EA047986B1 - CLAUDINN 6 ANTIBODIES AND THEIR APPLICATIONS - Google Patents

Description

Cross-reference to related applications

This application claims priority to U.S. Provisional Application No. 62/806,048, filed February 15, 2019, which is incorporated herein by reference in its entirety.

State of the art

Claudin 6 is a receptor overexpressed on the surface of cancer cells. Targeting claudin 6 with claudin 6-specific antibodies can help activate a cytotoxic response against a cancer in which claudin 6 is expressed. Thus, there is a need for antibodies that can bind to claudin 6 and antibodies that can modulate the activity of claudin 6. The present invention provides these and more.

Brief description of the essence of the invention

In some embodiments, isolated antibodies that bind to the protein, or a nucleic acid molecule encoding the same, are provided.

In some embodiments, methods of using antibodies are provided herein.

In some embodiments, antibodies are provided that bind to claudin 6 with an affinity of less than 10 nM and at least a 100-fold greater EC50 than to claudin 9, claudin 3, and/or claudin 4.

In some embodiments, peptides are provided comprising, consisting of, or consisting essentially of a sequence as provided herein or a variant thereof.

In some embodiments, peptides are provided that comprise, consist of, or consist essentially of a sequence that is 90-99% identical to a sequence as provided herein or a variant thereof.

In some embodiments, antibodies are provided, such as a monoclonal antibody or ScFv, that bind to an epitope on claudin 6 (SEQ ID NO: 1) whose binding residues include T33, N38, D68, P74, D76, D146, V152, A153, E154, Q156, R158, or any combination thereof. In some embodiments, the antibody binds to an epitope on claudin 6 that includes residues E48, D68, P74, D76, and R158 of claudin 6 (SEQ ID NO: 1). In some embodiments, the antibody binds to an epitope on claudin 6 that includes residues T33, N38, E48, D76, A153, E154, Q156, and R158 of claudin 6 (SEQ ID NO: 1). In some embodiments, the antibody binds to an epitope on claudin 6 that includes residues N38, E48, Y67, P74, D76, D146, V152, E154, Q156, and R158 on claudin 6. In some embodiments, the antibody binds to an epitope on claudin 6 that includes residues E48, Y67, Q156, and R158 of claudin 6.

In some embodiments, provided herein are bispecific antibodies comprising a first VH peptide that binds to claudin 6 and a second VH peptide that binds to a different moiety.

In some embodiments, nucleic acid molecules encoding an antibody or amino acid sequence described herein are provided. In some embodiments, vectors comprising the nucleic acid molecules are provided. In some embodiments, cells comprising the vectors or nucleic acid molecules are provided herein.

In some embodiments, antibodies or isolated forms thereof are provided that bind to claudin 6 with an affinity of less than 10 nM and an EC ₅₀ of at least 100-fold greater than to claudin 9, claudin 3, and/or claudin 4.

In some embodiments, antibodies or isolated forms thereof, wherein the antibody comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, 95, 139, 141, 143, or 145, or a variant of any of the above; The heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, 102, 140, 142, 144 or 146, or a variant of any of the above; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97, or a variant of any of the above.

In some embodiments, an antibody according to any one of claims 1-3 is provided, wherein said antibody comprises a light chain variable region comprising a sequence of any one of the sequences set forth in SEQ ID NO: 127-135.

In some embodiments, antibodies are provided comprising a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 23, 29, 41, 51, 59, 68, 84, 88, or 99, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, 94, or variants of any of the above.

In some embodiments, antibodies or antigen-binding fragments thereof are provided.

- 1 047986 you, wherein the antibodies or antigen-binding fragments thereof comprise: (i) a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90 or 95; the heavy chain CDR2 has the amino acid sequence of 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101 or 102; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97, or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93 or 98; the light chain CDR2 sequence has an amino acid sequence of 23, 29, 41, 51, 59, 68, 84, 88, or 99, and the light chain CDR3 sequence has an amino acid sequence of 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, 94, or variants of any of the foregoing.

In some embodiments, a peptide is provided comprising, consisting of, or consisting essentially of a sequence as provided herein or a variant thereof.

In some embodiments, antibodies are provided, such as a monoclonal antibody or scFv, that bind to an epitope on claudin 6, residues of which include T33, N38, D68, P74, D76, D146, V152, A153, E154, Q156, R158, or any combination thereof.

In some embodiments, antibodies are provided, such as a monoclonal antibody or scFv, that preferentially bind to claudin 6 over claudin 9, wherein the antibody binds to an epitope on claudin 6 containing Q156.

In some embodiments, bispecific antibodies are provided comprising a first VH peptide that binds to claudin 6 and a second VH peptide that binds to a different moiety.

In some embodiments, a pharmaceutical composition is provided comprising one or more antibodies described herein, or a nucleic acid molecule encoding them.

In some embodiments, nucleic acid molecules encoding an antibody or amino acid sequence provided herein are provided.

In some embodiments, methods are provided for modulating claudin 6 activity by contacting a cell expressing claudin 6 with an antibody to claudin 6 or a pharmaceutical composition comprising the same that binds to claudin 6 on the surface of the cell.

In some embodiments, methods are provided for inhibiting claudin 6 function by contacting a cell expressing claudin 6 with an antibody or pharmaceutical composition comprising the same that inhibits claudin 6 function by binding to claudin 6.

In some embodiments, methods are provided for treating a subject with a claudin 6-mediated disorder, the method comprising administering to the subject a pharmaceutical composition comprising an antibody to claudin 6, such as any antibody provided herein, or a nucleic acid molecule encoding the same.

In some embodiments, methods are provided for treating an oncological disorder in a subject comprising administering a therapeutic agent that specifically binds to claudin 6 and binds to CD3 and/or 4-1BB.

In some embodiments, methods are provided for treating an oncological disease in a subject comprising administering to the subject a pharmaceutical composition comprising an antibody that binds to the Q156 residue of claudin 6 or a nucleic acid molecule encoding it.

In some embodiments, chimeric receptors are provided that comprise an antibody domain as provided herein.

In some embodiments, compositions are provided comprising an antibody and an antibody domain as provided herein linked to a drug or other therapeutic agent.

In some embodiments, compositions comprising a peptide as provided herein, such as a peptide comprising one or more of SEQ ID NOs: 2-135.

In some embodiments, methods are provided for detecting the presence or absence of claudin 6 in a sample, comprising contacting the sample with an antibody as provided herein and any of the preceding claims, and detecting binding to an antigen by claudin 6 by the antibody, wherein detection of binding indicates the presence of claudin 6; or failure to detect binding to claudin 6 indicates the absence of claudin 6.

In some embodiments, methods are provided for delivering a composition to a cell expressing claudin 6, wherein the method comprises contacting the cell with an antibody as provided herein, wherein the antibody is linked to another molecule that will be delivered to the cell expressing claudin 6.

In some embodiments, methods are provided for contacting a composition with a cell expressing claudin 6, wherein the method comprises contacting the cell with an antibody as provided herein, wherein the antibody is linked to another molecule to bring

- 2 047986 in contact with a cell expressing claudin 6.

Brief description of graphic materials

Fig. 1 illustrates the binding of exemplary, non-limiting embodiments of antibodies that bind to claudin 6.

Fig. 2 illustrates various embodiments proposed in this document.

Fig. 3 illustrates various embodiments proposed in this document.

Fig. 4 illustrates various embodiments as presented herein, including a demonstration that IM136 and IM171 bind to PA-1 cells naturally expressing claudin 6, as detected by flow cytometry.

Fig. 5 illustrates various embodiments as presented herein, including MAb binding to PA-1 cells naturally expressing claudin 6, as detected by flow cytometry.

Fig. 6 illustrates various embodiments as presented herein, including an illustration that MAb IM171 binds to a proteome chip consisting of 5300 human membrane proteins expressed in human HEK-293 cells and a demonstration that IM171 is highly specific for claudin 6.

Fig. 7 illustrates various embodiments as presented herein, including an illustration that CAR-T cells expressing the claudin 6 antibody IM136 are activated by cells expressing human or mouse claudin 6. CAR-T cells without claudin antibodies (CAR-negative T cells) are not activated by cells expressing claudin 6. Cell activation is measured by CD69 expression after overnight co-incubation of the cells, as determined by flow cytometry with the CD69 antibody.

Fig. 8 illustrates various embodiments as presented in this document.

Detailed description of the essence of the invention

The present document describes and discloses the isolation and characterization of MAbs (monoclonal antibodies) that recognize claudin 6. In some embodiments, MAbs to claudin 6 were generated using virus-like particles (VLPs) to produce this multilayer membrane protein in its natural conformation. In some embodiments, the antibodies bind to claudin 6 but do not bind significantly to claudin 9. In some embodiments, the antibody binds to claudin 6 with an affinity of at least the EC ₅₀ or KD, or about 10, 20, 30, 40, 50, 75, 100, 200, or 300 times greater than it binds to claudin 9. In some embodiments, the antibodies bind to claudin 6 but do not bind significantly to claudin 3. In some embodiments, the antibody binds to claudin 6 with an affinity of at least the EC ₅₀ or KD, or about 10, 20, 30, 40, 50, 75, 100, 200, or 300 times greater than it binds to claudin 3. In some embodiments embodiments, the antibodies bind to claudin 6 but do not bind significantly to claudin 4. In some embodiments, the antibody binds to claudin 6 with an affinity of at least the EC ₅₀ or KD, or about 10, 20, 30, 40, 50, 75, 100, 200, or 300 times greater than it binds to claudin 4.

In some embodiments, claudin 6 comprises an amino acid sequence comprising:

claudin 6 (human) SEQIDNO: 1 MASAGMQILGVVLTLLGWVNGLVSCALPMWK VTAFIGNSIVVAQVVWEGLWMSCVVQSTGQMQ CKVYDSLLALPQDLQAARALCVIALLVALFGLL VYL AGAKCTTC VEEKD SKARL VLT SGIVF VISG VLTLIPVCWTAHAVIRDFYNPLVAEAQKRELGA SLYLGWAASGLLLLGGGLLCCTCPSGGSQ GPSH YMARYSTSAPAISRGPSEYPTKNYV

As used herein, the term antibody is intended to be broad and includes immunoglobulin or antibody molecules, including polyclonal antibodies, monoclonal antibodies, including murine, human, humanized and chimeric monoclonal antibodies, and antibody fragments such as ScFv or hexaantibodies (PLOS Biology | DOI:10.1371/journal.pbio.1002344 January 6, 2016, which is incorporated herein by reference in its entirety).

As used herein, the term humanized antibody, engineered antibody, human adapted framework region, and HFA are intended to include antibodies having variable region framework regions derived from sequences of human origin. Additionally, if the antibody comprises a constant region, the constant region may be derived from such human sequences, such as germline sequences.

- 3 047986 human germline sequences, or naturally occurring (e.g., allotypes) or mutated versions of human germline sequences. Humanized antibodies may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or somatic mutation in vivo).

Antibodies are generally proteins or polypeptides that exhibit binding specificity for a particular antigen. Intact antibodies are heterotetrameric glycoproteins consisting of two identical light chains and two identical heavy chains. Typically, each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide bonds varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (VH) at one end followed by a series of constant domains. Each light chain has a variable domain at one end (V _L ) and a constant domain at the other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the variable domain of the light chain is aligned with the variable domain of the heavy chain. The light chains of antibodies of any vertebrate species can be classified into one of two distinct types, namely kappa and lambda, based on the amino acid sequences of their constant domains. Immunoglobulins can be classified into five major classes, namely IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subdivided into the isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG ₄ .

The term antibody fragment means a portion of an intact antibody, typically binding an antigen or the variable region of an intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2 and Fv fragments, diabodies, single-chain antibody molecules and multispecific antibodies formed from at least two intact antibodies.

As used in this document, the term antigen means any molecule that can directly or indirectly generate antibodies. The definition of antigen includes nucleic acid encoding a protein.

As used herein, the terms specific binding or immunospecific binding or binds immunospecifically refer to binding of an antibody to a predetermined antigen (e.g., claudin 6) or an epitope present on an antigen. In some embodiments, the antibody binds with a dissociation constant ( _KD ) of ^10-7 M or less, and binds to a predetermined antigen with a KD that is at least two times smaller than its _KD for binding to a non-specific antigen (e.g., BSA, casein, or other non-specific polypeptide) other than the predetermined antigen. The phrases "an antibody that recognizes claudin 6" and "an antibody specific for claudin 6" are used herein interchangeably with the term "an antibody that immunospecifically binds to claudin 6." Reference may be made to claudin 6 throughout the description. In some embodiments, the antibody is specific for claudin 6 and does not specifically bind to claudin 3, claudin 4, and/or claudin 9.

CDRs are defined as the amino acid sequences of the complementarity determining region of an antibody, which are the hypervariable regions of the heavy and light chains of immunoglobulin. See, e.g., Kabat et al, Sequences of Proteins of Immunological Interest, 4th ed., U.S. Department of Health and Human Services, National Institutes of Health (1987). In the variable portion of an immunoglobulin, there are three heavy chain CDRs and three light chain CDRs. Thus, CDRs as used herein refer to all three heavy chain CDRs, or all three light chain CDRs, or both all heavy chain CDRs and all light chain CDRs, as appropriate.

CDRs provide the majority of contact residues for binding of an antibody to an antigen or epitope. CDRs of interest may be derived from the variable heavy and light chain sequences of a donor antibody and include analogs of naturally occurring CDRs that also have the same antigen binding specificity and/or neutralizing capacity as the donor antibody from which they were derived.

The term "homolog" refers to protein sequences that have between 40% and 100% sequence identity with a reference sequence. The percent identity between two peptide chains can be determined by pairwise alignment using the default settings of the AlignX module in Vector NTI v.9.0.0 (Invitrogen Corp., Carlsbad, Calif.). In some embodiments, the antibody or fragment thereof has at least 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identity to a sequence described herein. In some embodiments, the antibody has conservative substitutions compared to a sequence described herein. In some embodiments, the number of substitutions may be 1, 2, 3, 4, 5, 6, 7, 8, or 9. These molecules that differ based on % identity or substitutions may also be referred to as variants. Antibodies having conservative substitutions in the heavy and light chain sequences shown in Table 1 are within the scope of the disclosed subject matter. The conservative substitution may be in the framework regions or in the antigen binding sites, as long as they are not

- 4 047986 adversely affect the properties of the antibody. Substitutions may be made to improve the properties of the antibody, such as stability or affinity. Conservative substitutions will produce molecules that have functional and chemical characteristics similar to those molecules into which such modifications are made. Examples of amino acid substitutions are shown in the table below.

Table: Typical conservative substitutions: Original balance Typical conservative substitutions Ala Vai, Leu, He Arg Lys, Gin, Asn Asn Gin Asp Glu Cys Sir, Ala Gin Asn Gly Pro, Ala His Asn, Gin, Lys, Arg He Leu, Vai, Met, Ala, Phe Leu He, Vai, Met, Ala, Phe Lys Arg, Gin, Asn Met Leu, Phe, He Phe Leu, Vai, He, Ala, Tyr Pro Ala Ser Thr, Ala, Cys Thr Ser Trp Tyr, Phe Tyr Trp, Phe, Thr, Ser Vai He, Met, Leu, Phe, Ala

As used herein, the term in combination with means that the described agents may be administered to an animal together in a mixture, simultaneously as separate agents, or sequentially as separate agents in any order.

Polyclonal antibodies are heterogeneous populations of antibody molecules obtained from the sera of animals immunized with an antigen. A monoclonal antibody comprises a substantially homogeneous population of antibodies specific for an antigen, the population containing substantially similar epitope binding sites. MAbs can be prepared by methods known to those skilled in the art. See, e.g., Kohler and Milstein, Nature 256:495,497 (1975); U.S. Patent No. 4,376,110; Ausubel et al., eds., Current Protocols in Molecular Biology, Greene Publishing Assoc. and Wiley Interscience, N.Y., (1987, 1992); and Harlow and Lane ANTIBODIES: A Laboratory Manual Cold Spring Harbor Laboratory (1988); Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, N.Y., (1992, 1993), the contents of which are incorporated herein by reference in their entirety. Such antibodies may be of any immunoglobulin class, including IgG, IgM, IgE, IgA, GILD, and any subclass thereof. The hybridoma producing the mAb may be cultured in vitro, in situ, or in vivo. The production of high titers of mAb in vivo or in situ makes this method of production currently preferred.

Chimeric antibodies are molecules in which different portions are derived from different animal species, such as having a variable region derived from a mouse mAb and a constant region from a human immunoglobulin, which are primarily used to reduce immunogenicity in use and increase yield in production, such as when mouse mAbs have higher yield from hybridomas but higher immunogenicity in humans, so that human/mouse chimeric mAbs are used. Chimeric antibodies and methods for producing them are known in the art (Cabilly et al., Proc. Natl. Acad. Sci. USA 81:3273 3277 (1984); Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851 6855 (1984); Boulianne et al., Nature 312:643 646 (1984); Cabilly et al., European Patent Application 125,023 (published November 14, 1984); Neuberger et al., Nature 314:268 270 (1985); Taniguchi et al., European Patent Application 171,496 (published February 19, 1985); Morrison et al., European

- 5 047 986 Chinese Patent Application 173 494 (published March 5, 1986); Neuberger et al., PCT Application WO 86/01533, (published March 13, 1986); Kudo et al., European Patent Application 184 187 (published June 11, 1986); Morrison et al., European Patent Application 173 494 (published March 5, 1986); Sahagan et al., J. Immunol. 137:1066 1074 (1986); Robinson et al., International Patent Application Publication WO 1987/002671 (published May 7, 1987); Liu et al., Proc. Natl. Acad. Sci. USA 84:3439 3443 (1987); Sun et al., Proc. Natl. Acad. Sci. USA 84:214 218 (1987); Better et al., Science 240:1041 1043 (1988); and Harlow and Lane Antibodies. a Laboratory Manual Cold Spring Harbor Laboratory (1988)). These references are incorporated herein by reference in their entirety.

An anti-idiotypic (anti-Id) antibody is an antibody that recognizes unique determinants normally associated with the antigen-binding site of an antibody. An anti-Id antibody can be produced by immunizing an animal of the same species and genetic type (e.g., mouse strain) as the source of the mAb with a mAb to which an anti-Id is produced. The immunized animal will recognize the idiotypic determinants of the immunizing antibody and respond to them by producing an antibody to those idiotypic determinants (an anti-M antibody). See, e.g., U.S. Patent No. 4,699,880, which is incorporated herein by reference in its entirety. An anti-Id antibody can also be used as an immunogen to induce an immune response in another animal that produces a so-called anti-Id antibody. The anti-anti-Id may be epitopically identical to the original mAb that induced the anti-Id. Thus, using antibodies to the idiotypic determinants of the mAb, other clones expressing antibodies with identical specificity can be identified.

As used herein, the term monoclonal antibody (mAb) means an antibody (or antibody fragment) obtained from a population of substantially homogeneous antibodies. Monoclonal antibodies are highly specific and are usually directed against a single antigenic determinant. The modifier monoclonal indicates the substantially homogeneous nature of the antibody and does not require production of the antibody by any particular method. For example, murine mAbs can be produced by the hybridoma method Kohler et al., Nature 256: 495-497 (1975). Chimeric monoclonal antibodies comprising a light chain and heavy chain variable region derived from a donor antibody (usually murine) in association with a light chain and heavy chain constant region derived from an acceptor antibody (usually another mammalian species, such as a human) can be prepared by the method described in U.S. Patent 4,816,567. Humanized mAbs having CDRs derived from a non-human donor immunoglobulin (usually murine) and the remaining immunoglobulin-derived portions of the molecule derived from one or more human immunoglobulins, optionally having altered framework support residues to maintain binding affinity, can be prepared by the techniques disclosed in Queen et al., Proc. Natl. Acad. Sci. (USA), 86:10029-10032 (1989) and Hodgson et al., Bio/Technology, 9:421 (1991).

In addition to the antibodies described herein, exemplary human framework sequences useful for humanization are disclosed, for example, at www“dot”ncbi“dot”nlm“dot”nih“dot”gov/entrez/query“dot”fcgi;

www“dot”ncbi“dot”nih“dot”gov/igblast; www“dot”atcc“dot”org/phage/hdb“dot”html;

www“dot”mrc-cpe“dot”cam“dot”ac“dot”uk/ALIGNMENTS“dot”php; “dot” www“dot”kabatdatabase“dot”com/top“dot”html; ftp“dot”ncbi“dot”nih“dot”gov/repository/kabat; www“dot”sciquest“dot”com;

www“dot”abcam“dot”com; www“dot”antibodyresource“dot”com/onlinecomp“dot”html; www“dot”public“dot”iastate“dot”edu/“dot”about“dot”pedro/research_tools“dot”html;

www“dot”whfreeman“dot”com/immunology/CH05/kuby05“dot”htm;

www“dot”hhmi“dot”org/grants/lectures/1996/vlab;

www“dot”path“dot”cam“dot”ac“dot”uk/“dot”about“dot”mrc7/mikeimages“dot”html;

mcb“dot”harvard“dot”edu/BioLinks/Immunology“dot”html;

www“dot”immunologylink“dot”com;

pathbox“dot”wustl“dot”edu/“dot”about“dot”hcenter/index“dot”html;

www“dot”appliedbiosystems“dot”com; www“dot”nal“dot”usda“dot”gov/awic/pubs/antibody;

www“dot”m“dot”ehime-u“dot”ac“dot”jp/“dot”about“dot”yasuhito/Elisa“dot”html;

- 6 047986 www“dot”biodesign“dot”com; www“dot”cancerresearchuk“dot”org;

www“dot”biotech“dot”ufl“dot”edu; www“dot”isac-net“dot”org;

baserv“dot”uci“dot”kun“dot”nl/“dot”about“dot”jraats/linksl“dot”html;

www“dot”recab“dot”uni-hd“dot”de/immuno“dot”bme“dot”nwu“dot”edu; www“dot”mrccpe“dot”cam“dot”ac“dot”uk; www“dot”ibt“dot”unam“dot”mx/vir/V_mice“dot”html;

https://www“dot”bioinf‘dot”org“dot”uk/abs; antibody“dot”bath“dot”ac“dot”uk;

www“dot”unizh“dot”ch; www“dot”cryst“dot”bbk“dot”ac“dot”uk/“dot”about“dot”ubcg07s;

www“dot”nimr“dot”mrc“dot”ac“dot”uk/CC/ccaewg/ccaewg“dot”html;

www“dot”path“dot”cam“dot”ac“dot”uk/“dot”about“dot”mrc7/humanisation/TAHHP“dot”html; www“dot”ibt“dot”unam“dot”mx/vir/structure/stat_aim“dot”html;

www“dot”biosci“dot”missouri“dot”edu/smithgp/index“dot”html; www“dot”jerini“dot”de;

imgt“dot”cines“dot”fr; and Kabat et al., Sequences of Proteins of Immunological Interest, U.S.

Dept. Health (1987), each of which is incorporated herein by reference in its entirety. The dot in World Wide Web addresses referenced in this document may be replaced by . as appropriate.

The antibodies described herein may comprise, but are not limited to, at least one of a heavy chain constant region (Hc), a heavy chain variable region ( _Hv ), a light chain variable region ( _Lv ), and a light chain constant region ( _Lc ), wherein the polyclonal Ab, monoclonal Ab, fragment, and/or regions thereof comprise at least one heavy chain variable region ( _Hv ) or light chain variable region ( _Lv ) that binds a portion of claudin 6 and can be used to detect an antigen. The antibodies may also be monoclonal antibodies produced by immunizing chickens. Variable chains from nucleic acid sequences encoding isolated monoclonal antibodies can be isolated using methods such as, but not limited to, PCR. The variable chains isolated by these methods can then be placed into a human Fc scFv vector. Accordingly, the antibodies can be antibodies having a human Fc and two scFv arms. Antibodies such as those described herein and throughout the present disclosure can then be modified to be human antibodies or humanized antibodies. Examples of how to modify an antibody, including chicken antibodies, can be found, for example, in Riechmann L, Clark M, Waldmann H, Winter G (1988). Reshaping human antibodies for therapy. Nature 332 (6162): 332-323; Tsurushita N, Park M, Pakabunto K, Ong K, Avdalovic A, Fu H, Jia A, Vasquez M, Kumar S. (2004); and Humanization of a chicken anti-IL-12 monoclonal antibody Immunol Methods 295 (1-2): 9-19; Nishibori N, Horiuchi H, Furusawa S, Matsuda H. (2006) Humanization of chicken monoclonal antibody using phage display system Mol Immunol. 43(6):634–42, each of which is incorporated by reference in its entirety.

Methods for determining the specificity and affinity of mAbs by competitive inhibition can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988), Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, N.Y., (1992, 1993), and Muller, Meth. Enzymol. 92:589 601 (1983), the references of which are incorporated herein by reference in their entireties.

Methods for producing antibodies to small peptide sequences that recognize and bind to these sequences in free or conjugated form, or when they are presented as a native sequence in the context of a large protein, are well known in the art. Such antibodies include mouse, mouse-human, and human-human antibodies produced by hybridoma or recombinant methods known in the art. Antibodies can also be produced in chickens, goats, rabbits, or other small animals.

As used herein, the term antigen-binding region refers to that portion of an antibody molecule that contains amino acid residues that interact with an antigen (e.g., claudin 6) and confer on the antibody its specificity and affinity for the antigen. The region of the antibody includes framework amino acid residues necessary to maintain the proper conformation of the antigen-binding residues. In some embodiments, the antigen-binding region will be of murine origin. In some embodiments, the antigen-binding region may be of other animal species, particularly rodents such as rabbits, rats, or hamsters, or birds such as chickens. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed by the term antigen-binding portion of an antibody include a Fab fragment, a monovalent

- 7 047 986 a band fragment having VL, VH, CL and CH1 domains; an F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by disulfide bridge(s) in the hinge region; an Fd fragment comprising VH and CH1 domains; an Fv fragment having the VL and VH domains of one arm of an antibody; an antibody domain or dAb fragment (Ward et al., 1989 Nature 341:544-546) which consists of a VH domain; and an isolated complementarity determining region (CDR), especially CDR3 (see, for example, WO03/025019, the contents of which are incorporated herein by reference).

The term complementarity-determining regions (CDRs) is based on sequence variability (Wu and Kabat, J. Exp. Med. 132:211-250, 1970). There are six CDRs—three in the variable heavy chain, or VH, and are usually designated H-CDR1, H-CDR2, and H-CDR3, and three in the variable light chain, or VL, and are usually designated L-CDR1, L-CDR2, and L-CDR3 (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991). Hypervariable region, HVR or HV refers to the regions of the variable domain of an antibody that are variable in structure as defined by Chothia and Lesk (Mol. Biol. 196:901-917, 1987). There are six HVRs, three in VH (H1, H2, H3) and three in VL (L1, L2, L3). Chothia and Lesk refer to the structurally conserved HVs as the canonical structures. Another method of describing the regions that form the antigen-binding site was proposed by Lefranc (Lefranc et al., Developmental & Comparative Immunology 27:55-77, 2003), based on a comparison of the V domains of immunoglobulins and T-cell receptors (Lefranc et al., Developmental & Comparative Immunology 27:55-77, 2003). The antigen-binding site can also be defined based on the specificity determining residue utilization (SDRU) according to Almagro (Almagro, Mol. Recognit. 17:132-43, 2004), where SDRU refers to the amino acid residues of the immunoglobulin that are directly involved in contact with the antigen.

Furthermore, although the two domains of the Fv fragment, VL and VH, are naturally encoded by separate genes, they can be joined using recombinant techniques by a synthetic linker that allows them to form a single protein chain in which pairs of the VL and VH regions form monovalent molecules (known as single-chain Fv (scFv); see, e.g., Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Nat. Acad. Sci. 85:5879-5883). Such single-chain antibodies are encompassed by the term antigen-binding portion of an antibody. These antibody fragments are prepared using conventional techniques known to those skilled in the art and can be used in the same way as intact antibodies.

The term "isolated antibody" as used herein refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds claudin 6 is substantially free of antibodies that specifically bind antigens other than claudin 6). Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals. An isolated antibody may also be sterile, pyrogen-free, or formulated as an injectable pharmaceutical as described herein.

In some embodiments, the source of DNA encoding the non-human antibody includes cell lines that produce antibodies, such as hybrid cell lines, commonly known as hybridomas.

An antigen is a molecule or a portion of a molecule capable of binding to an antibody that is further capable of inducing in an animal the production of an antibody capable of binding to an epitope of the antigen. An antigen may have one or more epitopes. The aforementioned specific reaction is intended to indicate that the antigen will react in a highly selective manner with its corresponding antibody and not with a variety of other antibodies that may be elicited by other antigens. In some embodiments, the antigens, antibody-binding fragments and regions of antibodies comprise at least 5 amino acids. In some embodiments, the antigen is a claudin 6 protein expressed on the surface of a cell or particle. In some embodiments, the cell is an intact cell. An intact cell is a cell that has not been lysed or dissected using detergents or other reagents. A cell treated with detergents or other reagents that disrupt the cell membrane or punch holes in the cell membrane is not an intact cell. By expressing a receptor on the surface of a cell or particle, such as a lipoparticle, the receptor can present conformational epitopes that may otherwise be absent if a purified protein is used. An example is provided herein. In some embodiments, an adjuvant is not used, but may be used. In some embodiments, the particles are administered to a bird (e.g., a chicken) to stimulate an immune response and produce antibodies to the protein present on the surface of the particle. Particles suitable for generating antibodies are described in U.S. Patents 8,377,691, 7,763,258, 8,158,130, and U.S. Patent Application Publication Nos. 20050123563 and 20120195882, each of which is incorporated herein by reference. These publications and patents describe the production of various particles, including lipoparticles, that can be used to express membrane spanning proteins (e.g., membrane spanning proteins)

- 8 047986 (containing many membranes, ion channels, etc.).

The term epitope is intended to refer to that portion of any molecule that is capable of being recognized and bound by an antibody in one or more of the antigen-binding regions of an Ab. Epitopes typically consist of chemically active surface groups of molecules, such as amino acids or sugar side chains, and have certain three-dimensional structural characteristics as well as specific charge characteristics. Examples of epitopes include, but are not limited to,

As used herein, the term chimeric antibody includes monovalent, divalent, or multivalent immunoglobulins. A monovalent chimeric antibody is a dimer (HL) formed by a chimeric H chain linked via disulfide bridges to a chimeric L chain. A divalent chimeric antibody is a tetramer (H2L2) formed by two HL dimers linked via at least one disulfide bridge. A multivalent chimeric antibody can also be produced, for example, using a CH region that aggregates (e.g., from an H chain or μ chain of IgM). In some embodiments, murine and chimeric antibodies, fragments, and regions comprise separate heavy (H) and/or light (L) chains of immunoglobulin.

Antibodies, fragments or derivatives having chimeric H chains and L chains with the same or different variable region binding specificities can also be prepared by appropriately associating the individual polypeptide chains according to known method steps, for example, according to Ausubel below, Harlow below, and Colligan below, the contents of which are incorporated herein by reference in their entirety. In this approach, hosts expressing the chimeric H chains (or derivatives thereof) are separately cultured from hosts expressing the chimeric L chains (or derivatives thereof), and the immunoglobulin chains are separately isolated and then associated. Alternatively, the hosts can be co-cultured and the chains allowed to spontaneously associate in the culture medium, followed by isolation of the assembled immunoglobulin, fragment or derivative.

Hybrid cells are formed by fusing a non-human antibody-producing cell, usually a spleen cell from an animal immunized against a natural or recombinant antigen, or a peptide fragment of an antigenic protein sequence. Alternatively, the non-human antibody-producing cell may be a B lymphocyte obtained from the blood, spleen, lymph nodes, or other tissue of an animal immunized with the antigen.

The second fusion partner that provides the immortalization function may be a lymphoblastoid cell or a plasmacytoma or myeloma cell, which is not itself an antibody-producing cell but is malignant. Fusion partner cells include, but are not limited to, the SP2/0-Ag14 hybridoma, abbreviated SP2/0 (ATCC CRL1581), and the P3X63Ag8 myeloma (ATCC TIB9), or derivatives thereof. See, for example, Ausubel, infra, Harlow, infra, and Colligan, infra, the contents of which are incorporated herein by reference in their entirety.

Antibodies can be prepared according to the examples given herein. Once the sequences are known, antibodies can also be prepared by known methods. Antibodies can also be converted into different types, such as human IgG, etc. By converting antibodies into a human antibody, the antibody should not be detected as foreign by the human. This will result in a more effective response. Conversion of a non-human IgG antibody into a human IgG antibody is well known and can be carried out routinely if the native sequence is known. As discussed herein, antibodies can be modified by known methods. Such methods are described in, for example, Riechmann L, Clark M, Waldmann H, Winter G (1988). Reshaping human antibodies for therapy. Nature 332 (6162): 332-323; Tsurushita N, Park M, Pakabunto K, Ong K, Avdalovic A, Fu H, Jia A, Vasquez M, Kumar S. (2004); and Humanization of a chicken anti-IL-12 monoclonal antibody Immunol Methods 295 (1–2): 9–19; Nishibori N, Horiuchi H, Furusawa S, Matsuda H. (2006) Humanization of chicken monoclonal antibody using phage display system Mol Immunol. 43 (6): 634–42, each of which is incorporated by reference in its entirety.

An antibody-producing cell introducing nucleotide sequences encoding the antigen-binding region of a chimeric antibody can also be produced by transforming a non-human cell, such as a primate or a human cell. For example, a B lymphocyte that produces an antibody can be infected and transformed with a virus, such as Epstein-Barr virus, to form immortalized antibody-producing cells (Kozbor et al., Immunol. Today 4:72 79 (1983)). Alternatively, a B lymphocyte can be transformed by providing a transforming gene or a transforming gene product, as is well known in the art. See, for example, Ausubel, infra, Harlow, infra, and Colligan, infra, the contents of which are incorporated herein by reference in their entirety.

The cell fusion is accomplished by standard procedures well known to those skilled in the art of immunology. Fusion partner cell lines and methods for fusion and selection of hybridomas and screening of mAbs are well known in the art. See, for example, Ausubel below, Harlow below, and Colligan below, the contents of which are incorporated herein by reference in their entirety.

- 9 047986

Antigen-specific murine or chimeric mAbs can be produced in large quantities by injecting antibody-secreting hybridoma or transfectoma cells into the peritoneal cavity of mice and, after an appropriate time, collecting ascites fluid containing a high titer of mAb and isolating the mAb therefrom. For such in vivo production of mAbs with a non-murine hybridoma (e.g., rat or human), the hybridoma cells are preferably grown in irradiated or athymic mice. Alternatively, antibodies can be produced by culturing hybridoma or transfectoma cells in vitro and isolating secreted mAbs from the cell culture medium or recombinantly in eukaryotic or prokaryotic cells.

In some embodiments, the antibody is a MAb that binds to claudin 6. In some embodiments, the antibody binds to amino acids of an epitope of claudin 6. The epitopes are described herein, for example, in the tables provided in the figures and described in the examples. In some embodiments, the antibody specifically binds to the proteins and antigens described herein.

In some embodiments, the antibody comprises a sequence as provided herein.

The antibody sequences can be modified to produce human IgG antibodies. The sequences provided herein can be modified to produce other types of antibodies. The CDRs can also be linked to other antibodies, proteins or molecules to create antibody fragments that bind to claudin 6. The CDRs and antibody sequences provided herein can also be humanized or made fully human according to known methods. The sequences can also be converted into chimeric antibodies as described herein.

In some embodiments, the antibody comprises an amino acid sequence comprising the sequence provided herein, or a fragment thereof. In some embodiments, the antibody comprises one or more amino acid sequences as provided herein, their antigen-binding fragments, or a human IgG variant thereof. A human IgG variant thereof refers to an antibody that has been modified into a human IgG, when the original antibody is not a human IgG antibody.

As described herein, obtaining antibodies of known sequence is routine and can be accomplished by any method. Accordingly, in some embodiments, a nucleic acid encoding an antibody or fragment thereof is provided. In some embodiments, the nucleic acid encodes a sequence as provided herein. The antibodies can also be modified to be chimeric antibodies or human antibodies. The antibodies can also be used in pharmaceutical compositions for injection. As also described herein, the antibodies can be isolated antibodies or engineered antibodies.

In some embodiments, derivatives of antibodies, fragments, regions or derivatives thereof are provided, this term includes those proteins that are encoded by truncated or modified genes to produce molecular species that functionally resemble immunoglobulin fragments. Modifications include, but are not limited to, the addition of genetic sequences encoding cytotoxic proteins, such as plant toxins and bacterial toxins. The modification may also include a reporter protein, such as a fluorescent or chemiluminescent label. Fragments and derivatives can be produced by any method.

Fragments include, for example, Fab, Fab', F(ab')2, and Fv. These fragments lack the Fc portion of the intact antibody, are cleared more rapidly from the circulation, and may have less nonspecific tissue binding than the intact antibody (Wahl et al, J. Nucl. Med. 24:316-325 (1983)). These fragments are prepared from intact antibodies using methods well known in the art, such as proteolytic cleavage with enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab')f fragments).

Identification of this antigen-binding region and/or epitopes recognized by the Abs described herein provides information necessary to generate additional monoclonal antibodies with similar binding characteristics and therapeutic or diagnostic utility that are similar to embodiments of this invention.

The nucleic acid sequence encoding the antibody described herein may be genomic DNA or cDNA or RNA (e.g., mRNA) that encodes at least one of the variable regions described herein. A convenient alternative to using chromosomal gene fragments as a source of DNA encoding the antigen-binding segment of the V region is to use cDNA to construct chimeric immunoglobulin genes, such as reported by Liu et al. (Proc. Natl. Acad. Sci., USA 84:3439 (1987) and J. Immunology 139:3521 (1987), the references to which are incorporated herein by reference in their entireties. The use of cDNA requires that gene expression elements appropriate for the host cell be combined with the gene to achieve synthesis of the desired protein. The use of sequentially

- 10,047,986 cDNA sequences are advantageous compared to genomic sequences (which contain introns) in that cDNA sequences can be expressed in bacteria or other hosts that lack appropriate RNA splicing systems.

For example, a cDNA encoding an antigen-binding segment of a V region capable of detecting, binding, or neutralizing the claudin 6 antigen can be provided using known techniques based on the use of the amino acid sequences provided herein. Since the genetic code is degenerate, more than one codon can be used to encode a particular amino acid (Watson, et al., below). Using the genetic code, one or more different oligonucleotides can be identified, each of which can encode an amino acid. The likelihood that a particular oligonucleotide will actually constitute the actual coding sequence can be estimated by taking into account the anomalous base pairing relationships and the frequency with which a particular codon is actually used (to encode a particular amino acid) in eukaryotic or prokaryotic cells expressing the antibody or fragment. Such codon usage rules are disclosed by Lathe, et al., J. Molec. Biol. 183:1 12 (1985). Using Lathe codon usage rules, a single oligonucleotide or set of oligonucleotides is identified that contains the theoretical most likely nucleotide sequence capable of encoding the variable or constant region sequences of an antibody.

The variable regions described herein can be combined with any type of constant region, including a human constant region or a mouse constant region. Human genes that encode constant (C) regions of antibodies, fragments and regions can be obtained from a human fetal liver library by known methods. Human C region genes can be from any human cell, including cells that express and produce human immunoglobulins. The human CH region can be from any of the known human H chain classes or isotypes, including gamma, μ, α, δ or ε, and their subtypes such as G1, G2, G3 and G4. Since the H chain isotype is responsible for various effector functions of the antibody, the choice of CH region will be determined by the desired effector functions, such as complement fixation or antibody-dependent cellular cytotoxicity (ADCC) activity. Preferably, the CH region is derived from gamma1 (IgG1), gamma3 (IgG3), gamma4 (IgG4), or μ (IgM). The human C _L region may be derived from the human L chain isotype, kappa or lambda.

Genes encoding human immunoglobulin C regions can be obtained from human cells by standard cloning techniques (Sambrook, et al. (Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Press, Cold Spring Harbor, NY (1989) and Ausubel et al., eds. Current Protocols in Molecular Biology (1987 1993)). Human C region genes are readily available from known clones containing genes representing the two classes of L chains, the five classes of H chains, and their subclasses. Chimeric antibody fragments such as F(ab') ₂ and Fab can be produced by constructing an H chain of the chimeric gene that is appropriately truncated. For example, a chimeric gene encoding the H chain portion of the F(ab') ₂ fragment would include DNA sequences encoding the CHi domain and the hinge region of the H chain, followed by A translation stop codon follows to produce a truncated molecule.

Typically, the mouse, human, or mouse antibodies and chimeric antibodies, fragments, and regions of the antibodies described herein are prepared by cloning DNA segments encoding the antigen-binding regions of the H and L chains of a claudin 6 antigen-specific antibody and joining these DNA segments to DNA segments encoding the C _H and C _L regions, respectively, to produce genes encoding a mouse, human, or chimeric immunoglobulin.

Thus, in some embodiments, a fusion chimeric gene is created that comprises a first DNA segment that encodes at least a non-human antigen-binding region, such as a functionally rearranged V region with a joining (J) segment linked to a second DNA segment encoding at least a portion of a human C region.

Therefore, the cDNA encoding the V and C regions of the antibody, the method of producing a chimeric antibody according to some embodiments described herein comprises several steps as illustrated below: 1. Isolating messenger RNA (mRNA) from a cell line producing an antibody to the claudin 6 antigen and from optional additional antibodies providing the constant regions of the heavy and light chains; cloning and preparing cDNA therefrom; 2. Preparing a full-length cDNA library from the purified mRNA, from which the corresponding V and/or C region gene segments of the L and H chain genes can be: (i) identified by appropriate probes, (ii) sequenced, and (iii) made compatible with a C or V gene segment from another antibody to the chimeric antibody; 3. Construction of complete H or L chain coding sequences by linking cloned segments of a specific V region gene to a cloned C region gene as described above; 4. Expression and production of L and H chains in selected hosts, including prokaryotic and eukaryotic cells, to produce mouse-mouse, human-mouse, human-human, or human-mouse antibodies.

- 11 047986

A common feature of all immunoglobulin H and L chain genes and the mRNAs they encode is the J region. The H and L chain J regions have different sequences, but there is a high degree of sequence homology (greater than 80%) among each group, particularly near the C region. This homology is exploited in this method, and consensus sequences of the H and L chain J regions can be used to design oligonucleotides for use as primers to introduce useful restriction sites into the J region for subsequent linkage of V region segments to human C region segments.

C region cDNA vectors derived from human cells can be modified by site-directed mutagenesis to place a restriction site at an analogous position in the human sequence. For example, the complete C region (C _k ) of the human kappa chain and the complete C region of human gamma-1 (Cy-1) can be cloned. In this case, an alternative method based on the C region clones of the genome as a source of C region vectors will prevent these genes from being expressed in bacterial systems that lack the enzymes required to remove the intervening sequences. The cloned V region segments are excised and ligated to L or H chain C region vectors. Alternatively, the human Cy-1 region can be modified by introducing a stop codon, thereby generating a gene sequence that codes for the H chain portion of the Fab molecule. The coding sequences with associated V and C regions are then transferred into appropriate expression vehicles for expression in appropriate hosts, prokaryotic or eukaryotic.

Two DNA coding sequences are said to be operably linked if the linkage results in a continuously translated sequence without alteration or interruption of the triplet reading frame.

A DNA coding sequence is operably linked to a gene expression element if the linkage results in the proper functioning of the gene expression element, resulting in expression of the coding sequence.

Expression carriers include plasmids or other vectors. Preferred among these are carriers carrying a functionally complete human CH or _CL sequence having suitable restriction sites designed so that any VH or V _L sequence with appropriate sticky ends can be easily inserted into it. Thus, carriers containing the human CH or CL chain sequence serve as intermediates for the expression of any desired complete H or L chain in any suitable host.

A chimeric antibody, such as a mouse-human or human-human antibody, will typically be synthesized from genes driven by chromosomal gene promoters native to the mouse H and L chain V regions used in the constructs; splicing typically occurs between a splice donor site in the mouse J region and a splice acceptor site preceding the human C region, as well as at splice regions that occur in the human C region; polyadenylation and transcription termination occur at native chromosomal sites downstream of the human coding regions.

As used in this document and unless otherwise specified, the term about is intended to mean ±5% of the value it changes. Thus, about 100 means between 95 and 105.

In some embodiments, the antibodies described herein are used to detect the presence of an antigen. The present antibody can be used in any device or method for detecting the presence of an antigen.

The term purified, when applied to an antibody, refers to an antibody that is substantially free of other material that is associated with the molecule in its natural environment. For example, a purified protein is substantially free of cellular material or other proteins of the cell or tissue from which it is obtained. The term refers to preparations in which the isolated protein is sufficiently pure for analysis or is at least 70-80% (w/w) pure, at least 80-90% (w/w) pure, at least 90-95% pure; and at least 95%, 96%, 97%, 98%, 99%, or 100% (w/w) pure. In some embodiments, the antibody is purified.

The terms specific binding, specifically binds, etc. mean that two or more molecules form a complex that is measurable under physiological or assay conditions and is selective. An antibody or antigen-binding protein or other molecule is said to bind specifically to a protein, antigen, or epitope if, under appropriately selected conditions, such binding is not substantially inhibited and at the same time non-specific binding is inhibited. Specific binding is characterized by high affinity and is selective for the compound, protein, epitope, or antigen. Non-specific binding is usually of low affinity. Binding in IgG antibodies, for example, is typically characterized by an affinity of at least about 10 ^-7 M or higher, such as at least about 10 ^-8 M or higher, or at least about 10 ^-9 M or higher, or at least about 10 ^-10 or higher, or at least about 10 ^-11 M or higher, or at least about 10 ^-12 M or higher. This term also applies to

- 12 047986 where, for example, the antigen-binding domain is specific for a particular epitope that is not tolerated by numerous antigens, in which case an antibody or antigen-binding protein bearing the antigen-binding domain will typically not bind other antigens. In some embodiments, the capture reagent has a Kd equal to or less than 10 ^-9 M, 10 ^-10 M, or 10 ^-11 M for its binding partner (e.g., an antigen). In some embodiments, the capture reagent has a Ka for its binding partner greater than or equal to 10 ⁹ M ^-1 .

Intact antibodies, also known as immunoglobulins, are typically tetrameric glycosylated proteins consisting of two light (L) chains of approximately 25 kDa each and two heavy (H) chains of approximately 50 kDa each. There are two types of light chain in antibodies, called lambda and kappa. Depending on the amino acid sequence of the constant domain of the heavy chains, immunoglobulins are divided into five main classes: A, D, E, G, and M, and some of them can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. Each light chain consists of an N-terminal variable (V) domain (VL) and a constant (C) domain (CL). Each heavy chain consists of an N-terminal V domain (VH), three or four C domains (CH), and a hinge region. The CH domain most proximal to VH is designated CH1. The VH and VL domains consist of four regions of relatively conserved sequences called framework regions (FR1, FR2, FR3, and FR4) that provide a framework for three regions of hypervariable sequences (complementarity determining regions, CDRs). The CDRs contain most of the residues responsible for specific interactions of an antibody or antigen-binding protein with an antigen. The CDRs are designated CDR1, CDR2, and CDR3. Accordingly, the heavy chain CDR components are designated H1, H2, and H3, and the light chain CDR components are designated L1, L2, and L3. CDR3 represents the greatest source of molecular diversity within an antibody or antigen-binding protein binding site. For example, H3 may be composed of two amino acid residues or more than 26 amino acids. The subunit structures and three-dimensional configurations of the various classes of immunoglobulins are well known in the art. For a review of the structure of antibodies, see Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Eds. Harlow et al., 1988. One skilled in the art will appreciate that each subunit structure, such as a CH, VH, CL, VL, CDR, and/or FR structure, contains active moieties. For example, the active moieties may consist of a portion of a VH, VL, or CDR subunit that binds antigen, i.e., an antigen-binding moiety, or a portion of a CH subunit that binds to and/or activates an Fc receptor and/or complement.

In addition to the fragments described herein, non-limiting examples of binding fragments encompassed by the term antigen-specific antibody as used herein include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) an F(ab') ₂ fragment, a divalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of one arm of an antibody, (v) a dAb fragment that consists of a VH domain; and (vi) an isolated CDR. Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be recombinantly joined by a synthetic linker, creating a single protein chain in which the VL and VH domains are paired to form monovalent molecules (known as single-chain Fv (scFv)). The most commonly used linker is a 15-residue peptide (Gly4Ser) ₃ , but other linkers are also known in the art. Single-chain antibodies are also encompassed by the terms antibody or antigen-binding protein or antigen-binding fragment of an antibody. An antibody can also be a polyclonal antibody, a monoclonal antibody, a chimeric antibody, an antigen-binding fragment, an Fc fragment, a single-chain antibody, or any derivative thereof.

These antibodies can be prepared using conventional techniques known to those skilled in the art and described herein, and the fragments are used in the same manner as intact antibodies.

Antibody diversity is generated by multiple germline genes encoding variable domains and multiple somatic events. Somatic events include recombination of variable gene segments with diversity (D) and joining (J) gene segments to form a complete VH domain, and recombination of variable and joining gene segments to form a complete VL domain. The recombination process itself is imprecise, resulting in the loss or addition of amino acids at V(D)J junctions. These mechanisms of diversity occur in developing B cells prior to antigen exposure. Following antigen stimulation, expressed antibody genes in B cells undergo somatic mutation. Based on the estimated number of germline gene segments, random recombination of these segments, and random VH-VL pairing, up to 1.6 x 10 ⁷ different antibodies could be generated (Fundamental Immunology, 3rd ed. (1993), ed. Paul, Raven Press, New York, NY). When other processes that contribute to antibody diversity are taken into account (e.g., somatic mutation), it is estimated that up to

- 13 047986 more than 1 x 10 ¹⁰ different antibodies (Immunoglobulin Genes, 2nd ed. (1995), eds. Jonio et al., Academic Press, San Diego, CA). Because of the many processes involved in generating antibody diversity, it is unlikely that independently produced monoclonal antibodies with the same antigen specificity will have identical amino acid sequences.

Antibody or antigen-binding protein molecules capable of specifically interacting with the antigens, epitopes, or other molecules described herein can be produced by methods well known to those skilled in the art. For example, monoclonal antibodies can be produced by generating hybridomas according to known methods. Hybridomas formed in this manner can then be screened using standard methods, such as enzyme-linked immunosorbent assay (ELISA) and biosensor assays, to identify one or more hybridomas producing an antibody that specifically interacts with a molecule or compound of interest.

As an alternative to producing hybridomas that secrete monoclonal antibodies, a monoclonal antibody to the polypeptide can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with the polypeptide described herein to thereby isolate members of the immunoglobulin library that bind to the polypeptide. Methods and commercially available kits for generating and screening phage display libraries are well known to those skilled in the art. In addition, examples of methods and reagents particularly suitable for use in generating and screening antibody or antigen-binding protein display libraries can be found in the literature. Accordingly, the epitopes described herein can be used to screen other antibodies that can be used for therapeutic, diagnostic, or research purposes.

Introduction, compositions and kits containing antibodies

Given that the isolated antibody binds an epitope on the claudin 6 protein or another protein described herein and exhibits in vitro and/or in vivo claudin 6 inhibitory or therapeutic activity, the antibodies or antigen-binding fragments thereof are capable of inhibiting claudin 6 function, and are suitable as both therapeutic and prophylactic agents for the treatment or prevention of claudin 6-associated pathological conditions in humans and animals. These pathological conditions include, but are not limited to, benign and metastatic forms of cancer such as ovarian cancer (e.g., ovarian carcinoma), cancer of the reproductive system (breast cancer, cervical cancer, testicular cancer, uterine cancer, and placental cancer), lung cancer, gastric cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, kidney cancer, colon cancer, small bowel cancer, skin cancer, head and neck cancer, sarcoma, or germ cell tumors, among others.

In some embodiments, the methods comprise administering a therapeutically or prophylactically effective amount of one or more monoclonal antibodies or antigen-binding antibody fragments described herein to a susceptible subject or a subject experiencing a condition in which claudin 6 is known to cause the observed pathology. Any active form of the antibody may be administered, including, but not limited to, Fab and F(ab') ₂ fragments.

In this context, claudin 6-related pathology refers to pathological conditions that are caused by the function or aberrant function of the claudin 6 receptor. These pathological conditions include, but are not limited to, benign and metastatic forms of cancer, such as ovarian cancer (e.g., ovarian carcinoma), cancer of the reproductive system (breast cancer, cervical cancer, testicular cancer, uterine cancer, and placental cancer), lung cancer, gastric cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, kidney cancer, colon cancer, small bowel cancer, skin cancer, head and neck cancer, sarcoma, germ cell tumors, and the like.

In some embodiments, the antibodies used are compatible with the recipient species such that the immune response to the MAb does not result in an unacceptably short half-life in the bloodstream or does not elicit an immune response to the MAb in the subject. In some embodiments, the administered MAb exhibits some secondary functions, such as binding to the subject's Fc receptors and activating antibody-dependent cellular cytotoxicity (ADCC) mechanisms.

- 14 047986

Treatment of individuals may include administration of a therapeutically effective amount of the antibodies described herein. The antibodies may be provided in a kit as described below. The antibodies may be used or administered alone or in admixture with another therapeutic, analgesic or diagnostic agent. When providing a patient with an antibody or fragment thereof capable of binding to claudin 6, or an antibody capable of protecting against claudin 6, a pathology in a recipient patient, the dosage of the agent administered will vary depending on factors such as the patient's age, weight, height, gender, general health, previous medical history, etc.

Suitable carriers, their composition and packaging are described, for example, in Remington: The Science and Practice of Pharmacy (21st ed., Troy, D. ed., Lippincott Williams & Wilkins, Baltimore, Md. (2005) Chapters 40 and 41). Additional pharmaceutical techniques may be used to control the duration of action. Controlled-release preparations may be prepared by using polymers to complex or absorb the compounds. Another possible method of controlling the duration of action with controlled-release preparations is the incorporation of compounds into particles of polymeric material such as polyesters, polyamino acids, hydrogels, poly(lactic acid) copolymers or ethylene vinyl acetate. Alternatively, instead of incorporating these agents into polymer particles, these materials can be enclosed in microcapsules obtained, for example, by interfacial polymerization, for example, hydroxymethylcellulose or gelatin microcapsules, and polymethylmethacrylate microcapsules, respectively, or in a colloidal drug delivery system, for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules, or in macroemulsions.

In general, when a systemic dose of an antibody is administered, it is desirable to provide the recipient with a dose of the antibody that is in the range of about 1 ng/kg-100 ng/kg, 100 ng/kg-500 ng/kg, 500 ng/kg-1 mcg/kg, 1 mcg/kg-100 mcg/kg, 100 mcg/kg-500 mcg/kg, 500 mcg/kg-1 mg/kg, 1 mg/kg-50 mg/kg, 50 mg/kg-100 mg/kg, 100 mg/kg-500 mg/kg (recipient body weight), although a lower or higher dose may be administered. Doses as low as about 1.0 mg/kg can be expected to show some efficacy. Preferably, the acceptable dosage is about 5 mg/kg, although dosage levels up to about 50 mg/kg are also preferred, especially for therapeutic use. Alternatively, administration of a specific amount of antibody that is independent of the patient's weight may be prescribed, such as an amount in the range of 1 μg-100 μg, 1 mg-100 mg, or 1 mg-100 mg. For example, site-specific administration can be into a compartment or cavity of the body, such as by intra-articular, intrabronchial, intraperitoneal, intracapsular, intracartilaginous, intracavitary, intraventricular, intracerebellar, intracerebroventricular, colonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, intrapelvic, intrapericardial, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, vaginal, rectal, buccal, sublingual, intranasal, or transdermal administration.

The antibody compositions described herein can be prepared for parenteral (subcutaneous, intramuscular or intravenous) or any other administration, especially in the form of liquid solutions or suspensions. The composition can also be suitable for an injection composition. In some embodiments, the injection composition is sterile. In some embodiments, the injection composition is pyrogen-free. In some embodiments, the composition does not contain other antibodies that bind to antigens other than the antigen described herein.

An antibody capable of treating a pathological condition associated with claudin 6 activity or used to treat a pathology associated with claudin 6 is intended to be provided to subjects in an amount sufficient to affect the reduction, resolution or amelioration of symptoms or pathology associated with claudin 6. Such pathology includes a benign neoplasm or metastatic cancer, such as an ovarian cancer (e.g., ovarian carcinoma), a cancer of the reproductive system (cancer of the breast, cervix, testicles, uterus or placenta), a lung cancer, a gastric cancer, a liver cancer, a pancreatic cancer, a bile duct cancer, a bladder cancer, a kidney cancer, a colon cancer, a small bowel cancer, a skin cancer, a head and neck cancer, a sarcoma or a germ cell tumor in a subject.

An amount is said to be sufficient or a therapeutically effective amount to affect the reduction of symptoms if the dosage, route of administration, and schedule of administration of the agent are sufficient to affect such a response. Responses to antibody administration can be measured by analyzing the affected tissues, organs, or cells of the subject using imaging techniques or by analyzing ex vivo tissue samples. An agent is physiologically significant if its presence results in a measurable change in the physiology of the recipient patient. In some embodiments, the amount

- 15 047986 is a therapeutically effective amount if it is an amount that can be used to treat, alleviate or prevent benign neoplasm and metastatic forms of cancer, such as ovarian cancer (e.g. ovarian carcinoma), cancer of the reproductive system (breast cancer, cervical cancer, testicular cancer, uterine cancer and placental cancer), lung cancer, gastric cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, kidney cancer, colon cancer, small bowel cancer, skin cancer, head and neck cancer, sarcoma, or germ cell tumors, such as but not limited to, by modulating claudin 6-mediated function claudin 6 regulation of tight junction integrity, etc. In some embodiments, the antibody or therapeutic agent does not bind to other claudin proteins, such as, but not limited to, claudin 9, claudin 3, and/or claudin 4. In some embodiments, the antibody is specific for claudin 6.

The antibodies can be formulated according to known methods for the preparation of pharmaceutically useful compositions, whereby these materials or functional derivatives thereof are combined in admixture with a pharmaceutically acceptable carrier. The treatment can be carried out according to a single dose schedule or according to a multiple dose schedule, in which the initial course of treatment can consist of 1-10 individual doses, followed by other doses administered at subsequent time intervals necessary to maintain or enhance the response, for example, after 1-4 months for a second dose and, if necessary, subsequent doses after several months. Examples of suitable treatment schedules include: (i) 0, 1 month and 6 months, (ii) 0, 7 days and 1 month, (iii) 0 and 1 month, (iv) 0 and 6 months or other schedules sufficient to elicit the desired responses that are expected to reduce the symptoms of the disease or reduce the severity of the disease.

Also provided are kits that may be useful for performing the embodiments described herein. The present kits include a first container containing or packaged together with the antibodies described above. Said kit may also include another container containing or packaged in an association solution necessary or convenient for performing the embodiments. Said containers may be glass, plastic or made of foil, and be a vial, bottle, bag, tube, bag, etc. Said kit may also contain written information, such as procedures for performing the embodiments or analytical information, such as the amount of reagent contained in the first container. Said container may be in another container device, such as a box or bag, together with written information.

Another aspect provided in this document is a kit for detecting claudin 6 protein in a biological sample. The kit includes a container containing one or more antibodies that bind an epitope of claudin 6 protein, and instructions for using the antibody to bind to claudin 6 protein to form an immunological complex and detect the formation of the immunological complex such that the presence or absence of the immunological complex correlates with the presence or absence of claudin 6 protein in the sample. Examples of containers include multi-well plates that allow simultaneous detection of claudin 6 protein in multiple samples.

In some embodiments, antibodies are provided that bind to the claudin 6 protein. In some embodiments, antibodies are provided, such as a monoclonal antibody or ScFv, that bind to an epitope on claudin 6 whose binding residues include T33, N38, D68, P74, D76, D146, V152, A153, E154, Q156, R158, or any combination thereof. In some embodiments, the antibody binds to an epitope on claudin 6 that includes residues E48, D68, P74, D76, and R158 of claudin 6. In some embodiments, the antibody binds to an epitope on claudin 6 that includes residues T33, N38, E48, D76, A153, E154, Q156, and R158 of claudin 6. In some embodiments, the antibody binds to an epitope on claudin 6 that includes residues N38, E48, Y67, P74, D76, D146, V152, E154, Q156, and R158 of claudin 6. In some embodiments, the antibody binds to an epitope on claudin 6 that includes residues E48, Y67, Q156, and R158 of claudin 6. In some embodiments, the antibody binds to an epitope on claudin 6 that includes residues E48, Y67, Q156, and R158 of claudin 6. In some embodiments, the antibody In the present invention, the antibody binds to an epitope of claudin 6 that includes residue Q156.

In some embodiments, the antibody is isolated. In some embodiments, the antibody specifically binds. In some embodiments, the antibody binds to a claudin 6 protein that is folded correctly. In some embodiments, the antibody binds to a claudin 6 protein in a cell membrane. In some embodiments, the antibody binds to a claudin 6 protein that is in the cell membrane of an intact cell. In some embodiments, the antibody inhibits or neutralizes the function of the claudin 6 protein.

- 16 047986 As used herein, the term "neutralize" means that the activity or function of a protein is inhibited. In some embodiments, the antibody inhibits the regulation of tight junction integrity by claudin 6. In some embodiments, the antibody is used as a targeting moiety to deliver another therapeutic agent to cells expressing (e.g., tumor cells) claudin 6. In some embodiments, the anti-claudin 6 antibody is part of a multispecific therapeutic agent, wherein one portion of the molecule binds to claudin 6 and another portion of the therapeutic agent binds to another target. In some embodiments, the other portion is a CD3 binding molecule (e.g., an anti-CD3 antibody) or another molecule that promotes ADC, ADCC, or CAR-T therapy. The inhibition may be complete or partial. In some embodiments, the activity or function of the protein is inhibited by at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99%. The percentage of inhibition may be based on the function or activity of the protein in the absence of the antibody. In some embodiments, the antibody inhibits interactions or functions that are facilitated by claudin 6.

In some embodiments, the antibody comprises a sequence as provided herein, or an antigen-binding fragment thereof. In some embodiments, the antibody comprises a heavy chain CDR or an antigen-binding fragment thereof as described herein. The heavy chain may be one or more of the heavy chains described herein. In some embodiments, the antibody comprises a light chain or an antigen-binding fragment thereof as described herein.

In some embodiments, methods are provided for treating, inhibiting, or ameliorating a claudin 6-associated pathology. In some embodiments, the methods comprise administering an antibody as described herein or a pharmaceutical composition as described herein to a subject to treat, inhibit, or ameliorate a claudin 6-associated pathology. In some embodiments, the pathology is a benign neoplasm or metastatic cancer, such as an ovarian cancer (e.g., ovarian carcinoma), a cancer of the reproductive system (breast, cervical, testicular, uterine, endometrium, or placenta cancer), a lung cancer, a gastric cancer, a stomach cancer, a liver cancer, a pancreatic cancer, a bile duct cancer, a bladder cancer, a kidney cancer, a colon cancer, a small bowel cancer, a lung cancer (e.g., lung adenocarcinoma), skin cancer, head and neck cancer, sarcoma or germ cell tumor.

In some embodiments, the antibodies provided herein are administered to a subject as a nucleic acid molecule encoding the antibody. In some embodiments, the nucleic acid molecule is a DNA, RNA, or mRNA molecule encoding the antibody. The nucleic acid molecule can be delivered in any form suitable for in vivo expression, such as a viral vector, a plasmid, a linear nucleic acid molecule, and the like. In some embodiments, the antibody produced by the nucleic acid molecule can function as a vaccine or a circulating antibody that is used to identify and kill cells that express claudin 6. The expression of the antibody can be sustained or controlled stimulation. Without being bound by theory, in some embodiments, a subject that develops a cancer that expresses claudin 6 will be treated with a circulating antibody that recognizes the cancer cell. Thus, in some embodiments, an antibody delivered by a nucleic acid molecule can be used to treat or prevent the growth of an oncological disease. In some embodiments, a nucleic acid molecule encoding an antibody is integrated into the genome of a cell of a subject such that expression is constant. Examples of viral vectors that can be used include, but are not limited to, AAV, AV, retroviral vectors that integrate into the genome, and the like.

In some embodiments, methods are provided for detecting the presence or absence of claudin 6 in a sample, the method comprising contacting the sample with one or more antibodies described herein to detect binding of the antibody to a claudin 6 antigen. In some embodiments, detection of binding indicates the presence of a claudin 6 antigen; or lack of detection of binding to a claudin 6 antigen indicates the absence of a claudin 6 antigen. The detection can be accomplished by any known method, such as using a biosensor, ELISA, sandwich assay, etc. However, in some embodiments, the method comprises detecting the presence of a protein under non-denaturing conditions. Non-denaturing conditions can be used such that the protein of interest is detected in its native or correctly folded form.

In some embodiments, methods are provided for identifying a test antibody that binds to an epitope on the claudin 6 protein, the method comprising providing the test

- 17 047986 of the test antibody in contact with an epitope on the claudin 6 protein and determining whether the test antibody binds to the epitope. In some embodiments, the determining comprises determining whether the test antibody binds to the protein and is competitively inhibited by an antibody comprising a sequence as provided herein. In some embodiments, the determining comprises mutating one or more residues of the epitope or protein and determining binding of the test antibody to the mutated epitope, wherein if the mutation reduces binding of the test antibody compared to the non-mutated epitope, the test antibody is considered to bind to that epitope.

In some embodiments, methods are provided for inducing an immune response against a claudin 6 antigen, wherein the methods comprise administering the claudin 6 antigen to a subject under conditions sufficient to induce an immune response. In some embodiments, the claudin 6 antigen is delivered as a nucleic acid molecule encoding the claudin 6 antigen. As discussed herein, in some embodiments, the methods comprise administering to the subject a lipoparticle comprising the claudin 6 antigen to induce an immune response. In some embodiments, antibodies produced by the immune response are isolated. The antibodies can then be cloned, isolated, and/or otherwise modified as described herein. In some embodiments, the subject is a chicken.

In some embodiments of the methods provided herein, the antibody is any antibody or fragment thereof as provided herein.

In some embodiments, the antibody comprises a VH and VL sequence as shown in the following table:

ID Ab IM Vh V _L 136 AVTLDESGGGLQTPGGVLSLVCKASG FSFSSYDMGWVRQAPGKGLEWVASIY S S AS ST YYAP AVKGRATITRDNGQST V RLQLNNLRAEDTGTYYCAKAAGRTY RGWATYIADSIDAWGHGTEVIVSS (SEQ ID NO: 2) ALTQPSSVSANPGESVEITCSGDSSW YGYGWYQQKSPGSAPVTLIYESGKR PSDIPSRFSGSTSGSTATLTITGVQAD DEAVYYCGSADSNSIGIFGAGTTLTV L (SEQ ID NO: 3)

- 18 047986

171 AVTLDESGGGLQTPGGALSLVCKASG FDFSSYAMNWVRQAPGKGLEWVAGI GSTGSSTGYGPAVKGRATISRDNGQST LRLQLNNLRAEDTAIYYCAKSVGNGN SWSGYIATSIDAWGHGTEVIVSS (SEQ ID NO: 4) ALTQPSSVSANLGGTVKLTCSGGSSG YGWYQQKSPGSAPVTVIYSNDKRPS DIPSRFSGSLSGSTGTLTITGVQADDE AVYFCGSTDNSYVGIFGAGTTLTVL (SEQ ID NO: 5) 172 AVTLDESGGGLQTPGGALSLVCKGSG FSISSYTMQWVRQAPGKGLEWVAGIY SGSRTYYGAAVQGRATISRDNGQSTV RLQLNNLRAEDTGT YYC AKS S YCT A WTGCD VY AGGSID AWGHGTE VI VS S (SEQ ID NO: 6) ALTQPSSVSATPGGTVEITCSGDSSD DGSYYYGWYQQKSPGSAPVTVIYSN DKRPSSIPSRFSGSASGSTATLTITGV QADDEAVYFCGSYDSSTGIFGAGTTL TVL (SEQ ID NO: 7) 173 AVTLDESGGGLQTPGGALSLVCKASG FTFSSYSMFWVRRAPGKGLEWVAGID SGSTTFYGSAVKGRATISRDNGQSTVR LQLNNLRAEDTATYYCAKDAYGYCG WSGCSADSIDAWGHGTEVIVSS (SEQ ID NO: 8) ALTQPSSVSANPGGTVEITCSGGNNY YGWYQQKSPGSAPVTVIYYNDKRPS DIPSRFSGSKSGSTGTLTITGVQADDE AVYFCGGWDSSGGIFGAGTTLTVL (SEQ ID NO: 9) 179 EVQLLESGGGLVQPGGSLRLSCAASGF SFSSYDMGWVRQAPGKGLEWVASIYS SASSTYYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCAKAAGRTYR GWATYIADSIDAWGQGTLVTVSS (SEQ ID NO: 10) SYELTQPPSVSVSPGQTARITCSGDSS WYGYGWYQQKPGQAPVLVIYESGK RPSGIPERFSGSSSGTTTVTLTISGVQA EDEAD YYCGSADSNSIGIFGGGTKLT VL (SEQ ID NO: 11) 180 EVQLLESGGGLVQPGGSLRLSCAASGF DFSSYAMNWVRQAPGKGLEWVAGIG STGSSTGYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSVGNGN SWSGYIATSIDAWGQGTLVTVSS (SEQ ID NO: 12) SYELTQPPSVSVSPGQTARITCSGGSS GYGWYQQKPGQAPVLVIYSNDKRPS GIPERFSGS S SGTT VTLTISGVQAEDE ADYYCGSTDNSYVGIFGGGTKLTVL (SEQ ID NO: 13) 181 EVQLLESGGGLVQPGGSLRLSCAASGF SIS S YTMQWVRQ APGKGLEWVAGIYS GSRTYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDT AVYYC AKS S YCT AWT GCDVY AGGSID AWGQGTLVT VS S SYELTQPPSVSVSPGQTARITCSGDD GSYYYGWYQQKPGQAPVLVIYSND KRPSGIPERFSGSSSGTTTVTLTISGVQ AEDEADYYCGSYDSSTGIFGGGTKLT VL (SEQ ID NO: 15)

- 19 047986

(SEQ ID NO: 14) 182 EVQLLESGGGLVQPGGSLRLSCAASGF TFSSYSMFWVRQAPGKGLEWVAGIDS GSTTFYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCAKDAYGYCG WSGCSADSIDAWGQGTLVTVSS (SEQ ID NO: 16) SYELTQPPSVSVSPGQTARITCSGGN NYYGWYQQKPGQAPVLVIYYNDKR PSGIPERFSGSSSGTTVTLTISGVQAE DEADYYCGGWDSSGGIFGGGTKLTV L (SEQ ID NO: 17) 271 EVQLLESGGGLVQPGGSLRLSCAASGF TF S S YAMS WVRQ APGKGLEWV AGIS S SGRYTGYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSVGNGN SWSGYIATSIDAWGQGTLVTVSS (SEQ ID NO: 18) SYELTQPPSVSVSPGQTARITCSGGSG SYGWYQQKPGQAPVLVIYGTNKRPS GIPERFSGS S SGTT VTLTISGVQAEDE ADYYCGSADSSTNAGIFGGGTKLTV L (SEQ ID NO: 19) 272 EVQLLESGGGLVQPGGSLRLSCAASGF TF S SYAMNWVRQ APGKGLEWV AGIS S SGRYTGYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSVGNGN SWSGYIATSIDAWGQGTLVTVSS (SEQ ID NO: 20) SYELTQPPSVSVSPGQTARITCSGGSG SYGWYQQKPGQAPVTVIYGTNKRPS GIPERFSGS S SGTT VTLTISGVQAEDE ADYYCGSADSSTNAGIFGGGTKLTV L (SEQ ID NO: 21) CH- HAM F51HA Q EVQLLESGGGLVQPGGSLRLSCAASGF TF S S YAMS WVRQ APGKGLEWV AGIS S SGRYTGYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSVGNGN SWSGYVATSIDAWGQGTLVTVSS (SEQ ID NO: 103) SYELTQPPSVSVSPGQTARITCSGGSG SYGWYQQKPGQAPVLVIYGTNKRPS GIPERFSGS S SGTT VTLTISGVQAEDE ADYYCGSADSSTNAGIFGGGTKLTV L (SEQ ID NO: 104) CH- HAM F5- 1HBF EVQLLESGGGLVQPGGSLRLSCAASGF TF S SYAMNWVRQ APGKGLEWV AGIS S SGRYTGYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSVGSGV SWSGYVATSIDAWGQGTLVTVSS (SEQ ID NO: 105) SYELTQPPSVSVSPGQTARITCSAGSG LYGWYQQKPGQAPVLVIYGTNKRPS GIPERFSGS S SGTT VTLTISGVQAEDE ADYYCGSADSSTNAGIFGGGTKLTV L (SEQ ID NO: 106) CH- HAM F5- EVQLLESGGGLVQPGGSLRLSCAASGF TF S SYAMNWVRQ APGKGLEWV AGIS S SGRYTGYADSVKGRFTISRDNSKNTL SYELTQPPSVSVSPGQTARITCSAGSG LYGWYQQKPGQAPVLVIYGTNKRPS GIPERFSGS S SGTT VTLTISGVQAEDE

- 20 047986

NTV G YLQMNSLRAEDTAVYYCAKSMGSGV SWSGYVATSIDAWGQGTLVTVSS (SEQ ID NO: 107) ADYYCGSADSSTNAGIFGGGTKLTV L (SEQ ID NO: 108) CH- HAM F5- IHFJ EVQLLESGGGLVQPGGSLRLSCAASGF TF S S YAMNWVRQ APGKGLEWV AGIS S SGRYTGYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSMGSGV SWSGYVATSIDVWGQGTLVTVSS (SEQ ID NO: 109) SYELTQPPSVSVSPGQTARITCSAGSG LYGWYQQKPGQAPVLVIYGTNKRPS GIPERFSGS S SGTT VTLTISGVQAEDE ADYYCGSADSSTNAGIFGGGTKLTV L (SEQ ID NO: 110) CH- HAM F5- 1HEP EVQLLESGGGLVQPGGSLRLSCAASGF TF S S YAMNWVRQ APGKGLEWV AGIS S SGRYTGYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSVGSGV SWSGYVATSLD AWGQGTLVTVS S (SEQ ID NO: 111) SYELTQPPSVSVSPGQTARITCSAGSG LYGWYQQKPGQAPVLVIYGTNKRPS GIPERFSGS S SGTT VTLTISGVQAEDE ADYYCGSADSSTNAGIFGGGTKLTV L (SEQ ID NO: 112) CH- HAM F5- 1HFB EVQLLESGGGLVQPGGSLRLSCAASGF TF S S YAMNWVRQ APGKGLEWV AGIS S SGRYTGYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSMGSGV SWSGYVATSIDAWGQGTLVTVSS (SEQ ID NO: 113) SYELTQPPSVSVSPGQTARITCSGGSG SYGWYQQKPGQAPVLVIYGTYKRPS GIPERFSGS S SGTT VTLTISGVQAEDE ADYYCGSADSSTNAGIFGGGTKLTV L (SEQ ID NO: 114) CH- HAM F5- 1HH R EVQLLESGGGLVQPGGSLRLSCAASGF TF S S YAMNWVRQ APGKGLEWV AGIS S SGRYTGYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSMGSGV SWSGYVATSLD VWGQGTLVTVS S (SEQ ID NO: 115) SYELTQPPSVSVSPGQTARITCSGGSG SYGWYQQKPGQAPVLVIYGTYKRPS GIPERFSGS S SGTT VTLTISGVQAEDE ADYYCGSADSSTNAGIFGGGTKLTV L (SEQ ID NO: 116) CH- HAM F5- IHHP EVQLLESGGGLVQPGGSLRLSCAASGF TF S S YAMNWVRQ APGKGLEWV AGIS S SGRYTGYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSVGSGV SWSGYVATSLD VWGQGTLVTVS S (SEQ ID NO: 117) SYELTQPPSVSVSPGQTARITCSGGSG SYGWYQQKPGQAPVLVIYGTYKRPS GIPERFSGS S SGTT VTLTISGVQAEDE ADYYCGSADSSTNAGIFGGGTKLTV L (SEQ ID NO: 118) CH- EVQLLESGGGLVQPGGSLRLSCAASGF SYELTQPPSVSVSPGQTARITCSAGSG

- 21 047986

HAM F5- 1HG T TF S S YAMNWVRQ APGKGLEWV AGIS S SGRYTGYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKSVGSGV SWSGYVATSLDVWGQGTLVTVSS (SEQ ID NO: 119) LYGWYQQKPGQAPVLVIYGTNKRPS GIPERFSGS S SGTT VTLTISGVQAEDE ADYYCGSNDASTNAGIFGGGTKLTV L (SEQ ID NO: 120) 35- N1F0 9- 1HA EVQLLESGGGLVQPGGSLRLSCAASGF TFSSYGMSWVRQ APGKGLEWV AGIGS SGIYTHYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCAKSPGDSDW CGWAGYGIYSCRVAGFIDAWGQGTL VTVSS (SEQ ID NO: 121) SYELTQPPSVSVSPGQTARITCSGGY NGHYGWYQQKPGQAPVLVIYGTNK RPSGIPERFSGSSSGTTTVTLTISGVQA EDEAD YYCGGYDSSAGIFGGGTKLT VL (SEQ ID NO: 122) 35- N2H0 7- 1HA EVQLLESGGGLVQPGGSLRLSCAASGF TFSGYAMSWVRQAPGKGLEWVAGIY SSGSYTFYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKGTGYCD WSGWC YSGAANID AWGQGTLVT VS S (SEQ ID NO: 123) SYELTQPPSVSVSPGQTARITCSGGSG SYGYYGWYQQKPGQAPVLVIYGTN KRPSGIPERFSGSSSGTTTVTLTISGVQ AEDEAD YYCGSED S S SGAGIFGGGT KLTVL (SEQ ID NO: 124)

As provided herein, variants of any of the sequences described herein are also provided. For example, in some embodiments, peptides that are at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical are also provided. In some embodiments, a protein comprising a sequence that is at least or about 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such sequences disclosed herein. In some embodiments, the sequences or variants comprise 1, 2, 3, 4, 5, 6, 7, 8, or 9 substitutions compared to the sequences provided herein. In some embodiments, the substitution is a conservative substitution. In some embodiments, the mutation or substitution occurs in the framework region of the light chain or the heavy chain. In some embodiments, the substitution occurs in CDR regions, such as CDR1, CDR2, or CDR3. In some embodiments, the mutation or substitution is in CDR1 and not in CDR2 or CDR3. In some embodiments, the heavy chain contains substitutions or changes in the framework region and not in the CDR regions, as described herein. In some embodiments, heavy chain proteins are provided wherein the sequence is at least or about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 109, SEQ ID NO: 111, SEQ ID NO: 113, SEQ ID NO: 115, SEQ ID NO: 117, SEQ ID NO: 119, SEQ ID NO: 121, SEQ ID NO: 123, provided that the sequence comprises a first amino acid sequence or a first CDR selected from the group consisting of: SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, 95, 139, 141, 143 or 145; a second amino acid sequence or a second CDR selected from the group consisting of: 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101, 102, 140, 142, 144 or 146; and a third amino acid sequence or a third CDR selected from the group consisting of: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97. Thus, in some embodiments, the heavy chain CDRs are not variants of those provided herein.

In some embodiments, the antibody comprises a VH comprising the sequence of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 109, SEQ ID NO: 111, SEQ ID NO: 113, SEQ ID NO: 115, SEQ ID NO: 117, SEQ ID NO: 119, SEQ ID NO: 121, or SEQ ID NO: 123, or a variant thereof.

In some embodiments, light chain proteins are provided wherein the sequence is at least or about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122 or SEQ ID NO: 124, provided that the sequence comprises

- 22 047986 a first amino acid sequence or a first CDR selected from the group consisting of: SEQ ID NO: 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93 or 98; a second amino acid sequence or a second CDR selected from the group consisting of: 23, 29, 41, 51, 59, 68, 84, 88 or 99; and a third amino acid sequence or a third CDR selected from the group consisting of: 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, 94. Thus, in some embodiments, the heavy chain CDRs are not variants of those presented herein.

In some embodiments, the antibody comprises a VL comprising the sequence of SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122, or SEQ ID NO: 124, or a variant thereof.

In some embodiments, the antibody comprises a VH and VL chain comprising the sequence of SEQ ID NO: 2 and SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, SEQ ID NO: 16 and SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21, SEQ ID NO: 103 and SEQ ID NO: 104, SEQ ID NO: 105 and SEQ ID NO: 106, SEQ ID NO: 107 and SEQ ID NO: 108, SEQ ID NO: 109 and SEQ ID NO: 110, SEQ ID NO: 111 and SEQ ID NO: 112, SEQ ID NO: 113 and SEQ ID NO: 114, SEQ ID NO: 115 and SEQ ID NO: 116, SEQ ID NO: 117 and SEQ ID NO: 118, SEQ ID NO: 119 and SEQ ID NO: 120, SEQ ID NO: 121 and SEQ ID NO: 122 or SEQ ID NO: 123, and SEQ ID NO: 123.

In some embodiments, the sequence is at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% homologous or identical to a sequence provided herein, which includes the VH, VL, and/or CDR sequences provided herein. Sequences can also be a variant if they have 1, 2, 3, 4, 5, 6, 7, 8, or 9 substitutions, deletions, or insertions. In some embodiments, the substitution (mutation) is a conservative substitution.

In some embodiments, the CDRs of the peptides or antibodies are as follows:

ID # LCDR1 LCDR 2 LCDR3 HCDR1 HCDR2 HCDR3 13 6 CSGDSSWY GYG (SEQ ID NO: 22) IYESG KRP (SEQ ID NO: 23) CGSADSN SIGIF (SEQ ID NO: 24) GFSFSSY DMGWV (SEQ ID NO: 25) VASIYSSA SSTYYA (SEQ ID NO: 26) CAKAAGRTYRGW ATYIADSIDA (SEQ ID NO: 27) 17 1 CSGGSSGYG (SEQ ID NO: 28) IYSN DKRP (SEQ ID CGSTDNS YVGIF (SEQ ID NO: 30) GFDFSSY AMNWV (SEQ ID NO: 31) VAGIGSTG SSTGYG (SEQ ID NO: 32) CAKSVGNGNSWS GYIATSIDA (SEQ ID NO: 33)

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NO: 29) 17 2 CSGDSSDD GSYYYG (SEQ ID NO: 34) IYSN DKRP (SEQ ID NO: 29) CGSYDSS TGIF (SEQ ID NO: 36) GFSISSYT MQWV (SEQ ID NO: 37) VAGIYSGS RTYYG (SEQ ID NO: 38) CAKSSYCTAWTGC DVYAGGSIDA (SEQ ID NO: 39) 17 3 CSGGNNY YG (SEQ ID NO: 40) IYYN DKRP (SEQ ID NO: 41) CGGWDS SGGIF (SEQ ID NO: 42) GFTFSSYS MFWV (SEQ ID NO: 43) VAGIDSGS TTFYG (SEQ ID NO: 44) CAKDAYGYCGWS GCSADSIDA (SEQ ID NO: 45) 17 9 CSGDSSWY GYG (SEQ ID NO: 22) IYESG KRP (SEQ ID NO: 23) CGSADSN SIGIF (SEQ ID NO: 24) GFSFSSY DMGWV (SEQ ID NO: 25) VASIYSSA SSTYYA (SEQ ID NO: 26) CAKAAGRTYRGW ATYIADSIDA (SEQ ID NO: 27) 55 CSGGSSGYG (SEQ ID NO: 28) IYSN DKRP (SEQ ID NO: 29) CGSTDNS YVGIF (SEQ ID NO: 30) GFDFSSY AMNWV (SEQ ID NO: 31) VAGIGSTG SSTGYA (SEQ ID NO: 46) CAKSVGNGNSWS GYIATSIDA (SEQ ID NO: 33) 18 1 CSGDDGSY YYG (SEQ ID NO: 47) IYSN DKRP (SEQ ID NO: 29) CGSYDSS TGIF (SEQ ID NO: 36) GFSISSYT MQWV (SEQ ID NO: 37) VAGIYSGS RTYYA (SEQ ID NO: 48) CAKSSYCTAWTGC DVYAGGSIDA (SEQ ID NO: 39) 18 2 CSGGNNY YG (SEQ ID IYYN DKRP CGGWDS SGGIF GFTFSSYS MFWV VAGIDSGS TTFYA CAKDAYGYCGWS GCSADSIDA (SEQ

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NO: 40) (SEQ ID NO: 41) (SEQ ID NO: 42) (SEQ ID NO: 43) (SEQ ID NO: 49) ID NO: 45) 27 1 CSGGSGSYG (SEQ ID NO: 50) IYGT NKRP (SEQ ID NO: 51) CGSADSS TNAGIF (SEQ ID NO: 52) GFTFSSY AMSWV (SEQ ID NO: 53) VAGISSSG RYTGYA (SEQ ID NO: 54) CAKSVGNGNSWS GYIATSIDA (SEQ ID NO: 33) 27 2 CSGGSGSYG (SEQ ID NO: 50) IYGT NKRP (SEQ ID NO: 51) CGSADSS TNAGIF (SEQ ID NO: 52) GFTFSSY AMNWV (SEQ ID NO: 55) VAGISSSG RYTGYA (SEQ ID NO: 54) CAKSVGNGNSWS GYIATSIDA (SEQ ID NO: 33)

In some embodiments, the CDRs of the peptides or antibodies are as follows:

ID# HCD RI HCDR2 HCDR3 LCDR1 LCDR 2 LCDR3 VH- CH- HAM F5- 1HU SYA MS (SEQ ID NO: 56) GISSSGRYT GYADSVKG (SEQ ID NO: 125) SVGNGNSWSGYIATSI DA (SEQ ID NO: 57) SGGSGSYG (SEQ ID NO: 58) GTN KRPS (SEQ ID NO: 59) GSADSS TNAGI (SEQ ID NO: 60) VH- CH- HAM F51HA Q SYA MS (SEQ ID NO: 56) GISSSGRYT GYADSVKG (SEQ ID NO: 125) SVGNGNSWSGYVAT SID A (SEQ ID NO: 61) SGGSGSYG (SEQ ID NO: 58) GTN KRPS (SEQ ID NO: 59) GSADSS TNAGI (SEQ ID NO: 60) VH- SYA GISSSGRYT SVGSGVSWSGYVATS SAGSGLY GTN GSADSS

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CH- HAM F5- 1HBF MN (SEQ ID NO: 62) GYADSVKG (SEQ ID NO: 125) IDA (SEQ ID NO: 63) G (SEQ ID NO: 64) KRPS (SEQ ID NO: 59) TNAGI (SEQ ID NO: 60) VHCH- HAM F5- 1HB G SYA MN (SEQ ID NO: 62) GISSSGRYT GYADSVKG (SEQ ID NO: 125) SMGSGVSWSGYVAT SID A (SEQ ID NO: 65) SAGSGLYG (SEQ ID NO: 64) GTN KRPS (SEQ ID NO: 59) GSADSS TNAGI (SEQ ID NO: 60) VH- CH- HAM F5- IHFJ SYA MN (SEQ ID NO: 62) GISSSGRYT GYADSVKG (SEQ ID NO: 125) SMGSGVSWSGYVAT SIDV (SEQ ID NO: 66) SAGSGLYG (SEQ ID NO: 64) GTN KRPS (SEQ ID NO: 59) GSADSS TNAGI (SEQ ID NO: 60) VH- CH- HAM F5- 1HEP SYA MN (SEQ ID NO: 62) GISSSGRYT GYADSVKG (SEQ ID NO: 125) SVGSGVSWSGYVATS LDA (SEQ ID NO: 67) SAGSGLYG (SEQ ID NO: 64) GTN KRPS (SEQ ID NO: 59) GSADSS TNAGI (SEQ ID NO: 60) VH- CH- HAM F5- 1HFB SYA MN (SEQ ID NO: 62) GISSSGRYT GYADSVKG (SEQ ID NO: 125) SMGSGVSWSGYVAT SID A (SEQ ID NO: 65) SGGSGSYG (SEQ ID NO: 58) GTY KRPS (SEQ ID NO: 68) GSADSS TNAGI (SEQ ID NO: 60) VH- CH- HAM F5- 1HH R SYA MN (SEQ ID NO: 62) GISSSGRYT GYADSVKG (SEQ ID NO: 125) SMGSGVSWSGYVAT SLDV (SEQ ID NO: 126) SGGSGSYG (SEQ ID NO: 58) GTY KRPS (SEQ ID NO: 68) GSADSS TNAGI (SEQ ID NO: 60)

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VHснHAM F5- IHHP SYA MN (SEQ ID NO: 62) GISSSGRYT GYADSVKG (SEQ ID NO: 125) SVGSGVSWSGYVATS LDV (SEQ ID NO: 69) SGGSGSYG (SEQ ID NO: 58) GTY KRPS (SEQ ID NO: 68) GSADSS TNAGI (SEQ ID NO: 60) VH- CH- HAM F5- 1HGT SYA MN (SEQ ID NO: 62) GISSSGRYT GYADSVKG (SEQ ID NO: 125) SVGSGVSWSGYVATS LDV (SEQ ID NO: 69) SAGSGLYG (SEQ ID NO: 64) GTN KRPS (SEQ ID NO: 59) GSNDAS TNAGI (SEQ ID NO: 70) VH35N1F0 91HA SYG MS (SEQ ID NO: 71) GIGSSGIYTH YADSVKG (SEQ ID NO: 72) SPGDSDWCGWAGYG IYSCRVAGFIDA (SEQ ID NO: 73) SGGYNGH YG (SEQ ID NO: 74) GTN KRPS (SEQ ID NO: 59) GGYDSS AGI (SEQ ID NO: 75) VH35N2H0 71HA GYAMS (SEQ ID NO: 76) GIYSSGSYTF YADSVKG (SEQ ID NO: 77) GTGYCDWSGWCYSG AANIDA (SEQ ID NO: 78) SGGSGSYG (SEQ ID NO: 58) GTN KRPS (SEQ ID NO: 59) GSEDSS SGAGI (SEQ ID NO: 79) VH- 30- 08F12 -1CA SYD MG (SEQ ID NO: 80) SIYSSASSTY YAPAVKG (SEQ ID NO: 81) AAGRTYRGWATYIA DSIDA (SEQ ID NO: 82) SGDSSWYGYG (SEQ ID NO: 83) ESGK RPS (SEQ ID NO: 84) GSADSN SIGI (SEQ ID NO: 85) VH- 30- 18G0 1- 1CA SYA MN (SEQ ID NO: GIGSTGSST GYGPAVKG (SEQ ID NO: 86) SVGNGNSWSGYIATSI DA (SEQ ID NO: 57) SGGSSGYG (SEQ ID NO: 87) SNDK RPS (SEQ ID NO: GSTDNS YVGI (SEQ ID NO: 89)

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62) 88) VH- 30- 19B0 6- 1CA SYT MQ (SEQ ID NO: 90) GIYSGSRTY YGAAVQG (SEQ ID NO: 91) S S YCT AWTGCD VY A GGSIDA (SEQ ID NO: 92) SGDSSDD GSYYYG (SEQ ID NO: 93) SNDK RPS (SEQ ID NO: 88) GSYDSS TGI (SEQ ID NO: 94) VH- 30- 20D1 0- 1CA SYS MF (SEQ ID NO: 95) GIDSGSTTF YGSAVKG (SEQ ID NO: 96) DAYGYCGWSGCSAD SID A (SEQ ID NO: 97) SGGNNYYG (SEQ ID NO: 98) YND KRPS (SEQ ID NO: 99) GGWDS SGGI (SEQ ID NO: 100) VH- CHA MF51HQ SYA MN (SEQ ID NO: 62) GISSSGRYT GYADSVKG (SEQ ID NO: 101) SVGNGNSWSGYIATSI DA (SEQ ID NO: 57) SGGSGSYG (SEQ ID NO: 58) GTN KRPS (SEQ ID NO: 59) GSADSS TNAGI (SEQ ID NO: 60) 30- 18G0 1- 1HA SYA MN (SEQ ID NO: 62) GIGSTGSST GYADSVKG (SEQ ID NO: 102) SVGNGNSWSGYIATSI DA (SEQ ID NO: 57) SGGSSGYG (SEQ ID NO: 87) SNDK RPS (SEQ ID NO: 88) GSTDNS YVGI (SEQ ID NO: 89)

In some embodiments of the invention, the VH chain comprises one or more CDRs selected from the tables provided herein or from the group consisting of:

GFSFSSY (SEQ ID NO: 139); YSSASSTY (SEQ

ID NO: 140); AAGRTYRGWATYIADSIDA (SEQ ID NO: 82); GFDFSSY (SEQ ID NO: 141);

GSTGSS (SEQ ID NO: 142); SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); GFSISSY (SEQ

ID NO: 143); YSGSR (SEQ ID NO: 144); SSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 92);

GFTFSSY (SEQ ID NO: 145); DSGST (SEQ ID NO: 146); DAYGYCGWSGCSADSIDA (SEQ

ID NO: 97); CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23);

CGSADSNSIGIF (SEQ ID NO: 24); GFSFSSYDMGWV (SEQ ID NO: 25);

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VASIYSSASSTYYA (SEQ ID NO: 26); CAKAAGRTYRGWATYIADSIDA (SEQ ID NO: 27); CSGGSSGYG (SEQ ID NO: 28); IYSNDKRP (SEQ ID NO: 29); CGSTDNSYVGIF(SEQ ID NO: 30); GFDFSSYAMNWV (SEQ ID NO: 31); VAGIGSTGSSTGYG (SEQ ID NO: 32); CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); CSGDSSDDGSYYYG (SEQ ID NO: 34); IYSNDKRP (SEQ ID NO: 29); CGSYDSSTGIF (SEQ ID NO: 36); GFSISSYTMQWV (SEQ ID NO: 37); VAGIYSGSRTYYG (SEQ ID NO: 38); CAKSSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 39); CSGGNNYYG (SEQ ID NO: 40); IYYNDKRP (SEQ ID NO: 41); CGGWDSSGGIF (SEQ ID NO: 42); GFTFSSYSMFWV (SEQ ID NO: 43); VAGIDSGSTTFYG (SEQ ID NO: 44); CAKDAYGYCGWSGCSADSIDA (SEQ ID NO: 45); CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); CGSADSNSIGIF (SEQ ID NO: 24); GFSFSSYDMGWV (SEQ ID NO: 25); VASIYSSASSTYYA (SEQ ID NO: 26); CAKAAGRTYRGWATYIADSIDA (SEQ ID NO: 27); CSGGSSGYG (SEQ ID NO: 28); IYSNDKRP (SEQ ID NO: 29); CGSTDNSYVGIF(SEQ ID NO: 30); GFDFSSYAMNWV (SEQ ID NO: 31); VAGIGSTGSSTGYA (SEQ Ш NO: 46); CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); CSGDDGSYYYG (SEQ ID NO: 47); IYSNDKRP (SEQ ID NO: 29); CGSYDSSTGIF (SEQ ID NO: 36); GFSISSYTMQWV (SEQ ID NO: 37); VAGIYSGSRTYYA (SEQ ID NO: 48); CAKSSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 39); CSGGNNYYG (SEQ ID NO: 40); IYYNDKRP (SEQ ID NO: 41); CGGWDSSGGIF (SEQ ID NO: 42); GFTFSSYSMFWV (SEQ ID NO: 43); VAGIDSGSTTFYA (SEQ ID NO: 49); CAKDAYGYCGWSGCSADSIDA (SEQ ID NO: 45); CSGGSGSYG (SEQ ID NO: 50); IYGTNKRP (SEQ ID NO: 51); CGSADSSTNAGIF (SEQ ID NO: 52); GFTFSSYAMSWV (SEQ ID NO: 53); VAGISSSGRYTGYA (SEQ Ш NO: 54); CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); CSGGSGSYG (SEQ ID NO: 50); IYGTNKRP (SEQ ID NO: 51); CGSADSSTNAGIF (SEQ ID NO: 52); GFTFSSYAMNWV (SEQ ID NO: 55); VAGISSSGRYTGYA (SEQ ID NO: 54); CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33), SYAMS (SEQ ID NO: 56); GISSSGRYTGYADSVKG (SEQ ID NO: 101); SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); SVGNGNSWSGYVATSIDA (SEQ ID NO: 61); SYAMN (SEQ ID NO: 62); SVGSGVSWSGYVATSIDA (SEQ ID NO: 63); GISSSGRYTGYADSVKG (SEQ ID NO: 101); SMGSGVSWSGYVATSIDA (SEQ ID NO: 65); SMGSGVSWSGYVATSIDV (SEQ ID NO: 66); SVGSGVSWSGYVATSLDA (SEQ ID NO: 67); SMGSGVSWSGYVATSIDA (SEQ ID NO: 65); SMGSGVSWSGYVATSLDV (SEQ ID NO: 126); SVGSGVSWSGYVATSLDV (SEQ ID NO: 69); SVGSGVSWSGYVATSLDV (SEQ ID NO: 69); SYGMS (SEQ ID NO: 71); GIGSSGIYTHYADSVKG (SEQ ID NO: 72); SPGDSDWCGWAGYGIYSCRVAGFIDA (SEQ ID NO: 73); GYAMS (SEQ ID NO: 76); GIYSSGSYTFYADSVKG (SEQ ID NO: 77); GTGYCDWSGWCYSGAANIDA (SEQ ID NO: 78); SYDMG (SEQ ID NO: 80); SIYSSASSTYYAPAVKG (SEQ ID NO: 81); AAGRTYRGWATYIADSIDA (SEQ ID NO: 82); GIGSTGSSTGYGPAVKG (SEQ ID NO: 86); SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); SYTMQ (SEQ ID NO: 90); GIYSGSRTYYGAAVQG (SEQ ID NO: 91); SSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 92); SYSMF (SEQ ID NO: 95); GIDSGSTTFYGSAVKG (SEQ ID NO: 96); DAYGYCGWSGCSADSIDA (SEQ ID NO: 97); GISSSGRYTGYADSVKG (SEQ ID NO: 101); SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); GIGSTGSSTGYADSVKG (SEQ ID NO: 102) or SVGNGNSWSGYIATSIDA (SEQ ID NO: 57).

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In some embodiments, the VH consists of the CDRs:

1H. GFSFSSY (SEQ ID NO: 139); YSSASSTY (SEQ ID NO: 140); and AAGRTYRGWATYIADSIDA (SEQ ID NO: 82); or

2H. GFDFSSY (SEQ ID NO: 141); GSTGSS (SEQ ID NO: 142); and SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); or

3H. GFSISSY (SEQ ID NO: 143); YSGSR (SEQ ID NO: 144); and SSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 92); or

4H. GFTFSSY (SEQ ID NO: 145); DSGST (SEQ ID NO: 146); and DAYGYCGWSGCSADSIDA (SEQ ID NO: 97); or

5H. GFSFSSYDMGWV (SEQ ID NO: 25); VASIYSSASSTYYA (SEQ ID NO: 26); and CAAAGRTYRGWATYIADSIDA (SEQ ID NO: 27); or

6H. GFDFSSYAMNWV (SEQ ID NO: 31); VAGIGSTGSSTGYG (SEQ ID NO: 32); and CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); or

7H. GFSISSYTMQWV (SEQ ID NO: 37); VAGIYSGSRTYYG (SEQ ID NO: 38); and CAKSSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 39); or

8H. GFTFSSYSMFWV (SEQ ID NO: 43); VAGIDSGSTTFYG (SEQ

ID NO: 44); and CAKDAYGYCGWSGCSADSIDA (SEQ ID NO: 45); or

9H. GFSFSSYDMGWV (SEQ ID NO: 25); VASIYSSASSTYYA (SEQ ID NO: 26); and CAAAGRTYRGWATYIADSIDA (SEQ ID NO: 27); or

YN. GFDFSSYAMNWV (SEQ ID NO: 31); VAGIGSTGSSTGYA (SEQ ID NO: 46); and CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); or

11H. GFSISSYTMQWV (SEQ ID NO: 37); VAGIYSGSRTYYA (SEQ

ID NO: 48); and CAKSSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 39); or

12H. GFTFSSYSMFWV (SEQ ID NO: 43); VAGIDSGSTTFYA (SEQ

ID NO: 49); and CAKDAYGYCGWSGCSADSIDA (SEQ ID NO: 45); or

13H. GFTFSSYAMSWV (SEQ ID NO: 53); VAGISSSGRYTGYA (SEQ ID NO: 54); and CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); or

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14H. GFTFSSYAMNWV (SEQ ID NO: 55); VAGISSSGRYTGYA (SEQ ID NO: 54); and CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); or

15H. SYAMS (SEQ ID NO: 56); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); or

16H. SYAMS (SEQ ID NO: 56); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGNGNSWSGYVATSIDA (SEQ ID NO: 61); or

17H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGSGVSWSGYVATSIDA (SEQ ID NO: 63); or

18H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SMGSGVSWSGYVATSIDA (SEQ ID NO: 65); or

19H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SMGSGVSWSGYVATSIDV (SEQ ID NO: 66); or

20H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGSGVSWSGYVATSLDA (SEQ ID NO: 67); or

21H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SMGSGVSWSGYVATSIDA (SEQ ID NO: 65); or

22H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SMGSGVSWSGYVATSLDV (SEQ ID NO: 126); or

23H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGSGVSWSGYVATSLDV (SEQ ID NO: 69); or

24H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGSGVSWSGYVATSLDV (SEQ ID NO: 69); or

25H. SYGMS (SEQ ID NO: 71); GIGSSGIYTHYADSVKG (SEQ ID NO: 72); and SPGDSDWCGWAGYGIYSCRVAGFIDA (SEQ ID NO: 73); or

26H. GYAMS (SEQ ID NO: 76); GIYSSGSYTFYADSVKG (SEQ ID NO: 77); and GTGYCDWSGWCYSGAANIDA (SEQ ID NO: 78); or

27H. SYDMG (SEQ ID NO: 80); SIYSSASSTYYAPAVKG (SEQ ID NO: 81); and AAGRTYRGWATYIADSIDA (SEQ ID NO: 82); or

28H. SYAMN (SEQ ID NO: 62); GIGSTGSSTGYGPAVKG (SEQ ID NO: 86); and SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); or

29H. SYTMQ (SEQ ID NO: 90); GIYSGSRTYYGAAVQG (SEQ ID NO: 91); and SSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 92); or

ZON. SYSMF (SEQ ID NO: 95); GIDSGSTTFYGSAVKG (SEQ ID NO: 96); and DAYGYCGWSGCSADSIDA (SEQ ID NO: 97); or

31H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); or

32H. SYAMN (SEQ ID NO: 62); GIGSTGSSTGYADSVKG (SEQ ID NO: 102); and SVGNGNSWSGYIATSIDA (SEQ ID NO: 57).

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In some embodiments, the antibody comprises a VL comprising the sequence:

ID Ab IM V _L 136 ALTQPSSVSANPGESVEITCSGDSSWYGYGWYQQKSPGSAPVTLIYESGK RPSDIPSRFSGSTSGSTATLTITGVQADDEAVYYCGSADSNSIGIFGAGTTL TVL (SEQ ID NO: 3) 171 ALTQPSSVSANLGGTVKLTCSGGSSGYGWYQQKSPGSAPVTVIYSNDKR PSDIPSRFSGSLSGSTGTLTITGVQADDEAVYFCGSTDNSYVGIFGAGTTLT VL (SEQ ID NO: 5) 172 ALTQPSSVSATPGGTVEITCSGDSSDDGSYYYGWYQQKSPGSAPVTVIYS NDKRPSSIPSRFSGSASGSTATLTITGVQADDEAVYFCGSYDSSTGIFGAGT TLTVL (SEQ ID NO: 7) 173 ALTQPSSVSANPGGTVEITCSGGNNYYGWYQQKSPGSAPVTVIYYNDKR PSDIPSRFSGSKSGSTGTLTITGVQADDEAVYFCGGWDSSGGIFGAGTTLT VL (SEQ ID NO: 9) 179 SYELTQPPSVSVSPGQTARITCSGDSSWYGYGWYQQKPGQAPVLVIYESG KRPSGIPERFSGSSSGTTTVTLTISGVQAEDEADYYCGSADSNSIGIFGGGTK LTVL (SEQ ID NO: 11) 180 SYELTQPPSVSVSPGQTARITCSGGSSGYGWYQQKPGQAPVLVIYSNDKR PSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCGSTDNSYVGIFGGGTKL TVL (SEQ ID NO: 13) 181 SYELTQPPSVSVSPGQTARITCSGDDGSYYYGWYQQKPGQAPVLVIYSND KRPSGIPERFSGSSSGTTTVTLTISGVQAEDEADYYCGSYDSSTGIFGGGTKL TVL (SEQ ID NO: 15) 182 SYELTQPPSVSVSPGQTARITCSGGNNYYGWYQQKPGQAPVLVIYYNDK RPSGIPERFSGS S SGTT VTLTISGVQAEDEAD YYCGGWD S SGGIFGGGTKL TVL (SEQ ID NO: 17) 271 SYELTQPPSVSVSPGQTARITCSGGSGSYGWYQQKPGQAPVLVIYGTNKR PSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCGSADSSTNAGIFGGGTK

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LTVL (SEQ ID NO: 19) 272 SYELTQPPSVSVSPGQTARITCSGGSGSYGWYQQKPGQAPVTVIYGTNKR PSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCGSADSSTNAGIFGGGTK LTVL (SEQ ID NO: 21) CH- HAMF 5- 1HAQ SYELTQPPSVSVSPGQTARITCSGGSGSYGWYQQKPGQAPVLVIYGTNKR PSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCGSADSSTNAGIFGGGTK LTVL (SEQ ID NO: 104) CH- HAMF 5- 1HBF SYELTQPPSVSVSPGQTARITCSAGSGLYGWYQQKPGQAPVLVIYGTNKR PSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCGSADSSTNAGIFGGGTK LTVL (SEQ ID NO: 106) CH- HAMF 5- IHBG SYELTQPPSVSVSPGQTARITCSAGSGLYGWYQQKPGQAPVLVIYGTNKR PSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCGSADSSTNAGIFGGGTK LTVL (SEQ ID NO: 108) CH- HAMF 5- IHFJ SYELTQPPSVSVSPGQTARITCSAGSGLYGWYQQKPGQAPVLVIYGTNKR PSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCGSADSSTNAGIFGGGTK LTVL (SEQ ID NO: 110) CH- HAMF 5- 1HEP SYELTQPPSVSVSPGQTARITCSAGSGLYGWYQQKPGQAPVLVIYGTNKR PSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCGSADSSTNAGIFGGGTK LTVL (SEQ ID NO: 112) CH- HAMF 5- 1HFB SYELTQPPSVSVSPGQTARITCSGGSGSYGWYQQKPGQAPVLVIYGTYKR PSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCGSADSSTNAGIFGGGTK LTVL (SEQ ID NO: 114) CH- HAMF 5- 1HHR SYELTQPPSVSVSPGQTARITCSGGSGSYGWYQQKPGQAPVLVIYGTYKR PSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCGSADSSTNAGIFGGGTK LTVL (SEQ ID NO: 116) CH- HAMF SYELTQPPSVSVSPGQTARITCSGGSGSYGWYQQKPGQAPVLVIYGTYKR PSGIPERFSGSSSGTTVTLTISGVQAEDEADYYCGSADSSTNAGIFGGGTK

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5- IHHP LTVL (SEQ ID NO: 118) sn- SYELTQPPSVSVSPGQTARITCSAGSGLYGWYQQKPGQAPVLVIYGTNKR HAMF PSGIPERFSGSSSGTTTVTLTISGVQAEDEADYYCGSNDASTNAGIFGGGTK 5- LTVL (SEQ ID NO: 120) 1HGT 35- SYELTQPPSVSVSPGQTARITCSGGYNGHYGWYQQKPGQAPVLVIYGTN N1F09 KRPSGIPERFSGSSSGTTTVTLTISGVQAEDEADYYCGGYDSSAGIFGGGTK -1NA LTVL (SEQ ID NO: 122) 35- SYELTQPPSVSVSPGQTARITCSGGSGSYGYYGWYQQKPGQAPVLVIYGT N2H0 NKRPSGIPERFSGS S SGTT VTLTISGVQAEDEAD YYCGSEDS S SGAGIFGG 7-1NA GTKLTVL (SEQ ID NO: 124)

In some embodiments, the VL comprises the sequence:

ID Sequence Vl F10-VL ALTQPSSVSANPGETVKITCSGGYNGHYGWYQQKSPGSAPVTVIYSNN QRPSNIPSRFSGSTSGSSTTLTITGVRAEDEAVYFCGGYDSSAGIFGAGTT LTVL (SEQ ID NO: 127) FlOh-VL SYELTQPPSVSVSPGQTARITCSGGYNGHYGWYQQKPGQAPVLVIYSN NQRPSGIPERFSGSSSGTTTVTLTISGVQAEDEADYYCGGYDSSAGIFGGG TKLTVL (SEQ ID NO: 128) B9-VL ALTQPSSVSANPGETVKITCSGGGSSNYYGWYQQKSPGSAPVTLIYGTN KRPSDIPSRFSKSGSTGTLTITGVQADDEAVYFCGSADSSTNAGIFGA GTTLTVL (SEQ ID NO: 129) B9h-VL SYELTQPPSVSVSPGQTARITCSGGGSSNYAGWYGYYQQKPGQAPVTVI YGTNKRPSGIPERFSGSSGTTVTLTISGVQAEDEAVYYCGSADSSTNAG IFGAGTKLTVL (SEQ ID NO: 130) N6-G3 SYELTQPPSVSVSPGQTARITCSGGSGSYGYYGWYQQKPGQAPVLVIYG TNKRPSGIPERFSGSSSGTTTVTLTISGVQAEDEADYYCGSTDSNYVGIFG GGTKLTVL (SEQ ID NO: 131) N6-C5 SYELTQPPSVSVSPGQTARITCSGGYNGHYGWYQQKPGQAPVLVIYSN NQRPSGIPERFSGSSSGTTTVTLTISGVQAEDEADYYCGNADSNYVGIFGG GTKLTVL (SEQ ID NO: 132) N6-F11 SYELTQPPSVSVSPGQTARITCSGGGSSNYYGWYQQKPGQAPVLVIYSN NQRPSGIPERFSGSSSGTTTVTLTISGVQAEDEADYYCGSADSSTNAGIFG GGTKLTVL (SEQ ID NO: 133) N5-B4 SYELTQPPSVSVSPGQTARITCSGGSGSYGYYGWYQQKPGQAPVLVIYS NNQRPSGIPERFSGSSSGTTTVTLTISGVQAEDEADYYCGSADSSTNAGIF GGGTKLTVL (SEQ ID NO: 134) N5-B7 SYELTQPPSVSVSPGQTARITCSGGSGSYGYYGWYQQKPGQAPVLVIYG TNKRPSGIPERFSGSSSGTTTVTLTISGVQAEDEADYYCGSADSSTNAGIF GGGTKLTVL (SEQ ID NO: 135)

A VL sequence may contain a VL sequence, a CDR, a set of CDRs, or a set of FWs,

- 34,047,986, or any combination thereof, as provided in PCT Application No. PCT/US2020/018026, filed February 13, 2020, and/or U.S. Application No. 16/789,626, filed February 13, 2020, each of which is incorporated by reference in its entirety.

In some embodiments, any of the VH, or a VH comprising one or more (e.g., 3) CDRs, as provided herein, can be combined with any of the VLs provided herein. As shown herein, the VLs can be swapped and the antibodies are still capable of binding to claudin 6. In some embodiments, the V _H is combined with one of F10-VL; 2. F10h-VL; 3. B9-VL; or B9h-VL.

In some embodiments, the sequence is at least 80, 85, 90, 95, 96, 97, 98, or 99% homologous or identical to a sequence provided herein, which includes VH, VL, and CDR sequences. In some embodiments, the VL chain comprises one or more CDRs selected from the group consisting of:

SGDSSWYGYG (SEQ ID NO: 83);

ESGKRPS (SEQ ID NO: 84); GSADSNSIGI (SEQ ID NO: 85); SGGSSGYG (SEQ ID NO: 87); SNDKRPS(SEQ ID NO: 88); GSTDNSYVGI (SEQ ID NO: 89); SGDSSDDGSYYYG (SEQ ID NO: 93); SNDKRPS(SEQ ID NO: 88); GSYDSSTGI (SEQ ID NO: 94); SGGNNYYG (SEQ ID NO: 98); YNDKRPS (SEQ ID NO: 99); GGWDSSGGI (SEQ ID NO: 100), CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); CGSADSNSIGIF (SEQ ID NO: 24); CSGGSSGYG (SEQ ID NO: 28); IYSNDKRP (SEQ ID NO: 29); CGSTDNSYVGIF(SEQ ID NO: 30); CSGDSSDDGSYYYG (SEQ ID NO: 34); IYSNDKRP (SEQ ID NO: 29); CGSYDSSTGIF (SEQ ID NO: 36); CSGGNNYYG (SEQ ID NO: 40);

IYYNDKRP (SEQ ID NO: 41); CGGWDSSGGIF (SEQ ID NO: 42); CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); CGSADSNSIGIF (SEQ ID NO: 24); CSGGSSGYG (SEQ ID NO: 28); IYSNDKRP (SEQ ID NO: 29); CGSTDNSYVGIF(SEQ ID NO: 30); CSGDDGSYYYG (SEQ ID NO: 47); IYSNDKRP (SEQ ID NO: 29); CGSYDSSTGIF (SEQ ID NO: 36); CSGGNNYYG (SEQ ID NO: 40); IYYNDKRP (SEQ ID NO: 41); CGGWDSSGGIF (SEQ ID NO: 42); CSGGSGSYG (SEQ ID NO: 50); IYGTNKRP (SEQ ID NO: 51); CGSADSSTNAGIF (SEQ ID NO: 52); CSGGSGSYG (SEQ ID NO: 50); IYGTNKRP (SEQ ID NO: 51); and CGSADSSTNAGIF (SEQ ID NO: 52); SGGSGSYG (SEQ ID NO: 58); GTNKRPS (SEQ ID NO: 59); GSADSSTNAGI (SEQ ID NO: 60); SAGSGLYG (SEQ ID NO: 64); GTYKRPS(SEQ ID NO: 68); GSNDASTNAGI (SEQ ID NO: 70); SGGYNGHYG (SEQ ID NO: 74); GGYDSSAGI (SEQ ID NO: 75); SGGSGSYGYYG; or GSEDSSSGAGI (SEQ ID NO: 79).

- 35 047986

In some embodiments, the VL contains the CDR:

IL. SGDSSWYGYG (SEQ ID NO: 83); ESGKRPS (SEQ ID NO: 84); and GSADSNSIGI (SEQ ID NO: 85); or

2L. SGGSSGYG (SEQ ID NO: 87); SNDKRPS(SEQ ID NO: 88); and GSTDNSYVGI (SEQ ID NO: 89); or

3L. SGDSSDDGSYYYG (SEQ ID NO: 93); SNDKRPS(SEQ ID NO: 88); and GSYDSSTGI (SEQ ID NO: 94); or

4L. SGGNNYYG (SEQ ID NO: 98); YNDKRPS (SEQ ID NO: 99); and GGWDSSGGI (SEQ ID NO: 100); or

5L. CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); and CGSADSNSIGIF (SEQ ID NO: 24); or

6L. CSGGSSGYG (SEQ ID NO: 28); IYSNDKRP (SEQ ID NO: 29); and CGSTDNSYVGIF (SEQ ID NO: 30); or

7L. CSGDSSDDGSYYYG (SEQ ID NO: 34); IYSNDKRP (SEQ ID NO: 29); and CGSYDSSTGIF (SEQ ID NO: 36); or

8L. CSGGNNYYG (SEQ ID NO: 40); IYYNDKRP (SEQ ID NO: 41); and CGGWDSSGGIF (SEQ ID NO: 42); or

9L. CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); and CGSADSNSIGIF (SEQ ID NO: 24); or

10L. CSGGSSGYG (SEQ ID NO: 28); IYSNDKRP (SEQ ID NO: 29); and CGSTDNSYVGIF (SEQ ID NO: 30); or

11L. CSGDDGSYYYG (SEQ ID NO: 47); IYSNDKRP (SEQ ID NO: 29); and CGSYDSSTGIF (SEQ ID NO: 36); or

12L. CSGGNNYYG (SEQ ID NO: 40); IYYNDKRP (SEQ ID NO: 41); and CGGWDSSGGIF (SEQ ID NO: 42); or

- 36 047986

13L. CSGGSGSYG (SEQ ID NO: 50); IYGTNKRP (SEQ ID NO: 51); and CGSADSSTNAGIF (SEQ ID NO: 52); or

14L. CSGGSGSYG (SEQ ID NO: 50); IYGTNKRP (SEQ ID NO: 51); and CGSADSSTNAGIF (SEQ ID NO: 52);

15L. SGGSGSYG (SEQ ID NO: 58); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

16L. SGGSGSYG (SEQ ID NO: 58); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

17L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

18L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

19L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

20L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

21L. SGGSGSYG (SEQ ID NO: 58); GTYKRPS(SEQ ID NO: 68); and GSADSSTNAGI (SEQ ID NO: 60); or

22L. SGGSGSYG (SEQ ID NO: 58); GTYKRPS(SEQ ID NO: 68); and GSADSSTNAGI (SEQ ID NO: 60); or

23L. SGGSGSYG (SEQ ID NO: 58); GTYKRPS(SEQ ID NO: 68); and GSADSSTNAGI (SEQ ID NO: 60); or

24L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); and GSNDASTNAGI (SEQ ID NO: 70); or

25L. SGGYNGHYG (SEQ ID NO: 74); GTNKRPS (SEQ ID NO: 59);

and GGYDSSAGI (SEQ ID NO: 75); or

26L. SGGSGSYGYYG; GTNKRPS (SEQ ID NO: 59); and GSEDSSSGAGI (SEQ ID NO: 79); or

27L. SGDSSWYGYG (SEQ ID NO: 83); ESGKRPS (SEQ ID NO: 84);

and GSADSNSIGI (SEQ ID NO: 85); or

28L. SGGSSGYG (SEQ ID NO: 87); SNDKRPS (SEQ ID NO: 88); and GSTDNSYVGI (SEQ ID NO: 89); or

29L. SGDSSDDGSYYYG (SEQ ID NO: 93); SNDKRPS (SEQ ID NO:

88); and GSYDSSTGI (SEQ ID NO: 94); or

30L. SGGNNYYG (SEQ ID NO: 98); YNDKRPS (SEQ ID NO: 99); and GGWDSSGGI (SEQ ID NO: 100); or

31L. SGGSGSYG (SEQ ID NO: 58); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

32L. SGGSSGYG (SEQ ID NO: 87); SNDKRPS(SEQ ID NO: 88); and GSTDNSYVGI (SEQ ID NO: 89).

In some embodiments, the antibody comprises CDRs selected from

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1H and IL, 1H and 2L, 1H and 3L, 1H and 4L, 1H and 5L, 1H and 6L, 1H and 7L, 1H and 8L, 1H and 9L, 1H and 10L, 1H and 11L, 1H and 12L, 1H and 13L, 1H and 14L, 1H and 15L, 1H and 16L, 1H and 17L, 1H and 18L, 1H and 19L, 1H and 20L, 1H and 2IL, 1H and 22L, 1H and 23L, 1H and 24L, 1H and 25L, 1H and 26L, 1H and 27L, 1H and 28L, 1H and 29L, 1H and 30L, 1H and 31L, 1H and 32L, 2H and IL, 2H and 2L, 2H and 3L, 2H and 4L, 2H and 5L, 2H and 6L, 2H and 7L, 2H and 8L, 2H and 9L, 2H and 10L, 2H and 11L, 2H and 12L, 2H and 13L, 2H and 14L, 2H and 15L, 2H and 16L, 2H and 17L, 2H and 18L, 2H and 19L, 2H and 20L, 2H and 21L, 2H and 22L, 2H and 23L, 2H and 24L, 2H and 25L, 2H and 26L, 2H and 27L, 2H and 28L, 2H and 29L, 2H and 30L, 2H and 3 IL, 2H and 32L, 3H and IL, 3H and 2L, 3H and 3L, 3H and 4L, 3H and 5L , ZN and 6L, ZN and 7L, ZN and 8L, ZN and 9L, ZN and 10L, ZN and 11L, ZN and 12L, ZN and 13L, ZN and 14L, ZN and 15L, ZN and 16L, ZN and 17L, ZN and 18L, ЗН and 19L, ЗН and 20L, ЗН and 21L, ЗН and 22L, ЗН and 23L, ЗН and 24L, ZN and 25L, ZN and 26L, ZN and 27L, ZN and 28L, ZN and 29L, ZN and 30L, ZN and 31L, ZN and 32L, 4N and IL, 4N and 2L, 4N and 3L, 4N and 4L, 4H and 5L, 4H and 6L, 4H and 7L, 4H and 8L, 4H and 9L, 4H and 10L, 4H and 11L, 4H and 12L, 4H and 13L, 4H and 14L, 4H and 15L, 4H and 16L, 4H and 17L, 4H and 18L, 4H and 19L, 4H and 20L, 4H and 21L, 4H and 22L, 4H and 23L, 4H and 24L, 4H and 25L, 4H and 26L, 4H and 27L, 4H and 28L, 4H and 29L, 4H and 30L, 4H and 3 IL, 4H and 32L, 5H and IL , 5H and 2L, 5H and 3L, 5H and 4L, 5H and 5L, 5H and 6L, 5H and 7L, 5H and 8L, 5H and 9L, 5H and 10L, 5H and 1 IL, 5H and 12L, 5H and 13L, 5H and 14L, 5H and 15L, 5H and 16L, 5H and 17L, 5H and 18L, 5H and 19L, 5H and 20L, 5H and 21L, 5H and 22L, 5H and 23L, 5H and 24L, 5H and 25L, 5H and 26L, 5H and 27L, 5H and 28L, 5H and 29L, 5H and 30L, 5H and 31L, 5H and 32L, 6H and IL, 6H and 2L, 6H and 3L, 6H and 4L, 6H and 5L, 6H and 6L, 6H and 7L, 6H and 8L, 6H and 9L, 6H and 10L, 6H and 11L, 6H and 12L, 6H and 13L, 6H and 14L, 6H and 15L, 6H and 16L, 6H and 17L, 6H and 18L, 6H and 19L, 6H and 20L, 6H and 21L, 6H and 22L, 6H and 23L, 6H and 24L, 6H and 25L, 6H and 26L, 6H and 27L, 6H and 28L, 6H and 29L, 6H and 30L, 6H and 3 IL, 6H and 32L, 7H and IL, 7H and 2L, 7H and 3L, 7H and 4L, 7H and 5L, 7H and 6L, 7H and 7L, 7H and 8L, 7H and 9L, 7H and 10L, 7H and 1 IL, 7H and 12L, 7H and 13L, 7H and 14L, 7H and 15L, 7H and 16L, 7H and 17L, 7H and 18L, 7H and 19L, 7H and 20L, 7H and 21L , 7H and 22L, 7H and 23L, 7H and 24L, 7H and 25L, 7H and 26L, 7H and 27L, 7H and 28L, 7H and 29L, 7H and 30L, 7H and 31L, 7H and 32L, 8H and IL, 8H and 2L, 8H and 3L, 8H and 4L, 8H and 5L, 8H and 6L, 8H and 7L, 8H and 8L, 8H and 9L, 8H and 10L, 8H and 11L, 8H and 12L, 8H and 13L, 8H and 14L, 8H and 15L, 8H and 16L, 8H and 17L, 8H and 18L, 8H and 19L, 8H and 20L, 8H and 21L, 8H and 22L, 8H and 23L, 8H and 24L, 8H and 25L, 8H and 26L, 8H and 27L, 8H and 28L, 8H and 29L, 8H and 30L, 8H and 3 IL, 8H and 32L, 9H and IL, 9H and 2L, 9H and 3L, 9H and

- 38 047986

4L, 9H and 5L, 9H and 6L, 9H and 7L, 9H and 8L, 9H and 9L, 9H and 10L, 9H and 1 IL, 9H and 12L, 9H and 13L, 9H and 14L, 9H and 15L, 9H and 16L , 9Н and 17L, 9Н and 18L, 9Н and 19L, 9Н and 20L, 9Н and 21L, 9Н and 22L, 9Н and 23L, 9Н and 24L, 9Н and 25L, 9Н and 26L, 9Н and 27L, 9Н and 28L, 9Н and 29L, 9H and 30L, 9H and 31L, 9N and 32L, YN and IL, YN and 2L, YN and 3L, YN and 4L, YN and 5L, YN and 6L, YN and 7L, YN and 8L, YN and 9L, YN and 10L, YN and 11L, YN and 12L, YN and 13L, YN and 14L, YN and 15L, YN and 16L, YN and 17L, YN and 18L, YN and 19L, YN and 20L, YN and 21L, YN and 22L, YN and 23L, YN and 24L, YN and 25L, YN and 26L, YN and 27L, YN and 28L, YN and 29L, YN and 30L, YN and 31L, YN and 32L, 11H and IL, 11H and 2L, 11H and 3L, 11H and 4L, 11H and 5L, 11H and 6L, 11H and 7L, 11H and 8L, IN and 9L, IN and 10L, IN and 11L, IN and 12L, IN and 13L, IN and 14L, IN and 15L, IN and 16L, IN and 17L, IN and 18L, IN and 19L, 11Hh20L, 11Hh21L, 11Hh22L, 11Hh23L, IN and 24L, 11Hh25L, 6L, 11Hh27L, 11Hh28L, 11Hh29L, INiZOb, 11Hh31L, INi 32L, 12H and IL, 12H and 2L, 12H and 3L, 12H and 4L, 12H and 5L, 12H and 6L, 12H and 7L, 12H and 8L, 12H and 9L, and 10L , 12Н and 11L, 12Н and 12L, 12Н and 13L, 12Н and 14L, 12Н and 15L, 12Н and 16L, 12Н and 17L, 12Н and 18L, 12Н and 19L, 12Н and 20L, 12Н and 21L, 12Н and 22L, 12Н and 23L, 12Н and 24L, 12Н and 25L, 12Н and 26L, 12Н and 27L, 12Н and 28L, 12Н and 29L, 12Н and 30L, 12Н and 31L, 12Н and 32L, 13Н and IL, 13Н and 2L . 13Ni 16L, 13Ni 17L, 13Н and 18L, 13Н and 19L, 13Н and 20L, 13Н and 21L, 13Н and 22L, 13Н and 23L, 13Н and 24L, 13Н and 25L, 13Н and 26L, 13Hh27L, 8L, 13Hh29L, 13Hh30L, 13Hh31L, 13Hh32L, 14H and IL, 14H and 2L, 14H and 3L, 14H and 4L, 14H and 5L, 14H and 6L, 14H and 7L, 14H and 8L, 14H and 9L, 14Н and 10L, 14Н and 11L, 14Н and 12L, 14Н and 13L, 14Н and 14L, 14Н and 15L, 14Н and 16L, 14Н and 17L, 14Н and 18L, 14Н and 19L, 14Н and 20L, 14Н and 14, N and 22L, 14Н and 23L, 14Н and 24L, 14Н and 25L, 14Н and 26L, 14Н and 27L, 14Н and 28L, 14Н and 29L, 14Н and 30L, 14Н and 31L, 14Н and 32L, 15Н and IL, 15Н and 2L, 15H and 3L, 15H and 4L, 15H and 5L, 15H and 6L, 15H and 7L, 15H and 8L, 15H and 9L, 15H and 10L, 15H and 11L, 15H and 12L, 15H and 13L, 15H and 14L, 15Н and 15L, 15Н and 16L, 15Н and 17L, 15Н and 18L, 15Н and 19L, 15Н and 20L, 15Н and 21L, 15Н and 22L, 15Н and 23L, 15Н and 24L, 15Н and 25L, 15Н and 26L, N and 27L, 15H and 28L, 15H and 29L, 15H and 30L, 15H and 31L, 15H and 32L, 16H and IL, 16H and 2L, 16H and 3L, 16H and 4L, 16H and 5L, 16H and 6L, 16H and 7L, 16Н and 8L, 16Н and 9L, 16Н and 10L, 16Н and 1 IL, 16Н and 12L, 16Н and 13L, 16Н and 14L, 16Н and 15L, 16Н and 16L, 16Н and 17L, 16Н and 18L, 16Н and 19L, 16Н and 20L, 16Н and 21L, 16Н and 22L, 16Н and 23L, 16Н and 24L, 16Н and 25L, 16Н and 26L, 16Н and 27L, 16Н and 28L, 16Н and 29L, 16Н and 30L, 16Н and 31L, 16Н and 32L, N and IL, 17Н and 2L, 17Н and 3L, 17Н and 4L, 17Н and 5L, 17Н and 6L, 17Н and 7L, 17Н and 8L, 17Н and 9L, 17Н and 10L, 17Н and 1 IL, 17Н and 12L, 17Н and 13L , 17N and 14L, 17Н and 15L, 17Н and 16L, 17Н and 17L, 17Н and 18L, 17Н and 19L, 17Н and 20L, 17Н and 21L, 17Н and 22L, 17Н and 23L, 17Н and 24L, 17Н and 25L, 17Н and 26 L, 17Н and 27L, 17Н and 28L, 17Н and 29L, 17Н and 30L, 17Н and 31L, 17Н and 32L, 18Н and IL, 18Н and 2L, 18Н and 3L, 18Н and 4L, 18Н and 5L,

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18Hh6L, 18Hh7L, 18Hh8L, 18Hh9L, 18Ni 10L, 18Ni 11L, 18Ni 12L, 18Ni 13L, 18H and 14L, 18H and 15L, 18H and 16L, 18H and 17L, 18H and 18L, 18H and 19L, 18H and 20L, 18H and 21L, 18Н and 22L, 18Н and 23L, 18Н and 24L, 18Н and 25L, 18Н and 26L, 18Н and 27L, 18Н and 28L, 18Н and 29L, 18Н and 30L, 18Н and 31L, 18Н and 32L, 19Н and IL, 19Н and 2L, 19Н and 3L, 19Н and 4L, 19Н and 5L, 19Н and 6L, 19Н and 7L, 19Н and 8L, 19Н and 9L, 19Н and 10L, 19Н and 11L, 19Н and 12L, 19Н and 13L, 19Н and 14L, 19Н and 15L, 19Н and 16L, 19Н and 17L, 19Н and 18L, 19Н and 19L, 19Н and 20L, 19Н and 21L, 19Н and 22L, 19Н and 23 L, 19N and 24L, 19Н and 25L, 19Н and 26L, 19Н and 27L, 19Н and 28L, 19Н and 29L, 19Н and 30L, 19Н and 3 IL, 19Н and 32L, 20Н and IL, 20Н and 2L, 20Н and 3L, 20Н and 4L . and 17L, 20Н and 18L, 20Н and 19L, 20Н and 20L, 20Н and 21L, 20Н and 22L, 20Н and 23L, 20Н and 24L, 20Н and 25L, 20Н and 26L, 20Н and 27L, 20Н and 28L, 20Н and 29L, N and 30L, 20Н and 31L, 20Н and 32L, 21Н and IL, 21Н and 2L, 21Н and 3L, 21Н and 4L, 21Н and 5L, 21Н and 6L, 21Н and 7L, 21Н and 8L, 21Н and 9L, 21Н and 10L, 21N and 11L, 21Н and 12L, 21Н and 13L, 21Н and 14L, 21Н and 15L, 21Н and 16L, 21Н and 17L, 21Н and 18L, 21Н and 19L, 21Н and 20L, 21Н and 21L, 21Н and 22L, 21Н and 23 L, 21Н and 24L, 21Н and 25L, 21Н and 26L, 21Н and 27L, 21Н and 28L, 21Н and 29L, 21Н and 30L, 21Н and 31L, 21Н and 32L, 22Н and IL, 22Н and 2L, 22Н and 3L, 22Н and 4L, 22H and 5L, 22H and 6L, 22H and 7L, 22H and 8L, 22H and 9L, 22H and 10L, 22H and 11L, 22H and 12L, 22H and 13L, 22H and 14L, 22H and 15L, 22H and 16L, 22Н and 17L, 22Н and 18L, 22Н and 19L, 22Н and 20L, 22Н and 21L, 22Н and 22L, 22Н and 23L, 22Н and

24L, 22Н and 25L, 22Н and 26L, 22Н and 27L, 22Н and 28L, 22Н and 29L, 22Н and 30L, 22Н and 3 IL, 22Н and

32L, 23Н and IL, 23Н and 2L, 23Н and 3L, 23Н and 4L, 23Н and 5L, 23Н and 6L, 23Н and 7L, 23Н and 8L, 23Н and 9L, 23Н and 10L, 23Н and 1 IL, 23Н and 12L , 23Н and 13L, 23Н and 14L, 23Н and 15L, 23Н and 16L, 23Н and

17L, 23Н and 18L, 23Н and 19L, 23Н and 20L, 23Н and 21L, 23Н and 22L, 23Н and 23L, 23Н and 24L, 23Н and

25L, 23Н and 26L, 23Н and 27L, 23Н and 28L, 23Н and 29L, 23Н and 30L, 23Н and 3 IL, 23Н and 32L, 24Н and

IL, 24Н and 2L, 24Н and 3L, 24Н and 4L, 24Н and 5L, 24Н and 6L, 24Н and 7L, 24Н and 8L, 24Н and 9L, 24Н and 10L, 24Н and 1 IL, 24Н and 12L, 24Н and 13L . N and 26L, 24Н and 27L, 24Н and 28L, 24Н and 29L, 24Н and 30L, 24Н and 3 IL, 24Н and 32L, 25Н and IL, 25Н and

2L, 25Н and 3L, 25Н and 4L, 25Н and 5L, 25Н and 6L, 25Н and 7L, 25Н and 8L, 25Н and 9L, 25Н and 10L, 25Н and 1 IL, 25Н and 12L, 25Н and 13L, 25Н and 14L . N And 27L, 25H and 28L, 25H and 29L, 25H and 30L, 25H and 3 IL, 25H and 32L, 26H and IL, 26H and 2L, 26H and 3L, 26H and 4L, 26H and 5L, 26H and 6L, 26H and 7L , 26H and 8L, 26H and 9L, 26H and 10L, 26H and 11L, 26H and 12L, 26H and 13L, 26H and 14L, 26H and 15L, 26H and 16L, 26H and 17L, 26H and 18L, 26H and 19L, 26H and 20L, 26Н and 21L, 26Н and 22L, 26Н and 23L, 26Н and 24L, 26Н and 25L, 26Н and 26L, 26Н and 27L, 26Н and 28L, 26Н and 29L, 26Н and 30L, 26Н and 31L, 26Н and 32L, N and IL, 27H and 2L, 27H and 3L,

- 40 047986

27H and 4L, 27H and 5L, 27H and 6L, 27H and 7L, 27H and 8L, 27H and 9L, 27H and 10L, 27H and 1 IL, 27H and 12L, 27H and 13L, 27H and 14L, 27H and 15L, 27H and 16L, 27Н and 17L, 27Н and 18L, 27Н and 19L, 27Н and 20L, 27Н and 21L, 27Н and 22L, 27Н and 23L, 27Н and 24L, 27Н and 25L, 27Н and 26L, 27Н and 27L, 27Н and 28L, 27H and 29L, 27H and 30L, 27H and 31L, 27H and 32L, 28H and IL, 28H and 2L, 28H and 3L, 28H and 4L, 28H and 5L, 28H and 6L, 28H and 7L, 28H and 8L, 28H and 9L, 28H and 10L, 28H and 1 IL, 28H and 12L, 28H and 13L, 28H and 14L, 28H and 15L, 28H and 16L, 28H and 17L, 28H and 18L, 28H and 19L, 28H and 20L, 28H and 21L, 28H and 22L, 28H and 23L, 28H and 24L, 28H and 25L, 28H and 26L, 28H and 27L, 28H and 28L, 28H and 29L, 28H and 30L, 28H and 31L, 28H and 32L, 29H and IL, 29H and 2L, 29H and 3L, 29H and 4L, 29H and 5L, 29H and 6L, 29H and 7L, 29H and 8L, 29H and 9L, 29H and 10L, 29H and 1 IL, 29H and 12L, 29H and 13L, 29H and 14L , 29N and 15L, 29H and 16L, 29H and 17L, 29H and 18L, 29H and 19L, 29H and 20L, 29H and 21L, 29H and 22L, 29H and 23L, 29H and 24L, 29H and 25L, 29H and 26L, 29H and 27L, 29H and 28L, 29H and 29L, 29H and 30L, 29H and 3 IL, 29H and 32L, ZON and 1L, ZON and 2L, ZON and 3L, ZON and 4L, ZON and 5L, ZON and 6L,

ZON and 7L, ZON and 8L, ZON and 9L, ZON and 10L, ZON and 11L, ZON and 12L, ZON and 13L, ZON and 14L, ZON and 15L, ZON and 16L, ZON and 17L, ZON and 18L, ZON and 19L, ZON and 20L, ZON and 21L, ZON and 22L, ZON and 23L, ZON and 24L, ZON and 25L, ZON and 26L, ZON and 27L, ZON and 28L, ZON and 29L, ZON and 30L, ZON and 32L , 31Нi IL, 31Н and 2L, 31Н and 3L, 31Hh4L, 31Ni5Ts 31Ni6Ts 31Ni 7L, 31Ni and 8L, 31Ni and 9L, 31Ni and 10L, 31Ni and 11L, 31Ni and 12L, 31Ni and 13L, 31Ni and 14L, 31Ni and 15L, 31Ni 16L, 31Ni 17L, 31Ni 18 L, 31Ni 19L, 31Hh20L , 31Hh21L, 31Hh22L, 31Нi 23L, 31Н and 24L, 31Н and 25L, 31Н and 26L, 31Н and 27L, 31Н and 28L, 31Н and 29L, 31Н and 30L, 31H and 31L, 31H and 32L, 32H and IL, 32H and 2L, 32H and 3L, 32H and 4L, 32H and 5L, 32H and 6L, 32H and 7L, 32H and 8L, 32H and 9L, 32H and 10L, 32Н and 11L, 32Н and 12L, 32Н and 13L, 32Н and 14L, 32Н and 15L, 32Н and 16L, 32Н and 17L, 32Н and 18L, 32Н and 19L, 32Н and 20L, 32Н and 21L, 32Н and 32, N and 23L, 32Н and 24L, 32Н and 25L, 32Н and 26L, 32Н and 27L, 32Н and 28L, 32Н and 29L, 32Н and 30L, 32Н and 31L or 32Н and 32L.

In some embodiments, a peptide comprising CDRs 1H, 2H, 3H, 4H, 5H, 6H, 7H, 8H, 9H, 10H, 11H, 12H, 13H, 14H, 15H, 16H, 17H, 18H, 19H, 20H, 21H, 22H, 23H, 24H, 25H, 26H, 27H, 28H, 29H, 30H, 31H, or 32H is combined with, linked to, or expressed together with a peptide comprising SEQ ID NO: 82; SEQ ID NO: 83; SEQ ID NO: 84; SEQ ID NO: 85; SEQ ID NO: 86; SEQ ID NO: 87; SEQ ID NO: 88; SEQ ID NO: 89; SEQ ID NO: 90, or a variant thereof. In some embodiments, the sequences are at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the specified sequence.

In some embodiments, an antibody is provided, including an isolated form thereof, wherein the antibody comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, or 95; The heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101 or 102, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 26; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 27, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 31; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 32; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the foregoing.

- 41 047986

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 38; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 39, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 43; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 44; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 45, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 31; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 46; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 48; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 39, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 43; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 49; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 45, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 53; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 55; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 56; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 56; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 61, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 63, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein

- 42 047986 the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 65, or variants of any of the above.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 66, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 67, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 126, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 69, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 71; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 72; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 73, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 76; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 77; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 78, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 80; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 82, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 86; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 90; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 91; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 92, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 95; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 96; and the sequence

- 43 047986

The heavy chain CDR3 has the amino acid sequence of SEQ ID NO: 97, or variants of any of the above.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 101; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 102; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the foregoing.

In some embodiments, the heavy chain variable region or proteins provided herein are linked to a light chain variable region. In some embodiments, the linker is a peptide linker, such as, but not limited to,

GQSSRSSGGGGSSGGGGS (SEQ ID NO: 136);

(GGGGS)n (SEQ ID NO: 137), (GGGGA) _n (SEQ ID NO: 138), or any combination thereof, wherein each n is independently 1-5. The linked peptide format can be represented by the formula VH-Z-VL or VL-Z-VH, wherein Z is a peptide linker. In some embodiments,

Z GQSSRSSGGGGSSGGGGS (SEQ ID NO: 136);

(GGGGS)n (SEQ ID NO: 137), (GGGGA) _n (SEQ ID NO: 138), or any combination thereof, where each n is independently 1-5.

In some embodiments, the light chain variable region comprises a sequence of any one of SEQ ID NOs: 127-135. In some embodiments, the light chain variable region comprises light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NOs: 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 23, 29, 41, 51, 59, 68, 84, 88, or 99, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, 94, or variants of any of the above.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 22; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 23, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 24, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 30, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 34; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 36, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 41, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 42, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 47;

- 44 047986 the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 36, or variants of any of the above.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 51, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 52, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 68, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 70, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 74; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 75, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 79, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 83; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 84, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 85, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 89, or variants of any of the foregoing.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 93; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 94, or a variant

- 45 047986 you are any of the above.

In some embodiments, the antibody or isolated form thereof comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 99, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 100, or variants of any of the foregoing.

In some embodiments, an antibody or antigen-binding fragment thereof is provided, wherein the antibody or antigen-binding fragment thereof comprises: (i) a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, or 95; The heavy chain CDR2 has an amino acid sequence of 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101 or 102 and the heavy chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97, or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence of 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has an amino acid sequence of 23, 29, 41, 51, 59, 68, 84, 88, or 99, and the light chain CDR3 sequence has an amino acid sequence of 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, 94, or variants of any of the foregoing.

In some embodiments, the following embodiments are provided in this document.

1. An antibody or isolated form thereof that binds to claudin 6 with an affinity of less than 10 nM and with an EC ₅₀ of at least 100-fold greater than to claudin 9, claudin 3 and/or claudin 4.

2. The antibody of embodiment 1 or an isolated form thereof, wherein the antibody comprises a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90 or 95; The heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101 or 102, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97, or variants of any of the foregoing.

3. The antibody of embodiment 1 or an isolated form thereof, wherein the antibody comprises: a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 26; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 27, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 32; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 38; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 39, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 43; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 44; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 45, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 46; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 48; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 39, or variants of any of the above;

- 46 047986 a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 43; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 49; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 45, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 53; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 55; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 56; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 56; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 61, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 63, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 65, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 66, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 67, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 126, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 69, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 71; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 72; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 73, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence

- 47 047986

SEQ ID NO: 76; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 77; and the heavy chain CDR3 has the amino acid sequence of SEQ ID NO: 78, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 80; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 82, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 86; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 90; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 91; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 92, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 95; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 96; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 97, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 101; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the foregoing; or a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 102; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 139; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 140; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 82, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 141; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 142; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 143; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 144; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 92, or variants of any of the foregoing; or a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 145; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 146; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 97, or variants of any of the foregoing.

4. The antibody of any one of embodiments 1-3, wherein the antibody comprises a light chain variable region comprising a sequence of any one of the sequences indicated in SEQ ID NO: 127-135.

5. The antibody of any one of embodiments 1-3, wherein the antibody comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 23, 29, 41, 51, 59, 68, 84, 88, or 99, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, 94,

- 48 047986 or variations of any of the above.

6. The antibody according to embodiment 5, wherein the antibody comprises:

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 22; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 23, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 24, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 30, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 34; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 36, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 41, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 42, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 47; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 36, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 51, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 52, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 68, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 70, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 74; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 75, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 79, or variants of any of the above;

- 49 047986 a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 83; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 84, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 85, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 89, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 93; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 94, or variants of any of the above; or a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 99, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 100, or variants of any of the above.

7. The antibody of embodiment 1 or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises:

(i) a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90 or 95; The heavy chain CDR2 has an amino acid sequence of 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101 or 102 and the heavy chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97, or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence of 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has an amino acid sequence of 23, 29, 41, 51, 59, 68, 84, 88, or 99, and the light chain CDR3 sequence has an amino acid sequence of 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, 94, or variants of any of the foregoing.

8. An antibody or antigen-binding fragment thereof according to embodiment 3, wherein the antibody or antigen-binding fragment thereof comprises:

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 56; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 has the amino acid sequence of SEQ ID NO: 57; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 56; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 61; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 63; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid

- 50 047986 the amino acid sequence of SEQ ID NO: 60; or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 65; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 66; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 67; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 65; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 126; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 69; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 69; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 70; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 71; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 72; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 73; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 74; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 75; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 76; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 77; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 78; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 79; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 80; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 82; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 83; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 84; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 85; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 86; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 89; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 90; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 91; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 92; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 93; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 94; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 95; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 96; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 97; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 99; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 100; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 101; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has

- 52 047986 the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the above; or a heavy chain variable region comprising the heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 102; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57; or variants of any of the above; and a light chain variable region comprising the light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 87;

the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 89; or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 26; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 27; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 22; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 23; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 24; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 32; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 30; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 28; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 29; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 34; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 26; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 43; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 44; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 45; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 41; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 42; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 46; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 30; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 48; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 39; or

- 53 047986 variants of any of the above; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 47; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 36; or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 43; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 49; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 45; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 41; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 42; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 53; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 51; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 52; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 55; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 51; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 52; or variants of any of the foregoing.

9. The antibody of any one of embodiments 1-8, wherein the antibody is a monoclonal antibody.

10. The antibody of any one of embodiments 1-9, wherein the antibody is a humanized antibody.

11. An antibody according to any one of embodiments 1-8, wherein said antibody is a chicken antibody.

12. The antibody of any one of embodiments 1-11, wherein the antibody comprises a sequence as provided herein.

13. An isolated antibody according to any of the preceding embodiments, wherein the antibody comprises a CDR sequence as provided herein.

14. The isolated antibody of any one of the preceding embodiments, wherein said antibody comprises the VL sequence of SeQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122, or SEQ ID NO: 124, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, or SEQ ID NO: 135, or any variants of the above.

15. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the VL sequence of SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, or SEQ ID NO: 135, or any variants thereof.

16. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the VL sequence of SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, or SEQ ID NO: 130, or any variants thereof.

17. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the VL sequence of SEQ ID NO: 127 or SEQ ID NO: 128.

18. The isolated antibody of any one of the preceding embodiments, wherein said antibody comprises the VH sequence of SeQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 109, SEQ ID NO: 111, SEQ ID NO: 113, SEQ ID

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NO: 115, SEQ ID NO: 117, SEQ ID NO: 119, SEQ ID NO: 121 or SEQ ID NO: 123, or any variant thereof.

19. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the VH sequence of SEQ ID NO: 103.

20. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the VH sequence of SEQ ID NO: 105.

21. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the V _H sequence of SEQ ID NO: 107.

22. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the V _H sequence of SEQ ID NO: 109.

23. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the V _H sequence of SEQ ID NO: 111.

24. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the VH sequence of SEQ ID NO: 113.

25. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the VH sequence of SEQ ID NO: 115.

26. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the VH sequence of SEQ ID NO: 117.

27. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the VH sequence of SEQ ID NO: 119.

28. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the VH sequence of SEQ ID NO: 121.

29. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises the VH sequence of SEQ ID NO: 123.

30. An isolated antibody according to any of the preceding embodiments, wherein the antibody comprises

CDR GFSFSSY (SEQ ID NO: 139); YSSASSTY (SEQ ID NO: 140); AAGRTYRGWATYIADSIDA (SEQ ID NO: 82); GFDFSSY (SEQ ID NO: 141); GSTGSS (SEQ ID NO: 142); SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); GFSISSY (SEQ ID NO: 143); YSGSR (SEQ ID NO: 144); SSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 92); GFTFSSY (SEQ ID NO: 145); DSGST (SEQ ID NO: 146); DAYGYCGWSGCSADSIDA (SEQ ID NO: 97), SGDSSWYGYG (SEQ ID NO: 83); ESGKRPS (SEQ ID NO: 84); GSADSNSIGI (SEQ ID NO: 85); SGGSSGYG (SEQ ID NO: 87); SNDKRPS(SEQ ID NO: 88); GSTDNSYVGI (SEQ ID NO: 89); SGDSSDDGSYYYG (SEQ ID NO: 93); SNDKRPS(SEQ ID NO: 88); GSYDSSTGI (SEQ ID NO: 94); SGGNNYYG (SEQ ID NO: 98);

YNDKRPS (SEQ ID NO: 99); GGWDSSGGI (SEQ ID NO: 100), or otherwise described herein.

31. An isolated antibody according to any of the preceding embodiments, wherein the antibody comprises

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CDR V _H GFSFSSY (SEQ ID NO: 139); YSSASSTY (SEQ ID NO: 140); AAGRTYRGWATYIADSIDA (SEQ ID NO: 82); GFDFSSY (SEQ ID NO: 141); GSTGSS (SEQ ID NO: 142); SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); GFSISSY (SEQ ID NO: 143); YSGSR (SEQ ID NO: 144); SSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 92); GFTFSSY (SEQ ID NO: 145); DSGST (SEQ ID NO: 146); DAYGYCGWSGCSADSIDA (SEQ ID NO: 97); CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23);

CGSADSNSIGIF (SEQ ID NO: 24); GFSFSSYDMGWV (SEQ ID NO: 25); VASIYSSASSTYYA (SEQ ID NO: 26); CAK AAGRTYRGWATYIADSIDA (SEQ ID NO: 27); CSGGSSGYG (SEQ ID NO: 28); IYSNDKRP (SEQ ID NO: 29); CGSTDNSYVGIF(SEQ ID NO: 30); GFDFSSYAMNWV (SEQ ID NO: 31); VAGIGSTGSSTGYG (SEQ ID NO: 32); CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); CSGDSSDDGSYYYG (SEQ ID NO: 34);

IYSNDKRP (SEQ ID NO: 29); CGSYDSSTGIF (SEQ ID NO: 36); GFSISSYTMQWV (SEQ ID NO: 37); VAGIYSGSRTYYG (SEQ ID NO: 38); CAKSSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 39); CSGGNNYYG (SEQ ID NO: 40); IYYNDKRP (SEQ ID NO: 41); CGGWDSSGGIF (SEQ ID NO: 42); GFTFSSYSMFWV (SEQ ID NO: 43);

VAGIDSGSTTFYG (SEQ ID NO: 44); CAKDAYGYCGWSGCSADSIDA (SEQ ID NO: 45); CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); CGSADSNSIGIF (SEQ ID NO: 24); GFSFSSYDMGWV (SEQ ID NO: 25); VASIYSSASSTYYA (SEQ ID NO: 26); CAKAAGRTYRGWATYIADSIDA (SEQ ID NO: 27); CSGGSSGYG (SEQ ID NO: 28);

IYSNDKRP (SEQ ID NO: 29); CGSTDNSYVGIF(SEQ ID NO: 30); GFDFSSYAMNWV (SEQ ID NO: 31); VAGIGSTGSSTGYA (SEQ ID NO: 46); CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); CSGDDGSYYYG (SEQ ID NO: 47); IYSNDKRP (SEQ ID NO: 29);

CGSYDSSTGIF (SEQ ID NO: 36); GFSISSYTMQWV (SEQ ID NO: 37); VAGIYSGSRTYYA (SEQ ID NO: 48); CAKSSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 39); CSGGNNYYG (SEQ ID NO: 40); IYYNDKRP (SEQ ID NO: 41); CGGWDSSGGIF (SEQ ID NO: 42); GFTFSSYSMFWV (SEQ ID NO: 43); VAGIDSGSTTFYA (SEQ ID NO: 49); CAKDAYGYCGWSGCSADSIDA (SEQ ID NO: 45); CSGGSGSYG (SEQ ID NO: 50);

IYGTNKRP (SEQ ID NO: 51); CGSADSSTNAGIF (SEQ ID NO: 52); GFTFSSYAMSWV (SEQ ID NO: 53); VAGISSSGRYTGYA (SEQ ID NO: 54); CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); CSGGSGSYG (SEQ ID NO: 50); IYGTNKRP (SEQ ID NO: 51);

CGSADSSTNAGIF (SEQ ID NO: 52); GFTFSSYAMNWV (SEQ ID NO: 55); or VAGISSSGRYTGYA (SEQ ID NO: 54); CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33), or otherwise described herein.

32. An isolated antibody according to any of the preceding embodiments, wherein said antibody comprises

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CDR V _L SGDSSWYGYG (SEQ ID NO:

83); ESGKRPS (SEQ ID NO: 84); GSADSNSIGI (SEQ ID NO: 85); SGGSSGYG (SEQ ID NO: 87); SNDKRPS(SEQ ID NO: 88); GSTDNSYVGI (SEQ ID NO: 89); SGDSSDDGSYYYG (SEQ ID NO: 93); SNDKRPS(SEQ ID NO: 88); GSYDSSTGI (SEQ ID NO: 94); SGGNNYYG (SEQ ID NO: 98); YNDKRPS (SEQ ID NO: 99); GGWDSSGGI (SEQ ID NO: 100), CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); CGSADSNSIGIF (SEQ ID NO: 24); CSGGSSGYG (SEQ ID NO: 28); IYSNDKRP (SEQ ID NO: 29); CGSTDNSYVGIF(SEQ ID NO: 30); CSGDSSDDGSYYYG (SEQ ID NO: 34); IYSNDKRP (SEQ ID NO: 29); CGSYDSSTGIF (SEQ ID NO: 36); CSGGNNYYG (SEQ ID NO: 40);

IYYNDKRP (SEQ ID NO: 41); CGGWDSSGGIF (SEQ ID NO: 42); IYESGKRP (SEQ ID NO: 23); CGSADSNSIGIF (SEQ ID NO: 24); CSGGSSGYG (SEQ ID NO: 28); IYSNDKRP (SEQ ID NO: 29); CGSTDNSYVGIF(SEQ ID NO: 30); CSGDDGSYYYG (SEQ ID NO: 47); IYSNDKRP (SEQ ID NO: 29); CGSYDSSTGIF (SEQ ID NO: 36); CSGGNNYYG (SEQ ID NO: 40); IYYNDKRP (SEQ ID NO: 41); CGGWDSSGGIF (SEQ ID NO: 42); CSGGSGSYG (SEQ ID NO: 50); IYGTNKRP (SEQ ID NO: 51); CGSADSSTNAGIF (SEQ ID NO: 52); CSGGSGSYG (SEQ ID NO: 50); IYGTNKRP (SEQ ID NO: 51); or CGSADSSTNAGIF (SEQ ID NO: 52) or otherwise described in this document.

33. An isolated antibody according to any of the preceding embodiments, wherein the VH CDRs comprise

1H. GFSFSSY (SEQ ID NO: 139); YSSASSTY (SEQ ID NO: 140); and AAGRTYRGWATYIADSIDA (SEQ ID NO: 82); or

2H. GFDFSSY (SEQ ID NO: 141); GSTGSS (SEQ ID NO: 142); And

SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); or

3H. GFSISSY (SEQ ID NO: 143); YSGSR (SEQ ID NO: 144); And

SSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 92); or

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4H. GFTFSSY (SEQ ID NO: 145); DSGST (SEQ ID NO: 146); and DAYGYCGWSGCSADSIDA (SEQ ID NO: 97); or

5H. GFSFSSYDMGWV (SEQ ID NO: 25); VASIYSSASSTYYA (SEQ ID NO: 26); and CAKAAGRTYRGWATYIADSIDA (SEQ ID NO: 27); or

6H. GFDFSSYAMNWV (SEQ ID NO: 31); VAGIGSTGSSTGYG (SEQ ID NO: 32); and CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); or

7H. GFSISSYTMQWV (SEQ ID NO: 37); VAGIYSGSRTYYG (SEQ ID NO: 38); and CAKSSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 39); or

8H. GFTFSSYSMFWV (SEQ ID NO: 43); VAGIDSGSTTFYG (SEQ ID NO: 44); and CAKDAYGYCGWSGCSADSIDA (SEQ ID NO: 45); or

9H. GFSFSSYDMGWV (SEQ ID NO: 25); VASIYSSASSTYYA (SEQ ID NO: 26); and CAKAAGRTYRGWATYIADSIDA (SEQ ID NO: 27); or

YN. GFDFSSYAMNWV (SEQ ID NO: 31); VAGIGSTGSSTGYA (SEQ ID NO: 46); and CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); or

11H. GFSISSYTMQWV (SEQ ID NO: 37); VAGIYSGSRTYYA (SEQ ID NO: 48); and CAKSSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 39); or

12H. GFTFSSYSMFWV (SEQ ID NO: 43); VAGIDSGSTTFYA (SEQ ID NO: 49); and CAKDAYGYCGWSGCSADSIDA (SEQ ID NO: 45); or

13H. GFTFSSYAMSWV (SEQ ID NO: 53); VAGISSSGRYTGYA (SEQ ID NO: 54); and CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); or

14H. GFTFSSYAMNWV (SEQ ID NO: 55); VAGISSSGRYTGYA (SEQ ID NO: 54); and CAKSVGNGNSWSGYIATSIDA (SEQ ID NO: 33); or

15H. SYAMS (SEQ ID NO: 56); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); or

16H. SYAMS (SEQ ID NO: 56); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGNGNSWSGYVATSIDA (SEQ ID NO: 61); or

17H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGSGVSWSGYVATSIDA (SEQ ID NO: 63); or

18H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SMGSGVSWSGYVATSIDA (SEQ ID NO: 65); or

19H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SMGSGVSWSGYVATSIDV (SEQ ID NO: 66); or

20H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGSGVSWSGYVATSLDA (SEQ ID NO: 67); or

21H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); And

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SMGSGVSWSGYVATSIDA (SEQ ID NO: 65); or

22H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SMGSGVSWSGYVATSLDV (SEQ ID NO: 126); or

23H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGSGVSWSGYVATSLDV (SEQ ID NO: 69); or

24H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGSGVSWSGYVATSLDV (SEQ ID NO: 69); or

25H. SYGMS (SEQ ID NO: 71); GIGSSGIYTHYADSVKG (SEQ ID NO: 72); and SPGDSDWCGWAGYGIYSCRVAGFIDA (SEQ ID NO: 73); or

26H. GYAMS (SEQ ID NO: 76); GIYSSGSYTFYADSVKG (SEQ ID NO: 77); and GTGYCDWSGWCYSGAANIDA (SEQ ID NO: 78); or

27H. SYDMG (SEQ ID NO: 80); SIYSSASSTYYAPAVKG (SEQ ID NO: 81); and AAGRTYRGWATYIADSIDA (SEQ ID NO: 82); or

28H. SYAMN (SEQ ID NO: 62); GIGSTGSSTGYGPAVKG (SEQ ID NO: 86); and SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); or

29H. SYTMQ (SEQ ID NO: 90); GIYSGSRTYYGAAVQG (SEQ ID NO: 91); and SSYCTAWTGCDVYAGGSIDA (SEQ ID NO: 92); or

ZON. SYSMF (SEQ ID NO: 95); GIDSGSTTFYGSAVKG (SEQ ID NO: 96); and DAYGYCGWSGCSADSIDA (SEQ ID NO: 97); or

31H. SYAMN (SEQ ID NO: 62); GISSSGRYTGYADSVKG (SEQ ID NO: 101); and SVGNGNSWSGYIATSIDA (SEQ ID NO: 57); or

32H. SYAMN (SEQ ID NO: 62); GIGSTGSSTGYADSVKG (SEQ ID NO: 102); and SVGNGNSWSGYIATSIDA (SEQ ID NO: 57).

34. An isolated antibody according to any of the preceding embodiments, wherein the VL comprises a CDR:

IL. SGDSSWYGYG (SEQ ID NO: 83); ESGKRPS (SEQ ID NO: 84); and GSADSNSIGI (SEQ ID NO: 85); or

2L. SGGSSGYG (SEQ ID NO: 87); SNDKRPS(SEQ ID NO: 88); and GSTDNSYVGI (SEQ ID NO: 89); or

3L. SGDSSDDGSYYYG (SEQ ID NO: 93); SNDKRPS(SEQ ID NO: 88); and GSYDSSTGI (SEQ ID NO: 94); or

4L. SGGNNYYG (SEQ ID NO: 98); YNDKRPS (SEQ ID NO: 99); and GGWDSSGGI (SEQ ID NO: 100); or

5L. CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); And

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CGSADSNSIGIF (SEQ ID NO: 24); or

6L. CSGGSSGYG (SEQ ID NO: 28); IYSNDKRP (SEQ ID NO: 29); and CGSTDNSYVGIF (SEQ ID NO: 30); or

7L. CSGDSSDDGSYYYG (SEQ ID NO: 34); IYSNDKRP (SEQ ID NO: 29); and CGSYDSSTGIF (SEQ ID NO: 36); or

8L. CSGGNNYYG (SEQ ID NO: 40); IYYNDKRP (SEQ ID NO: 41); and CGGWDSSGGIF (SEQ ID NO: 42); or

9L. CSGDSSWYGYG (SEQ ID NO: 22); IYESGKRP (SEQ ID NO: 23); and CGSADSNSIGIF (SEQ ID NO: 24); or

10L. CSGGSSGYG (SEQ ID NO: 28); IYSNDKRP (SEQ ID NO: 29); and CGSTDNSYVGIF (SEQ ID NO: 30); or

11L. CSGDDGSYYYG (SEQ ID NO: 47); IYSNDKRP (SEQ ID NO: 29); and CGSYDSSTGIF (SEQ ID NO: 36); or

12L. CSGGNNYYG (SEQ ID NO: 40); IYYNDKRP (SEQ ID NO: 41); and CGGWDSSGGIF (SEQ ID NO: 42); or

13L. CSGGSGSYG (SEQ ID NO: 50); IYGTNKRP (SEQ ID NO: 51); and CGSADSSTNAGIF (SEQ ID NO: 52); or

14L. CSGGSGSYG (SEQ ID NO: 50); IYGTNKRP (SEQ ID NO: 51); and CGSADSSTNAGIF (SEQ ID NO: 52); or

15L. SGGSGSYG (SEQ ID NO: 58); GTNKRPS (SEQ ID NO: 59); And

GSADSSTNAGI (SEQ ID NO: 60); or

16L. SGGSGSYG (SEQ ID NO: 58); GTNKRPS (SEQ ID NO: 59); And

GSADSSTNAGI (SEQ ID NO: 60); or

17L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); And

GSADSSTNAGI (SEQ ID NO: 60); or

18L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); And

GSADSSTNAGI (SEQ ID NO: 60); or

19L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); And

GSADSSTNAGI (SEQ ID NO: 60); or

20L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); And

GSADSSTNAGI (SEQ ID NO: 60); or

21L. SGGSGSYG (SEQ ID NO: 58); GTYKRPS(SEQ ID NO: 68); And

GSADSSTNAGI (SEQ ID NO: 60); or

22L. SGGSGSYG (SEQ ID NO: 58); GTYKRPS(SEQ ID NO: 68); And

GSADSSTNAGI (SEQ ID NO: 60); or

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23L. SGGSGSYG (SEQ ID NO: 58); GTYKRPS(SEQ ID NO: 68); And

GSADSSTNAGI (SEQ ID NO: 60); or

24L. SAGSGLYG (SEQ ID NO: 64); GTNKRPS (SEQ ID NO: 59); And

GSNDASTNAGI (SEQ ID NO: 70); or

25L. SGGYNGHYG (SEQ ID NO: 74); GTNKRPS (SEQ ID NO: 59); and GGYDSSAGI (SEQ ID NO: 75); or

26L. SGGSGSYGYYG; GTNKRPS (SEQ ID NO: 59); and GSEDSSSGAGI (SEQ ID NO: 79); or

27L. SGDSSWYGYG (SEQ ID NO: 83); ESGKRPS (SEQ ID NO: 84); and GSADSNSIGI (SEQ ID NO: 85); or

28L. SGGSSGYG (SEQ ID NO: 87); SNDKRPS(SEQ ID NO: 88); and GSTDNSYVGI (SEQ ID NO: 89); or

29L. SGDSSDDGSYYYG (SEQ ID NO: 93); SNDKRPS(SEQ ID NO: 88); and GSYDSSTGI (SEQ ID NO: 94); or

30L. SGGNNYYG (SEQ ID NO: 98); YNDKRPS (SEQ ID NO: 99); and GGWDSSGGI (SEQ ID NO: 100); or

31L. SGGSGSYG (SEQ ID NO: 58); GTNKRPS (SEQ ID NO: 59); and GSADSSTNAGI (SEQ ID NO: 60); or

32L. SGGSSGYG (SEQ ID NO: 87); SNDKRPS(SEQ ID NO: 88); and GSTDNSYVGI (SEQ ID NO: 89).

35. The antibody of any of the previous embodiments, wherein the antibody comprises CDRs selected from

1H and IL, 1H and 2L, 1H and 3L, 1H and 4L, 1H and 5L, 1H and

6L, 1H and 7L, 1H and 8L, 1H and 9L, 1H and 10L, 1H and 11L, 1H and 12L, 1H and 13L, 1H and 14L, 1H and 15L, 1H and 16L, 1H and 17L, 1H and 18L, 1H and 19L, 1H and 20L, 1H and 21L, 1H and 22L, 1H and 23L, 1H and 24L, 1H and 25L, 1H and 26L, 1H and 27L, 1H and 28L, 1H and 29L, 1H and 30L, 1H and 31L, 1H and 32L, 2H and IL, 2H and 2L, 2H and 3L, 2H and 4L, 2H and 5L, 2H and 6L, 2H and 7L, 2H and 8L, 2H and 9L, 2H and 10L, 2H and 11L, 2H and 12L, 2H and 13L, 2H and 14L, 2H and 15L, 2H and 16L, 2H and 17L, 2H and 18L, 2H and 19L, 2H and 20L, 2H and 21L, 2H and 22L, 2H and 23L, 2H and 24L, 2H and 25L, 2H and 26L, 2H and 27L, 2H and 28L, 2H and 29L, 2H and 30L, 2H and 31L, 2H and 32L, ZH and IL, ZH and 2L, ZH and 3L, ZH and 4L, ZH and 5L, ZH and 6L, ZH and 7L, ZH and 8L, ZH and 9L, ZH and 10L, ЗН and 11L, ЗН and 12L, ЗН and 13L, ЗН and 14L, ЗН and 15L, ЗН and 16L, ЗН and 17L, ЗН and 18L, ЗН and 19L, ЗН and 20L, ЗН and 21L, ЗН and 22L, ЗН and 23L, ЗН and 24L, ЗН and 25L, ЗН and 26L, ЗН and 27L, ЗН and 28L, ЗН and 29L, ZN and 30L, ZN and 31L, ZN and 32L, 4H and IL, 4H and 2L, 4H and 3L, 4H and 4L, 4H and 5L, 4H and 6L, 4H and 7L, 4H and 8L, 4H and 9L, 4H and 10L, 4H and 11L, 4H and 12L, 4H and 13L, 4H and 14L, 4H and 15L, 4H and 16L, 4H and 17L, 4H and 18L,

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4H and 19L, 4H and 20L, 4H and 21L, 4H and 22L, 4H and 23L, 4H and 24L, 4H and 25L, 4H and 26L, 4H and 27L, 4H and 28L, 4H and 29L, 4H and 30L, 4H and 31L, 4H and 32L, 5H and IL, 5H and 2L, 5H and 3L, 5H and 4L, 5H and 5L, 5H and 6L, 5H and 7L, 5H and 8L, 5H and 9L, 5H and 10L, 5H and 1 IL , 5H and 12L, 5H and 13L, 5H and 14L, 5H and 15L, 5H and 16L, 5H and 17L, 5H and 18L, 5H and 19L, 5H and 20L, 5H and 21L, 5H and 22L, 5H and 23L, 5H and 24L, 5H and 25L, 5H and 26L, 5H and 27L, 5H and 28L, 5H and 29L, 5H and 30L, 5H and 3 IL, 5H and 32L, 6H and IL, 6H and 2L, 6H and 3L, 6H and 4L, 6H and 5L, 6H and 6L, 6H and 7L , 6H and 8L, 6H and 9L, 6H and 10L, 6H and 1 IL, 6H and 12L, 6H and 13L, 6H and 14L, 6H and 15L, 6H and 16L, 6H and 17L, 6H and 18L, 6H and 19L, 6H and 20L, 6H and 21L, 6H and 22L, 6H and 23L , 6H and 24L, 6H and 25L, 6H and 26L, 6H and 27L, 6H and 28L, 6H and 29L, 6H and 30L, 6H and 3 IL, 6H and 32L, 7H and IL, 7H and 2L, 7H and 3L, 7H and 4L, 7H and 5L, 7H and 6L, 7H and 7L, 7H and 8L, 7H and 9L, 7H and 10L, 7H and 1 IL, 7H and 12L, 7H and 13L, 7H and 14L, 7H and 15L, 7H and 16L, 7H and 17L, 7H and 18L, 7H and 19L , 7H and 20L, 7H and 21L, 7H and 22L, 7H and 23L, 7H and 24L, 7H and 25L, 7H and 26L, 7H and 27L, 7H and 28L, 7H and 29L, 7H and 30L, 7H and 3 IL, 7H and 32L, 8H and IL, 8H and 2L, 8H and 3L, 8H and 4L, 8H and 5L, 8H and 6L, 8H and 7L, 8H and 8L, 8H and 9L, 8H and 10L, 8H and 1 IL, 8H and 12L, 8H and 13L, 8H and 14L, 8H and 15L , 8Н and 16L, 8Н and 17L, 8Н and 18L, 8Н and 19L, 8Н and 20L, 8Н and 21L, 8Н and 22L, 8Н and 23L, 8Н and 24L, 8Н and 25L, 8Н and 26L, 8Н and 27L, 8Н and 28L, 8Н and 29L, 8Н and 30L, 8Н and 3 IL, 8H and 32L, 9H and IL, 9H and 2L, 9H and 3L, 9H and 4L, 9H and 5L, 9H and 6L, 9H and 7L, 9H and 8L, 9H and 9L, 9H and 10L, 9H and 1 IL, 9H and 12L, 9H and 13L, 9H and 14L, 9H and 15L, 9H and 16L, 9H and 17L, 9H and 18L, 9H and 19L, 9H and 20L, 9H and 21L, 9H and 22L, 9H and 23L, 9H and 24L, 9H and 25L, 9H and 26L, 9H and 27L, 9N and 28L, 9N and 29L, 9N and 30L, 9N and 31L, 9N and 32L, YN and IL, YN and 2L, YN and 3L, YN and 4L, YN and 5L, YN and 6L, YN and 7L, YN and 8L, YN and 9L, YN and 10L, YN and 11L, YN and 12L, YN and 13L, YN and 14L, YN and 15L, YN and 16L, YN and 17L, YN and 18L, YN and 19L, YN and 20L, YN and 21L, YN and 22L, YN and 23L, YN and 24L, YN and 25L, YN and 26L, YUN and 27L, YUN and 28L, YUN and 29L, YUN and 30L, YUN and 31L, YUN and 32L, IN and IL, IN and 2L, IN and 3L, IN and 4L, IN and 5L, IN and 6L, IN and 7L, IN and 8L, IN and 9L, IN and 10L, IN and 11L, IN and 12L, IN and 13L, IN and 14L, IN and 15L, IN and 16L, IN and 17L, IN and 18L, PN and 19L, 11Hh20L, 11Hh21L, 11Hh22L, 11H and 23L, 11H and 24L, 11H and 25L, 11H and 26L, 11H and 27L, 11H and 28L, 11H and 29L, 11H and 30L, 11H and 3 IL, 11H and 32L, 12H and IL, 12H and 2L, 12H and 3L, 12H and 4L, 12H and 5L, 12H and 6L, 12H and 7L, 12H and 8L, 12H and 9L, 12H and 10L, 12H and 11L, 12H and 12L, 12H and 13L, 12H and 14L, 12H and 15L, 12H and 16L, 12H and 17L, 12H and 18L, 12H and 19L, 12H and 20L, 12H and 21L, 12H and 22L, 12H and 23L, 12H and 24L, 12H and 25L, 12H and 26L, 12H and 27L, 12H and 28L, 12H and 29L, 12H and 30L, N and 31L, 12H and 32L, 13H and IL, 13H and 2L, 13H and 3L, 13H and 4L, 13H and 5L, 13H and 6L, 13H and 7L, 13H and 8L, 13H and 9L, 13H and 10L, 13H and 11L, 13H and 12L, 13Н and 13L, 13Н and 14L, 13Н and 15L, 13Н and 16L, 13Н and 17L, 13Н and 18L, 13Н and 19L, 13Н and 20L, 13Н and 21L, 13Н and 22L, 13Н and 23L, 13Н and 24 L, 13Н and 25L, 13Н and 26L, 13Н and 27L, 13Н and 28L, 13Н and 29L, 13Н and 30L, 13Н and 31L,

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13H and 32L, 14H and IL, 14H and 2L, 14H and 3L, 14H and 4L, 14H and 5L, 14H and 6L, 14H and 7L, 14H and 8L, 14H and 9L, 14H and 10L, 14H and 11L, 14H and 12L, 14Н and 13L, 14Н and 14L, 14Н and 15L, 14Н and 16L, 14Н and 17L, 14Н and 18L, 14Н and 19L, 14Н and 20L, 14Н and 21L, 14Н and 22L, 14Н and 23L, 14Н and 24 L, 14Н and 25L, 14Н and 26L, 14Н and 27L, 14Н and 28L, 14Н and 29L, 14Н and 30L, 14Н and 31L, 14Н and 32L, 15Н and IL, 15Н and 2L, 15Н and 3L, 15Н and 4L, 15Н and 5L, 15N and 6L, 15N and 7L, 15N and 8L, 15N and 9L, 15Ni 10L, 15Ni 11L, 15Ni 12L, 15Ni 13L, 15Ni 14L, 15Ni 15L, 15N and 16L, 15Ni 17L, 15N and 18L, 15H and 19L, 15H and 20L, 15H and 21L, 15H and 22L, 15H and 23L, 15H and 24L, 15H and 25L, 15H and 26L, 15H and 27L, 15H and 28L, 15H and 29L, 15H and 30 L, 15H and 31L, 15H and 32L, 16H and IL, 16H and 2L, 16H and 3L, 16H and 4L, 16H and 5L, 16H and 6L, 16H and 7L, 16H and 8L, 16H and 9L, 16H and 10L, 16H and 11L, 16Н and 12L, 16Н and 13L, 16Н and 14L, 16Н and 15L, 16Н and 16L, 16Н and 17L, 16Н and 18L, 16Н and 19L, 16Н and 20L, 16Н and 21L, 16Н and 22L, 16Н and 23L, N and 24L, 16Н and 25L, 16Н and 26L, 16Н and 27L, 16Н and 28L, 16Н and 29L, 16Н and 30L, 16Н and 31L, 16Н and 32L, 17Н and IL, 17Н and

2L, 17Н and 3L, 17Н and 4L, 17Н and 5L, 17Н and 6L, 17Н and 7L, 17Н and 8L, 17Н and 9L, 17Н and 10L, 17Н and 11L, 17Н and 12L, 17Н and 13L, 17Н and 14L, 17Н and 15L, 17Н and 16L, 17Н and 17L, 17Н and 18L, 17Н and 19L, 17Н and 20L, 17Н and 21L, 17Н and 22L, 17Н and 23L, 17Н and 24L, 17Н and 25L, 17Н and 26L, N and 27L, 17Н and 28L, 17Н and 29L, 17Н and 30L, 17Н and 31L, 17Н and 32L, 18Н and IL, 18Н and 2L, 18Н and 3L, 18Н and 4L, 18Н and 5L, 18Н and 6L, 18Н and 7L, 18Н и 8L, 18Н и 9L, 18Н и 10L, 18Н и 11L, 18Н и 12L, 18Н и 13L, 18Н и 14L, 18Н и 15L, 18Н и 16L, 18Н и 17L, 18Н и 18L, 18Н и 19L, 18Н и 20L, 18Н and 21L, 18Н and 22L, 18Н and 23L, 18Н and 24L, 18Н and 25L, 18Н and 26L, 18Н and 27L, 18Н and 28L, 18Н and 29L, 18Н and 30L, 18Н and 31L, 18Н and 32L, N and IL, 19H and 2L, 19H and 3L, 19H and 4L, 19H and 5L, 19H and 6L, 19H and 7L, 19H and 8L, 19H and 9L, 19H and 10L, 19H and 1 IL, 19H and 12L, 19H and 13L , 19N and 14L, 19H and 15L, 19H and 16L, 19H and 17L, 19H and 18L, 19H and 19L, 19H and 20L, 19H and 21L, 19H and 22L, 19H and 23L, 19H and 24L, 19H and 25L, 19H and 26L, 19H and 27L, 19H and 28L, 19H and 29L, 19H and 30L, 19H and 31L, 19H and 32L, 20H and IL, 20H and 2L, 20H and 3L, 20H and 4L, 20H and 5L, 20H and 6L, 20H and 7L, 20Н and 8L, 20Н and 9L, 20Н and 10L, 20Н and 1 IL, 20Н and 12L, 20Н and 13L, 20Н and 14L, 20Н and 15L, 20Н and 16L, 20Н and 17L, 20Н and 18L, 20Н and 19L . 20N and 32L, 21H and IL, 21H and 2L, 21H and 3L, 21H and 4L, 21H and 5L, 21H and 6L, 21H and 7L, 21H and 8L, 21H and 9L, 21H and 10L, 21H and 1 IL, 21H and 12L, 21Н and 13L, 21Н and 14L, 21Н and 15L, 21Н and 16L, 21Н and 17L, 21Н and 18L, 21Н and 19L, 21Н and 20L, 21Н and 21L, 21Н and 22L, 21Н and 23L, 21Н and 24 L, 21H and 25L, 21Н and 26L, 21Н and 27L, 21Н and 28L, 21Н and 29L, 21Н and 30L, 21Н and 3 IL, 21Н and 32L, 22Н and IL, 22Н and 2L, 22Н and 3L, 22Н and 4L, 22Н and 5L, 22Н and 6L, 22Н and 7L, 22Н and 8L, 22Н and 9L, 22Н and 10L, 22Н and 11L, 22Н and 12L, 22Н and 13L, 22Н and 14L, 22Н and 15L, 22Н and 16L, 22Н and 17L, 22Н and 18L , 22N and 19L, 22Н and 20L, 22Н and 21L, 22Н and 22L, 22Н and 23L, 22Н and 24L, 22Н and 25L, 22Н and 26L, 22Н and 27L, 22Н and 28L, 22Н and 29L, 22Н and 30L,

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22H and 3 IL, 22H and 32L, 23H and IL, 23H and 2L, 23H and 3L, 23H and 4L, 23H and 5L, 23H and 6L, 23H and 7L, 23H and 8L, 23H and 9L, 23H and 10L, 23H and 11L, 23Н and 12L, 23Н and 13L, 23Н and 14L, 23Н and 15L, 23Н and 16L, 23Н and 17L, 23Н and 18L, 23Н and 19L, 23Н and 20L, 23Н and 21L, 23Н and 22L, 23Н and 2 3L , 23Н and 24L, 23Н and 25L, 23Н and 26L, 23Н and 27L, 23Н and 28L, 23Н and 29L, 23Н and 30L, 23Н and 31L, 23Н and 32L, 24Н and IL, 24Н and 2L, 24Н and 3L, 24Н and 4L, 24H and 5L, 24H and 6L, 24H and 7L, 24H and 8L, 24H and 9L, 24H and 10L, 24H and 11L, 24H and 12L, 24H and 13L, 24H and 14L, 24H and 15L, 24H and 16L, 24H and 17L, 24Н and 18L, 24Н and 19L, 24Н and 20L, 24Н and 21L, 24Н and 22L, 24Н and 23L, 24Н and 24L, 24Н and 25L, 24Н and 26L, 24Н and 27L, 24Н and 28L, 24Н and 29 L, 24Н and 30L, 24Н and 31L, 24Н and 32L, 25Н and IL, 25Н and 2L, 25Н and 3L, 25Н and 4L, 25Н and 5L, 25Н and 6L, 25Н and 7L, 25Н and 8L, 25Н and 9L, 25Н and 10L, 25Н and 11L, 25Н and 12L, 25Н and 13L, 25Н and 14L, 25Н and 15L, 25Н and 16L, 25Н and 17L, 25Н and 18L, 25Н and 19L, 25Н and 20L, 25Н and 21L, 25Н and 25, N and 23L, 25Н and 24L, 25Н and 25L, 25Н and 26L, 25Н and 27L, 25Н and 28L, 25Н and 29L, 25Н and 30L, 25Н and 3 IL, 25Н and 32L, 26Н and IL, 26Н and 2L, 26Н and 3L , 26Н and 4L, 26Н and 5L, 26Н and 6L, 26Н and 7L, 26Н and 8L, 26Н and 9L, 26Н and 10L, 26Н and 1 IL, 26Н and 12L, 26Н and 13L, 26Н and 14L, 26Н and 15L, 26Н and 16L, 26Н and 17L, 26Н and 18L, 26Н and 19L, 26Н and 20L, 26Н and 21L, 26Н and 22L, 26Н and 23L, 26Н and 24L, 26Н and 25L, 26Н and 26L, 26Н and 27L, 26Н and 2 8L , 26Н and 29L, 26Н and 30L, 26Н and 3 IL, 26Н and 32L, 27Н and IL, 27Н and 2L, 27Н and 3L, 27Н and 4L, 27Н and 5L, 27Н and 6L, 27Н and 7L, 27Н and 8L, 27Н and 9L, 27Н and 10L, 27Н and 1 IL, 27Н and 12L, 27Н and 13L, 27Н and 14L, 27Н and 15L, 27Н and 16L, 27Н and 17L, 27Н and 18L, 27Н and 19L, 27Н and 20L, 27Н and 21L, 27H and 22L, 27Н and 23L, 27Н and 24L, 27Н and 25L, 27Н and 26L, 27Н and 27L, 27Н and 28L, 27Н and 29L, 27Н and 30L, 27Н and 3 IL, 27Н and 32L, 28Н and IL, 28Н and 2L , 28Н and 3L, 28Н and 4L, 28Н and 5L, 28Н and 6L, 28Н and 7L, 28Н and 8L, 28Н and 9L, 28Н and 10L, 28Н and 11L, 28Н and 12L, 28Н and 13L, 28Н and 14L, 28Н and 15L, 28H and 16L, 28H and 17L, 28H and 18L, 28H and 19L, 28H and 20L, 28H and 21L, 28H and 22L, 28H and 23L, 28H and 24L, 28H and 25L, 28H and 26L, 28H and 27L, 28H and 28L, 28H and 29L, 28H and 30L, 28H and 3 IL, 28H and 32L, 29H and IL, 29H and 2L, 29H and 3L, 29H and 4L, 29H and 5L, 29H and 6L, 29H and 7L, 29H and 8L , 29N and 9L, 29H and 10L, 29H and 11L, 29H and 12L, 29H and 13L, 29H and 14L, 29H and 15L, 29H and 16L, 29H and 17L, 29H and 18L, 29H and 19L, 29H and 20L, 29H and 21L, 29H and 22L, 29H and 23L, 29H and 24L, 29H and 25L, 29H and 26L, 29H and 27L, 29H and 28L, 29H and 29L, 29H and 30L, 29H and 31L, 29H and 32L, ZON and 1L, ZON and 2L, ZON and 3L, ZON and 4L, ZON and 5L, ZON and 6L, ZON and 7L, ZON and 8L, ZON and 9L, ZON and 10L, ZON and 11L, ZON and 12L, ZON and 13L, ZON and 14L, ZON and 15L, ZON and 16L, ZON and 17L, ZON and 18L, ZON and 19L, ZON and 20L, ZON and 21L, ZON and 22L, ZON and 23L, ZON and 24L, ZON and 25L, ZON and 26L, ZON and 27L, ZON and 28L, ZON and 29L, ZON and 30L, ZON and 31L, ZON and 32L, 31H and 1L, 31N and 2L, 31N and 3L, 31N and 4L, 31Ni 5L, 31Hh6L, 31Hh7L, 31Ni 8L, 31Hh9L, 31Ni 10L, 31Ni 11L, 31Ni 12L, 31Ni 13L, 31Ni 14L, 31Ni 15L, 1Nor 16L, 31Nor 17L, 31Nor 18L , 31Нi 19L, 31Hh20L, 31Нi 21L, 31Н and 22L, 31Н and 23L, 31Н and 24L, 31Н and 25L, 31Н and 26L, 31Н and 27L, 31H and 28L, 31H and 29L, 31H and 30L, 31H and 31L, 31H and 32L, 32H and IL, 32H and 2L, 32H and 3L, 32H and 4L, 32H and 5L, 32H and 6L, 32H and 7L, 32Н and 8L, 32Н and 9L, 32Н and 10L, 32Н and 1 IL, 32Н and 12L, 32Н and 13L, 32Н and 14L, 32Н and 15L, 32Н and 16L, 32Н and 17L, 32Н and 18L, 32Н and 19L, 32Н and 20L, 32Н and 21L, 32Н and 22L, 32Н and 23L, 32Н and 24L, 32Н and 25L, 32Н and 26L, 32Н and 27L, 32Н and 28L, 32Н and 29L, 32Н and 30L, 32Н and 31L or 32Н and 32L.

36. An isolated antibody according to any of the preceding embodiments, wherein the antibody is humanized.

37. An isolated antibody according to any of the preceding embodiments, wherein the antibody is chimeric or fused to a non-antibody protein.

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38. An isolated antibody according to any of the preceding embodiments, wherein the antibody does not significantly bind to claudin 9.

39. An isolated antibody according to any of the preceding embodiments, wherein the antibody binds to claudin 6 with an affinity, EC50, or KD that is at least 100-fold, 200-fold, or 300-fold greater than it binds to claudin 9.

40. An isolated antibody according to any of the preceding embodiments, wherein the amino acid sequence of the CDR, VL or VH peptide is at least or about 90-99% identical to a sequence as provided herein, or the sequence has 1, 2, 3, 4 or 5 substitutions.

41. A peptide comprising, consisting of, or consisting essentially of a sequence as provided herein or a variant thereof.

42. The peptide of embodiment 41, wherein the peptide is a CDR, VL, or VH peptide.

43. The peptide of embodiment 41, wherein the peptide comprises, consists of, or consists essentially of the sequence of SEQ ID NO: 2-138, or a variant thereof, or as otherwise provided herein.

44. A peptide comprising, consisting of, or consisting essentially of a sequence that is 90-99% identical to the sequence provided herein.

45. The peptide of embodiment 44, wherein the peptide comprises 1, 2, 3, 4 or 5 substitutions, deletions or insertions compared to the sequence presented herein.

46. A peptide according to embodiment 44 or 45, wherein the peptide is a CDR, VL or VH peptide.

47. The peptide of embodiment 44 or 45, wherein the sequence provided herein comprises the sequence of SEQ ID NO: 2-135, or a variant thereof, or as otherwise provided herein.

48. An antibody, such as a monoclonal antibody or scFv, that binds to an epitope on claudin 6, the residues of which include T33, N38, D68, P74, D76, D146, V152, A153, E154, Q156, R158, or any combination thereof.

49. An antibody, such as a monoclonal antibody or scFv, that preferentially binds to claudin 6 over claudin 9, wherein said antibody binds to an epitope on claudin 6 containing Q156.

50. A bispecific antibody comprising a first VH peptide that binds to claudin 6 and a second VH peptide that binds to a different fragment.

51. The antibody of embodiment 46, wherein the second VH peptide binds to CD3 or 4-1BB.

52. The antibody of embodiment 50 or 51, wherein the antibody is a bispecific antibody or wherein the antibody is a fusion protein.

53. The antibody of embodiment 50-52, further comprising a linker domain that binds an antibody that binds to claudin 6 and a second VH peptide.

54. The antibody of any one of embodiments 50-53, wherein the linker domain comprises 1, 2, 3, 4, or 5 or more repeats of GGGGS (SEQ ID NO: 137).

55. The antibody of any one of embodiments 50-54, wherein the antibody comprises heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID no: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90, or 95; The heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101 or 102, and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97, or variants of any of the foregoing.

56. An antibody according to any one of embodiments 50-55, wherein the antibody comprises:

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 26; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 27, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 32; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 38; and

- 65 047986 the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 39, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 43; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 44; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 45, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 46; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 48; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 39, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 43; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 49; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 45, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 53; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 55; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 56; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 56; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 61, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 63, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 65, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 66, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 67, or variants of any of the above;

- 66 047986 a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 126, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 69, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 71; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 72; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 73, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 76; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 77; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 78, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 80; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 82, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 86; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 90; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 91; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 92, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 95; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 96; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 97, or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 101; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the foregoing; or a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 102; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57, or variants of any of the foregoing.

57. The antibody of any one of embodiments 50-56, wherein the antibody comprises a light chain variable region comprising a sequence of any one of the sequences set forth in SEQ ID NO: 127-135.

58. The antibody of any one of embodiments 50-56, wherein the antibody comprises a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 23, 29, 41, 51, 59, 68, 84, 88, or 99, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, 94, or variants of any of the above.

59. The antibody of any one of embodiments 50-56, wherein the antibody comprises a light chain variable region comprising the light chain CDR1, CDR2, and CDR3 sequences

- 67 047986 chains, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 22; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 23, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 24, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 30, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 34; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 36, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 41, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 42, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 47; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 36, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 51, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 52, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 68, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 70, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 74; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 75, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 79, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 83; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO:

- 68 047986

84, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 85, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 89, or variants of any of the above;

a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 93; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 94, or variants of any of the above; or a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 99, and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 100, or variants of any of the above.

60. The antibody of any one of embodiments 50-56, or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises:

(i) a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25, 31, 37, 43, 53, 55, 56, 62, 71, 76, 80, 90 or 95; The heavy chain CDR2 has an amino acid sequence of 26, 32, 38, 44, 46, 48, 49, 54, 125, 72, 77, 81, 86, 91, 96, 101 or 102 and the heavy chain CDR3 sequence has an amino acid sequence of SEQ ID NO: 27, 33, 39, 45, 57, 61, 63, 65, 66, 67, 126, 69, 73, 82, 57, 92 or 97, or variants of any of the foregoing; and (ii) a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has an amino acid sequence of 22, 28, 34, 40, 47, 50, 58, 64, 74, 83, 87, 93, or 98; the light chain CDR2 sequence has an amino acid sequence of 23, 29, 41, 51, 59, 68, 84, 88, or 99, and the light chain CDR3 sequence has an amino acid sequence of 24, 30, 36, 42, 52, 60, 70, 75, 79, 85, 89, 94, or variants of any of the foregoing.

61. An antibody according to any one of embodiments 50-56, wherein the antibody or antigen-binding fragment thereof comprises:

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 56; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 56; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 61; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 63; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence

- 69 047986

SEQ ID NO: 62; a heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125; and a heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 65; or variants of any of the above; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64;

the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 66; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 67; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 65; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 126; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 69; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 68; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 125; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 69; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 70; or variants of any of the foregoing;

- 70 047986 a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 71; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 72; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 73; or variants of any of the above; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 74; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 75; or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 76; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 77; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 78; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 79; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 80; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 81; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 82; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 83; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 84; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 85; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 86; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 89; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 90; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 91; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 92; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 93; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 94; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 95; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 96; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 97; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 98; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 99; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 100; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 101; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 58; the light chain CDR2 sequence has the amino acid

- 71 047986 amino acid sequence of SEQ ID NO: 59; and a light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60; or variants of any of the above; or a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 102; and a heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 57; or variants of any of the above; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 87; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 88; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 89; or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 25; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 26; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 27; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 22; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 23; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 24; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 32; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 30; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2, and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 28; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 29; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2, and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 34; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 26; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 43; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 44; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 45; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 41; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 42; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 31; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 46; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 28; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 30; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 37; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 48; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 39; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has

- 72 047986 the amino acid sequence of SEQ ID NO: 47; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 29; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 36; or variants of any of the above;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 43; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 49; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 45; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 40; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 41; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 42; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 53; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 51; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 52; or variants of any of the foregoing;

a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 55; the heavy chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 54; and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 33; or variants of any of the foregoing; and a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 50; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 51; and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 52; or variants of any of the foregoing.

62. A nucleic acid molecule encoding an antibody or amino acid sequence according to any of the preceding embodiments.

63. A vector containing a nucleic acid molecule according to embodiment 62.

64. A cell containing a nucleic acid comprising a nucleic acid molecule according to embodiment 62 or a vector according to embodiment 63.

65. A pharmaceutical composition comprising an isolated antibody according to any one of embodiments 1-61 or a nucleic acid molecule encoding it.

66. A pharmaceutical composition according to embodiment 65, wherein said composition is a pharmaceutical composition for injection.

67. Pharmaceutical compositions according to embodiments 65 or 66, wherein said composition is sterile.

68. Pharmaceutical compositions according to any of embodiments 65-67, wherein said composition does not contain pyrogens.

69. Pharmaceutical compositions according to any one of embodiments 65-68, wherein the composition does not contain antibodies that do not bind to claudin 6.

70. A method for modulating the activity of claudin 6 by contacting a cell expressing claudin 6 with an antibody to claudin 6 or a pharmaceutical composition containing it that binds to claudin 6 on the surface of the cell.

71. The method of embodiment 70, wherein the antibody is any of the antibodies provided herein, or an antibody of any of embodiments 1-61, or a nucleic acid molecule encoding the same.

72. Methods for inhibiting claudin 6 function by contacting a cell expressing claudin 6 with an antibody or pharmaceutical composition containing the same that inhibits claudin 6 function by binding to claudin 6.

73. The method of embodiment 61, wherein the antibody is any of the antibodies provided herein, or an antibody of any of embodiments 1-61, or a nucleic acid molecule encoding the same.

74. The method of embodiment 72, wherein the antibody is an antibody or peptide of any one of embodiments 1-61.

75. The method according to any one of embodiments 72-74, wherein the antibody is administered to a subject in need of such antibody.

76. The method according to embodiment 75, wherein the function is integrity control

- 73 047986 tight contact.

77. A method of treating a subject with a disorder mediated by claudin 6, comprising administering to the subject a pharmaceutical composition comprising an antibody to claudin 6, such as any antibody provided herein or an antibody of any of embodiments 1-61, or a nucleic acid molecule encoding them.

78. The method according to embodiment 77 of the invention, wherein the disease is a benign neoplasm or a metastatic oncological disease, for example, an oncological disease of the ovaries (for example, ovarian carcinoma), an oncological disease of the reproductive system (an oncological disease of the breast, an oncological disease of the cervix, an oncological disease of the testes, an oncological disease of the uterus, or a malignant neoplasm of the placenta), an oncological disease of the lungs, an oncological disease of the stomach, an oncological disease of the liver, an oncological disease of the pancreas, an oncological disease of the bile ducts, an oncological disease of the bladder, an oncological disease of the kidneys, an oncological disease of the colon, an oncological disease of the small intestine, an oncological disease of the skin, an oncological disease of the head and neck, a sarcoma, or a germ cell tumor.

79. The method according to embodiment 77 or 78, wherein the antibody is the antibody of any one of embodiments 1-61, or a nucleic acid molecule encoding it, or a pharmaceutical composition comprising the antibody or a nucleic acid molecule encoding them.

80. A method of treating an oncological disease in a subject, comprising administering a therapeutic agent that specifically binds to claudin 6 and binds to CD3 and/or 4-1BB.

81. The method of embodiment 80, wherein the therapeutic agent comprises an antibody of any one of embodiments 1-61 or a nucleic acid molecule encoding it.

82. A method for treating an oncological disease in a subject, comprising administering to the subject a pharmaceutical composition comprising an antibody that binds to the Q156 residue of claudin 6, or a nucleic acid molecule encoding it.

83. The method of embodiment 77, wherein the antibody comprises a CDR, VL, or VH as provided herein, or the sequence of SEQ ID NO: 2-135.

84. The method according to embodiment 82 or 83, wherein the antibody is a hexaantibody.

85. The method of embodiment 82, wherein the pharmaceutical composition comprises a chimeric receptor, such as a chimeric antigen receptor (CAR), wherein the receptor comprises an extracellular domain of an antibody that comprises the antibody of any one of embodiments 1-61 or an antibody that binds to residue Q156 of claudin 6.

86. The method of embodiment 85, wherein the chimeric receptor comprises a transmembrane domain and an intracellular domain.

87. The method according to embodiment 85 and 86, wherein the cell comprises a chimeric receptor.

88. The method of embodiment 87, wherein the cell is an immune cell such as a T cell, a macrophage, a dendritic cell, an NK cell, etc.

89. A multispecific antibody, wherein the multispecific antibody comprises an antibody domain as provided herein.

90. A multispecific antibody according to embodiment 89, wherein the antibody domain comprises an antibody, CDR, VL or VH peptide as provided herein or according to any of embodiments 1-61.

91. A chimeric receptor comprising an antibody domain as provided herein.

92. The chimeric receptor of embodiment 91, wherein the antibody domain comprises an antibody, CDR, VL or VH peptide as provided herein or any of embodiments 1-61.

93. A composition comprising an antibody according to any one of embodiments 1-61, or an antibody domain as provided herein, linked to a drug or other therapeutic agent.

94. The composition of embodiment 93, wherein the therapeutic agent is a cytokine, such as IL-2.

95. The composition of embodiment 93, wherein the composition is an antibody-drug conjugate (ADC).

96. The composition of any one of embodiments 93-95, wherein the antibody domain comprises an antibody, CDR, VL or VH peptide as provided herein or any one of embodiments 1-61.

97. A hexaantibody comprising an antibody domain as provided herein.

98. The hexaantibody of embodiment 97, wherein the antibody domain comprises an antibody, CDR, VL or VH peptide as provided herein or any of embodiments 1-61, or a sequence comprising one or more of SEQ ID NOs: 2-135.

99. A composition comprising a peptide as provided herein, such as a peptide comprising

- 74 047986 containing one or more sequences of SEQ ID NO: 2-135.

100. The composition of embodiment 99, wherein the peptide is an antibody, a CDR, VL or VH peptide as provided herein, or is a peptide or antibody of any one of embodiments 1-61.

101. A method for detecting the presence or absence of claudin 6 in a sample, comprising contacting the sample with an antibody as provided herein and any of the preceding embodiments, and detecting binding of claudin 6 to an antigen by the antibody, wherein detection of binding indicates the presence of claudin 6; or failure to detect binding of claudin 6 indicates the absence of claudin 6.

102. A method for delivering a composition to a cell expressing claudin 6, wherein the method comprises contacting the cell with an antibody as provided herein or an antibody of any of embodiments 1-61, wherein the antibody is linked to another molecule that is to be delivered to the cell expressing claudin 6.

103. The method of embodiment 102, wherein the antibody is an antibody, a CDR, VL, or VH peptide as provided herein, or is a peptide or antibody of any of embodiments 1-61, or comprises one or more of SEQ ID NOs: 2-135.

104. The methods of embodiments 102 or 103, wherein the other molecule is a drug.

105. A method for contacting a composition with a cell expressing claudin 6, wherein the method comprises contacting the cell with an antibody as provided herein, wherein the antibody is linked to another molecule for contacting the cell expressing claudin 6.

106. The method of embodiment 105, wherein the antibody is an antibody, a CDR, VL or VH peptide as provided herein, or is a peptide or antibody of any of embodiments 1-61, or comprises one or more of SEQ ID NOs: 2-135.

107. The methods of embodiment 105 or 106, wherein the other molecule is a drug.

108. The method according to any one of embodiments 105-107, wherein the cell expressing claudin 6 is in the body of the subject.

109. The method according to any one of embodiments 105-108, wherein the cell is a tumor cell.

110. The method according to embodiment 109, wherein the tumor cell is a solid tumor cell.

111. The method of embodiment 110, wherein the tumor cell is an ovarian tumor cell, a non-small cell lung cancer tumor cell, a teratoma tumor cell, a gastric tumor cell, a lung tumor cell, a breast tumor cell, or a colon tumor cell, or another type of tumor cell or cancer cell provided herein.

As provided herein, DNA (or RNA sequences) that may encode a protein may vary due to the degeneracy of the genetic code. Such variations are encompassed by the embodiments provided herein.

The subject matter of the invention is now described with reference to the following examples. These examples are provided for illustrative purposes only, and the claims should not be construed as limiting these examples in any way, but should be construed as covering any and all variations that become apparent from the teachings herein. Those skilled in the art will readily recognize many non-critical parameters that can be changed or modified to obtain substantially similar results.

Examples

Example 1: Antibodies to claudin 6 bind to claudin 6.

Figure 1 shows the results of a binding assay showing that anti-CL6 MAbs bind to human CL6. Human embryonic kidney 293T (HEK-293T) cells were transiently transfected with human CL6 DNA (hsCLDN6) or empty vector plus GFP (pUC) for 22 h. Anti-CL6 MAbs (IM136, IM171, IM172, and IM173) were added in serial dilutions (0.0-10 μg/ml) and incubated for 90 min with shaking. After a wash step, secondary detection antibody (allophycocyanin-conjugated mouse anti-human IgG Fc; Southern Biotech) was added and incubated for 30-45 min. Cells were washed and fluorescence was detected using Intellicyt high-throughput flow cytometry with gating by plotting forward scatter versus side scatter. Data were analyzed in GraphPad Prism software based on the geometric mean fluorescence intensity for the cell population in each well.

Example 2. Anti-claudin 6 antibodies bind preferentially to claudin 6 over other claudin proteins. Figure 2 illustrates the results of a binding assay showing that anti-claudin 6 MAbs bind preferentially to human claudin 6 over other claudin proteins. Human embryonic kidney 293T (HEK-293T) cells were transiently transfected with

- 75 047986

DNA of the specified claudin protein or empty vector together with GFP (pUC) for 22 hours. The results demonstrate that the antibodies can bind preferentially to claudin 6 rather than to other members of the family.

Example 3. Flow cytometry of HEK-293T cells transfected with plasmids expressing the indicated proteins. Fig. 3 illustrates the specificity of antibodies tested by flow cytometry as performed in Example 2.

Example 4. Binding of IM136 and IM171 to PA-1 cells naturally expressing claudin 6. Detection by flow cytometry by staining PA-1 cells with the indicated antibodies. Fig. 4 illustrates the binding of antibodies to PA-1 cells naturally expressing claudin 6. Detection by flow cytometry.

Example 5. Antibodies bind to cells naturally expressing claudin 6. Figure 5 illustrates binding of additional antibodies to PA-1 cells naturally expressing claudin 6. Detection by flow cytometry as performed in Example 4. DENV is the negative control antibody (against dengue virus).

Example 6. Figure 6 illustrates the binding specificity of MAb LM171 to claudin 6 to a membrane proteome chip (MPA) consisting of 5,300 human membrane proteins expressed in human HEK-293 cells. The cells were permeabilized with 0.1% saponin, the antibody was added to the MPA at a concentration of 1 μg/ml, and binding in the protein library was measured by high-throughput flow cytometry (Intellicyt HTFC) using a fluorescent secondary antibody. LM171 is highly specific for claudin 6.

Example 7. Specific antibodies to claudin 6 can function with a universal common light chain. Antibodies specific to claudin 6 were modified to replace the originally identified light chain with a common light chain. The results presented in the table below demonstrate that the common light chain can also support binding to claudin 6 or antibody expression/production. The results demonstrate that binding to claudin 6 is primarily determined by any variable heavy chains and the CDRs contained therein, and that these heavy chains can be paired with these or other conventional light chains.

Table 1. Expression and binding of anti-CL6 MAbs. Anti-CL6 MAbs produced using their natural light chain or produced using a different light chain. Yield represents the recovery of purified MAb and µg protein obtained from this preparation. Binding represents the binding of 66 nM of the indicated MAb to HEK-293T cells expressing the target CL6. Controls are the same MAbs staining HEK-293T cells not transfected with CL6. Staining was detected by flow cytometry (geometric mean fluorescence intensity), n/a, no data. Target MAY Yield (mcg) Linking CLDN6 IM179 116.2 n/a CLDN6 IM179 cFlOhcLC 152,0 n/a CLDN6 IM180 178.5 46 870 CLDN6 IM180 cFlOhcLC 166.3 10 085 Control (- CLDN6) IM180 cFlOhcLC 166.3 288 CLDN6 IM271 112.6 62 993 CLDN6 IM271 cFlOhcLC 124.2 160 301 Control (- CLDN6) IM271 cFlOhcLC 124.2 312

Example 8. Identification of critical residues for Ab binding.

Results of epitope mapping using shotgun mutagenesis. Average binding reactivities (and ranges) are listed for all identified critical residues. Critical residues for Ab binding (shaded in gray) were residues

- 76 047986 mutations of which were negative for binding to the test Abs (<30% wild-type reactivity) but positive for binding to the control MAb 3656. MAbs 3001-D5 and 3656 are claudin antibodies that are cross-reactive and bind claudin 6 and claudin 9. Thus, the epitope for MAb IM136 includes residues E48, D68, P74, D76, and R158. The epitope for MAb IM171 includes T33, N38, E48, D76, A153, E154, Q156, and R158. The epitope for MAb IM172 includes N38, E48, Y67, P74, D76, D146, V152, E154, Q156, and R158. The epitope for MAb IM173 includes E48, Y67, Q156, and R158. For example, the data show that an antibody that has preferential binding to claudin 6 over claudin 9 preferably contains Q156 as an epitope residue. The data are illustrated in Fig. 8.

Example 9. CAR-T cells expressing the anti-claudin 6 antibody IM136 are activated by cells expressing human or murine claudin 6. CAR-T cells lacking the claudin antibody (CAR negative T cells) are not activated by cells expressing claudin 6. Cell activation was measured by CD69 expression after overnight coincubation of the cells, as determined by flow cytometry with the anti-CD69 antibody. The data are shown in Fig. 7. The chimeric receptor comprises an extracellular domain comprising the anti-claudin 6 antibody (IM136) described herein as an scFv (VL-linker-VH) fused to the CD8 transmembrane domain, 4-1BB, and CD3-zeta signaling domains. This construct is based on the CAR construct described in Milone et al., Molecular Therapy vol. 17 no. 8, 1453-1464 August 2009, which is incorporated herein by reference in its entirety.

Example 10. Antibodies to claudin 6 specifically bind to claudin 6.

The table below provides information on the binding of various antibodies. Antibodies were tested for binding to claudin 6 and also to demonstrate specificity of such binding to CLDN9, CLDN4 and CLDN3.

Antibody CLDN6 binding (EC50) CLDN9 CLDN 4 CLDN 3 IM-271 less than 4 nM +/- - - IM-271-1HAQ less than 4 nM +/- +/- - IM-271-1HBG less than 4 nM - - - IM-271-1HFJ less than 4 nM - - - IM-271-1HEP less than 4 nM - - - IM-271-1HHP less than 4 nM - +/- - IM-35-N1F09- 1NA less than 4 nM + + + IM-271-1HBF less than 4 nM - +/- - IM-271-1HFB less than 4 nM - - - IM-271-1HHR less than 4 nM - +/- +/- IM-271-1HGT less than 4 nM + + +/- IM-35-N2H07- 1NA less than 4 nM + +/- -

The affinity of different antibodies to CLDN6 compared to CLDN9, CLDN3 and CLDN4 was measured using a biosensor. The biosensor measurement of the affinity of different antibodies to proteins was determined using Forte Octet, which was used for biosensor measurements using intact claudin proteins incorporated into virus-like particles (lipoparticles). The KD for different antibodies is shown below.

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Claims (21)

Antibody CLDN6 (K _D ) CLDN9 (K _D ) IM-136 12 nM 386 nM IM-171 3.0 nM 902 nM IM-172 Less than 0.1 nM 81 nM IM-173 0.32 nM n/a Clinical landmark 0.11 nM 94 nM The data demonstrate that the antibodies can specifically bind to claudin 6 without significant binding to CLDN9, CLDN4, and CLDN3. Thus, the embodiments and examples described herein demonstrate the production and specificity of antibodies to claudin 6 that can be used for the various methods described herein. The disclosures of any and all patents, patent applications, publications, and accession numbers cited in this document are hereby incorporated by reference herein in their entirety. Although the present invention has been disclosed with reference to various embodiments, it is obvious that other embodiments and variations thereof may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to include all such embodiments and equivalent variations. CLAUSE OF THE INVENTION 1. An antibody that binds to claudin 6, which comprises a heavy chain variable region comprising the sequences CDR1 (HCDR1), CDR2 (HCDR2) and CDR3 (HCDR3) of the heavy chain, and a light chain variable region comprising the sequences CDR1 (LCDR1), CDR2 (LCDR2) and CDR3 (LCDR3) of the light chain, wherein the antibody has HCDR1 according to SEQ ID NO: 62, HCDR2 according to SEQ ID NO: 125, HCDR3 according to SEQ ID NO: 66, LCDR1 according to SEQ ID NO: 64, LCDR2 according to SEQ ID NO: 59, LCDR3 according to SEQ ID NO: 60; HCDR1 according to SEQ ID NO: 62, HCDR2 according to SEQ ID NO: 125, HCDR3 according to SEQ ID NO: 65, LCDR1 according to SEQ ID NO: 64, LCDR2 according to SEQ ID NO: 59, LCDR3 according to SEQ ID NO: 60; or HCDR1 according to SEQ ID NO: 62, HCDR2 according to SEQ ID NO: 125, HCDR3 according to SEQ ID NO: 67, LCDR1 according to SEQ ID NO: 64, LCDR2 according to SEQ ID NO: 59, LCDR3 according to SEQ ID NO: 60; and binds to claudin 6 with an affinity of less than 10 nM and with an EC ₅₀ at least 100-fold greater than that for claudin 9, claudin 3 and/or claudin 4. 2. The antibody according to claim 1, characterized in that the antibody contains 1, 2, 3, 4 or 5 conservative substitutions, deletions or insertions compared to the sequence of SEQ ID NO: 62, SEQ ID NO: 125, SEQ ID NO: 66, SEQ ID NO: 64; SEQ ID NO: 59 or SEQ ID NO: 60. 3. A bispecific antibody comprising a first V _H peptide that binds to claudin 6 and a second V H peptide that binds to another fragment, wherein the bispecific antibody comprises heavy chain CDR1, CDR2 and CDR3 sequences, wherein the heavy chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 62; heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 125 and the heavy chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 65, 66 or 67; wherein the bispecific antibody comprises a light chain variable region comprising light chain CDR1, CDR2 and CDR3 sequences, wherein the light chain CDR1 sequence has the amino acid sequence of SEQ ID NO: 64; the light chain CDR2 sequence has the amino acid sequence of SEQ ID NO: 59 and the light chain CDR3 sequence has the amino acid sequence of SEQ ID NO: 60. 4. A nucleic acid molecule encoding the antibody according to claim 1 or 2 or the bispecific antibody according to claim 3. 5. A vector containing a nucleic acid molecule according to item 4. 6. A host cell containing a nucleic acid molecule according to claim 4 or a vector according to claim 5. 7. A pharmaceutical composition containing an antibody according to claim 1 or 2 or a bispecific antibody according to claim 3. 8. A method for modulating the activity of claudin 6 by contacting a cell expressing claudin 6 with an antibody to claudin 6 or a pharmaceutical composition comprising an antibody to claudin 6 that binds to claudin 6 on the surface of the cell, wherein said antibody is the antibody of claim 1 or 2 or the bispecific antibody of claim 3. - 78 047986 9. A method for inhibiting claudin 6 function by contacting a cell expressing claudin 6 with an antibody or a pharmaceutical composition comprising an antibody that inhibits claudin 6 function by binding to claudin 6, wherein said antibody is the antibody of claim 1 or 2 or the bispecific antibody of claim 3. 10. A method of treating a subject with a disorder mediated by claudin 6, comprising administering to the subject a pharmaceutical composition comprising an antibody to claudin 6, wherein said antibody is the antibody of claim 1 or 2 or the bispecific antibody of claim 3. 11. The method according to claim 10, characterized in that the disorder mediated by claudin 6 is a benign neoplasm or metastatic cancer, for example, ovarian cancer, ovarian carcinoma, cancer of the reproductive system, breast cancer, cervical cancer, testicular cancer, uterine cancer, placental cancer, lung cancer, gastric cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, kidney cancer, colon cancer, small intestine cancer, skin cancer, head and neck cancer, sarcoma, or germ cell tumor. 12. A method for treating a subject with an oncological disease, comprising administering the antibody of claim 1 or 2 or the bispecific antibody of claim 3, wherein the oncological disease is a benign neoplasm or metastatic oncological disease, ovarian cancer, ovarian carcinoma, reproductive system cancer, breast cancer, cervical cancer, testicular cancer, uterine cancer, placental cancer, lung cancer, gastric cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, kidney cancer, colon cancer, small intestine cancer, skin cancer, head and neck cancer, sarcoma or germ cell tumor. 13. The method according to claim 12, characterized in that the antibody comprises CDR, VL or VH containing one or more protein sequences of SEQ ID NO: 107-112. 14. The method according to claim 12, characterized in that the extracellular domain of the antibody according to claim 1 or 2 or the bispecific antibody according to claim 3 is part of a chimeric receptor or is contained in a chimeric receptor. 15. A pharmaceutical composition for treating a disorder mediated by claudin 6, comprising an antibody according to claim 1 or 2 or a bispecific antibody according to claim 3, conjugated to a drug or other therapeutic agent. 16. The composition according to claim 15, characterized in that the therapeutic agent is a cytokine. 17. The composition of claim 16, wherein the cytokine is IL-2. 18. The composition according to claim 15, characterized in that the composition is an antibody-drug conjugate (ADC). 19. The antibody of claim 1, which comprises a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 110 and/or a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 109. 20. The antibody of claim 1, which comprises a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 108 and/or a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107. 21. The antibody of claim 1, which comprises a light chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 112 and/or a heavy chain variable region that is at least 95% identical to the amino acid sequence of SEQ ID NO: 111. -