WO2021263040A1 - Formulations de pepticorps stables - Google Patents

Formulations de pepticorps stables Download PDF

Info

Publication number
WO2021263040A1
WO2021263040A1 PCT/US2021/038976 US2021038976W WO2021263040A1 WO 2021263040 A1 WO2021263040 A1 WO 2021263040A1 US 2021038976 W US2021038976 W US 2021038976W WO 2021263040 A1 WO2021263040 A1 WO 2021263040A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
peptibody
glp
pth
histidine
Prior art date
Application number
PCT/US2021/038976
Other languages
English (en)
Other versions
WO2021263040A8 (fr
Inventor
Christian Fiedler
Michael Graninger
Dominik MITTERGRADNEGGER
Tanvir TABISH
Joris Hoefinghoff
Original Assignee
Shire-Nps Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shire-Nps Pharmaceuticals, Inc. filed Critical Shire-Nps Pharmaceuticals, Inc.
Publication of WO2021263040A1 publication Critical patent/WO2021263040A1/fr
Publication of WO2021263040A8 publication Critical patent/WO2021263040A8/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to formulations of peptibodies comprising glucagon-like peptide-2 (GLP-2) or parathyroid hormone (PTH), or specified portions or variants thereof, fused to an immunoglobulin or a derivative thereof, which remain stable during storage.
  • GLP-2 glucagon-like peptide-2
  • PTH parathyroid hormone
  • the invention further relates to methods of making, storing, and using the peptibody formulations and, still further, to kits comprising said formulations.
  • Therapeutic polypeptide formulations that remain stable during storage are needed.
  • Therapeutic polypeptides can be particularly difficult to formulate because of their tendency to degrade over time and/or undergo aggregation and precipitation. Degradation, aggregation, and precipitation are all indicative of an unstable formulation. Such an unstable formulation is not commercially viable, as it cannot pass U.S. Food and Drug Administration approval.
  • Formulation variables that affect the degradation of polypeptides during storage include, but are not limited to, pH, the quantity of salts present, and the type and quantity of excipients.
  • temperatures, pressures, and time for freezing and drying cycles can affect the stability of a lyophilized peptide formulation. The role of most of these variables has been studied; however, the synergistic effect of the variables is still poorly understood.
  • GLP-2 Glucagon-like peptide-2
  • GLP-2 is a 33 amino acid peptide having therapeutic applications in the treatment of diseases of the gastrointestinal tract.
  • GLP-2 and analogs thereof act as trophic agents to enhance and maintain the functioning of the gastrointestinal tract and to promote growth of intestinal tissue.
  • GLP-2 peptibodies which include fusion proteins of GLP-2 with an Fc domain of an antibody via a linker sequence, are described in International Patent Publication Nos.
  • Parathyroid hormone is a secreted, 84 amino acid product of the mammalian parathyroid gland that controls serum calcium levels through its action on various tissues, including bone. Studies in humans with certain forms of PTH have demonstrated an anabolic effect on bone and have prompted significant interest in its use for the treatment of osteoporosis and related bone disorders, as well as hypoparathyroidism. Hypoparathyroidism is a life-long disease characterized by an inadequate production of parathyroid hormone (PTH) by the parathyroid glands. Because PTH is critical for regulation of calcium and phosphate levels, loss of PTH reduces calcium levels in blood and bones and increases phosphate levels (hypocalcemia and hyperphosphatemia).
  • hypocalcemia leads to symptoms such as neuromuscular irritability, including paresthesia, muscle twitching, laryngeal spasms (which can lead to inability to speak and to alert health providers to the underlying medical condition, which has led to delayed or incorrect treatment), and possibly tetany and seizures.
  • PTH(1-84) has recently been approved as a safe and effective treatment for hypoparathyroidism (sold by Shire-NPS Pharmaceuticals under the brand name Natpara®), and Natpara® PTH variants have also since been described. See e.g., U.S. Patent No. 5,496,801 and U.S. Publication No. US 2020/0247865.
  • PTH peptibodies which include fusion proteins of PTH and variants thereof with an Fc domain of an antibody directly or via a linker sequence, are described in U.S. Publication No. US 2020/0247865. Unlike other proteins that have been successfully formulated, PTH is particularly sensitive to various forms of degradation.
  • PTH may also be adsorbed to surfaces, form unspecific aggregates and/or precipitate, thereby reducing the available concentration of the drug.
  • the present disclosure provides for a formulation comprising a GLP-2 peptibody, a carrier, a buffer, at least one amino acid, and at least one excipient.
  • the formulation has a pH of from about 5 to about 8.
  • the present disclosure provides for a formulation comprising a parathyroid hormone (PTH) peptibody, a carrier, a buffer, at least one amino acid, and at least one excipient.
  • the formulation has a pH of from about 5 to about 8.
  • the carrier is an aqueous carrier.
  • the formulation is buffered to a pH of from about 6 to about 8. In some embodiments, the formulation is buffered to a pH of from about 6.5 to about 7.5.
  • the formulation comprises from about 5 mg/ml to about 1 g/ml of the GLP-2 peptibody or the PTH peptibody. In some embodiments, the formulation comprises from about 25 mg/ml to about 200 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the buffer is an arginine buffer, a lysine buffer, a glycine buffer, a glutamic acid buffer, a methionine buffer, a phosphate buffer, a histidine buffer, a histidine and glycine buffer, or an arginine and lysine buffer.
  • the buffer is a phosphate buffer, a histidine buffer, a histidine and glycine buffer, or an arginine and lysine buffer.
  • the buffer is a phosphate buffer. In some embodiments, the buffer concentration is from about 10 mM to about 1000 mM. In some embodiments, the buffer concentration is from about 50 mM to about 200 mM.
  • the buffer is a histidine buffer. In some embodiments, the buffer concentration is from about 1 mM to about 500 mM. In some embodiments, the buffer concentration is from about 5 mM to about 100 mM.
  • the buffer comprises histidine and glycine. In some embodiments, the buffer comprises from about 0.2 mM histidine to about 20 mM histidine and from about 1 mM glycine to about 100 mM glycine. In some embodiments, the buffer comprises from about 1 mM histidine to about 4 mM histidine and from about 5 mM glycine to about 20 mM glycine.
  • the buffer is an arginine and lysine buffer.
  • the buffer comprises from about 2 mM arginine to about 200 mM arginine and from about 2 mM lysine to about 200 mM lysine.
  • the buffer comprises from about 10 mM arginine to about 40 mM arginine and from about 10 mM lysine to about 40 mM lysine.
  • the at least one amino acid is selected from the group consisting of histidine, glycine, lysine, arginine, glutamic acid, methionine, and pharmaceutically acceptable salts thereof.
  • the at least one amino acid consists of at least two amino acids selected from the group consisting of histidine, glycine, lysine, arginine, glutamic acid, methionine, and pharmaceutically acceptable salts thereof.
  • the at least one amino acid consists of at least three amino acids selected from the group consisting of histidine, glycine, lysine, arginine, glutamic acid, methionine, and pharmaceutically acceptable salts thereof.
  • the at least one amino acid consists of at least four amino acids selected from the group consisting of histidine, glycine, lysine, arginine, glutamic acid, methionine, and pharmaceutically acceptable salts thereof.
  • the formulation comprises histidine, arginine, glutamic acid, and methionine.
  • the formulation comprises histidine and glycine.
  • the formulation comprises histidine, glycine, and methionine.
  • the formulation comprises arginine and lysine.
  • the formulation comprises from about 0.2 mM histidine to about 200 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 1 mM histidine to about 100 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 1 mM glycine to about 500 mM glycine or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 5 mM glycine to about 100 mM glycine or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 2 mM lysine to about 200 mM lysine or a pharmaceutically acceptable salt thereof.
  • the formulation comprises from about 10 mM lysine to about 40 mM lysine or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 9 mM arginine to about 900 mM arginine or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 5 mM arginine to about 200 mM arginine or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 9 mM glutamic acid to about 900 mM glutamic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 5 mM to glutamic acid about 200 mM glutamic acid or a pharmaceutically acceptable salt thereof.
  • the formulation comprises from about 0.2 mM methionine to about 800 mM methionine or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises from about 1 mM methionine to about 16 mM methionine or a pharmaceutically acceptable salt thereof.
  • the formulation comprises equimolar amounts of arginine and glutamic acid. In some embodiments, the formulation comprises equimolar amounts of arginine and lysine.
  • the at least one excipient comprises a polyol, an inorganic salt, a carbohydrate, a derivative of a carbohydrate, or a surfactant. In some embodiments, the at least one excipient comprises a carbohydrate and a surfactant. In some embodiments, the at least one excipient comprises a polyol selected from sorbitol, mannitol, xylitol, erythritol, threitol, glycerol, and ribitol.
  • the at least one excipient comprises a carbohydrate selected from sorbitol, mannitol, xylitol, erythritol, threitol, glycerol, ribitol, maltodextrin, sucrose, galactose, trehalose, arabinose, cellobiose, glyceraldehyde, fructose, xylose, ribose, dextrin, glucose, mannose, lactose, maltose, and raffmose.
  • the at least one excipient comprises a non-reducing sugar.
  • the non-reducing sugar is trehalose or sucrose.
  • the at least one excipient comprises sucrose.
  • the formulation comprises from about 0.2% to about 20% (wt/wt) sucrose.
  • the formulation comprises from about 1% to about 4% (wt/wt) sucrose.
  • the at least one excipient comprises trehalose.
  • the formulation comprises from about 0.5% to about 50% (wt/wt) trehalose.
  • the formulation comprises from about 3% to about 10% (wt/wt) trehalose.
  • the at least one excipient comprises a non-ionic surfactant.
  • the non-ionic surfactant is a sorbitan fatty acid ester, a glycerin fatty acid ester, a polyglycerin fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, NP-40, a polyoxyethylene sorbitol fatty acid ester, a polyoxyethylene glycerin fatty acid ester, a polyethylene glycol (PEG), a polyethylene glycol fatty acid ester, a polyethylene alkyl ether, Triton X-100, a polyoxyethylene polyoxypropylene alkyl ether; a polyoxyethylene alkylphenyl ether; a polyoxypropylene-polyethylene ester, a polyoxyethylene hydrogenated castor oil, a polyoxyethylene beeswax derivative, a polyoxyethylene lanolin derivative, a polyoxyethylene fatty
  • the non-ionic surfactant is a poloxamer. In some embodiments, the nonionic surfactant is PEG or a sorbitan fatty acid ester. In some embodiments, the sorbitan fatty acid ester is polysorbate. In some embodiments, the sorbitan fatty acid ester is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. In some embodiments, the sorbitan fatty acid ester is polysorbate 80 (PS80). In some embodiments, the formulation comprises from about 0.0005% to about 0.05% (wt/wt) PS80. In some embodiments, the formulation comprises from about 0.001% to about 0.01% (wt/wt) PS80.
  • the at least one excipient comprises an inorganic salt.
  • the inorganic salt is NaCl.
  • the formulation comprises from about 10 mM to about 1500 mM NaCl. In some embodiments, the formulation comprises from about 50 mM to about 300 mM NaCl.
  • the formulation has an osmolality of from about 250 mOsmol / kg water to about 650 mOsmol / kg water. In some embodiments, the formulation has an osmolality of at least about 300 mOsmol / kg water.
  • the formulation comprises from 90 to 130 mM phosphate, from 15 to 30 mM histidine, from 75 to 125 mM arginine and glutamic acid, from 3 to 7 mM methionine, and from 75 to 125 mM NaCl and has a pH of from 6.6 to 6.8. In some embodiments, the formulation comprises from 90 to 130 mM phosphate, from 15 to 30 mM histidine, from 75 to 125 mM arginine and glutamic acid, from 4 to 12 mM methionine, and from 75 to 125 mM NaCl and has a pH of from 6.4 to 6.6.
  • the formulation comprises from 90 to 130 mM phosphate, from 15 to 30 mM histidine, from 75 to 125 mM arginine and glutamic acid, from 4 to 12 mM methionine, and from 1 to 4% (wt/wt) sucrose and has a pH of from 6.4 to 6.6.
  • the formulation comprises from 30 to 70 mM histidine, from 75 to 125 mM arginine and glutamic acid, from 4 to 12 mM methionine, and from 75 to 125 mM NaCl and has a pH of from 6.45 to 6.55.
  • the formulation comprises from 30 to 70 mM histidine, from 75 to 125 mM arginine and glutamic acid, from 4 to 12 mM methionine, and from 75 to 125 mM NaCl and has a pH of from about 6.65 to 6.75. In some embodiments, the formulation comprises from 5 to 15 mM histidine, from 25 to 75 mM glycine, from 75 to 125 mM NaCl, from 3 to 8% (wt/wt) trehalose, and from 0.001 to 0.010% (wt/wt) PS80 and has a pH of from 6.5 to 7.5.
  • the formulation comprises from 1 to 5 mM histidine, from 1 to 20 mM glycine, and from 100 to 200 mM NaCl and has a pH of from 6.5 to 7.5. In some embodiments, the formulation comprises from 1 to 5 mM histidine, from 1 to 20 mM glycine, from 100 to 200 mM NaCl, and from 0.001 to 0.010% (wt/wt) PS80 and has a pH of from 6.5 to 7.5.
  • the formulation comprises from 1 to 5 mM histidine, from 1 to 20 mM glycine, from 0.1 to 5 mM methionine, from 100 to 200 mM NaCl, and from 0.001 to 0.010% (wt/wt) PS80 and has a pH of from 6.75 to 7.25.
  • the formulation comprises from 10 to 30 mM arginine, from 10 to 30 mM lysine, from 80 to 150 mM NaCl, and from 0.001 to 0.010% (wt/wt) PS80 and has a pH of from 7.2 to 7.6.
  • a method for stably storing a formulation comprising a GLP-2 peptibody.
  • the method comprises providing the formulation, dispensing a volume of the formulation within a vessel, sealing the vessel, and storing the vessel at a temperature of from about 0°C to about 37°C.
  • the formulation is stable during storage over a period of time greater than one month.
  • a method for stably storing a formulation comprising a PTH peptibody.
  • the method comprises providing the formulation, dispensing a volume of the formulation within a vessel, sealing the vessel, and storing the vessel at a temperature of from about 0°C to about 37°C.
  • the formulation is stable during storage over a period of time greater than one month.
  • the vessel forms part of a prefilled syringe system.
  • a surface of the vessel in contact with the formulation comprises glass.
  • a surface of the vessel in contact with the formulation comprises plastic.
  • the vessel is stored at a temperature of from about 2°C to about 8°C. In some embodiments, the vessel is stored at a temperature of about 25°C.
  • the formulation maintains a visual appearance rating of at least A/2 on a scale of from A/1 (no particles visible / clear solution) to E/5 (particles visible ⁇ 1 mm / very turbid solution) over the period of time. In some embodiments, the formulation has a micro- flow imaging (MFI) measurement of less than 3000 particles / ml for ⁇ 10 ⁇ m-particles and less than 300 particles / ml for ⁇ 25 ⁇ m-particles over the period of time.
  • MFI micro- flow imaging
  • the formulation has an MFI of less than 1000 particles / ml for ⁇ 10 ⁇ m-particles and less than 200 particles / ml for ⁇ 25 ⁇ m-particles over the period of time.
  • the formulation shows a decrease in size-exclusion chromatography (SEC) main peak area of less than 10% over the period of time.
  • the formulation shows a decrease in the SEC main peak area of less than 5% over the period of time.
  • the formulation shows a decrease in SEC main peak area of less than 2% over the period of time.
  • the period of time is at least 2 months. In some embodiments, the period of time is at least 4 months. In some embodiments, the period of time is at least 6 months.
  • kits for use in treating a subject suffering a condition and in need of treatment for the condition comprising a vessel and the formulation or a lyophilized form of the formulation, optionally wherein the formulation has been stored according to any of the methods described above.
  • the vessel is part of a prefilled syringe system.
  • a surface of the vessel in contact with the formulation comprises glass.
  • the subject is human.
  • the formulation comprises a GLP-2 peptibody and the condition is a gastrointestinal condition.
  • the formulation comprises a GLP-2 peptibody and the condition is short bowel syndrome.
  • the subject is a human.
  • the formulation comprises a PTH peptibody and the condition is hypoparathyroidi sm .
  • a method for treatment of a subject suffering from a gastrointestinal condition and in need of treatment for the gastrointestinal condition comprises administering to the subject the formulation or the formulation stored by the method described above.
  • the formulation or the formulation stored by the method described above comprises a GLP-2 peptibody described above.
  • a method for treatment of a subject suffering from short bowel syndrome and in need of treatment for the short bowel syndrome comprises administering to the subject the formulation or the formulation stored by the method described above.
  • the formulation or the formulation stored by the method described above comprises a GLP-2 peptibody described above.
  • a method for treatment of a subject suffering from a hypoparathyroidism condition and in need of treatment for the hypoparathyroidism condition is provided.
  • the method comprises administering to the subject the formulation or the formulation stored by the method described above.
  • the formulation or the formulation stored by the method described above comprises a PTH peptibody described above.
  • glucagon-like peptide-2 GLP-2
  • PTH parathyroid hormone
  • the beneficial effects of the present invention include, as non-limiting examples thereof, stability, an in vivo long half-life, good efficacy, and suitability for the treatment prophylaxis, palliation or amelioration of e.g., short bowel syndrome and related disease, conditions, and/or symptoms, or hypoparathyroidism and related disease, conditions, and/or symptoms.
  • the terms “about” and “approximately” are used as equivalents. Any numerals used in this application with or without “about” or “approximately” are meant to cover any normal fluctuations appreciated by one of ordinary skill in the relevant art.
  • the term “approximately” or “about,” as applied to one or more values of interest refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%,
  • a “GLP-2 peptibody,” “GLP-2 peptibody portion,” or “GLP-2 peptibody fragment,” “GLP-2 peptibody variant,” or “GLP-2 variant peptibody” and the like can have, mimic or simulate at least one biological activity, such as but not limited to ligand binding, in vitro , in situ and/or preferably in vivo , of at least one GLP-2 peptide.
  • a suitable GLP-2 peptibody, specified portion, or variant can also modulate, increase, modify, activate, at least one GLP-2 receptor signaling or other measurable or detectable activity.
  • GLP-2 peptibodies may have suitable affinity -binding to protein ligands, for example, GLP-2 receptors, and optionally have low toxicity.
  • the GLP-2 peptibodies can be used to treat patients for extended periods with good to excellent alleviation of symptoms and low toxicity.
  • a “PTH peptibody,” “PTH peptibody portion,” or “PTH peptibody fragment,” “PTH peptibody variant,” or “PTH variant peptibody” and the like can have, mimic or simulate at least one biological activity, such as but not limited to ligand binding, in vitro , in situ and/or preferably in vivo , of at least one PTH peptide.
  • a suitable PTH peptibody, specified portion, or variant can also modulate, increase, modify, activate, at least one PTH receptor (PTH-R) signaling or other measurable or detectable activity.
  • PTH-R PTH receptor
  • PTH peptibodies may have suitable affinity -binding to protein ligands, for example, PTH receptors, and optionally have low toxicity.
  • the PTH peptibodies can be used to treat patients for extended periods with good to excellent alleviation of symptoms and low toxicity.
  • Non-limiting examples of PTH peptibodies are Natpara® PTH peptibody and Natpara® PTH variant peptibody, e.g., PTH-66.
  • PTH variant refers to any derivative of a full-length PTH, e.g., PTH(1-84), including, without limitation, a PTH(1-84) derivative comprising amino acid additions, deletions, and/or substitutions, a truncated (e.g., a C-terminally truncated) PTH(1-84), a PTH fused to a peptide or protein or protein domain, either directly or via a linker or spacer, and a PTH that has been post-translationally modified in any way known in the art (e.g., glycosylated, PEGylated, and the like) or combinations thereof.
  • control subject is a subject afflicted with the same form of disease as the subject being treated, who is about the same age as the subject being treated.
  • in vitro refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi- cellular organism.
  • in vivo refers to events that occur within a multi-cellular organism, such as a human and a non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur within a living cell (as opposed to, for example, in vitro systems).
  • linker refers to, in a peptibody, an amino acid sequence other than that appearing at a particular position in the natural protein and is generally designed to be flexible or to interpose a structure, such as an a-helix, between two protein moieties.
  • a linker is also referred to as a spacer.
  • a linker or a spacer typically does not have biological function on its own.
  • PEG includes polyethylene glycol) in any of its forms, including alkoxy PEG, difunctional PEG, multi-arm PEG, forked PEG, branched PEG, pendent PEG (i.e. PEG or related polymers having one or more functional groups pendant to the polymer backbone), or PEG with degradable linkages therein.
  • polypeptide refers to a sequential chain of amino acids linked together via peptide bonds.
  • the term is used to refer to an amino acid chain of any length, but one of ordinary skill in the art will understand that the term is not limited to lengthy chains and can refer to a minimal chain comprising two amino acids linked together via a peptide bond.
  • polypeptides may be processed and/or modified.
  • polypeptide and peptide are used interchangeably.
  • polypeptide can also refer to proteins.
  • prevent when used in connection with the occurrence of a disease, disorder, and/or condition, refers to reducing the risk of developing the disease, disorder and/or condition. See the definition of “risk.”
  • the term “subject” or “patient” are used interchangeably herein and refer to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse or primate).
  • a human includes pre- and post-natal forms.
  • a subject is a human being.
  • a subject can be a patient, which refers to a human presenting to a medical provider for diagnosis or treatment of a disease.
  • the term “subject” is used herein interchangeably with “individual” or “patient.”
  • a subject can be afflicted with or is susceptible to a disease or disorder but may or may not display symptoms of the disease or disorder.
  • the “subject” can be a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey, such as a cynomolgus monkey, chimpanzee, baboon and a human), and more preferably a human.
  • a non-primate e.g., a cow, pig, horse, cat, dog, rat, and mouse
  • a primate e.g., a monkey, such as a cynomolgus monkey, chimpanzee, baboon and a human
  • the subject is a mammal, preferably a human, with one or more diseases or disorders.
  • the subject is a mammal, preferably a human, at risk of developing one or more diseases and/or disorders.
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • the term “therapeutically effective amount” of a therapeutic agent means an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the symptom(s) of the disease, disorder, and/or condition. It will be appreciated by those of ordinary skill in the art that a therapeutically effective amount is typically administered via a dosing regimen comprising at least one unit dose.
  • treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and/or reduce incidence of one or more symptoms or features of a particular disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease and/or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.
  • the term “subcutaneous tissue” is defined as a layer of loose, irregular connective tissue immediately beneath the skin.
  • the subcutaneous administration may be performed by injecting a composition into areas including, but not limited to, the thigh region, abdominal region, gluteal region, or scapular region.
  • Subcutaneous administration may be accomplished by injecting the composition with a syringe.
  • other devices for administration of the formulation are available such as injection devices (e.g., the Inject-easeTM and GenjectTM devices); injector pens (such as the GenPenTM); needleless devices (e.g., MediJectorTM and BioJectorTM); and subcutaneous patch delivery systems.
  • the term “isolated” in the context of a polypeptide refers to a polypeptide that is substantially free of cellular material or contaminating proteins from the cell or tissue source from which it is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized.
  • substantially free of cellular material includes preparations of a polypeptide in which the polypeptide is separated from cellular components of the cells from which it is isolated or recombinantly produced.
  • a polypeptide that is substantially free of cellular material includes preparations of a polypeptide having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein, polypeptide, peptide, or antibody (also referred to as a “contaminating protein”).
  • the polypeptide When the polypeptide is recombinantly produced, it may also be substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, or 5% of the volume of the polypeptide preparation.
  • culture medium represents less than about 20%, 10%, or 5% of the volume of the polypeptide preparation.
  • the polypeptide is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the polypeptide.
  • an “isolated” polypeptide is purified by a multi-step purification process that comprises two chromatography steps (e.g. cation exchange and anion exchange), a 100K ultrafiltration step, followed by a buffer exchange and concentration step in Ultrafiltration/Diafiltration mode.
  • the terms “stability” and “stable” as used herein in the context of a formulation comprising a polypeptide comprising one or more single variable domains refer to the resistance of the polypeptide in the formulation to aggregation, to particle generation, to the formation of degradation products, and/or to the formation of fragmentation products under given transportation and/or storage conditions. For example, a comparatively stable first formulation will have a longer shelf life than a comparatively less stable second formulation.
  • the stability of said polypeptide can be assessed by degrees of aggregation, particle generation, degradation and/or fragmentation compared to a reference measurement, optionally the reference measurement is taken of a reference formulation at any time or of the formulation comprising the polypeptide at a zero time point prior to being subjected to a stress condition.
  • a reference formulation may be a reference standard frozen at -20° C. or below -65° C. (such as e.g.
  • Degrees of aggregation, degradation and/or fragmentation may be measured by, as non- limiting examples, visual appearance, subvisible particle counting, size-exclusion chromatography (SEC) (e.g. HPLC-SEC), A350 nm turbidity, micro-flow imaging (MFI), high- performance size exclusion chromatography (SE-HPLC), RP-HPLC, IEX-HPLC, subvisible particle counting, analytical ultracentrifugation (AUC), dynamic light scattering (DLS), static light scattering (SLS), Fourier Transform Infrared Spectroscopy (FTIR), circular dichroism (CD), urea-induced protein unfolding techniques, intrinsic tryptophan fluorescence, differential scanning calorimetry techniques, OD320/OD280 ratio measurement, elastic light scattering, or various combinations thereof.
  • SEC size-exclusion chromatography
  • MFI micro-flow imaging
  • SE-HPLC high-performance size exclusion chromatography
  • RP-HPLC RP-HPLC
  • the term “effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a subject in need thereof. Note that when a combination of active ingredients is administered, the effective amount of the combination may or may not include amounts of each ingredient that would have been effective if administered individually. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug or drugs employed, the mode of administration, and the like.
  • carrier and “diluent” refers to a pharmaceutically acceptable (e.g., safe and non-toxic for administration to a human) carrier or diluting substance useful for the preparation of a pharmaceutical formulation.
  • exemplary diluents include sterile water, bacteriostatic water for injection (BWFI), a pH buffered solution (e.g. phosphate-buffered saline), sterile saline solution, Ringer's solution or dextrose solution.
  • fusion protein or “chimeric protein” refers to a protein created through the joining of two or more originally separate proteins, or portions thereof. In some embodiments, a linker or spacer will be present between each protein.
  • compositions of the invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce unwanted reactions when administered to a mammal (e.g., a human).
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • pharmaceutically acceptable salts described herein include, by way of non-limiting example, a nitrate, chloride, bromide, phosphate, sulfate, acetate, hexafluorophosphate, citrate, gluconate, benzoate, propionate, butyrate, subsalicylate, maleate, laurate, malate, fumarate, succinate, tartrate, amsonate, pamoate, p-tolunenesulfonate, mesylate and the like.
  • pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium- dependent or potassium), ammonium salts and the like.
  • the present invention provides a formulation comprising a GLP-2 peptibody or a PTH peptibody, a carrier, a buffer, at least one amino acid, and at least one excipient.
  • the formulation has a pH of from about 5 to about 8.
  • the carrier is an aqueous carrier.
  • the peptibodies of the present invention may have unique characteristics unlike those of recombinant human antibodies.
  • the present invention provides a formulation comprising a GLP-2 peptibody, wherein the GLP-2 peptibody is a GLP-2 receptor agonist.
  • GLP-2 receptor agonists are characterized as molecules that bind with, preferably selectively, and stimulate the human GLP-2 receptor, as reported by Monroe et al. in U.S. Patent No. 6,077,949 issued June 20, 2000, incorporated herein by reference. Briefly, GLP-2 receptor agonists are revealed as agents that trigger production of, or trigger an elevation in the level of, a second messenger coupled to the human GLP-2 receptor when exposed to a host cell that produces that receptor naturally or is transfected with DNA encoding that receptor.
  • the GLP-2 peptibody may be PEGylated, attached to PEG, or otherwise conjugated to PEG at one or more amino acids.
  • the PEG may be of any molecular weight and degree of branching suitable to increase the in vivo half-life of the GLP-2 peptibody.
  • h(Gly2)GLP-2 comprises the following peptide sequence:
  • GLP-2 peptibodies may include GLP-2 fused to an Fc sequence or an albumin sequence.
  • Exemplary GLP-2 peptibodies include one or more of the following:
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such amino acid sequence;
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%,
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such amino acid sequence;
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%,
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%,
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%,
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%,
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such amino acid sequence;
  • a GLP-2 peptibody comprising the amino acid sequence of or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%,
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such amino acid sequence;
  • a GLP-2 peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%,
  • GLP-2 peptibodies a linker sequence may be present between the GLP-2 sequence and another sequence, such as IgG1 Fc or human serum albumin.
  • the GLP-2 peptibody K274 has the amino acid sequence set forth in SEQ ID NO: 4.
  • the GLP-2 peptibody B264 has the amino acid sequence set forth in SEQ ID NO: 2.
  • the GLP-2 peptibody may be processed as a GLP-2 precursor polypeptide that comprises a signal peptide directly linked with GLP-2. Any number of signal peptides may be used, with an exemplary signal peptides having the following sequences: METPAQLLFLLLWLPDTTG (SEQ ID NO: 17) and METPAQLLFLLLLWLPDTTG (SEQ ID NO: 18).
  • h(Gly2)GLP-2 is described in U.S. Patent No. 7,847,061, issued December 7, 2010.
  • GLP-2 peptibodies are described in U.S. Application No. 16/640,965, filed February 21, 2020, or in International Application No. PCT/US18/59175, filed November 5, 2018, both of which are incorporated herein in their entirety for all purposes.
  • GLP-2 analogs and derivatives have been described in the literature. See U.S. Patent No. 5,789,379 issued June 20, 2000; W002/066511 published August 27, 2003; W099/43361 published October 14, 1999; WO04/035624 published April 29, 2004 and W004/085471 published October 7, 2004. Any of these GLP-2 analogs and derivatives may be conjugated to PEG.
  • Exemplary GLP-2 peptibodies include, but are not limited to, those comprising a sequence of SEQ ID NOS: 2-16. Any of the GLP-2 peptibody sequences above may further comprise a lysine (K) at the C-terminus. Also, the GLP-2 sequence in the GLP-2 peptibody may incorporate an amino acid substitution that renders the peptide resistant to the endogenous enzyme dipeptidyl peptidase IV (DPP-IV). Such analogs incorporate an appropriate substitution of the Ala2 residue desirably, but not essentially, by a genetically encoded amino acid, to permit recombinant production of the desired protein.
  • DPP-IV dipeptidyl peptidase IV
  • Amino acids that can usefully substitute at Alanine-2 to provide GLP-2 analogs that retain GLP-2 receptor agonist activity and are less susceptible to DPP-IV include Gly, D-Ala, Val, Glu, Lys, Arg, Leu and Ile. Still, other GLP-2 analogs include those substituted at Met-10 by an amino acid that is less sensitive to oxidation.
  • the GLP-2 peptibody can be derivatized, for instance at an internal or substituted lysine, to prolong serum half-life by conjugation with lipophilic groups, with polyethylene glycol groups, the Fc domain of immunoglobulins, with albumin or with any other functional group having the desired effect of reducing the rate at which the peptide is degraded endogenously following its administration.
  • Such derivatized forms may be derivatized analogs of GLP-2, which carry substitutions, such as conserved or non-conserved lysine substitutions having no appreciable negative effect on GLP-2 receptor activation but allowing for conjugation of the desired functional group.
  • GLP-2 or of GLP-2 analogs are considered to be GLP-2 receptor agonists if they exert their endogenous effect through the GLP-2 receptor after administration, even if this GLP-2 receptor agonist property is not displayed while in the pro-drug, pre-administration form.
  • GLP-2 peptibodies of the present invention can provide at least one suitable property as compared to known proteins, such as, but not limited to, at least one of increased half-life, increased activity, more specific activity, increased avidity, increased or decreased off rate, a selected or more suitable subset of activities, less immunogenicity, increased quality or duration of at least one desired therapeutic effect, less side effects, and the like.
  • a suitable GLP-2 peptibody e.g., a GLP-2 peptibody comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 4
  • a recombinant GLP-2 peptibody has an in vivo half-life of between 2 and 48 hours, between 2 and 44 hours, between 2 and 40 hours, between 3 and 36 hours, between 3 and 32 hours, between 3 and 28 hours, between 4 and 24 hours, between 4 and 20 hours, between 6 and 18 hours, between 6 and 15 hours, and between 6 and 12 hours.
  • the GLP-2 peptibodies or specified portion or variants thereof may be produced by at least one cell line, mixed cell line, immortalized cell or clonal population of immortalized and/or cultured cells. Immortalized protein-producing cells can be produced using suitable methods.
  • the at least one GLP-2 peptibody or specified portion or variant is generated by providing nucleic acid or vectors comprising DNA derived or having a substantially similar sequence to, at least one human immunoglobulin locus that is functionally rearranged, or which can undergo functional rearrangement, and which further comprises a peptibody structure as described herein.
  • the GLP-2 peptibodies can bind human protein ligands with a wide range of affinities (KD).
  • KD affinities
  • at least one human GLP-2 peptibody of the formulations described herein can optionally bind at least one protein-ligand with high affinity.
  • At least one GLP-2 peptibody can bind at least one protein-ligand with a K D equal to or less than about 10 -7 M or, more preferably, with a KD equal to or less than about 0.1-9.9 (or any range or value therein) ⁇ 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , or 10 -13 M, or any range or value therein.
  • K lysine
  • lysine can be added to C-terminus.
  • the GLP-2 peptibody is processed from a GLP-2 precursor polypeptide that comprises a signal peptide directly linked with GLP-2, with a linker between GLP-2 and an Fc region of any of IgG1, IgG2, IgG3, and IgG4.
  • the Fc region may be IgG1 with the LALA mutation.
  • the GLP-2 precursor polypeptide may have the following formula:
  • LALA refers to the L234A and L235A (EU numbering) mutations in an antibody.
  • the LALA mutations can greatly reduce binding to Fc gamma-Rs and in turn prevent the GLP-2 peptibodies from causing unwanted antibody effector functions. See Leabman, M.K. et al., “Effects of altered Fc gammaR binding on antibody pharmacokinetics in cynomolgus monkeys” mAbs 5(6):2013.
  • Silenced effector functions can be obtained by mutation in the Fc region of the antibodies, and different IgGs may have different silencer regions known to those of skill in the art.
  • IgG1 the following silencer regions are known and have been described in the art: LALA and N297A (Strohl, W., 2009, Curr. Opin. Biotechnol. vol. 20(6):685-691); and D265A (Baudino et al., 2008, J. Immunol. 181: 6664-69; Strohl, W., supra).
  • silent Fc IgG1 antibodies comprise the so-called LALA mutant (“hFcLALA”) comprising L234A and L235A (EU numbering) mutation in the IgG1 Fc amino acid sequence.
  • Another example of a silent IgG1 antibody comprises the D265A mutation.
  • Another silent IgG1 antibody comprises the N297A mutation, which results in aglycosylated/non-glycosylated antibodies.
  • the GLP-2 peptibodies disclosed herein comprise an IgG1 Fc region that may comprise the LALA mutation.
  • GLP-2 peptibodies may comprise GLP-2 fused to an Fc domain.
  • the Fc domain may be further modified to further extend the half-life of the GLP-2 peptibody.
  • half-life extension technology e.g. NHance technology by ArGenX, may be utilized in combination with the GLP-2 peptibodies of the disclosure.
  • the NHance technology is described, e.g., in U.S. Pat. No. 8,163,881, the contents of which are incorporated by reference herein in their entirety for all purposes.
  • the GLP-2 peptibodies according to the invention are provided as a divalent structure, i.e., having two copies of GLP-2 or portion or variant thereof and one copy of Fc.
  • the GLP-2 peptibodies according to the invention are provided as a monovalent structure, i.e., having one copy of GLP-2 or portion or variant thereof and one copy of Fc.
  • a suitable Fc domain comprises one or more amino acid mutations that lead to improved binding to FcRn.
  • Various mutations within the Fc domain that effect improved binding to FcRn are known in the art and can be adapted to practice the present invention.
  • a suitable Fc domain comprises one or more mutations at one or more positions corresponding to Thr 250, Met 252, Ser 254, Thr 256, Thr 307, Glu 380, Met 428, His 433, and/or Asn 434 of human IgG1.
  • a GLP-2 peptibody, or specified portion or variant thereof, that partially or preferably substantially provides at least one GLP-2 biological activity, can bind the GLP-2 ligand and thereby provide at least one activity that is otherwise mediated through the binding of GLP-2 to at least one ligand, such as a GLP-2 receptor, or through other protein-dependent or mediated mechanisms.
  • GLP-2 peptibody activity refers to a GLP-2 peptibody that can modulate or cause at least one GLP-2 dependent activity by about 20-10,000% as compared to wildtype GLP-2 peptide or a GLP-2 [A2G] peptide, preferably by at least about 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000% or more as compared to a wildtype GLP-2 peptide or a GLP-2[A2G] peptide, depending on the assay.
  • a human GLP-2 peptibody or specified portion or variant of the invention can be similar to any immunoglobulin class (IgG, IgA, IgM, etc.) or isotype and can comprise at least a portion of a kappa or lambda light chain.
  • the human GLP-2 peptibody or specified portion or variant comprises IgG heavy chain CH2 and CH3 of, at least one of subclass, e.g., IgG1, IgG2, IgG3 or IgG4.
  • At least one GLP-2 peptibody or specified portion or variant of the invention binds at least one ligand, subunit, fragment, portion or any combination thereof.
  • the at least one GLP-2 peptibody, variant or derivative of at least one GLP-2 peptibody, specified portion or variant of the present invention can optionally bind at least one specified epitope of the ligand.
  • the binding epitope can comprise any combination of at least one amino acid sequence of at least 1-3 amino acids to the entire specified portion of contiguous amino acids of the sequences of a protein ligand, such as a GLP-2 receptor or portion thereof.
  • GLP-2 peptibodies include GLP-2 ligand-binding fragments and immunoglobulin chains comprising amino acids in a sequence that is substantially the same as an amino acid sequence described herein.
  • GLP-2 peptibodies or GLP-2 ligand-binding fragments thereof can bind human GLP-2 ligands, such as receptors, with high affinity (e.g., K D less than or equal to about 10 -7 M).
  • Amino acid sequences that are substantially the same as the sequences described herein, e.g., GLP-2 peptibody sequences, include sequences comprising conservative amino acid substitutions, as well as amino acid deletions and/or insertions.
  • a conservative amino acid substitution refers to the replacement of a first amino acid by a second amino acid that has chemical and/or physical properties (e.g., charge, structure, polarity, hydrophobicity/hydrophilicity) that are similar to those of the first amino acid.
  • Conservative substitutions include replacement of one amino acid by another within the following groups: lysine (K), arginine (R) and histidine (H); aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine (C) and glycine (G); F, W and Y; C, S and T.
  • formulations that comprise at least one biologically active GLP-2 peptibody or specified portion or variant of the present invention.
  • biologically active GLP-2 peptibodies or specified portions or variants have a specific activity at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, or 15%, of that of the native (non- synthetic), endogenous or related and known inserted or fused protein or specified portion or variant.
  • the formulation comprises the GLP-2 peptibody in an amount of from about 5 mg/ml to about 1 g/ml, from about 25 mg/ml to about 200 mg/ml, from about 25 mg/ml to about 75 mg/ml, from about 5 mg/ml to about 500 mg/ml, from about 50 mg/ml to about 200 mg/ml, from about 10 mg/ml to about 1 g/ml, from about 1 mg/ml to about 500 mg/ml, from about 50 mg/ml to about 150 mg/ml, from about 40 mg/ml to about 50 mg/ml, from about 150 mg/ml to about 160 mg/ml, or from about 100 mg/ml to about 200 mg/ml.
  • the formulation comprises the GLP-2 peptibody in an amount of about 10 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 350 mg/ml, 400 mg/ml, 450 mg/ml, or 500 mg/ml.
  • the formulation comprises 25 mg/ml of the GLP-2 peptibody. In some embodiments, the formulation comprises 50 mg/ml of the GLP-2 peptibody. In some embodiments, the formulation comprises 100 mg/ml of the GLP-2 peptibody.
  • the present invention provides a formulation comprising a parathyroid hormone (PTH), or specified portions or variants thereof such as, but not limited to, a full-length PTH(1-84) that has recently been approved as a safe and effective treatment for hypoparathyroidism (sold by Shire-NPS Pharmaceuticals under the brand name Natpara®), and Natpara® PTH variants.
  • PTH parathyroid hormone
  • a full-length PTH(1-84) that has recently been approved as a safe and effective treatment for hypoparathyroidism (sold by Shire-NPS Pharmaceuticals under the brand name Natpara®), and Natpara® PTH variants.
  • PTH is a polypeptide secreted by the mammalian parathyroid gland.
  • the native, full length PTH is 84 amino acids long, which may be referred to herein as PTH(1-84), and has the following amino acid sequence (SEQ ID NO: 24):
  • PTH peptibodies of the present disclosure may comprise a PTH sequence that may be a derivative of the native (non-synthetic), full-length PTH(1-84) (SEQ ID NO: 24).
  • the PTH peptibody may comprise a PTH sequence that may be a PTH(1-84) derivative comprising amino acid additions, deletions, and/or substitutions that may occur at specified PTH amino acid sequence positions, or residues.
  • PTH amino acid sequence positions it is with respect to SEQ ID NO: 24.
  • the PTH peptibody may comprise a PTH sequence that may be directly or indirectly linked to an Fc domain.
  • Fc domains from any IgG may be used.
  • Fc domains of IgG1, or IgG2, or IgG3, or IgG4 may be used, as well as various combinations of Fc domains originating from different IgGs, such as, e.g., half IgG2 and half IgG4.
  • PTH peptibodies of the invention may comprise Fc domains of a human IgG1 antibody.
  • PTH may be linked to an Fc domain directly.
  • PTH may be linked to an Fc domain by an amino acid linker or spacer.
  • Silenced effector functions can be obtained by mutation in the Fc region of the antibodies, and different IgGs may have different silencer regions known to those of skill in the art. For example, for IgG1 the following silencer regions are known and have been described in the art: LALA and N297A (Strohl, W., 2009, Curr. Opin. Biotechnol. vol. 20(6):685-691); and D265A (Baudino et al., 2008, J. Immunol. 181: 6664-69; Strohl, W., supra).
  • silent Fc IgG1 antibodies comprise the so-called LALA mutant (“hFcLALA”) comprising L234A and L235A (EU numbering) mutation in the IgG1 Fc amino acid sequence.
  • Another example of a silent IgG1 antibody comprises the D265A mutation.
  • Another silent IgG1 antibody comprises the N297A mutation, which results in aglycosylated/non-glycosylated antibodies.
  • the PT peptibodies disclosed herein comprise an IgG1 Fc region that may comprise the LALA mutation.
  • the PTH peptibody of the present disclosure may comprise a PTH sequence which may be directly or indirectly linked to an Fc domain.
  • PTH is linked to an Fc domain directly.
  • PTH is linked to an Fc domain by an amino acid linker.
  • the Fc domain may be further modified to further extend the half-life of the PTH peptibody.
  • half-life extension technology e.g. NHance technology by ArGenX
  • ArGenX may be utilized in combination with the PTH peptibodies of the disclosure.
  • the NHance technology is described, e.g., in U.S. Pat. No. 8,163,881, the contents of which are incorporated by reference herein in their entirety for all purposes.
  • the PTH peptibodies according to the invention are provided as a divalent structure, i.e., having two copies of PTH or portion or variant thereof and one copy of Fc.
  • the PTH peptibodies according to the invention are provided as a monovalent structure, i.e., having one copy of PTH or portion or variant thereof and one copy of Fc.
  • the monovalent PTH peptibody may be prepared using heavy chain mutations known in the art (e.g., knob and hole or the like). One method known in the art is described, e.g., in U.S. Pat. No. 8,679,785.
  • monovalent PTH-Fc variants may be prepared using a monomeric Fc, where the two Fc moieties may be connected via a linker, e.g., an amino acid linker.
  • PTH peptibodies may comprise PTH which may be fused, directly or via a linker, to albumin, or a domain of albumin.
  • PTH-albumin fusions according to the invention may be prepared by methods described in U.S. Pat. No. 7,592,010.
  • the PTH-albumin fusions may be monovalent structures, i.e., having one copy of PTH and one copy of albumin or a domain of albumin.
  • the in vivo half- life of the PTH-albumin fusion is longer than the in vivo half-life of PTH that is not fused to albumin.
  • the PTH peptibody may be PEGylated, attached to PEG, or otherwise conjugated to PEG at one or more amino acids.
  • the PEG may be of any molecular weight and degree of branching suitable to increase the in vivo half-life of the PTH peptibody.
  • Glycosylation is a reaction in which a carbohydrate (a glycan) is attached to a peptide or a protein.
  • a glycan carbohydrate
  • Different classes of glycans are recognized, in which the two most prominent are: N-linked glycans attached to a nitrogen or arginine side chains and O-linked glycans attached to the hydroxyl oxygen of serine, threonine, tyrosine, hydroxylysine, or hydroxyproline side chains.
  • amino acid substitutions to insert a glycosylation site are introduced into PTH peptibodies of the invention.
  • these amino acid substitutions may introduce a serine moiety into the PTH.
  • PTH peptibodies of the invention may comprise a F34A, F34D, and/or a V35S, or V35T mutation to insert a glycan site into the PTH variant.
  • amino acid changes may be made at F34 (e.g., F34A or F34D) and/or V35 (e.g., V35S or V35T) to minimize proteolysis observed in this area during expression of the molecules in particular cell types, e.g., CHO cells.
  • F34A and F34D mutations reduce proteolysis.
  • the combination of F34A and V35S (orV35T) mutations reduces proteolysis to an even greater degree.
  • insertion of the glycan site at N33 reduces protein cleavage during host cell expression.
  • Glycans introduce additional size and bulk to the PTH peptibodies.
  • Glycan sites may also improve solubility of the PTH peptibodies.
  • Glycan sites may also extend the half-life (T 1/2 ) of the PTH peptibody.
  • Glycan insertion at the site of protein mutation may also reduce potential immunogenicity of the mutated sequence.
  • amino acid substitution to insert a glycosylation site may be combined with other mutations or sequence truncations or posttranslational modification for the PTH peptibody.
  • amino acid changes may be made at L59 (e.g., L59S or L59T). This mutation creates a glycosylation site at position N57, which may reduce protein cleavage during host cell expression.
  • amino acid substitutions are introduced into PTH peptibodies improve developability characteristics. In some embodiments, these amino acid substitutions result in reduced cleavage of the PTH peptibodies during expression. In some embodiments, these amino acid substitutions result in improved solubility of the PTH peptibodies. In some embodiments, these amino acid substitutions result in glycan insertion. In some embodiments, these amino acid substitutions may introduce an aspartate into the sequence.
  • PTH peptibodies of the invention may comprise a F34D mutation to decrease protein cleavage during expression.
  • PTH variants containing F34D may be combined with other mutations or sequence truncations or posttranslational modifications for the PTH peptibody.
  • PTH(1-N) means parathyroid hormone peptide residues 1 through N, where N can be 84 (for native length PTH and variants) or less than 84 (for C-terminal truncated PTH variants).
  • N can be 84 (for native length PTH and variants) or less than 84 (for C-terminal truncated PTH variants).
  • PTH(1-84) means parathyroid hormone peptide residues 1 through 84 (full-length sequence);
  • PTH(1-74) means parathyroid hormone peptide residues 1 through 74, i.e., C- terminal truncated variant of PTH(1-84) which is the first 74 residues of PTH, with the last 10 residues having been removed;
  • PTH(1-34) means parathyroid hormone peptide residues 1 through 34, (i.e., C-terminal truncated variant of PTH(1-84) which is the first 34 residues with the last 50 residues having been removed, etc
  • Point mutation in the variant sequences are designated according to the standard convention; e.g., F34A means the phenylalanine amino acid in position 34 is replaced by an alanine amino acid; F34D means that the phenylalanine amino acid in position 34 is replaced by an aspartate residue, V35S means the valine in position 35 is replaced by a serine, etc.
  • D means [deleted sequence], e.g., ⁇ Lys means removal of a lysine residue.
  • Lys removed is the C-terminal region of the Fc molecule to, inter alia, improve homogeneity of the drug product.
  • the PTH peptibody may comprise a full-length PTH(1-84), e.g., a mutated PTH(1-84).
  • the PTH peptibody may comprise a truncated PTH of any length from PTH(1-35) to PTH(1-83).
  • the PTH peptibody of the present disclosure may comprise PTH(1-33).
  • the PTH peptibody may comprise PTH(1-84), or PTH(1-83), or PTH(1-82), or PTH(1-81), or PTH(1-80), or PTH(1-79), or PTH(1-78), or PTHQ-77), or PTH(1-76), or PTH(1-75), or PTH(1-74), or PTH(1-73), or PTH(1-72), or PTH(1- 71), or PTH(1-70), or PTH(1-69), or PTH(1-68), or PTH(1-67), or PTH(1-66), or PTH(1-65), or PTH(1-64), or PTH(1-63), or PTH(1-62), or PTH(1-61), or PTH(1-60), or PTH(1-59), or PTH(1- 58), or PTH(1-57), or PTH(1-56), or PTH(1-55), or PTH
  • the amino acid sequence of the PTH peptibody comprises further modifications selected from amino acid substitution, addition, or deletion.
  • the PTH peptibody comprises a F34A substitution, a F34D substitution, a V35S substitution, or a V35T substitution, or a combination thereof.
  • the PTH peptibody may be further modified, e.g., PEGylated, glycosylated, etc.
  • the PTH peptibody is PEGylated.
  • the PTH peptibody is glycosylated.
  • the Fc is a native Fc form.
  • the Fc comprises further modifications selected from amino acid substitution, addition, or deletion.
  • the Fc is hFcLALA comprising L234A and L235A substitutions.
  • the Fc may be modified for increased half-life extension, e.g. as described in Yang et al, mAbs, 2017, 9, 1105 and other methods commonly known in the art.
  • the PTH region is bolded, with any mutations therein underlined, and any Fc sequence marked by a wave underline.
  • Molecule designation ‘PTH-67’ (SEQ ID NO: 20) Description: PTH(1-64)-[F34A, V35S]-hFcLALA- ⁇ Lys PTH1-64, mutations to insert glycan site, Fc
  • Exemplary PTH peptibodies include one or more of the following:
  • a PTH peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such amino acid sequence;
  • a PTH peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such amino acid sequence;
  • a PTH peptibody comprising the amino acid sequence of or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such amino acid sequence; [00155] d) a PTH peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such amino acid sequence;
  • a PTH peptibody comprising the amino acid sequence of , or a sequence having 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to such amino acid sequence, or 99% identity to such amino acid sequence; or any of the PTH sequences described U.S. Patent No. 5,496,801, filed December 23, 1993, and U.S. Publication No. US 2020/0247865, filed January 29, 2020, both of which are incorporated herein in their entirety for all purposes.
  • a linker sequence may be present between the PTH sequence and another sequence, such as IgG1 Fc or human serum albumin.
  • a linker sequence may be absent from the PTH peptibodies of the present disclosure and the PTH sequence and another sequence may be fused directly.
  • the PTH peptibody may be processed as a PTH precursor polypeptide that comprises a signal peptide directly linked with PTH. Any number of signal peptides may be used, with exemplary signal peptides having the following sequences: METPAQLLFLLLWLPDTTG (SEQ ID NO: 17) and METPAQLLFLLLLWLPDTTG (SEQ ID NO: 18)..
  • the PTH peptibody can be derivatized, for instance at an internal or substituted lysine, to prolong serum half-life by conjugation with lipophilic groups, with polyethylene glycol groups, the Fc domain of immunoglobulins, with albumin or with any other functional group having the desired effect of reducing the rate at which the peptide is degraded endogenously following its administration.
  • Such derivatized forms may be derivatized analogs of PTH, which carry substitutions, such as conserved or non-conserved lysine substitutions having no appreciable negative effect on PTH receptor activation but allowing for conjugation of the desired functional group.
  • PTH peptibodies of the present invention can provide at least one suitable property as compared to known proteins, such as, but not limited to, at least one of increased half-life, increased activity, more specific activity, increased avidity, increased or decreased off rate, a selected or more suitable subset of activities, less immunogenicity, increased quality or duration of at least one desired therapeutic effect, less side effects, and the like.
  • a suitable PTH peptibody e.g., a PTH peptibody comprising the amino acid sequence of SEQ ID NOS: 19-23, has an in vivo half-life of or greater than about 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 hours, 34 hours, 36 hours, 38 hours, 40 hours, 42 hours, 44 hours, 46 hours, or 48 hours.
  • a recombinant PTH peptibody has an in vivo half-life of between 2 and 48 hours, between 2 and 44 hours, between 2 and 40 hours, between 3 and 36 hours, between 3 and 32 hours, between 3 and 28 hours, between 4 and 24 hours, between 4 and 20 hours, between 6 and 18 hours, between 6 and 15 hours, and between 6 and 12 hours.
  • the PTH peptibodies or specified portion or variants thereof may be produced by at least one cell line, mixed cell line, immortalized cell or clonal population of immortalized and/or cultured cells. Immortalized protein-producing cells can be produced using suitable methods.
  • the at least one PTH peptibody or specified portion or variant is generated by providing nucleic acid or vectors comprising DNA derived or having a substantially similar sequence to, at least one human immunoglobulin locus that is functionally rearranged, or which can undergo functional rearrangement, and which further comprises a PTH peptibody structure as described herein.
  • the PTH peptibodies can bind human protein ligands with a wide range of affinities (K D ).
  • at least one human PTH peptibody of the formulations described herein can optionally bind at least one protein-ligand with high affinity.
  • at least one PTH peptibody can bind at least one protein-ligand with a K D equal to or less than about 10 -7 M or, more preferably, with a K D equal to or less than about 0.1-9.9 (or any range or value therein) ⁇ 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , or 10 -13 M, or any range or value therein.
  • K lysine
  • lysine can be added to C-terminus.
  • the PTH peptibody is processed from a PTH precursor polypeptide that comprises a signal peptide directly linked with PTH, with a linker between PTH and an Fc region of any of IgG1, IgG2, IgG3, and IgG4.
  • the Fc region may be IgG1 with the LALA mutation.
  • the PTH precursor polypeptide may have the following formula:
  • the PTH peptibody is processed from a PTH precursor polypeptide that comprises a signal peptide directly linked with PTH, without a linker between PTH and an Fc region of any of IgG1, IgG2, IgG3, and IgG4, which are directly linked.
  • the Fc region may be IgG1 with the LALA mutation.
  • the PTH precursor polypeptide may have the following formula:
  • PTH peptibodies may comprise PTH fused to an Fc domain. It is contemplated that improved binding between Fc domain and the FcRn receptor results in prolonged serum half-life.
  • a suitable Fc domain comprises one or more amino acid mutations that lead to improved binding to FcRn.
  • Various mutations within the Fc domain that effect improved binding to FcRn are known in the art and can be adapted to practice the present invention.
  • a suitable Fc domain comprises one or more mutations at one or more positions corresponding to Thr 250, Met 252, Ser 254, Thr 256, Thr 307, Glu 380, Met 428, His 433, and/or Asn 434 of human IgG1.
  • a PTH peptibody, or specified portion or variant thereof, that partially or preferably substantially provides at least one PTH biological activity, can bind the PTH ligand and thereby provide at least one activity that is otherwise mediated through the binding of PTH to at least one ligand, such as a PTH receptor, or through other protein-dependent or mediated mechanisms.
  • PTH peptibody activity refers to a PTH peptibody that can modulate or cause at least one PTH-dependent activity by about 20-10,000% as compared to wildtype PTH peptide, preferably by at least about 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000% or more as compared to a wildtype PTH peptide, depending on the assay.
  • a human PTH peptibody or specified portion or variant of the invention can be similar to any immunoglobulin class (IgG, IgA, IgM, etc.) or isotype and can comprise at least a portion of a kappa or lambda light chain.
  • the human PTH peptibody or specified portion or variant comprises IgG heavy chain CH2 and CH3 of, at least one of subclass, e.g., IgG1, IgG2, IgG3 or IgG4.
  • At least one PTH peptibody or specified portion or variant of the invention binds at least one ligand, subunit, fragment, portion or any combination thereof.
  • the at least one PTH peptibody, variant or derivative of at least one PTH peptibody, specified portion or variant of the present invention can optionally bind at least one specified epitope of the ligand.
  • the binding epitope can comprise any combination of at least one amino acid sequence of at least 1-3 amino acids to the entire specified portion of contiguous amino acids of the sequences of a protein ligand, such as a PTH receptor or portion thereof.
  • PTH peptibodies include PTH ligand-binding fragments and immunoglobulin chains comprising amino acids in a sequence that is substantially the same as an amino acid sequence described herein.
  • PTH peptibodies or PTH ligand-binding fragments thereof can bind human PTH ligands, such as receptors, with high affinity (e.g., K D less than or equal to about 10 -7 M).
  • Amino acid sequences that are substantially the same as the sequences described herein, e.g., PTH peptibody sequences include sequences comprising conservative amino acid substitutions, as well as amino acid deletions and/or insertions. .
  • formulations that comprise at least one biologically active PTH peptibody or specified portion or variant of the present invention.
  • biologically active PTH peptibodies or specified portions or variants have a specific activity at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, or 15%, of that of the native (non- synthetic), endogenous or related and known inserted or fused protein or specified portion or variant.
  • the formulation comprises the PTH peptibody in an amount of from about 5 mg/ml to about 1 g/ml, from about 25 mg/ml to about 200 mg/ml, from about 25 mg/ml to about 75 mg/ml, from about 5 mg/ml to about 500 mg/ml, from about 50 mg/ml to about 200 mg/ml, from about 10 mg/ml to about 1 g/ml, from about 1 mg/ml to about 500 mg/ml, from about 50 mg/ml to about 150 mg/ml, from about 40 mg/ml to about 50 mg/ml, from about 150 mg/ml to about 160 mg/ml, or from about 100 mg/ml to about 200 mg/ml.
  • the formulation comprises the PTH peptibody in an amount of about 10 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml, 200 mg/ml, 250 mg/ml, 300 mg/ml, 350 mg/ml, 400 mg/ml, 450 mg/ml, or 500 mg/ml.
  • the formulation comprises 25 mg/ml of the PTH peptibody. In some embodiments, the formulation comprises 50 mg/ml of the PTH peptibody. In some embodiments, the formulation comprises 100 mg/ml of the PTH peptibody Carriers
  • the carrier is any substrate, substrate, solute, solvent, or diluent used in the process of drug delivery that serves to improve selectivity, effectiveness, and/or safety of administration of any of the GLP-2 peptibodies or PTH peptibodies or portions or variants thereof of the present disclosure.
  • the carrier is selected so that the GLP-2 peptibody or PTH peptibody can be homogeneously dispersed throughout the formulation.
  • the carrier is used to facilitate delivery of the GLP-2 peptibody or PTH peptibody, or control release of the GLP-2 peptibody or PTH peptibody.
  • the carrier improves bioavailability of the GLP-2 peptibody or PTH peptibody.
  • the carrier is an aqueous solvent.
  • the carrier is a liquid.
  • the carrier is an aqueous carrier.
  • aqueous carriers include sterile water, bacteriostatic water for injection (BWFI), and Ringer's solution.
  • the carrier is any carrier known to one of skill in the art, such as, to provide non-limiting examples, liposomes or nanoparticles.
  • Non-limiting examples of carriers include liposomes, polymeric micelles, microspheres, nanodiamonds, nanofibers, protein-DNA complexes, virosomes, dendrimers, and various combinations thereof.
  • the carrier is a solvent.
  • the solvent is selected based on solvents recognized by those skilled in the art as safe to administer to mammals (GRAS).
  • Safe solvents can be non-toxic aqueous solvents such as water and other non- toxic solvents that are soluble or miscible in water.
  • suitable solvents include water, ethanol, polyols (e.g., propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (e.g., olive oil, soybean oil, corn oil, cottonseed oil, etc.), injectable organic esters (e.g., ethyl oleate), and mixtures thereof.
  • the solvent is water.
  • Non-limiting examples of buffers or buffer components that suitable for use in the formulations described herein include HEPES, ADA, ACES, MOPSO, DIPSO, MOBS, HEPPSO, POPSO, TEA, EPPS, tricine, HEPBS, TAPS, AMDP, TABS, AMPSO, CAPSO,
  • AMP CAPS, CABS, BIS-TRIS, BES, BIS-TRIS propane, MOPS, PIPES, TES, TRIS, TRIS- HCL, CHES, TAPSO, bicine, PIPES, citrate, histidine lactic acid, tromethamine, triethanolamine, gluconic acid, lactic acid, aspartic acid, glutamic acid, tartaric acid, malic acid, fumaric acid, glycylglycine, ammonium chloride, ammonium acetate, ammonium formate, ammonium hydroxide, TRIS HC1, carbonic acid, diethanolamine, ethanolamine, triethylamine, triethylamine HC1, pyrrolidine, tris-(hydroxymethyl) amino methane (THAM), sodium diethylbarbiturate, ethylenediaminetetraacetic acid, phosphophosphoric acid, a-ketoglutaric acid, MES, a citrate salt, citrate phosphate,
  • the buffer is a phosphate buffer, a histidine buffer, a histidine and glycine buffer, an arginine and lysine buffer, various combinations thereof, and various pharmaceutically acceptable salts or alternative pharmaceutically acceptable salts thereof.
  • the buffer comprises arginine, lysine, histidine, glycine, glutamic acid, phosphate, methionine, various pharmaceutically acceptable salts thereof, or various combinations thereof.
  • the buffer is an arginine buffer, a lysine buffer, a glycine buffer, a glutamic acid buffer, a methionine buffer, a phosphate buffer, a histidine buffer, a histidine and glycine buffer, or an arginine and lysine buffer.
  • the buffer concentration in the formulation is at least or about 1 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 90 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, or
  • the buffer concentration in the formulation is less than about 1 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 90 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, or
  • the buffer is a phosphate buffer.
  • the phosphate buffer concentration in the formulation is from about 10 mM to about 1000 mM, from about 20 mM to about 500 mM, from about 30 mM to about 300 mM, from about 25 mM to about 400 mM, from about 50 mM to about 200 mM, from about 50 mM to about 150 mM.
  • the phosphate buffer concentration in the formulation is about 10 mM, 20 mM, 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, 110 mM, 120 mM,
  • the phosphate buffer concentration can be about 100 mM. In various embodiments, the phosphate buffer concentration is 100 mM. [00182] In some embodiments, the buffer is a histidine buffer.
  • the histidine buffer concentration in the formulation is from about 5 mM to about 500 mM, from about 10 mM to about 250 mM, from about 15 mM to about 200 mM, from about 25 mM to about 100 mM, from about 10 mM to about 100 mM, from about 1 mM to about 50 mM, from about 1 mM to about 500 mM, from about 5 mM to about 100 mM, from about 1 mM to about 100 mM, from about 30 mM to about 70 mM, or from about 40 mM to about 60 mM.
  • the histidine buffer concentration in the formulation is about 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 90 mM, or 100 mM.
  • the histidine buffer concentration in the formulation can be about 50 mM. In various embodiments, the histidine buffer concentration in the formulation is 50 mM.
  • the histidine buffer concentration in the formulation can be about 10 mM. In various embodiments, the histidine buffer concentration in the formulation is 10 mM.
  • the buffer comprises histidine and glycine.
  • the buffer is a histidine and glycine buffer.
  • the histidine and glycine buffer comprises histidine and glycine.
  • the histidine concentration in the formulation is from about 0.2 mM to about 20 mM, from about 0.5 mM to about 8 mM, from about 1 mM to about 6 mM, or from about 1 mM to about 4 mM.
  • the histidine concentration in the formulation is about 0.1 mM, 0.25 mM, 0.50 mM, 0.75 mM, 1 mM, 1.25 mM, 1.5 mM, 1.75 mM, 2 mM, 2.25 mM, 2.50 mM, 2.75 mM, or 3 mM.
  • the glycine concentration in the formulation is from about 1 mM to about 100 mM, from about 2 mM to about 50 mM, from about 2 mM to about 40 mM, from about 3 mM to about 30 mM, or from about 5 mM to about 20 mM.
  • the glycine concentration in the formulation is about 5 mM, 5.5 mM, 6 mM, 6.5 mM, 7 mM, 7.5 mM, 8 mM, 8.5 mM, 9 mM, 9.5 mM, 10 mM, 10.5 mM, 11 mM, 11.5 mM, 12 mM, 12.5 mM,
  • the histidine and glycine buffer can comprise about 2 mM histidine and about 10 mM glycine. In various embodiments, the histidine and glycine buffer comprises 2 mM histidine and 10 mM glycine.
  • the buffer comprises arginine and lysine.
  • the buffer is an arginine and lysine buffer.
  • the arginine and lysine buffer comprises arginine and lysine.
  • the arginine concentration in the formulation is from about 2 mM to about 200 mM, from about 4 mM to about 100 mM, from about 5 mM to about 80 mM, from about 10 mM to about 60 mM, or from about 10 mM to about 40 mM.
  • the arginine concentration in the formulation is about 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, or 30 mM.
  • the lysine concentration in the formulation is from about 2 mM to about 200 mM, from about 4 mM to about 100 mM, from about 5 mM to about 80 mM, from about 10 mM to about 60 mM, or from about 10 mM to about 40 mM.
  • the lysine concentration in the formulation is about 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 26 mM, 27 mM, 28 mM, 29 mM, or 30 mM.
  • the arginine and lysine buffer comprises equimolar amounts of lysine and arginine.
  • the arginine and lysine buffer can comprise about 20 mM arginine and about 20 mM lysine.
  • the arginine and lysine buffer comprises 20 mM arginine and 20 mM lysine.
  • the buffer is citrate phosphate.
  • the citrate phosphate can be at a concentration in the formulation of from about 1 mM to about 1,000 mM, from about 50 mM to about 300 mM, from about 1 mM to about 150 mM, from about 1 mM to about 200 mM, from about 50 mM to about 300 mM, from about 1 mM to about 100 mM, from about 100 mM to about 300 mM, from about 50 mM to about 150 mM, from about 25 mM to about 200 mM, from about 50 mM to about 150 mM, from about 25 mM to about 75 mM, or from about 50 mM to about 300 mM.
  • the citrate phosphate buffer concentration in the formulation is at least or about 1 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 90 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, or 1000 mM.
  • the citrate phosphate buffer concentration in the formulation is less than about 1 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 90 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, or 1000 mM.
  • the buffer is a citrate salt at a concentration in the formulation of from about 5 mM to about 30 mM.
  • the concentration of the citrate salt in the formulation is from about 5 mM to about 25 mM, from about 5 mM to about 20 mM, from about 5 mM to about 15 mM, from about 5 mM to about 12.5 mM, from about 5 mM to about 10 mM, from about 7.5 mM to about 30 mM, from about 7.5 mM to about 25 mM, from about 7.5 mM to about 20 mM, from about 7.5 mM to about 15 mM, from about 7.5 mM to about 12.5 mM, from about 7.5 mM to about 10 mM, from about 8 to about 30 mM, from about 8 to about 25 mM, from about 8 to about 20 mM, from about 8 to about 15 mM, from about 8 mM to about 12.5
  • the pH of the formulation ranges from about 5 to about 8.
  • the pH range is selected to stabilize the GLP-2 peptibody or PTH peptibody.
  • the pH range can be selected to be suitable for parenteral administration and to promote activity of the GLP-2 peptibody or PTH peptibody.
  • the formulation is buffered to a pH.
  • the pH is an acidic pH.
  • the pH is a basic pH.
  • the pH of the formulation is buffered to from about 5 to about 8, from about 5.5 to about 7.5, from about 6 to about 7, from about 6.25 to about 6.75, from about 7 to about 8, from 7.0 to 7.4, from about 6 to about 8, from about 6.5 to about 7.5, from about 6.5 to about 7.4, from about 6.25 to about 7.75, from about 6.75 to about 7.75, from about 6.75 to about 7.5, from about 7.3 to about 7.5, or from about 6.5 to about 6.75.
  • the pH of the formulation is buffered to about or to at least about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6,
  • the pH of the formulation is less than 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,
  • the pH of the formulation can be about 6.7. In various embodiments, the pH of the formulation is 6.7. The pH of the formulation can be about 6.5. In various embodiments, the pH of the formulation is 6.5. The pH of the formulation can be about 7. In various embodiments, the pH of the formulation 7. The pH of the formulation can be about 7.4. In various embodiments, the pH of the formulation is 7.4. The pH of the formulation can be greater than about 7.0. In various embodiments, the pH of the formulation is greater than 7.0. The pH of the formulation can be from about 7.0 to about 7.4. In various embodiments, the pH of the formulation is from 7.0 to 7.4. The pH of the formulation can be greater than about 6.5. In various embodiments, the pH of the formulation is greater than 6.5. In various embodiments, the pH of the formulation is greater than 6.5. The pH of the formulation can be greater than or equal to about 6.7. In various embodiments, the pH of the formulation is greater than or equal to about 6.7.
  • one or more of the amino acids in the formulation can function as an osmoregulator and/or a stabilizer in the formulations.
  • at least one amino acid and the concentration thereof is selected to adjust the osmotic pressure of the formulation so that it is suitable for parenteral administration and the like.
  • at least one amino acid and the concentration thereof is selected to stabilize the GLP-2 peptibody or PTH peptibody.
  • any reference to an amino acid is understood to include any and all pharmaceutically acceptable salts or solvates of the amino acid.
  • any mention throughout the disclosure of any peptibody, buffer, or compound is understood to include any and all pharmaceutically acceptable salts thereof.
  • Any natural or non-natural pharmaceutically acceptable amino acids may be used in the formulation.
  • Non-limiting examples of amino acids that are suitable for use in the formulations described herein include histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, arginine, cysteine, glutamine, glycine, proline, tyrosine, alanine, aspartic acid, asparagine, glutamic acid, serine, selenocysteine, pyrrolysine, and various pharmaceutically acceptable salts and isomers (e.g., L- or D- isomers) thereof.
  • the at least one amino acid comprises an L-amino acid. In various embodiments, the at least one amino acid comprises a D-amino acid. In some embodiments, the at least one amino acid is selected from the group consisting of histidine, glycine, lysine, arginine, glutamic acid, methionine, and various pharmaceutically acceptable salts thereof. In some embodiments, the at least one amino acid consists of at least one, two, three, four, or five amino acids selected from the group consisting of histidine, glycine, lysine, arginine, glutamic acid, methionine, and various pharmaceutically acceptable salts thereof.
  • the formulation comprises histidine, arginine, glutamic acid, methionine, or various pharmaceutically acceptable salts thereof. In various embodiments, the formulation comprises histidine and glycine, or various pharmaceutically acceptable salts thereof. In some embodiments, the formulation comprises histidine, glycine, and methionine, or various pharmaceutically acceptable salts thereof. In some embodiments, the formulation comprises arginine and lysine, or various pharmaceutically acceptable salts thereof.
  • the formulation comprises a concentration of an amino acid that is about or greater than about 0.5 mM, 1.0 mM, 1.5 mM, 2.0 mM, 2.5 mM, 3 mM, 3.5 mM,
  • the formulation comprises a concentration of an amino acid that is less than about 0.5 mM, 1.0 mM, 1.5 mM, 2.0 mM, 2.5 mM, 3 mM, 3.5 mM, 4 mM, 4.5 mM, 5 mM, 5.1 mM, 5.2 mM, 5.3 mM, 5.4 mM, 5.5 mM, 5.6 mM, 5.7 mM, 5.8 mM, 5.9 mM, 6 mM, 6.5 mM, 7 mM, 7.5 mM, 8 mM, 8.5 mM, 9 mM, 9.5 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 21 mM, 22 mM, 23 mM, 24 mM, 25 mM, 20
  • the at least one amino acid comprises histidine.
  • the concentration of histidine in the formulation is from about 0.2 to about 500 mM, about 0.2 mM to about 200 mM, from about 2 mM to about 200 mM, from about 5 mM to about 100 mM, from about 4 to about 100 mM, from about 5 to about 80 mM, from about 15 to about 20 mM, from about 4 to about 40 mM, from about 5 to about 80 mM, from about 8 to about 60 mM, from about 10 mM to about 40 mM, from about 15 mM to about 25 mM, from about 5 mM to about 500 mM, from about 1 mM to about 500 mM, from about 5 mM to about 200 mM, from about 10 mM to about 250 mM, from about 25 to about 100 mM, from about 25 mM to about 75 mM, from about 1 mM to about 100 mM to about 100 mM, from
  • the concentration of histidine in the formulation is about or at least about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM. 2.6 mM. 2.7 mM, 2.8 mM, 2.9 mM,
  • the concentration of histidine in the formulation is less than about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM.
  • the formulation can comprise about 20 mM histidine. In various embodiments, the formulation comprises 20 mM histidine. The formulation can comprise about 50 mM histidine. In various embodiments, the formulation comprises 50 mM histidine. The formulation can comprise about 10 mM histidine. In various embodiments, the formulation comprises 10 mM histidine. The formulation can comprise about 2 mM histidine. In various embodiments, the formulation comprises 2 mM histidine.
  • the at least one amino acid comprises glycine.
  • the concentration of glycine in the formulation is from about 0.2 to about 500 mM, about 0.2 mM to about 200 mM, from about 2 mM to about 200 mM, from about 4 to about 100 mM, from about 5 mM to about 100 mM, from about 5 to about 80 mM, from about 15 to about 20 mM, from about 4 to about 40 mM, from about 5 to about 80 mM, from about 8 to about 60 mM, from about 10 mM to about 40 mM, from about 15 mM to about 25 mM, from about 5 mM to about 500 mM, from about 1 mM to about 500 mM, from about 5 mM to about 200 mM, from about 10 mM to about 250 mM, from about 25 to about 100 mM, from about 25 mM to about 75 mM, from about 1 mM to about
  • the concentration of glycine in the formulation is about or at least about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM. 2.6 mM.
  • the concentration of glycine in the formulation is less than about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM. 2.6 mM. 2.7 mM, 2.8 mM, 2.9 mM, 3.0 mM, 3.1 mM, 3.2 mM, 3.4 mM, 3.5 mM, 3.6 mM, 3.7 mM,
  • the formulation can comprise about 50 mM glycine. In various embodiments, the formulation comprises 50 mM glycine. The formulation can comprise about 10 mM glycine. In various embodiments, the formulation comprises 10 mM glycine. [00196] In some embodiments the at least one amino acid comprises lysine.
  • the concentration of lysine in the formulation is from about 0.2 to about 500 mM, about 0.2 mM to about 200 mM, from about 2 mM to about 200 mM, from about 4 to about 100 mM, from about 5 mM to about 100 mM, from about 5 to about 80 mM, from about 15 to about 20 mM, from about 4 to about 40 mM, from about 5 to about 80 mM, from about 8 to about 60 mM, from about 10 mM to about 40 mM, from about 15 mM to about 25 mM, from about 5 mM to about 500 mM, from about 1 mM to about 500 mM, from about 5 mM to about 200 mM, from about 10 mM to about 250 mM, from about 25 to about 100 mM, from about 25 mM to about 75 mM, from about 1 mM to about 100 mM, from about 2 mM to about 50 mM, from about
  • the concentration of lysine in the formulation is about or at least about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM. 2.6 mM.
  • the concentration of lysine in the formulation is less than about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM. 2.6 mM.
  • the at least one amino acid comprises arginine.
  • the concentration of arginine in the formulation is from about 0.2 to about 500 mM, about 0.2 mM to about 200 mM, from about 2 mM to about 200 mM, from about 4 to about 100 mM, from about 5 mM to about 100 mM, from about 5 to about 80 mM, from about 15 to about 20 mM, from about 4 to about 40 mM, from about 5 to about 80 mM, from about 8 to about 60 mM, from about 10 mM to about 40 mM, from about 15 mM to about 25 mM, from about 5 mM to about 500 mM, from about 1 mM to about 500 mM, from about 5 mM to about 200 mM, from about 10 mM to about 250 mM, from about 25 to about 100 mM, from about 25 mM to about 75 mM, from about 1 mM to about
  • the concentration of arginine in the formulation is about or at least about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM. 2.6 mM.
  • the concentration of arginine in the formulation is less than about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM. 2.6 mM.
  • the formulation can comprise about 90 mM arginine. In various embodiments, the formulation comprises 90 mM arginine. The formulation can comprise about 100 mM arginine. In various embodiments, the formulation comprises 100 mM arginine. The formulation can comprise about 20 mM arginine. In various embodiments, the formulation comprises 20 mM arginine.
  • the at least one amino acid comprises glutamic acid.
  • the concentration of glutamic acid in the formulation is from about 0.2 to about 500 mM, about 0.2 mM to about 200 mM, from about 2 mM to about 200 mM, from about 4 to about 100 mM, from about 5 mM to about 100 mM, from about 5 to about 80 mM, from about 15 to about 20 mM, from about 4 to about 40 mM, from about 5 to about 80 mM, from about 8 to about 60 mM, from about 10 mM to about 40 mM, from about 15 mM to about 25 mM, from about 5 mM to about 500 mM, from about 1 mM to about 500 mM, from about 5 mM to about 200 mM, from about 10 mM to about 250 mM, from about 25 to about 100 mM, from about 25 mM to about 75 mM, from about 1 mM to
  • the concentration of glutamic acid in the formulation is about or at least about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM. 2.6 mM.
  • the concentration of glutamic acid in the formulation is less than about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM.
  • the at least one amino acid comprises methionine.
  • the concentration of methionine in the formulation is from about 0.2 to about 500 mM, about 0.2 mM to about 200 mM, from about 2 mM to about 200 mM, from about 4 to about 100 mM, from about 5 mM to about 100 mM, from about 5 to about 80 mM, from about 15 to about 20 mM, from about 4 to about 40 mM, from about 5 to about 80 mM, from about 8 to about 60 mM, from about 10 mM to about 40 mM, from about 15 mM to about 25 mM, from about 5 mM to about 500 mM, from about 1 mM to about 500 mM, from about 5 mM to about 200 mM, from about 10 mM to about 250 mM, from about 25 to about 100 mM, from about 25 mM to about 75 mM, from about 1 mM to about
  • the concentration of methionine in the formulation is about or at least about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM. 2.6 mM. 2.7 mM, 2.8 mM,
  • the concentration of methionine in the formulation is less than about 0.1 mM, 0.5 mM, 1.0 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.0 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM. 2.6 mM. 2.7 mM, 2.8 mM, 2.9 mM, 3.0 mM, 3.1 mM, 3.2 mM, 3.4 mM, 3.5 mM, 3.6 mM,
  • the formulation can comprise about 5.6 mM methionine. In various embodiments, the formulation comprises 5.6 mM methionine. The formulation can comprise about 8 mM methionine. In various embodiments, the formulation comprises 8 mM methionine. The formulation can comprise about 8 mM methionine. In various embodiments, the formulation comprises 8 mM methionine. The formulation can comprise about 2 mM methionine. In various embodiments, the formulation comprises 2 mM methionine.
  • the formulation comprises equimolar amounts of at least two amino acids. In some embodiments, the formulation comprises equimolar amounts of glutamic acid and arginine. In some embodiments, the formulation comprises equimolar amounts of arginine and lysine.
  • Non-limiting examples of excipients that are suitable for use in the formulations described herein include a carbohydrate (e.g., a sugar, a sugar alcohol, or a polyol), a salt, stabilizers, bulking agents, viscosity enhancers/reducers, chelating agents, adjuvants, a derivative of a carbohydrate, a surfactant, and various combinations thereof.
  • the salt is an inorganic salt.
  • the at least one excipient comprises a carbohydrate and a surfactant.
  • the formulation may or may not include a carbohydrate.
  • the formulation does not include a carbohydrate.
  • the formulation may or may not include a surfactant.
  • the formulation does not include a surfactant.
  • the at least one excipient comprises a sugar and a non-ionic surfactant.
  • the excipient is an osmoregulator.
  • the excipient is a stabilizer.
  • the formulation of the invention is isotonic or slightly hypotonic and/or has an osmolality of about 290 ⁇ 60 mOsmol/kg water, such as about 240 mOsmol/kg water or higher, 250 mOsmol/kg water or higher or 260 mOsmol/kg water or higher.
  • Isotonicity of the formulation can be further adjusted by the addition of the at least one amino acid and/or one or more excipients.
  • the formulation of the invention has an osmolality of about or of at least about 300 mOsmol/kg water, 310 mOsmol/kg water, 320 mOsmol/kg water, 330 mOsmol/kg water, 340 mOsmol/kg water, 350 mOsmol/kg water, 360 mOsmol/kg water, 370 mOsmol/kg water, 380 mOsmol/kg water, 390 mOsmol/kg water, 400 mOsmol/kg water, 410 mOsmol/kg water, 420 mOsmol/kg water, 430 mOsmol/kg water, 440 mOsmol/kg water, 450 mOsmol/kg water, 460 mOsmol/kg water, 470 mOsmol/kg water, 480 mOsmol/kg water, 490 mOsmol/kg water, 500 mOsmol/kg water, 510 mO
  • the formulation of the invention has an osmolality of from about 300 mOsmol/kg water to about 600 mOsmol/kg water, from about 250 mOsmol/kg water to about 350 mOsmol/kg water, from about 400 mOsmol/kg water to about 600 mOsmol/kg water, from about 400 mOsmol/kg water to about 500 mOsmol/kg water, or from about 500 mOsmol/kg water to about 600 mOsmol/kg water.
  • the formulation has an osmolality of from about 250 mOsmol/kg water to about 650 mOsmol/kg water. In some embodiments, the formulation has an osmolality of at least about 300 mOsmol/kg water.
  • the at least one excipient comprises a salt.
  • suitable salts include a nitrate, chloride, bromide, phosphate, sulfate, acetate, hexafluorophosphate, citrate, gluconate, benzoate, propionate, butyrate, subsalicylate, maleate, laurate, malate, fumarate, succinate, tartrate, amsonate, pamoate, p-tolunenesulfonate, mesylate, the like, and various combinations thereof.
  • salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), ammonium salts, the like, and various combinations thereof.
  • the salt comprises a halide ion.
  • the formulation does not comprise any inorganic salt.
  • the concentration of NaCl in the formulation is about or at least about 1 mM, 5mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 155 mM, 160 mM, 165 mM, 170 mM, 175 mM, 180 mM, 185 mM, 190 mM, 195 mM, 200 mM, 210 mM, 220 mM, 230
  • the NaCl concentration in the formulation may be about 100 mM. In various embodiments, the NaCl concentration in the formulation is 100 mM. The NaCl concentration in the formulation may be about 150 mM. In various embodiments, the NaCl concentration in the formulation is 150 mM. The NaCl concentration in the formulation may be about 120 mM. In various embodiments, the NaCl concentration in the formulation is 120 mM.
  • the conductivity of the formulation may be greater than about 2.6 mS/cm 2 /25°C. In some embodiments, the conductivity of the formulation is greater than 2.6 mS/cm 2 /25°C.
  • the conductivity of the formulation may be from about 2 to about 3 mS/cm 2 /25°C, from about 2.5 to about 3 mS/cm 2 /25°C, from about 2.6 to about 4 mS/cm 2 /25°C, from about 2.25 to about 2.75 mS/cm 2 /25°C, from about 2.6 to about 3 mS/cm 2 /25°C, or from about 2.6 mS/cm 2 /25°C to about 5 mS/cm 2 /25°C.
  • the conductivity of the formulation may be greater than about or be about 2.6 mS/cm 2 /25°C, 2.7 mS/cm 2 /25°C, 2.8 mS/cm 2 /25°C, 2.9 mS/cm 2 /25°C, 3 mS/cm 2 /25°C, 3.1 mS/cm 2 /25°C, 3.2 mS/cm 2 /25°C, 3.3 mS/cm 2 /25°C, 3.4 mS/cm 2 /25°C, 3.5 mS/cm 2 /25°C, 3.6 mS/cm 2 /25°C, 3.7 mS/cm 2 /25°C, 3.8 mS/cm 2 /25°C, 3.9 mS/cm 2 /25°C, 4.0 mS/cm 2 /25°C, 4.25 mS/cm 2 /25°C,
  • the inorganic salt is NaCl or KC1. In some embodiments, the inorganic salt is NaCl. In various embodiments, the concentration of NaCl in the formulation is from about 10 mM to about 1,500 mM, from about 50 mM to about 300 mM, from about 10 mM to about 1,000 mM, from about 10 mM to about 160 mM, from about 50 mM to about 200 mM, from about 50 mM to about 175 mM, from about 75 mM to about 175 mM, from about 100 mM to about 150 mM, from about 90 mM to about 160 mM, from about 1 mM to about 500 mM, from about 90 mM to about 110 mM, from about 140 mM to about 160 mM, from about 90 mM to about 130 mM, from about 110 mM to about 130 mM, or from about 50 mM to about 150 mM.
  • the concentration of NaCl in the formulation is about or less than about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 155 mM, 160 mM, 165 mM, 170 mM, 175 mM, 180 mM, 185 mM, 190 mM, 195 mM, or 200 mM.
  • Non-limiting examples of carbohydrates that are suitable for use in the formulations described herein include the sugars sucrose, trehalose, arabinose, cellobiose, glyceraldehyde, fructose, xylose, ribose, galactose, glucose, mannose, lactose, maltose, raffmose, maltodextrin, dextrin, and various combinations thereof.
  • the carbohydrate is a monosaccharide, such as, to provide non-limiting examples thereof, glucose or mannose.
  • the carbohydrate is a disaccharide, such as, to provide non-limiting examples thereof, trehalose or sucrose.
  • Non-limiting examples of carbohydrates suitable for use in the formulations described herein include polyols and sugar alcohols such as, to provide nonlimiting examples thereof, sorbitol, mannitol, xylitol, erythritol, threitol, glycerol, ribitol, and various combinations thereof.
  • the at least one excipient comprises a nonreducing sugar.
  • Non-limiting examples of carbohydrate derivatives include sugar acids, such as, to provide non-limiting examples thereof, L-gluconate.
  • the non-reducing sugar is trehalose or sucrose.
  • the formulation may or may not comprise mannitol. In various embodiments, the formulation does not comprise mannitol.
  • the concentration of the carbohydrate or carbohydrate derivative in the formulation is about or at least about 0.1% (wt/wt), 0.2% (wt/wt), 0.3% (wt/wt), 0.4% (wt/wt), 0.5% (wt/wt), 0.6% (wt/wt), 0.7% (wt/wt), 0.8% (wt/wt), 0.9% (wt/wt), 1.0% (wt/wt), 1.1% (wt/wt), 1.2% (wt/wt), 1.3% (wt/wt), 1.4% (wt/wt), 1.5% (wt/wt), 1.6% (wt/wt), 1.7% (wt/wt), 1.8% (wt/wt), 1.9% (wt/wt), 2% (wt/wt), 2.1% (wt/wt), 2.2% (wt/wt), 2.3% (wt/wt), 2.4% (wt/wt), 2.5% (wt/wt), 2.5% (wt/wt
  • the concentration of the carbohydrate or carbohydrate derivative in the formulation is less than about 0.1% (wt/wt), 0.2% (wt/wt), 0.3% (wt/wt), 0.4% (wt/wt), 0.5% (wt/wt), 0.6% (wt/wt), 0.7% (wt/wt), 0.8% (wt/wt), 0.9% (wt/wt), 1.0% (wt/wt), 1.1% (wt/wt), 1.2% (wt/wt), 1.3% (wt/wt), 1.4% (wt/wt), 1.5% (wt/wt), 1.6% (wt/wt), 1.7% (wt/wt), 1.8% (wt/wt), 1.9% (wt/wt), 2% (wt/wt), 2.1% (wt/wt), 2.2% (wt/wt), 2.3% (wt/wt), 2.4% (wt/wt), 2.5% (wt/wt), 2.6% (wt/wt), 2.
  • the at least one excipient comprises sucrose.
  • the concentration of sucrose in the formulation is from about 0.2% (wt/wt) to about 20% (wt/wt), from about 1% (wt/wt) to about 4% (wt/wt), from about 0.5% (wt/wt) to about 8% (wt/wt), or from about 1.5% (wt/wt) to about 2.5% (wt/wt).
  • the concentration of sucrose in the formulation is about or at least about 0.1% (wt/wt), 0.2% (wt/wt), 0.3% (wt/wt), 0.4% (wt/wt), 0.5% (wt/wt), 0.6% (wt/wt), 0.7% (wt/wt), 0.8% (wt/wt), 0.9% (wt/wt), 1.0% (wt/wt), 1.1% (wt/wt), 1.2% (wt/wt), 1.3% (wt/wt), 1.4% (wt/wt), 1.5% (wt/wt), 1.6% (wt/wt), 1.7% (wt/wt), 1.8% (wt/wt), 1.9% (wt/wt), 2% (wt/wt), 2.1% (wt/wt), 2.2% (wt/wt), 2.3% (wt/wt), 2.4% (wt/wt), 2.5% (wt/wt), 2.6% (wt/wt), 2.7%
  • the concentration of sucrose in the formulation is less than about 0.1% (wt/wt), 0.2% (wt/wt), 0.3% (wt/wt), 0.4% (wt/wt), 0.5% (wt/wt), 0.6% (wt/wt), 0.7% (wt/wt), 0.8% (wt/wt), 0.9% (wt/wt), 1.0% (wt/wt), 1.1% (wt/wt), 1.2% (wt/wt), 1.3% (wt/wt), 1.4% (wt/wt), 1.5% (wt/wt), 1.6% (wt/wt), 1.7% (wt/wt), 1.8% (wt/wt), 1.9% (wt/wt), 2% (wt/wt), 2.1% (wt/wt), 2.2% (wt/wt), 2.3% (wt/wt), 2.4% (wt/wt), 2.5% (wt/wt), 2.6% (wt/wt), 2.7% (wt/wt
  • the at least one excipient comprises trehalose.
  • the concentration of trehalose in the formulation is from about 0.5% (wt/wt) to about 50% (wt/wt), from about 3% (wt/wt) to about 10% (wt/wt), from about 4% (wt/wt) to about 6% (wt/wt), from about 3 % (wt/wt) to about 8 % (wt/wt), from about 2% (wt/wt) to about 15% (wt/wt), or from about 1% (wt/wt) to about 20% (wt/wt).
  • the concentration of trehalose in the formulation is about or at least about 0.1% (wt/wt), 0.2% (wt/wt), 0.3% (wt/wt), 0.4% (wt/wt), 0.5% (wt/wt), 0.6% (wt/wt), 0.7% (wt/wt), 0.8% (wt/wt), 0.9% (wt/wt), 1.0% (wt/wt), 1.1% (wt/wt), 1.2% (wt/wt), 1.3% (wt/wt), 1.4% (wt/wt), 1.5% (wt/wt), 1.6% (wt/wt), 1.7% (wt/wt), 1.8% (wt/wt), 1.9% (wt/wt), 2% (wt/wt), 2.1% (wt/wt), 2.2% (wt/wt), 2.3% (wt/wt), 2.4% (wt/wt), 2.5% (wt/wt), 2.6% (wt/wt), 2.6% (w
  • the concentration of trehalose in the formulation is less than about 0.1% (wt/wt), 0.2% (wt/wt), 0.3% (wt/wt), 0.4% (wt/wt), 0.5% (wt/wt), 0.6% (wt/wt), 0.7% (wt/wt), 0.8% (wt/wt), 0.9% (wt/wt), 1.0% (wt/wt), 1.1% (wt/wt), 1.2% (wt/wt), 1.3% (wt/wt), 1.4% (wt/wt), 1.5% (wt/wt), 1.6% (wt/wt), 1.7% (wt/wt), 1.8% (wt/wt), 1.9% (wt/wt), 2% (wt/wt), 2.1% (wt/wt), 2.2% (wt/wt), 2.3% (wt/wt), 2.4% (wt/wt), 2.5% (wt/wt), 2.6% (wt/wt), 2.7%
  • Surfactants are amphiphilic organic compounds, that is, compounds containing groups having different soluble properties.
  • a surfactant refers to a surface-active agent comprising a hydrophobic portion and a hydrophilic portion.
  • the formulation comprises a single surfactant.
  • the formulation comprises two surfactants.
  • the formulation comprises a plurality of surfactants.
  • the formulation comprises a non-ionic surfactant and an ionic surfactant.
  • the surfactant is a non-ionic surfactant.
  • non-ionic surfactants that are suitable for use in the formulations described herein include: sorbitan fatty acid esters, non-limiting examples thereof including sorbitan monocaprylate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan trioleate; glycerin fatty acid esters, non- limiting examples thereof including, glycerin monocaprylate, glycerin monomyri state, glycerin monostearate; polyglycerin fatty acid esters, non-limiting examples thereof including decaglyceryl monostearate, decaglyceryl distearate, decaglyceryl monolinoleate; polyoxyethylene sorbitan fatty acid esters, non-limiting examples thereof including polyoxyethylene sorbitan monolaurate, wherein polyoxyethylene (20) sorbitan monolaurate is TWEEN-20 and poly
  • polyoxyethylene sorbitan monostearate wherein polyoxyethylene (20) sorbitan monostearate is TWEEN-60, polyoxyethylene sorbitan trioleate is TWEEN-85, and polyoxyethylene sorbitan tristearate is TWEEN-65; nonyl phenoxypolyethoxylethanol (NP-40); polyoxyethylene sorbitol fatty acid esters, non-limiting examples thereof including polyoxyethylene sorbitol tetrastearate, polyoxyethylene sorbitol tetraoleate; polyoxyethylene glycerin fatty acid esters, a non-limiting example thereof being polyoxyethylene glyceryl monostearate; polyethylene glycol, a non-limiting example thereof including PEG8000; polyethylene glycol fatty acid esters, a non-limiting example thereof being polyethylene glycol distearate; polyoxyethylene alkyl ethers, a non-limiting example thereof being polyoxyethylene lauryl ether;
  • the surfactant is PEG or a sorbitan fatty acid ester.
  • the sorbitan fatty acid ester is polysorbate.
  • the non-ionic surfactant is PS80.
  • the sorbitan fatty acid ester is polysorbate 20, polysorbate 40, polysorbate 60, and/or polysorbate 80.
  • the surfactant is a poloxamer.
  • the poloxamer is poloxamer 124, poloxamer 181, poloxamer 188, etc.
  • the surfactant is an ionic surfactant. In some embodiments, the surfactant is a cationic surfactant. In some embodiments, the surfactant is a cationic surfactant.
  • ionic surfactants include: C10-C18 alkyl sulfates, non- limiting examples thereof including sodium cetyl sulfate, sodium lauryl sulfate, sodium oleyl sulfate; polyoxyethylene C10-06 alkyl ether sulfate with an average of 2 to 4 moles of ethylene oxide units added, a non-limiting example thereof including sodium polyoxyethylene lauryl sulfate; and C1-08 alkyl sulfosuccinate ester salts, a non-limiting example thereof including sodium lauryl sulfosuccinate ester; and natural surfactants, non-limiting examples thereof including lecithin, glycerophospholipid, sphingophospholipids
  • the concentration of the surfactant in the formulation is from about 0.001% (wt/wt) to about 1% (wt/wt), from about 0.001% (wt/wt) to about 0.1% (wt/wt), from about 0.01% (wt/wt) to about 0.1% (wt/wt), from about 0.0005% (wt/wt) to about 0.05% (wt/wt), from about 0.003% (wt/wt) to about 0.01% (wt/wt), from about 0.01% (wt/wt) to about 0.2% (wt/wt), from about 0.01% (wt/wt) to about 0.15% (wt/wt), from about 0.01% (wt/wt) to about 0.1% (wt/wt), from about 0.01% (wt/wt) to about 0.05% (wt/wt), from about 0.01%
  • the concentration of the surfactant in the formulation is about or at least about 0.0001% (wt/wt), 0.0002% (wt/wt), 0.0003% (wt/wt), 0.0004% (wt/wt), 0.0005% (wt/wt), 0.0006% (wt/wt), 0.0007% (wt/wt), 0.0008% (wt/wt), 0.0009% (wt/wt), 0.001% (wt/wt), 0.002% (wt/wt), 0.003% (wt/wt), 0.004% (wt/wt), 0.005% (wt/wt), 0.006% (wt/wt), 0.007% (wt/wt), 0.007% (wt/wt), 0.008% (wt/wt), 0.009% (wt/wt), 0.01% (wt/wt), 0.02% (wt/wt), 0.03% (wt/wt), 0.04% (wt/wt), 0.05% (wt/w
  • the concentration of the surfactant in the formulation is less than about 0.0001% (wt/wt), 0.0002% (wt/wt), 0.0003% (wt/wt), 0.0004% (wt/wt), 0.0005% (wt/wt), 0.0006% (wt/wt), 0.0007% (wt/wt), 0.0008% (wt/wt), 0.0009% (wt/wt), 0.001% (wt/wt), 0.002% (wt/wt), 0.003% (wt/wt), 0.004% (wt/wt), 0.005% (wt/wt), 0.006% (wt/wt), 0.007% (wt/wt), 0.007% (wt/wt), 0.008% (wt/wt), 0.009% (wt/wt), 0.01% (wt/wt), 0.02% (wt/wt), 0.03% (wt/wt), 0.04% (wt/wt), 0.05% (wt/wt),
  • the concentration of PS80 in the formulation is from about 0.0005% (wt/wt) to about 0.05% (wt/wt), from 0.001% (wt/wt) to about 0.01% (wt/wt), from about 0.003% (wt/wt) to about 0.01% (wt/wt), from about 0.003% (wt/wt) to about 0.015% (wt/wt), from about 0.001% (wt/wt) to about 0.020% (wt/wt), from about 0.001% (wt/wt) to about 0.025% (wt/wt), from about 0.0001% (wt/wt) to about 0.01% (wt/wt), from about 0.0001% (wt/wt) to about 0.05% (wt/wt), or from about 0.001% (wt/wt) to about 0.01% (wt/wt).
  • the concentration of PS80 in the formulation is about or at least about 0.0001% (wt/wt), 0.0002% (wt/wt), 0.0003% (wt/wt), 0.0004% (wt/wt), 0.0005% (wt/wt), 0.0006% (wt/wt), 0.0007% (wt/wt), 0.0008% (wt/wt), 0.0009% (wt/wt), 0.001% (wt/wt), 0.002% (wt/wt), 0.003% (wt/wt), 0.004% (wt/wt), 0.005% (wt/wt), 0.006% (wt/wt), 0.007% (wt/wt), 0.007% (wt/wt), 0.008% (wt/wt), 0.009% (wt/wt), 0.01% (wt/wt), 0.02% (wt/wt), 0.03% (wt/wt), 0.04% (wt/wt), 0.05% (wt/wt),
  • the concentration of PS80 in the formulation is less than about 0.0001% (wt/wt), 0.0002% (wt/wt), 0.0003% (wt/wt), 0.0004% (wt/wt), 0.0005% (wt/wt), 0.0006% (wt/wt), 0.0007% (wt/wt), 0.0008% (wt/wt), 0.0009% (wt/wt), 0.001% (wt/wt), 0.002% (wt/wt), 0.003% (wt/wt), 0.004% (wt/wt), 0.005% (wt/wt), 0.006% (wt/wt), 0.007% (wt/wt), 0.007% (wt/wt), 0.008% (wt/wt), 0.009% (wt/wt), 0.01% (wt/wt), 0.02% (wt/wt), 0.03% (wt/wt), 0.04% (wt/wt), 0.05% (wt/wt), 0.0
  • the dynamic viscosity of the formulation is from about 0.5 mPas to about 50 mPas, from about 2 mPas to about 10 mPas, from about 4 mPas to about 6 mPas, or from about 4.25 mPas to about 5.5 mPas.
  • a formulation that comprises from 50mM to 200 mM phosphate, from 10 mM to 40 mM histidine, from 50 to 200 mM arginine and glutamic acid, from 3 to 10 mM methionine, from 50 to 200 mM NaCl, and from 25 to 125 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 50 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 100 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the pH of the formulation may be from 6.4 to 7.0, or from 6.6 to 6.8.
  • the pH of the formulation may be 6.7.
  • the formulation may comprise from 50 to 75 mM, from 70 to 100 mM, from 90 to 130 mM, from 120 to 180 mM, or from 150 to 200 mM phosphate.
  • the formulation may comprise about 100 mM phosphate.
  • the formulation may comprise 100 mM phosphate.
  • the formulation may comprise from 10 to 20 mM, from 15 to 30 mM, or from 25 to 40 mM histidine.
  • the formulation may comprise about 20 mM histidine.
  • the formulation may comprise 20 mM histidine.
  • the formulation may comprise from 50 to 100 mM, from 75 to 125 mM, or from 100 to 200 mM arginine and glutamic acid.
  • the formulation may comprise about 90 mM arginine and glutamic acid.
  • the formulation may comprise 90 mM arginine and glutamic acid.
  • the formulation may comprise from 3 to 5 mM, from 3 to 7 mM, from 4 to 8 mM, or from 5 to 10 mM methionine.
  • the formulation may comprise about 5.6 mM methionine.
  • the formulation may comprise 5.6 mM methionine.
  • the formulation may comprise from 50 to 125 mM, from 75 to 125 mM, from 80 to 150 mM, or from 100 to 200 mM NaCl.
  • the formulation may comprise about 100 mM NaCl.
  • the formulation may comprise 100 mM NaCl.
  • the formulation may or may not comprise glycine.
  • the formulation does not comprise glycine.
  • the formulation may or may not comprise lysine.
  • the formulation does not comprise lysine.
  • the formulation may or may not comprise sucrose.
  • the formulation does not comprise sucrose.
  • the formulation may or may not comprise trehalose.
  • the formulation does not comprise trehalose.
  • the formulation comprises equimolar parts sodium hydrogen phosphate and sodium dihydrogen phosphate.
  • the formulation may have an osmolality of from about 550 mOsmol/kg water to about 600 mOsmol/kg water.
  • the formulation may have an osmolality of about 587 mOsmol/kg water.
  • the formulation may or may not comprise polysorbate 80. In various embodiments, the formulation does not comprise polysorbate 80.
  • the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 4 months at 2-8°C.
  • 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 6 months at 2-8°C.
  • less than 6%, 5.9%, 5.8%, 5.7%, 5.6%, 5.5%, 5.4%, 5.3%. 5.2%, 5.1%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, or 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • a formulation that comprises from 50mM to 200 mM phosphate, from 10 mM to 40 mM histidine, from 50 to 200 mM arginine and glutamic acid, from 4 to 16 mM methionine, from 50 to 200 mM NaCl, and from 25 to 125 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 50 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 100 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the pH of the formulation may be from 6.25 to 6.75, or from 6.4 to 6.6.
  • the pH of the formulation may be 6.5.
  • the formulation may comprise from 50 to 75 mM, from 70 to 100 mM, from 90 to 130 mM, from 120 to 180 mM, or from 150 to 200 mM phosphate.
  • the formulation may comprise about 100 mM phosphate.
  • the formulation may comprise 100 mM phosphate.
  • the formulation may comprise from 10 to 20 mM, from 15 to 30 mM, or from 25 to 40 mM histidine.
  • the formulation may comprise about 20 mM histidine.
  • the formulation may comprise 20 mM histidine.
  • the formulation may comprise from 50 to 100 mM, from 75 to 125 mM, or from 100 to 200 mM arginine and glutamic acid.
  • the formulation may comprise about 100 mM arginine and glutamic acid.
  • the formulation may comprise 100 mM arginine and glutamic acid.
  • the formulation may comprise from 4 to 12 mM, from 8 to 20 mM, or from 1 to 8 mM methionine.
  • the formulation may comprise about 8 mM methionine.
  • the formulation may comprise 8 mM methionine.
  • the formulation may comprise from 50 to 125 mM, from 80 to 150 mM, from 75 to 125 mM, or from 100 to 200 mM NaCl.
  • the formulation may comprise about 100 mM NaCl.
  • the formulation may comprise 100 mM NaCl.
  • the formulation may or may not comprise glycine. In various embodiments, the formulation does not comprise glycine.
  • the formulation may or may not comprise lysine. In various embodiments, the formulation does not comprise lysine.
  • the formulation may or may not comprise sucrose. In various embodiments, the formulation does not comprise sucrose.
  • the formulation may or may not comprise trehalose. In various embodiments, the formulation does not comprise trehalose.
  • the formulation may or may not comprise polysorbate 80. In various embodiments, the formulation does not comprise polysorbate 80.
  • the formulation may have an osmolality of from about 575 mOsmol/kg water to about 625 mOsmol/kg water.
  • the formulation may have an osmolality of about 596 mOsmol/kg water. In some embodiments, less than 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4,
  • GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 2-8°C. In some embodiments, less than 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4,
  • the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 4 months at 2-8°C. In some embodiments, less than 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4,
  • GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 6 months at 2-8°C. In some embodiments, less than 6%, 5.9%, 5.8%, 5.7%, 5.6%, 5.5%, 5.4%, 5.3%.
  • a formulation that comprises from 50mM to 200 mM phosphate, from 10 mM to 40 mM histidine, from 50 to 200 mM arginine and glutamic acid, from 4 to 16 mM methionine, from 1 to 4 % (wt/wt) sucrose, and from 25 to 125 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 50 mg/ml of the GLP-2 peptibody or the PTH peptibody. In some embodiments, the formulation comprises 100 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the pH of the formulation may be from 6.25 to 6.75 or from 6.4 to 6.6. The pH of the formulation may be 6.5.
  • the formulation may comprise from 50 to 75 mM, from 70 to 100 mM, from 90 to 130 mM, from 120 to 180 mM, or from 150 to 200 mM phosphate. The formulation may comprise about 100 mM phosphate.
  • the formulation may comprise 100 mM phosphate.
  • the formulation may comprise from 10 to 20 mM, from 15 to 30 mM, or from 25 to 40 mM histidine.
  • the formulation may comprise about 20 mM histidine.
  • the formulation may comprise 20 mM histidine.
  • the formulation may comprise from 50 to 100 mM, from 75 to 125 mM, or from 100 to 200 mM arginine and glutamic acid.
  • the formulation may comprise about 100 mM arginine and glutamic acid.
  • the formulation may comprise 100 mM arginine and glutamic acid.
  • the formulation may comprise from 4 to 12 mM, from 8 to 20 mM, or from 1 to 8 mM methionine.
  • the formulation may comprise about 8 mM methionine.
  • the formulation may comprise 8 mM methionine.
  • the formulation may comprise from about 1 to 4% (wt/wt), from 0.1 to 2% (wt/wt), or from 2 to 5% (wt/wt) sucrose.
  • the formulation may comprise about 2% (wt/wt) sucrose.
  • the formulation may comprise % (wt/wt) sucrose.
  • the formulation may or may not comprise NaCl. In various embodiments, the formulation does not comprise NaCl.
  • the formulation may or may not comprise glycine. In various embodiments, the formulation does not comprise glycine.
  • the formulation may or may not comprise lysine. In various embodiments, the formulation does not comprise lysine.
  • the formulation may or may not comprise trehalose.
  • the formulation does not comprise trehalose.
  • the formulation may or may not comprise polysorbate 80.
  • the formulation does not comprise polysorbate 80.
  • the formulation may have an osmolality of from about 450 mOsmol/kg water to about 500 mOsmol/kg water.
  • the formulation may have an osmolality of about 483 mOsmol/kg water.
  • the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 6 months at 2-8°C.
  • less than 6%, 5.9%, 5.8%, 5.7%, 5.6%, 5.5%, 5.4%, 5.3%. 5.2%, 5.1%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, or 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • a formulation that comprises from 25 mM to 100 mM histidine, from 50 to 200 mM arginine and glutamic acid, from 4 to 16 mM methionine, from 50 to 200 mM NaCl, and from 25 to 125 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 50 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 100 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the pH of the formulation may be from 6.25 to 7.0, from 6.45 to 6.55, or from 6.65 to 6.75.
  • the pH of the formulation may be 6.5.
  • the pH of the formulation may be 6.7.
  • the formulation may comprise from 20 to 60 mM, from 30 to 70 mM, from 40 to 100 mM, or from 40 to 60 mM histidine.
  • the formulation may comprise about 50 mM histidine.
  • the formulation may comprise 50 mM histidine.
  • the formulation may comprise from 50 to 90 mM, from 75 to 125 mM, or from 100 to 200 mM arginine and glutamic acid.
  • the formulation may comprise about 100 mM arginine and glutamic acid.
  • the formulation may comprise 100 mM arginine and glutamic acid.
  • the formulation may comprise from 4 to 12 mM, from 8 to 20 mM, or from 1 to 8 mM methionine.
  • the formulation may comprise about 8 mM methionine.
  • the formulation may comprise 8 mM methionine.
  • the formulation may comprise from 50 to 125 mM, from 75 to 125 mM, from 80 to 150 mM, or from 120 to 200 mM NaCl.
  • the formulation may comprise about 100 mM NaCl.
  • the formulation may comprise 100 mM NaCl.
  • the formulation may or may not comprise phosphate. In various embodiments, the formulation does not comprise phosphate.
  • the formulation may or may not comprise glycine. In various embodiments, the formulation does not comprise glycine.
  • the formulation may or may not comprise lysine.
  • the formulation does not comprise lysine.
  • the formulation may or may not comprise sucrose. In various embodiments, the formulation does not comprise sucrose.
  • the formulation may or may not comprise trehalose. In various embodiments, the formulation does not comprise trehalose.
  • the formulation may or may not comprise polysorbate 80. In various embodiments, the formulation does not comprise polysorbate 80.
  • the formulation may have an osmolality of from about 425 mOsmol/kg water to about 475 mOsmol/kg water.
  • the formulation may have an osmolality of from about 450 mOsmol/kg water to about 455 mOsmol/kg water.
  • 3%, 2.5%, 2%, 1.5%, or 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • less than 6%, 5.9%, 5.8%, 5.7%, 5.6%, 5.5%, 5.4%, 5.3%. 5.2%, 5.1%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, or 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 4 months at 25°C.
  • a formulation that comprises from 5 mM to 20 mM histidine, from 25 to 100 mM glycine, from 50 to 200 mM NaCl, from 2.5 to 10% (wt/wt) trehalose, from 0.0025 to 0.010% (wt/wt) polysorbate 80, and from 25 to 125 mg/ml of the GLP- 2 peptibody or the PTH peptibody.
  • the formulation comprises 50 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 100 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the pH of the formulation may be from 6.5 to 7.5.
  • the pH of the formulation may be 7.0.
  • the formulation may comprise from 1 to 50 mM, from 1 to 10 mM, from 10 to 50 mM, or from 5 to 15 mM histidine.
  • the formulation may comprise about 10 mM histidine.
  • the formulation may comprise 10 mM histidine.
  • the formulation may comprise from 10 to 60 mM, from 40 to 100 mM, from 25 to 75 mM, or from 40 to 60 mM glycine.
  • the formulation may comprise about 50 mM glycine.
  • the formulation may comprise 50 mM glycine.
  • the formulation may comprise from 50 to 125 mM, from 80 to 150 mM, or from 100 to 200 mM NaCl.
  • the formulation may comprise about 100 mM NaCl.
  • the formulation may comprise 100 mM NaCl.
  • the formulation may comprise from 1 to 10% (wt/wt), from 3 to 8% (wt/wt), or from 4 to 10% (wt/wt) trehalose.
  • the formulation may comprise about 5% (wt/wt) trehalose.
  • the formulation may comprise 5% (wt/wt) trehalose.
  • the formulation may comprise from 0.001 to 0.010% (wt/wt), from 0.002 to 0.007% (wt/wt), or from 0.004 to 0.010% (wt/wt) polysorbate 80.
  • the formulation may comprise about 0.005% (wt/wt) polysorbate 80.
  • the formulation may comprise 0.005% (wt/wt) polysorbate 80.
  • the formulation may or may not comprise phosphate. In various embodiments, the formulation does not comprise phosphate.
  • the formulation may or may not comprise lysine. In various embodiments, the formulation does not comprise lysine.
  • the formulation may or may not comprise arginine. In various embodiments, the formulation does not comprise arginine.
  • the formulation may or may not comprise glutamic acid. In various embodiments, the formulation does not comprise glutamic acid.
  • the formulation may or may not comprise methionine. In various embodiments, the formulation does not comprise methionine.
  • the formulation may or may not comprise sucrose. In various embodiments, the formulation does not comprise sucrose.
  • the formulation may have an osmolality of from about 400 mOsmol/kg water to about 450 mOsmol/kg water.
  • the formulation may have an osmolality of about 423 mOsmol/kg water.
  • the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 6 months at 2-8°C.
  • less than 6%, 5.9%, 5.8%, 5.7%, 5.6%, 5.5%, 5.4%, 5.3%. 5.2%, 5.1%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, or 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • a formulation that comprises from 1 mM to 4 mM histidine, from 5 to 20 mM glycine, from 75 to 300 mM NaCl, and from 25 to 125 mg/ml of the GLP-2 peptibody or the PTH peptibody. In some embodiments, the formulation comprises 50 mg/ml of the GLP-2 peptibody. In some embodiments, the formulation comprises 100 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the pH of the formulation may be from 6.5 to 7.5, or from 6.75 to 7.25. The pH of the formulation may be 7.0.
  • the formulation may comprise from 1 to 5 mM, from 2 to 10 mM, from 2 to 5 mM, or from 5 to 15 mM histidine.
  • the formulation may comprise about 2 mM histidine.
  • the formulation may comprise 2 mM histidine.
  • the formulation may comprise from 1 to 50 mM, from 1 to 20 mM, or from 5 to 15 mM glycine.
  • the formulation may comprise about 10 mM glycine.
  • the formulation may comprise 10 mM glycine.
  • the formulation may comprise from 50 to 125 mM, from 80 to 150 mM, or from 100 to 200 mM NaCl.
  • the formulation may comprise about 150 mM NaCl.
  • the formulation may comprise 150 mM NaCl.
  • the formulation may or may not comprise phosphate. In various embodiments, the formulation does not comprise phosphate.
  • the formulation may or may not comprise lysine. In various embodiments, the formulation does not comprise lysine
  • the formulation may or may not comprise arginine. In various embodiments, the formulation does not comprise arginine.
  • the formulation may or may not comprise glutamic acid. In various embodiments, the formulation does not comprise glutamic acid.
  • the formulation may or may not comprise methionine. In various embodiments, the formulation does not comprise methionine.
  • the formulation may or may not comprise sucrose. In various embodiments, the formulation does not comprise sucrose.
  • the formulation may or may not comprise trehalose. In various embodiments, the formulation does not comprise trehalose.
  • the formulation may or may not comprise polysorbate 80. In various embodiments, the formulation does not comprise polysorbate 80.
  • the formulation may have an osmolality of from about 275 mOsmol/kg water to about 325 mOsmol/kg water.
  • the formulation may have an osmolality of about 308 mOsmol/kg water. In some embodiments, less than 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4,
  • GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 2-8°C. In some embodiments, less than 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4,
  • the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 4 months at 2-8°C. In some embodiments, less than 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4,
  • GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 6 months at 2-8°C. In some embodiments, less than 6%, 5.9%, 5.8%, 5.7%, 5.6%, 5.5%, 5.4%, 5.3%.
  • a formulation that comprises from 1 mM to 4 mM histidine, from 5 to 20 mM glycine, from 75 to 300 mM NaCl, from 0.0025 to 0.010% (wt/wt) polysorbate 80, and from 25 to 125 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 50 mg/ml of the GLP-2 peptibody or the PTH peptibody. In some embodiments, the formulation comprises 100 mg/ml of the peptibody or the PTH peptibody.
  • the pH of the formulation may be from 6.5 to 7.5, or from 6.75 to 7.25. The pH of the formulation may be 7.0.
  • the formulation may comprise from 1 to 5 mM, from 2 to 10 mM, from 2 to 5 mM, or from 5 to 15 mM histidine.
  • the formulation may comprise about 2 mM histidine.
  • the formulation may comprise 2 mM histidine.
  • the formulation may comprise from 10 to 50 mM, from 1 to 20 mM, or from 5 to 15 mM glycine.
  • the formulation may comprise about 10 mM glycine.
  • the formulation may comprise 10 mM glycine.
  • the formulation may comprise from 50 to 125 mM, from 80 to 150 mM, or from 100 to 200 mM NaCl.
  • the formulation may comprise about 150 mM NaCl.
  • the formulation may comprise 150 mM NaCl.
  • the formulation may comprise from 0.001 to 0.010% (wt/wt), from 0.002 to 0.007% (wt/wt), or from 0.004 to 0.010% (wt/wt) polysorbate 80.
  • the formulation may comprise about 0.005% (wt/wt) polysorbate 80.
  • the formulation may comprise 0.005% (wt/wt) polysorbate 80.
  • the formulation may or may not comprise phosphate. In various embodiments, the formulation does not comprise phosphate.
  • the formulation may or may not comprise lysine. In various embodiments, the formulation does not comprise lysine.
  • the formulation may or may not comprise arginine. In various embodiments, the formulation does not comprise arginine.
  • the formulation may or may not comprise glutamic acid. In various embodiments, the formulation does not comprise glutamic acid.
  • the formulation may or may not comprise methionine. In various embodiments, the formulation does not comprise methionine.
  • the formulation may or may not comprise sucrose.
  • the formulation does not comprise sucrose.
  • the formulation may or may not comprise trehalose.
  • the formulation does not comprise trehalose.
  • the formulation may have an osmolality of from about 275 mOsmol/kg water to about 325 mOsmol/kg water.
  • the formulation may have an osmolality of about 300 mOsmol/kg water. In some embodiments, less than 3.0, 2.9, 2.8, 2.7,
  • GLP-2 peptibody or PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 2-8°C. In some embodiments, less than 3.0, 2.9, 2.8,
  • 3%, 2.5%, 2%, 1.5%, or 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 4 months at 25°C.
  • less than 6%, 5.9%, 5.8%, 5.7%, 5.6%, 5.5%, 5.4%, 5.3%. 5.2%, 5.1%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, or 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • a formulation that comprises from 1 mM to 4 mM histidine, from 5 to 20 mM glycine, from 1 to 4 mM methionine, from 75 to 300 mM NaCl, from 0.0025 to 0.010% (wt/wt) polysorbate 80, and from 25 to 125 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 50 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 100 mg/ml of the peptibody.
  • the pH of the formulation may be from 6.5 to 7.5, or from 6.75 to 7.25.
  • the pH of the formulation may be 7.0.
  • the formulation may comprise from 1 to 5 mM, from 2 to 10 mM, from 2 to 5 mM, or from 5 to 15 mM histidine.
  • the formulation may comprise about 2 mM histidine.
  • the formulation may comprise 2 mM histidine.
  • the formulation may comprise from 1 to 50 mM, from 1 to 20 mM, or from 5 to 15 mM glycine.
  • the formulation may comprise about 10 mM glycine.
  • the formulation may comprise 10 mM glycine.
  • the formulation may comprise from 1 to 15 mM, from 1.5 to 5 mM, from 3 to 8 mM, from 0.1 to 5 mM, or from 5 to 15 mM methionine.
  • the formulation may comprise about 2 mM methionine.
  • the formulation may comprise 2 mM methionine.
  • the formulation may comprise from 50 to 200 mM, from 80 to 160 mM, or from 100 to 200 mM NaCl.
  • the formulation may comprise about 150 mM NaCl.
  • the formulation may comprise 150 mM NaCl.
  • the formulation may comprise from 0.001 to 0.010% (wt/wt), from 0.002 to 0.007% (wt/wt), or from 0.004 to 0.010% (wt/wt) polysorbate 80.
  • the formulation may comprise about 0.005% (wt/wt) polysorbate 80.
  • the formulation may comprise 0.005% (wt/wt) polysorbate 80.
  • the formulation may or may not comprise phosphate.
  • the formulation does not comprise phosphate.
  • the formulation may or may not comprise lysine. In various embodiments, the formulation does not comprise lysine.
  • the formulation may or may not comprise arginine. In various embodiments, the formulation does not comprise arginine.
  • the formulation may or may not comprise glutamic acid. In various embodiments, the formulation does not comprise glutamic acid.
  • the formulation may or may not comprise sucrose. In various embodiments, the formulation does not comprise sucrose.
  • the formulation may or may not comprise trehalose. In various embodiments, the formulation does not comprise trehalose. In various embodiments, the formulation may have an osmolality of from about 275 mOsmol/kg water to about 325 mOsmol/kg water.
  • the formulation may have an osmolality of about 307 mOsmol/kg water.
  • the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 4 months at 2-8°C.
  • 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 6 months at 2-8°C.
  • less than 6%, 5.9%, 5.8%, 5.7%, 5.6%, 5.5%, 5.4%, 5.3%. 5.2%, 5.1%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, or 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • a formulation that comprises from 10 mM to 40 mM arginine, from 10 to 40 mM lysine, from 60 to 240 mM NaCl, from 0.0025 to 0.010% (wt/wt) polysorbate 80, and from 25 to 125 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 50 mg/ml of the GLP-2 peptibody or the PTH peptibody.
  • the formulation comprises 100 mg/ml of the peptibody or the PTH peptibody.
  • the pH of the formulation may be from 7.2 to 7.8, from 7.2 to 7.6, or from 7.3 to 7.5.
  • the pH of the formulation may be 7.40.
  • the formulation may comprise from 10 to 40 mM, from 10 to 30 mM, from 15 to 30 mM, or from 25 to 40 mM arginine.
  • the formulation may comprise about 20 mM arginine.
  • the formulation may comprise 20 mM arginine.
  • the formulation may comprise from 10 to 40 mM, from 10 to 30 mM, from 15 to 30 mM, or from 25 to 40 mM lysine.
  • the formulation may comprise about 20 mM lysine.
  • the formulation may comprise 20 mM lysine.
  • the formulation may comprise from 50 to 125 mM, from 80 to 150 mM, or from 100 to 200 mM NaCl.
  • the formulation may comprise about 120 mM NaCl.
  • the formulation may comprise 120 mM NaCl.
  • the formulation may comprise from 0.001 to 0.010% (wt/wt), from 0.003 to 0.008% (wt/wt), or from 0.004 to 0.010% (wt/wt) polysorbate 80.
  • the formulation may comprise about 0.005% (wt/wt) polysorbate 80.
  • the formulation may comprise 0.005% (wt/wt) polysorbate 80.
  • the formulation may or may not comprise phosphate. In various embodiments, the formulation does not comprise phosphate.
  • the formulation may or may comprise histidine.
  • the formulation does not comprise histidine.
  • the formulation may or may not comprise glycine. In various embodiments, the formulation does not comprise glycine.
  • the formulation may or may not comprise glutamic acid. In various embodiments, the formulation does not comprise glutamic acid.
  • the formulation may or may not comprise methionine. In various embodiments, the formulation does not comprise methionine.
  • the formulation may or may not comprise sucrose. In various embodiments, the formulation does not comprise sucrose.
  • the formulation may or may not comprise trehalose. In various embodiments, the formulation does not comprise trehalose. In various embodiments, the formulation may have an osmolality of from about 275 mOsmol/kg water to about 325 mOsmol/kg water.
  • the formulation may have an osmolality of about 313 mOsmol/kg water.
  • the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 4 months at 2-8°C.
  • 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 6 months at 2-8°C.
  • less than 6%, 5.9%, 5.8%, 5.7%, 5.6%, 5.5%, 5.4%, 5.3%. 5.2%, 5.1%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, or 1% of the GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • GLP-2 peptibody or the PTH peptibody has undergone degradation, oxidation, or aggregation after being present in the formation for 2 months at 25°C.
  • the present invention provides a method for stably storing a formulation comprising a GLP-2 peptibody or a PTH peptibody.
  • the method comprises preparing the formulation, dispensing a volume of the formulation within a vessel, sealing the vessel, and storing the vessel at a temperature of from about 0°C to about 37°C.
  • the formulation is stable during storage over a period of time greater than one month.
  • preparing the formulation comprises resuspending a lyophilized powder in a carrier.
  • preparing the formulation comprises thawing a previously frozen composition comprising the GLP-2 peptibody or the PTH peptibody.
  • the carrier is an aqueous carrier.
  • preparing the formulation comprises lyophilizing the GLP-2 peptibody or the PTH peptibody.
  • preparing the formulation comprises a dialysis step wherein a composition is dialyzed against a buffer composition comprising non-peptibody components of the formulation.
  • preparing the formulation comprises sterile filtration.
  • preparing the formulation comprises concentrating the GLP-2 peptibody or the PTH peptibody in the formulation.
  • preparing the formulation comprises a buffer-exchange step, optionally achieved by dialysis.
  • the volume dispensed within or stored within the vessel is about or at least about 0.5 ml, 1 ml, 1.5 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 11 ml, 12 ml, 13 ml, 14 ml, 15 ml, 16 ml, 17 ml, 18 ml, 19 ml, 20 ml, 21 ml, 22 ml, 23 ml, 24 ml, 25 ml, 30 ml, 35 ml, 40 ml, 45 ml, 50 ml, or 100 ml.
  • the volume dispensed within the vessel is less than about 0.5 ml, 1 ml, 1.5 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 11 ml, 12 ml, 13 ml, 14 ml, 15 ml, 16 ml, 17 ml, 18 ml, 19 ml, 20 ml, 21 ml, 22 ml, 23 ml, 24 ml, 25 ml, 30 ml, 35 ml, 40 ml, 45 ml, 50 ml, or 100 ml.
  • the vessel forms part of a prefilled syringe system.
  • the vessel is a siliconized glass syringe.
  • the vessel is a non- siliconized plastic syringe.
  • suitable syringes include a BD NEOPAK glass pre-fillable glass syringes, including XSiTM syringes, and Daikyo Crystal ZenithTM plastic ready-to-use syringes.
  • a surface of the vessel in contact with the formulation comprises glass or plastic.
  • a surface in contact with the formulation is 100%, 95%, 90%, 85%, or 80% siliconized glass. In some embodiments, the surface in contact with the formulation is 100%, 95%, 90%, 85%, or 80% a polymeric material. In various embodiments, the polymeric material comprises polypropylene, polystyrene, a siloxane, or a fluoropolymer. In some embodiments, the vessel forms part of an ISO type I siliconized glass- or non-siliconized plastic prefilled syringe system.
  • the formulation is stored at from about 0°C to about 37°C, about 0°C to about 30°C, about 0°C to about 25 °C, from about 0°C to about 20°C, from about 0°C to about 15°C, from about 0°C to about 10°C, from about 0°C to about 5°C, from about 2°C to about 8°C, from about 10°C to about 30°C, from about 15°C to about 30°C, from about 20°C to about 30°C, from about 23°C to about 27°C, or from about 1°C to about 9°C.
  • the formulation is stored at about or less than about 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, or 30°C.
  • the formulations have demonstrated improved stability during storage.
  • the GLP-2 peptibody or the PTH peptibody is stable, as demonstrated by, as nonlimiting examples, minimal aggregation, minimal flocculation, minimal fragmentation, minimal denaturation, and/or the GLP-2 peptibody or the PTH peptibody retaining potency during storage such that the formulation may be removed from storage, administered to a patient, and still exhibit therapeutic efficacy against a condition for which the formulation is administered.
  • the formulation is stable during storage over a period of time greater than 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In some embodiments, the formulation is stable during storage from 1 to 3 months, from 2 to 4 months, from 3 to 6 months, or from 4 to 8 months. In some embodiments, the formulation is stable during storage over a period of time greater than 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, or 5 years. In various embodiments, the formulation is stable during storage over a period of time greater than 1 year. In various embodiments, the formulation is stable during storage over a period of time of at least 2 months. In various embodiments, the formulation is stable during storage over a period of time of at least 4 months. In various embodiments, the formulation is stable during storage over a period of time of at least 6 months.
  • Stability of the formulations may be measured and defined according to any of various techniques available for such purposes and familiar to one of skill in the art. Stability of the formulations can be assessed by various analytical and/or immunological methods known in the art as well as by various combinations thereof.
  • stability of the formulations of the present invention can be demonstrated by the fact that the formulations show only low to undetectable levels of aggregation and/or particulate formation even during storage under one or more of the above stress conditions (e.g., storage at a specified temperature for a period of time).
  • Degrees of aggregation, degradation and/or fragmentation may be measured by, as non-limiting examples, visual appearance, subvisible particle counting, size-exclusion chromatography (SEC), A350 nm turbidity, viscosity, osmolality, aggregation temperature (T agg ), melting temperature (T m ), micro- flow imaging (MFI), high-performance size exclusion chromatography (SE-HPLC), RP-HPLC, IEX-HPLC, subvisible particle counting, analytical ultracentrifugation (AUC), dynamic light scattering (DLS), static light scattering (SLS), Fourier Transform Infrared Spectroscopy (FTIR), circular dichroism (CD), urea-induced protein unfolding techniques, intrinsic tryptophan fluorescence, differential scanning calorimetry techniques, OD320/0D280 ratio measurement, elastic light scattering (ELS), or various combinations thereof.
  • SEC size-exclusion chromatography
  • A350 nm turbidity viscosity,
  • the formulation is stable during storage over one of the above specified periods of time.
  • stability of the formulation may be measured by spectrophotometrical methods.
  • stability of the formulation can be measured using a visual appearance rating or score.
  • the visual appearance rating or score is determined following the evaluation schema provided in Table 3 or Table 13 of the Examples provided herein.
  • the formulation is considered stable for as long as the visual appearance rating is at least A/1, A/1.5, A/2, B/l, B/1.5, or B/2.
  • the formulation is considered stable for as long as the visual appearance rating is at least A/1.5.
  • stability of the formulation can be measured using Micro-Flow Imaging (MFI).
  • MFI Micro-Flow Imaging
  • the formulation is considered stable for as long as, as measured by MFI, the formulation comprises less than 3,000, 2,500, 2,000, 1,500, 1,000, 950,
  • the formulation comprises less than 600, 575, 550,
  • stability of the formulation can be measured using Size- Exclusion Chromatography (e.g., HPLC-SEC).
  • the formulation is considered stable for that period of time over which a decrease in SEC-main peak area is about or less than about 15%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6%, 6.5%, 6%, 5.5%, 5%, 4.5%,
  • stability of the formulation may be measured by measuring the potency (alternatively, “biological activity”) of the formulation.
  • the formulation is considered stable for that period of time over which a decrease in the potency of the formulation is about or less than about 15%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6%,
  • the formulation is considered stable for that period of time over which a decrease in the potency of the formulation is less than 10%. In various embodiments, the formulation is considered stable for that period of time over which a decrease in the potency of the formulation is less than 5%.
  • the formulation is considered stable for that period of time over which a decrease in the potency of the formulation is less than 2.5%. In various embodiments, the formulation is considered stable for that period of time over which a decrease in the potency of the formulation is less than 1%.
  • the molecular size distribution and the relative amounts of a polypeptide of the invention and protein impurities can be measured by Size Exclusion High-Performance Liquid Chromatography (SE-HPLC). The relative amount of a specific protein impurity, expressed as area %, can be calculated by dividing the peak area corresponding to the impurity by the total integrated area.
  • stability of the formulation can be measured using dynamic light scattering (also known as Photon Correlation Spectroscopy or quasi-elastic light scattering).
  • Dynamic light scattering is a technique in physics, which can be used to determine the size distribution profile of small particles in solution.
  • the particles or droplets scatter some of the light in all directions.
  • the intensity of the scattered light is uniform in all directions (Rayleigh scattering); for larger particles (above approximately 250 nm diameter), the intensity is angle-dependent (Mie scattering).
  • a suitable detector such as a photomultiplier capable of operating in photon counting mode.
  • Stability of the formulations can also be measured by the PAMAS SVSS-C (Small Volume Syringe System-C) instrument (PArtikelMess and AnalyseSysteme GMBH), which is a particle size distribution analyzer for low viscous fluids. It uses the principle of light obscuration to detect sub-visible particles in the size range of 1 nm to 200 nm. USP ⁇ 787> has established threshold limits for particle size distributions within a pharmaceutical compositions comprising a polypeptide (e.g., the peptibody).
  • Stability of the formulations can also be measured by the OD320/OD280 ratio, which is a measure for turbidity or the presence of particulates in the formulations. In some embodiments, the formulation is considered stable for as long as the OD320/OD280 ratio is about 0.05 or lower, about 0.01 or lower, or about 0.005 or lower.
  • Stability of the formulations can also be measured by elastic light scattering.
  • Elastic light scattering can be measured in a spectrofluorometer (e.g. excitation and emission wavelength 500 nm) by temperature-induced denaturation as measured e.g. at an angle of 90°.
  • the maximum scatter will stay within the absorption detection limit.
  • the formulation is considered stable for as long as the scatter is about 1000 abs or lower, about 750 abs or lower, or 500 abs or lower.
  • the present invention provides a method for treatment of a subject suffering a disease, disorder, and/or condition and in need of treatment for the disease, disorder, and/or condition.
  • the disease, disorder, and/or condition is one of those described below.
  • the method for treatment comprises administering to the subject the formulation or the formulation having been stored according to the methods described above.
  • the present invention provides a use of a kit (described further below) to treat the subject.
  • a method for treatment of a patient suffering from a gastrointestinal condition and/or in need of treatment for the gastrointestinal condition comprising administering to the patient any of various peptibody formulations disclosed herein, e.g., GLP-2 peptibody formulations.
  • a patient treated with the GLP-2 peptibody formulations of the present invention may have short bowel syndrome with Crohn's disease or secondary to Crohn's disease.
  • the patient has a gastrointestinal condition.
  • the patient has short bowel syndrome.
  • the patient may have enterocutaneous fistula.
  • the patient may have obstructive jaundice.
  • the patient may be suffering from a gastrointestinal disorder, including the upper gastrointestinal tract of the esophagus.
  • the patient can be an adult, a human, or an adult human.
  • Such patient may have short bowel syndrome with mesenteric infarction or secondary to mesenteric infarction.
  • Such patient may have short bowel syndrome with volvulus or secondary to volvulus.
  • Such patient may have short bowel syndrome with congenital intestinal abnormalities or secondary to congenital intestinal abnormalities.
  • Such patient may have short bowel syndrome with, or secondary to, multiple strictures due to adhesions or radiation.
  • Such patient may have short bowel syndrome with, or secondary to, vascular ischemia.
  • the patient may have limited, but some detectable, meal-stimulated GLP-2 secretion (as compared to a normal healthy individual).
  • the patient may have less, but some detectable, GLP-2 producing tissue (as compared to a normal healthy individual).
  • the patient may have elevated basal levels of endogenous GLP-2 (as compared to a normal healthy individual).
  • GLP-2 peptibody formulations of the present invention may be used to treat or prevent enterocutaneous fistulae, mucosal epithelial damage, radiation damage to the gastrointestinal tract, radiation-induced enteritis, chemotherapy-induced mucositis, ischemia-reperfusion injury, dextran sulfate-induced colitis, genetic inflammatory bowel disease, obstructive jaundice, and/or short bowel syndrome.
  • the formulations may be used to treat or prevent a variety of gastrointestinal conditions including, but not limited to, intestinal disease or injury.
  • the formulations may be administered to the patient to reduce apoptosis of cells of the gastrointestinal tract and/or to increase villus height in the small intestine.
  • the GLP-2 peptibody formulations may be used to treat and/or prevent one or a combination of the diseases and conditions mentioned in International Application No. PCT/US2018/047171, which is incorporated herein by reference in its entirety for all purposes.
  • the GLP-2 peptibody formulations disclosed herein may be used to treat and/or prevent liver disease.
  • GLP-2 peptibody formulations may be useful for liver regeneration or promotion of liver growth as described in El-Jamal et al., Glucagon-like peptide- 2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration. Am J Physiol Gastrointest Liver Physiol.
  • any of the GLP-2 peptibody formulations disclosed herein may produce a proliferative effect on the liver such as that which may be desirable following hepatectomy.
  • the GLP-2 peptibody formulations of the present invention can be used to treat irritable bowel syndrome, and other diseases that benefit from decreasing plasma glucose, inhibition of gastric and/or bowel movement, inhibition of gastric and/or intestinal emptying, or inhibition of food intake.
  • the patient may have short bowel syndrome with Crohn's disease or secondary to Crohn's disease.
  • the patient may have short bowel syndrome with mesenteric infarction, or secondary to mesenteric infarction.
  • the patient may have short bowel syndrome with volvulus, or secondary to volvulus.
  • the patient may have short bowel syndrome with congenital intestinal abnormalities, or secondary to congenital intestinal abnormalities.
  • the patient may have short bowel syndrome with, or secondary to, multiple strictures due to adhesions or radiation.
  • the patient may have short bowel syndrome with, or secondary to, vascular ischemia.
  • the patient may have limited, but some detectable, meal-stimulated GLP-2 secretion (as compared to a normal healthy individual).
  • the patient may have less, but some detectable, GLP-2 producing tissue (as compared to a normal healthy individual).
  • the patient may have elevated basal levels of endogenous GLP-2 (as compared to a normal healthy individual).
  • the patient may have short bowel syndrome without inflammatory bowel disease.
  • the short bowel syndrome is not secondary to inflammatory bowel disease.
  • the patient has short bowel syndrome but does not have inflammatory bowel disease.
  • the patient may have at least 25% colon-in-continuity with remnant small intestine and receive an amount of parenteral nutrition each week.
  • the patient has at least 30% colon-in-continuity.
  • the patient has at least 35% colon-in- continuity.
  • the patient has at least 40% colon-in-continuity.
  • the patient has at least 45% colon-in-continuity.
  • the patient has at least 50% colon-in-continuity.
  • the patient has at least 60% colon-in-continuity.
  • the patient has at least 70% colon-in-continuity.
  • the patient has at least 80% colon-in-continuity.
  • the patient has at least 90% colon-in-continuity.
  • the patient may have short bowel syndrome colon-in-continuity and remnant small intestine ranging from about 25 cm to about 200 cm.
  • the patient may have a length of small intestine ranging from about 50 to 150 cm.
  • the patient may have at least about 50 cm of remnant small intestine and receive an amount of parenteral nutrition each week.
  • the patient may have at least about 10% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 15% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 20% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 25% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 30% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 35% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 40% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 45% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 50% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 55% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 60% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 65% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 70% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 75% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 80% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may have at least about 90% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 10 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 15 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 20 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 25 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 30 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 35 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 40 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 45 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 50 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 55 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 60 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 65 pmol/L of endogenous GLP-2 levels in the fed state.
  • the patient may produce at least about 70 pmol/L of endogenous GLP-2 levels in the fed state.
  • glucagon-like peptide (GLP-2) peptibodies before surgery, during surgery, or within a period of time after surgery.
  • surgery refers to intestinal resection that would give rise to short bowel syndrome (SBS).
  • Surgery may also include other operations that may exacerbate SBS.
  • a goal of administering GLP-2 peptibody formulations before surgery, during surgery, or within a period of time after surgery is to increase intestinal absorption after surgery so as to reduce the degree of parenteral nutrition required.
  • the parenteral nutrition support may be short term, medium term, or long term.
  • GLP-2 peptibody formulations before surgery or during surgery may allow for avoidance of short term parenteral nutrition, or at least greatly decrease the time during which short term parenteral nutrition is needed. Also, administration of GLP-2 peptibody formulations after surgery may decrease the time period during which short term and medium term parenteral nutrition is needed. Administration of GLP-2 peptibody formulations may reduce inflammation or enhance the rate of small intestinal wound healing, which may in turn decrease the time period during which short term and medium term parenteral nutrition is needed. The methods herein may avoid or minimize complications of weaning a patient from parenteral nutrition.
  • the patient has a non-malignant disease.
  • the patient receives an amount of parenteral nutrition each week, and who presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation described herein to the patient just before surgery, during surgery, or within a period of time after surgery, using a dosing regimen effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the formulation is used for treating short bowel syndrome with non-malignant disease just before surgery, during surgery, or within a period of time after surgery.
  • PN parenteral nutrition
  • GLP-2 peptibody formulations before, during, or shortly after surgery can reduce the need for PN, allow for a reduced amount and/or time of PN administration, or even allow for avoidance of PN.
  • GLP-2 peptibodies have numerous activities that include slowing gastric emptying, reducing gastric secretions, increasing intestinal blood- flow, and stimulating growth of the small and large intestine. Growth of the small and large intestine can occur by stimulation of crypt cell proliferation and inhibition of enterocyte apoptosis. The surface area of the intestine increases and thus improved absorption of water, nutrients, and energy may occur. Such improved absorption can reduce or even eliminate the need for parenteral nutrition.
  • GLP-2 peptibody formulations pre-surgery, during surgery, or even post-surgery can be rapid, e.g., within 60 hours of administration, within 48 hours of administration, within 36 hours of administration, or within 24 hours of administration.
  • Such administration can rapidly improve GI transit within 48 hours after surgery.
  • Such administration can also enhance stem cell activity and even provide a long-term improvement in wound healing in the small intestine after the surgery.
  • administration of GLP-2 peptibody formulations can reduce inflammation from surgery. For example, administration of such 2, 3, 4, 5, or 6 hours before surgery can reduce the inflammatory response from resection of the small intestine. Reduction of the inflammatory response can expedite recovery from surgery and allow for other administrations of GLP-2 peptibody formulations to act more quickly to increase growth of the small and large intestine, e.g. by increasing crypt depth or by increasing villus height.
  • Treatment candidates include those short bowel syndrome patients who retain at least 50% or more of colon length in continuity with remnant small intestine after the surgery. Such a treatment candidate is identified herein as a patient with > 50% colon-in-continuity after the surgery.
  • the SBS patient with colon-in-continuity has or is expected to have a remnant small intestine at least about 50 cm in length after the surgery which, desirably but not essentially, incorporates at least a portion of the ileum.
  • the formulation comprising a GLP-2 peptibody is used in a method for treating a patient having short bowel syndrome with Crohn's disease or secondary to Crohn's disease.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents (or will present after surgery) with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation described herein to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the compositions described herein are for use in a method of treating short bowel syndrome with Crohn's disease, or secondary to Crohn's disease, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome with Crohn's disease, or secondary to Crohn's disease. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome with mesenteric infarction.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in- continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation described herein to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the compositions described herein are for use in a method of treating short bowel syndrome with mesenteric infarction, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome with mesenteric infarction. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome with volvulus or secondary to volvulus.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the compositions described herein are for use in a method of treating short bowel syndrome with volvulus, or secondary to volvulus, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome with volvulus, or secondary to volvulus. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for treating a patient having short bowel syndrome with congenital intestinal abnormalities.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the compositions described herein are for use in a method of treating short bowel syndrome with congenital intestinal abnormalities, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome with congenital intestinal abnormalities. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for treating a patient having short bowel syndrome with multiple strictures due to adhesions or radiation.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation described herein to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome with multiple strictures due to adhesions or radiation, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome with multiple strictures due to adhesions or radiation. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for treating a patient having short bowel syndrome with vascular ischemia or secondary to vascular ischemia.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation described herein to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome with vascular ischemia, or secondary to vascular ischemia, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome with vascular ischemia, or secondary to vascular ischemia. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for treating a patient having short bowel syndrome with limited (as compared to a normal healthy individual), but some detectable, meal-stimulated GLP-2 secretion.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase meal- stimulated GLP-2 secretion.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method for treating short bowel syndrome in a patient with limited (as compared to a normal healthy individual), but some detectable, meal-stimulated GLP- 2 secretion, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient with limited (as compared to a normal healthy individual), but some detectable, meal-stimulated GLP-2 secretion.
  • the formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome with at least 25% colon-in-continuity with remnant small intestine.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the method comprises administering a GLP-2 peptibody formulation described herein to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody is for use in a method of treating short bowel syndrome with at least 25% colon-in- continuity with remnant small intestine, the method comprising administering the GLP-2 peptibody just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome with at least 25% colon-in-continuity with remnant small intestine. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for treating a patient having short bowel syndrome with less (as compared to a normal healthy individual), but some detectable, GLP-2 producing tissue.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in- continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase the amount of GLP-2 producing tissue of the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome in a patient having short bowel syndrome with less (as compared to a normal healthy individual), but some detectable, GLP-2 producing tissue, the method comprising administering the GLP-2 peptibody just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient having short bowel syndrome with less (as compared to a normal healthy individual), but some detectable, GLP-2 producing tissue.
  • the formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for treating a patient having short bowel syndrome with elevated (as compared to a normal healthy individual) basal levels of endogenous GLP-2.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient with elevated (as compared to a normal healthy individual) basal levels of endogenous GLP-2, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome in a patient with elevated (as compared to a normal healthy individual) basal levels of endogenous GLP-2. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for treating a patient having short bowel syndrome with equal or elevated (as compared to a normal healthy individual) meal stimulated levels of endogenous GLP-2.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In another embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient with elevated (as compared to a normal healthy individual) meal stimulated levels of endogenous GLP-2, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient with elevated (as compared to a normal healthy individual) meal stimulated levels of endogenous GLP-2.
  • the formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for treating a patient having short bowel syndrome with colon-in-continuity and remnant small intestine ranging from about 25 cm to about 200 cm.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In another embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient with colon-in-continuity and remnant small intestine ranging from about 25 cm to about 200 cm, just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient with colon-in-continuity and remnant small intestine ranging from about 25 cm to about 200 cm, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient with colon-in-continuity and remnant small intestine ranging from about 25 cm to about 200 cm. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for treating a patient having short bowel syndrome with at least about 10% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state.
  • the patient receives an amount of parenteral nutrition each week, and who presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase the endogenous GLP-2 in the fed state of the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient with at least about 10% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state, just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient with at least about 10% (as compared to a normal healthy individual) endogenous GLP-2 levels in the fed state, just before surgery, during surgery, or within a period of time after surgery.
  • the formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for treating a patient having short bowel syndrome with colon-in-continuity and at least about 50 cm of remnant small intestine.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient with colon-in-continuity and at least about 50 cm of remnant small intestine, just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome in a patient with colon-in-continuity and at least about 50 cm of remnant small intestine, just before surgery, during surgery, or within a period of time after surgery. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for decreasing the fecal wet weight of a patient having short bowel syndrome.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to decrease the fecal wet weight of the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of decreasing the fecal wet weight of a patient having short bowel syndrome, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for decreasing the fecal wet weight of a patient having short bowel syndrome. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • Absolute wet weight absorption may be obtained by subtracting fecal wet weight from diet wet weight.
  • the GLP-2 peptibody formulation is used in a method for increasing the urine weight of a patient having short bowel syndrome.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase the urine weight of the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of increasing the urine weight of a patient expected to have short bowel syndrome after surgery, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for increasing the urine weight of a patient having short bowel syndrome. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome without inflammatory bowel disease.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or eliminate the weekly amount of parenteral nutrition received by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient without inflammatory bowel disease, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome in a patient without inflammatory bowel disease. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for increasing the crypt depth of a patient having short bowel syndrome and reduced crypt depth as compared to a normal healthy individual.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase the crypt depth of the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of increasing the crypt depth of a patient having short bowel syndrome and reduced crypt depth as compared to a normal healthy individual, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for increasing the crypt depth of a patient having short bowel syndrome and reduced crypt depth as compared to a normal healthy individual. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for increasing the number of mitotic figures per 100 crypt epithelial cells of a patient having short bowel syndrome and reduced mitotic figures per 100 crypt epithelial cells as compared to a normal healthy individual.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery, using a dosing regimen effective to increase the number of mitotic figures per 100 crypt epithelial cells of the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of increasing the number of mitotic figures per 100 crypt epithelial cells of a patient having short bowel syndrome and reduced mitotic figures per 100 crypt epithelial cells as compared to a normal healthy individual, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for increasing the number of mitotic figures per 100 crypt epithelial cells of a patient having short bowel syndrome and reduced mitotic figures per 100 crypt epithelial cells as compared to a normal healthy individual.
  • GLP-2 has been shown to diminish gastric acid secretion in sham-fed healthy humans and prolong gastric emptying in SBS patients.
  • Administration of a GLP-2 peptibody formulation may also diminish gastric acid secretion and prolong gastric emptying, as well as restore the physiological feedback (previously described as the ileal brake mechanism).
  • Supraphysiological doses of a GLP-2 peptibody formulation may produce locally high concentrations that suppress gastric secretion and induce small intestine growth. Regardless of the exact physiological mechanism, increases in intestinal absorption in relation to treatments that improve intestinal adaptation would preferably be converted into positive effects regarding body weight or composition, hydration, physical activity, and ultimately, quality of life.
  • the GLP-2 peptibody formulation is used in a method for restoring at least a portion of the ileal brake mechanism of a patient having short bowel syndrome and reduced or absent ileal brake mechanism.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in- continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to restore at least a portion of the ileal brake mechanism of the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of restoring at least a portion of the ileal brake mechanism of a patient having short bowel syndrome and reduced or absent ileal brake mechanism, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for restoring at least a portion of the ileal brake mechanism of a patient having short bowel syndrome and reduced or absent ileal brake mechanism. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for reducing gastric hypersecretion of a patient having short bowel syndrome and gastric hypersecretion.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce the gastric hypersecretion.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of reducing gastric hypersecretion of a patient having short bowel syndrome and gastric hypersecretion, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for reducing gastric hypersecretion of a patient having short bowel syndrome and gastric hypersecretion. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for reducing rapid gastric emptying of a patient having short bowel syndrome and rapid gastric emptying.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce the speed of gastric emptying.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of reducing rapid gastric emptying of a patient having short bowel syndrome and rapid gastric emptying, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for reducing rapid gastric emptying of a patient having short bowel syndrome and rapid gastric emptying. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for reducing or suppressing gastric secretion of a patient having short bowel syndrome.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce or suppress gastric secretion.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of reducing or suppressing gastric secretion of a patient having short bowel syndrome, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for reducing or suppressing gastric secretion of a patient having short bowel syndrome. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for inducing small intestine growth of a patient having short bowel syndrome.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to induce small intestine growth.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method for inducing small intestine growth of a patient having short bowel syndrome, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for inducing small intestine growth of a patient having short bowel syndrome. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for up- regulating protein transport of a patient having short bowel syndrome.
  • the patient receives an amount of parenteral nutrition each week or is expected to receive an amount of parenteral nutrition each week after surgery, e.g., resection of the small intestine.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to upregulate the protein transport in the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of up-regulating protein transport of a patient having short bowel syndrome, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for up-regulating protein transport of a patient having short bowel syndrome. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for reducing the occurrence of dehydration of a patient having short bowel syndrome, or who is expected to have short bowel syndrome, e.g., intestinal resection.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce the likelihood of dehydration occurrence in the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of reducing the occurrence of dehydration of a patient having short bowel syndrome, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for reducing the occurrence of dehydration of a patient having short bowel syndrome. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for reducing the occurrence of renal insufficiency of a patient having short bowel syndrome, or who is expected to have short bowel syndrome, e.g., intestinal resection.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce the likelihood of renal insufficiency occurrence in the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of reducing the occurrence of renal insufficiency of a patient having short bowel syndrome, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for reducing the occurrence of renal insufficiency of a patient having short bowel syndrome. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody formulation is used in a method for reducing the occurrence of kidney stones in a patient having short bowel syndrome, or who is expected to have short bowel syndrome after surgery, e.g., intestinal resection.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce the likelihood of kidney stone occurrence in the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of reducing the occurrence of kidney stones in a patient having short bowel syndrome, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for reducing the occurrence of kidney stones in a patient having short bowel syndrome. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • a method for treating a patient with short bowel syndrome presenting with colon-in-continuity with remnant small intestine, or expected to have short bowel syndrome presenting with colon-in-continuity with remnant small intestine post- surgery, e.g., intestinal resection comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to enhance intestinal absorption by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient presenting with colon-in-continuity with remnant small intestine, the method comprising administering the GLP- 2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient presenting with colon-in-continuity with remnant small intestine. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • a method for treating a patient with short bowel syndrome who is dependent on parenteral nutrition and is presenting with colon-in-continuity with remnant small intestine, or expected to have short bowel syndrome presenting with colon- in-continuity with remnant small intestine post-surgery, e.g., intestinal resection.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to enhance intestinal absorption by the patient. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient who is dependent on parenteral nutrition and is presenting with colon-in-continuity with remnant small intestine, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient who is dependent on parenteral nutrition and is presenting with colon-in-continuity with remnant small intestine.
  • the formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for increasing the villus height of a patient having or expected to have post-surgery, e.g., intestinal resection, short bowel syndrome and reduced villus height as compared to a normal healthy individual, who receives an amount of parenteral nutrition each week, and who presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase the villus height of the patient. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient who receives an amount of parenteral nutrition each week, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome in a patient who receives an amount of parenteral nutrition each week. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • GLP-2 peptibodies may be helpful to reduce the amount of total parenteral nutrition (TPN) needed immediately after surgery.
  • TPN total parenteral nutrition
  • GLP-2 peptibodies can increase villus height, crypt depth, and overall intestinal mucosal surface area.
  • the longer half-life of GLP-2 peptibodies as compared to GLP-2 may lead to a more quick and sustained increase.
  • the overall surface area increase could compensate for losses in the overall length of the small intestine.
  • TPN Total parenteral nutrition
  • Lei et al. has been described by Lei et al. as blunting the villi in the small intestine, or otherwise decreasing the villus height. See, Lei, Q. et al., Nutrients, 2016, 8:33.
  • Administration of a GLP-2 peptibody formulation disclosed herein may prevent the villi from becoming blunted, particularly if these are administered to the patient just before surgery, during surgery, or within a period of time after surgery. By preventing the villi from becoming blunted, absorption across the small intestine may be maximized after a surgery involving removing a portion of the small intestine followed by resection.
  • the formulation is used in a method for treating a patient having short bowel syndrome with non-malignant disease, who receives an amount of parenteral nutrition each week, and who presents with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation disclosed herein to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase wet weight absorption compared to a baseline wet weight absorption by the patient. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome with non-malignant disease in a patient who receives an amount of parenteral nutrition each week, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome with non-malignant disease in a patient who receives an amount of parenteral nutrition each week. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome with Crohn's disease.
  • the patient receives an amount of parenteral nutrition each week.
  • the patient also presents with colon-in-continuity with remnant small intestine.
  • the patient may not have short bowel syndrome but is expected post-surgery to have short bowel syndrome with Crohn's disease, receive an amount of parenteral nutrition each week, and present with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody is for use in a method of treating short bowel syndrome with Crohn's disease, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome with Crohn's disease.
  • the formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome with mesenteric infarction.
  • the patient receives an amount of parenteral nutrition each week and presents with colon-in-continuity with remnant small intestine.
  • the patient may not have short bowel syndrome but is expected post- surgery to have short bowel syndrome with mesenteric infarction, receive an amount of parenteral nutrition each week, and present with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase wet weight absorption compared to a baseline wet weight absorption by the patient. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome with mesenteric infarction, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome with mesenteric infarction. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome with, or secondary to, volvulus.
  • the patient receives an amount of parenteral nutrition each week and presents with colon-in-continuity with remnant small intestine.
  • the patient may not have short bowel syndrome but is expected postsurgery, e.g., intestinal resection to treat volvulus, to have short bowel syndrome, receive an amount of parenteral nutrition each week, and present with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome with, or secondary to, volvulus, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome with, or secondary to, volvulus. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome secondary to congenital intestinal abnormalities.
  • the patient receives an amount of parenteral nutrition each week and presents with colon-in-continuity with remnant small intestine.
  • the patient may not have short bowel syndrome but is expected to have post-surgery, e.g., intestinal resection, short bowel syndrome secondary to congenital intestinal abnormalities, receive an amount of parenteral nutrition each week, and present with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome secondary to congenital intestinal abnormalities, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome secondary to congenital intestinal abnormalities. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome without inflammatory bowel disease.
  • the patient receives an amount of parenteral nutrition each week and presents with colon-in-continuity with remnant small intestine.
  • the patient may not have short bowel syndrome but is expected to have post-surgery, e.g., intestinal resection, short bowel syndrome without inflammatory bowel disease, receive an amount of parenteral nutrition each week, and present with colon-in- continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome without inflammatory bowel disease, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome without inflammatory bowel disease. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome secondary to multiple strictures due to adhesions or radiation, and who receives an amount of parenteral nutrition each week.
  • the patient may not have short bowel syndrome but is expected to have post-surgery, e.g., intestinal resection, short bowel syndrome secondary to multiple strictures due to adhesions or radiation, and receive an amount of parenteral nutrition each week.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase wet weight absorption compared to a baseline wet weight absorption by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome secondary to multiple strictures due to adhesions or radiation in a patient who receives an amount of parenteral nutrition each week, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome secondary to multiple strictures due to adhesions or radiation in a patient who receives an amount of parenteral nutrition each week.
  • the formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome secondary to vascular ischemia.
  • the patient receives an amount of parenteral nutrition each week, and presents with colon-in-continuity with remnant small intestine.
  • the patient may not have short bowel syndrome but is expected to have post-surgery, e.g., intestinal resection, short bowel syndrome secondary to vascular ischemia, receive an amount of parenteral nutrition each week, and present with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome secondary to vascular ischemia in a patient who receives an amount of parenteral nutrition each week, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome secondary to vascular ischemia in a patient who receives an amount of parenteral nutrition each week. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome with at least 25% colon-in-continuity with remnant small intestine and who receives an amount of parenteral nutrition each week.
  • the patient may not have short bowel syndrome but is expected to have post-surgery, e.g., intestinal resection, short bowel syndrome with at least 25% colon-in-continuity with remnant small intestine and receive an amount of parenteral nutrition each week.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase wet weight absorption compared to a baseline wet weight absorption by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome with at least 25% colon-in-continuity with remnant small intestine in a patient who receives an amount of parenteral nutrition each week, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome with at least 25% colon-in-continuity with remnant small intestine in a patient who receives an amount of parenteral nutrition each week.
  • a method of treating a patient having short bowel syndrome with elevated (as compared to a normal healthy individual) basal levels of endogenous GLP-2 receives an amount of parenteral nutrition each week and presents with colon-in-continuity with remnant small intestine.
  • the patient may not have short bowel syndrome but is expected to have post-surgery, e.g., intestinal resection, short bowel syndrome with elevated (as compared to a normal healthy individual) basal levels of endogenous GLP-2, receive an amount of parenteral nutrition each week, and present with colon-in- continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase wet weight absorption compared to a baseline wet weight absorption by the patient. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient with elevated (as compared to a normal healthy individual) basal levels of endogenous GLP-2, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient with elevated (as compared to a normal healthy individual) basal levels of endogenous GLP-2. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • a method for treating a patient having short bowel syndrome with elevated (as compared to a normal healthy individual) basal levels of endogenous GLP-2 and who is dependent on parenteral nutrition comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to enhance intestinal absorption by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient with elevated (as compared to a normal healthy individual) basal levels of endogenous GLP-2 and who is dependent on parenteral nutrition, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient with elevated (as compared to a normal healthy individual) basal levels of endogenous GLP-2 and who is dependent on parenteral nutrition.
  • the formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome with equal or elevated (as compared to a normal healthy individual) meal stimulated levels of endogenous GLP-2.
  • the patient receives an amount of parenteral nutrition each week and presents with colon-in-continuity with remnant small intestine.
  • the patient may not have short bowel syndrome but is expected to have post-surgery, e.g., intestinal resection, short bowel syndrome with equal or elevated (as compared to a normal healthy individual) meal stimulated levels of endogenous GLP-2, receive an amount of parenteral nutrition each week, and present with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase wet weight absorption compared to a baseline wet weight absorption by the patient. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient with equal or elevated (as compared to a normal healthy individual) meal stimulated levels of endogenous GLP-2 and who is dependent on parenteral nutrition, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient with equal or elevated (as compared to a normal healthy individual) meal stimulated levels of endogenous GLP-2 and who is dependent on parenteral nutrition.
  • the formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • a method of treating a patient having short bowel syndrome with colon-in-continuity with remnant small intestine ranging from about 25 cm to about 200 cm and who receives an amount of parenteral nutrition each week may not have short bowel syndrome but is expected to have post-surgery, e.g., intestinal resection, short bowel syndrome with colon-in-continuity with remnant small intestine ranging from about 25 cm to about 200 cm and who receives an amount of parenteral nutrition each week.
  • the method comprises administering a formulation comprising a GLP-2 peptibody to the patient just before surgery, during surgery, or within a period of time after surgery.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient presenting with colon-in-continuity with remnant small intestine ranging from about 25 cm to about 200 cm and who receives an amount of parenteral nutrition each week, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient presenting with colon-in- continuity with remnant small intestine ranging from about 25 cm to about 200 cm and who receives an amount of parenteral nutrition each week.
  • the formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used in a method for treating a patient having short bowel syndrome with colon-in-continuity and at least about 50 cm of remnant small intestine and who receives an amount of parenteral nutrition each week.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce increase wet weight absorption compared to a baseline wet weight absorption by the patient. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient presenting with at least about 50 cm of remnant small intestine and who receives an amount of parenteral nutrition each week, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • the formulation is used for treating short bowel syndrome in a patient presenting with at least about 50 cm of remnant small intestine and who receives an amount of parenteral nutrition each week. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • a method of treating a patient having short bowel syndrome without inflammatory bowel disease receives an amount of parenteral nutrition each week and presents with colon-in-continuity with remnant small intestine.
  • the patient may not have short bowel syndrome but is expected to have short bowel syndrome without inflammatory bowel disease, receive an amount of parenteral nutrition each week, and present with colon-in-continuity with remnant small intestine.
  • the method comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to increase wet weight absorption compared to a baseline wet weight absorption by the patient.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome without inflammatory bowel disease in a patient who receives an amount of parenteral nutrition each week, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome without inflammatory bowel disease in a patient who receives an amount of parenteral nutrition each week. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • a method for treating a patient with short bowel syndrome who is dependent on parenteral nutrition and who presents with colon-in-continuity with remnant small intestine may not have short bowel syndrome but is expected to have post-surgery, e.g., intestinal resection, short bowel syndrome, be dependent on parenteral nutrition, and present with colon-in-continuity with remnant small intestine.
  • the method comprises administering to the patient a GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce the dependency on parenteral nutrition by the patient. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4. In one embodiment, the GLP-2 peptibody formulation is for use in a method of treating short bowel syndrome in a patient who is dependent on parenteral nutrition and who presents with colon-in-continuity with remnant small intestine, the method comprising administering the GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery. In another embodiment, the formulation is used for treating short bowel syndrome in a patient who is dependent on parenteral nutrition and who presents with colon-in-continuity with remnant small intestine. The formulation may be administered just before surgery, during surgery, or within a period of time after surgery.
  • a method for treating an adult patient with short bowel syndrome who is dependent on parenteral nutrition and who presents with colon-in- continuity with remnant small intestine may not have short bowel syndrome but is expected to have post-surgery, e.g., intestinal resection, short bowel syndrome, be dependent on parenteral nutrition, and present with colon-in-continuity with remnant small intestine.
  • the method comprises administering to the patient a GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce the dependency on parenteral nutrition by the patient. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • hypoparathyroidism is a life-long disease characterized by an inadequate production of parathyroid hormone (PTH) by the parathyroid glands. Because PTH is critical for regulation of calcium and phosphate levels, loss of PTH reduces calcium levels in blood and bones and increases phosphate levels (hypocalcemia and hyperphosphatemia). Hypocalcemia leads to symptoms such as neuromuscular irritability, including paresthesia, muscle twitching, laryngeal spasms (which can lead to inability to speak and to alert health providers to the underlying medical condition, which has led to delayed or incorrect treatment), and possibly tetany and seizures.
  • PTH parathyroid hormone
  • a method for treatment of a patient suffering from a hypoparathyroidism and/or in need of treatment for the hypoparathyroidism comprising administering to the patient any of various peptibody formulations disclosed herein, e.g., PTH peptibody formulations.
  • the method is effective to control serum calcium levels of a patient.
  • the method is effective to increase serum calcium levels of a patient with hypoparathyroidism and/or hypocalcemia due to hypoparathyroidism as compared to the serum calcium levels of said subject in the absence of administration of the PTH peptibody formulations of the invention.
  • the method is effective to reduce the amount of calcium supplements of a subject with hypoparathyroidism. In some embodiments, the method is effective to control urinary calcium secretion of a patient. In one embodiment, the method is effective to decrease urinary calcium output to the levels of healthy volunteers (reduce potential kidney complications).
  • the method comprises administering to the patient a peptibody formulation comprising the amino acid sequences of any of various PTH peptibodies disclosed herein.
  • the PTH peptibody in the formulation comprises the sequence of SEQ ID NO: 19-23.
  • the PTH peptibody in the formulation comprises the sequence of SEQ ID NO: 19.
  • the peptibody formulations may be administered subcutaneously or intravenously. [00321] In various embodiments, the above methods of treating hypoparathyroidism and/or hypocalcemia due to hypoparathyroidism are used in conjunction with other methods treat hypoparathyroidism and/or hypocalcemia due to hypoparathyroidism.
  • the administration of the formulation can be carried out by any effective route known to physicians skilled in the art.
  • Parenteral administration is one of the methods.
  • Parenteral administration is generally understood in the medical literature to inject a dosage form into an individual via a sterile syringe or some other mechanical devices such as an infusion pump.
  • Parenteral routes can include intravenous, intramuscular, subcutaneous, and intraperitoneal routes.
  • Subcutaneous administration is the preferred route.
  • peptibody formulations disclosed herein may be administered by subcutaneous injection. Administration by subcutaneous injection can be into the abdomen, thigh, or arm. In some embodiments, administration by subcutaneous injection may be conducted before surgery or after surgery.
  • a GLP-2 peptibody formulation may be administered during surgery by infusion or by any other route that delivers the drug to the target site on the serosal side of the intestinal tissue, such as by depot injection.
  • peptibody formulations disclosed herein may be administered by intravenous injection.
  • the drug can be formulated as a lyophilized powder for reconstitution by the user as the formulation, and as either unit or multiple doses.
  • non-liquid components of the formulation are provided as a lyophilized powder for reconstitution. This is usefully provided in a plastic or glass vial containing teduglutide, for reconstitution with a carrier (e.g., water) to form the formulation, optionally for immediate injection and self-administration.
  • a carrier e.g., water
  • peptibody formulations disclosed herein may be formulated for oral administration.
  • Formulations suitable for oral administration may include liquid solutions, capsules, sachets, tablets, lozenges, and troches, powders liquid suspensions in an appropriate liquid and emulsions.
  • the peptibody formulations for oral administration may be formulated for gastrointestinal drug delivery.
  • the peptibody formulations for oral administration may be formulated to counter degradation by enzymes in the gastrointestinal tract.
  • Non-limiting examples of enzymes in the gastrointestinal tract are salivary amylase, pancreatic amylase, maltase, pepsin, trypsin, peptidases, nucleases, nucleosidases, and lipase.
  • the peptibody formulations for oral administration are formulated to counter degradation by pepsin.
  • the effective amount of the GLP-2 peptibody in the formulation described herein is an amount that causes the desired therapeutic and/or prophylactic effect when administered to an individual in need of GLP-2R stimulation without causing undesirable side effects.
  • the GLP-2 peptibody is administered either once every two weeks or once a week. Depending on the disease, disorder, and/or condition being treated, it may be necessary to administer the peptibody more frequently such as two to three times per week. [00329]
  • the GLP-2 peptibody formulation may be administered to the patient at least once within one month before the surgery. GLP-2 peptibody may be administered once as soon as 24 hours before surgery, 18 hours before surgery, 12 hours before surgery, 9 hours before surgery, 6 hours before surgery, three hours before surgery, two hours before surgery, or one hour before surgery.
  • GLP-2 peptibody formulation may be administered once in a subcutaneous or intravenous formulation.
  • the GLP-2 peptibody formulation may again be administered three, four, five, six, seven, or more days after the first dose.
  • Administration may be undertaken 24 hours after surgery, 18 hours after surgery, 12 hours after surgery, 9 hours after surgery, 6 hours after surgery, three hours after surgery, two hours after surgery, or one hour after surgery.
  • the GLP-2 peptibody may be administered about every 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours over a period of one day, two days, three days, four days, five days, six days or seven days.
  • the GLP-2 peptibody formulation may be administered once in a subcutaneous or intravenous formulation.
  • the GLP-2 peptibody formulation may again be administered three, four, five, six, seven, or more days after the first dose.
  • the GLP-2 peptibody formulation is administered subcutaneously according to a dosage regimen of between 0.02 to 0.5 mg/kg once every 2-14 days. In some embodiments, the GLP-2 peptibody formulation is administered intravenously according to a dosage regimen of between 0.02 to 3.0 mg/kg once every 2-14 days. In some embodiments, the administered GLP-2 peptibody formulation is in a concentration of 10 to 200 mg/ml.
  • the GLP-2 peptibody in the formulation may be administered at a daily dosage of between 0.02 to 3.0 mg/kg, 0.02 to 0.5 mg/kg, 0.04 to 0.45 mg/kg, 0.08 to 0.4 mg/kg, 0.10 to 0.35 mg/kg, 0.20 to 0.30 mg/kg, 0.02 to 0.05 mg/kg, 0.03 to 0.04 mg/kg, 0.05 to 0.10 mg/kg,
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • a dosing regimen effective to treat the short bowel syndrome (SBS) patients with colon-in-continuity can comprise delivering the GLP-2 peptibody formulation to the patient for a time and at a dose sufficient to enhance intestinal absorption.
  • One suitable treatment regimen entails once-daily administration of the GLP-2 peptibody formulation by subcutaneous injection in the abdomen, thigh, or arm for a period of about 21 days.
  • the peptibody may be administered subcutaneously or intravenously.
  • the GLP-2 peptibody formulation may also be administered subcutaneously or intravenously.
  • the GLP-2 peptibody formulation can be administered subcutaneously according to a dosage regimen of between 0.02 to 3.0 mg/kg once every 2-14 days.
  • a GLP-2 peptibody formulation may be administered subcutaneously according to a dosage regimen of between 0.02 to 3.0 mg/kg, 0.02 to 0.5 mg/kg, 0.04 to 0.45 mg/kg, 0.08 to 0.4 mg/kg, 0.10 to 0.35 mg/kg, 0.20 to 0.30 mg/kg, 0.02 to 0.05 mg/kg, 0.03 to 0.04 mg/kg, 0.05 to 0.10 mg/kg, 0.10 to 0.15 mg/kg, 0.2 to 0.3 mg/kg, 0.3 to 0.4 mg/kg, 0.4 to 0.5 mg/kg, 0.5 to 0.8 mg/kg, 0.7 to 1.0 mg/kg, 0.9 to 1.2 mg/kg, 1.0 to 1.5 mg/kg, 1.2 to 1.8 mg/kg, 1.5 to 2.0 mg/kg, 1.7 to 2.5 mg/kg, or 2.0 to 3.0 mg/kg.
  • the GLP-2 peptibody in the formulation may be administered at a daily dose of from 5 to 500 ⁇ g/kg.
  • the GLP-2 peptibody in the formulation may be administered at a daily dose of from 30 to 150 ⁇ g/kg.
  • the GLP-2 peptibody in the formulation may be administered intravenously at a daily dose of 0.04 to 0.06 mg/kg body weight, e.g., 0.05 mg/kg body weight.
  • the GLP-2 peptibody in the formulation may be administered at a daily dosage of between 0.02 to 3.0 mg/kg, 0.02 to 0.5 mg/kg, 0.04 to 0.45 mg/kg, 0.08 to 0.4 mg/kg, 0.10 to 0.35 mg/kg, 0.20 to 0.30 mg/kg, 0.02 to 0.05 mg/kg, 0.03 to 0.04 mg/kg, 0.05 to 0.10 mg/kg,
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • a method for treating a patient with short bowel syndrome who is dependent on parenteral nutrition and who presents with colon-in-continuity with remnant small intestine may not have short bowel syndrome but is expected to have post-surgery, e.g., intestinal resection, short bowel syndrome, to be dependent on parenteral nutrition and present with colon-in-continuity with remnant small intestine.
  • the method comprises administering to the patient a GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to reduce the dependency on parenteral nutrition by the patient. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • the GLP-2 peptibody formulation is administered daily at a dose of from 30 to 150 ⁇ g/kg by subcutaneous injection into the abdomen, thigh, or arm.
  • a method for treating a patient with short bowel syndrome presenting with colon-in-continuity with remnant small intestine, or expected to have short bowel syndrome presenting with colon-in-continuity with remnant small intestine post- surgery, e.g., intestinal resection comprises administering to the patient a GLP-2 peptibody formulation just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to enhance intestinal absorption by the patient.
  • the GLP-2 peptibody formulation is administered at a dose of from 30 to 150 ⁇ g/kg by subcutaneous injection into the abdomen, thigh, or arm of the patient. The administration may be daily.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • a method for treating a patient with short bowel syndrome presenting with colon-in-continuity with remnant small intestine, or expected to have short bowel syndrome presenting with colon-in-continuity with remnant small intestine post- surgery, e.g., intestinal resection comprises administering a GLP-2 peptibody formulation to the patient just before surgery, during surgery, or within a period of time after surgery.
  • a dosing regimen is used that is effective to enhance intestinal absorption by the patient.
  • the GLP-2 peptibody formulation is administered at a dose of from 30 to 150 ⁇ g/kg by subcutaneous injection into the abdomen, thigh, or arm of the patient. The administration may be daily.
  • the GLP-2 peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 2-16. In some embodiments, the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 4.
  • twist daily administration can be beneficial. Twice daily (every 12 hours) dosing usefully delivers about 5 to 250 ⁇ g/kg/dose. Benefits can also accrue to schedules that entail more frequent dosing or less frequent dosing.
  • follow-up dosing can be undertaken. Such follow-up dosing can occur as part of a treatment plan for longer-term administration of GLP-2 peptibody formulation, or before such a treatment plan has been prepared.
  • Follow-up dosing usefully occurs at regular frequencies such as weekly, biweekly, every month, every three months, etc.
  • Continued dosing usefully provides to the patient a dose efficient to maintain the benefits of increased absorptive surface area with increased intestinal absorption that arise from initial treatment, and can be effected by dosing the patient at least once within every 1-28 days, e.g., every other day, 2-3 times per week, once per week, etc.
  • Continued or follow-up dosing can be important to preserve the medical benefits mediated by the GLP-2 receptor agonist; as noted in the examples, improvements in intestinal absorption following treatment with teduglutide, for instance, can be lost rapidly, for example within four weeks following cessation of dosing.
  • the dosing regimen is effective to increase the urine weight of said patient.
  • Such patient may have short bowel syndrome with Crohn's disease or secondary to Crohn's disease.
  • Such patient may have short bowel syndrome with mesenteric infarction or secondary to mesenteric infarction.
  • Such patient may have short bowel syndrome with volvulus or secondary to volvulus.
  • Such patient may have short bowel syndrome with congenital intestinal abnormalities or secondary to congenital intestinal abnormalities.
  • Such patient may have short bowel syndrome with, or secondary to, multiple strictures due to adhesions or radiation.
  • Such patient may have short bowel syndrome with, or secondary to, vascular ischemia.
  • the patient may have limited, but some detectable, meal-stimulated GLP-2 secretion (as compared to a normal healthy individual).
  • the patient may have less, but some detectable, GLP-2 producing tissue (as compared to a normal healthy individual).
  • the patient may have elevated basal levels of endogenous GLP-2 (as compared to a normal healthy individual).
  • the urine weight is increased by at least 5% as compared to the urine weight of said patient before said dosing regimen.
  • the urine weight is increased by at least 10% as compared to the urine weight of said patient before said dosing regimen.
  • the dosing regimen is effective to increase wet weight absorption compared to a baseline wet weight absorption by said patient.
  • Such patient may have short bowel syndrome with Crohn's disease or secondary to Crohn's disease.
  • Such patient may have short bowel syndrome with mesenteric infarction or secondary to mesenteric infarction.
  • Such patient may have short bowel syndrome with volvulus or secondary to volvulus.
  • Such patient may have short bowel syndrome with congenital intestinal abnormalities or secondary to congenital intestinal abnormalities.
  • Such patient may have short bowel syndrome with, or secondary to, multiple strictures due to adhesions or radiation.
  • Such patient may have short bowel syndrome with, or secondary to, vascular ischemia.
  • the patient may have limited, but some detectable, meal -stimulated GLP-2 secretion (as compared to a normal healthy individual).
  • the patient may have less, but some detectable, GLP-2 producing tissue (as compared to a normal healthy individual).
  • the patient may have elevated basal levels of endogenous GLP-2 (as compared to a normal healthy individual).
  • the patient having short bowel syndrome has reduced crypt depth as compared to a normal healthy individual and the dosing regimen is effective to increase the crypt depth in the patient.
  • the crypt depth may be in the small intestine.
  • the patient having short bowel syndrome has reduced mitotic figures per 100 crypt epithelial cells as compared to a normal healthy individual, and the dosing regimen is effective to increase the number of mitotic figures per 100 crypt epithelial cells of the patient.
  • the regimen involves administration of the GLP-2 peptibody over a period of at least 21 days.
  • the period may be at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, at least 50 days, at least 55 days, at least 60 days, or at least 65 days.
  • the patient is an adult and the GLP-2 peptibody is administered intravenously at a daily dose of 0.04 to 0.06 mg/kg body weight, e.g., 0.05 mg/kg body weight.
  • the dosing regimen is effective to restore at least a portion of, or to enhance, the ileal brake mechanism of the patient.
  • the dosing regimen is effective to reduce gastric hypersecretion in the patient with short bowel syndrome.
  • the dosing regimen is effective to reduce or suppress gastric secretion in the patient with short bowel syndrome.
  • the dosing regimen is effective to reduce the speed of gastric emptying in a patient with short bowel syndrome. The patient may have rapid gastric emptying.
  • the dosing regimen is effective to induce small intestine growth in the patient with short bowel syndrome.
  • the dosing regimen is effective to upregulate protein transport in the patient with short bowel syndrome.
  • the protein transport may be across the small intestine, such as across the villus, across the crypt, or across both the villus and crypt.
  • the dosing regimen is effective to reduce the likelihood of dehydration recurrence in the patient with short bowel syndrome. In some embodiments, the dosing regimen is effective to reduce the likelihood of renal insufficiency recurrence in the patient with short bowel syndrome. In some embodiments, the dosing regimen is effective to reduce the recurrence of kidney stones in the patient with short bowel syndrome. In some embodiments, the dosing regimen is effective to enhance intestinal absorption by the patient with short bowel syndrome. In some embodiments, the dosing regimen is effective to reduce the dependency on parenteral nutrition by the patient.
  • the dosing regimen is effective to increase the villus height (in the small intestine) of said patient.
  • Villus height and crypt depth may be measured using light microscopy (eyepiece micrometer) as the mean of ten well-oriented villi and crypts. The number of mitotic figures per 100 crypt epithelial cells can also be calculated.
  • the dosing regimen is effective to increase the crypt depth (in the small intestine) of said patient.
  • the dosing regimen is effective to decrease the fecal wet weight of said patient.
  • Such patient may have short bowel syndrome with Crohn's disease or secondary to Crohn's disease.
  • Such patient may have short bowel syndrome with mesenteric infarction or secondary to mesenteric infarction.
  • Such patient may have short bowel syndrome with volvulus or secondary to volvulus.
  • Such patient may have short bowel syndrome with congenital intestinal abnormalities or secondary to congenital intestinal abnormalities.
  • Such patient may have short bowel syndrome with, or secondary to, multiple strictures due to adhesions or radiation.
  • Such patient may have short bowel syndrome with, or secondary to, vascular ischemia.
  • the patient may have limited, but some detectable, meal-stimulated GLP-2 secretion (as compared to a normal healthy individual).
  • the patient may have less, but some detectable, GLP-2 producing tissue (as compared to a normal healthy individual).
  • the patient may have elevated basal levels of endogenous GLP-2 (as compared to a normal healthy individual).
  • the patient receives an amount of parenteral nutrition each week.
  • the dosing regimen is effective to reduce the parenteral nutrition by volume or frequency of administration.
  • the dosing regimen is effective to increase meal-stimulated GLP-2 secretion.
  • the effective amount of the PTH peptibody in the formulation described herein is an amount that causes the desired therapeutic and/or prophylactic effect when administered to an individual in need of PTH receptor stimulation without causing undesirable side effects.
  • the PTH peptibody formulation is administered either once every two weeks or once a week. Depending on the disease, disorder, and/or condition being treated, it may be necessary to administer the peptibody more frequently such as two to three times per week.
  • the PTH peptibody formulation is administered twice a day, or once daily, or every two days, or every three days, or every 5-8 days. In one embodiment, the PTH peptibody formulation is administered once daily. In one embodiment, the PTH peptibody is administered once weekly. In some embodiments, the PTH peptibody formulation is administered subcutaneously. In some embodiments, the PTH peptibody formulation is administered intravenously.
  • the PTH peptibody formulation may be administered about every 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours over a period of one day, two days, three days, four days, five days, six days or seven days.
  • the PTH peptibody formulation may be administered once in a subcutaneous or intravenous formulation. The PTH peptibody formulation may again be administered three, four, five, six, seven, or more days after the first dose.
  • the PTH peptibody formulation may be administered subcutaneously according to a dosage regimen of between 0.001 ⁇ g to 1,000 ⁇ g, twice a day, or once per day, or every two days, or every 5-8 days, or every week. Alternatively, the PTH peptibody formulation could be administered every three weeks or once a month, such as for maintenance purposes.
  • the dose of the PTH peptibody formulation may need to be titrated for individuals due to variance in the population.
  • the PTH peptibody formulation is administered in an amount from about 1 ⁇ g per day to about 500 ⁇ g per day, or about 2 ⁇ g per day to about 250 ⁇ g per day, or about 5 ⁇ g per day to about 100 ⁇ g per day, or about 10 ⁇ g per day to about 80 ⁇ g per day, or about 20 ⁇ g per day to about 100 ⁇ g per day, or about 50 ⁇ g per day to about 100 ⁇ g per day, or about 50 ⁇ g per day, or about 60 ⁇ g per day, or about 70 ⁇ g per day, or about 80 ⁇ g per day, or about 90 ⁇ g per day, or about 100 ⁇ g per day.
  • the PTH peptibody formulation may be administered in a concentration of 0.001 to 1,000 ⁇ g/mL.
  • the PTH peptibody in the formulation comprises the sequences of any of SEQ ID NOS: 19-23. In some embodiments, the PTH peptibody in the formulation comprises the sequence of SEQ ID NO: 19.
  • a method for treating a patient with hypoparathyroidism and/or hypocalcemia due to hypoparathyroidism comprises treating the patient with a PTH peptibody formulation of the invention using a dosing regimen effective to control serum and urinary calcium levels of the subject. Dose adjustments can be made on an individual basis based on achievement and maintenance of therapeutic goals.
  • the PTH peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 19-23.
  • the GLP-2 peptibody in the formulation comprises the sequence of SEQ ID NO: 19.
  • the method is effective to control serum calcium levels of a patient. In some embodiments, the method is effective to increase serum calcium levels of a subject with hypoparathyroidism and/or hypocalcemia due to hypoparathyroidism as compared to the serum calcium levels of said subject in the absence of administration of the PTH peptibody formulation of the invention. In some embodiments, the method is effective to reduce the amount of calcium supplements of a patient with hypoparathyroidism.
  • the PTH peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 19-23. In some embodiments, the PTH peptibody in the formulation comprises the sequence of SEQ ID NO: 19.
  • the method is effective to control urinary calcium secretion of a patient. In one embodiment, the method is effective to decrease urinary calcium output to the levels of healthy volunteers (reduce potential kidney complications).
  • the PTH peptibody in the formulation comprises the sequence of any of SEQ ID NOS: 19-23. In some embodiments, the PTH peptibody in the formulation comprises the sequence of SEQ ID NO: 19.
  • the dosing regimen involves administration of the PTH peptibody over a period of at least 21 days.
  • the period may be at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, at least 50 days, at least 55 days, at least 60 days, or at least 65 days.
  • the above dosing regimens may be conducted for a period of one month, or two months, or six months, or one year, or two years, or five years, or longer than five years to treat hypoparathyroidism and/or hypocalcemia due to hypoparathyroidism.
  • PTH peptibodies can be administered for the duration of a subject's lifetime for maintenance.
  • kits for use in treating a subject suffering a condition and in need of treatment for the condition comprises the formulation or a lyophilized form of the formulation.
  • the formulation of the kit has been stored according to the methods described above.
  • the kit includes a pre-filled syringe.
  • the syringe is prefilled with the formulation.
  • the kit comprises an ISO type I siliconized glass-prefilled syringe system.
  • the kit comprises an ISO type I non-siliconized plastic prefilled syringe system.
  • the kit includes instructions for administration of the formulation to a subject. In some embodiments, the kit includes instructions for proper storage of the formulation. In some embodiments, the kit includes a syringe and a sterile vial containing the formulation. In various embodiments, the kit includes expiration information (e.g., a “use by” date).
  • the kit is or has been stored at a temperature of from about stored at from about 0°C to about 37°C, about 0°C to about 30°C, about 0°C to about 25°C, from about 0°C to about 20°C, from about 0°C to about 15°C, from about 0°C to about 10°C, from about 0°C to about 5°C, from about 2°C to about 8°C, from about 10°C to about 30°C, from about 15°C to about 30°C, from about 20°C to about 30°C, from about 23°C to about 27°C, or from about 1°C to about 9°C.
  • the kit is stored or has been stored at about or less than about 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, or 30°C.
  • the kit has been stored for about or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, or 5 years. In some embodiments, the kit has been stored for less than about 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years, 4.5 years, or 5 years.
  • the kit comprises (1) a sterile vessel (e.g., a sterile vial or syringe) comprising a lyophilized formulation, (2) a carrier suitable for reconstitution thereof, (e.g., sterile water), (3) instructions for reconstitution; and (4) optionally instructions for administration.
  • a sterile vessel e.g., a sterile vial or syringe
  • a carrier suitable for reconstitution thereof e.g., sterile water
  • instructions for reconstitution e.g., sterile water
  • the kit may further comprise a device suitable for injection of the reconstituted preparation (e.g., a plastic or glass syringe).
  • kits are configured for use by, as a non-limiting example, a healthcare professional.
  • the kits comprise components necessary for parenteral administration (e.g., intradermally, intramuscularly, intraperitoneally, intravenously, and/or subcutaneously) of the formulations to a subject.
  • the kit can be used in prophylaxis and/or therapy.
  • the kit may be used to treat a subject.
  • Peptibodies comprising the sequence of SEQ ID NO: 4 were thawed and dialyzed against the buffer compositions of Table 1. If necessary, in order to reach the protein target concentration of 50 mg/ml or 100 mg/ml, after dialysis the resulting solution was diluted with the buffer solution or concentrated using Vivaspin® tubes. In case of a higher product volume, change of buffer/potential concentration was alternatively executed with a Pellicon XL Biomax module rather than by dialysis. If necessary polysorbate 80 (PS80) was added to the product solution. During this preparation procedure, the protein content was determined by measuring at A280 nm. Finally, the product solution was filtered through a sterile filter (e.g. Pall Supor EKV®) under laminar flow and filled in ISO type I siliconized glass vials or non-siliconized prefilled syringe systems.
  • a sterile filter e.g. Pall Supor EKV®
  • Peptibody compositions (alternatively referred to as “formulations”) comprising the following buffer compositions, see Table 1, were investigated for their stability at 2-8°C and 25°C for 6 months. Protein concentration was adjusted to approximately 100 mg/ml and 1 ml of the each of the 11 product solutions was filled in an ISO type I siliconized glass- and a non- siliconized plastic prefilled syringe system.
  • Table 2 provides all time points and the analytical methods used for the stability study at 2-8°C and 25 °C. Table 2. Time points and applied analytical tests for the 6 months stability study at 2-8°C and 25°C
  • Tables 4 to 7 show for both prefilled syringes types (glass and plastic) the subvisible particle counts by MFI for particles ⁇ 10 ⁇ m and ⁇ 25 ⁇ m at 2-8°C and 25°C. All values at 2-8°C over 6 months were well below the USP ⁇ 787> threshold limits of 3000 particles/ml for ⁇ 10 ⁇ m- particles and 300 particles/ml for ⁇ 25 ⁇ m-particles for light obscuration (LO), which was used as a benchmark.
  • LO light obscuration
  • Tables 8 and 9 the area of the main peak measured by SEC at 2-8°C and 25°C is provided.
  • Table 10 lists osmolality and dynamic viscosity values for the formulations.
  • a peptibody composition comprising Natpara® parathyroid hormone (PTH) variant peptibody (PTH-66) was prepared using a buffer composition of Example 1, see Table 1.
  • the peptibody comprised a sequence of . Briefly, the peptibody composition was prepared according to the methods described in Example 1. Stability of the peptibody in the composition was evaluated according to the methods described in Example 2. The peptibody was stabilized by the buffer composition of Example 1.
  • intermediate starting material which comprised 0.92 mg/ml PTH-66 Fc in 10 mM Citrate, 10 mM L-Methionine, 40 mM NaCl, 5.5% sucrose, at pH 6.0, was thawed and first concentrated on Vivacell 100 MWCO 30kD to approx.10 mg/ml protein. A five-fold buffer exchange was carried out to ensure the correct buffer matrix. Finally, the product solution was filtered through an appropriate sterile filter (e.g., Millex GV®) under laminar flow and filled in ISO type I glass vials. Protein content was determined by measuring at A280 nm of all samples. ii. Investigated formulations
  • Table 12 shows the analytical tests used for the investigation of the formulation selection for time point zero (TO), and for storage at 1 and 2 months at 2-8°C.
  • Table 15 shows the sub-visible particle counts by MFI for particles ( ⁇ 10 ⁇ m and > 25 ⁇ m) at 2-8°C. All values at 2-8°C over 2 months were well below the (USP) ⁇ 787> limits of >3000 particles/ml for ⁇ 10 ⁇ m-particles and ⁇ 300 particles/ml for ⁇ 25 ⁇ m-particles for light obscuration (LO), which is used for MFI only a benchmark.
  • USP USP
  • Table 17 contains the osmolality and dynamic viscosity values of all investigated formulations.
  • T m Mean inflection point for ratio (melting temperature, T m ) [00395]
  • the * in Table 19 indicates intermediate starting material (or intermediate) which comprised 0.92 mg/ml PTH-66 Fc in 10 mM Citrate, 10 mM L-Methionine, 40 mM NaCl, 5.5% sucrose, at pH 6.0.
  • the T m was measured using a nano differential scanning fluorimetry (nanoDSF) approach.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne des formulations comprenant GLP-2 ou PTH, ou des parties spécifiées ou des variants de celles-ci, fusionnées avec de l'immunoglobuline ou des dérivés de celle-ci. Les formulations peuvent comprendre un pepticorps de GLP-2 ou de PTH, un support, un tampon, au moins un acide aminé et au moins un excipient. Les formulations ont un pH variant d'environ 5 à environ 8. L'invention concerne en outre des procédés de fabrication, de stockage et d'utilisation des formulations de pepticorps et, en outre, des kits comprenant lesdites formulations.
PCT/US2021/038976 2020-06-26 2021-06-24 Formulations de pepticorps stables WO2021263040A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063044877P 2020-06-26 2020-06-26
US63/044,877 2020-06-26

Publications (2)

Publication Number Publication Date
WO2021263040A1 true WO2021263040A1 (fr) 2021-12-30
WO2021263040A8 WO2021263040A8 (fr) 2022-08-04

Family

ID=79281866

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/038976 WO2021263040A1 (fr) 2020-06-26 2021-06-24 Formulations de pepticorps stables

Country Status (1)

Country Link
WO (1) WO2021263040A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030176686A1 (en) * 1999-08-16 2003-09-18 Human Genome Sciences, Inc. Retinoid receptor interacting polynucleotides, polypeptides, and antibodies
WO2017148883A1 (fr) * 2016-03-01 2017-09-08 Ascendis Pharma Bone Diseases A/S Promédicaments de pth
WO2019040399A1 (fr) * 2017-08-22 2019-02-28 Shire-Nps Pharmaceuticals, Inc. Polypeptides de fusion glp-2 et leurs utilisations pour traiter et prévenir les troubles gastro-intestinaux
WO2019090209A1 (fr) * 2017-11-06 2019-05-09 Shire-Nps Pharmaceuticals, Inc. Analogues de glp-2 et peptibodies destinés à être administrés avant, pendant ou après une intervention chirurgicale

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030176686A1 (en) * 1999-08-16 2003-09-18 Human Genome Sciences, Inc. Retinoid receptor interacting polynucleotides, polypeptides, and antibodies
WO2017148883A1 (fr) * 2016-03-01 2017-09-08 Ascendis Pharma Bone Diseases A/S Promédicaments de pth
WO2019040399A1 (fr) * 2017-08-22 2019-02-28 Shire-Nps Pharmaceuticals, Inc. Polypeptides de fusion glp-2 et leurs utilisations pour traiter et prévenir les troubles gastro-intestinaux
WO2019090209A1 (fr) * 2017-11-06 2019-05-09 Shire-Nps Pharmaceuticals, Inc. Analogues de glp-2 et peptibodies destinés à être administrés avant, pendant ou après une intervention chirurgicale

Also Published As

Publication number Publication date
WO2021263040A8 (fr) 2022-08-04

Similar Documents

Publication Publication Date Title
EP2568960B1 (fr) PRÉPARATION LIQUIDE DE POLYPEPTIDES CONTENANT UN DOMAINE Fc D'UNE IMMUNOGLOBULINE
AU2012263100B2 (en) Stable liquid formulation of etanercept
CA2691695C (fr) Formulation de proteine de fusion glp-1-fc
US11660328B2 (en) GLP-2 analogs and peptibodies for administration before, during or after surgery
US20200405865A1 (en) Etanercept formulations stabilized with xylitol
CN106061468B (zh) 包含TNFR和Fc区的融合蛋白的液体制剂
TW201408337A (zh) 長效胰促泌素肽接合物之液體製劑
CN108348581B (zh) 胰岛素免疫球蛋白融合蛋白
KR102385802B1 (ko) Gm-csf 중화 화합물을 포함하는 액체 제제
US20190336601A1 (en) Etanercept Formulations Stabilized with Sodium Chloride
KR20230121822A (ko) Glp-1/glp-2 이중 효능제의 약학적 조성물
KR20190071760A (ko) 약학적 제형 및 그의 제조 방법
KR20230121824A (ko) Glp-1/glp-2 이중 효능제의 약학적 조성물
WO2021263040A1 (fr) Formulations de pepticorps stables
EP3257524B1 (fr) Préparation de solution stabilisée de protéine de fusion d'anticorps glp-1r pharmaceutique
WO2024141054A1 (fr) Composition pharmaceutique comprenant une protéine de fusion et son utilisation
CA3208945A1 (fr) Composition aqueuse d'une construction proteique modifiee comprenant un domaine fc
CA3144177A1 (fr) Compositions pharmaceutiques pour peptides co-agonistes du glucagon et du glp-1
WO2021028669A1 (fr) Nouvelle composition comprenant des anticorps

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21829656

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21829656

Country of ref document: EP

Kind code of ref document: A1