are taken.
  • photographs e.g., of whole body, selected plaques, or active regions of atopic dermatitis, or site of injection
  • photographs are taken on day 1, 29, and/or 57.
  • photographs are taken prior to day 1 or prior to start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • photographs are taken about 7 days prior to start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • pruritus is assessed using Peak Pruritus Numerical Rating Scale (e.g., for atopic dermatitis).
  • PP-NRS is an 11-point scale used by patients to rate their worst itch severity over the past 24 hours with 0 indicating “No itch” and 10 indicating “Worst itch imaginable”.
  • daily (24-hour) PP-NRS is recorded and the weekly mean of the daily PP-NRS is calculated.
  • PP-NRS scores are calculated between Day -7 and Day -1 and calculated a weekly average baseline score prior to Day 1.
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed by measuring specific cell populations (e.g., number of CD25 bright Treg cells, CD25 bright Treg/Tcon ratio, total Treg cells, conventional T cells (Tcon), - 88 - NAI-1537985011v1 and/or NK cells) in a subject before and/or after the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject (e.g., number of CD25 bright Treg cells, CD25 bright Treg/Tcon ratio, total Treg cells, conventional T cells (Tcon), and/or NK cells).
  • specific cell populations e.g., number of CD25 bright Treg cells, CD25 bright Treg/Tcon ratio, total Treg cells, conventional T cells (Tcon), - 88 - NAI-1537985011v1 and/or NK cells
  • a method of the disclosure comprises a single administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure to a subject.
  • cell population changes e.g., increases, decreases, or does not significantly increase or decrease
  • assessments are obtained on days -1, 0, 8, 10, 21, and/or 43, and/or at any suitable time point.
  • assessments are obtained on Day -1 (one day prior to administration of XmAb ® 27564 to the subject).
  • assessments are obtained on Day 0 (same day as administration of XmAb ® 27564 to the subject). In some embodiments, assessments are obtained on Day 8 (8 days after administration of XmAb ® 27564 to the subject). In some embodiments, assessments are obtained on Day 10 (10 days after administration of XmAb ® 27564 to the subject). In some embodiments, assessments are obtained on Day 21 (21 days after administration of XmAb ® 27564 to the subject). In some embodiments, assessments are obtained on Day 43 (43 days after administration of XmAb ® 27564 to the subject).
  • the CD25 bright Treg/Tcon ratio is about or at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, or more than 0.2. In some embodiments, the CD25 bright Treg/Tcon ratio is about 0.14 after administration of XmAb ® 27564.
  • administration of the IL-2 Fc fusion protein to a subject results in an increase in the number of CD25 bright Treg cells in the subject (e.g., biological sample) as compared to baseline or as compared to the number of CD25 bright Treg cells in the subject (e.g., biological sample) obtained from a previous time point.
  • administration of the IL-2 Fc fusion protein to a subject results in an increase in the number of CD25 bright Treg/Tcon ratio in the subject (e.g., biological sample) as compared to baseline or as compared to the number of CD25 bright Treg/Tcon ratio in the subject (e.g., biological sample) obtained from a previous time point.
  • administration of the IL-2 Fc fusion protein to a subject results in an increase in the number of total Treg cells in the subject (e.g., biological sample) as compared to baseline or as compared to the number of total Treg cells in the subject (e.g., biological sample) obtained from a previous time point.
  • Treg cells - 89 - NAI-1537985011v1 comprises CD25 bright FoxP3+ CD4 Treg cells.
  • Treg cells consists of CD25 bright FoxP3+ CD4 Treg cells.
  • the increase is an increase of about or at least about 2-fold, about or at least about 3-fold, about or at least about 4-fold, about or at least about 5-fold, about or at least about 6-fold, about or at least about 7-fold, about or at least about 8-fold, about or at least about 9-fold, about or at least about 10-fold, about or at least about 11- fold, about or at least about 12-fold, about or at least about 13-fold, about or at least about 14- fold, about or at least about 15-fold, about or at least about 16-fold, about or at least about 17- fold, about or at least about 18-fold, about or at least about 19-fold, about or at least about 20- fold, about or at least about 25-fold, about or at least about 30-fold, about or at least about 40- fold, about or at least about 50-fold, about or at least about 60-fold, about or at least about 70- fold, about or at least about 80-fold, about or at least about 90-fold, about or at least about 100- fold,
  • the increase is an increase of about or at least about 2%, about or at least about 3%, about or at least about 4%, about or at least about 5%, about or at least about 6%, about or at least about 7%, about or at least about 8%, about or at least about 9%, about or at least about 10%, about or at least about 11%, about or at least about 12%, about or at least about 13%, about or at least about 14%, about or at least about 15%, about or at least about 16%, about or at least about 17%, about or at least about 18%, about or at least about 19%, about or at least about 20%, about or at least about 25%, about or at least about 30%, about or at least about 35%, about or at least about 40%, about or at least about 45%, about or at least about 50%, about or at least about 55%, about or at least about 60%, about or at least about 65%, about or at least about 70%, about or at least about 75%, about or at least about 80%, about or at least about
  • a biological sample is blood, serum, plasma, and/or any other suitable biological sample.
  • administration of the IL-2 Fc fusion protein to a subject does not result in a significant increase in conventional T cells (Tcon) and/or NK cells in the subject as compared to baseline or as compared to the number of Tcon and/or NK cells obtained from the subject at a previous time point (e.g., in a biological sample obtained at a previous time point).
  • Tcon comprises of CD4 + Tcon cells.
  • Tcon - 90 - NAI-1537985011v1 comprises of CD8 + Tcon cells.
  • Tcon comprises of CD4 + and CD8 + Tcon cells.
  • Tcon consists of CD4 + Tcon cells. In some embodiments, Tcon consists of CD8 + Tcon cells. In some embodiments, Tcon consists of CD4 + and CD8 + Tcon cells. In some embodiments, a significant increase is not more than two standard deviations from baseline or those obtained from a previous time point. In some embodiments, a significant increase is not more than two standard deviations from baseline or those obtained from a previous time point. In some embodiments, a biological sample is blood, serum, plasma, and/or any other suitable biological sample. 5. EXAMPLES [00173] Examples are provided below to illustrate the present invention. These examples are not meant to constrain the present invention to any particular application or theory of operation.
  • EXAMPLE 1 Treatment of plaque psoriasis or atopic dermatitis using an IL-2 Fc fusion protein
  • XmAb ® 27564 is a potency-reduced monomeric human IL-2 Xtend heterodimeric Fc- fusion protein.
  • Xencor engineered XmAb ® 27564 IL-2 that decreases interactions with effector T cells (Teffs) and natural killer cells (NK cells), the largest cellular sink for IL-2, while preserving interactions with the autoimmune therapeutic target CD25, which is constitutively and highly expressed on Tregs.
  • recombinant IL-2 (rIL-2) was engineered to decrease interactions with cells containing predominantly complexes of IL2R ⁇ / ⁇ c (CD122/CD132; Teffs and NK cells) while simultaneously increasing affinity to the CD25 receptor thus preserving or increasing interactions for cells, such as Tregs, that express all 3 receptors IL2R ⁇ /IL2R ⁇ / ⁇ c (CD25/CD122/CD132).
  • Reduction of potency to CD122/CD132 resulted in increased serum persistence relative to the native IL-2 Fc fusion.
  • the dramatic increase in serum persistence - 91 - NAI-1537985011v1 offsets the significant reduction in potency, with a net increase in Tregs’ PD.
  • SC subcutaneous
  • HCV hepatitis C virus
  • SLE systemic lupus erythematosus
  • a single dose of ultra-low-dose IL-2 ( ⁇ 1.0 mIU) only induces a 10% to 20% increase in peripheral Treg numbers (Todd et al. PLOS Med.2016;13:e1002139), whereas daily dosing for 5 days can induce 2- to 8-fold expansion of Tregs (Table 2; Rosenzwajg et al. Ann Rheum Dis.2019;78:209–17).
  • the psoriasis cohorts consist of approximately 48 eligible adult (e.g., 18-65 years of age male and female) patients randomized to XmAb ® 27564 or placebo in 6 consecutive dose cohorts, 0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg (Cohorts 1 through 6). Each cohort consists of 8 patients with 6 patients receiving XmAb ® 27564 and 2 receiving placebo. Sentinel dosing can be employed for the first 3 patients in each cohort, with a block of 3 sentinel subjects, randomized 2:1 to XmAb ® 27564:placebo treated sequentially. Each sentinel subject in the same cohort is treated at least 24 hours after treatment of the previous sentinel subject.
  • the subsequent - 95 - NAI-1537985011v1 5 subjects to round out the 8-subject cohort are randomized 4:1 to XmAb ® 27564:placebo (4 XmAb ® 27564 and 1 placebo).
  • the subsequent 5 subjects may begin treatment after the third sentinel subject clears the first 24 hours.
  • the atopic dermatitis cohorts consist of approximately 80 eligible patients randomized to XmAb ® 27564 or placebo in 5 consecutive dose cohorts, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg (Cohorts A through E). Each cohort consists of 16 patients, with 12 patients receiving XmAb ® 27564 and 4 receiving placebo.
  • Each cohort in the psoriasis group consists of 8 patients, while each cohort in the atopic dermatitis group consists of 16 patients.
  • the increase in cohort size from 8 in the psoriasis cohorts to 16 in the atopic dermatitis cohorts is driven by the variability in the placebo response in skin assessments in atopic dermatitis.
  • Each patient either in the psoriasis or atopic dermatitis group
  • XmAb ® 27564 or placebo is administered in a double-blind fashion.
  • DERC Dose Escalation Review Committee
  • SAD single ascending dose
  • a DERC decision for escalation in a psoriasis cohort may trigger the start of dosing for an atopic dermatitis cohort at the same or lower dose studied previously for patients with psoriasis.
  • the DERC reviews Cohorts A through D and make a decision about dose escalation independently in atopic dermatitis based on safety considerations in atopic dermatitis.
  • placebo patients would also receive open-label XmAb ® 27564 at that cohort’s dose level. After each subsequent DERC meeting, all patients would be offered the higher dose that was cleared previously by the DERC for their disease population, at Investigator's discretion and upon consultation with the Medical Monitor.
  • the primary endpoint of the study is safety and tolerability of MAD SC administration of XmAb ® 27564, as measured by incidence of adverse events (AEs), including treatment-emergent AEs (TEAEs), treatment-emergent serious AEs (TE-SAEs), treatment- related TEAEs, treatment-related TE-SAEs, and TEAEs by severity that are defined by the National Cancer Institute’s Common Terminology Criteria for AEs (NCI-CTCAE), Version 5.0 (CTCAE v.5).
  • AEs adverse events
  • TEAEs treatment-emergent AEs
  • TE-SAEs treatment-emergent serious AEs
  • NCI-CTCAE Common Terminology Criteria for AEs
  • CTI-CTCAE Common Terminology Criteria for AEs
  • Safety assessments includes evaluating physical examinations, vital signs, electrocardiogram (e.g., twelve-lead ECG), dose-limiting toxicity (DLT), and clinical laboratory tests including clinical chemistry, hematology (including eosinophils), coagulation, troponin I CRP, ferritin, urinalysis, viral testing, and cardiac MRI.
  • the secondary endpoints of the study include characterizing PK and immunogenicity profiles of multiple-ascending doses (MAD) of XmAb ® 27564, including assessment of serum concentrations of XmAb ® 27564 and anti-XmAb ® 27564 antibodies (i.e., anti-drug antibodies (ADA) and immunogenicity).
  • MAD multiple-ascending doses
  • Subjects with psoriasis are randomized to XmAb ® 27564 or placebo in 6 consecutive dose cohorts, (i.e., 0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg every 14 days for four doses during 8 weeks of treatment), with 8 subjects in each cohort (6 subjects receive XmAb ® 27564 and 2 subjects receive placebo).
  • XmAb ® 27564 For patients with atopic dermatitis, 5 dose levels were selected for XmAb ® 27564: 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg, to be given Q14 days for four doses - 102 - NAI-1537985011v1 during 8 weeks of treatment. Each cohort has 16 patients; 12 patients are to receive XmAb ® 27564, and 4 patients are to receive placebo. [00188] Approximately 48 patients with psoriasis and 80 patients with atopic dermatitis receive XmAb ® 27564 or placebo at 20 to 25 clinical investigation sites in the US and outside of the US (OUS).
  • Approximately 96 patients receive XmAb ® 27564, and 32 patients in total receive placebo (12 psoriasis and 20 atopic dermatitis).
  • a total of 6 subjects receive XmAb ® 27564 and 2 subjects receive placebo.
  • the DERC may decide to either remove a planned cohort or add an unplanned cohort at a lower or intermediate dose level than planned. 5.1.3.
  • Treatment Assignment in the Open-Label Extension Phase Patients entering the OLE, receive active open label XmAb ® 27564 at the same dose level that was assigned to them in the core study, every 2 weeks. After each dose level has been reviewed by the DERC and is deemed safe, any patients who are receiving a lower dose of XmAb ® 27564 are offered the higher dose that was cleared by the DERC after discussion with the Investigator and upon consultation with the Medical Monitor. The increased dose is continued through the remainder of the extension phase, unless a new higher dose is cleared. 5.1.4. Treatment Assignment in the Core Study [00190] Randomization schedules for each dose cohort are generated prior to study start. XmAb ® 27564 or placebo are administered in a double-blind fashion.
  • Patient treatment assignment in patients with psoriasis includes MAD administration of SC XmAb ® 27564 (0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo.
  • Treatment assignment in patients with atopic dermatitis includes MAD administration of SC XmAb ® 27564 (0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo.
  • Sentinel dosing is employed for the first 3 patients with psoriasis in each cohort, with a block of 3 sentinel subjects, randomized 2:1 to XmAb ® 27564:placebo treated one each day sequentially with at least 24 hours between them (or over the first 3 days).
  • Each sentinel subject in the same cohort is treated at least 24 hours after treatment of the previous sentinel subject.
  • the subsequent 5 subjects to round out the 8-subject cohort are randomized 4:1 to XmAb ® 27564:placebo (4 XmAb ® 27564 and 1 placebo).
  • the subsequent 5 subjects begin treatment after the third sentinel subject clears the first 24 hours.
  • no sentinel dosing is employed for the atopic dermatitis - 103 - NAI-1537985011v1 cohorts.
  • a total of 16 patients are randomized in a 3:1 ratio to receive either XmAb ® 27564 or placebo in each cohort (FIG.3B).
  • the contract research organization maintain the randomization code in a secure location with controls to prevent unauthorized access, including the computer program written to generate the randomization, randomization codes, program log, seed number used by the program, copy of the randomization plan along with approval documentation as appropriate, and the write-protected electronic storage medium.
  • the CRO name an unblinded statistician to generate the randomization codes. The pharmacists are unblinded. Investigators and site staff, patients, CRO, and Xencor (excluding DAT) remain blinded to individual patients’ treatment assignment for the duration of the study until the study unblinding has been authorized.
  • Subject Inclusion Criteria - 104 - NAI-1537985011v1 [00197] In order to be eligible to participate in this study, an individual must meet all of the following criteria: Patients with psoriasis • Provision of signed and dated ICF • Stated willingness to comply with all study procedures and availability for the duration of the study • Male or female, aged 18 to 65 or 75 years of age (inclusive at the time of screening) • Weight between 40 to 150 kg, inclusive • BSA involved by psoriasis ⁇ 3% or ⁇ 2% • Static Investigator's Global Assessment (sIGA) of 2 (mild) - 4 (severe) • Washout of oral treatments for psoriasis for 4 weeks before randomization • Washout of biologic treatments for psoriasis for 12 weeks or 5 half-lives (whichever is longest) before randomization.
  • sIGA Static Investigator's Global Assessment
  • Highly effective methods of birth control include combined hormonal birth control (oral, intravaginal, or transdermal), or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or intrauterine), intrauterine devices (IUDs), intrauterine hormone-releasing system, - 105 - NAI-1537985011v1 bilateral tubal occlusion, vasectomized partner (provided partner is the sole sexual partner and there has been a medical assessment of surgical success), or sexual abstinence.
  • the baseline weekly average is calculated from the 7 consecutive days prior to Day 1 (between Day -7 and Day -1). A minimum of 4 daily scores out of the 7 days is needed.
  • Washout of oral treatments for atopic dermatitis for 4 weeks before randomization • Washout of biologic treatments for atopic dermatitis for 12 weeks or 5 half-lives (whichever is longest) before randomization - 106 - NAI-1537985011v1 • Washout of topical treatments for atopic dermatitis 2 weeks before randomization • Application of a stable dose of a non-prescription, non-urea containing emollient to all skin (normal skin and AD lesions) once or twice daily for 14 days preceding the randomization visit and willing to maintain stable dosing of the emollient from 14 days before randomization until at least the Day 57 visit • Washout for: ⁇ UV-B, PUVA, excimer laser, excessive sun for at least 4 weeks before randomization ⁇ IVIg for 12 weeks before randomization ⁇ Hydroxyzine or di
  • Female patients of childbearing potential must agree to use a highly effective method of birth control during and for 45 days after administration of IMP. Women are considered of childbearing potential or postmenopausal by history with no menses for 1 year and confirmed by FSH) or have a history of hysterectomy and/or bilateral oophorectomy or have a history of bilateral tubal ligation.
  • Highly effective methods of birth control include combined hormonal birth control (oral, intravaginal, or transdermal), or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or intrauterine), IUDs, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner (provided partner is the sole sexual partner and there has been a medical assessment of surgical success), or sexual abstinence.
  • hormonal birth control oral, intravaginal, or transdermal
  • progestogen-only hormonal contraception associated with inhibition of ovulation oral, injectable, or intrauterine
  • IUDs intrauterine hormone-releasing system
  • bilateral tubal occlusion bilateral tubal occlusion
  • vasectomized partner provided partner is the sole sexual partner and there has been a medical assessment of surgical success
  • sexual abstinence • Fertile male patients must be willing to practice a highly effective method of birth control during and for 45 days after administration of IMP with any female partners of childbearing potential. • Male patients
  • Patients have to be maintained on a medium dose inhaled corticosteroid plus a long-acting beta agonist as defined by GINA as a maximum • Patients who have evidence of any bacterial, viral, parasitic, or systemic fungal infections requiring treatment within the 21 days prior to randomization; or hospitalization due to infection within 3 months prior to randomization • Patients who do not agree to use medically acceptable methods of contraception (as defined in the protocol) • Patients who are pregnant or breast feeding, or planning to become pregnant within 45 days of administration of IMP • Patients who have had any prior investigational treatment with IL-2 therapies or have received any investigational agent within 5 half-lives of the study drug • Patients whose screening breathalyzer (for alcohol) and/or urine test is positive for drugs of abuse (including the following: amphetamines/ecstasy, barbiturates, benzodiazepines, cocaine, opiates, methadone metabolites, and phencyclidine).
  • drugs of abuse including the following: amphetamines/ecstasy, barb
  • results are positive or questionable, contact the Xencor Medical Monitor prior to enrollment • Patients with a known or suspected sensitivity to products from mammalian cell lines • Patients with a history of anaphylaxis • Patients who have received live vaccines ⁇ 2 months prior to screening or any vaccine within the past 14 days • Patients who have donated or lost more than 450 mL of blood in the 8 weeks prior to screening • Patients who have clinically significant abnormal laboratory values, as assessed by the Investigator or the Xencor Medical Monitor Patients with atopic dermatitis • Patients with history of any cardiovascular event, such as the following: heart failure, myocarditis, myocardial infarction, acute coronary syndrome, stroke, pulmonary embolism, and/or deep venous thrombosis • Patients with vital sign values outside these normal ranges: - 109 - NAI-1537985011v1 ⁇ Systolic Blood Pressure: 90–140 mmHg ⁇ Diastolic Blood Pressure: 50–90 mmHg ⁇ Heart Rate: 50–100 beats
  • Patients have to be maintained on a medium dose inhaled corticosteroid plus a long-acting beta agonist as defined by GINA as a maximum • Patients who have evidence of any bacterial, viral, parasitic, or systemic fungal infections requiring treatment within the 21 days prior to randomization; or hospitalization due to infection within 3 months prior to randomization • Patients who do not agree to use medically acceptable methods of contraception (as defined in the protocol) • Patients who are pregnant or breast feeding, or planning to become pregnant within 45 days of administration of IMP • Patients who have had any prior investigational treatment with IL-2 therapies or have received any investigational agent within 5 half-lives of the study drug • Patients whose screening breathalyzer (for alcohol) and/or urine test is positive for drugs of abuse (including the following: amphetamines/ecstasy, barbiturates, benzodiazepines, - 110 - NAI-1537985011v1 cocaine, opiates, methadone metabolites, and phencyclidine).
  • drugs of abuse including the following
  • results are positive or questionable, contact the Xencor Medical Monitor prior to enrollment.
  • Patients with a known or suspected sensitivity to products from mammalian cell lines • Patients with a history of anaphylaxis • Patients who have received live vaccines ⁇ 2 months prior to screening or any vaccine within the past 14 days • Patients who have donated or lost more than 450 mL of blood in the 8 weeks prior to screening • Patients who have clinically significant abnormal laboratory values, as assessed by the Investigator or Xencor Medical Monitor 5.1.5.3 Additional Subject Exclusion Criteria [00199] Patients must be withdrawn if the ⁇ -HCG pregnancy test is consistent with pregnancy. Pregnancy should be reported. [00200] Patients are encouraged to complete all study evaluations; however, they may withdraw from the study at any time and for any reason.
  • Patient participation may be terminated prior to completing the study and the reason recorded as follows: • Withdrawal from the study with or without withdrawing of consent • Administrative decision by the Investigator or Sponsor • Ineligibility • Significant protocol deviation • Patient noncompliance • Safety concern by the Investigator or Sponsor • Lost to follow-up • Other - 111 - NAI-1537985011v1 [00202] A comprehensive effort must be made to determine the reason(s) why a patient fails to return for the necessary visits or is discontinued from the study. If the patient is unreachable by email or telephone, a registered letter, at the minimum, should be sent to the patient requesting him/her to contact the study site. Patients withdrawn for a non-drug-related reason may be replaced if the Sponsor deems it necessary.
  • lymphopenia Patients with persistent (multiple measures at ⁇ 1000 lymphocytes/ ⁇ L and 75% below their baseline for more than 2 months after the last dose) or severe lymphopenia ( ⁇ 500 lymphocytes/ ⁇ L and > 75% below baseline) shall be referred to a primary care physician for treatment.
  • a patient withdraws prematurely all assessments as listed for the EOS visit should be performed and recorded on the EOS visit electronic case report form (eCRF) page.
  • the patient should be scheduled for follow-up safety visits (or after 5 half-lives, whichever is longer) after XmAb ® 27564 administration.
  • EOS patients Any patient who withdraws early who is lymphopenic on the last visit prior to withdrawal or at post-EOS visits is followed as with other EOS patients, every 28 days ( ⁇ 3 days). Patients are evaluated with CBC with differential, immunoglobulin levels, IL-2 levels and ADA, if feasible, until ADA levels return to baseline and after DERC review. Patients with persistent ( ⁇ 1000 lymphocytes/ ⁇ L for more than 2 months) or severe lymphopenia ( ⁇ 500 lymphocytes/ ⁇ L) (FDA, 2007) shall be referred to a primary care physician for treatment. 5.1.6. Dosing Schedule [00206] Each subject receives subcutaneous administration of XmAb ® 27564 or placebo every 2 weeks for 4 doses, as shown in FIGS.3A-3B.
  • XmAb ® 27564 or placebo is administered on - 112 - NAI-1537985011v1 Study Days 1, 15, 29, and 43. Up to 6 weeks screening and a follow up period of approximately 45 days may be used. Possible injection areas include upper arm, thigh, or abdomen. Injection administration is not at the same place twice. The area rotates from one dose to the next. [00207] Open-label Extension: Up to 336 days duration; follow-up period of approximately 45 days (FIG.3C). All patients who rollover into the extension phase of the study initially receive open-label XmAb ® 27564 every 2 weeks at the dose level of the cohort that they were assigned to during the core study.
  • Treatment Assignment will include MAD administration of SC XmAb27564 (0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo. [00211] Detail of treatment assignment, including randomization and blinding, is presented below. 5.1.9.
  • Advancement to subsequent cohorts will depend on acceptable interim safety, available immunogenicity, PK, and PD reviews from ongoing and completed cohorts. Advancement to a subsequent dose level will not occur until at least 8 patients from the prior - 113 - NAI-1537985011v1 dose level have each been administered investigational medicinal product (IMP) without safety concerns.
  • IMP investigational medicinal product
  • a DERC will be established to assess all available and relevant interim data from each cohort to determine the safety and appropriateness of dose reduction to a prior or intermediate dose or dose escalation to a new cohort. Dose escalation will follow pre-specified criteria.
  • the maximum tolerated dose will be defined by the dose in the previous cohort, unless an intermediate dose is subsequently tested by the same algorithm.
  • More conservative dose escalation i.e., evaluation of prior or intermediate dose levels, is permissible following DERC review, if needed, for patient safety or for a better understanding of the toxicity, exposure, PD, or other properties of the study drug.
  • the Sponsor may decide to add a cohort to repeat a dose level, but the dose level for any cohort will not exceed the planned dose level for that cohort, as specified in this protocol, below.
  • DAT Data Analysis Team
  • the blinded DERC will also include Xencor’s blinded Medical Monitor, Xencor’s blinded Head of Hematology, Clinical Development (or their designees), the Coordinating Principal Investigator (or Designee), and the CROs Safety Monitor (or designee), who will be responsible for all single-patient and administrative study discussions and decisions.
  • the blinded DERC will receive deidentified data in real time, enabling a prompt and effective - 114 - NAI-1537985011v1 response to safety and study administrative issues.
  • Voting DERC members will include 4 physicians: the Coordinating Principal Investigator, CROs Safety Monitor or their designees, and 2 from Xencor (blinded Medical Monitor and blinded Head of Hematology, Clinical Development or their designees).
  • DERC meetings are timed to review all blinded PD, PK, immunogenicity, and safety data before escalation to the next cohort. Progression to the next higher dose will only occur if the DERC determines that the previous dose level was safe and well tolerated after reviewing all patients’ data collected through at least Day 29. When it is not appropriate to escalate the dose, then the same dose, a previous dose, or an intermediate dose may be recommended by the DERC.
  • the DERC and DAT will have access to information relating to XmAb27564 clinical data in their deliberations regarding dose escalation in this study.
  • the dose escalation process, DERC and DAT function and personnel, and data to be reviewed will be described in a DERC Charter document, to be provided separately.
  • Dose Adjustment Criteria 5.1.11.1 Treatment Group Stopping Rules and Dose Level Adjustments [00220] Upon review of pooled cohort data by the DERC, following the final dose of the last patient in the previously completed cohort, dose escalation to the next higher-dose cohort may proceed upon review, confirmation, and documentation of acceptable interim safety, PK, and PD findings from all available interim data.
  • DLTs dose escalation will not proceed, if any of the following criteria (DLTs) are met: - 115 - NAI-1537985011v1
  • DLTs drug-related myocarditis resulting in a reduction in ejection fraction by cardiac MRI.
  • SAEs from placebo arm will be assessed as not related to study drug.
  • CCAE Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0: 2017.Available from: https_ctep_cancer_gov/protocoldevelopment/electronic_applications/docs/CTCA E_v5_Quick_R eference_5x7_pdf.) ⁇ Grade 3 hypersensitivity reaction in 2 or more subjects in a treatment group that is deemed drug related following unblinding of the study subjects o
  • the occurrence of Grade 3 eosinophilia with eosinophil-induced AEs in 2 or more subjects at any given dose level o
  • Drug-Induced Liver Injury Premarketing Clinical Evaluation. July 2009. Available from https_www_fda_gov/media/73679/download. Accessed 21 Oct 2020) of liver function parameters (confirmed by repeat sampling): o Three-fold or greater elevations above the upper limit of normal (ULN) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with elevation of serum total bilirubin to 2 ⁇ ULN, without initial findings of cholestasis (elevated serum ALP), and without another reason to explain the - 116 - NAI-1537985011v1 combination of increased aminotransferase (AT) and total bilirubin, such as viral hepatitis A, B, or C; or acute liver disease.
  • UPN alanine aminotransferase
  • AST aspartate aminotransferase
  • AT increased aminotransferase
  • total bilirubin such as viral hepatitis A, B
  • Criteria for Study Termination If the Investigator or the Sponsor become aware of conditions or events that suggest a possible hazard to patients if the clinical study continues, then the clinical study would be halted, pending full consideration of corrective measures to the protocol and/or termination. [00226] Conditions that may warrant termination of the clinical study include, but are not limited to, the following: [00227] The discovery of an unacceptable risk to the patients enrolled in the clinical study, [00228] Failure to enroll patients at the required rate; and/or [00229] A decision of the Sponsor to suspend or discontinue development of the IMP. 5.1.13.
  • End of Study Definition A participant is considered to have completed the study if he or she has completed all visits of the study including the last visit and the last scheduled procedure shown in the Schedule of Assessments, below. In some cases, end of study visit is 31 days after the last dose (1 study clinic visit). [00231] The end of the study is defined as completion of the last visit and the last scheduled procedure shown in the Schedule of Assessments in the trial globally (see below). 5.1.14. Study Assessments [00232] The Schedule of Assessments for the core study, for patients with psoriasis and for patients with atopic dermatitis, are shown in Table 6A and 6B (respectively) below.
  • the screening period (Day –42 to Day –1) includes required completion of all screening assessments (Tables 6A and 6B and Section 5.1.14.2). Vital sign assessments for eligibility can be repeated, and vital signs for eligibility may be used from any assessment performed between Day – 42 to Day – 1.
  • Patients who do not meet the criteria for participation in this trial may be rescreened once, if deemed acceptable by the Investigator after discussion with the Medical Monitor (except for troponin I levels in patients with psoriasis).
  • Baseline cardiac MRI assessments can be used for up to 6 months for re-screening patients with psoriasis. Patients should resign the ICF, re-do all procedures planned at the screening visit, and be assigned a new screening number.
  • Screening assessments are as follows: • Obtain signed informed consent - 118 - NAI-1537985011v1 • Review inclusion and exclusion criteria • For patients with psoriasis only: Cardiac MRI • Demographics • Medical and surgical history, and prior medication history. Prior medications should include general medications received within 30 days of start of screening. • Any previous therapies for psoriasis or atopic dermatitis (both topical and systemic agents, and phototherapy) should all be entered. All COVID vaccinations within the prior 3 years of the start of screening should be entered.
  • PE Physical examination
  • BMI body mass index
  • Vital signs These can be repeated for qualification for eligibility (see below, Patient Exclusion Criteria) • ECG, standard 12-lead, supine position •
  • ECG ECG
  • CRP C-reactive protein
  • Ferritin Coagulation panel (prothrombin time/international normalized ratio [PT/INR]), activated partial thromboplastin time (aPTT), and fibrinogen
  • CBC Complete blood count
  • CRP C-reactive protein
  • Ferritin Coagulation panel (prothrombin time/international normalized ratio [PT/INR]), activated partial thromboplastin time (aPTT), and fibrinogen
  • Patients are provided with a diary at the screening visit in order to complete the PP-NRS daily starting from screening and daily during the core study and at every visit during the OLE. Screening period must be a minimum of 7 days in order to collect PP- NRS between Day -7 and Day -1 and calculate a weekly average baseline score prior to Day 1.
  • Tests performed on Day 1 include the following: • Review inclusion and exclusion criteria • Weight • Medical, surgical, and prior medication history • PE including thorough skin examination • Vital signs • ECG, standard 12-lead, supine position • For patients with psoriasis only: Troponin I - 120 - NAI-1537985011v1 • CBC with differential • Chemistry panel • Immunoglobulin (IgG, IgM) • CRP • Ferritin • Coagulation panel (PT/INR, aPTT, and fibrinogen) • Urinalysis with micro
  • Double-Blind Study Treatment Period Days 3, 17, 31, and 45 procedures may include the following: • Brief physical examination (including a complete skin exam) • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Blood samples to check: - the level of XmAb27564 in the blood (Day 3 and Day 45 only) and for pharmacodynamics (to measure the response of the body to the study drug) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed.
  • Days 5, 19, 33, and 47 procedures may include the following: • Brief physical examination (including a complete skin exam) • Vital signs • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Blood samples to check: - the level of XmAb27564 in the blood (Day 5 and Day 47 only) and for pharmacodynamics (to measure the response of the body to the study drug) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed.
  • - the level of cytokines on Day 5 (soluble proteins naturally found in the blood) Days 8, 22, 36, and 50 procedures may include the following: - 122 - NAI-1537985011v1 • Brief physical examination (including a complete skin exam) • Vital signs • Electrocardiogram (ECG) • Lab tests (blood only) • Psoriasis Area and Severity Index (PASI): Measurement of the severity and extent of the psoriasis • Body Surface Area (BSA): Examination to measure the amount of the body surface that is affected by the psoriasis • Investigator Global Assessment (IGA): The study doctor assesses the severity of the disease • Dermatology Life Quality Index (DLQI): questions are asked about how the disease affects the quality of life (Day 50 only).
  • ECG Electrocardiogram
  • Psoriasis Area and Severity Index Psoriasis Area and Severity Index
  • BSA Body Surface Area
  • IGA Investigator Global Assessment
  • the study doctor assesses the severity of the
  • Days 12, 26, 40, and 54 procedures may include the following: • Brief physical examination (including a complete skin exam) • Vital signs • Lab tests (blood only) • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Additional blood samples will be taken to check: - 123 - NAI-1537985011v1 - the level of XmAb27564 in the blood (Day 12 and Day 54 only) and for pharmacodynamics (to measure the response of the body to the study drug) - the level of cytokines (soluble proteins naturally found in the blood) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed.
  • Days 15, 29, and 43 procedures may include the following: • Brief physical examination (including a complete skin exam) • Vital signs are measured 6 times; once before study drug injection and 5 times after study drug injection • Electrocardiogram (ECG) is performed 2 times: once before study drug injection and 1 time after study drug injection • Lab tests (blood and urine) • Urine pregnancy test for women of childbearing potential • COVID-19 antigen (rapid nasal swab test) • Skin biopsies and photography (Day 29 only) • Psoriasis Area and Severity Index (PASI): Measurement of the severity and extent of psoriasis • Body Surface Area (BSA): Examination to measure the amount of body surface that is affected by the psoriasis • Investigator Global Assessment (IGA): The study doctor assesses the severity of the disease • Receive study drug followed by an up to 6-hour observation period • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Additional blood samples to check: - the level of
  • a cardiac consultation and cMRI may be performed.
  • Patient remains at the study site for up to 6 hours after the study drug injection for further observation.
  • Day 57 procedures include the following: • Brief physical examination (including a complete skin exam) • Vital signs • Electrocardiogram (ECG) • Lab tests (blood and urine) • Skin biopsies and photography of total body and areas of plaque • Psoriasis Area and Severity Index (PASI): Measurement of the severity and extent of psoriasis • Body Surface Area (BSA): Examination to measure the amount of the body surface that is affected by the psoriasis • Dermatology Life Quality Index (DLQI): questions are asked about how the disease affects the quality of life.
  • BSA Body Surface Area
  • DLQI Dermatology Life Quality Index
  • IGA Investigator Global Assessment
  • the study doctor assesses the severity of disease.
  • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Additional blood samples to check: - the level of XmAb27564 in the blood and for pharmacodynamics (to measure the response of the body to the study drug) ⁇ - the level of cytokines (soluble proteins naturally found in the blood) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed.
  • IGA Investigator Global Assessment
  • the study doctor assesses the severity of disease • Review of any medications • Blood test for Myocarditis associated viruses and COVID-19 antibody. • Additional blood samples to check: - the level of XmAb27564 in the blood and for pharmacodynamics (to measure the response of the body to the study drug) - the level of cytokines (soluble proteins naturally found in the blood) - the level of anti-drug antibodies - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed.
  • ADAs anti-drug antibodies
  • ADAs have the potential for neutralizing the activity or altering the PK of XmAb27564 or endogenous IL-2.
  • ADAs may also confer cytotoxic activity to cell-bound XmAb27564 or endogenous IL-2. Because IL-2 supports the development and survival of lymphocytes, lymphopenia is a potential clinical impact of ADAs.
  • ADAs have the potential for neutralizing the activity or altering the PK of XmAb ® 27564 or endogenous IL-2. ADAs may also confer cytotoxic activity to cell-bound XmAb ® 27564 or endogenous IL-2. Because IL-2 supports the development and survival of lymphocytes, lymphopenia is a potential clinical impact of ADAs.
  • lymphopenia is a potential clinical impact of ADAs.
  • Prior and Concomitant Medication For patients with atopic dermatitis the patients are to apply a stable dose of a non- prescription, non-urea containing emollient to all skin (normal skin and AD lesions) once or twice daily for ⁇ 14 days preceding the randomization visit and also are willing to maintain stable dosing of the emollient until at least the Day 57 visit. Every effort should be made to keep - 129 - NAI-1537985011v1 the same emollient throughout the study for the same body region. However, the chosen emollient may differ depending on the body region (e.g., body vs face emollient may be different).
  • Concomitant medications are defined as medications started before and continued after the first dose of XmAb ® 27564/placebo in this study.
  • All therapies (prescriptions or over-the-counter [OTC] medications, including vitamins and herbal supplements) different from the study drug is recorded in the eCRF.
  • Randomization schedules for each dose cohort are generated for patients with psoriasis and patients with atopic dermatitis separately prior to study start.
  • Each psoriasis cohort consist of 8 patients, 3 sentinel patients are randomized in a 2:1 ratio to XmAb ® 27564 or placebo and five remainder patients are randomized in a 4:1 ratio to XmAb ® 27564 or placebo.
  • 6 patients are randomized to XmAb ® 27564 and 2 patients to placebo.
  • 16 patients are randomized in a 3:1 ratio to receive XmAb ® 27564 or placebo.
  • XmAb ® 27564 or placebo is administered in a double-blind fashion.
  • the contract research organization will maintain the randomization code in a secure location with controls to prevent unauthorized access, including the computer program written to generate the randomization, randomization codes, program log, seed number used by the program, copy of the randomization plan along with approval documentation as appropriate, and the write-protected electronic storage medium.
  • the CRO will name an unblinded statistician to generate the randomization codes.
  • the pharmacists will be unblinded.
  • the site follows their internal SOP for the back-up staff who can break the blind. If possible, the Investigator notifies the Xencor Medical Monitor prior to breaking the blind, but if not, they are informed immediately thereafter. [00269] If the treatment assignment is unblinded by the Investigator, then the Investigator must notify the Sponsor in writing and document the course of events in the source records. Any patient for whom the treatment code is prematurely released will be withdrawn from the study but will continue to be followed for safety events if IMP was received. 5.1.17.
  • Study Drug and Storage is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol and the Pharmacy Manual.
  • Investigational product, dosage and mode of administration includes the following: Multiple SC administration of XmAb ® 27564 solution at dose levels of (0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo, as shown in Table 4.
  • Table 4 Study Drug Information XmAb ® 27564 Drug Product (DP) a es gle - 132 - NAI-1537985011v1 Dose: Study drug preparations and dose administration information are provided in Example 1.
  • XmAb ® 27564 Drug Product is provided as a 30 mg vial (30 mg/mL, 1 mL fill) for SC administration. Prior to use, the XmAb ® 27564 DP vial should be visually inspected. If particulate matter and/or discoloration are noted, the drug should not be administered, and the Sponsor should be notified. Aseptic technique must be strictly observed when preparing the solution for injection since XmAb ® 27564 and XmAb ® 27564 placebo vials do not contain preservatives.
  • the XmAb ® 27564 placebo is provided as 5 mL of a solution of 250 mM sorbitol in a 20 mM histidine buffered solution of pH 6.5 in a 10 mL vial. The vial must not be shaken, as excess agitation may cause aggregate formation. Administration of XmAb ® 27564 and XmAb ® 27564 placebo should take place within 4 hours of dose preparation. If a delay is anticipated, XmAb ® 27564 and XmAb ® 27564 placebo may be stored at controlled room temperature (15oC-30oC; 59oF-86oF) for no more than 4 hours prior to injection (see the study Pharmacy Manual for specific instructions).
  • XmAb ® 27564 DP and XmAb ® 27564 placebo are administered via SC injection (1 mL syringe and 27-gauge needle).
  • Recommended sites of administration include the upper arm, thigh, and abdomen, with the regions used to be noted in the source document. Regions should be rotated from one dose to the next. The injection site should be marked with a small circle and date of injection to identify injection site and monitor reactions.
  • Dosing is weight based for all treatment groups. Calculate the dose based on the weight at the Day 1 visit. 5.1.20.
  • Psoriasis Area Severity Index (PASI) Scoring 4 main body areas are assessed: the head (h), the trunk (t), the upper extremities (u), and the lower extremities (l), corresponding to 10, 30, 20, and 40% of the total body area, respectively.
  • 3 target symptoms namely erythema (E), infiltration (I), and desquamation (D) are assessed according to a scale 0–4, where 0 means a complete lack of cutaneous involvement and 4 represents the severest possible involvement.
  • the severity rating for the 3 main target symptoms is multiplied with the numerical value of the areas involved and with the various percentages of the 4 body areas. These values are then added to obtain the PASI.
  • PASI 0.1 ⁇ Ah ⁇ (Eh + Ih + Dh) + 0.3 ⁇ At ⁇ (Et + It + Dt) + 0.2 ⁇ Au ⁇ (Eu + Iu + Du) + 0.4 ⁇ Al ⁇ (El + Il + Dl)
  • the index varies in steps of 0.1 units from 0.0 to 72.0.
  • the proportion of subjects with PASI 50, 75, and 90 represent the fraction of patients that have improvement of the PASI score of 50%, 75% and 90% over the baseline PASI (Oji and Luger. Clin Exp Rheumatol.2015;33(5 Suppl 93):S14–9.).
  • Static Investigator Global Assessment of Disease - 134 - NAI-1537985011v1 The Static Investigator Global Assessment (sIGA) of disease is a 5-point scale, without any reference to baseline (Langley et al. J Dermatolog Treat.2015;26(1):23–31.; Table 5). Table 5. sIGA of Disease for Psoriasis S core Description ; 5.1.20.3 Validated Investigator Global Assessment for Atopic Dermatitis Table 17.
  • Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD): Score Morphological Description , g - 135 - NAI-1537985011v1 [00279]
  • the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) is a static 5-point scale that was developed to assess the overall atopic dermatitis severity (Simpson et al. J Am Acad Dermatol.2020;83(3):839-846).
  • the IGA score is selected using the descriptors in Table 17 that best describe the overall appearance of the lesions at a given time point. It is not necessary that all characteristics under Morphological Description be present.
  • EASI Eczema Area and Severity Index
  • each region is assessed separately for 4 signs: erythema, edema/papulation, excoriation, and lichenification. Each sign is assigned an intensity score from 0 to 3, with 0 being absent; 1, mild; 2, moderate; and 3, severe. Half points may be used between points 1 and 3 (e.g., 1.5 and 2.5 but not 0.5) as any sign present should be treated as at least mild. It is important to note that only inflamed areas should be included in the assessment.
  • Regions that present with varying severity of a particular sign should be roughly averaged across involved areas only; half units may be useful in this scenario.
  • Region Score Each region is assigned an adult that reflects the relative contribution of that region to the total BSA. The region score is calculated separately for each region by multiplying the sum of the regional intensity score by the regional area score and the region-specific multiplier.
  • Final EASI Score The final EASI score is the summation of the 4 regional scores, ranging from 0 to 72.
  • a score of 0 indicates clear or no eczema, 0.1 to 1.0 indicates almost clear, 1.1 to 7 indicates mild disease, 7.1 to 21 indicates moderate disease, 21.1 to 50 indicates severe disease, and greater than 51 indicates very severe disease.
  • - 136 NAI-1537985011v1 5.1.20.5 Peak Pruritus Numerical Rating Scale (Atopic Dermatitis) [00285] Pruritus is assessed using the PP-NRS.
  • the PP-NRS is an 11-point scale used by patients to rate their worst itch severity over the past 24 hours with 0 indicating “No itch” and 10 indicating “Worst itch imaginable” (Yosipovitch et al., Br J Dermatol.2019;181(4):761-769).
  • Patient assessments are captured daily using a diary starting from screening until the EOS visit. Patients are provided with a diary at the screening visit and instructed to enter their pruritus scores daily.
  • the daily (24-hour) PP-NRS are recorded and the weekly mean of the daily PP- NRS are calculated. Therefore, a minimum of 7 days of screening is needed to collect PP-NRS scores between Day -7 and Day -1 and calculate a weekly average baseline score prior to Day 1.
  • Each plaque biopsied should have a photograph accompanying the biopsy. The location of the plaque(s) biopsied should be noted in the source document. 5.1.20.7 Body Surface Area of Psoriasis or Atopic Dermatitis - 137 - NAI-1537985011v1 [00288]
  • the body surface area (BSA) of psoriasis or atopic dermatitis is estimated by using the size of the handprint as 1% of the body surface area. The investigator totals the number of patient’s handprints across the patient’s body that have activity with psoriasis or atopic dermatitis (Ramsay and Lawrence. Br J Dermatol.1991;124(6):565–70.).
  • the Dermatology Life Quality Index [00289]
  • the DLQI is a short and simple quality of life (QOL) instrument that can be used in psoriasis or atopic dermatitis. It is self-administered with a mean completion time of 2 min. It consists of 10 questions concerning impact of skin diseases on different aspects of patient’s QOL over the last week.
  • the DLQI items include symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the side effects of treatment. Each item is scored on a 4-point scale: not at all/not relevant, a little, a lot and very much. Item scores (0-3) are added to give a total score (0-30); higher scores indicate greater impairment of QOL.
  • n e s s . n p e s ’ n i d t r l n e e h h e t a m o e n C d n ds t s p o e H S m r b . d o t o r o i e n o i .
  • RNA assessment The samples for RNA assessment are collected into PAXgene tubes for –70 ⁇ C freezer storage and batch shipped to the designated laboratory.
  • Treg and TBNK flow cytometry provides PD data for Treg and Teff/NK expansion and activation.
  • Isolated RNA is used for transcriptomic analysis of immune cell genes and gene signatures.
  • PBMCs is used for additional phenotypic and functional description of immune cells, including but not limited to analysis by flow cytometry or similar methods. 5.1.22.
  • AEs Adverse Events
  • Clinical laboratory safety assessments including troponin I for patients with psoriasis • ECG parameters • Vital signs • Physical exam findings • ADAs • Cardiac MRI for patients with psoriasis • Myocarditis-associated virus serology and PCR for patients with psoriasis • Pregnancy - 154 - NAI-1537985011v1 Overdose 5.1.22.1 Adverse Events [00297] An adverse event or AE is any untoward medical occurrence in a patient participating in a clinical study. The AE does not necessarily have a causal relationship with study treatment.
  • An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of an IMP.
  • AEs may include the onset of new illness and the exacerbation of preexisting conditions. AEs are classified as “serious” and “non-serious” for regulatory reporting purposes.
  • SAE Serious Adverse Event
  • Severity is a measure of intensity whereas seriousness is defined by the criteria above. For example, a mild degree of gastrointestinal bleeding requiring hospitalization for monitoring purposes would be considered an SAE but is not necessarily a severe (Grade 3) SAE. Similarly, - 155 - NAI-1537985011v1 an AE that is severe (Grade 3) is not necessarily an SAE. For example, alopecia may be assessed as severe (Grade 3) but would not be considered an SAE.
  • Adverse event monitoring begins upon the signing of the informed consent form (ICF).
  • ICF informed consent form
  • All SAEs and events of special interest, irrespective of causality, are monitored until the event has resolved or stabilized, until any abnormal laboratory values have returned to baseline or stabilized at a level acceptable to the Investigator and Sponsor’s medical representative, until there is a satisfactory explanation for the changes observed, or until the patient is lost to follow-up.
  • Adverse events may be volunteered spontaneously by the study patient, discovered by the study staff during physical examinations, or by asking an open, nonleading question such as “How have you been feeling since you were last asked by us?” or “Have you had any new or changed health problems since you were last here?” All AEs and any required remedial action are recorded.
  • the nature of AE, date (and time, if known) of AE onset, date (and time, if known) of AE outcome to date, severity, and action taken with the study drug because of - 156 - NAI-1537985011v1 the AE are documented together with the Investigator’s assessment of the seriousness on the AE and causal relationship to study drug and/or study procedure.
  • Non-serious AEs are recorded in electronic data capture (EDC) following administration of IMP through EOS, and any non-serious AEs that occur prior to dose administration are captured in the medical history. For screen failed patients recording of non-serious AEs after the ICF was signed is not needed.
  • Serious AEs or SAEs are recorded in the EDC on AE eCRF page and the completed SAE report form is emailed to Xencor/CRO vendor for all patients randomized. The Investigator is responsible, within 24 hours of becoming aware of the SAE, to complete all required details on the initial and follow-up SAE report form and email to Xencor.
  • AEs which are unlikely related or not related to study drug are considered to be not related events for the purposes of AE capture and regulatory reporting.
  • b AEs which are possibly related, probably related, or related to study drug are considered to be related events for the purposes of AE capture and regulatory reporting.
  • Xencor requests clarification of omitted and/or discrepant information from the initial notification or follow-up report(s) as needed. Xencor may also request additional information [00307] regarding the SAE in order to obtain the full clinical picture.
  • the Investigator or an authorized delegate is responsible for providing the requested information in a Data Clarification Form (DCF) to Xencor within 24 hours of the request and updating AE eCRF in EDC.
  • DCF Data Clarification Form
  • the initial SAE report from the investigational site must be followed up as soon as possible by completing a blank SAE report form (with the follow-up box checked). All additional events and existing event/s should be recorded with corresponding assessments, all new details should be included in the follow-up report.
  • These SAE report/s should be emailed along with clear photocopies of other documents as necessary (e.g., hospital reports, discharge summaries, consultant reports, autopsy reports, etc.) with the study patient’s personal identifiers redacted.
  • AE Severity/Intensity/Grades The Investigator can assess all AEs for severity, also known as intensity or grades, utilizing the NCI-CTCAE grading scale (Version 5.0). Note that some grades are not available for certain AEs (e.g., Headache can only be Grade 1, 2 or 3; and Sepsis can only be Grade 3, 4 or 5). AEs not contained within CTCAE Version 5.0 are rated on a 5-point scale (Table 9). - 158 - NAI-1537985011v1 Table 9.
  • Adverse Event Grades Mild Mild events are those which are easily tolerated with no disruption of normal daily activity. re at [00312]
  • the Investigator assess the causality/relationship between the IMP and the AE.
  • One of the following categories should be selected based on good medical and scientific judgment, considering the definitions in Table 10 and all contributing factors. Table 10.
  • Causality Assessment Guide For the purposes of regulatory reporting, if the Investigator chooses one of the following categories, “ ” e y - 159 - NAI-1537985011v1 If the Investigator chooses one of the following below, the AE is identified as “not related by the Investigator” e al ear ge. y p p g, g g .
  • the baseline laboratory test results for clinical assessment for a particular test is defined as the last measurement prior to the initial dose of study drug. • During the screening period, if a patient has an out-of-range value for a clinical laboratory parameter which the Investigator believes is not clinically significant, but the Investigator wants to confirm with a repeat laboratory test, a single repeat is allowed to confirm the initial result. If a subject tests positive for urine drugs of abuse (including the following: amphetamines/ecstasy, barbiturates, benzodiazepines, cocaine, opiates, methadone metabolites, and phencyclidine) and alcohol screens, the subject’s eligibility is discussed with the Xencor Medical Monitor.
  • urine drugs of abuse including the following: amphetamines/ecstasy, barbiturates, benzodiazepines, cocaine, opiates, methadone metabolites, and phencyclidine
  • cytokines including IL-6, IP-10, IL-23, IL-17 will be examined.
  • additional chemokines including TARC, MDC, cytokine IL-18 and Th2 biomarker periostin is examined.
  • Microscopic analysis is reflexive after urine dipstick is positive.
  • c Troponin I testing for patients with psoriasis only Serum IgE and allergen-specific. IgE for patients with atopic dermatitis only.
  • AEs Clinically significant abnormal laboratory results are recorded as AEs and the relationship to the study drug is indicated as below. Laboratory values outside the normal range assessed as clinically significant should be reported as AEs. In general, a clinically significant laboratory value or finding would require some diagnostic or therapeutic intervention other than repeating the test. 5.1.24.
  • Troponin I Cardiology Consultation, Myocarditis-associated Viruses, and Cardiac MRI
  • All patients with psoriasis have a cardiac MRI at Screening and are followed at baseline and throughout the study by serial high sensitivity Troponin I assays. Patients who have elevated Troponin I levels at screening should be screen failed.
  • a patient has a value for Troponin I above normal limits, the patient should be called back to clinic for an unscheduled visit and should have a directed physical examination, a 12-lead ECG, an urgent cardiology consultation, and a cardiac MRI.
  • Myocarditis should be diagnosed using cardiac MRI and graded by the Lake Louise criteria for myocarditis (Friedrich et al. J Am Coll Cardiol.2009 Apr 28;53(17):1475–87.; Ferreira et al. J Am Coll Cardiol.2018;72(24):3158–76.). If positive, serial cardiac MRI studies should be done until event resolution.
  • myocarditis-associated viruses should be assessed by serial titers and PCR: adenovirus, coxsackie B virus, echovirus, herpesviruses, parvovirus, and SARS-CoV-2 (Pollack et al. Nat Rev Cardiol.2015;12(11):670– 80.). - 165 - NAI-1537985011v1 [00320] Cardiac MRI data are collected and read centrally by a third party blinded to patient identity. Procedure specifics for cardiac MRI are detailed in the study manual. 5.1.25. Vital Signs [00321] Vital signs are assessed after the patient has been resting quietly for ⁇ 5 minutes and as indicated in the Schedule of Assessment (Tables 6A and 6B ).
  • vital signs should be measured prior to blood sampling.
  • the following vital signs are measured: • Blood pressure (systolic and diastolic [mmHg]) is measured after the patient has been resting quietly for at least 5 minutes. • Heart rate (beats per minute [bpm]) is collected after the patient has been resting and at rest for ⁇ 5 minutes. • Respiratory rate (breaths per minute) • Oral body temperature (°C) • Blood oxygen saturation by pulse oximetry. Oxygen saturation levels are captured at each vital sign collection. • The following vital signs abnormalities is recorded as AEs: 1. Vital signs are considered clinically significant initially and on confirmation 2. Require a patient to be discontinued from the study 3. Require a patient to receive treatment 4.
  • a complete PE (including thorough skin examination, and excluding genital, rectal, and breast examinations [unless indicated]) is performed at screening. For all other time points, - 166 - NAI-1537985011v1 symptom-directed PEs are performed; a thorough skin examination is performed at every visit. Abnormal findings is documented in the patient’s eCRF. [00325] A following abnormal PE finding that is considered clinically significant is recorded as an AE: 1. Requires the patient to be discontinued from the study, 2. Requires the patient to receive treatment; and/or 3. Requires a change or discontinuation of the study drug (if applicable) recorded as an AE. 5.1.27.
  • Electrocardiogram Assessments [00326] The timing of ECGs is noted in the Schedule of Assessment (Tables 6A and 6B). On all dosing days during the core study, supine ECGs are performed predose and 4 hours after SC injection. The 12-lead ECGs are performed after the patient has been resting supine for ⁇ 5 minutes. The ECG includes all 12 standard leads. The following ECG parameters are collected: PR interval, QRS interval, RR interval, QT interval, QTc, and QTcF interval.
  • Electrocardiogram assessments include interpretation of the tracings (e.g., rhythm, presence of arrhythmia or conduction defects, morphology, any evidence of myocardial infarction, or ST segment, T-wave, and U-wave abnormalities).
  • the Investigator or designee is responsible for reviewing and over-reading the ECG interpretation, for assessing whether the ECG machine interpretation findings are accurate, appropriate, normal or abnormal, and for providing corrected interpretations, as appropriate.
  • any abnormal ECGs are assessed for clinical significance.
  • Additional ECGs may be obtained if clinically indicated. Any additional relevant data obtained by the Investigator during the course of this study is supplied to the Sponsor.
  • ECG ECG that the Investigator considers clinically significant
  • the Investigator will: • Repeat the ECG; and/or • Follow-up ECG(s) are obtained if any significant abnormalities are detected after dose administration to document resolution and as clinically indicated.
  • Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., maternal serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, birth defect) and reported within 24 hours of awareness in accordance with the procedure for reporting SAEs.
  • Xencor-CRO vendor requests clarification of omitted or discrepant information from the initial notification. The Investigator or an authorized delegate is responsible for providing the requested information to Xencor within 24 hours of the request. 5.1.29.
  • Descriptive statistics include mean, median, standard deviation, quartiles, min and max for continuous variables, and frequency counts and percentages for categorical variables. Data is displayed graphically as appropriate.
  • PK/PD analysis of the blood include PK, ADA, transcriptomics, flow cytometry, and cytokine/soluble factor measurements as described in the following sections. [00341] After all subjects have completed the double-blind core study (subjects who did not enter extension phase had EOS visit and subjects who entered extension phase had Day 57 visit as defined in the core study assessment schedule), all the subjects’ data in the double-blind core study are locked and unblinded after the database has met the unblinding criteria as required by data management.
  • the database lock and unblinding are performed for patients with psoriasis and patients with atopic dermatitis separately. Analysis are performed on the unblinded core study data. - 169 - NAI-1537985011v1 [00342] Pharmacokinetic, ADA, and PD data are analyzed as described in the following sections. A statistical analysis plan (SAP) prespecifying details for all analyses is completed prior to database lock. Any deviations from the planned analyses is described in the final clinical study report. 5.1.30.1 Sample Size and Power [00343] No formal sample size calculations were performed. The study enrolls approximately 48 patients in total with psoriasis, with 8 patients per cohort, and approximately 80 patients with atopic dermatitis with 16 patients per cohort.
  • Analysis Set The following analysis sets are defined for the double-blind core study • Randomized Analysis Set: All patients who signed the informed consent, successfully complete screening, and receive a randomization number. • Safety Analysis Set: All patients who received any amount of XmAb ® 27564 or placebo. • Efficacy Analysis Set: All patients who received any amount of XmAb ® 27564 or placebo, have baseline and at least 1 post-baseline PASI score or EASI score for psoriasis and atopic dermatitis, respectively. • Pharmacokinetic Full Analysis Set: All patients who received a dose of XmAb ® 27564 and have at least 1 concentration data point.
  • the exploratory efficacy variables for patients with psoriasis include the following: - 170 - NAI-1537985011v1 • PASI • sIGA • BSA • DLQI
  • PASI, sIGA, BSA and DLQI The analysis of the exploratory efficacy objective of this study is based on the change from baseline to Day 57 of the efficacy variables (PASI, sIGA, BSA and DLQI).
  • PASI 75 The percentage of patients with a greater than or equal to 75% reduction from baseline in PASI score (PASI 75) is tabulated by dose cohort at each visit.
  • PASI 50 and PASI 90 are summarized in the similar manner. PASI observed values, change and percentage change from baseline values are summarized descriptively as continuous variables.
  • EASI 75 and EASI 90 are summarized in a similar manner.
  • EASI observed values, change and percent change from baseline are summarized descriptively as continuous variables.
  • the proportion of patients achieving a vIGA-AD of 0 or 1 and reduction from baseline ⁇ 2 points are summarized.
  • Observed values and change from baseline in vIGA- AD are summarized as continuous variables.
  • Observed values, change and percent change from baseline in BSA involvement and DLQI are summarized.
  • the observed values, change and percent change from baseline are summarized for weekly mean PP-NRS during the core study.
  • the weekly mean PP-NRS is calculated as the average of the reported daily PP-NRS within the week.
  • the proportion of patients achieving a reduction of ⁇ 4 points from baseline in weekly mean PP-NRS score during the core study are summarized for each week.
  • the daily PP-NRS score collected at the scheduled visits will be used in the analysis.
  • - 171 - NAI-1537985011v1 The line graphs of mean observed values, change and percent change from baseline in efficacy variables over time may be plotted.
  • the categorical response variables may be plotted in line or bar plots.
  • the SAP is provide a detailed description of analysis methods. Additional exploratory analyses may be specified in the SAP.
  • Safety variables include the following: • AEs • Physical examinations (including thorough skin examination) • Vital signs • ECG • Clinical laboratory testing: ⁇ Clinical chemistry, hematology including eosinophils, coagulation, troponin I (for patients with psoriasis only), CRP, ferritin, urinalysis, viral testing (for patients with psoriasis only), and cardiac MRI (for patients with psoriasis only) • Concomitant medications • Medical history [00353] The extent of exposure to XmAb ® 27564 or placebo is summarized by dose cohort. [00354] Summary tables and listings are provided for all reported AEs.
  • Drug names are classified by the WHO dictionary.
  • Adverse events are coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). The verbatim term recorded by the Investigator is mapped to System Organ Class (SOC) and Preferred Term using MedDRA.
  • SOC System Organ Class
  • Treatment-emergent AEs are defined as events with onset dates on or after the start of study treatment or events that are present before the first injection of XmAb ® 27654 and subsequently worsen in severity.
  • Adverse-event-related endpoints include the following: • TEAEs • Treatment-emergent SAEs (TE-SAEs) • Treatment-related TEAEs • Treatment-related TESAEs - 172 - NAI-1537985011v1 • TEAEs by severity that are defined by NCI-CTCAE, Version 5.0 [00358] All AE-related endpoints are summarized by MedDRA SOC and preferred term. At each level of summation, patient is counted once under the greatest severity and strongest study drug relationship. All AEs are included in the listings. [00359] The hematology, chemistry, and other laboratory values and change from baseline values are summarized descriptively by dose cohort.
  • the baseline value for each laboratory value is defined as the last assessment performed prior to administration of IMP.
  • Patient listings of all laboratory data collected during the study are generated. Laboratory values outside normal limits are identified in the patient listings and include flags for high and low values.
  • Vital sign results and change from baseline values are summarized descriptively for each scheduled time point.
  • the baseline value for each vital sign measurement is defined as the last assessment performed prior to administration of IMP.
  • the change in vital signs values from pre-injection are summarized for each post-injection point.
  • Pre-injection assessments are defined as last vital assessment prior to a specified injection.
  • Electrocardiogram values and change from baseline values are summarized descriptively for each scheduled time point. Patient listings of all ECG data collected during the study are generated.
  • 5.1.31. Pharmacodynamic Analyses All or key observed PD data and change from baseline data are summarized using descriptive statistics and are listed and summarized in tabular and/or graphical form. Descriptive statistics on continuous data include mean, median, standard deviation, and range, while categorical data may be summarized using frequency counts and percentages. 5.1.32. Pharmacokinetic Analysis [00363] The PK parameters are computed using noncompartmental and/or compartmental methods, whichever best describes the data. [00364] Data analysis may include assessment of dose proportionality, steady state conditions and drug accumulation with repeated dosing. [00365] In addition, population PK analysis may be conducted to develop a model to describe the concentration-time profile of XmAb ® 27564.
  • Immunogenicity is assessed by measuring serum levels of anti-XmAb ® 27564 binding antibodies by ICON Laboratory Services, Inc., using a fully validated electrochemiluminescent assay method. Immunogenicity results are listed and displayed graphically by overlaying immunogenicity parameter on drug serum concentrations over time. Incidence of confirmed positivity is summarized and additional analyses of time to onset of ADA, duration of ADA positivity, neutralizing antibodies, and impact on drug serum concentrations may also be performed. 5.1.34.
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • XmAb ® 27564 is a monovalent interleukin-2 Fc (IL-2-Fc) fusion protein, engineered to selectively activate and expand regulatory T cells (Tregs) for the treatment of patients with autoimmune diseases.
  • IL-2-Fc monovalent interleukin-2 Fc
  • Tregs prevent autoimmunity by suppressing other immune cells from attacking normal tissue; however, in many autoimmune diseases, Tregs become dysregulated.
  • Tregs have an important role in homeostasis and in autoimmune disease (FIG.4): 1) regulatory T cells (Tregs) are CD4+FoxP3+ cells expressing CD25 (IL-2R ⁇ ) that maintain immune tolerance in tissues by suppressing the function of both CD4 and CD8 effector T cells; 2) Tregs are dysfunctional in most autoimmune diseases; 3) a therapeutic approach has been to restore Treg numbers and function via a low-dose IL-2 regimen (e.g., Treg homeostasis depends on IL-2; and IL-2 as a drug suffers from fast in vivo clearance and a narrow therapeutic index). An existing approach to restore normal immune activity and improve outcomes for patients has been to activate Tregs with IL-2 provided therapeutically at low doses.
  • IL-2 is a highly potent molecule that also activates the immune cell populations that Tregs are intended to suppress.
  • XmAb ® 27564 was engineered with reduced binding affinity for IL-2’s beta receptor (IL-2R ⁇ , CD122) and increased binding affinity for its alpha receptor (IL-2R ⁇ , CD25) to selectively target Tregs, and with 400- to 1000-fold reduced potency to improve the half-life of XmAb ® 27564 and to reduce its toxicity compared to wildtype IL-2 (FIG.5).
  • XmAb ® 27564 is based on XmAb ® cytokines approach for creating cytokine therapies (e.g., overcomes native - 180 - NAI-1537985011v1 cytokine short half-life and high toxicity; and systematically engineer a broad portfolio of cytokines). Integration of XmAb ® heterodimeric Fc domain provides a stable protein scaffold and improves XmAb ® 27564 pharmacologic properties. The XtendTM technology enhanced XmAb ® 27564 circulating half-life. In preclinical studies, XmAb ® 27564 was well-tolerated, promoted the selective and sustained expansion of Tregs and exhibited a favorable pharmacokinetic profile.
  • XmAb® 27564 exhibited extended half-life and good tolerability in non-human primates (NHPs); and XmAb®27564 selectively promoted Tregs and extended half-life due to low potency and XtendTM Fc domain (FIGS.6A-6B).
  • Approximately 1000X reduction in binding of XmAb ® 27564 to IL2-R ⁇ resulted in reduced overall potency and greater selectivity for Treg activation over conventional T cells (Tcons) and natural killer (NK) cells (FIGS.6A-6B; Treg EC50 of 21nM and 0.06nM, respectively).
  • XmAb ® 306 The loss of internalization in vivo through IL-2R ⁇ resulted in large gains in pharmacological exposure (FIGS.6C-6D). It has been shown that second potency-tuned XmAb Cytokine program (e.g., XmAb ® 306) showed marked target cell expansion and good tolerability in human clinical trials. XmAb ® 306, an IL15-IL15R ⁇ -Fc fusion in oncology, showed consistent and robust dose-dependent NK cell expansion and accumulation upon repeat dosing, reaching 40-100x higher than baseline in higher dose cohorts.
  • the Phase 1a studies using XmAb ® 27564 showed that XmAb ® 27564’s design gave dramatic Treg increases and unprecedented durability for a single dose, with high levels of Treg populations sustained for at least 3 weeks.
  • the Phase 1a study enrolled 48 healthy subjects, with six dose-level cohorts each randomizing six subjects to an IL-2 Fc fusion protein (e.g., XmAb ® 27564) and two subjects to placebo.
  • a dose escalation review committee reviewed each cohort’s safety, immunogenicity, PK, and PD data before approving each dose escalation.
  • Each subject was admitted to the study unit for a total of 4 overnight stays; subjects returned for outpatient assessments through 21 days and were followed for safety an additional 30 days. After Cohort 3, the safety follow-up period was extended from 30 days to 45 days.
  • a total of 12 subjects received placebo (2 subjects for each of the six dose-level cohorts).
  • the demographics of the subjects in this study is provided in Table 15. Assessments were determined at Days -1, 0, 8, 10, 21, and 43.
  • the outcome measures were: - 181 - NAI-1537985011v1 1) safety and tolerability; and 2) pharmacokinetics in healthy subjects including analysis of immunomodulatory biomarkers (e.g., T-cell populations).
  • immunomodulatory biomarkers e.g., T-cell populations.
  • the most common adverse event was injection site reaction observed in 25 of 36 subjects (69%) of subjects receiving XmAb ® 27564, including: 4 of 6 (67%) receiving 0.003 mg/kg (Cohort 1); 2 of 6 (33%) receiving 0.007 mg/kg (Cohort 2); 3 of 6 (50%) receiving 0.015 mg/kg (Cohort 3); 5 receiving 0.025 mg/kg and 5 receiving 0.040 mg/kg (Cohorts 4 and 5, respectively), and in all subjects (100%) receiving 0.065 mg/kg XmAb ® 27564 (Cohort 6). All AEs of injection site reaction were mild in severity for Cohorts 1 through 3.
  • the dose-dependent PK profile is in line with the expected PD effect of XmAb ® 27564 represented by an increase in target receptor levels (CD25) on T-cells and the consequent impact of target mediated drug disposition on XmAb ® 27564 elimination.
  • One subject was confirmed positive for anti-drug antibody (ADA) at a low magnitude on day 45 postdose with no apparent impact on the PK or PD profile of XmAb ® 27564.
  • ADA anti-drug antibody
  • Treg expansion Further increases in Treg expansion were seen at dose levels higher than 0.015 mg/kg with the clearest increase observed at the highest 0.065 mg/kg dose level.
  • total Tregs increased to a peak mean 7.34-fold increase corresponding to a mean increase of 187 ⁇ 183 cells/microliter on Day 15 (FIGS.17A-17F).
  • the majority of these Tregs were CD25 hi Tregs, which were present at very low levels at baseline (mean of 2 ⁇ 1 cells/microliter) and were 117-fold induced to a maximum mean of 140 ⁇ 78 cells/microliter.
  • CD25hi Tregs are thought to be functionally highly immunosuppressive Tregs.
  • the expanded Tregs were characterized and the population was identified as activated/memory Treg (CD45RA-/FoxP3 high ) (FIGS.18A-18H), which is also positive for various immunoregulatory molecules including LAG3 (CD223), ICOS (CD278), TIGIT, 4-1BB (CD137), Fas (CD95), are HLA-DR high and Ki67 positive, consistent with a highly activated, proliferative, and immunosuppressive phenotype.
  • IL-10 an immunosuppressive cytokine produced by Tregs
  • serum levels of IL-10 were increased in a dose- dependent manner, and at the highest dose level of 0.065 mg/kg were 15-fold increased at Day 10 after treatment, and a peak mean 16-fold increase in serum IL-10/IFN-g ratio occurred at Day 15 (FIGS.19A-19B).
  • XmAb ® 27564 selectively induced Tregs that co-expressed - 183 - NAI-1537985011v1 high levels of FoxP3, CD25 as well as LAG3/4-1BB/ICOS/TIGIT and peripheral elevations in IL-10, consistent with systemic immunosuppressive bioactivity.
  • Treg expansion was not paralleled by a concomitant increase in effector lymphocyte expansion. Consistent with the intended Treg selectivity of XmAb27564, conventional or all non-Treg cells (Tcons) and NK cells were minimally increased at doses higher than 0.015 mg/kg ( ⁇ 2-fold increases).
  • Tecons non-Treg cells
  • NK cells were minimally increased at doses higher than 0.015 mg/kg ( ⁇ 2-fold increases).
  • Eosinophilia is also an expected class effect of low-dose IL-2 and engineered IL-2, likely secondary to production of the eosinophil recruitment factor IL-5 by CD25-positive ILC2 cells. IL-5 increased in a dose-responsive manner and was paralleled by asymptomatic eosinophilia (FIGS.20 and 21).
  • XmAb27564 by two design features: namely reduction of clearance as a consequence of reduced CD122/CD132 engagement and inclusion of the Fc-Xtend domain, enabling augmented duration of PK and PD activity. Indeed, subcutaneous XmAb27564 exhibited a prolonged terminal half-life of 9 to 11 days. Peak Treg expansion of 7.34-fold was seen at Day 15, and the expansion was durable with Treg expansion present at least 21 days after a single dose, boding well for MAD dosing at Q2W or longer. Table 15.
  • Terminal half-life is estimated to be 9-10 days at lower doses and 6-7 days at the highest dose, consistent with an increase in CD25 target-mediated clearance on the expanding Treg population.
  • the Phase 1a study showed that XmAb ® 27564 promoted robust and durable expansion of CD25 bright Tregs (FIGS.8A-8B).
  • the study demonstrated that a single dose of an - 185 - NAI-1537985011v1 IL-2 Fc fusion protein (e.g., XmAb ® 27564) was well tolerated and generated a durable, dose- dependent and selective expansion of Tregs (FIG.8A).
  • Tregs CD25 bright regulatory T cells
  • XmAb ® 27564 was well tolerated including at the highest dose evaluated (0.065 mg/kg).
  • a 117-fold mean peak expansion over baseline in CD25 bright cells was observed, with an 8-fold expansion in the bulk/total Treg population (FIG.8B and FIG.10B, respectively).
  • Treg baseline counts are low integer values, leading to variability in fold change calculations.
  • FIGS.8A-8B are the mean values. Peak fold change is the peak CD25 bright FoxP3 + CD4 Treg cell absolute count at a post-treatment time point divided by absolute count at baseline (NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test) [00383]
  • the Phase 1a study showed that XmAb ® 27564 promoted robust and durable expansion of CD25 bright Treg/Tcon ratio (FIGS.9A-9B). The ratio of Tregs to conventional T cells also increased significantly in a dose-dependent manner (FIGS.9A-9B). Treg baseline counts are not used in Treg/Tcon ratio calculations, leading to less variability in ratio values.
  • FIGS.9A-9B are the mean values. Dashed horizontal middle line represents the average of pre-dose values from all 48 subjects with ⁇ 2SD shown in grey lines above and below the middle dashed line (NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test). [00384] XmAb ® 27564 promoted robust and durable expansion of total Tregs (FIGS.10A- 10B). The numeric value in FIGS.10A-10C are the mean values.
  • the peak fold change is the peak CD25 + FoxP3 + CD4 Treg cell absolute count at a post-treatment time point divided by absolute count at baseline (NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test).
  • FIG.10A shows that at the highest dose level of 0.065 mg/kg, the peak total Tregs increased by 8.31-fold, corresponding to a mean increase of 193 ⁇ 122 cells/microliter on Day 15. The majority of these Tregs were CD25 bright Tregs (FIG.
  • CD25 bright Tregs are believed to be functionally highly immunosuppressive Tregs.
  • - 186 - NAI-1537985011v1 At day 21, both CD25 bright and total Treg counts remained markedly elevated, potentially supporting a multi-week dosing profile (FIGS.11A-11B).
  • the numeric values in FIGS.11A-11B are the mean values (NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test).
  • FIGS.12A-12C show that such increases are within normal ranges or within 2 SD of baseline. Dashed horizontal middle line in FIGS.12A-12C represent the average of pre-dose values from all 48 subjects with ⁇ 2SD shown in grey lines above and below the middle horizontal dashed line.
  • CD56 bright NK cells a potentially immunosuppressive cell type, were increased in a dose-dependent manner, as reported with other biologics in the class (FIG.12D).
  • Peak fold induction of CD25 bright and total Treg cells showed consistent dose response of Treg populations to XmAb ® 27564 (FIGS.13A-13B).
  • the numeric value in FIGS.13A-13B is the mean values (NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test).
  • the ratio of CD25 bright /Tcon and total Treg/Tcon peak fold induction showed consistent dose response of Treg populations to XmAb ® 27564 (FIGS.14A-14B).
  • the numeric value in FIGS.14A-14B is the mean value.
  • Pharmacokinetics (PK) The pharmacokinetics studies showed that the terminal half- life of about 9 to 11 days was observed across doses ranging from 0.003 mg/kg to 0.065 mg/kg of XmAb ® 27564 (FIG.15).
  • NK cells natural killer cells
  • Tcons conventional T cells
  • XmAb ® 27564 was well tolerated and generated a durable, dose-dependent and selective expansion of Tregs with a single dose. For example, 117-fold mean peak expansion over baseline in CD25 bright cells and 8-fold mean peak expansion in total Tregs at highest dose was observed; marked elevation of Tregs sustained through at least day 21: CD25 bright and total Tregs increased 44-fold and 4.5-fold at highest dose, respectively; Treg/Tcon ratio increased significantly in a dose-dependent manner; and all AEs Grade 1/2 resolved without intervention.
  • XmAb ® 27564 is a potency-tuned, monomeric human IL-2 heterodimeric Fc-fusion protein with extended half-life and increased binding affinity for IL-2 receptor alpha (CD25) designed o selectively expand regulatory T cells (Tregs).
  • XmAb ® 27564 - 188 - NAI-1537985011v1 selectively induced Tregs and was well tolerated.
  • XmAb ® 27564 PK and PD may support extended multi-week dosing intervals and has a Treg induction magnitude and durability that may be competitive or superior to other engineered IL-2 candidates in clinic.
  • the first patient has been dosed in a newly initiated Phase 1b, multiple-ascending dose study of XmAb ® 27564 in patients with atopic dermatitis and psoriasis. Multiple dosing schedules are to be explored based on pharmacodynamics data (e.g., initially at every two weeks (Q2W) for lowest doses). * * * * * * * [00394] It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof.

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Abstract

Provided herein, in certain aspects, are methods for treating plaque psoriasis or atopic dermatitis comprising administration of an interleukin-2 (IL-2) Fc fusion protein.

Description

Attorney Docket No.14718-052-228 METHODS FOR THE TREATMENT OF PLAQUE PSORIASIS AND ATOPIC DERMATITIS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No.63/404,476, filed September 7, 2022, U.S. Provisional Application No.63/423,467, filed November 7, 2022, and U.S. Provisional Application No.63/504,925, filed May 30, 2023, the content of each of which is incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY [0002] This application contains a computer readable Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14718-052-228_SEQ_LISTING.xml”, was created on September 6, 2023, and is 9,149 bytes in size. 1. FIELD [0003] Provided herein, in certain aspects, are methods for treating plaque psoriasis or atopic dermatitis comprising administration of an interleukin-2 (IL-2) Fc fusion protein. 2. SUMMARY [0004] In one aspect provided herein is a method of treating plaque psoriasis or atopic dermatitis in a subject in need thereof, comprising subcutaneously administering to the subject an interleukin-2 (IL-2) Fc fusion protein, wherein the IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject every 12 to 16 days or every 27 to 31 days at a dose of about 0.003 mg/kg to about 0.100 mg/kg. [0005] In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least four cycles. In some aspects, the subject is administered the dose of about 0.007 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose - 1 - NAI-1537985011v1 of about 0.007 mg/kg every 14 days or every 30 days. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least four cycles. In some aspects, the subject is administered the dose of about 0.015 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose of about 0.015 mg/kg every 14 days or every 30 days. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles. In some aspects, the subject is administered the dose of about 0.025 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose of about 0.025 mg/kg every 14 days or every 30 days. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles. In some aspects, the subject is administered the dose of about 0.040 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose of about 0.040 mg/kg every 14 days or every 30 days. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles. In some aspects, the subject is administered the dose of about 0.065 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose of about 0.065 mg/kg every 14 days or every 30 days. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles. In some aspects, the subject is administered the dose of about 0.100 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose of about 0.100 mg/kg every 14 days or every 30 days. [0006] In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for at least 3 - 2 - NAI-1537985011v1 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL- 2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose - 3 - NAI-1537985011v1 of about 0.065 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for 4 cycles. [0007] In some aspects, the IL-2 Fc fusion protein is XmAb®27564 (XmAb®564). In some aspects, the IL-2 Fc fusion protein is a biosimilar, biobetter, or bioequivalent of XmAb®27564 (XmAb®564). In some aspects, the subject is a human subject. In some aspects, the human subject is 18 to 75 years of age. In some aspects, the human subject has a body surface area (BSA) of psoriasis of ≥2%. In some aspects, the human subject has an Investigator’s Global Assessment of 2 (mild) to 4 (severe). In some aspects, the subject has not previously been administered a therapy for plaque psoriasis or atopic dermatitis. In some aspects, the subject has previously been administered a therapy for plaque psoriasis or atopic dermatitis. [0008] In some aspects, the subject has not previously been administered an oral treatment for plaque psoriasis or atopic dermatitis in the 4 weeks prior to the administration of the IL-2-Fc fusion protein. In some aspects, the subject has not previously been administered a biologic treatment for plaque psoriasis or atopic dermatitis for 12 weeks or 5 half-lives, whichever is longer, prior to the administration of the IL-2-Fc fusion protein. In some aspects, the subject has - 4 - NAI-1537985011v1 not previously been administered a phototherapy in the 4 weeks prior to the administration of the IL-2-Fc fusion protein. In some aspects, the subject has not previously been administered a topical treatment for psoriasis or atopic dermatitis in the 2 weeks prior to the administration of the IL-2-Fc fusion protein. In some aspects, the subject does not have any other inflammatory or dermatological condition besides the plaque psoriasis or atopic dermatitis. In some aspects, the subject does not have any other form of psoriasis or atopic dermatitis. [0009] In some aspects, the administering of the IL-2 Fc fusion protein results in an increase in the number of CD4+ regulatory T (Treg) cells in the subject as compared to before the administering. In some aspects, the number of CD4+ Treg cells is increased about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-fold, about 12-fold, about 13-fold, about 14-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, about 25-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, or about 100- fold. In some aspects, the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD4+ effector T (Teff) cells in the subject as compared to before the administering. [0010] In some aspects, the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of NK cells in the subject as compared to before the administering. In some aspects, the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD4+ conventional T (Tcon) cells in the subject as compared to before the administering. In some aspects, the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD8+ Tcon T cells in the subject as compared to before the administering. [0011] In some aspects, the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a Psoriasis Area and Severity Index (PASI) score of about 50% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein. In some aspects, the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a PASI score of about 75% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein. In some aspects, the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a PASI score of about 90% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein. - 5 - NAI-1537985011v1 [0012] In some aspects, the administering of the IL-2 Fc fusion protein results in the subject having a Static Investigator’s Global Assessment (sIGA) score of 0, 1 or 2. In some aspects, the administering of the IL-2 Fc fusion protein results in the subject having an improvement in a Dermatology Life Quality Index (DLQI) score as compared to the baseline DLQI score in the subject prior to the administering of the IL-2 Fc fusion protein. In some aspects, the administering of the IL-2 Fc fusion protein results in the subject having a decrease in body surface area (BSA) of psoriasis or atopic dermatitis as compared to the baseline BSA of psoriasis or atopic dermatitis in the subject prior to the administering of the IL-2 Fc fusion protein. In some aspects, the BSA of psoriasis is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 60%, about 80%, about 90%, or about 100%. [0013] In some aspects, the subject does not have another type of psoriasis besides the plaque psoriasis, or the subject has atopic dermatitis. [0014] In one aspect provided herein is a method of treating plaque psoriasis or atopic dermatitis in a subject in need thereof, comprising subcutaneously administering to the subject a single dose of an interleukin-2 (IL-2) Fc fusion protein, wherein the IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the single dose is an amount of about 0.003 mg/kg to about 0.1 mg/kg. [0015] In some aspects, the single dose is an amount of 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, 0.065 mg/kg, or 0.1 mg/kg. In some aspects, the single dose is an amount of 0.065 mg/kg. In some aspects, the IL-2 Fc fusion protein is XmAb®27564 (XmAb®564). In some aspects, the IL-2 Fc fusion protein is a biosimilar, biobetter, or bioequivalent of XmAb®27564 (XmAb®564). In some aspects, the subject is a human subject. In some aspects, the administering of the IL-2 Fc fusion protein results in an increase in the number of CD25bright Treg cells in the subject as compared to baseline. In some aspects, the administering of the IL-2 Fc fusion protein results in an increase in CD25bright Treg/Tcon ratio in the subject as compared to baseline. In some aspects, the administering of the IL-2 Fc fusion protein results in an increase in the number of total Treg cells in the subject as compared to baseline. In some aspects, the total Treg cells comprises CD25brightFoxP3+ CD4 Treg cells. In some aspects, the increase is an increase of about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-fold, about 12- - 6 - NAI-1537985011v1 fold, about 13-fold, about 14-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, about 25-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, or about 100-fold. In some aspects, the increase is an increase of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or more than about 100%. In some aspects, the administering of the IL-2 Fc fusion protein does not result in a significant increase in conventional T cells (Tcon) and/or NK cells in the subject as compared to baseline. In some aspects, the significant increase is not more than two standard deviations from baseline. In some aspects, the increase in CD25bright Treg/Tcon ratio is 0.14. 3. BRIEF DESCRIPTION OF THE DRAWINGS [0016] FIG.1 depicts an IL-2 Fc fusion protein of the disclosure. FIG.1 shows the structure of an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) engineered for reduced potency plus Treg selectivity. [0017] FIGS.2A-2B each depict a study design of XmAb®27564 with an ascending dose escalation. [0018] FIGS.3A-3C depict a study design using XmAb®27564. FIG.3A depicts a dose escalation of XmAb®27564 for psoriasis and FIG.3B for atopic dermatitis. For psoriasis, the first cohort is administered a dose of 0.007 mg/kg of XmAb®27564 every 14 days for 4 doses; the second cohort is administered a dose of 0.015 mg/kg of XmAb®27564 every 14 days for 4 doses; the third cohort is administered a dose of 0.025 mg/kg of XmAb®27564 every 14 days for 4 doses; the fourth cohort is administered a dose of 0.040 mg/kg of XmAb®27564 every 14 days for 4 doses; the fifth cohort is administered a dose of 0.065 mg/kg of XmAb®27564 every 14 days for 4 doses; and the sixth cohort is administered a dose of 0.100 mg/kg of XmAb®27564 every 14 days for 4 doses (FIG.3A). For atopic dermatitis, the first cohort is administered a dose of 0.015 mg/kg of XmAb®27564 every 14 days for 4 doses; the second cohort is administered a dose of 0.025 mg/kg of XmAb®27564 every 14 days for 4 doses; the third cohort is administered a dose of 0.040 mg/kg of XmAb®27564 every 14 days for 4 doses; the fourth cohort is administered a dose of 0.065 mg/kg of XmAb®27564 every 14 days for 4 doses; and the fifth - 7 - NAI-1537985011v1 cohort is administered a dose of 0.100 mg/kg of XmAb®27564 every 14 days for 4 doses (FIG. 3B). FIG.3C depicts an open-label extension phase using XmAb®27564. [0019] FIG.4 depicts a figure showing Tregs role in homeostasis and autoimmune diseases. [0020] FIG.5 depicts XmAb®27564 engineered to improve selectivity for Treg. [0021] FIGS.6A-6D depict XmAb®27564 designed to reduce potency and improve Treg selectivity. In vitro stimulation of human PBMCs with either XmAb®27564 (FIG.6A) or Fc- WT-IL-2 (FIG.6B) revealed approximately 400-fold potency reduction for IL-2 signaling in human Tregs (phosphorylated STAT5 induction), with enhanced Treg selectivity over Tcons, gamma delta T cells, or NK cells. The Treg EC50 is 21nM in FIG.6A and 0.06nM in FIG.6B. FIGS.6C-6D depict a comparison of pharmacological half–life in cynomolgus macaques showing prolonged exposure of low-potency XmAb®27564 vs. WT Fc-IL-2. [0022] FIG.7 depicts XmAb®27564 Phase 1a study design in healthy subjects. FIG.7 shows a randomized and double-blinded Phase 1a single-ascending dose (SAD) study. In brief, subcutaneous administration of XmAb®27564 was administered to healthy subjects (n=48) in one of 6 dose level cohorts (randomized 6:2; XmAb®27564:placebo). The outcome measures were: 1) safety and tolerability and 2) pharmacokinetics and activity biomarkers (e.g., T-cell populations). [0023] FIGS.8A-8B depict graphs showing that XmAb®27564 promotes robust and durable expansion of CD25bright Tregs. The numeric values in FIG.8B are the mean values. Peak fold change is the peak CD25brightFoxP3+ CD4 Treg cell absolute count at a post-treatment time point divided by absolute count at baseline. NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test. [0024] FIGS.9A-9B depict graphs showing that XmAb®27564 promotes robust and durable increase in CD25bright Tregs/Tcon ratio. The numeric values in FIG.9B are the mean values. The dashed horizontal middle line represents the average of pre-dose values from all 48 subjects with ±2SD shown in grey lines above and below the middle dashed line. NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test. [0025] FIGS.10A-10C depict graphs showing Treg responses after a single subcutaneous dose of XmAb®27564 in healthy subjects. FIGS.10A-10B show that XmAb®27564 promotes robust and durable expansion of total Treg cells. The numeric values in FIGS.10A-10C are the mean values. Peak fold change is the peak CD25+FoxP3+ CD4 Treg cell absolute count at a - 8 - NAI-1537985011v1 post-treatment time point divided by absolute count at baseline. NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test. FIG.10C depicts a graph showing CD25bright Treg cells (functionally highly immunosuppressive Tregs) after a single subcutaneous dose of XmAb®27564 in healthy subjects. The cohorts in FIGS.10A-10C included: placebo, 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, and 0.065 mg/kg of XmAb®27564. The dashed middle line in FIG.10C represent the average of pre-dose values from 48 subjects with +/-2SD (standard deviations) shown in the dashed lines above and below the middle dashed line. [0026] FIGS.11A-11B depict graphs showing that CD25bright and total Treg remain elevated for at least three weeks following administration of XmAb®27564. The numeric values in FIGS. 11A-11B are the mean values. NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test. [0027] FIGS.12A-12D depict graphs showing Tcon (CD4 Tcon and CD8 Tcon) and NK cells (CD56+ and CD56bright NK cells) after a single subcutaneous dose of XmAb®27564. FIGS.12A-12C depict graphs showing that XmAb®27564 induces minimal increases in conventional T cells and NK cells. FIG.12A is directed to CD4+ Tcon cell count; FIG.12B is directed to CD8+ Tcon cell count; and FIG.12C is directed to CD56+ NK cell count. FIG.12D depicts a graph showing CD25bright NK cells after a single subcutaneous dose of XmAb®27564. The cohorts in FIGS.12A-12D included: placebo, 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, and 0.065 mg/kg of XmAb®27564. Dashed horizontal middle line represent the average of pre-dose values from all 48 subjects with ±2SD shown in grey lines above and below the middle horizontal dashed line. [0028] FIGS.13A-13B depict graphs showing that peak fold induction of CD25bright and total Treg cells showed consistent dose response of Treg populations to XmAb®27564. FIG. 13A shows Treg peak fold induction and FIG.13B shows total Treg peak fold induction. The numeric values in FIGS.13A-13B are the mean values. The peak fold induction is the peak CD25bright Treg or total Treg cell absolute counts of each subject divided by the average of all pre-dose values from all subjects (n=48). NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test. [0029] FIGS.14A-14B depict graphs showing that ratio of CD25bright/Tcon and total Treg/Tcon peak fold induction showed consistent dose response of Treg populations to - 9 - NAI-1537985011v1 XmAb®27564. FIG.14A shows CD25bright Treg/Tcon peak fold induction (CD25hiFoxP3+CD4+) and FIG.14B shows total Treg/Tcon peak fold induction (CD25+FoxP3+CD4+). The numeric values in FIGS.14A-14B are the mean values. The peak fold induction is the peak CD25bright Treg/Tcon or total Treg/Tcon ratios of each subject divided by the average of all pre-dose values from all subjects (n=48). NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test. [0030] FIG.15 depicts a graph showing pharmacokinetics data after cohorts were injected with 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, or 0.065 mg/kg of XmAb®27564. [0031] FIGS.16A-16B depict pharmacodynamics data. FIG.16B shows selective and durable expansion and activation of Tregs through Day 21. *: p≤0.05, **: p≤0.01, ***:p≤0.001 by Wilcoxon test to compare median from 564-treated group to placebo-treated group. Dashed horizontal middle line in FIGS.16A-16B represents the average of pre-dose values from 48 subjects with ±2SD shown in dashed lines above and below the middle line. [0032] FIGS.17A-17F depict Treg (FIGS.17A-17B), Tcon (FIGS.17C-17D), and NK cells (FIGS.17E-17F) responses after a single subcutaneous dose of XmAb®27564 in healthy volunteers. [0033] FIGS.18A-18H depict graphs characterizing expanded Tregs after a single subcutaneous dose of XmAb®27564. [0034] FIGS.19A-19B depict graphs showing that serum levels of IL-10 increased in a dose-dependent manner, and at the highest dose level of 0.065 mg/kg there was a 15-fold increase at Day 10 after treatment. FIG.19B shows that a peak mean 16-fold increase was observed in a graph showing serum IL-10/IFN-γ ratio. [0035] FIG.20 depicts a graph showing induction of peripheral eosinophilia in adult healthy volunteers after a single subcutaneous dose of XmAb®27564. [0036] FIG.21 depicts a graph showing that IL5 increased in normal healthy volunteers after a single subcutaneous dose of XmAb®27564. 4. DETAILED DESCRIPTION 4.1 Definitions - 10 - NAI-1537985011v1 [0037] Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed. [0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. [0039] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. [0040] As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise. For example, the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value. In some cases, the numerical disclosed throughout can be “about” that numerical value even without specifically mentioning the term “about.” [0041] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. [0042] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the invention. [0043] As used herein, and unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present). [0044] As used herein, the conjunctive term “and/or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and/or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the - 11 - NAI-1537985011v1 first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and/or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and/or.” [0045] As used herein, the term “cycle” refers to a specified period of time during which a treatment (e.g., an IL2-Fc fusion protein) is administered to a subject. A treatment (e.g., an IL2- Fc fusion protein) can be administered to a subject for one cycle or for multiple cycles (e.g., one cycle, two cycles, three cycles, four cycles, or more than four cycles). When a treatment is administered to a subject for multiple cycles, the cycles can occur at regular intervals. For example, a cycle can be immediately followed by one or more additional cycles, or two or more cycles can be separated by a period without treatment. [0046] The terms “Fc,” “Fc region,” or “Fc domain” as used herein refer to the polypeptide comprising the CH2-CH3 domains of an IgG molecule, and in some cases, inclusive of the hinge. In EU numbering for human IgG1, the CH2-CH3 domain comprises amino acids 231 to 447, and the hinge is 216 to 230. Thus, the definition of “Fc domain” includes both amino acids 231-447 (CH2-CH3) or 216-447 (hinge-CH2-CH3), or fragments thereof. An “Fc fragment” in this context may contain fewer amino acids from either or both of the N- and C-termini but still retains the ability to form a dimer with another Fc domain or Fc fragment as can be detected using standard methods, generally based on size (e.g., non-denaturing chromatography, size exclusion chromatography, etc.) Exemplary human IgG Fc domains that can be used herein include human IgG1, IgG2, or IgG4. [0047] The terms “Fc variant” or “variant Fc” as used herein refer to a protein comprising an amino acid modification in an Fc domain. The Fc variants of the present disclosure are defined according to the amino acid modifications that compose them. Thus, for example, N434S or 434S is an Fc variant with the substitution serine at position 434 relative to the parent Fc polypeptide, wherein the numbering is according to the EU index. Likewise, M428L/N434S defines an Fc variant with the substitutions M428L and N434S relative to the parent Fc polypeptide. It is noted that the order in which substitutions are provided is arbitrary, that is to say that, for example, 428L/434S is the same Fc variant as M428L/N434S, and so on. The EU index or EU index as in Kabat or EU numbering scheme refers to the numbering of the EU antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, hereby entirely incorporated - 12 - NAI-1537985011v1 by reference.) The modification can be an addition, deletion, or substitution. Substitutions can include naturally occurring amino acids and, in some cases, synthetic amino acids. Examples include U.S. Pat. No.6,586,207; WO 98/48032; WO 03/073238; US2004-0214988A1; WO 05/35727A2 WO 05/74524A2; J. W. Chin et al., (2002), Journal of the American Chemical Society 124:9026-9027; J. W. Chin, & P. G. Schultz, (2002), ChemBioChem 11:1135-1137; J. W. Chin, et al., (2002), PICAS United States of America 99:11020-11024; and, L Wang, & P. G. Schultz, (2002), Chem.1-10, all entirely incorporated by reference. [0048] The term “Fc fusion protein” as used herein refers to a protein comprising an Fc region, generally linked (optionally through a linker moiety, which can be the hinge region of an IgG, such as IgG1) to a different protein, such as IL-2. Thus, an IL-2 Fc fusion protein is a protein comprising an IL-2 (in this case, variant IL-2) and Fc domain. These generally have the structure IL-2-hinge-CH2-CH3. As will be understood in the art, two Fc domains can self- assemble to provide dimeric Fc fusion proteins. [0049] The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same, when compared and aligned for maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. [0050] Sequence identity between two similar sequences can be measured by algorithms such as that of Smith, T.F. & Waterman, M.S. (1981) “Comparison of Biosequences,” Adv. Appl. Math.2:482 [local homology algorithm]; Needleman, S.B. & Wunsch, CD. (1970) “A General Method Applicable to the Search for Similarities in the Amino Acid Sequence of Two Proteins,” J. Mol. Biol.48:443 [homology alignment algorithm], Pearson, W.R. & Lipman, D.J. (1988) “Improved Tools for Biological Sequence Comparison,” Proc. Natl. Acad. Sci. (U.S.A.) 85:2444 [search for similarity method]; or Altschul, S.F. et al, (1990) “Basic Local Alignment - 13 - NAI-1537985011v1 Search Tool,” J. Mol. Biol.215:403-10, the “BLAST” algorithm, see, e.g., blast.ncbi.nlm.nih.gov/Blast.cgi. When using any of the aforementioned algorithms, the default parameters (for Window length, gap penalty, etc.) are used. In one embodiment, sequence identity is done using the BLAST algorithm, using default parameters. [0051] Examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1990) J. Mol. Biol.215: 403-410 and Altschul et al. (1997) Nucleic Acids Res. 25: 3389-3402, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased. [0052] Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) of 10, M=5, N=-4, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)). [0053] In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. Nat’l. Acad. Sci. USA 90:5873-5787 (1993)). One measure of similarity provided - 14 - NAI-1537985011v1 by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001. [0054] “Isolated,” when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Ordinarily, an isolated polypeptide can be prepared by at least one purification step. [0055] “Recombinant,” when used to describe the various polypeptides disclosed herein, means the polypeptides are generated using recombinant nucleic acid techniques in exogeneous host cells, and they can be isolated as well. [0056] As used herein, the terms “wild type or WT” refer to an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations. A WT protein has an amino acid sequence or a nucleotide sequence that has not been intentionally modified. [0057] As used herein, the terms “peptide,” “polypeptide,” or “protein” can refer to a molecule comprised of amino acids and can be recognized as a protein by those of skill in the art. The conventional one-letter or three-letter code for amino acid residues is used herein. The terms “peptide,” “polypeptide,” and “protein” can be used interchangeably herein to refer to polymers of amino acids of any length. The peptide sequences described herein are written according to the usual convention whereby the N-terminal region of the peptide is on the left and the C- terminal region is on the right. Although isomeric forms of the amino acids are known, it is the L-form of the amino acid that is represented unless otherwise expressly indicated. [0058] As used herein, the term “variant protein”, or “protein variant”, or “variant” refers to a protein that differs from that of a parent protein by virtue of at least one amino acid modification. Protein variant may refer to the protein itself, a composition comprising the protein, or the amino sequence that encodes it. In some embodiments, the protein variant has at least one amino acid modification compared to the parent protein, e.g., from about one to about seventy amino acid modifications, or from about one to about five amino add modifications compared to the parent. In some embodiments the parent polypeptide, for example an Fc parent - 15 - NAI-1537985011v1 polypeptide, is a human wild type sequence, such as the Fc region from human IgG1, IgG2, IgG3 or IgG4. In the context of the IL-2 variants, the parent polypeptide is human IL-2, the mature sequence of which is SEQ ID NO: 1. In some embodiments, he protein variant sequence herein can possess at least about 80% identity, at least about 90% identity, or at least about 95%, 98%, or 99% identity with a parent protein sequence. Variant protein can refer to the variant protein itself, compositions comprising the protein variant, or the DNA sequence that encodes it [0059] The term “linker” as used herein refers to a proteinaceous linker that is used to join two other protein domains (e.g., the variant IL-2 domain and the variant Fc domain). In some cases, the linker is a “domain linker”, used to link any two domains. While any suitable linker can be used, many embodiments utilize a glycine-serine polymer, including for example (GS)n, (GSGGS)n (SEQ ID NO: 4), (GGGGS)n (SEQ ID NO: 5), and (GGGS)n (SEQ ID NO: 6), where n is an integer of at least one (and generally from 3 to 4 to 5) as well as any peptide sequence that allows for recombinant attachment of the two domains with sufficient length and flexibility to allow each domain to retain its biological function. In some cases, charged domain linkers can be used. Additionally, the hinge domain of the human IgG1 protein can also be a domain linker. [0060] The terms “regulatory T cells” or “Tregs” as used herein refers to T cells that are CD3+/CD4+/CD8−/CD25+/FOXP3+. [0061] As used herein, the terms “treat,” “treatment,” and “treating” refer to the reduction or amelioration or elimination of the progression, severity and/or effect associated with plaque psoriasis or atopic dermatitis, as described herein, or the improvement in the plaque psoriasis or atopic dermatitis, or the improvement in the disease associated with the plaque psoriasis or atopic dermatitis, or the increase in the immune system response of the human subject, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of the plaque psoriasis or atopic dermatitis described herein resulting from the administration of one or more therapies. In some embodiments, treating plaque psoriasis or atopic dermatitis involves administering the IL2-Fc fusion protein for a pre-specified period of time, discontinuing administration for another specific period of time, and resuming administration of the IL2-Fc fusion protein for yet another specific period of time. In some embodiments, treating plaque psoriasis or atopic dermatitis involves administering the IL2-Fc fusion protein until one of the treatment effects described herein is achieved, pausing administration of the IL2-Fc fusion - 16 - NAI-1537985011v1 protein while this treatment effect continues to be observed, and resuming administration of the IL2-Fc fusion protein if this treatment effect ceases to be observed. [0062] As used herein, the term “psoriasis” refers to plaque-type psoriasis (or plaque psoriasis). Plaque-type psoriasis (or plaque psoriasis) treatment can be determined by standardized response criteria specific to the disease, e.g., by assessing the Psoriasis Area and Severity Index (PASI) score, Body Surface Area (BSA), Investigator’s Global assessment of improvement (IGA), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI), and/or based on photographs of whole body or specific plaques. [0063] As used herein, in some embodiments, atopic dermatitis refers to eczema, and/or a chronic (long-lasting) disease that causes inflammation, redness, and irritation of the skin. Atopic dermatitis treatment can be determined by standardized response criteria specific to the disease, e.g., by assessing Eczema Area and Severity Index (EASI), Body Surface Area (BSA), validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD), Peak Pruritis Numerical Rating Scale (PP-NRS), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI), and/or based on photographs of body. [0064] Treatment according to the present invention includes a “therapeutically effective amount” of the medicaments used. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the medicaments to elicit a desired response in the individual. Alternatively, this property of a composition may be evaluated by examining the ability of the compound to inhibit cell growth or to induce apoptosis by in vitro assays known to the skilled practitioner. A therapeutically effective amount can ameliorate at least one symptom in a subject. In some cases, a “therapeutically effective amount” refers to an amount of an IL-2 Fc fusion protein of the disclosure that is effective, upon single or multiple dose administration to a subject (such as a human patient) at treating, preventing, curing, delaying, reducing the severity of, ameliorating at least one symptom of a disorder (e.g., plaque psoriasis or atopic - 17 - NAI-1537985011v1 dermatitis) or recurring disorder, or prolonging the survival of the subject beyond that expected in the absence of such treatment. One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject’s size, the severity of the subject’s symptoms, and the particular composition or route of administration selected. [0065] The terms “patient,” “subject,” and “human subject” are used interchangeably herein. 4.2 Overview [0066] Provided herein, in certain aspects, are methods for treating plaque psoriasis using an IL2-Fc fusion protein, as described herein. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure can be used for treating atopic dermatitis. 4.3 Pharmaceutical Compositions [0067] The IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure can be incorporated into pharmaceutical compositions suitable for administration to a subject according to a dosage regimen described herein. As used herein, “dosage regimen” refers to a systematic plan of drug administration regarding formulation, route of administration, drug dose, dosing interval, and treatment duration. In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb®27564) and a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are physiologically compatible and are suitable for administration to a subject using the methods described herein. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as any combination thereof. In some cases, isotonic agents can be included, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffers (such as an organic acid, which as a citrate or an acetate), which enhance the shelf life or effectiveness of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. Examples of pharmaceutically acceptable carriers include polysorbates (polysorbate-80). [0068] In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure and a preservative or buffer. In some - 18 - NAI-1537985011v1 embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb®27564) and histidine. In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb®27564) and sorbitol. In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb®27564), histidine (or a comparable agent), and sorbitol (or a comparable agent). In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb®27564), 20 mM histidine (or a comparable agent), and 250 mM sorbitol (or a comparable agent), and the pH is 6.5. In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb®27564), between about 10 mM and about 40 mM histidine (or a comparable agent), and between about 100 mM and about 400 mM sorbitol (or a comparable agent). In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb®27564), between about 15 mM and about 25 mM histidine (or a comparable agent), and between about 200 mM and about 300 mM sorbitol (or a comparable agent). In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb®27564), between about 17 mM and about 23 mM histidine (or a comparable agent), and between about 240 mM and about 250 mM sorbitol (or a comparable agent). In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is packaged in a 1mL to 10 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is packaged in a 1mL to 30 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is packaged in a 10 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is packaged in a 5 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is packaged in a 2 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is packaged in a 1 mL vial (e.g., glass vial) or syringe. In some embodiments, about 30 mg of an IL-2 Fc fusion protein (e.g., XmAb®27564) is in a vial, in each vial (e.g., glass vial), or in a syringe. In some embodiments, between about 15 mg and about 50 mg of an IL-2 Fc fusion protein (e.g., XmAb®27564) is in a vial, in each vial (e.g., glass vial), or in a syringe. In some embodiments, between about 20 mg and about 40 mg of an IL-2 Fc fusion protein (e.g., XmAb®27564) is in a vial, in each vial (e.g., glass vial), or in a syringe. In some embodiments, between about 25 mg and about 35 mg of an IL-2 Fc fusion protein (e.g., XmAb®27564) is in a vial, in each vial (e.g., glass vial), or in a - 19 - NAI-1537985011v1 syringe. In some embodiments, about 30 mg/mL of an IL-2 Fc fusion protein (e.g., XmAb®27564) is in a vial, in each vial (e.g., glass vial), or in a syringe. In some embodiments, between about 15 mg/mL and about 50 mg/mL of an IL-2 Fc fusion protein (e.g., XmAb®27564) is in a vial, in each vial (e.g., glass vial), or in a syringe. In some embodiments, between about 20 mg/mL and about 40 mg/mL of an IL-2 Fc fusion protein (e.g., XmAb®27564) is in a vial, in each vial (e.g., glass vial), or in a syringe. In some embodiments, between about 25 mg/mL and about 35 mg/mL of an IL-2 Fc fusion protein (e.g., XmAb®27564) is in a vial, in each vial (e.g., glass vial), or in a syringe. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb®27564) is stored or shipped at a temperature of about 2° to about 8°C. In some embodiments, the vial with an IL-2 Fc fusion protein (e.g., XmAb®27564) is a single use vial. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb®27564) is a sterile liquid supplied in a single use vial. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb®27564) is supplied as a sterile liquid for injection. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb®27564) is lyophilized. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb®27564) is provided as an aqueous solution. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb®27564) is suitable for subcutaneous administration. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb®27564) is prepared by mixing an IL-2 Fc fusion protein (e.g., XmAb®27564) of a desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (e.g., as outlined in Remington’s Pharmaceutical Sciences, 16th edition, Osol, A. editor [1980]) for storage as a lyophilized formulation or as an aqueous solution. [0069] The pharmaceutical compositions can be in a variety of forms. These include, for example, liquid, lyophilized, liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions. The form depends on the intended mode of administration and therapeutic application. Exemplary compositions are in the form of subcutaneous solutions. [0070] Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. Sterile injectable solutions can be prepared by incorporating the IL- - 20 - NAI-1537985011v1 2 Fc fusion protein in the required amount in an appropriate solvent with one or any combination of ingredients enumerated herein, as required, followed by filtered sterilization. [0071] An IL-2 Fc fusion protein (e.g., XmAb®27564) provided herein can be administered by any known method. In one embodiment, the route/mode of administration is subcutaneous injection. The route and/or mode of administration can vary depending upon the desired results. [0072] In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is administered subcutaneously. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is administered until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated (whether voluntarily or involuntarily) by the human subject. [0073] In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is a front line therapy, second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy. [0074] A medical professional can readily determine and prescribe the effective amount of an IL-2 Fc fusion protein (e.g., XmAb®27564) composition required. For example, a physician could start doses of the medicament employed in an IL-2 Fc fusion protein (e.g., XmAb®27564) composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. 4.3.1. IL2-Fc Fusion Proteins [0075] Provided herein is a method of treating plaque psoriasis or atopic dermatitis in a subject with an IL-2 Fc fusion protein of the disclosure. In some embodiments, an IL-2 Fc fusion protein of the disclosure has three different domains: a Fc domain, one or more domain linkers, and an IL-2 domain. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a heterodimeric monovalent construct, in which a variant IL-2 domain is generally fused to a variant human IgG Fc domain using either the hinge as the domain linker (generally including a C220S variant) or using an additional linker attached to the hinge, with the other Fc domain (including the hinge) remaining “empty”. In some embodiments, monovalent IL-2-Fc with linker comprises IL-2 (or variant IL-2) recombinantly fused to the N-terminus of a heterodimeric Fc- region via a domain linker, with the other side of the molecule being “Fc-only” or “empty-Fc”. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a homodimeric bivalent construct, in which variant IL-2 domains are generally each fused to a variant human IgG1 Fc domain using either the hinge as the domain linker (generally including a C220S variant) or - 21 - NAI-1537985011v1 using an additional linker attached to the hinge. In some embodiments, bivalent IL-2-Fc with linker comprises IL-2 (or a variant IL-2) recombinantly fused to the N-terminus of both sides of a homodimeric Fc-region via a domain linker. In some embodiments, the domain linker is the IGG1 hinge, and in others it can include a linker selected from (GS)n, (GSGGS)n (SEQ ID NO: 4), (GGGGS)n (SEQ ID NO: 5), and (GGGS)n (SEQ ID NO: 6), where n is an integer of at least one. [0076] In some embodiments, an IL-2 Fc fusion protein of the disclosure is a heterodimeric protein complex comprising a first protein monomer comprising an IL-2 protein (e.g., a variant IL-2 protein) covalently linked to a first Fc domain (e.g., a first variant Fc domain) and a second protein monomer comprising a second Fc domain (e.g., a second variant Fc domain). In some embodiments, an IL-2 Fc fusion protein of the disclosure comprises an IL-2 protein consisting of an amino acid sequence of SEQ ID NO: 1. In some embodiments, an IL-2 Fc fusion protein of the disclosure comprises a variant human IL-2 protein (as compared to SEQ ID NO: 1). In some embodiments, an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence that is about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a wild-type IL-2 protein (e.g., SEQ ID NO: 1). In some embodiments, an IL-2 Fc fusion protein of the disclosure comprises amino acid substitution(s) as compared to a wild-type IL-2 protein (e.g., SEQ ID NO: 1) selected from T3A, D20N, T37R, N71K, T3A/D20N, T3A/D20N/T37R and T3A/D20N/N71K. [0077] In some embodiments, a first monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises SEQ ID NO: 2. In some embodiments, a second monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises SEQ ID NO: 3. In some embodiments, a first monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 2. In some embodiments, a first monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 2 and comprises one or more mutation(s) selected from C220S, S267K, L368D, K370S, M428L, and/or N434S (variant Fc domain). In some embodiments, a second monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, - 22 - NAI-1537985011v1 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 3. In some embodiments, a second monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 3 and comprises one or more mutation(s) selected from C220S, S267K, S364K, E357Q, M428L, and/or N434S (variant Fc domain). In some embodiments, a first monomer or chain of an IL-2 Fc fusion protein of the disclosure consists of an amino acid sequence of SEQ ID NO: 2. In some embodiments, a second monomer or chain of an IL-2 Fc fusion protein of the disclosure consists of an amino acid sequence of SEQ ID NO: 3. In some embodiments, a monomer (e.g., first monomer) or chain of an IL-2 Fc fusion protein of the disclosure comprises at least one of C220S, S267K, L368D, K370S, M428L, and N434S (compared to human IgG1 Fc domain). In some embodiments, a monomer (e.g., second monomer) or chain of an IL-2 Fc fusion protein of the disclosure comprises at least one of C220S, S267K, S364K, E357Q, M428L, and N434S (compared to human IgG1 Fc domain). In some embodiments, an IL-2 Fc fusion protein of the disclosure consists of: an amino acid sequence of SEQ ID NO: 1, an amino acid sequence of SEQ ID NO: 2, and an amino acid sequence of SEQ ID NO: 3. In some embodiments, an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to: SEQ ID NO: 1, SEQ ID NO: 2, and/or SEQ ID NO: 3. [0078] In some embodiments, N- and/or C-terminal clipping can occur during protein synthesis, whereby the heavy chains depicted herein may have the C-terminal lysine removed, as well as the penultimate glycine, and optionally additional amino acids residues (e.g., from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more C-terminal amino acids can be removed). Alternatively, the nucleic acids encoding the heavy chains of the IL-2 Fc fusion protein can be engineered such that these terminal residues are eliminated entirely to facilitate additional homogeneity. Thus, included within the definition of IL-2 Fc fusion protein (e.g., XmAb®27564) are C-terminally truncated versions. As is known in the art, this C-terminal clipping can also occur in vivo in the patient. [0079] In some embodiments, an IL-2 Fc fusion protein of the disclosure is XmAb®27564. In some embodiments, an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about, at least about, or at most about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to any amino acid sequence in Table 1. - 23 - NAI-1537985011v1 In some embodiments, an IL-2 Fc fusion protein of the disclosure is a biosimilar of an IL-2 Fc fusion protein provided in Table 1. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a biobeter of an IL-2 Fc fusion protein provided in Table 1. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a bioequivalent of an IL-2 Fc fusion protein provided in Table 1. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a biosimilar of XmAb®27564. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a biobeter of XmAb®27564. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a bioequivalent of XmAb®27564. Table 1. IL-2 Fc fusion protein IL-2 protein Sequence SEQ ID NO:
Figure imgf000025_0001
, Fc domain that is a variant human IgG1 Fc domain comprising the amino acid substitutions M428L/N434S (Xtend Fc). In some embodiments, an IL-2 Fc fusion protein of the disclosure comprises an Fc domain that comprises an ablation variant. In some embodiments, the normal binding of the Fc domain to one or more or all of the Fcγ receptors is reduced or eliminated to avoid additional mechanisms of action. In some embodiments, it is desirable to ablate FcγRIIIa binding to eliminate or significantly reduce ADCC (antibody-dependent cellular cytotoxicity) activity such that one of the Fc domains comprises one or more Fcγ receptor ablation variants. In some embodiments, ablation variants can be independently and optionally included or excluded. - 24 - NAI-1537985011v1 In some embodiments, an ablation variant includes, but is not limited to, C236R/L328R, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G, and E233P/L234V/L235A/G236del. In some embodiments, an IL-2 Fc fusion protein of the disclosure has a variant Fc domain that is a variant human IgG1 Fc domain comprising at least one amino acid substitution from E233P, L234V, L235A, G236del, and S267K (ablation variant). In some embodiments, the ablation variants of the disclosure ablate FcγR binding but generally not FcRn binding. [0081] In some embodiments, an IL-2 Fc fusion protein of the disclosure is any IL-2 variant or IL-2 Fc fusion protein disclosed in WO2019125732 (PCT/US2018/063443) (the content of which is herein incorporated by reference in its entirety). 4.4 Methods of Treatment [0082] Provided herein is a method of treating plaque psoriasis or atopic dermatitis in a subject with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, provided herein is a method for treating plaque psoriasis or atopic dermatitis in a human subject in need thereof, comprising administering to the subject an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure, wherein the subject is first administered a first dose of the an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure on day 1, and subsequently administered a second dose of the an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure about 2 weeks after the first dose and at regular intervals (e.g., every 2 weeks) thereafter. In some embodiments, the first dose and the second dose is the same. In some embodiments, provided herein is a method for treating plaque psoriasis or atopic dermatitis in a human subject in need thereof, comprising administering to the subject an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as a single dose administration. [0083] In some embodiments, a method of the disclosure is used in a subject who has previously been treated for plaque psoriasis or atopic dermatitis. In some embodiments, a method of the disclosure is used in a subject who has not been previously treated for plaque psoriasis or atopic dermatitis (e.g., a naïve subject). In some embodiments, provided herein is a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein (e.g., XmAb®27564) as the sole active agent or the sole treatment for plaque psoriasis or atopic dermatitis in the subject. In some embodiments, provided herein is - 25 - NAI-1537985011v1 a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564), wherein the subject does not have or has not been diagnosed with another type of psoriasis or atopic dermatitis, does not have or has not been diagnosed with another inflammatory condition (besides plaque psoriasis or atopic dermatitis), and/or does not have or has not been diagnosed with another dermatologic condition (besides plaque psoriasis or atopic dermatitis). In some embodiments, provided herein is a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) as a monotherapy treatment. In some embodiments, provided herein is a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) as a monotherapy treatment for plaque psoriasis or atopic dermatitis and at least one additional agent to treat or ameliorate at least one side effect of the IL-2 Fc fusion protein (e.g., XmAb®27564) administration or injection site in the subject. In some embodiments, provided herein is a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein (e.g., XmAb®27564) as a monotherapy treatment for plaque psoriasis or atopic dermatitis and at least one additional agent to treat or ameliorate at least one symptom associated with the IL-2 Fc fusion protein (e.g., XmAb®27564) treatment. In some embodiments, provided herein is a method of treating a subject diagnosed with or suspected of having severe plaque psoriasis or severe atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564). In some embodiments, provided herein is a method of treating a subject diagnosed with or suspected of having moderate plaque psoriasis or moderate atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564). In some embodiments, provided herein is a method of treating a subject diagnosed with or suspected of having mild plaque psoriasis or mild atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564). In some embodiments, provided herein is a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein (e.g., XmAb®27564) in combination with an additional agent to treat at least one side effect or at least one symptom associated with plaque psoriasis and/or atopic dermatitis and/or the IL-2 Fc fusion protein (e.g., XmAb®27564) treatment. 4.4.1. Plaque Psoriasis - 26 - NAI-1537985011v1 [0084] Plaque psoriasis is a chronic relapsing disease of the skin characterized by variable clinical features. Plaque psoriasis is an immune-mediated disease that causes raised, scaly patches on the skin due to systemic inflammation. In some embodiments, plaque psoriasis is triggered by at least one environmental factor. [0085] In some embodiments, the plaque psoriasis is chronic plaque psoriasis or chronic plaque-type psoriasis. In some embodiments, the plaque psoriasis is relapsing plaque psoriasis. In some embodiments, the plaque psoriasis is relapsing remitting plaque psoriasis. In some embodiments, the plaque psoriasis is non responsive to other plaque psoriasis treatment. In some embodiments, the plaque psoriasis is on the elbow(s) of the subject. In some embodiments, the plaque psoriasis is on the knee(s) of the subject. In some embodiments, the plaque psoriasis is on the scalp of the subject. In some embodiments, the plaque psoriasis is on the torso of the subject. [0086] In some embodiments, symptoms of plaque psoriasis include, but are not limited to, red or purple skin, itchy patches, shiny patches, and/or scaly skin. In some embodiments, symptoms of plaque psoriasis include, but are not limited to, thickening (plaque elevation, induration), and scaling (desquamation). In some embodiments, symptoms of plaque psoriasis include, but are not limited to, psoriasis-related itching, flaking, peeling, cracking, pain, scaling, and redness. 4.4.2. Atopic Dermatitis [0087] Atopic dermatitis is an immune-mediated skin disease. In some embodiments, atopic dermatitis is referred to as eczema. In some embodiments, the clinical characteristics of atopic dermatitis vary depending on age, disease stage, race or ethnic group, and/or geographic location. Typical acute lesions are circumscribed patches of eczema and erythema, which is more frequently violaceous or even invisible in patients with darker skin. The lesions are characterized by papules, papulovesicles, edema, crusting, and scaling with hyperpigmentation or hypopigmentation of lesions after healing. Atopic dermatitis may have disease stages. In some embodiments, a patient with atopic dermatitis has an eczema-free interval. In some embodiments, a patient with atopic dermatitis use emollients. In some embodiments, a topical immunosuppressive therapy is used when eczema occurs (e.g., in addition to XmAb®27564). In some embodiments, a patient has not been previously treated with an atopic dermatitis treatment. In some embodiments, a patient has been previously treated with an atopic dermatitis treatment. In some embodiments, a patient has been treated with or is being treated with monoclonal anti- - 27 - NAI-1537985011v1 interleukin-4, anti-interleukin-13, and/or anti-interleukin-31 antibodies, phosphodiesterase-4 inhibitors, and/or Janus kinase (JAK) inhibitors. 4.4.3. Target Patient Population [0088] Provided herein are methods of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject does not have any other type or form of psoriasis. In some embodiments, the subject does not have any other type or form of atopic dermatitis. In some embodiments, the subject does not have any other inflammatory or dermatological condition (besides the plaque psoriasis or atopic dermatitis treated with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the subject has or is suspected of having plaque psoriasis. In some embodiments, the subject has or is suspected of having chronic plaque-type psoriasis. In some embodiments, the subject has or is suspected of having plaque psoriasis on one or at least one part of the body. In some embodiments, the subject has or is suspected of having atopic dermatitis. In some embodiments, the subject has or is suspected of having chronic atopic dermatitis. In some embodiments, the subject has or is suspected of having atopic dermatitis on one or at least one part of the body. In some embodiments, the subject is a human subject. In some embodiments, the subject is a male human subject. In some embodiments, the subject is a female human subject. In some embodiments, the subject is a juvenile. In some embodiments, the subject is an adult. In some embodiments, the human subject is between 18 to 65 years of age. [0089] In some embodiments, the subject has been diagnosed with or is suspected of having plaque psoriasis or atopic dermatitis. In some embodiments, the subject has at least one symptom (e.g., psoriasis-related itching, atopic dermatitis-related itching, flaking, peeling, cracking, pain, scaling, and redness) related to plaque psoriasis or atopic dermatitis. In some embodiments, the subject is experiencing or has experienced at least one symptom associated with plaque psoriasis or atopic dermatitis, such as, red or purple skin, eczema, itchy patches, shiny patches, scaly skin, and/or thickening (plaque elevation, induration) of skin. In some embodiments, the subject is not experiencing a symptom related to plaque psoriasis or atopic dermatitis. In some embodiments, the subject had at least one episode of plaque psoriasis or atopic dermatitis. In some embodiments, the subject has mild plaque psoriasis or previously had mild plaque psoriasis. In some embodiments, the subject has moderate plaque psoriasis or previously had moderate plaque - 28 - NAI-1537985011v1 psoriasis. In some embodiments, the subject has severe plaque psoriasis or previously had severe plaque psoriasis. In some embodiments, severity of plaque psoriasis is determined based on the PASI scoring system. In some embodiments, severity of plaque psoriasis is determined based on the body surface area (BSA), Investigator’s Global Assessment (IGA) score, or any suitable assessment, assay, or scoring system (e.g., as disclosed in Section 4.4.8 of the disclosure). In some embodiments, the subject has mild atopic dermatitis or previously had mild atopic dermatitis. In some embodiments, the subject has moderate atopic dermatitis or previously had moderate atopic dermatitis. In some embodiments, the subject has severe atopic dermatitis or previously had severe atopic dermatitis. In some embodiments, severity of atopic dermatitis is determined based on the EASI scoring system. In some embodiments, severity of atopic dermatitis is determined based on the body surface area (BSA), vIGA-AD, or any suitable assessment, assay, or scoring system used for atopic dermatitis. [0090] In some embodiments, the subject has a relapse of plaque psoriasis or atopic dermatitis. In some embodiments, the subject has refractory plaque psoriasis. In some embodiments, the subject has chronic relapsing plaque psoriasis. In some embodiments, the subject is unresponsive to at least one treatment for plaque psoriasis. In some embodiments, the subject is unresponsive to several treatments for plaque psoriasis (e.g., unresponsive to several biologics). In some embodiments, the subject has refractory atopic dermatitis. In some embodiments, the subject has chronic relapsing atopic dermatitis. In some embodiments, the subject is unresponsive to at least one treatment for atopic dermatitis. In some embodiments, the subject is unresponsive to several treatments for atopic dermatitis (e.g., unresponsive to several biologics). [0091] In some embodiments, the subject has at least one risk factor associated with plaque psoriasis or atopic dermatitis (e.g., smoking, obesity or overweight, elevated body mass index (BMI), use of certain medications, infection, use of alcohol, vitamin D deficiency, stress, skin irritation or any injury to the skin). [0092] In some embodiments, the subject has been previously treated with an agent for plaque psoriasis or atopic dermatitis (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment). In some embodiments, the subject has been previously treated with a treatment for plaque psoriasis or atopic dermatitis (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical - 29 - NAI-1537985011v1 treatment) within the last 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months, prior to treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure to the subject. In some embodiments, the subject is a naïve subject (i.e., has not previously undergone treatment for plaque psoriasis or atopic dermatitis). In some embodiments, the subject has been previously treated with only one agent or only one treatment regimen for plaque psoriasis or atopic dermatitis. In some embodiments, the subject has been previously treated with at least one agent or with at least one treatment regimen for plaque psoriasis or atopic dermatitis. In some embodiments, the subject has been previously treated with two or more agents or two or more treatment regimens for plaque psoriasis or atopic dermatitis. [0093] In some embodiments, the subject has not been previously treated with a plaque psoriasis or atopic dermatitis agent or treatment (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment) within about or within the last 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 - 30 - NAI-1537985011v1 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, or more than 5 years prior to treatment or first administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure to the subject. In some embodiments, the subject has not been previously treated with a plaque psoriasis or atopic dermatitis agent or treatment (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment) within about 30 days prior to treatment or first administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure to the subject. In some embodiments, the subject has not been previously treated with any agent or any treatment regimen for plaque psoriasis or atopic dermatitis. In some embodiments, the subject has not been previously treated with two or more agents or two or more treatment regimens for plaque psoriasis or atopic dermatitis. In some embodiments, the subject has not previously been administered an oral treatment for plaque psoriasis or atopic dermatitis in the 4 weeks prior to the administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject has not previously been administered a topical treatment for plaque psoriasis or atopic dermatitis in the 2 weeks prior to the administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject has not previously been administered a phototherapy in the 4 weeks prior to the administration of an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject has not previously been administered a biologic treatment for plaque psoriasis or atopic dermatitis for 12 weeks or 5 half-lives, whichever is longer, prior to the administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. 4.4.4. Dosing Regimen [0094] A dose has a specific amount of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure that is administered to a subject over a defined time period. The amount of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure administered to a subject is also known as the dose amount. The time over which the dose amount is administered to a subject is also known as the administration time. The dosage may be determined based upon the weight of the subject, such as by multiplying the weight (in kg, for example) of the subject by a dose amount - 31 - NAI-1537985011v1 (such as those described herein). Prior to the administering of the first dose or cycle, such as the day before the first dose or cycle, the weight of the subject can be assessed. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject as a single dose. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject as part of a treatment cycle. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject more than once. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject at predetermined intervals. [0095] In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is about, at least about, or at most about 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45 mg, 1.5 mg, 1.55 mg, 1.6 mg, 1.65 mg, 1.7 mg, 1.75 mg, 1.8 mg, 1.85 mg, 1.9 mg, 1.95 mg, 2 mg, 2.1 mg, 2.15 mg, 2.2 mg, 2.25 mg, 2.3 mg, 2.35 mg, 2.4 mg, 2.45 mg, 2.5 mg, 2.55 mg, 2.6 mg, 2.65 mg, 2.7 mg, 2.75 mg, 2.8 mg, 2.85 mg, 2.9 mg, 2.95 mg, 3 mg, 3.1 mg, 3.15 mg, 3.2 mg, 3.25 mg, 3.3 mg, 3.35 mg, 3.4 mg, 3.45 mg, 3.5 mg, 3.55 mg, 3.6 mg, 3.65 mg, 3.7 mg, 3.75 mg, 3.8 mg, 3.85 mg, 3.9 mg, 3.95 mg, 4 mg, 4.1 mg, 4.15 mg, 4.2 mg, 4.25 mg, 4.3 mg, 4.35 mg, 4.4 mg, 4.45 mg, 4.5 mg, 4.55 mg, 4.6 mg, 4.65 mg, 4.7 mg, 4.75 mg, 4.8 mg, 4.85 mg, 4.9 mg, 4.95 mg, 5 mg, 5.1 mg, 5.15 mg, 5.2 mg, 5.25 mg, 5.3 mg, 5.35 mg, 5.4 mg, 5.45 mg, 5.5 mg, 5.55 mg, 5.6 mg, 5.65 mg, 5.7 mg, 5.75 mg, 5.8 mg, 5.85 mg, 5.9 mg, 5.95 mg, 6 mg, 6.1 mg, 6.15 mg, 6.2 mg, 6.25 mg, 6.3 mg, 6.35 mg, 6.4 mg, 6.45 mg, 6.5 mg, 6.55 mg, 6.6 mg, 6.65 mg, 6.7 mg, 6.75 mg, 6.8 mg, 6.85 mg, 6.9 mg, 6.95 mg, 7 mg, 7.1 mg, 7.15 mg, 7.2 mg, 7.25 mg, 7.3 mg, 7.35 mg, 7.4 mg, 7.45 mg, 7.5 mg, 7.55 mg, 7.6 mg, 7.65 mg, 7.7 mg, 7.75 mg, 7.8 mg, 7.85 mg, 7.9 mg, 7.95 mg, 8 mg, 8.1 mg, 8.15 mg, 8.2 mg, 8.25 mg, 8.3 mg, 8.35 mg, 8.4 mg, 8.45 mg, 8.5 mg, 8.55 mg, 8.6 mg, 8.65 mg, 8.7 mg, 8.75 mg, 8.8 mg, 8.85 mg, 8.9 mg, 8.95 mg, 9 mg, 9.1 mg, 9.15 mg, 9.2 mg, 9.25 mg, 9.3 mg, 9.35 mg, 9.4 mg, 9.45 mg, 9.5 mg, 9.55 mg, 9.6 mg, 9.65 mg, 9.7 mg, 9.75 mg, 9.8 mg, 9.85 mg, 9.9 mg, 9.95 mg, 10 mg, or more than 10 mg. [0096] In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is about, at least about, or at most about 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, - 32 - NAI-1537985011v1 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.010 mg/kg, 0.011 mg/kg, 0.012 mg/kg, 0.013 mg/kg, 0.014 mg/kg, 0.015 mg/kg, 0.016 mg/kg, 0.017 mg/kg, 0.018 mg/kg, 0.019 mg/kg, 0.020 mg/kb, 0.021 mg/kg, 0.022 mg/kg, 0.023 mg/kg, 0.024 mg/kg, 0.025 mg/kg, 0.026 mg/kg, 0.027 mg/kg, 0.028 mg/kg, 0.029 mg/kg, 0.030 mg/kg, 0.031 mg/kg, 0.032 mg/kg, 0.033 mg/kg, 0.034 mg/kg, 0.035 mg/kg, 0.036 mg/kg, 0.037 mg/kg, 0.038 mg/kg, 0.039 mg/kg, 0.040 mg/kg, 0.041 mg/kg, 0.042 mg/kg, 0.043 mg/kg, 0.044 mg/kg, 0.045 mg/kg, 0.046 mg/kg, 0.047 mg/kg, 0.048 mg/kg, 0.049 mg/kg, 0.050 mg/kg, 0.051 mg/kg, 0.052 mg/kg, 0.053 mg/kg, 0.054 mg/kg, 0.055 mg/kg, 0.056 mg/kg, 0.057 mg/kg, 0.058 mg/kg, 0.059 mg/kg, 0.060 mg/kg, 0.061 mg/kg, 0.062 mg/kg, 0.063 mg/kg, 0.064 mg/kg, 0.065 mg/kg, 0.066 mg/kg, 0.067 mg/kg, 0.068 mg/kg, 0.069 mg/kg, 0.070 mg/kg, 0.071 mg/kg, 0.072 mg/kg, 0.073 mg/kg, 0.074 mg/kg, 0.075 mg/kg, 0.076 mg/kg, 0.077 mg/kg, 0.078 mg/kg, 0.079 mg/kg, 0.080 mg/kg, 0.081 mg/kg, 0.082 mg/kg, 0.083 mg/kg, 0.084 mg/kg, 0.085 mg/kg, 0.086 mg/kg, 0.087 mg/kg, 0.088 mg/kg, 0.089 mg/kg, 0.090 mg/kg, 0.091 mg/kg, 0.092 mg/kg, 0.093 mg/kg, 0.094 mg/kg, 0.095 mg/kg, 0.096 mg/kg, 0.097 mg/kg, 0.098 mg/kg, 0.099 mg/kg, 0.1 mg/kg, 0.12 mg/kg, 0.15 mg/kg, and/or 0.2 mg/kg. [0097] In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is between about 0.001 mg/kg and about 0.150 mg/kg, between about 0.003 mg/kg and about 0.120 mg/kg, between about 0.005 mg/kg and about 0.02 mg/kg, between about 0.005 mg/kg and about 0.0270 mg/kg, between about 0.005 mg/kg and about 0.025 mg/kg, between about 0.003 mg/kg and about 0.007 mg/kg, between about 0.003 mg/kg and about 0.1 mg/kg, between about 0.002 mg/kg and about 0.008 mg/kg, between about 0.005 mg/kg and about 0.045 mg/kg, between about 0.005 mg/kg and about 0.050 mg/kg, between about 0.005 mg/kg and about 0.070 mg/kg, between about 0.005 mg/kg and about 0.15 mg/kg, between about 0.005 mg/kg and about 0.1 mg/kg, between about 0.007 mg/kg and about 0.015 mg/kg, between about 0.010 mg/kg and about 0.030 mg/kg, between about 0.035 mg/kg and about 0.045 mg/kg, between about 0.050 mg/kg and about 0.070 mg/kg, between about 0.090 mg/kg and about 0.12 mg/kg, and between about 0.006 mg/kg and about 0.15 mg/kg. [0098] In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is between about 0.003 mg/kg and about 0.12 mg/kg, 0.007 mg/kg and about 0.100 mg/kg, between about 0.006 mg/kg and about 0.020 mg/kg, between about 0.006 mg/kg and about 0.030 mg/kg, between about 0.006 mg/kg and about 0.040 mg/kg, between about 0.006 - 33 - NAI-1537985011v1 mg/kg and about 0.06 mg/kg, between about 0.006 mg/kg and about 0.070 mg/kg, 0.006 mg/kg and about 0.08 mg/kg, 0.006 mg/kg and about 0.090 mg/kg, 0.006 mg/kg and about 0.100 mg/kg, between about 0.006 mg/kg and about 0.120 mg/kg, between about 0.010 mg/kg and about 0.020 mg/kg, between about 0.010 mg/kg and about 0.030 mg/kg, between about 0.010 mg/kg and about 0.04 mg/kg, between about 0.01 mg/kg and about 0.050 mg/kg, between about 0.010 mg/kg and about 0.060 mg/kg, between about 0.010 mg/kg and about 0.070 mg/kg, between about 0.010 mg/kg and about 0.080 mg/kg, between about 0.010 mg/kg and about 0.090 mg/kg, between about 0.010 mg/kg and about 0.100 mg/kg, between about 0.010 mg/kg and about 0.110 mg/kg, between about 0.020 mg/kg and about 0.030 mg/kg, between about 0.020 mg/kg and about 0.040 mg/kg, between about 0.020 mg/kg and about 0.050 mg/kg, between about 0.020 mg/kg and about 0.060 mg/kg, between about 0.020 mg/kg and about 0.070 mg/kg, between about 0.020 mg/kg and about 0.080 mg/kg, between about 0.020 mg/kg and about 0.090 mg/kg, between about 0.020 mg/kg and about 0.100 mg/kg, between about 0.0200 mg/kg and about 0.110 mg/kg, between about 0.020 mg/kg and about 0.150 mg/kg, between about 0.030 mg/kg and about 0.040 mg/kg, between about 0.030 mg/kg and about 0.050 mg/kg, between about 0.030 mg/kg and about 0.060 mg/kg, between about 0.030 mg/kg and about 0.070 mg/kg, between about 0.030 mg/kg and about 0.080 mg/kg, between about 0.030 mg/kg and about 0.090 mg/kg, between about 0.030 mg/kg and about 0.100 mg/kg, between about 0.030 mg/kg and about 0.110 mg/kg, between about 0.030 mg/kg and about 0.150 mg/kg, between about 0.040 mg/kg and about 0.050 mg/kg, between about 0.040 mg/kg and about 0.060 mg/kg, between about 0.040 mg/kg and about 0.070 mg/kg, between about 0.040 mg/kg and about 0.080 mg/kg, between about 0.040 mg/kg and about 0.090 mg/kg, between about 0.040 mg/kg and about 0.100 mg/kg, between about 0.040 mg/kg and about 0.110 mg/kg, between about 0.040 mg/kg and about 0.150 mg/kg, between about 0.050 mg/kg and about 0.060 mg/kg, between about 0.050 mg/kg and about 0.070 mg/kg, between about 0.050 mg/kg and about 0.080 mg/kg, between about 0.050 mg/kg and about 0.090 mg/kg, between about 0.050 mg/kg and about 0.100 mg/kg, between about 0.050 mg/kg and about 0.110 mg/kg, between about 0.050 mg/kg and about 0.150 mg/kg, between about 0.060 mg/kg and about 0.070 mg/kg, between about 0.060 mg/kg and about 0.080 mg/kg, between about 0.060 mg/kg and about 0.090 mg/kg, between about 0.060 mg/kg and about 0.100 mg/kg, between about 0.060 mg/kg and about 0.110 mg/kg, between about 0.060 mg/kg and about 0.150 mg/kg, between about 0.070 mg/kg and about 0.080 mg/kg, - 34 - NAI-1537985011v1 between about 0.070 mg/kg and about 0.090 mg/kg, between about 0.070 mg/kg and about 0.100 mg/kg, between about 0.070 mg/kg and about 0.110 mg/kg, between about 0.070 mg/kg and about 0.150 mg/kg, between about 0.080 mg/kg and about 0.090 mg/kg, between about 0.080 mg/kg and about 0.100 mg/kg, between about 0.080 mg/kg and about 0.110 mg/kg, between about 0.080 mg/kg and about 0.150 mg/kg, between about 0.090 mg/kg and about 0.10 mg/kg, between about 0.090 mg/kg and about 0.110 mg/kg, or between about 0.090 mg/kg and about 0.150 mg/kg. [0099] In another aspect, provided herein is a method of treating plaque psoriasis or atopic dermatitis in a subject, comprising subcutaneously administering to the subject a single dose of an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564). In some embodiments, a single dose of an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) includes any dosage of the disclosure. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of about 0.003 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of 0.003 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of about 0.007 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of 0.007 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of about 0.015 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of 0.015 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of about 0.025 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of 0.025 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of about 0.04 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of 0.04 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of about 0.065 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of 0.065 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of about 0.1 mg/kg. In certain embodiments, an - 35 - NAI-1537985011v1 IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of 0.1 mg/kg. [00100] In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of between about 0.002 mg/kg to about 0.1 mg/kg, between about 0.003 mg/kg to about 0.07 mg/kg, between about 0.003 mg/kg to about 0.065 mg/kg, between about 0.002 mg/kg to about 0.004 mg/kg, between about 0.006 mg/kg to about 0.008 mg/kg, between about 0.010 mg/kg to about 0.020 mg/kg, between about 0.020 mg/kg to about 0.030 mg/kg, between about 0.030 mg/kg to about 0.050 mg/kg, between about 0.060 mg/kg to about 0.070 mg/kg, between about 0.050 mg/kg to about 0.080 mg/kg, between about 0.040 to about 0.07 mg/kg, or between about 0.060 to about 0.1 mg/kg. [00101] In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at least about 0.003 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at most about 0.003 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at least about 0.007 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at most about 0.007 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at least about 0.015 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at most about 0.015 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at least about 0.025 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at most about 0.025 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at least about 0.04 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at most about 0.04 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at least about 0.065 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at most about 0.065 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at least about 0.1 mg/kg. - 36 - NAI-1537985011v1 In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564) is administered at a single dose of at most about 0.1 mg/kg. [00102] In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject as a single dose. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject for 1 dose or 1 cycle, 2 doses or 2 cycles, 3 doses or 3 cycles, 4 doses or 4 cycles, 5 doses or 5 cycles, 6 doses or 6 cycles, 7 doses or 7 cycles, 8 doses or 8 cycles, 9 doses or 9 cycles, 10 doses or 10 cycles, 15 doses or 15 cycles, 20 doses or 20 cycles, 25 doses or 25 cycles, 30 doses or 30 cycles, 35 doses or 35 cycles, 40 doses or 40 cycles, 45 doses or 45 cycles, 50 doses or 50 cycles, 100 doses or 100 cycles, or more than 100 doses or 100 cycles. In some embodiments, a dose is administered about every 2 weeks. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered every 12, 13, 14, 15, 16, or 17 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered about or every 12 to 17 days, 13 to 17 days, 14 to 17 days, 15 to 17 days, 16 to 17 days, 12 to 16 days, 13 to 16 days, 14 to 16 days, 15 to 16 days, 12 to 15 days, 13 to 15 days, or 14 to 15 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered about every 25, 26, 27, 28, 29, 30, 31, or 32 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered about or every 22 to 32 days, 25 to 31 days, 26 to 31 days, 27 to 31 days, 28 to 31 days, 29 to 31 days, 30 to 31 days, 25 to 31 days, 26 to 30 days, 27 to 30 days, 28 to 30 days, 29 to 30 days, 28 to 30 days, or 29 to 30 days. In some embodiments, a dose of an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered monthly (or once per month). In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered twice per month. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered every four weeks. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered every two weeks. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered twice a month or three times a month. In some embodiments, a cycle is about 12, 13, 14, 15, 16, or 17 days. In some embodiments, a cycle is about 25, 26, 27, 28, 29, 30, 31, or 32 days. In some embodiments, a cycle is about two weeks. In - 37 - NAI-1537985011v1 some embodiments, a cycle is about four weeks. In some embodiments, one cycle comprises administration of one dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, a dose is the same as an earlier dose and/or a subsequent dose. In some embodiments, a dose in a cycle is the same from an earlier dose and/or subsequent dose in a different cycle. In some embodiments, the number of cycles or doses varies based on the plaque psoriasis or atopic dermatitis of the subject. In some embodiments, the number of cycles or doses varies based on the treatment regimen for the plaque psoriasis or atopic dermatitis in the subject. [00103] In some embodiments, about, at least about, or at most about 0.003 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject (e.g., every two weeks or every four weeks). In some embodiments, about, at least about, or at most about 0.007 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks). In some embodiments, about, at least about, or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks). In some embodiments, about, at least about, or at most about 0.025 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks). In some embodiments, about, at least about, or at most about 0.040 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks). In some embodiments, about, at least about, or at most about 0.065 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks). In some embodiments, about, at least about, or at most about 0.100 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks). [00104] In some embodiments, a dose amount (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject for a period of time (e.g., for about, at least about, or at most about: one dose, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200 doses or cycles, or more than 200 doses or cycles). In some embodiments, the subsequent dose is the same as the first dose or earlier dose. In some embodiments, a first dose amount (e.g., - 38 - NAI-1537985011v1 between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject and a second dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject. In some embodiments, a first dose amount (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject, a second dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject, and a third dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject. In some embodiments, a first dose amount (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject, a second dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject, a third dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject, and a fourth dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject. In some embodiments, more than four doses (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure are administered to a subject. In some embodiments, a fifth dose and/or any subsequent dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is/are administered to a subject. In some embodiments, a dose or a subsequent dose is administered about 2 weeks after a previous dose (e.g., the second dose is administered about 2 weeks after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered about 4 weeks after a previous dose (e.g., the second dose is administered about 4 weeks after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered about 13-15 days after a previous dose (e.g., the second dose is administered about 13-15 days after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered about 14 days after a previous dose (e.g., the second dose is administered about 14 days after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered about 27-31 days after a previous dose (e.g., the second dose is administered about - 39 - NAI-1537985011v1 24-31 days after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered about 24, 25, 26, 27, 28, 29, 30, or 31 days after a previous dose (e.g., the second dose is administered about 24, 25, 26, 27, 28, 29, 30, or 31 days after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered every four weeks (e.g., 24-31 days; or about 24, 25, 26, 27, 28, 29, 30, or 31 days). In some embodiments, a subsequent dose (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200 doses, or more than 200 doses; e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject. [00105] In some embodiments, a dose amount (e.g., between about 0.005 mg/kg and about 0.009 mg/kg, or about 0.007 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks). In some embodiments, a dose amount (e.g., between about 0.010 mg/kg and about 0.020 mg/kg, or about 0.015 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks). In some embodiments, a dose amount (e.g., between about 0.020 mg/kg and about 0.030 mg/kg, or about 0.025 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks). In some embodiments, a dose amount (e.g., between about 0.035 mg/kg and about 0.045 mg/kg, or about 0.40 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks). In some embodiments, a dose amount (e.g., between about 0.06 mg/kg and about 0.07 mg/kg, or about 0.065 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks). In some embodiments, a dose amount (e.g., between about 0.095 mg/kg and about 0.15 mg/kg, or about 0.1 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks). In some embodiments, a subsequent dose (e.g., 5, 6, 7, 8, 9, and/or 10, or - 40 - NAI-1537985011v1 more than 10 doses) (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject (e.g., after about 2 weeks from a previous dose; about 13-16 days after a previous dose; or about 14 days after a previous dose; or every four weeks). In some embodiments, a subsequent dose is the same as the previous dose. [00106] In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject for 4 doses (e.g., between about 0.003 mg/kg and about 0.2 mg/kg). In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject for more than 4 doses (e.g., between about 0.003 mg/kg and about 0.2 mg/kg). In some embodiments, a cycle includes one administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure to a subject (e.g., between about 0.003 mg/kg and about 0.2 mg/kg). In some embodiments, a cycle is about two weeks. In some embodiments, a cycle is about four weeks. [00107] In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once between about 12 and about 17 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once between about 13 and about 15 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 13-15 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once between about 12 and about 16 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 12-16 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 14-16 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once about every 13 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 13 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once about every 14 days. In some - 41 - NAI-1537985011v1 embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 14 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once about every two weeks. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every two weeks. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once between about 13 and about 17 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 13-17 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once about every 15 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 15 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once about every 16 days. [00108] In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once between about 24 and about 32 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once between about 27 and about 31 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 28-31 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once between about 28 and about 30 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 24-32 days or 27-31 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 28-30 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once about every 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) - 42 - NAI-1537985011v1 of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once about every 24, 25, 26, 27, 28, 29, or 30 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 24, 25, 26, 27, 28, 29, or 30 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once about every four weeks. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every four weeks. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once between about 24 and about 32 days or between about 27 and about 30 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 27-30 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once about every 28, 29, 30, or 31 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once every 28 or 30 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered once about every 28, 29, 30, or 31 days. [00109] In some embodiments, treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure to a subject results in a reduced relapsed rate of plaque psoriasis or atopic dermatitis. 4.4.5. Administration [00110] In some embodiments, a method of the disclosure comprises administration (e.g., subcutaneous) of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure to a subject. In some embodiments, administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is via subcutaneous administration. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject for a period of time. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject until plaque psoriasis or atopic dermatitis is treated. In some embodiments, the IL- - 43 - NAI-1537985011v1 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject until plaque psoriasis or atopic dermatitis is improved in the subject (e.g., improved based on at least one efficacy assessment or assay for plaque psoriasis or atopic dermatitis (e.g., Section 4.4.8 and Section 5 of the disclosure)). In some embodiments, administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure stops after a positive therapeutic response (e.g., based on at least one efficacy assessment or assay for plaque psoriasis or atopic dermatitis (e.g., Section 4.4.8 or Section 5 of the disclosure)) is achieved. In some embodiments, a positive therapeutic response is a therapeutic response that ameliorates at least one symptom of plaque psoriasis or atopic dermatitis and/or ameliorates the severity (e.g., severe to moderate or mild) of plaque psoriasis or atopic dermatitis in a subject after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject. In some embodiments, administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure begins again once the positive therapeutic response diminishes or disappears. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject at the start of relapse from a prior plaque psoriasis or atopic dermatitis treatment. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject after the subject has undergone at least one treatment for plaque psoriasis or atopic dermatitis. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject after the subject has been diagnosed with plaque psoriasis or atopic dermatitis. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject in combination with at least one agent that ameliorates at least one symptom associated with plaque psoriaris or atopic dermatitis. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject in combination with at least one agent that ameliorates at least one symptom associated with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00111] In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject as a single dose administration. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about every 2 weeks. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about every 4 weeks. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about, at - 44 - NAI-1537985011v1 least about, or at most about once a month, twice a month, three times a month. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about, at least about, or at most about every 12, 13, 14, 15, 16, or 17 days.. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about, at least about, or at most about every 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about every 14 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about every 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject every 12 to 17 days, 12 to 16 days, 12 to 15 days, 12 to 14 days, 13 to 15 days, 13 to 16 days, 13 to 17 days, 14 to 15 days, 14 to 16 days, 14 to 17 days, or any suitable time period. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about every two weeks. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject every 24 to 32 days, 24 to 31 days, 24 to 30 days, 25 to 32 days, 26 to 31 days, 27 to 31 days, 27 to 30 days, 28 to 30 days, 29 to 30 days, 28 to 31 days, 28 to 30 days, or any suitable time period. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about every four weeks. [00112] In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about every 14 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about every two weeks. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject about every four weeks. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject on Day 1, Day 15, Day 19, and/or Day 43. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject on Day 1, Day 15, Day 19, Day 43, and/or every 14 days thereafter or every 14 days until end of treatment. In some embodiments, treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure comprises about, at least about, or at most about, 4 doses (or cycles). In some embodiments, treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure comprises about, at least about, or at most about, 1 dose (or cycle), 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, - 45 - NAI-1537985011v1 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 350, 400, 450, 500 doses (or cycles), or more than about 500 doses (or cycles). In some embodiments, each dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject every 12, 13, 14, 15, 16, or 17 days. In some embodiments, each dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject every 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, a cycle is about 12, 13, 14, 15, 16, or 17 days. In some embodiments, a cycle is about 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, each dose is administered to a subject every 12 to 17 days. In some embodiments, each dose is administered to a subject every 25 to 32 days. In some embodiments, each dose is administered to a subject every 14 days. In some embodiments, each dose is administered to a subject every 24, 25, 26, 27, 28, 29, 30, or 31. In some embodiments, each dose is administered to a subject every 13 to 15 days. In some embodiments, each dose is administered to a subject every 24 to 30 days, 24 to 31 days, 25 to 32, 27 to 31, or 28 to 30 days. In some embodiments, each cycle is 12 to 17 days. In some embodiments, each cycle is 14 days. In some embodiments, each cycle is 13 to 15 days. In some embodiments, a dose is administered every 2 weeks. In some embodiments, a cycle is about two weeks. In some embodiments, each cycle is 24 to 31 days or 26 to 31 days. In some embodiments, each cycle is 14 days. In some embodiments, each cycle is 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, each cycle is 27 to 30 days. In some embodiments, a dose is administered every 4 weeks. In some embodiments, a cycle is about 4 weeks. 4.4.5.1 Subcutaneous administration [00113] In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject via a subcutaneous administration. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject via a single dose subcutaneous administration. In some embodiments, the term “subcutaneous” infusion or injection is meant to encompass any method of transcutaneous delivery to a subject. In some embodiments, a needle device is inserted at a selected site within the body of a subject for subcutaneous delivery of an IL-2 Fc fusion protein (e.g., XmAb®27564) to the subject. In some embodiments, a pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb®27564) is administered subcutaneously to the subject. In some embodiments, a solution comprising an IL-2 Fc fusion protein (e.g., XmAb®27564), histidine - 46 - NAI-1537985011v1 (e.g., 20 mM), and sorbitol (e.g., 250 mM) is subcutaneously administered to the subject. In some embodiments, the solution is a sterile liquid for injection and practically free of visible particulates. In some embodiments, a solution comprising an IL-2 Fc fusion protein (e.g., XmAb®27564) suitable for subcutaneous administration is provided in a vial or ampule. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is subcutaneously administered to a subject about every 2 weeks or every 2 weeks. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is subcutaneously administered to a subject about every 4 weeks or every 4 weeks. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is subcutaneously administered to a subject every 12 to 17 days, 12 to 16 days, 12 to 15 days, 12 to 14 days, 13 to 17 days, 13 to 16 days, 13 to 15 days, 13 to 14 days, 14 to 17 days, 14 to 16 days, or 14 to 15 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is subcutaneously administered to a subject about every, at least every, or at most every: 12 days, 13 days, 14 days, 15 days, 16 days, or 17 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is subcutaneously administered to a subject every 22 to 32 days, 24 to 30 days, 25 to 31 days, 27 to 30 days, or 28 to 30 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is subcutaneously administered to a subject about every, at least every, or at most every: 24, 25, 26, 27, 28, 29, 30, 31, or 32 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is subcutaneously administered to a subject about every 14 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is subcutaneously administered to a subject about every 24, 25, 26, 27, 28, 29, or 30 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb®27564) is subcutaneously administered to a subject once in a month, twice in a month, or three times in a month. [00114] In some embodiments, an autoinjector is used for subcutaneous administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) to the subject. In some embodiments, a syringe is used for subcutaneous administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) to the subject. In some embodiments, a 27 gauge syringe is used to administer an IL-2 Fc fusion protein (e.g., XmAb®27564) to the subject. In some embodiments, a 25 gauge to 30 gauge syringe is used (e.g., to administer an IL-2 Fc fusion protein to the subject). In some embodiments, a 3/8 inches to 5/8 inches needle is used. In some embodiments, a prefilled syringe is used to administer an IL-2 Fc fusion protein to the subject. In some embodiments, the syringe is a 1 mL - 47 - NAI-1537985011v1 syringe. In some embodiments, a syringe is a 2 mL syringe. In some embodiments, a syringe is a 5 mL syringe. In some embodiments, the syringe is at most a 10 mL syringe. In some embodiments, the syringe is at most a 30 mL syringe. In some embodiments, subcutaneous injection is administered at a 45- to 90-degree angle. In some embodiments, the injection is administered in any suitable body part of a subject. In some embodiments, the injection is administered in the left upper lateral arm (deltoid). In some embodiments, the injection is administered in the right upper lateral arm (deltoid). [00115] In some embodiments, the injection site is marked with a small circle and date of injection to identify injection site and to monitor reaction(s). In some embodiments, the injection site is monitored for pain, tenderness, erythema and/or swelling (e.g., Example 1 and/or by using a Canfield photography system). In some embodiments, a subject is assessed for allergic and non-allergic injection-related reactions after a subcutaneous administration of an IL-2 Fc fusion protein (e.g., XmAb®27564). In some embodiments, a subject is assessed for adverse event (e.g., within about 6 hours) from the start of a subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb®27564). In some embodiments, an adverse event (AE) is a sign and/or symptom associated with hypersensitivity/anaphylactic reaction (e.g., skin, gastrointestinal, respiratory, cardiovascular, and neurologic systems) from a subcutaneous injection. In some embodiments, an electrocardiogram (ECG) assessment is performed predose and/or after (e.g., about 4 hours after) a subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb®27564). In some embodiments, blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected prior to subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb®27564). In some embodiments, blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected after subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb®27564). In some embodiments, blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected about 30 minutes after subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb®27564). In some embodiments, blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected every 60 minutes for 4 hours after subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb®27564). 4.4.6. Previous Treatment For Plaque Psoriasis or Atopic Dermatitis - 48 - NAI-1537985011v1 [00116] Provided herein is a method of treating plaque psoriasis or atopic dermatitis in a subject with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure, wherein the subject has been previously treated with a previous therapy or treatment for plaque psoriasis or atopic dermatitis that is not the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the previous therapy or treatment for plaque psoriasis or atopic dermatitis includes one agent for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy or treatment for plaque psoriasis or atopic dermatitis means that the subject has undergone one treatment regimen for plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy or treatment for plaque psoriasis or atopic dermatitis means at least one agent for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy or treatment for plaque psoriasis or atopic dermatitis means that the subject has undergone at least one treatment regimen for plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy or treatment for plaque psoriasis or atopic dermatitis means two or at least two agents for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy or treatment for plaque psoriasis or atopic dermatitis means that the subject has undergone two or at least two treatment regimen for plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy is used to treat the plaque psoriasis or atopic dermatitis that an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is used to treat in the subject. In some embodiments, a method of the disclosure further comprises administering an additional agent for treating at least one side effect or symptom associated with IL-2 Fc fusion protein (e.g., XmAb®27564) treatment and/or associated with the previous therapy. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis is one agent for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis are two or more agents for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis are three or more agents for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy is administered prior to the administration with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00117] In some embodiments, a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a non-responder. In some embodiments, a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a responder. In some - 49 - NAI-1537985011v1 embodiments, a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a relapser. In some embodiments, a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a rebounder. In some embodiments, a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a partial responder. [00118] In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis is a topical therapy. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis is phototherapy (UVB, PUVA). In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis is a biologic, such as efalizumab. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis is a biologic, such as an antagonist of TNF, IL-12/23, IL-23, and IL-17. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis is a non-biologic, such as cyclosporine. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis is a small molecule systemic therapy or small molecule immunomodulators, such as methotrexate, acitretin, apremilast, and cyclosporin. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis is a systemic agent for plaque psoriasis or atopic dermatitis. Examples of a systemic agent for treating plaque psoriasis or atopic dermatitis include, but are not limited to, methotrexate, cyclosporine, fumaric acid esters, acitretin, alefacept, adalimumab, efalizumab, etanercept, infliximab, golimumab and/or ustekinumab. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis is secukinumab. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis is adalimumab, alefacept, etanercept, infliximab, and/or ustekinumab. [00119] In some embodiments, a previous therapy for atopic dermatitis is a monoclonal anti- interleukin-4, -13, and -31 antibodies, phosphodiesterase-4 inhibitors, and Janus kinase (JAK) inhibitors. In some embodiments, a previous therapy for atopic dermatitis is a topical immunosuppressive therapy. [00120] In some embodiments, the previous therapy is an IL-17 binding molecule (e.g., an IL- 17 antibody, such as secukinumab), a topical therapy (over the counter, non-steroidal compounds and steroidal compound), phototherapy, and/or systemic treatment (e.g., with biologics or chemical entities). Non-limiting examples of topical agents include salicylic acid, coal tar, Dovonex® (calcipotriene), Taclonex® (calcipotriene and betamethasone dipropionate), Tazorec® (tazarotene), pimecrolimus, castellani’s paint (Castederm), tacrolimus, Vectical® (calcitriol), - 50 - NAI-1537985011v1 Zithranol-RR® (anthralin), and topical steroids (e.g., corticosteroids). Non-limiting examples of phototherapy include treatment with psoralen+UVA or treatment with UVB (with or without tar). Non-limiting examples of phototherapy include retionoids such as Acitretin (Soriatane®), cyclosporine, methotrexate, Hydrea® (hydroxyurea), isotretinoin, tildrakizumab, risankizumab, broadalumab, ixekizumab, mycophenolate mofetil, mycophenolic acid, sulfasalazine, 6- thioguanine, fumarates (e.g, dimethylfumarate and fumaric acid esters), azathioprine, corticosteroids, leflunomide, tacrolimus, T-cell blockers (such as Amevive® (alefacept) and Raptiva® (efalizumab), tumor necrosis factor-alpha (TNF-alpha) blockers (such as Enbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab) and Simponi® (golimumab)) and interleukin 12/23 blockers (such as Stelara® (ustekinumab), tasocitinib, Efalizumab, and briakinumab. [00121] In some embodiments, the previous therapy includes, but it is not limited to, apremilast, mometasome, voclosporin, Ketokonazol, Neuroskin Forte, recombinant human interleukin-10, voclosporin, VX-765, dovonex, MED-I545, fluphenazine decanoate, bimosiamose cream, doxycycline, vancomycin, AbGn168, Vitamin D3, RO5310074, fludarabine Calcipotriol and hydrocortisone (LEO 80190), LE80185 (Taclonex® Scalp topical suspension/Xamiol® gel), Focetria (Monovalent MF59-Adjuvanted vaccine, tgAAC94 gene therapy vector, Apremilast, Capsaicin, Psirelax, ABT-874 (anti IL-12), IDEC-114, MEDI-522, INCB018424 phosphate cream, LE29102, BMS 587101, CD 2027, CRx-191, 8-methoxypsoralen or 5-methoxypsoralen, Bicillin L-A, LY2525623, INCB018424, LY2439821, CEP-701, CC- 10004, certolizumab (CZP), GW786034 (pazopanib), doxycycline Curcuminoids C3 Complex, NYC 0462, RG3421, hOKT3gamma1(Ala-Ala), BT061, teplizumab, Chondroitin sulphate, CNTO 1275, monoclonal antibody to IL-12p40 and IL-23 p40 subunits, BMS-582949, MK0873, MEDI-507, M518101, ABT-874, AMG 827, AN2728, AMG 714, AMG 139, PTH (1-34), U0267 Foam, CNTO 1275, QRX-101, CNTO 1959, LEO 22811, Imiquimod, CTLA4Ig, Alga Dunaliella Bardawil, AS101 Cream, pioglitazone, pimecrolimus, ranibizumab, Zidovudine CDP870 (Certolizumab pegol), Onercept (r-hTBP-1), ACT-128800, 4,4-dimethyl-benziso-2H- selenazine, CRx-191, CRx-197, doxercalciferol, LEO 19123 Cream (calcipotriol plus LEO 80122), LAS 41004, WBI-1001, tacrolimus, RAD001, rapamycin, rosiglitazone, pioglitazone, ABT-874, Aminopterin, AN2728, CD2027, ACT-128800, mometasone furoate, CT 327, clobetasol+LCD, BTT1023, E6201, topical vitamin B12, INCB018424 Phosphate Cream, - 51 - NAI-1537985011v1 Xamiol gel, IP10.C8, BFH772, LEO 22811, Fluphenazine, MM-093, Clobex, SCH 527123, CF101, SRT2104, BIRT2584, CC10004, Tetrathiomolybdate, CP-690,550, U0267, ASP015K, VB-201, Acitretin (also called U0279), RWJ-445380, Psoralait, Clobetasol propionate, botulinum toxin type A, alefacept, erlotinib, BCT194, Ultravate Ointment, Roflumilast, CNTO 1275, halobetasol, CTA018 cream, ILV-094, COL-121, MEDI-507, AEB071, secukinumab, IL- 6 antagonists, CD20 antagonists, CTLA4 antagonists, IL-17 antagonists, IL-8 antagonists, IL-21 antagonists, IL-22 antagonist, VGEF antagonists, CXCL antagonists, MMP antagonists, defensin antagonists, IL-1beta antagonists, and IL-23 antagonists (e.g., receptor decoys, antagonistic antibodies, etc.). 4.4.7. Additional Agents [00122] An IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure and at least one additional therapeutic agent (e.g., agent for treating a side effect) can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure can be administered first, and the additional agent can be administered second, or vice versa. [00123] An IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure and/or one or more additional therapeutic agents (e.g., agent for treating a side effect), procedures or modalities can be administered during periods of active disorder (plaque psoriasis or atopic dermatitis), or during a period of positive therapeutic response or less active disease. An IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure can be administered before the other treatment or agent, concurrently with the treatment, post-treatment, or during a positive therapeutic response to the disorder. [00124] When administered in combination, an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure and the one or more additional agents (e.g., second or third agent; agent for treating a side effect) can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each agent used individually. [00125] In some embodiments, an additional agent is an agent that ameliorates at least one side effect associated with plaque psoriasis or atopic dermatitis or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject. In some embodiments, a steroid is administered to a subject. In one embodiment, a steroid is administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one - 52 - NAI-1537985011v1 embodiment, the steroid is administered in an amount between about 5 mg and about 30 mg. In one embodiment, the steroid described herein is administered in an amount between about 5 mg and about 25 mg. In one embodiment, the steroid is administered in an amount between about 5 mg and about 15 mg. In one embodiment, the steroid is administered in an amount between about 8 mg and about 12 mg. In one embodiment, the steroid is administered in an amount between about 10 mg and about 20 mg. In one embodiment, the steroid is administered in an amount of about 10 mg. In one embodiment, the steroid is administered in an amount of 10 mg. In one embodiment, the steroid is administered in an amount between about 18 mg and about 22 mg. In one embodiment, the steroid is administered in an amount of about 20 mg. In one embodiment, the steroid is administered in an amount of 20 mg. In one embodiment, the steroid is dexamethasone. In one embodiment, the steroid is dexamethasone and is administered in an amount between about 10 mg and about 20 mg. In one embodiment, the steroid is dexamethasone and is administered in an amount of about 10 mg. In one embodiment, the steroid is dexamethasone. In some embodiments, dexamethasone is administered intravenously. In one embodiment, the steroid is dexamethasone and is administered in an amount of about 20 mg. In one embodiment, the steroid is dexamethasone and is administered between about 45 minutes and 75 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, the steroid is dexamethasone and is administered about 60 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, the steroid is dexamethasone and is administered about 60 minutes before an administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, about 20 mg of dexamethasone is administered about 60 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, about 20 mg of dexamethasone is administered about 60 minutes before an administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, a corticosteroid is administered to a subject. [00126] In some embodiments, an antidiarrheal treatment (e.g., Imodium or an equivalent) is administered to a subject. In some embodiments, electrolytes is administered to a subject. In some embodiments, acetaminophen (e.g., 650 mg orally) or an equivalent is administered to a subject. In some embodiments, an antipyretic is administered to a subject. In some embodiments, - 53 - NAI-1537985011v1 an analgesic is administered to a subject. In some embodiments, diphenhydramine (e.g., 25 to 50 mg intravenously or orally) or an equivalent is administered to a subject for treating rash, pruritus, or other signs and/or symptoms of hypersensitivity (allergic) reaction. In some embodiments, tocilizumab (e.g., 8 mg/kg IV over 1 hour) or an equivalent is administered to a subject with or without dexamethasone (e.g., 10 to 20 mg IV) or equivalent. In some embodiments, about 10 mg dexamethasone is administered to a subject. In some embodiments, pressors, fluids, oxygen, epinephrine, bronchodilators, ventilatory support, antipyretic, and/or analgesic is administered to a subject. [00127] In one embodiment, an antihistamine is administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, the antihistamine is an H1 antagonist. In one embodiment, the H1 antagonist is a first generation H1 antagonist. In one embodiment, the antihistamine is an ethanolamine. In one embodiment, the ethanolamine is diphenhydramine, carbinoxamine, doxylamine, orphenadrine, bromazine, clemastine, dimenhydrinate, or any combination thereof. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is administered in an amount between about 20 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount between about 20 mg and 30 mg. In one embodiment, the antihistamine is administered in an amount of about 25 mg. In one embodiment, the antihistamine is administered in an amount of 25 mg. In one embodiment, the antihistamine is administered in an amount between about 40 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount between about 45 mg and 55 mg. In one embodiment, the antihistamine is administered in an amount of about 50 mg. In one embodiment, the antihistamine is administered in an amount of 50 mg. In one embodiment, the antihistamine is diphenhydramine and the amount between about 20 mg and about 30 mg. In one embodiment, the antihistamine is diphenhydramine and the amount is about 25 mg. In one embodiment, the antihistamine is diphenhydramine and is administered between about 20 minutes and 70 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes before an IL- - 54 - NAI-1537985011v1 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, about 25 mg of diphenhydramine is administered between about 30 minutes and 60 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, about 25 mg of diphenhydramine is administered between about 30 minutes and 60 minutes before an administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00128] In one embodiment, acetaminophen is administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, acetaminophen is administered in an amount between about 100 mg and 1000 mg. In one embodiment, acetaminophen is administered in an amount between about 400 mg and 600 mg. In one embodiment, acetaminophen is administered in an amount of about 500 mg. In one embodiment, acetaminophen is administered in an amount of 500 mg. In one embodiment, acetaminophen is administered in an amount between about 500 mg and 800 mg. In one embodiment, acetaminophen is administered in an amount between about 550 mg and 750 mg. In one embodiment, acetaminophen is administered in an amount between about 600 mg and 700 mg. In one embodiment, acetaminophen is administered in an amount of about 650 mg. In one embodiment, acetaminophen is administered in an amount of 650 mg. In one embodiment, the acetaminophen is administered between about 15 minutes and about 45 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, the acetaminophen is administered about 30 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, the acetaminophen is administered between about 60 minutes and about 30 minutes before an administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, the acetaminophen is administered between about 60 minutes and about 30 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, about 650 mg of acetaminophen is administered about 30 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00129] In one embodiment, a steroid, an H1 antagonist, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, dexamethasone, an H1 antagonist, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, a - 55 - NAI-1537985011v1 steroid, diphenhydramine, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, dexamethasone, diphenhydramine, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In one embodiment, dexamethasone is administered in an amount of about 10 mg or about 20 mg, diphenhydramine is administered in an amount of about 25 mg to 50 mg, and/or acetaminophen is administered in an amount of about 650 mg prior to or after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. 4.4.8. Response to Treatment, Efficacy Assessments, and Assays [00130] In some embodiments, response to treatment after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject can be determined based on at least one efficacy assessment or assay for plaque psoriasis or atopic dermatitis as disclosed herein. In some embodiments, treatment efficacy or assessment is determined for a method of the disclosure. In some embodiments, treatment efficacy or assessment is determined before and/or after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. It will be understood that any assay available for determining improvement or used for assessing plaque psoriasis or atopic dermatitis can be used with a method of the disclosure. It will be understood that maximum response, partial response, improvement, lost improvement, start of relapse, etc., may be measured by any available scoring system for plaque psoriasis, e.g., physician’s assessed efficacy measures, such as Psoriasis Area an Severity Index (PASI), Body Surface Measurement (BSA), clinical signs score: Investigator’s Global assessment of improvement (IGA), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), or health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI)). It will be understood that maximum response, partial response, improvement, lost improvement, start of relapse, etc., may be measured by any available scoring system for atopic dermatitis, e.g., physician’s assessed efficacy measures, such as Eczema Area and Severity Index (EASI), Body Surface Measurement (BSA), clinical signs score: validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA-AD), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), or health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI)). In some embodiments, efficacy of treatment after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to a subject - 56 - NAI-1537985011v1 can be determined based on the number of regulatory T cells (e.g., CD4+ regulatory T (Treg) cells), NK cells, and/or conventional T cells (e.g., CD4+ conventional T (Tcon) cells, CD8+ Tcon T cells, or all non-Treg cells). [00131] In some embodiments, treatment efficacy or assessment is determined by comparing the score or outcome from at least one of the assessments or assays of the disclosure after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline score or outcome taken before treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564); compared to the score or outcome taken from the subject at an earlier time point; and/or compared to the score or outcome taken from at least one subject with plaque psoriasis or atopic dermatitis). In some embodiments, treatment efficacy or assessment is determined 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. 4.4.8.1 Increase in the number of regulatory T (Treg) cells [00132] In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed based on the number of Treg cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is determined by flow cytometry. In some embodiments, a Treg cell is CD4+ Treg cell. In some embodiments, a Treg cell is CD4+ CD25high Foxp3+ Tregs. In some embodiments, a Treg cell is CD3+/CD4+/CD8−/CD25+/FOXP3+. In some embodiments, the number of Treg cells can be assessed at any time before or after administration - 57 - NAI-1537985011v1 of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week. In some embodiments, an increase in the number of Treg cells is observed while no increase or no significant increase in the number of convention T cells is observed after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure In some embodiments, conventional T cells are all non-Treg cells. In some embodiments, an increase in the number of Treg cells is observed within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure results in an increase in the number of Treg cells or the number of Treg cells in a population of cells in the subject as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the increase is an increase of about, at least about, or at most about, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, or more than 300% as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some - 58 - NAI-1537985011v1 embodiments, the increase is an increase of about, at least about, or at most about, 0.5 fold, 1 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 5 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, or more than 50 fold as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the increase is an increase of about, at least about, or at most about, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, or more than 100 fold as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). [00133] In some embodiments, the number of Treg cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00134] In some embodiments, the number of Treg cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 5 post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on - 59 - NAI-1537985011v1 Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 12 post administration of an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on the last day of treatment (e.g., about Day 88). [00135] In some embodiments, the number of Treg cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Treg cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 - 60 - NAI-1537985011v1 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after the last dose of an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. 4.4.8.2 Effect on the number of effector T (Teff) cells [00136] In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed based on the number of effector T (Teff) cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is determined by flow cytometry. In some embodiments, the number of Teff cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week. In some embodiments, little or no increase is observed in the number of Teff cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to the number of Teff cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, an amount of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure used in a method of the disclosure, is an amount that does not result in an increase or a significant increase in the number of Teff cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to the number of Teff cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or - 61 - NAI-1537985011v1 standard deviation). In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%. In some embodiments, little or no increase or no significant increase in the number of Teff cells is observed within 1 day, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or longer than 24 weeks after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00137] In some embodiments, the number of Teff cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00138] In some embodiments, the number of Teff cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 5 post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on - 62 - NAI-1537985011v1 Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 12 post administration of an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on the last day of treatment (e.g., about Day 88). [00139] In some embodiments, the number of Teff cells is assessed after treatment with an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of Teff cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 - 63 - NAI-1537985011v1 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after the last dose of an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. 4.4.8.3 Effect on the number of NK cells [00140] In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed based on the number of NK cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of NK cells is determined by flow cytometry. In some embodiments, the number of NK cells or the total number of NK cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of NK cells or the total number of NK cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of NK cells or the total number of NK cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week. In some embodiments, the NK cells refers to CD45+CD3-CD56+ NK cells. In some embodiments, little or no increase is observed in the number of NK cells or total NK cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to the number of NK cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, an amount of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure used in a method of the disclosure, is an amount that does not result in an increase or a significant increase in the number of NK cells or total NK cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to the number of NK cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase - 64 - NAI-1537985011v1 that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or standard deviation). In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%. In some embodiments, little or no increase or no significant increase in the number of NK cells or total NK cells is observed within 1 day, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or longer than 24 weeks after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00141] In some embodiments, the number of NK cells or the total of NK cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00142] In some embodiments, the number of NK cells or total NK cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. - 65 - NAI-1537985011v1 In some embodiments, the number of NK cells or total NK cells is assessed on Day 5 post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 12 post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on the last day of treatment (e.g., about Day 88). [00143] In some embodiments, the number of NK cells or total NK cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 - 66 - NAI-1537985011v1 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after the last dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. 4.4.8.4 Effect on the number of CD4+ conventional T (Tcon) cells [00144] In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed based on the number of CD4+ conventional T (Tcon) cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is determined by flow cytometry. In some embodiments, the number of CD4+ Tcon cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week. In some embodiments, little or no increase is observed in the number of CD4+ Tcon cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to the number of CD4+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, an amount of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure used in a method of the disclosure, is an amount that does not result in an increase or a significant increase in the number of CD4+ Tcon cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to the number of CD4+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some - 67 - NAI-1537985011v1 embodiments the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or standard deviation). In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%. In some embodiments, little or no increase or no significant increase in the number of CD4+ Tcon cells is observed within 1 day, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or longer than 24 weeks after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00145] In some embodiments, the number of CD4+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. - 68 - NAI-1537985011v1 [00146] In some embodiments, the number of CD4+ Tcon cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 5 post administration of an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 12 post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on the last day of treatment (e.g., about Day 88). [00147] In some embodiments, the number of CD4+ Tcon cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the - 69 - NAI-1537985011v1 number of CD4+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after the last dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. 4.4.8.5 Effect on the number of CD8+ Tcon T cells [00148] In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed based on the number of CD8+ conventional T (Tcon) cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is determined by flow cytometry. In some embodiments, the number of CD8+ Tcon cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week. In some embodiments, little or no increase is observed in the number of CD8+ Tcon cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to the number of CD8+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, an amount of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure used in a method of the disclosure, is an amount that does not result in an increase or a significant increase in the number of CD8+ Tcon cells after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as - 70 - NAI-1537985011v1 compared to a reference (e.g., compared to the number of CD8+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or standard deviation). In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%. In some embodiments, little or no increase or no significant increase in the number of CD8+ Tcon cells is observed within 1 day, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or longer than 24 weeks after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00149] In some embodiments, the number of CD8+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 - 71 - NAI-1537985011v1 months, or longer than 24 months after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00150] In some embodiments, the number of CD8+ Tcon cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 5 post administration of an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 12 post administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL- 2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on the last day of treatment (e.g., about Day 88). - 72 - NAI-1537985011v1 [00151] In some embodiments, the number of CD8+ Tcon cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after the last dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. 4.4.8.6 Improvement of a Psoriasis Area and Severity Index (PASI) score [00152] In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed based on a Psoriasis Area and Severity Index (PASI) score. For calculation of the PASI, 4 main body areas are assessed: the head (h), the trunk (t), the upper extremities (u), and the lower extremities (l), corresponding to 10, 30, 20, and 40% of the total body area, respectively. The area (A) of psoriatic involvement of these 4 main areas (Ah, At, Au, and Al) is given a numerical value: 0 = no involvement; 1 = < 10%; 2 = 10 < 30%; 3 = 30 < 50%; 4 = 50 < 70%; 5 = 70 < 90%, and 6 = 90–100%. To evaluate the severity of the psoriatic lesions, 3 target symptoms, namely erythema (E), infiltration (I), and desquamation (D) are assessed according to a scale 0–4, where 0 means a complete lack of cutaneous involvement and 4 represents the severest possible involvement. The severity rating for the 3 main target symptoms is multiplied with the numerical value of the areas involved and with the various percentages of the 4 body areas. These values are then added to obtain the PASI. The formula can be written as follows: PASI = 0.1 × Ah × (Eh + Ih + Dh) + 0.3 × At × (Et + It + Dt) + 0.2 × Au × (Eu + Iu + Du) + 0.4 × Al × (El + Il + Dl). The index varies in steps of 0.1 units from 0.0 to - 73 - NAI-1537985011v1 72.0. The PASI 50, 75, and 90 represent the fraction of patients that have improvement of the PASI score of 50%, 75% and 90% over the baseline PASI (Oji V, Luger TA. The skin in psoriasis: assessment and challenges. Clin Exp Rheumatol.2015;33(5 Suppl 93):S14–9; Schmitt J, Wozel G. The psoriasis area and severity index is the adequate criterion to define severity in chronic plaque-type psoriasis. Dermatology.2005;210:194–199). [00153] In some embodiments, PASI can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, PASI is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, PASI is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week. [00154] In some embodiments, the subject achieves an improvement in PASI score of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline PASI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to PASI score of other subjects with plaque psoriasis; and/or compared to PASI score of the same subject taken at an earlier time point). In some embodiments, the subject achieves an improvement in PASI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, -24, -25, -26, -27, -28, -29, or -30, for example, at about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 - 74 - NAI-1537985011v1 months after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline PASI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to PASI score of other subjects with plaque psoriasis; and/or compared to PASI score of the same subject taken at an earlier time point). [00155] In some embodiments, the subject achieves a PASI 50, 75, 90, or 100 by about, or at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline PASI score of the subject, e.g., PASI score obtained prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to PASI score of other subjects with plaque psoriasis; and/or compared to PASI score of the same subject taken at an earlier time point). In some embodiments, the subject achieves a PASI 50, 75, or 90 by 70 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a PASI 50, 75, 90, or 100, by 60 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a PASI 50, 75, 90, or 100, by 90 days or less (e.g., at 88 days or less) after administration (e.g., first administration, second administrations, or any - 75 - NAI-1537985011v1 administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a PASI 50, 75, 90, or 100, by 100 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a PASI 50, 75, 90, or 100, by 200 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a PASI 50, 75, 90, or 100 before the end of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a PASI 75 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a PASI 50 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a PASI 90 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a PASI 100 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00156] In some embodiments, PASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration (e.g., each administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, PASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 - 76 - NAI-1537985011v1 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after the last dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. 4.4.8.7 Improvement of a Eczema Area and Severity Index (EASI) score [00157] In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed based on Eczema Area and Severity Index (EASI) score. In some embodiments, EASI is assessed based on the area of involvement, intensity of lesions, region score, and final EASI score. In some embodiments, area of involvement includes four body regions, such as head and neck, upper extremities, trunk, and lower extremities. In some embodiments, an area score can be: 0 (no involvement), 1 (1%–9%), 2 (10%–29%), 3 (30%–49%), 4 (50%–69%), 5 (70%–89%), and 6 (90%–100%). In some embodiments, the intensity of lesions is assessed separately for 4 signs including erythema, edema/papulation, excoriation, and lichenification. In some embodiments, each sign is assigned an intensity score from 0 to 3, with 0 being absent; 1, mild; 2, moderate; and 3, severe. In some embodiments, each region is assigned based on the relative contribution of that region to the total BSA. In some embodiments, a region score is calculated separately for each region by multiplying the sum of the regional intensity score by the regional area score and the region-specific multiplier. In some embodiments, the final EASI score is the summation of the 4 regional scores, ranging from 0 to 72. A score of 0 indicates clear or no eczema, 0.1 to 1.0 indicates almost clear, 1.1 to 7 indicates mild disease, 7.1 to 21 indicates moderate disease, 21.1 to 50 indicates severe disease, and greater than 51 indicates very severe disease. - 77 - NAI-1537985011v1 [00158] In some embodiments, EASI can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, EASI is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, EASI is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week. [00159] In some embodiments, the subject achieves an improvement in EASI score of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline EASI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to EASI score of other subjects with atopic dermatitis; and/or compared to EASI score of the same subject taken at an earlier time point). In some embodiments, the subject achieves an improvement in EASI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, - 24, -25, -26, -27, -28, -29, or -30, for example, at about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline EASI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to EASI score of other subjects with atopic dermatitis; and/or compared to EASI score of the same subject taken at an earlier time point). - 78 - NAI-1537985011v1 [00160] In some embodiments, the subject achieves EASI 50, 75, 90, or 100 by about, or at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline EASI score of the subject, e.g., EASI score obtained prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to EASI score of other subjects with atopic dermatitis; and/or compared to EASI score of the same subject taken at an earlier time point). In some embodiments, the subject achieves a EASI 50, 75, or 90 by 70 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a EASI 50, 75, 90, or 100, by 60 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a EASI 50, 75, 90, or 100, by 90 days or less (e.g., at 88 days or less) after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a EASI 50, 75, 90, or 100, by 100 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a EASI 50, 75, 90, or 100, by 200 days or less after - 79 - NAI-1537985011v1 administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a EASI 50, 75, 90, or 100 before the end of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a EASI 75 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a EASI 50 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a EASI 90 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a EASI 100 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00161] In some embodiments, EASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration (e.g., each administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, EASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 - 80 - NAI-1537985011v1 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after the last dose of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. 4.4.8.8 Improvement in a Dermatology Life Quality Index (DLQI) score [00162] In some embodiments, treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure results in improvement of at least one health-related quality of life (HRQOL) outcome (e.g., Dermatology Life Quality Index (DLQI)). In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed based on DLQI. DLQI is self-administered with a mean completion time of 2 min. In some embodiments, DLQI consists of 10 questions concerning impact of skin diseases on different aspects of subject’s quality of life (QOL) over, for example, the last week (e.g., 1 week after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). In some embodiments, the DLQI items include symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the side effects of treatment (Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple practical measure for routine clinical use. Clin Exp Dermatol.1994;19:210–216). Each item is scored on a 4-point scale: not at all/not relevant, a little, a lot and very much. Item scores (0-3) are added to give a total score (0-30); higher scores indicate greater impairment of QOL. In some embodiments, the minimal clinically important difference of the DLQI varies from 3 to 5 (Basra MK, Salek MS, Camilleri L, et al. Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data. Dermatology.2015;230(1):27–33). [00163] In some embodiments, the subject achieves a Dermatology Life Quality Index (DLQI) score of about 0 or 1 after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject achieves a Dermatology Life Quality Index (DLQI) score of about or at most about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the - 81 - NAI-1537985011v1 disclosure. In some embodiments, the subject achieves an improvement in DLQI score of about or at least about -1 (i.e., a decrease of 1) after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline DLQI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to DLQI score of other subjects with plaque psoriasis or atopic dermatitis; and/or compared to DLQI score of the same subject taken at an earlier time point). In some embodiments, the subject achieves an improvement in DLQI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, - 24, -25, -26, -27, -28, -29, or -30 after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline DLQI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to DLQI score of other subjects with plaque psoriasis or atopic dermatitis; and/or compared to DLQI score of the same subject taken at an earlier time point). In some embodiments, the subject achieves an improvement in DLQI score of about or at least about -5 after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference. In some embodiments, the subject achieves an improvement in DLQI score of about or at least about -7 after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference. In some embodiments, the subject achieves an improvement in DLQI score of about or at least about -8 after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference. In some embodiments, the subject achieves an improvement in DLQI score of about or at least about -9 after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference. In some embodiments, the subject achieves a clinically meaningful reduction in Dermatology Life Quality Index (DLQI) score. In some embodiments, a clinically meaningful reduction in DLQI score is a decrease of 5 points or greater than 5 points in DLQI score compared to a reference. In some embodiments, a clinically meaningful reduction in DLQI score is a decrease of 3 points or greater than 3 points in DLQI score compared to a reference. In some embodiments, a clinically meaningful reduction in DLQI score is a decrease of 4 points or greater than 4 points in DLQI score compared to a reference. [00164] In some embodiments, the subject achieves an improvement in DLQI score at about or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 - 82 - NAI-1537985011v1 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline DLQI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to DLQI score of other subjects with plaque psoriasis or atopic dermatitis; and/or compared to DLQI score of the same subject taken at an earlier time point). In some embodiments, the subject achieves an improvement in DLQI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, - 23, -24, -25, -26, -27, -28, -29, or -30 at about or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline DLQI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to DLQI score of other subjects with plaque psoriasis or atopic dermatitis; and/or compared to DLQI score of the same subject taken at an earlier time point). [00165] In some embodiments, a reference is the baseline DLQI score obtained from the same subject prior to start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, a reference is the DLQI score obtained from the same subject at an earlier time point. In some embodiments, a reference is the DLQI score of at least one subject with plaque psoriasis or atopic dermatitis (e.g., an average DLQI score based on the DLQI scores from other subjects with plaque psoriasis or atopic dermatitis). In some embodiments, the at least one subject and/or the other subjects have the same plaque psoriasis or atopic dermatitis as the subject. In some embodiments, the at least one subject and/or the other subjects have the same plaque psoriasis or atopic dermatitis with the same level of severity (e.g., mild, moderate, or severe plaque psoriasis or atopic dermatitis) as the subject. In some - 83 - NAI-1537985011v1 embodiments, the at least one subject and/or the other subjects have been diagnosed with a different level of severity of plaque psoriasis or atopic dermatitis as the subject. 4.4.8.9 Decrease in body surface area (BSA) of psoriasis or atopic dermatitis [00166] In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed based on the Body Surface Area (BSA) of plaque psoriasis or atopic dermatitis. In some embodiments, the body surface area of plaque psoriasis is estimated by using the size of the handprint as 1% of the body surface area. In some embodiments, the number of handprints across the patient’s body that have activity with plaque psoriasis or atopic dermatitis is counted to determine BSA (Ramsay B, Lawrence CM. Measurement of involved surface area in patients with plaque psoriasis or atopic dermatitis. Br J Dermatol.1991;124(6):565–70). In some embodiments, the subject has a body surface area (BSA) of plaque psoriasis of ≥3%. In some embodiments, the subject has a body surface area (BSA) of plaque psoriasis of ≥2%. In some embodiments, the BSA is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the BSA of the subject is decreased by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, or more than 300% after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline BSA score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to BSA score of other subjects with - 84 - NAI-1537985011v1 plaque psoriasis or atopic dermatitis; and/or compared to BSA score of the same subject taken at an earlier time point). In some embodiments, the BSA of the subject is decreased after about or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure as compared to a reference (e.g., compared to baseline BSA score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure; compared to BSA score of other subjects with plaque psoriasis or atopic dermatitis; and/or compared to BSA score of the same subject taken at an earlier time point). In some embodiments, the subject had about, less than about, or at most about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% body surface area (BSA) affected by plaque psoriasis or atopic dermatitis prior to administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the subject has about, less than about, or at most about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% body surface area (BSA) affected by plaque psoriasis or atopic dermatitis after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. 4.4.8.10 Improvement in additional plaque psoriasis or atopic dermatitis related assays or assessments [00167] In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed based on a Physician’s Global Assessment (PGA) test or an Investigator’s Global Assessment test (IGA) or a Static Investigator Global Assessment (sIGA) (Langley RG, Feldman SR, Nyirady J, et al. The 5-point Investigator's Global Assessment (IGA) Scale: A modified tool for evaluating plaque psoriasis severity in clinical trials. J Dermatolog Treat.2015;26(1):23–31; Robinson A, Kardos M, Kimball AB. Physician Global Assessment (PGA) and Psoriasis Area and Severity Index (PASI): why do both? a systematic analysis of randomized controlled trials of biologic agents for moderate to severe plaque psoriasis. J Am Acad Dermatol.2012;66(3):369-375). In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed using - 85 - NAI-1537985011v1 Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) for atopic dermatitis. In some embodiments, the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) is a static 5-point scale that was developed to assess the overall atopic dermatitis severity. In some embodiments, a score of 0 (clear) to 4 (severe) is provided based on a morphological description (refer to Table 17). In some embodiments, the IGA or sIGA is a 5- point system that measures severity of plaque psoriasis or atopic dermatitis. In some embodiments, the PGA is a 5 or 6 point scoring system used to assess severity of plaque psoriasis or atopic dermatitis in a subject. In some embodiments, the PGA or IGA or sIGA or vIGA-AD is about or at most about 2 (mild) after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the PGA or IGA or sIGA or vIGA-AD is about or at most about 0 or 1 (clear, almost clear, or mild) after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the PGA or IGA or sIGA or vIGA-AD is about or at most about 0 or 1 or 2 after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the PGA or IGA or sIGA or vIGA-AD is about or at most about 0 or 1 by about or by at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, or more than 5 years after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, the PGA or IGA or sIGA or vIGA-AD is about or at most about 0, 1, 2, 3, after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure (e.g., by about or by at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 - 86 - NAI-1537985011v1 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, or more than 5 years after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure). [00168] In some embodiments, efficacy of treatment after an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed based on photography of whole body and/or selected plaques or active regions of atopic dermatitis (e.g., utilizing a Canfield photography system (Canfield Scientific, Parsippany, NJ)). In some embodiments, photographs (e.g., of the whole body, selected plaques, or active regions of atopic dermatitis, or site of injection) are taken at baseline or before treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, photographs taken at baseline or before treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is compared with photographs taken after the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, photographs are taken at different time points after the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, photographs taken at a later time point after the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is compared with photographs taken at an earlier time point. In some embodiments, photographs are taken prior to the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, photographs are taken at about or by at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 - 87 - NAI-1537985011v1 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, 5 years, or more than 5 years after treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, photographs of injection site reactions are taken. In some embodiments, photographs (e.g., of whole body, selected plaques, or active regions of atopic dermatitis, or site of injection) are taken on day 1, 29, and/or 57. In some embodiments, photographs (e.g., of whole body, selected plaques, or active regions of atopic dermatitis, or site of injection) are taken prior to day 1 or prior to start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. In some embodiments, photographs (e.g., of whole body, selected plaques, or active regions of atopic dermatitis, or site of injection) are taken about 7 days prior to start of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure. [00169] In some embodiments, pruritus is assessed using Peak Pruritus Numerical Rating Scale (e.g., for atopic dermatitis). In some embodiments, PP-NRS is an 11-point scale used by patients to rate their worst itch severity over the past 24 hours with 0 indicating “No itch” and 10 indicating “Worst itch imaginable”. In some embodiments, daily (24-hour) PP-NRS is recorded and the weekly mean of the daily PP-NRS is calculated. In some embodiments, PP-NRS scores are calculated between Day -7 and Day -1 and calculated a weekly average baseline score prior to Day 1. 4.4.8.11 Outcome in cell populations using a single dose administration [00170] In some embodiments, efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is assessed by measuring specific cell populations (e.g., number of CD25bright Treg cells, CD25bright Treg/Tcon ratio, total Treg cells, conventional T cells (Tcon), - 88 - NAI-1537985011v1 and/or NK cells) in a subject before and/or after the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject (e.g., number of CD25bright Treg cells, CD25bright Treg/Tcon ratio, total Treg cells, conventional T cells (Tcon), and/or NK cells). In some embodiments, a method of the disclosure comprises a single administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure to a subject. In some embodiments, cell population changes (e.g., increases, decreases, or does not significantly increase or decrease) after administration of an IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure to a subject (e.g., as compared to baseline). In some embodiments, assessments are obtained on days -1, 0, 8, 10, 21, and/or 43, and/or at any suitable time point. In some embodiments, assessments are obtained on Day -1 (one day prior to administration of XmAb®27564 to the subject). In some embodiments, assessments are obtained on Day 0 (same day as administration of XmAb®27564 to the subject). In some embodiments, assessments are obtained on Day 8 (8 days after administration of XmAb®27564 to the subject). In some embodiments, assessments are obtained on Day 10 (10 days after administration of XmAb®27564 to the subject). In some embodiments, assessments are obtained on Day 21 (21 days after administration of XmAb®27564 to the subject). In some embodiments, assessments are obtained on Day 43 (43 days after administration of XmAb®27564 to the subject). In some embodiments, the CD25bright Treg/Tcon ratio is about or at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, or more than 0.2. In some embodiments, the CD25bright Treg/Tcon ratio is about 0.14 after administration of XmAb®27564. [00171] In some embodiments, administration of the IL-2 Fc fusion protein to a subject results in an increase in the number of CD25bright Treg cells in the subject (e.g., biological sample) as compared to baseline or as compared to the number of CD25bright Treg cells in the subject (e.g., biological sample) obtained from a previous time point. In some embodiments, administration of the IL-2 Fc fusion protein to a subject results in an increase in the number of CD25bright Treg/Tcon ratio in the subject (e.g., biological sample) as compared to baseline or as compared to the number of CD25bright Treg/Tcon ratio in the subject (e.g., biological sample) obtained from a previous time point. In some embodiments, administration of the IL-2 Fc fusion protein to a subject results in an increase in the number of total Treg cells in the subject (e.g., biological sample) as compared to baseline or as compared to the number of total Treg cells in the subject (e.g., biological sample) obtained from a previous time point. In some embodiments, Treg cells - 89 - NAI-1537985011v1 comprises CD25brightFoxP3+ CD4 Treg cells. In some embodiments, Treg cells consists of CD25brightFoxP3+ CD4 Treg cells. In some embodiments, the increase is an increase of about or at least about 2-fold, about or at least about 3-fold, about or at least about 4-fold, about or at least about 5-fold, about or at least about 6-fold, about or at least about 7-fold, about or at least about 8-fold, about or at least about 9-fold, about or at least about 10-fold, about or at least about 11- fold, about or at least about 12-fold, about or at least about 13-fold, about or at least about 14- fold, about or at least about 15-fold, about or at least about 16-fold, about or at least about 17- fold, about or at least about 18-fold, about or at least about 19-fold, about or at least about 20- fold, about or at least about 25-fold, about or at least about 30-fold, about or at least about 40- fold, about or at least about 50-fold, about or at least about 60-fold, about or at least about 70- fold, about or at least about 80-fold, about or at least about 90-fold, about or at least about 100- fold, or more than about 100-fold (e.g., as compared to baseline or as compared to a previous time point). In some embodiments, the increase is an increase of about or at least about 2%, about or at least about 3%, about or at least about 4%, about or at least about 5%, about or at least about 6%, about or at least about 7%, about or at least about 8%, about or at least about 9%, about or at least about 10%, about or at least about 11%, about or at least about 12%, about or at least about 13%, about or at least about 14%, about or at least about 15%, about or at least about 16%, about or at least about 17%, about or at least about 18%, about or at least about 19%, about or at least about 20%, about or at least about 25%, about or at least about 30%, about or at least about 35%, about or at least about 40%, about or at least about 45%, about or at least about 50%, about or at least about 55%, about or at least about 60%, about or at least about 65%, about or at least about 70%, about or at least about 75%, about or at least about 80%, about or at least about 85%, about or at least about 90%, about or at least about 95%, about or at least about 100%, or more than about 100% (e.g., as compared to baseline or as compared to a previous time point). In some embodiments, a biological sample is blood, serum, plasma, and/or any other suitable biological sample. [00172] In some embodiments, administration of the IL-2 Fc fusion protein to a subject does not result in a significant increase in conventional T cells (Tcon) and/or NK cells in the subject as compared to baseline or as compared to the number of Tcon and/or NK cells obtained from the subject at a previous time point (e.g., in a biological sample obtained at a previous time point). In some embodiments, Tcon comprises of CD4+ Tcon cells. In some embodiments, Tcon - 90 - NAI-1537985011v1 comprises of CD8+ Tcon cells. In some embodiments, Tcon comprises of CD4+ and CD8+ Tcon cells. In some embodiments, Tcon consists of CD4+ Tcon cells. In some embodiments, Tcon consists of CD8+ Tcon cells. In some embodiments, Tcon consists of CD4+ and CD8+ Tcon cells. In some embodiments, a significant increase is not more than two standard deviations from baseline or those obtained from a previous time point. In some embodiments, a significant increase is not more than two standard deviations from baseline or those obtained from a previous time point. In some embodiments, a biological sample is blood, serum, plasma, and/or any other suitable biological sample. 5. EXAMPLES [00173] Examples are provided below to illustrate the present invention. These examples are not meant to constrain the present invention to any particular application or theory of operation. 5.1 EXAMPLE 1 – Treatment of plaque psoriasis or atopic dermatitis using an IL-2 Fc fusion protein [00174] A phase 1b, randomized, double-blind, placebo-controlled, multiple-ascending dose (MAD) study to investigate the safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of XmAb®27564 in patients with plaque psoriasis or atopic dermatitis (e.g., moderate to severe atopic dermatitis). [00175] XmAb®27564 is a potency-reduced monomeric human IL-2 Xtend heterodimeric Fc- fusion protein. [00176] To optimize the biological half-life of IL-2 and improve upon its natural selective activation of Tregs, Xencor engineered XmAb®27564 IL-2 that decreases interactions with effector T cells (Teffs) and natural killer cells (NK cells), the largest cellular sink for IL-2, while preserving interactions with the autoimmune therapeutic target CD25, which is constitutively and highly expressed on Tregs. [00177] Specifically, recombinant IL-2 (rIL-2) was engineered to decrease interactions with cells containing predominantly complexes of IL2Rβ/γc (CD122/CD132; Teffs and NK cells) while simultaneously increasing affinity to the CD25 receptor thus preserving or increasing interactions for cells, such as Tregs, that express all 3 receptors IL2Rα/IL2R β/γc (CD25/CD122/CD132). Reduction of potency to CD122/CD132 resulted in increased serum persistence relative to the native IL-2 Fc fusion. The dramatic increase in serum persistence - 91 - NAI-1537985011v1 offsets the significant reduction in potency, with a net increase in Tregs’ PD. Binding to conventional Fc gamma receptors (FcγR) was eliminated to avoid Fc domain-mediated effector functions. Additional half-life extension of XmAb®27564 was achieved with the Xtend Fc domain which has enhanced binding to the human neonatal receptor FcRn at low pH, promoting recycling (FIG.1). [00178] In single-arm and small randomized controlled studies, use of a subcutaneous (SC) daily “ultra-low-dose IL-2” approach has been reported to ameliorate disease activity in several autoimmune/inflammatory conditions (Table 2), including acute and chronic graft versus-host (GVH) disease, hepatitis C virus (HCV)-associated vasculitis, systemic lupus erythematosus (SLE), psoriasis, and inflammatory bowel disease. A range of IL-2 has been evaluated from 0.1 mIU to 3 mIU, with most studies using 1.0 mIU daily for the first week (Table 2). In all of these reports, a dose-dependent Treg expansion of up to 3-to 8- fold was documented. - 92 - NAI-1537985011v1 .l ; a 4 1 I C; ; . d s n oit i d n o C y r o t a m malf n I / e n u m mi o t u A n i 2-L I e s o D-w o L s u o e n a t u
Figure imgf000094_0001
c b u s s e e s e e e S E n n e c s n n , A S o o n b o o y N N O a N N l i a D h d t e ) 4 s 4 - - I i v w o e r i I R S s y p d u t ) R S %e c i a H mt i s n 3 e m 0 6 %0 0 d ci f f V st c r e e v = 0 3 1) u t E G d ) e j v o o r p N ) ( s v 8 3 Sl e c 2 a u 1 b u s 5 9 m i 0 1 T C% = 5 c i d e = % = = R 5 N ( n 0 %0 ) ) i R N ( 5 N ( 8 N ( 1 2 l 1 v C 1 1 . 0 2 e s e t c e H i si n H ti l 5 8 9 l a e b si u c V o r V V Cu c E L 7 3 5 a D A G h C G Hs a S 1- I T V A N e c n e r e f e R ) 6 U I 01 x ( 2-L I es o D n ff o i e s n T a p x E
Figure imgf000095_0001
v s n S . 0 e C rK Nt n h g i o i ) n s a it r t = f l 4 - o d e l o -r s n 2 d d i i d t a a n I R s o f-0 4 b 6 5 a l l p o f o e c p e gi s S ; d n 0 5 9 -Dx - d 3 l o f- 3 u d n d l o h d s u a 3 C E ) f e 1 - 2 ) 3 e i R k f s - 2 = e V t C a l s o m u h t y t r a h - r n n Ho m e n i o - ft g o i e e s r n d l s a o d i ; d t s h p s h t t y s ri n u T a p f- % e r l o f e s o h o h r E f o c x 3 5 2 c n i - 3 a e d l - s p s 4 6 c a E r ) 1 ) 2 ) c n 3 n i I k o f s - u s 2 r = u e p 5 7 t o v 5 - u 2 n t T f A L ® c i b s e s a r T Ao E A e S n e o n e n e g S p me t m d Xe c No N o n N o = ; N Hc i s Vt y e S d e n e l s n t G i = n n a a v i ni ; k o E o L l p u q p D e d 5 n i s e y s a d c a S ; e h e t r d n P / it p f o t n a e s = m r t n , a s l o y c ) e K a 8 ci 4 l = a P ) e p 4 e ci e 4 s 2 - mi d d o = C n i e e ; a t h e v d h t v o n n p e i s u a l = e . sr l l a m e br e a l p f f E Nn ( i l d - N e w r p m p s K P e v c l o m i Tc Co e l ( v o r o r m I m n a ; d a T y m s s R Ng n i T p g e st S C Rm 6 i o i r r c e t r t c i s r j 4 u wm a u o t a i a n h t , ) ) ) i a b u = a 1 o r n y oi r e l u o , r e 1 2 3 H s N 1 r a d m o c s g e r n o v . a = si e ) s 1 r w o y a v 1 e s a i e n E =s a p h s s 1 0 a c a t s r o e s D i 1 e p a e b m r r e a A S g e m; h n a 5 8 = h ; 9 s r T o c i k 5 T 7 3 D T o l A A t p O T = e i ; s r M d o u e l A 5 1- BD P u l t l F o T I s e c a r P S p A N [00179] A major limitation of this approach has been the poor pharmacologic properties of IL- 2, with rapid clearance due to target-mediated disposition, namely binding and internalization by its own receptors, widely expressed on lymphoid cells. A single dose of ultra-low-dose IL-2 (< 1.0 mIU) only induces a 10% to 20% increase in peripheral Treg numbers (Todd et al. PLOS Med.2016;13:e1002139), whereas daily dosing for 5 days can induce 2- to 8-fold expansion of Tregs (Table 2; Rosenzwajg et al. Ann Rheum Dis.2019;78:209–17). Even with daily SC dosing, exposures are still problematic, and doses required to sustain Treg activation at trough may require Cmax concentrations that unfortunately also activate Teffs and NK cells (Todd et al., PLOS Med.2016;13:e1002139). This fact suggests that persistent CD122 engagement by wild type IL-2 may not optimize Treg expansion without also activating NK/Teffs. Indeed, a 2-fold increase in CD56bright NK cells are seen across studies with ultra-low-dose SC IL-2 (Table 2; Rosenzwajg et al. Ann Rheum Dis.2019;78:209–17). Furthermore, in a Type I diabetes study (Todd et al., PLOS Med.2016;13:e1002139), it was noted that hyperacute pSTAT5 activation could be seen at 90 minutes after SC dosing in both Teffs and NK cells at doses higher than 0.2 mIU. Although the clinical significance of transient activation of Teffs/NK cells is not clear, undesirable activation of Teffs/NKs may compromise clinical activity of low-dose IL-2 in autoimmunity. [00180] Thus, low-dose IL-2 is clinically active with promising Treg expansion seen across a wide range of disease indications and on background anti-inflammatory medicines including disease-modifying antirheumatic drugs and steroids. However, concomitant activation of NK cells has been seen in most studies. 5.1.1. Treatment Regimens [00181] This multiple-ascending dose (MAD) study enrolls patients with psoriasis and patients with atopic dermatitis (e.g., moderate to severe atopic dermatitis) in separate and parallel cohorts. The psoriasis cohorts consist of approximately 48 eligible adult (e.g., 18-65 years of age male and female) patients randomized to XmAb®27564 or placebo in 6 consecutive dose cohorts, 0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg (Cohorts 1 through 6). Each cohort consists of 8 patients with 6 patients receiving XmAb®27564 and 2 receiving placebo. Sentinel dosing can be employed for the first 3 patients in each cohort, with a block of 3 sentinel subjects, randomized 2:1 to XmAb®27564:placebo treated sequentially. Each sentinel subject in the same cohort is treated at least 24 hours after treatment of the previous sentinel subject. The subsequent - 95 - NAI-1537985011v1 5 subjects to round out the 8-subject cohort are randomized 4:1 to XmAb®27564:placebo (4 XmAb®27564 and 1 placebo). The subsequent 5 subjects may begin treatment after the third sentinel subject clears the first 24 hours. The atopic dermatitis cohorts consist of approximately 80 eligible patients randomized to XmAb®27564 or placebo in 5 consecutive dose cohorts, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg (Cohorts A through E). Each cohort consists of 16 patients, with 12 patients receiving XmAb®27564 and 4 receiving placebo. [00182] Each cohort in the psoriasis group consists of 8 patients, while each cohort in the atopic dermatitis group consists of 16 patients. The increase in cohort size from 8 in the psoriasis cohorts to 16 in the atopic dermatitis cohorts is driven by the variability in the placebo response in skin assessments in atopic dermatitis. Each patient (either in the psoriasis or atopic dermatitis group) receives subcutaneous (SC) administration of study drug (XmAb®27564 or placebo) every 2 weeks for 4 doses (on Study Days 1, 15, 29, and 43). XmAb®27564 or placebo is administered in a double-blind fashion. [00183] In patients with psoriasis, dose escalation to the next cohort only occurs after review by the Dose Escalation Review Committee (DERC) of safety data through at least Day 29 for all patients in a cohort. During dose-decision making on the present study, especially during escalation to higher dosing cohorts, DERC has access to the data and decisions from the ongoing single ascending dose (SAD) study XmAb®27564-01. In addition, a DERC decision for escalation in a psoriasis cohort may trigger the start of dosing for an atopic dermatitis cohort at the same or lower dose studied previously for patients with psoriasis. For each cohort of patients with atopic dermatitis that had their dose cleared by the DERC for safety in psoriasis, including troponin I and cardiac MRI assessments, further troponin I and cardiac MRI surveillance is not needed for patients with atopic dermatitis in that cohort. In atopic dermatitis cohorts, the DERC reviews Cohorts A through D and make a decision about dose escalation independently in atopic dermatitis based on safety considerations in atopic dermatitis. [00184] All patients with atopic dermatitis and any patient with psoriasis who had Day 1 predose baseline PASI scores ≥ 12 and BSA involvement of ≥ 10%, who are candidates for a systemic agent, can participate in the OLE (FIG.3C) except those who had a Grade 3 AE or SAE related to study drug, through Day 57 of the core study (FIGS.3A-3B). This is an open- label extension of 336 days duration with a 45-day safety follow-up. All patients who rollover into the extension phase of the study will initially receive open-label XmAb®27564 every 2 - 96 - NAI-1537985011v1 weeks at the dose level of the cohort that they were assigned to during the core study. Thus, placebo patients would also receive open-label XmAb®27564 at that cohort’s dose level. After each subsequent DERC meeting, all patients would be offered the higher dose that was cleared previously by the DERC for their disease population, at Investigator's discretion and upon consultation with the Medical Monitor. 5.1.1.1 Primary Endpoints [00185] The primary endpoint of the study is safety and tolerability of MAD SC administration of XmAb®27564, as measured by incidence of adverse events (AEs), including treatment-emergent AEs (TEAEs), treatment-emergent serious AEs (TE-SAEs), treatment- related TEAEs, treatment-related TE-SAEs, and TEAEs by severity that are defined by the National Cancer Institute’s Common Terminology Criteria for AEs (NCI-CTCAE), Version 5.0 (CTCAE v.5). Safety assessments includes evaluating physical examinations, vital signs, electrocardiogram (e.g., twelve-lead ECG), dose-limiting toxicity (DLT), and clinical laboratory tests including clinical chemistry, hematology (including eosinophils), coagulation, troponin I CRP, ferritin, urinalysis, viral testing, and cardiac MRI. 5.1.1.2 Secondary Endpoints. [00186] The secondary endpoints of the study include characterizing PK and immunogenicity profiles of multiple-ascending doses (MAD) of XmAb®27564, including assessment of serum concentrations of XmAb®27564 and anti-XmAb®27564 antibodies (i.e., anti-drug antibodies (ADA) and immunogenicity). 5.1.1.3 Exploratory Endpoints. Patients with psoriasis • Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 50 at each study visit during the core study (e.g., up to Day 57) and open-label extension (OLE) study (up to Day 393) • Proportion of patients achieving PASI 75 at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) • Proportion of patients achieving PASI 50 at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) - 97 - NAI-1537985011v1 • Proportion of patients achieving PASI 90 at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) • Change and percent change from baseline in PASI at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) • Proportion of patients achieving sIGA 0/1 at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) • Change from baseline in sIGA at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) • Change from baseline to Day in sIGA at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) • Change and percent change from baseline in BSA involvement of psoriasis at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) Change from baseline to Day 57 in DLQI score • Change from baseline to Day 57 in BSA of psoriasis Patients with atopic dermatitis • Proportion of patients achieving EASI 50 at each study visit during the core study e.g., (up to Day 57) and OLE study (up to Day 393) • Proportion of patients achieving EASI 75 at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) • Proportion of patients achieving EASI 90 at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) • Change and percent change from baseline in EASI at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) • Proportion of patients achieving vIGA-AD 0/1 and reduction of vIGA-AD from baseline ≥ 2 at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) • Change from baseline in vIGA-AD at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) • Change and percent change from baseline in DLQI score at each study visit during the core study (e.g., up to Day 57) and OLE study (up to Day 393) - 98 - NAI-1537985011v1 • Change and percent change from baseline in BSA involvement of atopic dermatitis at each study visit during the core study (e.g., up to Day 577) and OLE study (up to Day 393) • Change and percent change from baseline in weekly mean of the daily PP-NRS score during the core study (e.g., up to Day 57) • Change and percent change from baseline at each study visit in the PP-NRS score during OLE study (up to Day 393) • Proportion of patients achieving ≥ 4 points of improvement from baseline in the weekly mean of the daily PP-NRS score during the core study (e.g., up to Day 57) • Proportion of patients achieving ≥ 4 points of improvement from baseline in the PP-NRS score at each study visit during OLE study (up to Day 393) All patients • Flow cytometry to enumerate Tregs, CD4+ Teffs, CD8+ Teffs, and NK cells • Soluble factors including but not limited to proinflammatory cytokines and soluble CD25 • mRNA transcriptome in blood • Immunofluorescent and immunohistochemical assays to enumerate, define the architectural distribution and activation state of Tregs, CD4+ Teffs, CD8+ Teffs in psoriatic lesions. • mRNA transcriptome in lesional and non-lesional biopsies. Table 3. Exploratory Endpoints Objective Endpoints o
Figure imgf000100_0001
- 99 - NAI-1537985011v1 Teffs, and NK cells and other leukocyte • Proportion of patients achieving PASI 90 subsets over time at each study visit during the core study o e e 1 o e e o o
Figure imgf000101_0001
- 100 - NAI-1537985011v1 (e.g., up to Day 57) and OLE study (up to Day 393) e e D ch e e o e re e s s
Figure imgf000102_0001
- 101 - NAI-1537985011v1 NRS score at each study visit during OLE study (up to Day 393) e -
Figure imgf000103_0001
er RNA; NK = natural killer; PP-NRS= Peak Pruritis Numerical Rating Scael; PASI = Psoriasis Area and Severity Index; PCR =polymerase chain reaction; PD = pharmacodynamics; PK = pharmacokinetic; SC= subcutaneous; sIGA = static Investigator’s Global Assessment Score; Teff = effector T cells; Tregs = regulatory T cells; vIGA-AD= validated Investigator Global Assessment for Atopic Dermatitis. 5.1.2. Number of Subjects [00187] The study screens approximately 100 or 200 individuals to enroll approximately 48 eligible subjects with psoriasis with 8 patients per cohort, and approximately 80 patients with atopic dermatitis with 16 patients per cohort. The number of patients enrolled is considered to be typical for similar Phase 1 MAD studies and sufficient to meet the study objectives. Subjects with psoriasis are randomized to XmAb®27564 or placebo in 6 consecutive dose cohorts, (i.e., 0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg every 14 days for four doses during 8 weeks of treatment), with 8 subjects in each cohort (6 subjects receive XmAb®27564 and 2 subjects receive placebo). For patients with atopic dermatitis, 5 dose levels were selected for XmAb®27564: 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg, to be given Q14 days for four doses - 102 - NAI-1537985011v1 during 8 weeks of treatment. Each cohort has 16 patients; 12 patients are to receive XmAb®27564, and 4 patients are to receive placebo. [00188] Approximately 48 patients with psoriasis and 80 patients with atopic dermatitis receive XmAb®27564 or placebo at 20 to 25 clinical investigation sites in the US and outside of the US (OUS). Approximately 96 patients (36 psoriasis and 60 atopic dermatitis) receive XmAb®27564, and 32 patients in total receive placebo (12 psoriasis and 20 atopic dermatitis). For each psoriasis cohort, a total of 6 subjects receive XmAb®27564 and 2 subjects receive placebo. As planned, approximately 36 patients with psoriasis receive XmAb®27564, and 12 patients in total receive placebo. However, the DERC may decide to either remove a planned cohort or add an unplanned cohort at a lower or intermediate dose level than planned. 5.1.3. Treatment Assignment in the Open-Label Extension Phase [00189] Patients entering the OLE, receive active open label XmAb®27564 at the same dose level that was assigned to them in the core study, every 2 weeks. After each dose level has been reviewed by the DERC and is deemed safe, any patients who are receiving a lower dose of XmAb®27564 are offered the higher dose that was cleared by the DERC after discussion with the Investigator and upon consultation with the Medical Monitor. The increased dose is continued through the remainder of the extension phase, unless a new higher dose is cleared. 5.1.4. Treatment Assignment in the Core Study [00190] Randomization schedules for each dose cohort are generated prior to study start. XmAb®27564 or placebo are administered in a double-blind fashion. Patient treatment assignment in patients with psoriasis includes MAD administration of SC XmAb®27564 (0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo. Treatment assignment in patients with atopic dermatitis includes MAD administration of SC XmAb®27564 (0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo. [00191] Sentinel dosing is employed for the first 3 patients with psoriasis in each cohort, with a block of 3 sentinel subjects, randomized 2:1 to XmAb®27564:placebo treated one each day sequentially with at least 24 hours between them (or over the first 3 days). Each sentinel subject in the same cohort is treated at least 24 hours after treatment of the previous sentinel subject. The subsequent 5 subjects to round out the 8-subject cohort are randomized 4:1 to XmAb®27564:placebo (4 XmAb®27564 and 1 placebo). The subsequent 5 subjects begin treatment after the third sentinel subject clears the first 24 hours. For the atopic dermatitis - 103 - NAI-1537985011v1 cohorts, no sentinel dosing is employed. A total of 16 patients are randomized in a 3:1 ratio to receive either XmAb®27564 or placebo in each cohort (FIG.3B). 5.1.4.1 Processes and Procedures to Ensure Maintenance of Blinding [00192] The contract research organization (CRO) maintain the randomization code in a secure location with controls to prevent unauthorized access, including the computer program written to generate the randomization, randomization codes, program log, seed number used by the program, copy of the randomization plan along with approval documentation as appropriate, and the write-protected electronic storage medium. [00193] The CRO name an unblinded statistician to generate the randomization codes. The pharmacists are unblinded. Investigators and site staff, patients, CRO, and Xencor (excluding DAT) remain blinded to individual patients’ treatment assignment for the duration of the study until the study unblinding has been authorized. However, if a patient has suffered an SAE and when knowledge of the treatment assignment impacts the clinical management of the patient, the Investigator has the ability to unblind the treatment assignment for that patient. Investigators are encouraged to discuss with the Xencor Medical Monitor before unblinding, if possible. [00194] To preserve the blind, study drug is prepared and administered in a manner that masks the content for the patient and clinical team managing the study. 5.1.4.2 Unblinding due to Adverse Events/Safety or Other Reasons [00195] Should an AE or other emergency circumstance occur which would require that the blind be broken to ensure patient safety, the Investigator must immediately notify the Xencor Medical Monitor as soon as possible and following a discussion with the Xencor Medical Monitor, the treatment assignment of the patient is released to the appropriate personnel in accordance with the applicable study-specific procedure. [00196] If the treatment assignment is unblinded by the Investigator, then the Investigator must notify the Sponsor in writing and document the course of events in the source records. Any patient for whom the treatment code is prematurely released is withdrawn from the study but continue to be followed for safety events if IMP was received. 5.1.5. Selection and Withdrawal of Subjects 5.1.5.1 Subject Inclusion Criteria - 104 - NAI-1537985011v1 [00197] In order to be eligible to participate in this study, an individual must meet all of the following criteria: Patients with psoriasis • Provision of signed and dated ICF • Stated willingness to comply with all study procedures and availability for the duration of the study • Male or female, aged 18 to 65 or 75 years of age (inclusive at the time of screening) • Weight between 40 to 150 kg, inclusive • BSA involved by psoriasis ≥ 3% or ≥ 2% • Static Investigator's Global Assessment (sIGA) of 2 (mild) - 4 (severe) • Washout of oral treatments for psoriasis for 4 weeks before randomization • Washout of biologic treatments for psoriasis for 12 weeks or 5 half-lives (whichever is longest) before randomization. • No phototherapy within 4 weeks before randomization • No topical treatments for psoriasis for 2 weeks before randomization • Screening high sensitivity troponin I at screening is within normal limits • Screening cardiac MRI has no evidence of myocarditis assessed by Lake Louise Criteria (Ferreira, 2018) and ejection fraction is ≥ 50% • All subjects should have the last recommended dose of an authorized and/or approved coronavirus disease 2019 (COVID-19) vaccine > 2 weeks prior to Day -1. • Female Patients of childbearing potential must agree to use a highly effective method of birth control during and for 45 days after administration of investigational medicinal product (IMP) with any female partners of childbearing potential. Women are considered of childbearing potential OR postmenopausal by history with no menses for 1 year and confirmed by FSH OR have a history of hysterectomy and/or bilateral oophorectomy OR have a history of bilateral tubal ligation. Highly effective methods of birth control include combined hormonal birth control (oral, intravaginal, or transdermal), or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or intrauterine), intrauterine devices (IUDs), intrauterine hormone-releasing system, - 105 - NAI-1537985011v1 bilateral tubal occlusion, vasectomized partner (provided partner is the sole sexual partner and there has been a medical assessment of surgical success), or sexual abstinence. • Fertile male patients must be willing to practice a highly effective method of birth control during and for 45 days after administration of IMP. • Male Patients must agree not to donate sperm from screening through 45 days after administration of IMP. • Patients cannot be participants in any other investigational study of any drug or medical device during the screening period, treatment period, and safety follow-up period of the current study or have used an investigational drug in any clinical trial within 5 half-lives prior to randomization. • Ability to communicate effectively with the study personnel. Patients with atopic dermatitis • Provision of signed and dated ICF • Stated willingness to comply with all study procedures and availability for the duration of the study • Chronic atopic dermatitis according to the American Academy of Dermatology definition for at least 6 months before the screening visit (Eichenfield, JAAD, 2013) • Male or female, aged 18 to 75 years of age (inclusive at the time of screening) • Weight between 40 to 150 kg, inclusive • Eczema Area and Severity Index (EASI) score ≥ 16 at the baseline visit • ≥ 10% BSA involved with atopic dermatitis at baseline visit • Validated Investigator's Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3 at the baseline visit • Baseline weekly average of the daily Peak Pruritus Numerical Rating Scale (PP-NRS) score ≥ 2. Note: The baseline weekly average is calculated from the 7 consecutive days prior to Day 1 (between Day -7 and Day -1). A minimum of 4 daily scores out of the 7 days is needed. • Washout of oral treatments for atopic dermatitis for 4 weeks before randomization • Washout of biologic treatments for atopic dermatitis for 12 weeks or 5 half-lives (whichever is longest) before randomization - 106 - NAI-1537985011v1 • Washout of topical treatments for atopic dermatitis 2 weeks before randomization • Application of a stable dose of a non-prescription, non-urea containing emollient to all skin (normal skin and AD lesions) once or twice daily for 14 days preceding the randomization visit and willing to maintain stable dosing of the emollient from 14 days before randomization until at least the Day 57 visit • Washout for: − UV-B, PUVA, excimer laser, excessive sun for at least 4 weeks before randomization − IVIg for 12 weeks before randomization − Hydroxyzine or diphenhydramine for 1 week before randomization − Systemic antibiotics for 2 weeks or topical antibiotics for 1 week before randomization • All subjects should have the last recommended dose of an authorized and/or approved COVID vaccine > 2 weeks prior to Day 1. • Female patients of childbearing potential must agree to use a highly effective method of birth control during and for 45 days after administration of IMP. Women are considered of childbearing potential or postmenopausal by history with no menses for 1 year and confirmed by FSH) or have a history of hysterectomy and/or bilateral oophorectomy or have a history of bilateral tubal ligation. Highly effective methods of birth control include combined hormonal birth control (oral, intravaginal, or transdermal), or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or intrauterine), IUDs, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner (provided partner is the sole sexual partner and there has been a medical assessment of surgical success), or sexual abstinence. • Fertile male patients must be willing to practice a highly effective method of birth control during and for 45 days after administration of IMP with any female partners of childbearing potential. • Male patients must agree not to donate sperm from screening through 45 days after administration of IMP. • Patients cannot be participants in any other investigational study of any drug or medical device during the screening period, treatment period, and safety follow-up period of the current study or have used an investigational drug in any clinical trial within 5 half-lives prior to randomization. - 107 - NAI-1537985011v1 • Ability to communicate effectively with the study personnel 5.1.5.2 Subject Exclusion Criteria [00198] An individual who meets any of the following criteria are excluded from participation in this study: Patients with psoriasis • Patients with history of any cardiovascular event, such as the following: heart failure, myocarditis, myocardial infarction, acute coronary syndrome, stroke, pulmonary embolism, and/or deep venous thrombosis • Patients with vital sign values outside these normal ranges: o Systolic Blood Pressure: 90–140 mmHg o Diastolic Blood Pressure: 50–90 mmHg o Heart Rate: 50–100 beats per minute o Respiratory Rate: 8–22 breaths per minute o Oral Temperature: 96 °F / 35.5 °C to 99.5 °F / 37.5 °C • Patients are excluded if they have another inflammatory or dermatologic condition, including forms of psoriasis other than plaque psoriasis, that would increase risk for the patient or would interfere with study evaluations, in the opinion of the investigator • Patients with a history of alcohol and/or substance abuse within 12 months prior to screening • Patients who are positive for mycobacterium tuberculosis (MTB) QuantiFERON, hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen, or HIV Type I or Type II tests at screening • Patients with a known exposure to COVID-19 or Influenza within the past 14 days • Patients with signs or symptoms consistent with active viral infection (fever, rash other than psoriasis, chills, body aches, sore throat, cough, nasal congestion, gastrointestinal symptoms) • Patients with screening eosinophil elevation or a history of urticaria, asthma, atopic dermatitis, food allergy, or eosinophilic esophagitis - 108 - NAI-1537985011v1 • Patients with a history of active asthma within 5 years of screening, except those that have well controlled asthma symptoms at screening visit as assessed by the Global Initiative for Asthma (GINA) assessment of asthma control. Patients have to be maintained on a medium dose inhaled corticosteroid plus a long-acting beta agonist as defined by GINA as a maximum • Patients who have evidence of any bacterial, viral, parasitic, or systemic fungal infections requiring treatment within the 21 days prior to randomization; or hospitalization due to infection within 3 months prior to randomization • Patients who do not agree to use medically acceptable methods of contraception (as defined in the protocol) • Patients who are pregnant or breast feeding, or planning to become pregnant within 45 days of administration of IMP • Patients who have had any prior investigational treatment with IL-2 therapies or have received any investigational agent within 5 half-lives of the study drug • Patients whose screening breathalyzer (for alcohol) and/or urine test is positive for drugs of abuse (including the following: amphetamines/ecstasy, barbiturates, benzodiazepines, cocaine, opiates, methadone metabolites, and phencyclidine). If results are positive or questionable, contact the Xencor Medical Monitor prior to enrollment • Patients with a known or suspected sensitivity to products from mammalian cell lines • Patients with a history of anaphylaxis • Patients who have received live vaccines ≤ 2 months prior to screening or any vaccine within the past 14 days • Patients who have donated or lost more than 450 mL of blood in the 8 weeks prior to screening • Patients who have clinically significant abnormal laboratory values, as assessed by the Investigator or the Xencor Medical Monitor Patients with atopic dermatitis • Patients with history of any cardiovascular event, such as the following: heart failure, myocarditis, myocardial infarction, acute coronary syndrome, stroke, pulmonary embolism, and/or deep venous thrombosis • Patients with vital sign values outside these normal ranges: - 109 - NAI-1537985011v1 − Systolic Blood Pressure: 90–140 mmHg − Diastolic Blood Pressure: 50–90 mmHg − Heart Rate: 50–100 beats per minute − Respiratory Rate: 8–22 breaths per minute − Oral Temperature: 96°F / 35.5°C to 99.5°F / 37.5°C • Patients are excluded if they have another inflammatory or dermatologic condition that would increase risk for the patient or would interfere with study evaluations, in the opinion of the investigator • Patients with a history of alcohol and/or substance abuse within 12 months prior to screening • Patients who are positive for MTB QuantiFERON, HBsAg, HCV antibody, SARS-CoV- 2 antigen, or HIV Type I or Type II tests at screening • Patients with a known exposure to COVID-19 or Influenza within the past 14 days • Patients with signs or symptoms consistent with active viral infection (fever, rash other than psoriasis, chills, body aches, sore throat, cough, nasal congestion, and gastrointestinal symptoms) • Patients with a history of active asthma within 5 years of screening, except those that have well controlled asthma symptoms at screening visit as assessed by the GINA assessment of asthma control. Patients have to be maintained on a medium dose inhaled corticosteroid plus a long-acting beta agonist as defined by GINA as a maximum • Patients who have evidence of any bacterial, viral, parasitic, or systemic fungal infections requiring treatment within the 21 days prior to randomization; or hospitalization due to infection within 3 months prior to randomization • Patients who do not agree to use medically acceptable methods of contraception (as defined in the protocol) • Patients who are pregnant or breast feeding, or planning to become pregnant within 45 days of administration of IMP • Patients who have had any prior investigational treatment with IL-2 therapies or have received any investigational agent within 5 half-lives of the study drug • Patients whose screening breathalyzer (for alcohol) and/or urine test is positive for drugs of abuse (including the following: amphetamines/ecstasy, barbiturates, benzodiazepines, - 110 - NAI-1537985011v1 cocaine, opiates, methadone metabolites, and phencyclidine). If results are positive or questionable, contact the Xencor Medical Monitor prior to enrollment. • Patients with a known or suspected sensitivity to products from mammalian cell lines • Patients with a history of anaphylaxis • Patients who have received live vaccines ≤ 2 months prior to screening or any vaccine within the past 14 days • Patients who have donated or lost more than 450 mL of blood in the 8 weeks prior to screening • Patients who have clinically significant abnormal laboratory values, as assessed by the Investigator or Xencor Medical Monitor 5.1.5.3 Additional Subject Exclusion Criteria [00199] Patients must be withdrawn if the β-HCG pregnancy test is consistent with pregnancy. Pregnancy should be reported. [00200] Patients are encouraged to complete all study evaluations; however, they may withdraw from the study at any time and for any reason. In the event of a patient’s withdrawal, the Investigator notifies the Xencor’s Medical Monitor and make every effort to complete the EOS assessments (Day 88). Every effort is made to determine why any patient withdraws from the study prematurely. All patients who withdraw from the study with an ongoing SAE and/or an event of medical importance and/or pregnancy must be followed, if at all possible, until the event is resolved or deemed stable by the Investigator. [00201] Patient participation may be terminated prior to completing the study and the reason recorded as follows: • Withdrawal from the study with or without withdrawing of consent • Administrative decision by the Investigator or Sponsor • Ineligibility • Significant protocol deviation • Patient noncompliance • Safety concern by the Investigator or Sponsor • Lost to follow-up • Other - 111 - NAI-1537985011v1 [00202] A comprehensive effort must be made to determine the reason(s) why a patient fails to return for the necessary visits or is discontinued from the study. If the patient is unreachable by email or telephone, a registered letter, at the minimum, should be sent to the patient requesting him/her to contact the study site. Patients withdrawn for a non-drug-related reason may be replaced if the Sponsor deems it necessary. The decision regarding the replacement of patients are documented. [00203] Patients withdrawn due to a DLT are not replaced. Patients withdrawn for any other reason may be replaced if the Sponsor deems it necessary. The decision regarding the replacement of patients are documented. [00204] Patients who are lymphopenic at EOS/ET (< 1000 lymphocytes/μL and 75% below their baseline) are scheduled for a follow-up visit in 28 days (± 3 days). Follow-up visit assessments include ADA, PK, cytokine (IL-2 levels only), immunoglobulin levels, and a CBC with differential. If the patient’s last prior ADA test result was confirmed positive and the patient is lymphopenic at the follow-up visit, then the patient is scheduled for another follow-up visit in 28 days (± 3 days). This cycle is repeated until lymphopenia resolves. Patients with persistent (multiple measures at < 1000 lymphocytes/μL and 75% below their baseline for more than 2 months after the last dose) or severe lymphopenia (< 500 lymphocytes/μL and > 75% below baseline) shall be referred to a primary care physician for treatment. [00205] If a patient withdraws prematurely, all assessments as listed for the EOS visit should be performed and recorded on the EOS visit electronic case report form (eCRF) page. In addition, the patient should be scheduled for follow-up safety visits (or after 5 half-lives, whichever is longer) after XmAb®27564 administration. Any patient who withdraws early who is lymphopenic on the last visit prior to withdrawal or at post-EOS visits is followed as with other EOS patients, every 28 days (± 3 days). Patients are evaluated with CBC with differential, immunoglobulin levels, IL-2 levels and ADA, if feasible, until ADA levels return to baseline and after DERC review. Patients with persistent (< 1000 lymphocytes/μL for more than 2 months) or severe lymphopenia (< 500 lymphocytes/μL) (FDA, 2007) shall be referred to a primary care physician for treatment. 5.1.6. Dosing Schedule [00206] Each subject receives subcutaneous administration of XmAb®27564 or placebo every 2 weeks for 4 doses, as shown in FIGS.3A-3B. XmAb®27564 or placebo is administered on - 112 - NAI-1537985011v1 Study Days 1, 15, 29, and 43. Up to 6 weeks screening and a follow up period of approximately 45 days may be used. Possible injection areas include upper arm, thigh, or abdomen. Injection administration is not at the same place twice. The area rotates from one dose to the next. [00207] Open-label Extension: Up to 336 days duration; follow-up period of approximately 45 days (FIG.3C). All patients who rollover into the extension phase of the study initially receive open-label XmAb®27564 every 2 weeks at the dose level of the cohort that they were assigned to during the core study. Thus, placebo patients would also receive open-label XmAb®27564 at that cohort’s dose level. [00208] Dose escalation to the next cohort only occurs after review by the DERC of safety data through at least Day 29 for all patients in a cohort. The DERC has access to the data and decisions from the ongoing SAD study XmAb®27564-01 during dose decisions on the present study, especially during escalation to higher dosing cohorts. 5.1.7. Number of Patients [00209] Approximately 48 patients are planned to receive XmAb27564 or placebo at 15 to 20 clinical investigation sites in Canada and the United States. The DERC may decide to either remove a planned cohort or add an unplanned cohort at a lower or intermediate dose level than planned. Six cohorts are planned for the MAD, with each cohort comprising a total of 6 patients receiving XmAb27564 and 2 patients receiving placebo (48 patients total). As planned, approximately 36 patients will receive XmAb27564, and 12 patients in total will receive placebo. Approximately 100 patients will be screened such that approximately 48 patients will complete the study. 5.1.8. Treatment Assignment [00210] Patient treatment assignment will include MAD administration of SC XmAb27564 (0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo. [00211] Detail of treatment assignment, including randomization and blinding, is presented below. 5.1.9. Cohort Management [00212] Advancement to subsequent cohorts will depend on acceptable interim safety, available immunogenicity, PK, and PD reviews from ongoing and completed cohorts. Advancement to a subsequent dose level will not occur until at least 8 patients from the prior - 113 - NAI-1537985011v1 dose level have each been administered investigational medicinal product (IMP) without safety concerns. A DERC will be established to assess all available and relevant interim data from each cohort to determine the safety and appropriateness of dose reduction to a prior or intermediate dose or dose escalation to a new cohort. Dose escalation will follow pre-specified criteria. If dose escalation is stopped due to dose-limiting toxicities (DLTs), the maximum tolerated dose will be defined by the dose in the previous cohort, unless an intermediate dose is subsequently tested by the same algorithm. [00213] More conservative dose escalation, i.e., evaluation of prior or intermediate dose levels, is permissible following DERC review, if needed, for patient safety or for a better understanding of the toxicity, exposure, PD, or other properties of the study drug. Based on DERC input, the Sponsor may decide to add a cohort to repeat a dose level, but the dose level for any cohort will not exceed the planned dose level for that cohort, as specified in this protocol, below. [00214] Patients withdrawn from treatment before completing planned dosing, for reasons other than a DLT, may be replaced within the cohort, at the discretion of the Sponsor. 5.1.10. Dose Escalation Review Committee and Data Analysis Team [00215] The blinded Dose Escalation Review Committee (DERC) cannot review patient-level PD data because it would result in unblinding. In order to utilize and analyze real-time (unblinded) PK, PD, and safety data to inform DERC decisions on dose selection for MAD cohorts, it will be necessary to provide a management structure that preserves the ability to effectively analyze incoming data while retaining the blinded nature of the study. This will be accomplished by having 2 parallel teams, with a partition between them: the Data Analysis Team (DAT) will be unblinded to the patient-level data, whereas the second team, which will retain the name of DERC, will remain blinded and receive anonymized data from the DAT, including patient-level, identifier-redacted and summary data. No individual can be a member of both teams, and information can only be exchanged with all patient identifiers redacted. [00216] The blinded DERC will also include Xencor’s blinded Medical Monitor, Xencor’s blinded Head of Hematology, Clinical Development (or their designees), the Coordinating Principal Investigator (or Designee), and the CROs Safety Monitor (or designee), who will be responsible for all single-patient and administrative study discussions and decisions. As such, the blinded DERC will receive deidentified data in real time, enabling a prompt and effective - 114 - NAI-1537985011v1 response to safety and study administrative issues. Voting DERC members will include 4 physicians: the Coordinating Principal Investigator, CROs Safety Monitor or their designees, and 2 from Xencor (blinded Medical Monitor and blinded Head of Hematology, Clinical Development or their designees). [00217] DERC meetings are timed to review all blinded PD, PK, immunogenicity, and safety data before escalation to the next cohort. Progression to the next higher dose will only occur if the DERC determines that the previous dose level was safe and well tolerated after reviewing all patients’ data collected through at least Day 29. When it is not appropriate to escalate the dose, then the same dose, a previous dose, or an intermediate dose may be recommended by the DERC. [00218] The DERC and DAT will have access to information relating to XmAb27564 clinical data in their deliberations regarding dose escalation in this study. [00219] The dose escalation process, DERC and DAT function and personnel, and data to be reviewed will be described in a DERC Charter document, to be provided separately. 5.1.11. Dose Adjustment Criteria 5.1.11.1 Treatment Group Stopping Rules and Dose Level Adjustments [00220] Upon review of pooled cohort data by the DERC, following the final dose of the last patient in the previously completed cohort, dose escalation to the next higher-dose cohort may proceed upon review, confirmation, and documentation of acceptable interim safety, PK, and PD findings from all available interim data. In case DLT criteria are met in a cohort, dose escalation is not allowed in either cohort (psoriasis or atopic dermatitis) unless the DLTs observed are related to the particular disease under study in a cohort. [00221] In addition to the pooled cohort criteria that prospectively define the events that will result in halting escalation to the next cohort, under certain additional circumstances, enrolment, and dosing of new patients may be halted until the DERC deems it safe to proceed, based on a comprehensive review of all relevant case and interim study data. [00222] Specifically, dose escalation will not proceed, if any of the following criteria (DLTs) are met: - 115 - NAI-1537985011v1 • In psoriasis cohorts, the occurrence of 1 or more instances of symptomatic drug- related myocarditis confirmed by Lake Louise protocol criteria on cardiac MRI or any drug-related myocarditis resulting in a reduction in ejection fraction by cardiac MRI. • The occurrence of 1 or more SAEs at any dose level that is deemed drug related following unblinding of the study subject (SAEs from placebo arm will be assessed as not related to study drug). • The occurrence of a severe (Grade 3) AE, related to the study drug, of similar origin in 2 or more subjects within the same treatment group including, but not limited to, the following: o The occurrence of National Cancer Institute’s Common Terminology Criteria for AEs (National Cancer Institute Cancer Therapy Evaluation Program (CTEP). Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0: 2017.Available from: https_ctep_cancer_gov/protocoldevelopment/electronic_applications/docs/CTCA E_v5_Quick_R eference_5x7_pdf.) ≥ Grade 3 hypersensitivity reaction in 2 or more subjects in a treatment group that is deemed drug related following unblinding of the study subjects o The occurrence of Grade 3 eosinophilia with eosinophil-induced AEs in 2 or more subjects at any given dose level o The occurrence of Grade 3 constitutional symptoms in 2 or more subjects at any given dose level • Any subject at any given dose level meeting the components of Hy’s law (Food and Drug Administration Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. July 2009. Available from https_www_fda_gov/media/73679/download. Accessed 21 Oct 2020) of liver function parameters (confirmed by repeat sampling): o Three-fold or greater elevations above the upper limit of normal (ULN) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with elevation of serum total bilirubin to 2 × ULN, without initial findings of cholestasis (elevated serum ALP), and without another reason to explain the - 116 - NAI-1537985011v1 combination of increased aminotransferase (AT) and total bilirubin, such as viral hepatitis A, B, or C; or acute liver disease. [00223] Finally, after a single DLT in a patient in the ongoing cohort, that patient will have further dosing stopped. An ad hoc meeting of the DERC should be called to determine if the rest of the patients in the same cohort should continue dosing. This applies to both psoriasis and atopic dermatitis cohorts. 5.1.11.2 Termination of the Clinical Study [00224] Should the study be terminated and/or a site closed for any reason, all documentation pertaining to the study and study drug(s) must be returned to the Sponsor. Any actions required for assessing or maintaining study patient safety will continue as required, despite termination of the study by the Sponsor. 5.1.12. Criteria for Study Termination [00225] If the Investigator or the Sponsor become aware of conditions or events that suggest a possible hazard to patients if the clinical study continues, then the clinical study would be halted, pending full consideration of corrective measures to the protocol and/or termination. [00226] Conditions that may warrant termination of the clinical study include, but are not limited to, the following: [00227] The discovery of an unacceptable risk to the patients enrolled in the clinical study, [00228] Failure to enroll patients at the required rate; and/or [00229] A decision of the Sponsor to suspend or discontinue development of the IMP. 5.1.13. End of Study Definition [00230] A participant is considered to have completed the study if he or she has completed all visits of the study including the last visit and the last scheduled procedure shown in the Schedule of Assessments, below. In some cases, end of study visit is 31 days after the last dose (1 study clinic visit). [00231] The end of the study is defined as completion of the last visit and the last scheduled procedure shown in the Schedule of Assessments in the trial globally (see below). 5.1.14. Study Assessments [00232] The Schedule of Assessments for the core study, for patients with psoriasis and for patients with atopic dermatitis, are shown in Table 6A and 6B (respectively) below. The - 117 - NAI-1537985011v1 sampling days for special laboratory assessments during the core study are defined in Table 7A below. The schedule of Assessments for the OLE, including sampling days for special laboratory assessments, is shown in Table 7B. [00233] Study procedures, including pretreatment and end of study (EOS) are detailed below. 5.1.14.1 Pretreatment Evaluations [00234] All potential study participants must sign an informed consent form (ICF) of their own volition prior to undergoing any screening or study-related procedure. After the ICF has been signed, all screening procedures for eligibility should be performed as early as possible. Only those subjects who meet all inclusion criteria and none of the specified exclusion criteria will be considered as potentially enrolled in the study. Each of these individuals receives a unique patient screening number. [00235] The screening period (Day –42 to Day –1) includes required completion of all screening assessments (Tables 6A and 6B and Section 5.1.14.2). Vital sign assessments for eligibility can be repeated, and vital signs for eligibility may be used from any assessment performed between Day – 42 to Day – 1. [00236] Patients who do not meet the criteria for participation in this trial (screen failure) may be rescreened once, if deemed acceptable by the Investigator after discussion with the Medical Monitor (except for troponin I levels in patients with psoriasis). Baseline cardiac MRI assessments can be used for up to 6 months for re-screening patients with psoriasis. Patients should resign the ICF, re-do all procedures planned at the screening visit, and be assigned a new screening number. [00237] All screening procedures should be completed before sending the eligibility checklist to the Xencor’s Medical Monitor. Prior to first administration of XmAb27564, each patient must have completed all screening activities and have received approval via the eligibility checklist from the Xencor Medical Monitor. [00238] Note: Eligible patients will not be considered enrolled in the study until approved as such by the Xencor Medical Monitor. 5.1.14.2 Screening Period (Day –42 to –1) [00239] Prior to the planned administration of XmAb27564, patients will undergo a screening visit (Day -42 to Day -1). Screening assessments are as follows: • Obtain signed informed consent - 118 - NAI-1537985011v1 • Review inclusion and exclusion criteria • For patients with psoriasis only: Cardiac MRI • Demographics • Medical and surgical history, and prior medication history. Prior medications should include general medications received within 30 days of start of screening. • Any previous therapies for psoriasis or atopic dermatitis (both topical and systemic agents, and phototherapy) should all be entered. All COVID vaccinations within the prior 3 years of the start of screening should be entered. • Physical examination (PE), including thorough skin examination, height, weight, and body mass index (BMI) • Vital signs: These can be repeated for qualification for eligibility (see below, Patient Exclusion Criteria) • ECG, standard 12-lead, supine position • For patients with psoriasis only: Troponin I • Complete blood count (CBC) with differential • Chemistry panel • CRP (C-reactive protein) • Ferritin • Coagulation panel (prothrombin time/international normalized ratio [PT/INR]), activated partial thromboplastin time (aPTT), and fibrinogen • Urinalysis with microscopy, reflexive • Serum beta human chorionic gonadotropin (β-hCG) and urine pregnancy test for women of child-bearing potential or follicle-stimulating hormone (FSH) for postmenopausal women • Urine drugs of abuse test. If positive, the patient’s eligibility should be discussed with the Xencor Medical Monitor. • Alcohol breath test. If positive, the patient’s eligibility should be discussed with the Xencor Medical Monitor. - 119 - NAI-1537985011v1 • Screening tests for HIV Type I and Type II antibodies and HCV antibodies, as well as screening tests for hepatitis B surface antigen (HBsAg) and QuantiFERON (mycobacterium tuberculosis [MTB]) • For patients with psoriasis only: Myocarditis-associated virus titers and PCR • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Antigen and Antibody • Tests for immunoglobulins (IgG and IgM) • For patients with psoriasis only: Psoriasis Area and Severity Index (PASI), BSA involvement of psoriasis and Static Investigator's Global Assessment (sIGA) • For patients with atopic dermatitis only: the Peak Pruritis Numerical Rating Scale (PP- NRS). Patients are provided with a diary at the screening visit in order to complete the PP-NRS daily starting from screening and daily during the core study and at every visit during the OLE. Screening period must be a minimum of 7 days in order to collect PP- NRS between Day -7 and Day -1 and calculate a weekly average baseline score prior to Day 1. • For all patients: Dermatology Life Quality Index (DLQI) • Record AEs and SAEs (using CTCAE for grading) • Record concomitant medications 5.1.14.3 Assessments Prior to Administration of Investigational Product (Day 1) [00240] Before first-dose administration of XmAb27564 and after a patient has provided informed consent, met all the inclusion and none of the exclusion criteria, the following assessments are to be completed on Day 1 as follows: [00241] Tests performed on Day 1 include the following: • Review inclusion and exclusion criteria • Weight • Medical, surgical, and prior medication history • PE including thorough skin examination • Vital signs • ECG, standard 12-lead, supine position • For patients with psoriasis only: Troponin I - 120 - NAI-1537985011v1 • CBC with differential • Chemistry panel • Immunoglobulin (IgG, IgM) • CRP • Ferritin • Coagulation panel (PT/INR, aPTT, and fibrinogen) • Urinalysis with microscopy, reflexive • Urine β-hCG pregnancy test for women • Serum beta human chorionic gonadotropin (β-hCG) for women • SARS-CoV-2 Antigen and Antibody • Blood for flow cytometry: immune cell subsets and markers, including but not limited to, receptor occupancy T, B, and NK cells (TBNK), and Treg quantification; peripheral blood mononuclear cells (PBMCs); and PAXgene RNA sample (see Laboratory Manual for detailed instructions) • For patients with atopic dermatitis only: serum IgE and allergen-specific IgE • Serum samples for PK, anti-drug antibodies (ADAs), and cytokines/soluble factors (see the Laboratory Manual for detailed instructions) • For patients with psoriasis only: Myocarditis-associated virus titers and polymerase chain reaction (PCR) • For patients with psoriasis only: Psoriasis Area and Severity Index (PASI), BSA involvement of psoriasis, and Static Investigator's Global Assessment (sIGA) • For patients with atopic dermatitis only: EASI, BSA involvement of atopic dermatitis, and Validated Investigator’s Global Assessment of Atopic Dermatitis (vIGA-AD) • For patients with atopic dermatitis only: PP-NRS. Patients are provided with a diary at least 7 days prior to the randomization visit and instructed to enter their pruritis scores daily during the core study and at every visit during the OLE. • Canfield Photography of total body and plaque to be followed and biopsied can be done within the screening prior to Day 1 if it is within 7 days from Day 1. Photography of whole body and selected psoriasis plaques or active dermatitis can be done within the screening prior to Day 1 if it is within 7 days from Day 1. - 121 - NAI-1537985011v1 • Skin punch biopsies of involved and uninvolved areas at the plaque/lesion to be followed can be done within the screening prior to Day 1 if it is within 7 days from Day 1 (see Biopsy and Photography Manuals for detailed instructions). • For all patients: Dermatology Life Quality Index (DLQI) • Record AEs and SAEs (using CTCAE system for grading) • Record concomitant medications 5.1.14.4 Double-Blind Study Treatment Period Days 3, 17, 31, and 45 procedures may include the following: • Brief physical examination (including a complete skin exam) • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Blood samples to check: - the level of XmAb27564 in the blood (Day 3 and Day 45 only) and for pharmacodynamics (to measure the response of the body to the study drug) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed. Days 5, 19, 33, and 47 procedures may include the following: • Brief physical examination (including a complete skin exam) • Vital signs • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Blood samples to check: - the level of XmAb27564 in the blood (Day 5 and Day 47 only) and for pharmacodynamics (to measure the response of the body to the study drug) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed. - the level of cytokines on Day 5 (soluble proteins naturally found in the blood) Days 8, 22, 36, and 50 procedures may include the following: - 122 - NAI-1537985011v1 • Brief physical examination (including a complete skin exam) • Vital signs • Electrocardiogram (ECG) • Lab tests (blood only) • Psoriasis Area and Severity Index (PASI): Measurement of the severity and extent of the psoriasis • Body Surface Area (BSA): Examination to measure the amount of the body surface that is affected by the psoriasis • Investigator Global Assessment (IGA): The study doctor assesses the severity of the disease • Dermatology Life Quality Index (DLQI): questions are asked about how the disease affects the quality of life (Day 50 only). • Review of area where injection was given • Review of medications • Review of any new or worsening medical conditions • Additional blood samples to check: - the level of XmAb27564 in the blood and for pharmacodynamics (to measure the response of the body to the study drug) - the level of cytokines (soluble proteins naturally found in the blood) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed. Days 12, 26, 40, and 54 procedures may include the following: • Brief physical examination (including a complete skin exam) • Vital signs • Lab tests (blood only) • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Additional blood samples will be taken to check: - 123 - NAI-1537985011v1 - the level of XmAb27564 in the blood (Day 12 and Day 54 only) and for pharmacodynamics (to measure the response of the body to the study drug) - the level of cytokines (soluble proteins naturally found in the blood) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed. Days 15, 29, and 43 procedures may include the following: • Brief physical examination (including a complete skin exam) • Vital signs are measured 6 times; once before study drug injection and 5 times after study drug injection • Electrocardiogram (ECG) is performed 2 times: once before study drug injection and 1 time after study drug injection • Lab tests (blood and urine) • Urine pregnancy test for women of childbearing potential • COVID-19 antigen (rapid nasal swab test) • Skin biopsies and photography (Day 29 only) • Psoriasis Area and Severity Index (PASI): Measurement of the severity and extent of psoriasis • Body Surface Area (BSA): Examination to measure the amount of body surface that is affected by the psoriasis • Investigator Global Assessment (IGA): The study doctor assesses the severity of the disease • Receive study drug followed by an up to 6-hour observation period • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Additional blood samples to check: - the level of XmAb27564 in the blood 1 time before each study drug injection and 1 time after that on Day 43, and for pharmacodynamics (to measure the response of the body to the study drug) 1 time before study drug injection - the level of anti-drug antibodies 1 time before study drug injection - 124 - NAI-1537985011v1 - the level of cytokines (soluble proteins naturally found in the blood), 1 time before and 1 time after study drug injection - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed. • Patient remains at the study site for up to 6 hours after the study drug injection for further observation. Day 57 procedures include the following: • Brief physical examination (including a complete skin exam) • Vital signs • Electrocardiogram (ECG) • Lab tests (blood and urine) • Skin biopsies and photography of total body and areas of plaque • Psoriasis Area and Severity Index (PASI): Measurement of the severity and extent of psoriasis • Body Surface Area (BSA): Examination to measure the amount of the body surface that is affected by the psoriasis • Dermatology Life Quality Index (DLQI): questions are asked about how the disease affects the quality of life. • Investigator Global Assessment (IGA): The study doctor assesses the severity of disease. • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Additional blood samples to check: - the level of XmAb27564 in the blood and for pharmacodynamics (to measure the response of the body to the study drug) ^ - the level of cytokines (soluble proteins naturally found in the blood) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed. Day 88 (end of study visit): • Brief physical examination (including a complete skin exam and weight) - 125 - NAI-1537985011v1 • Vital signs • Electrocardiogram ECG • Lab tests (blood and urine) • Urine pregnancy test for women of childbearing potential • Psoriasis Area and Severity Index (PASI): Measurement of the severity and extent of psoriasis • Body Surface Area (BSA): Examination to measure the amount of the body surface that is affected by the psoriasis • Dermatology Life Quality Index (DLQI): questions are asked about how the disease affects the quality of life. • Investigator Global Assessment (IGA): The study doctor assesses the severity of disease • Review of any medications • Blood test for Myocarditis associated viruses and COVID-19 antibody. • Additional blood samples to check: - the level of XmAb27564 in the blood and for pharmacodynamics (to measure the response of the body to the study drug) - the level of cytokines (soluble proteins naturally found in the blood) - the level of anti-drug antibodies - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed. 5.1.14.5 Patient Enrollment and Study Drug Dosing [00242] Patients who have completed screening activities and whose eligibility has been confirmed by the Xencor Medical Monitor will be considered enrolled in the study. [00243] Patients will be randomized into a treatment group on Study Day 1 and assigned a Randomization Number. Patients will be discharged from clinic after a 6-hour (window allowance of -2 hours) observation period after study drug dosing at Days 1, 15, 29, and 43. During the OLE part of the study, patients are discharged from the clinic after a 6-hour observation (window allowance of -2 hours) for the first visit (Day 57) and after a 2-hour observation period at subsequent visits. 5.1.14.6 Subsequent Visits During the Core Study - 126 - NAI-1537985011v1 [00244] The schedule of required procedures and clinical site study days are detailed in the Schedule of Assessments (Tables 6A and 6B). [00245] Following the final set of outpatient visits (if the patient does not enter the OLE), all patients will complete an EOS visit (End-of-Study Visit). [00246] Patients will have their EOS visit after the last treatment or on Day 88. If a patient terminates prior to completing all on-study visits and scheduled assessments, the EOS assessments detailed in the Schedule of Assessments will be performed on Day 88. An exception to this general directive is when a patient terminates early in the study and is scheduled for a EOT visit, followed by an EOS visit, which will be scheduled 45 days after the date of the last administered dose of study treatment (Table 6A and 6B). [00247] Patients will be screened for lymphopenia to monitor for an unlikely clinical effect of immunogenicity (the development of anti-drug antibodies [ADAs]). ADAs have the potential for neutralizing the activity or altering the PK of XmAb27564 or endogenous IL-2. ADAs may also confer cytotoxic activity to cell-bound XmAb27564 or endogenous IL-2. Because IL-2 supports the development and survival of lymphocytes, lymphopenia is a potential clinical impact of ADAs. [00248] Patients who are lymphopenic at EOS/ET (< 1000 lymphocytes/µL and 75% below their baseline) will be scheduled for a follow-up visit in 28 days (± 3 days). Follow-up visit assessments will include ADAs, PK, cytokine (IL-2 levels only), immunoglobulin levels (IgM, IgG), and a CBC with differential. If the patient’s last prior ADA test result was confirmed positive and the patient is lymphopenic at the follow-up visit, then the patient will be scheduled for another follow-up visit in 28 days (± 3 days). This cycle will be repeated until lymphopenia resolves. Patients with persistent (multiple measures at < 1000 lymphocytes/μL and 75% below their baseline for more than 2 months after the last dose) or severe lymphopenia (< 500 lymphocytes/μL and 75% below their baseline) shall be referred to a primary care physician for treatment. 5.1.14.7 Open-Label Extension Phase [00249] All patients with atopic dermatitis and any patients with psoriasis who had Day 1 pre- dose PASI scores ≥ 12 and BSA involvement of ≥ 10%, who are candidates for a systemic agent, can participate in the open-label extension phase (FIG.3B; Table 7B) except those who had a Grade 3 AE or SAE related to study drug during the core study (FIGs.6A-6B). The schedule of - 127 - NAI-1537985011v1 required procedures and clinical site study days are detailed in the Schedule of Assessments (Table 7B). [00250] If the patient enters the OLE, following the final set of outpatient visits of the OLE, all patients complete an EOS visit (End-of-Study) at Day 438, as detailed in the Schedule of Assessments (Table 7B). An exception to this general directive is when a patient terminates early in the study and is scheduled for an EOT visit, followed by an EOS visit, which is scheduled 45 days after the date of the last administered dose of study treatment. [00251] Patients are screened for lymphopenia to monitor for an unlikely clinical effect of immunogenicity (the development of ADAs). ADAs have the potential for neutralizing the activity or altering the PK of XmAb®27564 or endogenous IL-2. ADAs may also confer cytotoxic activity to cell-bound XmAb®27564 or endogenous IL-2. Because IL-2 supports the development and survival of lymphocytes, lymphopenia is a potential clinical impact of ADAs. [00252] Patients who are lymphopenic (< 1000 lymphocytes/μL and 75% reduction in lymphocyte count from baseline) at EOS are scheduled for a follow-up visit in 28 days (± 3 days). Follow-up visit assessments include ADA, PK, cytokine (IL-2 levels only), immunoglobulin levels, and CBC with differential. If the patient’s last prior ADA test result was confirmed positive and the patient is lymphopenic at the follow-up visit, then the patient is scheduled for another follow-up visit in 28 days (± 3 days). This cycle is repeated until lymphopenia resolves. Patients with persistent (multiple measures at < 1000 lymphocytes/μL and 75% below their baseline for more than 2 months after the last dose) or severe lymphopenia (< 500 lymphocytes/μL and 75% below baseline) shall be referred to a primary care physician for treatment. 5.1.15. Treatment of Patients Description of Study Drug Investigational Product
Figure imgf000129_0001
- 128 - NAI-1537985011v1 Physical Description Sterile, liquid; practically free of Sterile, liquid; practically free of visible particulates visible particulates
Figure imgf000130_0001
Disallowed Medications • Patients cannot have used any investigational drug or any medical device in any clinical trial during the screening period, treatment period, and safety follow-up period of the current study or cannot have used an investigational drug in any clinical trial within 5 half-lives of the IMP, whichever is greater, prior to randomization. • Biologic treatments for psoriasis or atopic dermatitis for 12 weeks or 5 half-lives (whichever is longest) before randomization • No phototherapy within 4 weeks before randomization • No oral treatments for psoriasis or atopic dermatitis 4 weeks before randomization • No topical treatments for psoriasis or atopic dermatitis 2 weeks before randomization • No administration of live vaccines ≤ 2 months from screening or any vaccine within the past 14 days Additionally, for patients with atopic dermatitis: • UV-B, PUVA, excimer laser, excessive sun for at least 4 weeks before randomization • IVIg for 12 weeks before randomization • Hydroxyzine or diphenhydramine for 1 week before randomization • Systemic antibiotics for 2 weeks or topical antibiotics for 1 week before randomization [00253] Refer below for the full list of inclusion criteria. Prior and Concomitant Medication [00254] For patients with atopic dermatitis the patients are to apply a stable dose of a non- prescription, non-urea containing emollient to all skin (normal skin and AD lesions) once or twice daily for ≥ 14 days preceding the randomization visit and also are willing to maintain stable dosing of the emollient until at least the Day 57 visit. Every effort should be made to keep - 129 - NAI-1537985011v1 the same emollient throughout the study for the same body region. However, the chosen emollient may differ depending on the body region (e.g., body vs face emollient may be different). On the day of scheduled visits, patients cannot apply emollient before their scheduled visit time [00255] Details of all prior and concomitant medications will be recorded at study entry. [00256] Concomitant medications are defined as medications started before and continued after the first dose of XmAb®27564/placebo in this study. [00257] All therapies (prescriptions or over-the-counter [OTC] medications, including vitamins and herbal supplements) different from the study drug is recorded in the eCRF. Any prescribed medicinal product or OTC product (medicinal or other) following administration of IMP, including herbal and other nontraditional remedies, is considered a concomitant medication. Any changes in concomitant medication must be recorded at each visit whether or not prescribed by the study site. If the change might influence the patient’s eligibility to continue in the study, the Sponsor must be informed. All treatments must be recorded in each patient’s eCRF including the following: medication, dose, treatment duration, and indication. [00258] The information collected for each concomitant medication includes, at a minimum, start date, end date or ongoing, dose and unit, frequency, route of administration and indication. Other Restrictions [00259] Patients will be instructed to adhere to the following restrictions during the core study: • Strenuous activity is prohibited for 24 hours prior to each outpatient visit. • Abstain from alcohol for 24 hours prior to study dosing days • Patients should not donate blood for 2 months after the last study visit. • Patients are to remain fasted (NPO) from 30 minutes before starting the SC injection until at least 1 hour post SC injection. • Refrain from receiving any vaccines, including COVID-19 vaccines for a period of 45 days following administration of IMP, avoidance of exposure to individuals with COVID-19, and strict adherence to recommended guidelines for personal behaviors to reduce infection risk, avoidance of persons with known COVID-19 infection, and frequent hand washing. 5.1.16. Randomization and Blinding - 130 - NAI-1537985011v1 5.1.16.1 Treatment Assignment [00260] In the double-blind core study, patients are randomized to receive XmAb®27564 active dose or placebo. Randomization schedules for each dose cohort are generated for patients with psoriasis and patients with atopic dermatitis separately prior to study start. Each psoriasis cohort consist of 8 patients, 3 sentinel patients are randomized in a 2:1 ratio to XmAb®27564 or placebo and five remainder patients are randomized in a 4:1 ratio to XmAb®27564 or placebo. Overall, 6 patients are randomized to XmAb®27564 and 2 patients to placebo. For each atopic dermatitis cohort, 16 patients are randomized in a 3:1 ratio to receive XmAb®27564 or placebo. [00261] XmAb®27564 or placebo is administered in a double-blind fashion. In the event patients who are prematurely discontinued from the study drug are replaced, the replacement patients receive the same treatment group. [00262] In the OLE, all patients receive open-label XmAb®27564 active dose. 5.1.16.2 Processes and Procedures to Ensure Maintenance of Blinding [00263] The contract research organization (CRO) will maintain the randomization code in a secure location with controls to prevent unauthorized access, including the computer program written to generate the randomization, randomization codes, program log, seed number used by the program, copy of the randomization plan along with approval documentation as appropriate, and the write-protected electronic storage medium. [00264] The CRO will name an unblinded statistician to generate the randomization codes. [00265] The pharmacists will be unblinded. Investigators and site staff, patients, CRO, and Xencor (excluding DAT) will remain blinded to individual patients’ treatment assignment for the duration of the study until the study unblinding has been authorized. However, if a patient has suffered an SAE and when knowledge of the treatment assignment will impact the clinical management of the patient, the Investigator will have the ability to unblind the treatment assignment for that patient. Investigators are encouraged to discuss with the Xencor Medical Monitor before unblinding, if possible. [00266] To preserve the blind, study drug will be prepared and administered in a manner that masks the content for the patient and clinical team managing the study. 5.1.16.3 Unblinding due to Adverse Events/Safety or Other Reasons - 131 - NAI-1537985011v1 [00267] Should an AE or other emergency circumstance occur which would require that the blind be broken to ensure patient safety, the Investigator must immediately notify the Xencor as soon as possible and following a discussion with the Xencor Medical Monitor, the treatment assignment of the patient will be released to the appropriate personnel in accordance with the applicable study-specific procedure. [00268] If a qualified physician who is an Investigator in this study determines that the information is necessary (i.e., that it will alter the subject’s immediate course of treatment), the Investigator contacts the unblinded Site Pharmacist to break the blind for the impacted subject. In the event the unblinded Pharmacist is not available, the site follows their internal SOP for the back-up staff who can break the blind. If possible, the Investigator notifies the Xencor Medical Monitor prior to breaking the blind, but if not, they are informed immediately thereafter. [00269] If the treatment assignment is unblinded by the Investigator, then the Investigator must notify the Sponsor in writing and document the course of events in the source records. Any patient for whom the treatment code is prematurely released will be withdrawn from the study but will continue to be followed for safety events if IMP was received. 5.1.17. Study Drug and Storage [00270] Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol and the Pharmacy Manual. [00271] Investigational product, dosage and mode of administration includes the following: Multiple SC administration of XmAb®27564 solution at dose levels of (0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo, as shown in Table 4. Table 4. Study Drug Information XmAb®27564 Drug Product (DP) a es gle
Figure imgf000133_0001
- 132 - NAI-1537985011v1 Dose: Study drug preparations and dose administration information are provided in Example 1. of C te ch per of
Figure imgf000134_0001
[00272] XmAb®27564 Drug Product (DP) is provided as a 30 mg vial (30 mg/mL, 1 mL fill) for SC administration. Prior to use, the XmAb®27564 DP vial should be visually inspected. If particulate matter and/or discoloration are noted, the drug should not be administered, and the Sponsor should be notified. Aseptic technique must be strictly observed when preparing the solution for injection since XmAb®27564 and XmAb®27564 placebo vials do not contain preservatives. The XmAb®27564 placebo is provided as 5 mL of a solution of 250 mM sorbitol in a 20 mM histidine buffered solution of pH 6.5 in a 10 mL vial. The vial must not be shaken, as excess agitation may cause aggregate formation. Administration of XmAb®27564 and XmAb®27564 placebo should take place within 4 hours of dose preparation. If a delay is anticipated, XmAb®27564 and XmAb®27564 placebo may be stored at controlled room temperature (15ºC-30ºC; 59ºF-86ºF) for no more than 4 hours prior to injection (see the study Pharmacy Manual for specific instructions). - 133 - NAI-1537985011v1 5.1.19. Administration [00273] XmAb®27564 DP and XmAb®27564 placebo are administered via SC injection (1 mL syringe and 27-gauge needle). Recommended sites of administration include the upper arm, thigh, and abdomen, with the regions used to be noted in the source document. Regions should be rotated from one dose to the next. The injection site should be marked with a small circle and date of injection to identify injection site and monitor reactions. [00274] Dosing is weight based for all treatment groups. Calculate the dose based on the weight at the Day 1 visit. 5.1.20. Efficacy Measurements 5.1.20.1 Psoriasis Area Severity Index (PASI) Scoring [00275] For calculation of the PASI, 4 main body areas are assessed: the head (h), the trunk (t), the upper extremities (u), and the lower extremities (l), corresponding to 10, 30, 20, and 40% of the total body area, respectively. The area (A) of psoriatic involvement of these 4 main areas (Ah, At, Au, and Al) is given a numerical value: 0 = no involvement; 1 = < 10%; 2 = 10 < 30%; 3 = 30 < 50%; 4 = 50 < 70%; 5 = 70 < 90%, and 6 = 90–100%. To evaluate the severity of the psoriatic lesions, 3 target symptoms, namely erythema (E), infiltration (I), and desquamation (D) are assessed according to a scale 0–4, where 0 means a complete lack of cutaneous involvement and 4 represents the severest possible involvement. The severity rating for the 3 main target symptoms is multiplied with the numerical value of the areas involved and with the various percentages of the 4 body areas. These values are then added to obtain the PASI. The formula can be written as follows: PASI = 0.1 × Ah × (Eh + Ih + Dh) + 0.3 × At × (Et + It + Dt) + 0.2 × Au × (Eu + Iu + Du) + 0.4 × Al × (El + Il + Dl) [00276] The index varies in steps of 0.1 units from 0.0 to 72.0. [00277] The proportion of subjects with PASI 50, 75, and 90 represent the fraction of patients that have improvement of the PASI score of 50%, 75% and 90% over the baseline PASI (Oji and Luger. Clin Exp Rheumatol.2015;33(5 Suppl 93):S14–9.). 5.1.20.2 Static Investigator Global Assessment of Disease - 134 - NAI-1537985011v1 [00278] The Static Investigator Global Assessment (sIGA) of disease is a 5-point scale, without any reference to baseline (Langley et al. J Dermatolog Treat.2015;26(1):23–31.; Table 5). Table 5. sIGA of Disease for Psoriasis Score Description ;
Figure imgf000136_0001
5.1.20.3 Validated Investigator Global Assessment for Atopic Dermatitis Table 17. Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD): Score Morphological Description , g
Figure imgf000136_0002
- 135 - NAI-1537985011v1 [00279] The validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) is a static 5-point scale that was developed to assess the overall atopic dermatitis severity (Simpson et al. J Am Acad Dermatol.2020;83(3):839-846). The IGA score is selected using the descriptors in Table 17 that best describe the overall appearance of the lesions at a given time point. It is not necessary that all characteristics under Morphological Description be present. 5.1.20.4 Eczema Area and Severity Index (EASI) Score [00280] The EASI is assessed following these steps (refer to Hanifin et al. The Eczema Area and Severity Index-A Practical Guide. Dermatitis.2022;33(3):187-192). [00281] 1) Area of Involvement: First, the area of involvement of the 4 body regions (head and neck, upper extremities, trunk, and lower extremities) must be visually estimated as a percentage of the total area of that anatomic site and assigned an area score: 0 (no involvement), 1 (1%–9%), 2 (10%–29%), 3 (30%–49%), 4 (50%–69%), 5 (70%–89%), and 6 (90%–100%). The feet and buttocks are included as part of the lower extremities, whereas the axilla and groin are counted as part of the trunk. [00282] 2) Intensity of Lesions: Next, each region is assessed separately for 4 signs: erythema, edema/papulation, excoriation, and lichenification. Each sign is assigned an intensity score from 0 to 3, with 0 being absent; 1, mild; 2, moderate; and 3, severe. Half points may be used between points 1 and 3 (e.g., 1.5 and 2.5 but not 0.5) as any sign present should be treated as at least mild. It is important to note that only inflamed areas should be included in the assessment. Xerosis, ichthyosis, keratosis pilaris, urticaria, and post-inflammatory pigment changes should not be included unless underlying eczema is present. Regions that present with varying severity of a particular sign should be roughly averaged across involved areas only; half units may be useful in this scenario. [00283] 3) Region Score: Each region is assigned an adult that reflects the relative contribution of that region to the total BSA. The region score is calculated separately for each region by multiplying the sum of the regional intensity score by the regional area score and the region-specific multiplier. [00284] 4) Final EASI Score: The final EASI score is the summation of the 4 regional scores, ranging from 0 to 72. A score of 0 indicates clear or no eczema, 0.1 to 1.0 indicates almost clear, 1.1 to 7 indicates mild disease, 7.1 to 21 indicates moderate disease, 21.1 to 50 indicates severe disease, and greater than 51 indicates very severe disease. - 136 - NAI-1537985011v1 5.1.20.5 Peak Pruritus Numerical Rating Scale (Atopic Dermatitis) [00285] Pruritus is assessed using the PP-NRS. The PP-NRS is an 11-point scale used by patients to rate their worst itch severity over the past 24 hours with 0 indicating “No itch” and 10 indicating “Worst itch imaginable” (Yosipovitch et al., Br J Dermatol.2019;181(4):761-769). Patient assessments are captured daily using a diary starting from screening until the EOS visit. Patients are provided with a diary at the screening visit and instructed to enter their pruritus scores daily. The daily (24-hour) PP-NRS are recorded and the weekly mean of the daily PP- NRS are calculated. Therefore, a minimum of 7 days of screening is needed to collect PP-NRS scores between Day -7 and Day -1 and calculate a weekly average baseline score prior to Day 1. During the OLE portion of the study, PP-NRS is only recorded at each scheduled visit. 5.1.20.6 Photography of Whole Body and Selected Psoriasis Plaques or Active Regions of Atopic Dermatitis [00286] Photography of patients at baseline and during the double-blind period are assessed. Photographs are standardized across sites by utilizing a Canfield photography system (Canfield Scientific, Parsippany, NJ). Whole body images, and photographs of the plaque or area of active atopic dermatitis chosen for biopsy are taken. In addition, this equipment should be used to perform photography of injection site reactions. The photography procedures and other information are summarized in separate Photography Manual to be provided. [00287] However, for all patients (both psoriasis and atopic dermatitis) with low BSA involved, or with small plaques spread out, it may not be possible to do all biopsies on the same plaque or in the same anatomical area. In those cases, another representative plaque showing similar improvement should be selected for the next biopsy collections. If the baseline biopsy is from an extremity, the repeat biopsy should be from an extremity; if from the trunk, repeat biopsy should be from the trunk, with the caveat back (dorsal) skin is quite different from ventral (chest, abdomen) skin. There should never be a biopsy of scalp skin without having both biopsies in the scalp. Palmar/plantar skin should never be biopsied. Each plaque biopsied should have a photograph accompanying the biopsy. The location of the plaque(s) biopsied should be noted in the source document. 5.1.20.7 Body Surface Area of Psoriasis or Atopic Dermatitis - 137 - NAI-1537985011v1 [00288] The body surface area (BSA) of psoriasis or atopic dermatitis is estimated by using the size of the handprint as 1% of the body surface area. The investigator totals the number of patient’s handprints across the patient’s body that have activity with psoriasis or atopic dermatitis (Ramsay and Lawrence. Br J Dermatol.1991;124(6):565–70.). 5.1.20.8 The Dermatology Life Quality Index [00289] The DLQI is a short and simple quality of life (QOL) instrument that can be used in psoriasis or atopic dermatitis. It is self-administered with a mean completion time of 2 min. It consists of 10 questions concerning impact of skin diseases on different aspects of patient’s QOL over the last week. The DLQI items include symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the side effects of treatment. Each item is scored on a 4-point scale: not at all/not relevant, a little, a lot and very much. Item scores (0-3) are added to give a total score (0-30); higher scores indicate greater impairment of QOL. Estimates of the minimal clinically important difference of the DLQI have varied from 3 to 5 (Basra et al. Dermatology.2015;230(1):27–33.). 5.1.21. Pharmacokinetic and Pharmacodynamic Assessments Serum and Whole Blood Sampling [00290] The Sponsor or designee provides collection kits with cryotubes, labels, requisition forms, and shipping containers. [00291] Detailed instructions for processing and shipping serum cryotubes (PK/ADA/cytokines/soluble factors and total IgE and allergen-specific IgE for patients with atopic dermatitis) and whole blood (Treg/TBNK/PBMCs/PAXgene) are provided in the Laboratory Manual. Schedule of Assessments is shown in Tables 6A and 6B and the sampling days for special laboratory assessments are shown in Tables 7A and 7B. [00292] Unscheduled samples may be collected at the discretion of the Investigator. [00293] The exact time and date of the blood draw must be accurately recorded using an unambiguous format such as DD MON YYYY for the date, and HHMM for the time using a 24- hour clock. Missed samples are considered protocol deviations. - 138 - NAI-1537985011v1 T Or S b E o O E d o i r e P t n e m t a e r T d nil B e l b u o D
Figure imgf000141_0001
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n b a o n r a e r = it n T e e e d . n o l r a s e t n e o t ms it a t a t s t n d r a o i v 1 1 P a n i r/ s r n d e s o n o y D d y w ot e g e t T , g o bi m t o o i t l g e t a i o i s Aa / y r h t n e o i t b f s e r u s t e s s e s p l p a a l eit ct d r 0 5 t o l g n i l n i y 8 k c K n u n c a = a n i o n n i i s N Ry d o t n I ma n i o s u n d i n e i l a u d n s a l a n e e h a p n a e c 9 7 t u t i s S t S i n o c e j b Xp mo t V Mn i K P A P a s y w o N B m = C m u = C l F T ( m I b r a mRi r ; e o b i a l : t u e t mo mt c e e c m 0 t a if ll r o h t f ll g r d n 3 5 1 AB Ce T m i N o I s p mi t n a g e r o c a Ne r x e f f o e r 1 Pe A p ± a a h t a bF w o A u a - c I A N . r n e e t b f t 3 a s u y ± ( b ) - e V l o a r i As o C v d n s s l - d a e s l a e v y r h t g o n o i it u b n l s e h s t mt s r p ( e a y a 2 d V-e S R e t s a t s i s e a m a s h e d v e s e o s is r a c e u n c e i e j di n r d o r i s r l s Og 8 Cp ( A S c o t o t a s b e h n a r o f i mb u n o . 1 o t o 2 n - 3 r f i S 4 d n s a A n ti s - t o d we i t s h e h t o s o t n 0 S u 3 . g c r y a h P ti R , A 9 2 a , l a s a i e p e b d e i v p i a r t a p t r r a , t d o s e n o n i o l t a D d n s i v S e , 5 u ri d r e a r n k r t a c a g o t e n f e w i o t c p g i ma p h e m t s o r y s u - t 1 y v o c o h t a o c s mg n o h o d s h i t ll j a s e f p w y l a v r y b e e i p e e p f o n i v s o i o n Da M, n s u b n e e r b a r o f d n e s r e r C o o I y e a l d B l o o e t p l a , . S o i t r i v d l u e r u t d l u h t a e a S l s y y l r o t b h t 7 e e f i d s S a h e t e s O Ea v d e o c h s p s ll a c o h . y u a r e r t o 3 o a n h i h . e r o f w , a e u ri 8 e 8 l e t a i e t a o t s s d u t i r e v o s oir p f e t t G i s g p wo e i d d n i e r v s y I a c i n o s d e t y l h p s a e r r e p p u y b l d C s i -e e l u n e si e p r D i n s s a n o e i l p e t a y e ni t e t e r r g r o c n h t n a r E u y t i r p d e e r c t s e e h d n o p o s i t t c e mo a p o t o e An o c i d s a n a . f i e n h . i g h o c s s t t g , s a u , r t i d r j n i c e e s h p h t n n t si e e r i i d mm o G 1 y d e e r a d Ar 2 i v 1 y y n a a c e h v a d e l a i n ti n e w r e s o m i e r F. n C E a Db a) e e . mVo h a Dr o e y t d h t s m r o i t s i v r n y d a o d e t s n o i t g c n i o t d r l u n o i l l e a r it of o r C- c e , , s Rt f a m t e n n a, u o m f r i e d d 8 8 . c r s it a ut s . n c e g o o l l i s l e j n m r o o i r h s n e S C i p s o n t p a s a b e r p e R u r i St s i y v r o i t n e e b , t n a t f i o n i n t o r c e h t it o c at i f r d e i me ff r a A S v as t oll c e it a d e D a a c a s c a e e r i v C S e p oi r s p or i d b . 1 B e t c s ei a j n i p l u v e e M t s v e t l f o D I e l r a p e ti e , t s r e e r e a y a tf a o f p o i f n ht Ay i k e j l g b o i i w 2 a Dc a b r u a o t Ch c . r o h e h v a s e st S a e oti s t f h t - a c i s V m s d y n r y d g s r e b n i h c t c V C o d s x ll e h n e t s , 4 n o y h ot o n 2 4 e a O o C c o i r o ni u s e n e n u u d B C - n a o c a t t m s o p 6 5 Mp a r e s o 1 M d r 0 o 3 ll t c A n t e c t i a s o t t e j r o h u e r p e n r C S n i p d- 4 n i c s i k %d R g n , s n o A. s e r u 7 2 l a g o n o d - 5 n Ai n u r i n n o s s o h b c i d t o e o h ne . n i . 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X X X c mr o o t : c p a u r = Q e u r ; c A/ s P a e t w a c e j si n o T e f T Ti y P i l k m b Af g it o , ti r e n i n c P L r a a 2 o t s e N. s i h t e o i t si d a y a e n y - ) ; g E P Vn e v n d e v i e h t a n r n o l = = d o o m s I ri S On i d n i o yD e 4 g o t 1 it n a T E S c a C- s d e R mS e s s t u a q e r E n e a, ma d a m n x e ut s Q ( X X X a m = r ; e t Nr n - P a R h Ad i l e p A S l a r a y a b s o i e t n e h c e i k h t g D e P ; t a A = m t ; n = n b v o st d t . l = n e e g j n s s wn i u i h g e t e - ; I a e o i D X y d Qrt- t c P e ; v GD l E r A- m s o o L f a s l l a r me d C y S u l t o r p 1 5 bit D; o - e r l e e c s o r t A e o f r d s e a g G s s , t S u t s o o p h t m o c 1 - n n a i d e n e e ti s r a e v d it s I g t e v a i s ; 8 3 i v O E o t r u a o ; t d . n ei u o = n l c A v l l e 4 Td r r p T o i u n s u n I c y On d a e t h e e s t a a 1 m r o p d t e Ot c o oi c i T a E T l e t s o f d e r a X X X -i n vi Ee j n r t a y D a Or a e r e p e a t c ; = a y e d n i o e = m S t s r = = o e t a h t r E E l p e m i , o f r o At a si n t e Ar - u Dc t s- Rd o = f o S o l E l u t n d AA e f S o G g e l u st r o t - I ; b n E o P d h e tt ; l S I s e r m t d n e E o i ) b a AP d o y Rn it a a r ; e d i ; s = a u g e e r t h c m A t s s s 3 c d e e d j t c l g u n i do Ce r h c b X X i ; p a o e r f s e s e n i eri o h o g t t n n = d e ir c a u S z o Oi e i e e l n a T o i s d t ;s d n d n Aa r C d s S - s n e o e = c El ; a p c u l l e a . t G - m i s r m= u n c b e c / n y n e a e r o t p b d o a o d Ao mr ; l a r o n C o u M b i r s g e o r i t d a ut s mt d a e p c s p i e t m y b n h a t b g l n e e v t o e i a B n P; = = CT - n i e er n e u s ( c g u S n mh t t i r n i d n u r El d e p r a o i x A; o c t a e d Nn n r e l e t n i y d e ut p x m e t 0 a i p d n i y d s mo r o c r t n r e t n I R ; s gi l t a r y l r y l a r a s f e e 3 v v m. e r k s ut s X X X e v d = c e l n e i y ti y r a n d a / o l e e o a d s a o e e s h r f n o b b a d n a e h t AC w = B = = CG R e v Ne 4 y S 1 d y o n o a it h t r b i s t n o a h n o o i t i d d h e w O P c e n s Nj a y o n , s h t t p a d y a e s s : e t t i E ; a C I ; d e n e wm r r t e i n r t a a n r t r v A e o it p o p t : e r E; ni n a v e a- v n s t e t e t s n e i b t f o i o g o t l e r y t i a e n e r s n a e x e l u a e = 2 o c n e t n i n i t a s u e t p a e o h e v i 1 t v 1 p r/ e l r r/ r d at n l I ot m ot f n i o i o a mt i a t c a a d n b o c i f v r I l r u g ADs u = . i s y t s 4 s t i o n i s 1 ri a e it m p Q v n a o c it s i t p a p d a e m s d m p r a . i s 1 0 a ll a t d u t n d i n t d a ll l t ei a h n t o n it e s 5 8 9 7 y a a r Q i n s i n s r o c i e r y r e u a i ; n Tm ar n s a l l c e i t e l ar f n s u l h g 3 5 D o L o R o E o i F D MS I M A r n d P o e b c m b d v mr o e o r ; ll r Ao b e S m i s P mi t o c e c e o e D a F h e x wh t b E a c c P r i o c d F a E o s i 1- I e C f Ae r g H A N ± ( s - R l y S Cl l 3 a a a t y r e e ti s d R P 8 A l r a i a v r v d e, n o . 2 S n n d i v d n s e s t a 5 8 i t c oi i n t ti a d e a st e s e p s , e y a e j n e r i s t a i s v ur p i c o e s t a r i c o s D w si s b t i t u v s hti e n d s - o v s a- Ae t n e t w y ’ r r o w r o a l a l i a e o l p p d g g e A n i e v t a g o , f s d e r a e r b 2 n h n V n i e g r i o t f s e a s c o t a c o e s v r u o r f i v y o M b, s e C- b, h n p I e d e s l e . n o s S d i ur R n a a r g h t u p d r R Ct a i v A S 1 7 o t t o a e e e h h c , S t v e l d e . t 7 y a h p n o s s u e r a s e r i a v i I a s i 5 a c y D e r d e i n i n o s a ) .l s D h g u t p b d e a o h r o o n i i l t c e s p p a o - t a u o a c l u e n r s it g r h t o t o h s e a r , e s h b f u f r t t i i i y i d n i y d y w n r a fi l e t l s a e t s h m d v s a t r c o o rf ht B y a u c i a r p a r i e n e et f m q s i d n a p g o n w i kit a at i e i e o n d s s t o i t C c a c s p l s i o si a t d d e h p -u B x d C o l e c a v n t s r o s e t e t m r l a 2 r d n , o e i ll g e l p o f n o 5 1 a s u n l r a o . y A m r e iti - % 5 , s r i w a 7 l e v o a e t r s l n 2 o c p e d d d e h t o t n s V o e b a , > v e n e e t e m i ti C- b o d l t u n d l n a ni d r l a b d A. s s t a S t s o e h v e e u : d l u n o e s t s m r R A e l s e i b l o e o l s s o r g e h i s t a a e d S p v l a c i . y m y h h t l a s p a f o c o s i n m u s a st s e l / e e t e n o p I it i o t n r a o A g t e S D o t s s m b ll ll b n i d d ht i O A o h n o e m i i A c , ) l n o a, w Et d n p d e h 0 y w 0 l n s a e ri p s v o n r t oi s t t a a , l e t t e n e d n s r i f a 0 o d f r i a o n d 1 u r e o c t a t a e < s ( l e i v t a i s e si p 7 5 c a C . m r c i v e d n l e t c e a o s c s n d a t s r ’r o f y f a e y l of D l b e t a r e p 2- i c a o L h I o s -s s i n o t E g t t i r a g . s I a u l r d o s a p p e b p ( s a i o it s u r cif e / s e s d l me n - s d r a f i y e v i c ri e n d u y l i k e r o it t i d c o l n v o n I e h e u t p s q e i r k o . t r e e o t wo h s a y o c r h , a y c m s Ko y f t e o c h e t o - j t t n s e e g i t y c f , a l e l h r o f p a w S P A s , ms r b u . n r o e s l l e t Ke e r g A6 et i s d e p s a b . P Ad e , h t b o y ) s d l t o O EDg t n t o me r d n t a r t y a u o h p 1 a A n s r i l wa i r d r e o fr t n a 2 c e E V o i e d m t o o l e o d h 7 s e h v 1 1 0 n f e i ) l o S . m r e c g t s o p s e I C - n i s t y c ± ( s T 5 s R S . n 8 9 a y f 2 P a d e - fr s h Ve i l Ra mS v u r R a s t wh I o o t n ll i 7 t 3 5 1 3 i To p Cs i C n e A P o c j S k S i s i l o v l F m m Ac a e - r I A N 5.1.21.1 Serum Collection for Pharmacokinetic Analyses, Anti-Drug Antibodies, and Cytokines/Soluble Factors in Serum [00294] Serum samples for PK/ADA/cytokines/soluble factors and total IgE and allergen- specific IgE for patients with atopic dermatitis are stored on site at –70°C in aliquoted cryotubes until the Sponsor notifies the sites to ship the samples on dry ice to the designated laboratory for sample analysis. Detailed instructions for processing and shipping serum samples are provided in the Laboratory Manual. 5.1.21.2 Skin Biopsies and Biopsy PD Assessments [00295] Punch biopsies are collected from involved and uninvolved skin during each biopsy procedure (Catlett et al. J Allergy Clin Immunol.2021:S0091-6749(21)01690–0.). The biopsy procedure, processing of samples, and shipment information are summarized in separate Biopsy Manual to be provided. The biopsies are assessed for the following PD markers. Additional immunohistochemistry and/or quantitative PCR (qPCR) endpoints may be assessed based on emerging data: • Immunohistochemistry: − FoxP3 − IL-10 − CD25 − CD3 − K16 − Ki67 − CD11c+ DCs − BDCA3+ • qPCR: − FoxP3 − IL-2 − CD25 − IL23 p40 − IL-23 p19 − IL-17A − IL-17F - 153 - NAI-1537985011v1 − K16 − beta defensin − IL-36 − CCL-20 − IL-10 − CCL17 (TARC) for patients with atopic dermatitis − CCL18 (MDC) for patients with atopic dermatitis − CCL26 (Eotoaxin 3) for patients with atopic dermatitis − Keratin 16 for patients with atopic dermatitis − Housekeeping gene • RNA-Seq 5.1.21.3 Whole Blood Sample Collection for Pharmacodynamic Analyses of Immune Cells [00296] Baseline and serial assessment of immune cell subsets in whole blood is done by flow cytometry; Treg, TBNK flow cytometry samples, and PBMC tubes should be shipped immediately at ambient temperature. The samples for RNA assessment are collected into PAXgene tubes for –70 ^C freezer storage and batch shipped to the designated laboratory. Treg and TBNK flow cytometry provides PD data for Treg and Teff/NK expansion and activation. Isolated RNA is used for transcriptomic analysis of immune cell genes and gene signatures. PBMCs is used for additional phenotypic and functional description of immune cells, including but not limited to analysis by flow cytometry or similar methods. 5.1.22. Assessment of Safety Safety and tolerability assessments include the following: • Adverse Events (AEs) • Clinical laboratory safety assessments, including troponin I for patients with psoriasis • ECG parameters • Vital signs • Physical exam findings • ADAs • Cardiac MRI for patients with psoriasis • Myocarditis-associated virus serology and PCR for patients with psoriasis • Pregnancy - 154 - NAI-1537985011v1 Overdose 5.1.22.1 Adverse Events [00297] An adverse event or AE is any untoward medical occurrence in a patient participating in a clinical study. The AE does not necessarily have a causal relationship with study treatment. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of an IMP. AEs may include the onset of new illness and the exacerbation of preexisting conditions. AEs are classified as “serious” and “non-serious” for regulatory reporting purposes. [00298] A Serious Adverse Event (SAE) is an AE occurring during any study after the patient has signed the ICF that fulfills one or more of the following: • Results in death • Is life-threatening; this means that the patient was at immediate risk of death at the time of the event. It does not mean that the event hypothetically might have caused death if it were more severe. • Requires inpatient hospitalization or prolongation in existing hospitalization • Results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions • Results in a congenital anomaly or birth defect • Is an important medical event. Important medical events are events that may not be immediately life-threatening but are clearly of major clinical significance in the opinion of the Investigator. They may jeopardize the patient and may require intervention to prevent one of the other serious outcomes listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or in a physician’s office, blood dyscrasias or seizures that do not result in patient hospitalization, and the development of drug dependency or drug abuse. [00299] A distinction should be drawn between serious and severe AEs (Grade 3 AEs). Severity is a measure of intensity whereas seriousness is defined by the criteria above. For example, a mild degree of gastrointestinal bleeding requiring hospitalization for monitoring purposes would be considered an SAE but is not necessarily a severe (Grade 3) SAE. Similarly, - 155 - NAI-1537985011v1 an AE that is severe (Grade 3) is not necessarily an SAE. For example, alopecia may be assessed as severe (Grade 3) but would not be considered an SAE. [00300] Problem: The Office for Human Research Protections considers unanticipated problems involving risks to participants or others to include, in general, any incident, experience, or outcome that meets all of the following criteria: • Unexpected in terms of nature, severity, or frequency given • (a) the research procedures that are described in the protocol-related documents, such as the Institutional Review Board (IRB)-approved research protocol and informed consent document; and • (b) the characteristics of the participant population being studied; • Related or possibly related to participation in the research (“possibly related” means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and • Suggests that the research places participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized. 5.1.22.2 Adverse Event Monitoring, Recording, Reporting, Follow-up, and Assessments [00301] Adverse event monitoring begins upon the signing of the informed consent form (ICF). [00302] All SAEs and events of special interest, irrespective of causality, are monitored until the event has resolved or stabilized, until any abnormal laboratory values have returned to baseline or stabilized at a level acceptable to the Investigator and Sponsor’s medical representative, until there is a satisfactory explanation for the changes observed, or until the patient is lost to follow-up. [00303] Adverse events may be volunteered spontaneously by the study patient, discovered by the study staff during physical examinations, or by asking an open, nonleading question such as “How have you been feeling since you were last asked by us?” or “Have you had any new or changed health problems since you were last here?” All AEs and any required remedial action are recorded. The nature of AE, date (and time, if known) of AE onset, date (and time, if known) of AE outcome to date, severity, and action taken with the study drug because of - 156 - NAI-1537985011v1 the AE are documented together with the Investigator’s assessment of the seriousness on the AE and causal relationship to study drug and/or study procedure. [00304] Recording of AEs are done in the following manner: • Non-serious AEs are recorded in electronic data capture (EDC) following administration of IMP through EOS, and any non-serious AEs that occur prior to dose administration are captured in the medical history. For screen failed patients recording of non-serious AEs after the ICF was signed is not needed. • Serious AEs or SAEs are recorded in the EDC on AE eCRF page and the completed SAE report form is emailed to Xencor/CRO vendor for all patients randomized. The Investigator is responsible, within 24 hours of becoming aware of the SAE, to complete all required details on the initial and follow-up SAE report form and email to Xencor. If new information is added or details are changed, the submitted SAE report form should be retained as is, and a new (blank) SAE report form for the same case should be completed and marked as “follow-up,” signed and emailed to Xencor. [00305] All AEs should be recorded individually unless, in the opinion of the Investigator, the AEs constitute components of a recognized condition, disease, or syndrome. In the latter case, the condition, disease, or syndrome should be named rather than each individual symptom. Table 8 defines the windows for capturing serious and non-serious AEs. Table 8. Investigational Site Recording/Reporting of Adverse Events Type of Start of Reporting Window End of Reporting Window of
Figure imgf000158_0001
- 157 - NAI-1537985011v1 a AEs which are unlikely related or not related to study drug are considered to be not related events for the purposes of AE capture and regulatory reporting. b AEs which are possibly related, probably related, or related to study drug are considered to be related events for the purposes of AE capture and regulatory reporting. [00306] Xencor requests clarification of omitted and/or discrepant information from the initial notification or follow-up report(s) as needed. Xencor may also request additional information [00307] regarding the SAE in order to obtain the full clinical picture. The Investigator or an authorized delegate is responsible for providing the requested information in a Data Clarification Form (DCF) to Xencor within 24 hours of the request and updating AE eCRF in EDC. [00308] The initial SAE report from the investigational site must be followed up as soon as possible by completing a blank SAE report form (with the follow-up box checked). All additional events and existing event/s should be recorded with corresponding assessments, all new details should be included in the follow-up report. These SAE report/s should be emailed along with clear photocopies of other documents as necessary (e.g., hospital reports, discharge summaries, consultant reports, autopsy reports, etc.) with the study patient’s personal identifiers redacted. All relevant information obtained by the Investigator through review of these documents has to be recorded and forwarded to Xencor within 24 hours of receipt of the information. [00309] Should a death occur within the SAE reporting window (Table 6-Table 8), an AE record and an SAE report form should be completed, detailing the AE that resulted in the death (death is an outcome, not an event). The SAE must be reported to the Xencor Medical Monitor within 24 hours. [00310] The following assessments of AEs, shown below in the subsections, for both non- serious and serious events, should be done by the Investigators: 5.1.22.3 AE Severity/Intensity/Grades [00311] The Investigator can assess all AEs for severity, also known as intensity or grades, utilizing the NCI-CTCAE grading scale (Version 5.0). Note that some grades are not available for certain AEs (e.g., Headache can only be Grade 1, 2 or 3; and Sepsis can only be Grade 3, 4 or 5). AEs not contained within CTCAE Version 5.0 are rated on a 5-point scale (Table 9). - 158 - NAI-1537985011v1 Table 9. Adverse Event Grades Mild (Grade 1) Mild events are those which are easily tolerated with no disruption of normal daily activity. re at
Figure imgf000160_0001
[00312] The Investigator assess the causality/relationship between the IMP and the AE. One of the following categories should be selected based on good medical and scientific judgment, considering the definitions in Table 10 and all contributing factors. Table 10. Causality Assessment Guide For the purposes of regulatory reporting, if the Investigator chooses one of the following categories, “ ” e y
Figure imgf000160_0002
- 159 - NAI-1537985011v1 If the Investigator chooses one of the following below, the AE is identified as “not related by the Investigator” e al ear ge.
Figure imgf000161_0001
y p p g, g g . are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug-relatedness clearly exists (for example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia). b Rechallenge is when a drug suspected of causing an AE in a specific patient in the past is readministered to that patient. If the AE recurs upon exposure, this is termed a positive rechallenge. If the AE does not recur, this is termed a negative rechallenge. 5.1.22.5 Injection Site Reaction Assessments [00313] All local reactions at the site of injection are recorded as AEs. Injection sites are monitored for pain, tenderness, erythema and swelling using the intensity grading scheme presented in Table 11. All injection site reactions are also captured by using the Canfield photography system. Table 11. Injection Site Reaction Grading Scheme Intensity Grading
Figure imgf000161_0002
- 160 - NAI-1537985011v1 Intensity Grading Reaction Potentially
Figure imgf000162_0001
[00314] To identify cases of hypersensitivity reaction and in particular anaphylaxis in this study, the National Institute of Allergy and Infectious Diseases definition of anaphylaxis (Sampson et al. Ann Emerg Med.2006;47(4):373–80.) are used (Table 12), and the Immune System Disorders of NCI-CTCAE Version 5.0 are used to help characterize AEs related to hypersensitivity and immunogenicity. Table 12. Clinical Criteria for Diagnosing Anaphylaxis Anaphylaxis is highly likely when any one of the following three criteria are fulfilled: t
Figure imgf000162_0002
- 161 - NAI-1537985011v1 3. Reduced blood pressure after exposure to known allergen for that patient (minutes to several hours): a. Infants and children: low systolic blood pressure (age specific) or greater than 30% decrease at S [
Figure imgf000163_0001
p p pp y g non-allergic injection-related reactions. All patients with the onset of an AE event within 6 hours of the start of SC administration are queried and examined for signs and symptoms associated with hypersensitivity/anaphylactic reactions (skin, gastrointestinal, respiratory, cardiovascular, and neurologic systems). 5.1.22.7 Action Taken with Study Treatment Due to AEs Action taken with XmAb®27564 are reported as one of the following: • Dose not changed • Dose reduced • Drug interrupted • Drug withdrawn • Not applicable 5.1.22.8 Outcome of Adverse Event [00316] Outcome is defined as follows: • Not recovered or not resolved • Recovered or resolved • Recovered or resolved with sequelae • Recovering or resolving • Death related to AE • Unknown 5.1.23. Clinical Laboratory Safety Assessments [00317] Blood samples should be taken using standard venipuncture techniques. Blood sampling is performed according to site or laboratory standard operating procedures (SOPs). - 162 - NAI-1537985011v1 • The baseline laboratory test results for clinical assessment for a particular test is defined as the last measurement prior to the initial dose of study drug. • During the screening period, if a patient has an out-of-range value for a clinical laboratory parameter which the Investigator believes is not clinically significant, but the Investigator wants to confirm with a repeat laboratory test, a single repeat is allowed to confirm the initial result. If a subject tests positive for urine drugs of abuse (including the following: amphetamines/ecstasy, barbiturates, benzodiazepines, cocaine, opiates, methadone metabolites, and phencyclidine) and alcohol screens, the subject’s eligibility is discussed with the Xencor Medical Monitor. • A list of clinical laboratory tests to be performed during this study is presented in Table 13. Table 13. Clinical Laboratory Tests Hematology Chemistry Urinalysis Coagulation
Figure imgf000164_0001
- 163 - NAI-1537985011v1 Hematology Chemistry Urinalysis Coagulation Drugs of abuse testing Screening for Infection
Figure imgf000165_0001
hepatitis C antibody; MTB = mycobacterium tuberculosis; PBMC = peripheral blood mononuclear cell; PCR = polymerase chain reaction; SARS-CoV-2 Ab = severe acute respiratory syndrome coronavirus 2 antibody; SARS-CoV-2 Ag = severe acute respiratory syndrome coronavirus 2 antigen; TBNK = T, B, and natural killer cell; Treg = regulatory T cell a sCD25, IL-2, IL-5 is examined for both AD and psoriasis cohorts. For psoriasis cohort, additional cytokines including IL-6, IP-10, IL-23, IL-17 will be examined. For AD cohort, additional chemokines including TARC, MDC, cytokine IL-18 and Th2 biomarker periostin is examined. sCD25, IFN-gamma, IL-1, IL-4, IL-5, IL-6 IL-10, IL-12, TNF-alpha. b Microscopic analysis is reflexive after urine dipstick is positive. c Troponin I testing for patients with psoriasis only d Serum IgE and allergen-specific. IgE for patients with atopic dermatitis only. e Myocarditis-associated virus titers and PCR screening for patients with psoriasis only. - 164 - NAI-1537985011v1 [00318] For any laboratory test value outside the reference range that the Investigator considers clinically significant during the on-study period (i.e., following dose administration), the Investigator will: 1. Repeat the test to verify the out-of-range value and clinical significance. 2. Follow the out-of-range and clinically significant value to a satisfactory clinical resolution. 3. Record as an AE any laboratory test value that (1) is confirmed by repeat and the Investigator considers clinically significant, (2) requires a patient to be discontinued from the study, (3) requires a patient to receive treatment, or (4) requires a change or discontinuation of the study drug (if applicable). Clinically significant abnormal laboratory results are recorded as AEs and the relationship to the study drug is indicated as below. Laboratory values outside the normal range assessed as clinically significant should be reported as AEs. In general, a clinically significant laboratory value or finding would require some diagnostic or therapeutic intervention other than repeating the test. 5.1.24. Troponin I, Cardiology Consultation, Myocarditis-associated Viruses, and Cardiac MRI [00319] All patients with psoriasis have a cardiac MRI at Screening and are followed at baseline and throughout the study by serial high sensitivity Troponin I assays. Patients who have elevated Troponin I levels at screening should be screen failed. If a patient has a value for Troponin I above normal limits, the patient should be called back to clinic for an unscheduled visit and should have a directed physical examination, a 12-lead ECG, an urgent cardiology consultation, and a cardiac MRI. Myocarditis should be diagnosed using cardiac MRI and graded by the Lake Louise criteria for myocarditis (Friedrich et al. J Am Coll Cardiol.2009 Apr 28;53(17):1475–87.; Ferreira et al. J Am Coll Cardiol.2018;72(24):3158–76.). If positive, serial cardiac MRI studies should be done until event resolution. The following myocarditis-associated viruses should be assessed by serial titers and PCR: adenovirus, coxsackie B virus, echovirus, herpesviruses, parvovirus, and SARS-CoV-2 (Pollack et al. Nat Rev Cardiol.2015;12(11):670– 80.). - 165 - NAI-1537985011v1 [00320] Cardiac MRI data are collected and read centrally by a third party blinded to patient identity. Procedure specifics for cardiac MRI are detailed in the study manual. 5.1.25. Vital Signs [00321] Vital signs are assessed after the patient has been resting quietly for ≥ 5 minutes and as indicated in the Schedule of Assessment (Tables 6A and 6B ). On non-dosing days, vital signs should be measured prior to blood sampling. The following vital signs are measured: • Blood pressure (systolic and diastolic [mmHg]) is measured after the patient has been resting quietly for at least 5 minutes. • Heart rate (beats per minute [bpm]) is collected after the patient has been resting and at rest for ≥ 5 minutes. • Respiratory rate (breaths per minute) • Oral body temperature (°C) • Blood oxygen saturation by pulse oximetry. Oxygen saturation levels are captured at each vital sign collection. • The following vital signs abnormalities is recorded as AEs: 1. Vital signs are considered clinically significant initially and on confirmation 2. Require a patient to be discontinued from the study 3. Require a patient to receive treatment 4. Require a change or discontinuation from the study drug (if applicable) 5.1.26. Physical Examination [00322] Complete (at screening and Day 1) or abbreviated (symptom-directed on study) PEs, including height, weight and BMI, are performed as indicated in the Schedule of Assessment (Tables 6A and 6B). [00323] The complete PE includes an assessment of general appearance and a review of systems (dermatologic [thorough skin examination]), head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic, and psychiatric systems). [00324] An abbreviated PE is symptom-directed and need not include detailed examination of all systems. A complete PE (including thorough skin examination, and excluding genital, rectal, and breast examinations [unless indicated]) is performed at screening. For all other time points, - 166 - NAI-1537985011v1 symptom-directed PEs are performed; a thorough skin examination is performed at every visit. Abnormal findings is documented in the patient’s eCRF. [00325] A following abnormal PE finding that is considered clinically significant is recorded as an AE: 1. Requires the patient to be discontinued from the study, 2. Requires the patient to receive treatment; and/or 3. Requires a change or discontinuation of the study drug (if applicable) recorded as an AE. 5.1.27. Electrocardiogram Assessments [00326] The timing of ECGs is noted in the Schedule of Assessment (Tables 6A and 6B). On all dosing days during the core study, supine ECGs are performed predose and 4 hours after SC injection. The 12-lead ECGs are performed after the patient has been resting supine for ≥ 5 minutes. The ECG includes all 12 standard leads. The following ECG parameters are collected: PR interval, QRS interval, RR interval, QT interval, QTc, and QTcF interval. [00327] Electrocardiogram assessments include interpretation of the tracings (e.g., rhythm, presence of arrhythmia or conduction defects, morphology, any evidence of myocardial infarction, or ST segment, T-wave, and U-wave abnormalities). The Investigator or designee is responsible for reviewing and over-reading the ECG interpretation, for assessing whether the ECG machine interpretation findings are accurate, appropriate, normal or abnormal, and for providing corrected interpretations, as appropriate. In addition, any abnormal ECGs are assessed for clinical significance. [00328] Additional ECGs may be obtained if clinically indicated. Any additional relevant data obtained by the Investigator during the course of this study is supplied to the Sponsor. For any ECG that the Investigator considers clinically significant, the Investigator will: • Repeat the ECG; and/or • Follow-up ECG(s) are obtained if any significant abnormalities are detected after dose administration to document resolution and as clinically indicated. [00329] Record as an AE any ECG that (1) is confirmed and the Investigator considers clinically significant, (2) requires a patient to be discontinued from the study, (3) requires a patient to receive treatment, or (4) requires a change or discontinuation of the study drug (if applicable). All ECGs must be evaluated by a qualified physician for the presence of abnormalities. - 167 - NAI-1537985011v1 5.1.28. Pregnancy [00330] The teratogenic potential of XmAb®27564 is unknown. If a female patient, or the female partner of male patient, becomes pregnant despite use of contraception, the Investigator and Xencor have a responsibility to monitor the outcome of all pregnancies reported during the clinical study. [00331] Pregnancy alone is not regarded as an AE unless there is a suspicion that the IMP may have interfered with the effectiveness of a contraceptive medication. Elective abortions without complications should not be regarded as AEs, unless they were therapeutic abortions (see below). Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. All notifications of pregnancy should be documented on the pregnancy report form and reported through 120 days following cessation of study treatment, whether or not there is an associated AE or SAE. [00332] Each pregnancy notification must be reported by the Investigator to the Sponsor-CRO vendor within 24 hours after becoming aware of the pregnancy. The Investigator must follow-up and document the course and the outcome of all pregnancies even if the patient was withdrawn from the clinical study or if the clinical study has finished. Follow-ups occur at birth, at 6 months post-partum, and at 12 months post-partum. The follow-up period is deemed to have ended when the health status of the child has been determined on its birth or 1 year of age. [00333] All outcomes of pregnancy must be reported by the Investigator to the Sponsor on the pregnancy outcome report form within 24 hours after he/she has gained knowledge of the normal delivery or elective abortion, or other outcome. [00334] Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., maternal serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, birth defect) and reported within 24 hours of awareness in accordance with the procedure for reporting SAEs. [00335] Xencor-CRO vendor requests clarification of omitted or discrepant information from the initial notification. The Investigator or an authorized delegate is responsible for providing the requested information to Xencor within 24 hours of the request. 5.1.29. Treatment/Reporting of Overdose and Medication Errors - 168 - NAI-1537985011v1 [00336] In the event of an overdose (i.e., administration of study treatment which is above the maximum recommended dose) or medication errors (ie, errors in prescribing, storage, dispensing, preparation, or administration),, the physician should do the following: • Contact the Xencor Medical Monitor immediately, • Closely monitor the patient for any AE/SAE and laboratory abnormalities and document any AE/SAE and laboratory abnormalities in the appropriate form; • Obtain a serum PK sample if requested by the Xencor Medical Monitor (determined on a case by-case basis); and • Document the quantity and duration of the excess dose. Dosing error, if known, is documented by the unblinded pharmacist at the site. [00337] Decisions regarding dose interruptions or modifications are made by the Investigator in consultation with the Xencor Medical Monitor based on the clinical evaluation of the patient. There is no reversal agent available for XmAb®27564. All overdose cases should be reported as SAEs. 5.1.30. Statistics [00338] The statistical analysis are conducted following the principles as specified in International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Topic E9 (CPMP/ICH/363/96). [00339] All demographic, safety and efficacy data are listed and summarized in tabular format by dose cohort using descriptive statistics as appropriate. Descriptive statistics include mean, median, standard deviation, quartiles, min and max for continuous variables, and frequency counts and percentages for categorical variables. Data is displayed graphically as appropriate. [00340] PK/PD analysis of the blood include PK, ADA, transcriptomics, flow cytometry, and cytokine/soluble factor measurements as described in the following sections. [00341] After all subjects have completed the double-blind core study (subjects who did not enter extension phase had EOS visit and subjects who entered extension phase had Day 57 visit as defined in the core study assessment schedule), all the subjects’ data in the double-blind core study are locked and unblinded after the database has met the unblinding criteria as required by data management. The database lock and unblinding are performed for patients with psoriasis and patients with atopic dermatitis separately. Analysis are performed on the unblinded core study data. - 169 - NAI-1537985011v1 [00342] Pharmacokinetic, ADA, and PD data are analyzed as described in the following sections. A statistical analysis plan (SAP) prespecifying details for all analyses is completed prior to database lock. Any deviations from the planned analyses is described in the final clinical study report. 5.1.30.1 Sample Size and Power [00343] No formal sample size calculations were performed. The study enrolls approximately 48 patients in total with psoriasis, with 8 patients per cohort, and approximately 80 patients with atopic dermatitis with 16 patients per cohort. The number of patients enrolled is considered to be typical for similar phase 1 MAD studies and sufficient to meet the study objectives. Analysis Set: The following analysis sets are defined for the double-blind core study • Randomized Analysis Set: All patients who signed the informed consent, successfully complete screening, and receive a randomization number. • Safety Analysis Set: All patients who received any amount of XmAb®27564 or placebo. • Efficacy Analysis Set: All patients who received any amount of XmAb®27564 or placebo, have baseline and at least 1 post-baseline PASI score or EASI score for psoriasis and atopic dermatitis, respectively. • Pharmacokinetic Full Analysis Set: All patients who received a dose of XmAb®27564 and have at least 1 concentration data point. • Pharmacokinetic Evaluable Analysis Set: All patients who received a dose of XmAb®27564 and have a sufficient PK profile to derive at least 1 PK parameter. • Pharmacodynamic Analysis Set: All patients who received a dose of XmAb®27564 or placebo and have at least 1 PD data point. The definition applies to cytokine and flow cytometry data separately. • Immunogenicity Analysis Set: All patients who received a dose of XmAb®27564 and have at least 1 postdose ADA data point. 5.1.30.2 Efficacy Analyses [00344] The efficacy analysis are exploratory in nature. Unless otherwise specified, the efficacy analyses is performed by dose cohort at each visit if appropriate. No formal hypothesis testing is performed. The exploratory efficacy variables for patients with psoriasis include the following: - 170 - NAI-1537985011v1 • PASI • sIGA • BSA • DLQI [00345] The analysis of the exploratory efficacy objective of this study is based on the change from baseline to Day 57 of the efficacy variables (PASI, sIGA, BSA and DLQI). [00346] The percentage of patients with a greater than or equal to 75% reduction from baseline in PASI score (PASI 75) is tabulated by dose cohort at each visit. PASI 50 and PASI 90 are summarized in the similar manner. PASI observed values, change and percentage change from baseline values are summarized descriptively as continuous variables. [00347] The proportion of patients achieving a sIGA of 0 or 1 is summarized by dose cohort at each visit. The proportion of patients in each categorical level of sIGA score is also summarized. [00348] Observed values, change and percent change from baseline values in BSA and DLQI are summarized by dose cohort at each visit. [00349] The exploratory efficacy variables for patients with atopic dermatitis include EASI, vIGA-AD, PP-NRS, BSA involvement of atopic dermatitis, and DLQI. The percentage of patients with 50% or more reduction from baseline in EASI score (EASI 50) are tabulated by dose cohort at each visit. EASI 75 and EASI 90 are summarized in a similar manner. EASI observed values, change and percent change from baseline are summarized descriptively as continuous variables. The proportion of patients achieving a vIGA-AD of 0 or 1 and reduction from baseline ≥ 2 points are summarized. Observed values and change from baseline in vIGA- AD are summarized as continuous variables. Observed values, change and percent change from baseline in BSA involvement and DLQI are summarized. The observed values, change and percent change from baseline are summarized for weekly mean PP-NRS during the core study. The weekly mean PP-NRS is calculated as the average of the reported daily PP-NRS within the week. The proportion of patients achieving a reduction of ≥ 4 points from baseline in weekly mean PP-NRS score during the core study are summarized for each week. For the OLE, the daily PP-NRS score collected at the scheduled visits will be used in the analysis. - 171 - NAI-1537985011v1 [00350] The line graphs of mean observed values, change and percent change from baseline in efficacy variables over time may be plotted. The categorical response variables may be plotted in line or bar plots. [00351] The SAP is provide a detailed description of analysis methods. Additional exploratory analyses may be specified in the SAP. Safety Analyses [00352] Safety variables include the following: • AEs • Physical examinations (including thorough skin examination) • Vital signs • ECG • Clinical laboratory testing: − Clinical chemistry, hematology including eosinophils, coagulation, troponin I (for patients with psoriasis only), CRP, ferritin, urinalysis, viral testing (for patients with psoriasis only), and cardiac MRI (for patients with psoriasis only) • Concomitant medications • Medical history [00353] The extent of exposure to XmAb®27564 or placebo is summarized by dose cohort. [00354] Summary tables and listings are provided for all reported AEs. [00355] Drug names are classified by the WHO dictionary. [00356] Adverse events are coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). The verbatim term recorded by the Investigator is mapped to System Organ Class (SOC) and Preferred Term using MedDRA. [00357] Treatment-emergent AEs are defined as events with onset dates on or after the start of study treatment or events that are present before the first injection of XmAb®27654 and subsequently worsen in severity. Adverse-event-related endpoints include the following: • TEAEs • Treatment-emergent SAEs (TE-SAEs) • Treatment-related TEAEs • Treatment-related TESAEs - 172 - NAI-1537985011v1 • TEAEs by severity that are defined by NCI-CTCAE, Version 5.0 [00358] All AE-related endpoints are summarized by MedDRA SOC and preferred term. At each level of summation, patient is counted once under the greatest severity and strongest study drug relationship. All AEs are included in the listings. [00359] The hematology, chemistry, and other laboratory values and change from baseline values are summarized descriptively by dose cohort. The baseline value for each laboratory value is defined as the last assessment performed prior to administration of IMP. Patient listings of all laboratory data collected during the study are generated. Laboratory values outside normal limits are identified in the patient listings and include flags for high and low values. [00360] Vital sign results and change from baseline values are summarized descriptively for each scheduled time point. The baseline value for each vital sign measurement is defined as the last assessment performed prior to administration of IMP. The change in vital signs values from pre-injection are summarized for each post-injection point. Pre-injection assessments are defined as last vital assessment prior to a specified injection. Patient listings of all vital data collected during the study are presented. [00361] Electrocardiogram values and change from baseline values are summarized descriptively for each scheduled time point. Patient listings of all ECG data collected during the study are generated. 5.1.31. Pharmacodynamic Analyses [00362] All or key observed PD data and change from baseline data are summarized using descriptive statistics and are listed and summarized in tabular and/or graphical form. Descriptive statistics on continuous data include mean, median, standard deviation, and range, while categorical data may be summarized using frequency counts and percentages. 5.1.32. Pharmacokinetic Analysis [00363] The PK parameters are computed using noncompartmental and/or compartmental methods, whichever best describes the data. [00364] Data analysis may include assessment of dose proportionality, steady state conditions and drug accumulation with repeated dosing. [00365] In addition, population PK analysis may be conducted to develop a model to describe the concentration-time profile of XmAb®27564. 5.1.33. Immunogenicity Assays - 173 - NAI-1537985011v1 [00366] Immunogenicity is assessed by measuring serum levels of anti-XmAb®27564 binding antibodies by ICON Laboratory Services, Inc., using a fully validated electrochemiluminescent assay method. Immunogenicity results are listed and displayed graphically by overlaying immunogenicity parameter on drug serum concentrations over time. Incidence of confirmed positivity is summarized and additional analyses of time to onset of ADA, duration of ADA positivity, neutralizing antibodies, and impact on drug serum concentrations may also be performed. 5.1.34. Guidance for the management of possible adverse drug reactions - 174 - NAI-1537985011v1 l - a k e i r d t a e i u r o n a r l p l a a ) e y
Figure imgf000176_0001
se d a r Gl 3 l - 3 A 1 G 4 G 2 G 3 3 - 3- G G 1 1 G G 4 G 1 G 4 G siti t a s r e n o t e r i c d r t n n o s c u o a P i e s f c it n s e a y D r l a 1 i i/ dr s n o t i y i c l i o h t a c i g v 1 1 a n c o i t o t a v o h d e s p o m o l 0 o s e 5 8 y c i e t f c p a me r ni m s al r u h s 9 7 3 M n a I e r y c L n i o f E n e I N a 5 R 1- I A N t n e R De g Aa n a ht t i we n e t k a a e r T n o y i t c t A
Figure imgf000177_0001
e d a ) e r 0 . v G s 5 v o b y n o E 2 a t i c i r i t i A d n d n x o o ) d nC a a Go T 1 3 1 T ( CC ( G G G de t a l n e oi R t p g r ur s o s b e s ) S DR a l a e R e D a l l A e r C ( 1 v b i m / ss a e e e 1 o h n 1 r i m 0 k o r 5 8 P r 9 a i o t d n 7 3 D y C y 5 s 1- I A N t n e R De g Aa n a ht t i we n e t k a a e r T n o y i t c t A e d
Figure imgf000178_0001
a ) r 0 . G s y n5 t o v i E c i r i t i A x o d nC o ) Go T C 2 T ( C ( G de t a l e R g ur s DR e D l 1 v b A 1 i 1 s 0 s 5 o 8 P 9 7 3 5 1- I A N r t n e R De g Aa n a ht t i we n e t k a a e r T n o y i t c t A e
Figure imgf000179_0001
d a ) r G s 0 . n5 v y o E 4 t i r i t i A d c i x o d C n a o ) n G o T 3 T ( CC ( G de t a l e R g ur s DR e D l 1 b A v 1 i 1 s 0 s 5 o 8 P 9 7 3 5 1- I A N t e R De g Aa a
Figure imgf000180_0001
p M mD a t e s A ( e s h d s n t e o t a . l e i t u d e d o h , n t e l e e b h it o t bi v s c s e e s n n a e o h t u g s o l p f n u r c s a o a d n - s a t n o i i a t n t n g e it n v u l b a r it e o s e o s O f e t h t e r - • 9 7 1 - ht t i n we n m e t k a s a e r E T T A no y i d o t t e c u t A S u d e d a ) r 0 . G s 5 v y n t o i E c i r i t i A x o ) d nC o G o T T ( CC ( de t a l e R g ur s DR e D l A 1 v b 1 i 1 s 0 s 5 o 8 P 9 7 3 5 1- I A N 5.2 EXAMPLE 2 – Single dose Phase 1a study of an IL-2 Fc fusion protein (e.g., XmAb®27564) [00367] This study is the first-in-human, placebo-controlled, double-blind, single ascending- dose study, in which healthy adult subjects received XmAb®27564 subcutaneously and were evaluated for safety, tolerability, immunogenicity, pharmacokinetics (PK), and pharmacodynamic (PD) (e.g., for 30-45 days). Each subject was admitted to the study unit for a total of 4 overnight stays; subjects returned for outpatient assessments through 21 days and were followed for safety an additional 30 days. After Cohort 3, the safety follow-up period was extended from 30 days to 45 days. This study is directed to a single-dose Phase 1a study of an IL-2 Fc fusion protein (e.g., XmAb®27564) administered subcutaneously to healthy subjects. XmAb®27564 is a monovalent interleukin-2 Fc (IL-2-Fc) fusion protein, engineered to selectively activate and expand regulatory T cells (Tregs) for the treatment of patients with autoimmune diseases. XmAb®27564 was engineered with dramatically lowered potency and heightened binding affinity for the IL-2 alpha receptor (CD25), resulting in selective activation of regulatory T cells (Tregs). Tregs prevent autoimmunity by suppressing other immune cells from attacking normal tissue; however, in many autoimmune diseases, Tregs become dysregulated. Tregs have an important role in homeostasis and in autoimmune disease (FIG.4): 1) regulatory T cells (Tregs) are CD4+FoxP3+ cells expressing CD25 (IL-2Rα) that maintain immune tolerance in tissues by suppressing the function of both CD4 and CD8 effector T cells; 2) Tregs are dysfunctional in most autoimmune diseases; 3) a therapeutic approach has been to restore Treg numbers and function via a low-dose IL-2 regimen (e.g., Treg homeostasis depends on IL-2; and IL-2 as a drug suffers from fast in vivo clearance and a narrow therapeutic index). An existing approach to restore normal immune activity and improve outcomes for patients has been to activate Tregs with IL-2 provided therapeutically at low doses. These regimens, however, suffer from a narrow therapeutic window, because IL-2 is a highly potent molecule that also activates the immune cell populations that Tregs are intended to suppress. [00368] XmAb®27564 was engineered with reduced binding affinity for IL-2’s beta receptor (IL-2Rβ, CD122) and increased binding affinity for its alpha receptor (IL-2Rα, CD25) to selectively target Tregs, and with 400- to 1000-fold reduced potency to improve the half-life of XmAb®27564 and to reduce its toxicity compared to wildtype IL-2 (FIG.5). XmAb®27564 is based on XmAb® cytokines approach for creating cytokine therapies (e.g., overcomes native - 180 - NAI-1537985011v1 cytokine short half-life and high toxicity; and systematically engineer a broad portfolio of cytokines). Integration of XmAb® heterodimeric Fc domain provides a stable protein scaffold and improves XmAb®27564 pharmacologic properties. The Xtend™ technology enhanced XmAb®27564 circulating half-life. In preclinical studies, XmAb®27564 was well-tolerated, promoted the selective and sustained expansion of Tregs and exhibited a favorable pharmacokinetic profile. Studies with XmAb®27564 showed that: XmAb®27564 exhibited extended half-life and good tolerability in non-human primates (NHPs); and XmAb®27564 selectively promoted Tregs and extended half-life due to low potency and Xtend™ Fc domain (FIGS.6A-6B). Approximately 1000X reduction in binding of XmAb®27564 to IL2-Rβγ resulted in reduced overall potency and greater selectivity for Treg activation over conventional T cells (Tcons) and natural killer (NK) cells (FIGS.6A-6B; Treg EC50 of 21nM and 0.06nM, respectively). The loss of internalization in vivo through IL-2Rβγ resulted in large gains in pharmacological exposure (FIGS.6C-6D). It has been shown that second potency-tuned XmAb Cytokine program (e.g., XmAb®306) showed marked target cell expansion and good tolerability in human clinical trials. XmAb®306, an IL15-IL15Rα-Fc fusion in oncology, showed consistent and robust dose-dependent NK cell expansion and accumulation upon repeat dosing, reaching 40-100x higher than baseline in higher dose cohorts. [00369] The Phase 1a studies using XmAb®27564 showed that XmAb®27564’s design gave dramatic Treg increases and unprecedented durability for a single dose, with high levels of Treg populations sustained for at least 3 weeks. [00370] The Phase 1a study enrolled 48 healthy subjects, with six dose-level cohorts each randomizing six subjects to an IL-2 Fc fusion protein (e.g., XmAb®27564) and two subjects to placebo. The six dose-level cohorts included six subjects in each of 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, and 0.065 mg/kg cohorts (FIG.7). A dose escalation review committee (DERC) reviewed each cohort’s safety, immunogenicity, PK, and PD data before approving each dose escalation. Each subject was admitted to the study unit for a total of 4 overnight stays; subjects returned for outpatient assessments through 21 days and were followed for safety an additional 30 days. After Cohort 3, the safety follow-up period was extended from 30 days to 45 days. A total of 12 subjects received placebo (2 subjects for each of the six dose-level cohorts). The demographics of the subjects in this study is provided in Table 15. Assessments were determined at Days -1, 0, 8, 10, 21, and 43. The outcome measures were: - 181 - NAI-1537985011v1 1) safety and tolerability; and 2) pharmacokinetics in healthy subjects including analysis of immunomodulatory biomarkers (e.g., T-cell populations). [00371] Of the 48 subjects enrolled into the study, a single subject chose to withdraw early; all others completed the study. A total of 36 subjects received XmAb®27564; 12 subjects received placebo. [00372] Adverse events observed during the study were experienced by 72% of subjects receiving XmAb®27564. The most common adverse event was injection site reaction observed in 25 of 36 subjects (69%) of subjects receiving XmAb®27564, including: 4 of 6 (67%) receiving 0.003 mg/kg (Cohort 1); 2 of 6 (33%) receiving 0.007 mg/kg (Cohort 2); 3 of 6 (50%) receiving 0.015 mg/kg (Cohort 3); 5 receiving 0.025 mg/kg and 5 receiving 0.040 mg/kg (Cohorts 4 and 5, respectively), and in all subjects (100%) receiving 0.065 mg/kg XmAb®27564 (Cohort 6). All AEs of injection site reaction were mild in severity for Cohorts 1 through 3. In Cohort 4 (0.025 mg/kg), all events were mild with the exception of a single event reported as moderate in severity; in Cohorts 5 and 6 (0.040 and 0.065 mg/kg, respectively) approximately 50% of events were mild and 50% moderate across each cohort; no injection site reactions were reported to be severe. Treatment-emergent AEs occurring in 2 or more subjects receiving XmAb®27564 included thermal burn and pruritus (6% each), and headache (8%). No SAEs, AEs ≥ Grade 3 were observed; no DLTs were observed. There were no clinically significant laboratory abnormalities, changes in vital signs, or ECGs. [00373] Post single-dose SC administration of XmAb®27564, drug concentration was measurable at the first sampled time point with no lag and reached a maximum at approximately 48 hours. In general, Cmax increased dose-proportionally while area under the curve (AUC) increased less than dose-proportionally with increasing dose from 0.003 to 0.065 mg/kg. Inter- individual variability varied between 8.81% to 29.8% for Cmax and 10.2% to 18.3% for AUClast indicating that PK profiles are consistent within a cohort and distinguishable across dose levels explored. The dose-dependent PK profile is in line with the expected PD effect of XmAb®27564 represented by an increase in target receptor levels (CD25) on T-cells and the consequent impact of target mediated drug disposition on XmAb®27564 elimination. One subject was confirmed positive for anti-drug antibody (ADA) at a low magnitude on day 45 postdose with no apparent impact on the PK or PD profile of XmAb®27564. - 182 - NAI-1537985011v1 [00374] At the first 2 SAD dose levels, there was little evidence for total Treg expansion over 30 days of observation at the 0.003 or 0.007 dose levels. In contrast, at the third dose level of 0.015 mg/kg, all 6 subjects had at least a 1.8-fold expansion at one time point or more. The maximum mean-fold total Treg expansion was 4.0-fold on Day 15. CD25bright Treg subset, which represents activated Tregs, increased more dramatically with a mean 19.6-fold expansion in the 0.015 mg/kg cohort. Given the consistent increase in Treg populations at the 0.015 dose level, and the paucity of Treg changes at the two lower dose levels, the range for the minimally biologically active single dose was between the highest inactive dose level of 0.07 mg/kg and the lowest active dose level of 0.015 mg/kg. [00375] Further increases in Treg expansion were seen at dose levels higher than 0.015 mg/kg with the clearest increase observed at the highest 0.065 mg/kg dose level. At 0.065 mg/kg, total Tregs increased to a peak mean 7.34-fold increase corresponding to a mean increase of 187 ± 183 cells/microliter on Day 15 (FIGS.17A-17F). The majority of these Tregs were CD25hi Tregs, which were present at very low levels at baseline (mean of 2 ± 1 cells/microliter) and were 117-fold induced to a maximum mean of 140 ± 78 cells/microliter. CD25hi Tregs are thought to be functionally highly immunosuppressive Tregs. [00376] In brief, bulk Tregs (4+CD127loCD25+FoxP3+) and CD25bright Tregs were selectively expanded in healthy volunteers in a dose-responsive manner after a single administration of XmAb®27564. Treg elevations peaked at approximately Day 12-14 and remained elevated for at least 21 days following drug administration (FIGS.17A-17F). At the highest dose of 0.065 mg/kg, the mean peak increase in numbers of bulk Tregs and CD25bright Tregs were 8-fold and 117-fold above baseline, respectively. The expanded Tregs were characterized and the population was identified as activated/memory Treg (CD45RA-/FoxP3high) (FIGS.18A-18H), which is also positive for various immunoregulatory molecules including LAG3 (CD223), ICOS (CD278), TIGIT, 4-1BB (CD137), Fas (CD95), are HLA-DRhigh and Ki67 positive, consistent with a highly activated, proliferative, and immunosuppressive phenotype. Additionally, serum levels of IL-10, an immunosuppressive cytokine produced by Tregs, were increased in a dose- dependent manner, and at the highest dose level of 0.065 mg/kg were 15-fold increased at Day 10 after treatment, and a peak mean 16-fold increase in serum IL-10/IFN-g ratio occurred at Day 15 (FIGS.19A-19B). Overall, XmAb®27564 selectively induced Tregs that co-expressed - 183 - NAI-1537985011v1 high levels of FoxP3, CD25 as well as LAG3/4-1BB/ICOS/TIGIT and peripheral elevations in IL-10, consistent with systemic immunosuppressive bioactivity. [00377] The induction of Treg expansion was not paralleled by a concomitant increase in effector lymphocyte expansion. Consistent with the intended Treg selectivity of XmAb27564, conventional or all non-Treg cells (Tcons) and NK cells were minimally increased at doses higher than 0.015 mg/kg (< 2-fold increases). [00378] Eosinophilia is also an expected class effect of low-dose IL-2 and engineered IL-2, likely secondary to production of the eosinophil recruitment factor IL-5 by CD25-positive ILC2 cells. IL-5 increased in a dose-responsive manner and was paralleled by asymptomatic eosinophilia (FIGS.20 and 21). Although several subjects had increases of eosinophils outside the normal laboratory range, non of these subjects had AEs attributable to eosinophilia [00379] XmAb27564 by two design features: namely reduction of clearance as a consequence of reduced CD122/CD132 engagement and inclusion of the Fc-Xtend domain, enabling augmented duration of PK and PD activity. Indeed, subcutaneous XmAb27564 exhibited a prolonged terminal half-life of 9 to 11 days. Peak Treg expansion of 7.34-fold was seen at Day 15, and the expansion was durable with Treg expansion present at least 21 days after a single dose, boding well for MAD dosing at Q2W or longer. Table 15. Subject Baseline Characteristics Placebo 0.003 0.007 0.015 0.025 0.040 0.065 (N=12) m /k m /k m /k m /k m /k m /k
Figure imgf000185_0001
- 184 - NAI-1537985011v1 [00380] Safety: A single subcutaneous dose of XmAb®27564 was well tolerated, with no dose-limiting toxicities, no Grade 3 or greater adverse events (AEs), no serious AEs, no deaths, nor clinically significant laboratory safety abnormalities. AEs attributed to XmAb®27564 were mainly mild-to-moderate self-limited injection site reactions. Asymptomatic transient elevations of peripheral eosinophils were seen in a dose-dependent manner, similar to those reported with other biologics in the class. Table 16 shows the treatment related adverse events. Table 16. Treatment-related Adverse Events Number of Placebo 0.003 0.007 0.015 0.025 0.040 0.065 subjects (N=12) mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg
Figure imgf000186_0001
[00381] Laboratory findings and pharmacokinetics: Some subjects had transient, reversible elevations in blood eosinophils. However, no eosinophil-related AEs were observed. This laboratory increase may be related to the mechanism of action of CD25-targeting IL-2 drug candidate. No other clinically significant abnormalities in safety laboratory studies were observed. Terminal half-life is estimated to be 9-10 days at lower doses and 6-7 days at the highest dose, consistent with an increase in CD25 target-mediated clearance on the expanding Treg population. [00382] The Phase 1a study showed that XmAb®27564 promoted robust and durable expansion of CD25bright Tregs (FIGS.8A-8B). The study demonstrated that a single dose of an - 185 - NAI-1537985011v1 IL-2 Fc fusion protein (e.g., XmAb®27564) was well tolerated and generated a durable, dose- dependent and selective expansion of Tregs (FIG.8A). Results showed selective expansion of CD25bright regulatory T cells (Tregs) of 10x and higher beginning at 3rd dose level and reaching 117x increase over baseline at highest dose. Exceptional durability of Treg expansion relative to reported third-party data provided an opportunity to explore differentiated multi-week dosing schedules. XmAb®27564 was well tolerated including at the highest dose evaluated (0.065 mg/kg). In the highest dose cohort (0.065 mg/kg; Cohort 6), a 117-fold mean peak expansion over baseline in CD25bright cells was observed, with an 8-fold expansion in the bulk/total Treg population (FIG.8B and FIG.10B, respectively). Treg baseline counts are low integer values, leading to variability in fold change calculations. The numeric value in FIGS.8A-8B are the mean values. Peak fold change is the peak CD25brightFoxP3+ CD4 Treg cell absolute count at a post-treatment time point divided by absolute count at baseline (NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test) [00383] The Phase 1a study showed that XmAb®27564 promoted robust and durable expansion of CD25bright Treg/Tcon ratio (FIGS.9A-9B). The ratio of Tregs to conventional T cells also increased significantly in a dose-dependent manner (FIGS.9A-9B). Treg baseline counts are not used in Treg/Tcon ratio calculations, leading to less variability in ratio values. The numeric value in FIGS.9A-9B are the mean values. Dashed horizontal middle line represents the average of pre-dose values from all 48 subjects with ±2SD shown in grey lines above and below the middle dashed line (NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test). [00384] XmAb®27564 promoted robust and durable expansion of total Tregs (FIGS.10A- 10B). The numeric value in FIGS.10A-10C are the mean values. In FIG.10B, the peak fold change is the peak CD25+FoxP3+ CD4 Treg cell absolute count at a post-treatment time point divided by absolute count at baseline (NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test). FIG.10A shows that at the highest dose level of 0.065 mg/kg, the peak total Tregs increased by 8.31-fold, corresponding to a mean increase of 193 ± 122 cells/microliter on Day 15. The majority of these Tregs were CD25bright Tregs (FIG. 10C), which were present at very low levels at baseline (mean of 2 ± 1 cells/microliter) and were 117-fold induced to a maximum mean of 168 ± 98 cells/microliter. CD25bright Tregs are believed to be functionally highly immunosuppressive Tregs. - 186 - NAI-1537985011v1 [00385] At day 21, both CD25bright and total Treg counts remained markedly elevated, potentially supporting a multi-week dosing profile (FIGS.11A-11B). The numeric values in FIGS.11A-11B are the mean values (NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test). It was observed that CD25bright and bulk/total Treg remained expanded for at least 3 weeks (FIGS.11A-11B). All adverse events (AEs) were either Grade 1 or 2 (mild-to-moderate), self-limited, and resolved without intervention. Injection site reaction was the most reported AE. No serious AEs, dose-limiting toxicities or early discontinuations due to AEs were observed. No clinically significant abnormalities in vital signs and ECGs were observed. [00386] Results showed that the induction of Treg expansion was not paralleled by a concomitant increase in effector lymphocyte expansion. Consistent with the intended Treg selectivity of XmAb®27564, CD4+ or CD8+ Tcon or total NK cells (FIGS.12A-12C) were minimally increased (< than 2-fold). The Phase 1a study showed that XmAb®27564 induced minimal increases in conventional T cells and NK Cells (FIGS.12A-12C). FIGS.12A-12C show that such increases are within normal ranges or within 2 SD of baseline. Dashed horizontal middle line in FIGS.12A-12C represent the average of pre-dose values from all 48 subjects with ±2SD shown in grey lines above and below the middle horizontal dashed line. However, CD56bright NK cells, a potentially immunosuppressive cell type, were increased in a dose-dependent manner, as reported with other biologics in the class (FIG.12D). [00387] Peak fold induction of CD25bright and total Treg cells showed consistent dose response of Treg populations to XmAb®27564 (FIGS.13A-13B). The peak fold induction in FIGS.13A- 13B is the peak CD25bright Treg or total Treg cell absolute counts of each subject divided by the average of all pre-dose values from all subjects (n=48). The numeric value in FIGS.13A-13B is the mean values (NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test). The ratio of CD25bright/Tcon and total Treg/Tcon peak fold induction showed consistent dose response of Treg populations to XmAb®27564 (FIGS.14A-14B). The numeric value in FIGS.14A-14B is the mean value. The peak fold induction is the peak CD25bright Treg/Tcon or total Treg/Tcon ratios of each subject divided by the average of all pre- dose values from all subjects (n=48) (NS: p>0.05, *: p≤0.05, **: p≤0.01, ***:p≤0.001 compared with placebo treated cohort, Wilcoxon test). - 187 - NAI-1537985011v1 [00388] Pharmacokinetics (PK): The pharmacokinetics studies showed that the terminal half- life of about 9 to 11 days was observed across doses ranging from 0.003 mg/kg to 0.065 mg/kg of XmAb®27564 (FIG.15). The Cmax increased dose proportionally and the AUC increased less than dose proportionally due to target-mediated drug disposition as target population expands. A follow-up period increased from 30 to 45 days for cohorts 4-6 (0.025 mg/kg, 0.04 mg/kg, and 0.065 mg/kg of XmAb®27564, respectively). [00389] Pharmacodynamics (PD): As a single index of Treg selectivity and potential anti- inflammatory benefit, there was a dose responsive increase in the CD25bright Treg:CD4 Tcon ratio from 0.002 at baseline to a peak ratio of 0.14 on treatment, an increase largely maintained at 0.05 on Day 21 (FIGS.16A-16B). [00390] Overall, dose-dependent and selective expansion of CD25bright and total Tregs was observed throughout the study. The expansion of CD25bright Tregs with at least 10-fold increases over baseline began at the third dose level and reached a 117-fold increase over baseline at the highest dose. Total Tregs increased 8-fold over baseline at the highest dose. An important metric for selectivity, the ratio of Tregs to conventional T cells (which include effector T cells) increased consistently in a dose-dependent manner, with a ratio of 0.14 at the highest dose. Marked elevation of Tregs through at least day 21 provides potentially exceptional durability and supports exploring differentiated multi-week dosing schedules in further clinical studies. Minimal increases in natural killer (NK) cells and conventional T cells (Tcons) were observed [00391] This study showed that XmAb®27564 was well tolerated and generated a durable, dose-dependent and selective expansion of Tregs with a single dose. For example, 117-fold mean peak expansion over baseline in CD25bright cells and 8-fold mean peak expansion in total Tregs at highest dose was observed; marked elevation of Tregs sustained through at least day 21: CD25bright and total Tregs increased 44-fold and 4.5-fold at highest dose, respectively; Treg/Tcon ratio increased significantly in a dose-dependent manner; and all AEs Grade 1/2 resolved without intervention. [00392] Summary and Conclusion: XmAb®27564 is a potency-tuned, monomeric human IL-2 heterodimeric Fc-fusion protein with extended half-life and increased binding affinity for IL-2 receptor alpha (CD25) designed o selectively expand regulatory T cells (Tregs). Single-dose XmAb®27564 in healthy adult subjects induced Tregs and CD25bright Tregs 8-fold and 117-fold above baseline, respectively, and expansion persisted for at least 21 days. XmAb®27564 - 188 - NAI-1537985011v1 selectively induced Tregs and was well tolerated. XmAb®27564 PK and PD may support extended multi-week dosing intervals and has a Treg induction magnitude and durability that may be competitive or superior to other engineered IL-2 candidates in clinic. [00393] The first patient has been dosed in a newly initiated Phase 1b, multiple-ascending dose study of XmAb®27564 in patients with atopic dermatitis and psoriasis. Multiple dosing schedules are to be explored based on pharmacodynamics data (e.g., initially at every two weeks (Q2W) for lowest doses). * * * * * [00394] It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the present description. [00395] Although the invention is described in detail with reference to specific embodiments thereof, it will be understood that variations which are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. - 189 - NAI-1537985011v1

Claims

WHAT IS CLAIMED IS: 1. A method of treating plaque psoriasis or atopic dermatitis in a subject in need thereof, comprising subcutaneously administering to the subject an interleukin-2 (IL-2) Fc fusion protein, wherein the IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject every 12 to 16 days or every 27 to 31 days at a dose of about 0.003 mg/kg to about 0.100 mg/kg.
2. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least four cycles.
3. The method of claim 2, wherein the subject is administered the dose of about 0.007 mg/kg every 13 to 15 days or every 28 to 30 days.
4. The method of claim 3, wherein the subject is administered the dose of about 0.007 mg/kg every 14 days or every 30 days.
5. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least four cycles.
6. The method of claim 5, wherein the subject is administered the dose of about 0.015 mg/kg every 13 to 15 days or every 28 to 30 days.
7. The method of claim 6, wherein the subject is administered the dose of about 0.015 mg/kg every 14 days or every 30 days.
8. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles. - 190 - NAI-1537985011v1
9. The method of claim 8, wherein the subject is administered the dose of about 0.025 mg/kg every 13 to 15 days or every 28 to 30 days.
10. The method of claim 9, wherein the subject is administered the dose of about 0.025 mg/kg every 14 days or every 30 days.
11. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles.
12. The method of claim 11, wherein the subject is administered the dose of about 0.040 mg/kg every 13 to 15 days or every 28 to 30 days.
13. The method of claim 12, wherein the subject is administered the dose of about 0.040 mg/kg every 14 days or every 30 days.
14. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles.
15. The method of claim 14, wherein the subject is administered the dose of about 0.065 mg/kg every 13 to 15 days or every 28 to 30 days.
16. The method of claim 15, wherein the subject is administered the dose of about 0.065 mg/kg every 14 days or every 30 days.
17. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles.
18. The method of claim 17, wherein the subject is administered the dose of about 0.100 mg/kg every 13 to 15 days or every 28 to 30 days.
19. The method of claim 18, wherein the subject is administered the dose of about 0.100 mg/kg every 14 days or every 30 days. - 191 - NAI-1537985011v1
20. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
21. The method of claim 20, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles.
22. The method of claim 21, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 14 days or every 30 days for at least two cycles.
23. The method of any one of claims 20 to 22, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for at least 3 cycles.
24. The method of claim 23, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for at least 4 cycles.
25. The method of claim 24, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for 4 cycles.
26. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
27. The method of claim 26, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles.
28. The method of claim 27, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 14 days or every 30 days for at least two cycles.
29. The method of any one of claims 26 to 28, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for at least 3 cycles. - 192 - NAI-1537985011v1
30. The method of claim 29, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for at least 4 cycles.
31. The method of claim 30, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for 4 cycles.
32. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
33. The method of claim 32, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles.
34. The method of claim 33, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 14 days or every 30 days for at least two cycles.
35. The method of any one of claims 32 to 34, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for at least 3 cycles.
36. The method of claim 35, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for at least 4 cycles.
37. The method of claim 36, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for 4 cycles.
38. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
39. The method of claim 38, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. - 193 - NAI-1537985011v1
40. The method of claim 39, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 14 days or every 30 days for at least two cycles.
41. The method of any one of claims 38 to 40, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for at least 3 cycles.
42. The method of claim 41, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for at least 4 cycles.
43. The method of claim 42, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for 4 cycles.
44. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
45. The method of claim 44, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles.
46. The method of claim 45, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 14 days or every 30 days for at least two cycles.
47. The method of any one of claims 44 to 46, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for at least 3 cycles.
48. The method of claim 47, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for at least 4 cycles.
49. The method of claim 48, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for 4 cycles. - 194 - NAI-1537985011v1
50. The method of claim 1, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
51. The method of claim 50, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles.
52. The method of claim 51, wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 14 days or every 30 days for at least two cycles.
53. The method of any one of claims 50 to 52, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for at least 3 cycles.
54. The method of claim 53, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for at least 4 cycles.
55. The method of claim 54, wherein the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for 4 cycles.
56. The method of any one of claims 1 to 55, wherein the IL-2 Fc fusion protein is XmAb®27564 (XmAb®564).
57. The method of any one of claims 1 to 55, wherein the IL-2 Fc fusion protein is a biosimilar, biobetter, or bioequivalent of XmAb®27564 (XmAb®564).
58. The method of any one of claims 1 to 57, wherein the subject is a human subject.
59. The method of claim 58, wherein the human subject is 18 to 75 years of age.
60. The method claim 58 or 59, wherein the human subject has a body surface area (BSA) of psoriasis of ≥2%.
61. The method any one of claims 58 to 60, wherein the human subject has an Investigator’s Global Assessment of 2 (mild) to 4 (severe). - 195 - NAI-1537985011v1
62. The method of any one of claims 1 to 61, wherein the subject has not previously been administered a therapy for plaque psoriasis or atopic dermatitis.
63. The method of any one of claims 1 to 51, wherein the subject has previously been administered a therapy for plaque psoriasis or atopic dermatitis.
64. The method of any one of claims 1 to 63, wherein the subject has not previously been administered an oral treatment for plaque psoriasis or atopic dermatitis in the 4 weeks prior to the administration of the IL-2-Fc fusion protein.
65. The method of any one of claims 1 to 64, wherein the subject has not previously been administered a biologic treatment for plaque psoriasis or atopic dermatitis for 12 weeks or 5 half-lives, whichever is longer, prior to the administration of the IL-2-Fc fusion protein.
66. The method of any one of claims 1 to 65, wherein the subject has not previously been administered a phototherapy in the 4 weeks prior to the administration of the IL-2-Fc fusion protein.
67. The method of any one of claims 1 to 66, wherein the subject has not previously been administered a topical treatment for psoriasis or atopic dermatitis in the 2 weeks prior to the administration of the IL-2-Fc fusion protein.
68. The method of any one of claims 1 to 67, wherein the subject does not have any other inflammatory or dermatological condition besides the plaque psoriasis or atopic dermatitis.
69. The method of any one of claims 1 to 68, wherein the subject does not have any other form of psoriasis or atopic dermatitis.
70. The method of any one of claims 1 to 69, wherein the administering of the IL-2 Fc fusion protein results in an increase in the number of CD4+ regulatory T (Treg) cells in the subject as compared to before the administering.
71. The method of claim 70, wherein the number of CD4+ Treg cells is increased about 2- - 196 - NAI-1537985011v1 fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-fold, about 12-fold, about 13-fold, about 14-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, about 25-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, or about 100-fold.
72. The method of any one of claims 1 to 71, wherein the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD4+ effector T (Teff) cells in the subject as compared to before the administering.
73. The method of any one of claims 1 to 72, wherein the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of NK cells in the subject as compared to before the administering.
74. The method of any one of claims 1 to 73, wherein the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD4+ conventional T (Tcon) cells in the subject as compared to before the administering.
75. The method of any one of claims 1 to 74, wherein the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD8+ Tcon T cells in the subject as compared to before the administering.
76. The method of any one of claims 1 to 75, wherein the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a Psoriasis Area and Severity Index (PASI) score of about 50% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein.
77. The method of any one of claims 1 to 75, wherein the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a PASI score of about 75% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein.
78. The method of any one of claims 1 to 75, wherein the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a PASI score of about 90% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein. - 197 - NAI-1537985011v1
79. The method of any one of claims 1 to 78, wherein the administering of the IL-2 Fc fusion protein results in the subject having a Static Investigator’s Global Assessment (sIGA) score of 0, 1 or 2.
80. The method of any one of claims 1 to 79, wherein the administering of the IL-2 Fc fusion protein results in the subject having an improvement in a Dermatology Life Quality Index (DLQI) score as compared to the baseline DLQI score in the subject prior to the administering of the IL-2 Fc fusion protein.
81. The method of any one of claims 1 to 80, wherein the administering of the IL-2 Fc fusion protein results in the subject having a decrease in body surface area (BSA) of psoriasis or atopic dermatitis as compared to the baseline BSA of psoriasis or atopic dermatitis in the subject prior to the administering of the IL-2 Fc fusion protein.
82. The method of claim 81, wherein the BSA of psoriasis is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 60%, about 80%, about 90%, or about 100%.
83. The method of any one of claims 1 to 82, wherein the subject does not have another type of psoriasis besides the plaque psoriasis, or the subject has atopic dermatitis.
84. A method of treating plaque psoriasis or atopic dermatitis in a subject in need thereof, comprising subcutaneously administering to the subject a single dose of an interleukin-2 (IL-2) Fc fusion protein, wherein the IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the single dose is an amount of about 0.003 mg/kg to about 0.1 mg/kg.
85. The method of claim 84, wherein the single dose is an amount of 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, 0.065 mg/kg, or 0.1 mg/kg.
86. The method of claim 84 or 85, wherein the single dose is an amount of 0.065 mg/kg. - 198 - NAI-1537985011v1
87. The method of any one of claims 84 to 86, wherein the IL-2 Fc fusion protein is XmAb®27564 (XmAb®564).
88. The method of any one of claims 84 to 86, wherein the IL-2 Fc fusion protein is a biosimilar, biobetter, or bioequivalent of XmAb®27564 (XmAb®564).
89. The method of any one of claims 84 to 88, wherein the subject is a human subject.
90. The method of any one of claims 84 to 89, wherein the administering of the IL-2 Fc fusion protein results in an increase in the number of CD25bright Treg cells in the subject as compared to baseline.
91. The method of any one of claims 84 to 90, wherein the administering of the IL-2 Fc fusion protein results in an increase in CD25bright Treg/Tcon ratio in the subject as compared to baseline.
92. The method of any one of claims 84 to 91, wherein the administering of the IL-2 Fc fusion protein results in an increase in the number of total Treg cells in the subject as compared to baseline.
93. The method of claim 92, wherein the total Treg cells comprises CD25brightFoxP3+ CD4 Treg cells.
94. The method of any one of claims 90 to 93, wherein the increase is an increase of about 2- fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-fold, about 12-fold, about 13-fold, about 14-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, about 25-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, or about 100-fold.
95. The method of any one of claims 90 to 93, wherein the increase is an increase of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about - 199 - NAI-1537985011v1 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or more than about 100%.
96. The method of any one of claims 84 to 95, wherein the administering of the IL-2 Fc fusion protein does not result in a significant increase in conventional T cells (Tcon) and/or NK cells in the subject as compared to baseline.
97. The method of claim 96, wherein the significant increase is not more than two standard deviations from baseline.
98. The method of claim 91, wherein the increase in CD25bright Treg/Tcon ratio is 0.14. - 200 - NAI-1537985011v1
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JAMES A WELLS ET AL: "Attacking Cancer Cell Surfaceomes with Recombinant Antibodies Bispecific, Soluble TCR as the Next Therapeutic Platform 18-22 NOVEMBER 2019 ? LISBON, PORTUGAL ? LISBON CONGRESS CENTER Training Seminars n Deep Sequencing and Single Cell Analysis n Intro to Bispecifics n Genome Editing with CRISPR n Bi", 20 June 2019 (2019-06-20), XP055599264, Retrieved from the Internet <URL:https://www.pegsummiteurope.com/docs/librariesprovider8/agendaaa/pegs-europe-2019-brochure.pdf> [retrieved on 20190625] *

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