A method for treating or improving Cushing's syndrome using a protein that binds to the gastric suppressor peptide receptor (GIPR).

Abstract

A method is provided for treating subjects with disorders associated with elevated cortisol levels. [Solution] A method is provided comprising administering a therapeutically effective amount of an antigen-binding protein specific to the human gastric suppressor peptide receptor (GIPR) polypeptide to a target. In various embodiments, the disease or disorder is Cushing's syndrome.

Description

[Technical Field]

[0001] This disclosure relates to the treatment or improvement of Cushing's syndrome using an antigen-binding protein specific to the gastric suppressor peptide receptor (GIPR). [Background technology]

[0002] Cushing's syndrome is a rare disorder caused by an excess of adrenocortical hormones. The most common form of endogenous Cushing's syndrome is Cushing's disease, which is caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, which is involved in 70% of all cases of ACTH-dependent Cushing's syndrome. In Cushing's disease, cortisol levels become excessive as a result of the tumor's autologous ACTH secretion. Prolonged exposure to high cortisol levels in patients with Cushing's disease results in significant clinical burden, impaired health-related quality of life, and increased mortality.

[0003] A subset of Cushing's syndrome is ACTH-independent due to ectopic overexpression of glucose-dependent insulin-stimulating polypeptide receptor (GIPR) in adrenocortical adenomas (JCI Insight. 2017; 2(18): e92184). Glucose-dependent insulin-stimulating polypeptide (GIP) is a single 42-amino acid peptide secreted by K cells in the small intestine (duodenum and jejunum). Human GIP is produced by the processing of proGIP, a 153-amino acid precursor encoded by a gene localized on chromosome 17q (Inagaki et al., Mol Endocrinol 1989; 3: 1014-1021; Fehmann et al. Endocr Rev. 1995; 16: 390-410). GIP was formerly known as gastric suppressor polypeptide.

[0004] The GIP receptor (GIPR) is a member of the secretin - glucagon family of G - protein - coupled receptors (GPCRs) that has an extracellular N - terminus, seven transmembrane domains, and an intracellular C - terminus. The N - terminal extracellular domain of this receptor family is typically glycosylated and forms the recognition and binding domains of the receptor. GIPR is highly expressed in many tissues including the pancreas, intestine, adipose tissue, heart, pituitary gland, adrenal cortex, and brain (Usdin et al., Endocrinology. 1993, 133:2861 - 2870). The human GIPR contains 466 amino acids and is encoded by a gene located on chromosome 19q13.3 (Gremlich et al., Diabetes. 1995;44:1202 - 8; Volz et al., FEBS Lett. 1995, 373:23 - 29). In humans, rats, and mice, studies have suggested that alternative mRNA splicing results in GIP receptor variants of different lengths.

[0005] Thus, the inventors believe that GIPR - antagonistic antibodies can be used to prevent the symptoms of Cushing's disease in these patients. Furthermore, there is also evidence in the literature that GIPR is overexpressed in the adrenals of ACTH - dependent Cushing's disease (The Journal of Clinical Endocrinology & Metabolism 9(5):3009 - 3016), raising the possibility that GIPR antagonism may also be useful in treatment, given that the most common cause of Cushing's syndrome is ACTH over - secretion by an adenoma of the adrenocorticotropic hormone - secreting cells of the anterior pituitary gland.

Prior Art Documents

Non - Patent Documents

[0006]

Non - Patent Document 1

Non - Patent Document 2

[0007] In one aspect, the present disclosure provides a method for treating a subject with Cushing's syndrome, the method comprising administering to the subject a therapeutically effective amount of an antigen - binding protein that specifically binds to a protein having an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence of GIPR.

[0008] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human. In another embodiment, the GIPR is a human GIPR. In another embodiment, the administration is by parenteral injection. In another embodiment, the administration is by subcutaneous injection. [Brief Description of the Drawings]

[0009] [Figure 1] After GIP stimulation, compared with the vehicle, the corticosterone levels were significantly decreased in both the treatment groups of MuGIPR - Ab and GIPR - agonist at plasma and WAT levels. [Figure 2] Fasting [D-Ala2]-GIP Challenge-ARM 1 [Figure 3] Fasting [D-Ala2]-GIP Challenge-ARM 2 [Modes for carrying out the invention]

[0010] This disclosure provides a method for treating Cushing's syndrome by blocking or interfering with the biological activity of GIP. In one embodiment, a therapeutically effective amount of isolated human GIPR-binding protein is administered to a subject in need. A method of administration and a method of delivery are also provided.

[0011] The recombinant polypeptide and nucleic acid methods used herein, including in the examples, are generally described in Sambrook et al., Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1989) or Current Protocols in Molecular Biology (Ausubel et al., eds., Green Publishers Inc. and Wiley and Sons 1994), both of which are incorporated herein by reference for all purposes.

[0012] The section headings used herein are for organizational purposes only and should not be interpreted as limiting the subjects described.

[0013] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meanings generally understood by those skilled in the art. Furthermore, unless the context requires otherwise, singular terms shall include plural forms, and plural terms shall include singular forms.

[0014] In general, the nomenclature and techniques used in relation to cell and tissue culture, molecular biology, immunology, microbiology, genetics, and the chemistry and hybridization of proteins and nucleic acids described herein are well known and commonly used in the art. Unless otherwise stated, the methods and techniques of this application are generally carried out in accordance with conventional methods well known in the art and as described in the various general and more specific references cited and discussed throughout this specification. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (2001), Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), and Harlow and Lane Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1990) (incorporated herein by reference). Enzymatic reactions and purification techniques are carried out in accordance with the manufacturer's instructions, or as commonly achieved in the art, or as described herein. The terminology, laboratory procedures, and techniques used in relation to analytical chemistry, synthetic organic chemistry, medicinal chemistry, and pharmaceutical chemistry described herein are well-known and commonly used in the art. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and patient care.

[0015] The present invention is not limited to, and should therefore be understood to be, limited to, the specific methodologies, protocols, and reagents described herein. The technical terms used herein are for illustrative purposes only and are not intended to limit the scope of the disclosure, which is defined solely by the claims.

[0016] Unless otherwise described in the examples or elsewhere, all numbers indicating quantities of components or reaction conditions used herein should be understood to be modified in all cases by the term “approximately.” When used in relation to a percentage, the term “approximately” may mean ±1%.

[0017] Unless otherwise stated, “one (a)” and “one (an)” as used herein mean, by convention, “one or more.”

[0018] As used herein, the terms “amino acid” and “residue” are interchangeable, and when used in connection with peptides or polypeptides, they refer to both naturally occurring and synthetic amino acids, as well as amino acid analogs, amino acid mimes, and non-naturally occurring amino acids that are chemically similar to naturally occurring amino acids.

[0019] "Naturally occurring amino acids" are amino acids encoded by the genetic code, as well as amino acids encoded by the genetic code that are modified after synthesis (e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine). Amino acid analogs are compounds having the same basic chemical structure as naturally occurring amino acids, i.e., an α-carbon bonded to hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, and methylmethionine sulfonium. Such analogs may have a modified R group (e.g., norleucine) or a modified peptide skeleton, but will retain the same basic chemical structure as naturally occurring amino acids.

[0020] "Amino acid mimes" are chemical compounds that have a structure different from the general chemical structure of amino acids, but function in a manner similar to naturally occurring amino acids. Examples include methacryloyl or acryloyl derivatives of amides, β-amino acids, γ-amino acids, and δ-amino acids (such as piperidine-4-carboxylic acid).

[0021] "Non-natural amino acids" are compounds that have the same basic chemical structure as naturally occurring amino acids but are not incorporated into the elongated polypeptide chain by translational complexes. "Non-natural amino acids" also include, but are not limited to, amino acids that result from the modification (e.g., post-translational modification) of naturally encoded amino acids (including, but not limited to, 20 common amino acids) but are not naturally incorporated into the elongated polypeptide chain by translational complexes. An unrestricted list of examples of non-natural amino acids that can be inserted into polypeptide sequences or substituted for wild-type residues in polypeptide sequences includes, but is not limited to, β-amino acids, homoamino acids, cyclic amino acids, and amino acids with derivatized side chains. Examples include (in L-form or D-form;Abbreviations as shown in parentheses: Citrulline (Cit), Homocitrulline (hCit), Nα-Methylcitrulline (NMeCit), Nα-Methylhomocitrline (Nα-MeHoCit), Ornithine (Orn), Nα-Methylornithine (Nα-MeOrn or NMeOrn), Sarcosine (Sar), Homolysine (hLys or hK), Homoarginine (hArg or hR), Homoglutamine (hQ), Nα-Methylarginine (NMeR), Nα-Methylleucine (Nα-MeL or NMeL), N-Methylhomolisine (NMeHoK) ), Nα-methylglutamine (NMeQ), norleucine (Nle), norvaline (Nva), 1,2,3,4-tetrahydroisoquinoline (Tic), octahydroindole-2-carboxylic acid (Oic), 3-(1-naphthyl)alanine (1-Nal), 3-(2-naphthyl)alanine (2-Nal), 1,2,3,4-tetrahydroisoquinoline (Tic), 2-indanylglycine (IgI), para-indophenylalanine (pI-Phe), para-aminophenylalanine (4AmP or 4-amino-Phe), 4-guanidi Nophenylalanine (Guf), glycyrlysine (abbreviated as "K(Nε-glycyl)", "K(glycyl)", or "K(gly)"), nitrophenylalanine (nitrophe), aminophenylalanine (aminophe or amino-phe), benzylphenylalanine (benzylphe), γ-carboxyglutamic acid (γ-carboxyglu), hydroxyproline (hydroxypro), p-carboxyl-phenylalanine (Cpa), α-aminoadipic acid (Aad), Nα-methylvaline (NMeVal), N-α-methylvaline Tylleucine (NMeLeu), Nα-methylnorleucine (NMeNle), cyclopentylglycine (Cpg), cyclohexylglycine (Chg), acetylarginine (acetylarg), α,β-diaminopropionic acid (Dpr), α,γ-diaminobutyric acid (Dab), diaminopropionic acid (Dap), cyclohexylalanine (Cha), 4-methylphenylalanine (MePhe), β,β-diphenylalanine (BiPhA), aminobutyric acid (Abu), 4-phenylphenylalanine (or biphenylalanine;Examples include 4B ip), α-aminoisobutyric acid (Aib), beta-alanine, beta-aminopropionic acid, piperidine acid, aminocaprioic acid, aminoheptanoic acid, aminopimelic acid, desmosine, diaminopimelic acid, N-ethylglycine, N-ethylasparagine, hydroxylysine, allo-hydroxylysine, isodesmosine, allo-isoleucine, N-methylglycine, N-methylisoleucine, N-methylvaline, 4-hydroxyproline (Hyp), γ-carboxyglutamate, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, ω-methylarginine, 4-amino-O-phthalic acid (4APA), and other similar amino acids and any of the derivatized forms specifically listed.

[0022] The term “isolated nucleic acid molecule” refers to a polymer of single or double-stranded deoxyribonucleotides or ribonucleotide bases read from the 5' end to the 3' end (e.g., the GIPR nucleic acid sequence provided herein) or analogue thereof, from which at least about 50 percent of the polypeptides, peptides, lipids, carbohydrates, polynucleotides, or other substances naturally found with the nucleic acid when the whole nucleic acid is isolated from a cell source have been removed. Preferably, the isolated nucleic acid molecule is substantially free of any other contaminating nucleic acid molecules or other molecules that are found in the natural environment of the nucleic acid and are assumed to interfere with its use in polypeptide production or its therapeutic, diagnostic, prophylactic, or research use.

[0023] The term “isolated polypeptide” refers to a polypeptide (e.g., the GIPR polypeptide sequence provided herein or the antigen-binding protein of the present invention) from which at least about 50 percent of the polypeptides, peptides, lipids, carbohydrates, polynucleotides, or other materials naturally found with the polypeptide have been removed when the polypeptide is isolated from the cell source. The isolated polypeptide is preferably substantially free of any other contaminating polypeptides or other contaminants found in its natural environment that would be considered to interfere with its therapeutic, diagnostic, prophylactic, or research use.

[0024] The term "coding" refers to a polynucleotide sequence that codes for one or more amino acids. This term does not require a start or stop codon.

[0025] The terms “identical” and “identity” percentages, as used in relation to two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that are identical. “Identity percentage” means the percentage of residues that are identical between amino acids or nucleotides in the comparison molecule, calculated based on the size of the smallest one in the comparison molecule. In such calculations, any alignment gaps (if any) may be addressed by specific mathematical models or computer programs (i.e., “algorithms”). Methods that may be used to calculate the identity of aligned nucleic acids or polypeptides include those described in Computational Molecular Biology, (Lesk, AM, ed.), (1988) New York: Oxford University Press; Biocomputing Informatics and Genome Projects, (Smith, DW, ed.), 1993, New York: Academic Press; Computer Analysis of Sequence Data, Part I, (Griffin, AM, and Griffin, HG, eds.), 1994, New Jersey: Humana Press; von Heinje, G., (1987) Sequence Analysis in Molecular Biology, New York: Academic Press; Sequence Analysis Primer, (Gribskov, M. and Devereux, J., eds.), 1991, New York: M. Stockton Press; and Carillo et al., (1988) SIAM J. Applied Math. 48:1073.

[0026] In calculating the identity percentage, the sequences being compared are aligned to maximize the match between them. The computer program used to determine the identity percentage is the GCG program package, which includes GAP (Devereux et al., (1984) Nucl. Acid Res. 12:387; Genetics Computer Group, University of Wisconsin, Madison, WI). The computer algorithm GAP is used to align two polypeptides or polynucleotides to determine the sequence identity percentage. The sequences are aligned so that their respective amino acids or nucleotides match best (the "match span" determined by the algorithm). A gap-start penalty (calculated as 3x mean diagonal, where "mean diagonal" is the average of the diagonals of the comparison matrix used; "diagonal" is the score or number assigned to each perfect amino acid match by a particular comparison matrix) and a gap-extension penalty (usually 1 / 10th of the gap-start penalty), as well as a comparison matrix such as PAM 250 or BLOSUM 62, are used with the algorithm. In certain embodiments, standard comparison matrices (for the PAM 250 comparison matrix, Dayhoff et al., (1978) Atlas of Protein Sequence and Structure 5:345-352; for the BLOSUM 62 comparison matrix, Henikoff et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919) are also used by the algorithm.

[0027] The following are recommended parameters for determining the identity percentage of polypeptide or nucleotide sequences using the GAP program: Algorithm: Needleman et al., 1970, J.Mol.Biol.48:443-453; Comparison matrix: Henikoff et al., 1992, BLOSUM 62 from the above; Gap penalty: 12 (but no penalty for end gaps) Gap length penalty: 4 Similarity threshold: 0

[0028] In a given alignment scheme for aligning two amino acid sequences, only short regions of the two sequences may match, and these aligned small regions can have very high sequence identity even if there is no significant relationship between the two full-length sequences. Therefore, the chosen alignment method (e.g., the GAP program) can be adjusted, if desired, to produce alignment over at least 50 consecutive amino acids of the target polypeptide.

[0029] The terms “GIPR polypeptide” and “GIPR protein” are used interchangeably and refer to the naturally occurring wild-type polypeptide expressed in mammals such as humans or mice, including the natural allele (e.g., the natural allele form of human GIPR protein). For the purposes of this disclosure, the term “GIPR polypeptide” may be used interchangeably to refer to any full-length GIPR polypeptide, for example, SEQ ID NO: 3141, consisting of 466 amino acid residues and encoded by the nucleotide sequence of SEQ ID NO: 3142, or SEQ ID NO: 3143, consisting of 430 amino acid residues and encoded by the nucleic acid sequence of SEQ ID NO: 3144, or SEQ ID NO: 3145, consisting of 493 amino acid residues and encoded by the nucleic acid sequence of SEQ ID NO: 3146, or SEQ ID NO: 3147, consisting of 460 amino acid residues and encoded by the nucleic acid sequence of SEQ ID NO: 3148, or SEQ ID NO: 3149, consisting of 230 amino acid residues and encoded by the nucleic acid sequence of SEQ ID NO: 3150.

[0030] The term "GIPR polypeptide" also includes GIPR polypeptides modified from the natural GIPR polypeptide sequence (e.g., SEQ ID NOs. 3141, 3143, or 3145). Such modifications include, but are not limited to, one or more amino acid substitutions, including substitutions with unnatural amino acids, unnatural amino acid analogs, and amino acid mimes.

[0031] In various embodiments, the GIPR polypeptide comprises an amino acid sequence that is at least about 85 percent identical to a natural GIPR polypeptide (e.g., SEQ ID NOs. 3141, 3143, or 3145). In other embodiments, the GIPR polypeptide comprises an amino acid sequence that is at least about 90 percent, or about 95, 96, 97, 98, or 99 percent identical to a natural GIPR polypeptide amino acid sequence (e.g., SEQ ID NOs. 3141, 3143, or 3145). Such GIPR polypeptides preferably have at least one activity of the wild-type GIPR polypeptide, such as the ability to bind to GIP, although this is not necessarily required. The present invention also encompasses nucleic acid molecules encoding such GIPR polypeptide sequences.

[0032] The term “GIPR activity assay” (also called “GIPR function assay”) refers to an assay that may be used to measure the activity of GIP or GIP-binding protein in a cellular context. In one embodiment, the “activity” (or “function” assay) may be a cAMP assay in GIPR-expressing cells (where GIP can induce cAMP signaling), where the activity of the GIP / GIPR-binding protein may be measured in the presence or absence of a GIP ligand, in which case the IC50 / EC50 and degree of inhibition / activation can be obtained (Biochemical and Biophysical Research Communications (2002) 290:1420-1426). In another embodiment, the “activity” (or “function”) assay could be an insulin secretion assay in pancreatic beta cells (where GIP can induce glucose-dependent insulin secretion), in which the activity of the GIP / GIPR-binding protein could be measured in the presence or absence of the GIP ligand, in which case the IC50 / EC50 and degree of inhibition / activation could be obtained (Biochemical and Biophysical Research Communications (2002) 290:1420-1426).

[0033] The term “GIPR binding assay” refers to an assay that can be used to measure the binding of GIP to GIPR. In one embodiment, a “GIPR binding assay” may be an assay using FMAT or FACS to measure the binding of fluorescently labeled GIP to GIPR-expressing cells, and the activity of the GIP / GIPR binding protein may be measured in relation to the replacement of the binding of fluorescently labeled GIP to GIPR-expressing cells. In another embodiment, a “GIPR binding assay” may be an assay to measure the binding of radiolabeled GIP to GIPR-expressing cells, and the activity of the GIP / GIPR binding protein may be measured in relation to the replacement of the binding of radiolabeled GIP to GIPR-expressing cells (Biochimica et Biophysica Acta (2001) 1547:143-155).

[0034] The terms “GIP,” “gastric suppressor polypeptide,” “glucose-dependent insulinotropic peptide,” and “GIP ligand” are used interchangeably and refer to the naturally occurring wild-type polypeptide expressed in mammals such as humans or mice, including the natural allele (e.g., the natural allele form of the human GIP protein). For the purposes of this disclosure, the term “GIP” may be used interchangeably to refer to any mature GIP polypeptide.

[0035] The 42-amino acid sequence of mature human GIP is: YAEGTFISDY SIAMDKIHQQ DFVNWLLAQK GKKNDWKHNI TQ (Sequence ID 3151) DNA sequence: [ka] It is coded by.

[0036] The 42 amino acid sequence of mature mouse GIP is: YAEGTFISDY SIAMDKIRQQ DFVNWLLAQR GKKSDWKHNI TQ (Sequence ID 3153) DNA sequence: [ka] It is coded by.

[0037] The 42 amino acid sequence of mature rat GIP is: YAEGTFISDY SIAMDKIRQQ DFVNWLLAQK GKKNDWKHNL TQ (Sequence ID 3155) DNA sequence: [ka] Coded by

[0038] As used herein, “antigen-binding protein” means any protein that specifically binds to a particular target antigen, such as a GIPR polypeptide (e.g., a human GIPR polypeptide, such as those provided in SEQ ID NOs. 3141, 3143, or 3145). The term encompasses intact antibodies, as well as their derivatives, variants, fragments, and mutations, comprising at least two full-length heavy chains and two full-length light chains. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, and Fv fragments. Antigen-binding proteins also include domain antibodies such as nanobodies and scFv, as further described below.

[0039] Generally, GIPR antigen-binding proteins are said to "specifically bind" to their target antigen, GIPR, when the antigen-binding protein exhibits essentially background binding to non-GIPR molecules. However, antigen-binding proteins that specifically bind to GIPR can cross-react with GIPR polypeptides from different species. Typically, when GIPR antigen-binding proteins are measured via surface plasma resonance techniques (e.g., BIACore, GE-Healthcare Uppsala, Sweden) or binding equilibrium exclusion assays (KinExA, Sapidyne, Boise, Idaho), the dissociation constant (KD) is ≤10. -7 When M, it specifically binds to human GIPR. When the GIPR antigen-binding protein is measured using the method described, if the KD is ≤ 5x10-9 When M is present, it specifically binds to human GIPR with "high affinity," and KD is ≤ 5x10 -10 When M, it specifically binds to human GIPR with "very high affinity".

[0040] The "antigen-binding region" refers to a protein or a portion of a protein that specifically binds to a particular antigen. For example, the portion of an antigen-binding protein that contains amino acid residues that interact with the antigen and give the antigen its specificity and affinity is called the "antigen-binding region." An antigen-binding region typically contains one or more "complementary binding regions" ("CDRs") of an immunoglobulin, single-chain immunoglobulin, or antibody of a camelid animal. A particular antigen-binding region also contains one or more "framework" regions. The "CDR" is an amino acid sequence that contributes to the specificity and affinity of antigen binding. The "framework" regions can facilitate binding between the antigen-binding region and the antigen by helping to maintain the proper three-dimensional structure of the CDR.

[0041] "Recombinant proteins," including recombinant GIPR antigen-binding proteins, are proteins prepared using recombinant techniques, i.e., through the expression of recombinant nucleic acids as described herein. Methods and techniques for producing recombinant proteins are well known in the art.

[0042] The term “antibody” refers to a fragment of an intact immunoglobulin of some isotype or a target antigen that can compete with an intact antibody for specific binding, including, for example, chimeric, humanized, fully human, and bispecific antibodies. Thus, an “antibody” is a type of antigen-binding protein. An intact antibody generally contains at least two full-length heavy chains and two full-length light chains. An antibody may originate from only a single source, or it may be a “chimera,” i.e., different parts of the antibody may originate from two different antibodies, as further described below. Antigen-binding proteins, antibodies, or binding fragments can be produced in a hybridoma by recombinant DNA technology, or by enzymatic or chemical cleavage of an intact antibody.

[0043] The term "light chain" as used in reference to antibodies or fragments thereof includes the full-length light chain and fragments thereof that have a variable region sequence sufficient to confer binding specificity. The full-length light chain contains a variable region domain (VL) and a constant region domain (CL). The variable region domain of the light chain is located at the amino terminus of the polypeptide. The light chain contains a κ (kappa) chain and a λ (lambda) chain.

[0044] When used in reference to an antibody or a fragment thereof, the term “heavy chain” includes the full-length heavy chain and the fragment thereof having a variable region sequence sufficient to confer binding specificity. The full-length heavy chain comprises a variable region domain (VH) and three constant region domains (CH1, CH2, and CH3). The VH domain is located at the amino terminus of the polypeptide, the CH domain is located at the carboxyl terminus, and CH3 is located closest to the carboxyl terminus of the polypeptide. The heavy chain can be of any isotype, including IgG (including IgG1, IgG2, IgG3, and IgG4 subtypes), IgA (including IgA1 and IgA2 subtypes), IgM, and IgE.

[0045] As used herein, the term “immunologically functional fragment” (or simply “fragment”) of an antibody or immunoglobulin chain (heavy or light chain) is an antigen-binding protein that contains a portion of an antibody (regardless of how the portion is obtained or synthesized) that lacks at least some of the amino acids present in the full-length chain but has the ability to specifically bind to an antigen. Such a fragment is biologically active in that it specifically binds to a target antigen and may compete with other antigen-binding proteins, including intact antibodies, for specific binding to a given epitope.

[0046] These biologically active fragments can be produced by recombinant DNA technology or by enzymatic or chemical cleavage of antigen-binding proteins, including intact antibodies. Immunologically functional immunoglobulin fragments include, but are not limited to, Fab, Fab', and F(ab')2 fragments.

[0047] In another embodiment, these may be Fv, a domain antibody, and scFv, which may be derived from the antibodies of the present invention.

[0048] For example, it is further intended that the functional portions of antigen-binding proteins disclosed herein, such as one or more CDRs, can be covalently bonded to a second protein or small molecule to create therapeutic agents targeting specific targets in the body, giving them bifunctional therapeutic properties, or extending their serum half-life.

[0049] A "Fab fragment" consists of one light chain and one heavy chain CH1 and a variable region. The heavy chain of a Fab molecule cannot form disulfide bonds with other heavy chain molecules.

[0050] The "Fc" region contains two heavy chain fragments, each containing the CH2 and CH3 domains of the antibody. These two heavy chain fragments are held together by two or more disulfide bonds and hydrophobic interactions of the CH3 domain.

[0051] A "Fab' fragment" consists of one light chain and a portion of a heavy chain that includes the VH domain and the CH1 domain, as well as the region between the CH1 and CH2 domains. As a result, an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form an F(ab')2 molecule.

[0052] The "F(ab')2 fragment" consists of two light chains and two heavy chains that include a portion of the constant region between the CH1 and CH2 domains, resulting in the formation of an interchain disulfide bond between the two heavy chains. Thus, the F(ab')2 fragment is composed of two Fab' fragments held together by a disulfide bond between the two heavy chains.

[0053] The "Fv region" includes variable regions derived from both heavy and light chains, but lacks a steady region.

[0054] A "single-chain antibody" or "scFv" is an Fv molecule in which the heavy chain and light chain variable regions are linked by a flexible linker to form a single polypeptide chain in which the antigen-binding region is located. scFv is discussed in detail in International Publication No. 88 / 01649 and U.S. Patent Nos. 4,946,778 and 5,260,203, which are incorporated by reference.

[0055] A "domain antibody" or "single-chain immunoglobulin" is an immunologically functional immunoglobulin fragment that contains only the variable region of the heavy chain or the variable region of the light chain. Examples of domain antibodies include Nanobodies®. In some cases, two or more VH regions are covalently linked via a peptide linker to create a bivalent domain antibody. The two VH regions of a bivalent domain antibody may target the same or different antigens.

[0056] A "bivalent antigen-binding protein" or "bivalent antibody" contains two antigen-binding regions. In some cases, the two binding regions have the same antigen specificity. Bivalent antigen-binding proteins and bivalent antibodies can be bispecific; see below for more information.

[0057] A "multispecific antigen-binding protein" or "multispecific antibody" targets multiple antigens or epitopes.

[0058] "Dual-specific," "bispecific," or "dual-functional" antigen-binding proteins or antibodies are hybrid antigen-binding proteins or antibodies, each possessing two distinct antigen-binding sites. Dual-specific antigen-binding proteins and antibodies are a type of polyspecific antigen-binding protein or polyspecific antibody, and can be produced by various methods, including but not limited to hybridoma fusion or Fab' fragment linking. See, for example, Songsivilai and Lachmann, 1990, Clin. Exp. Immunol. 79:315-321; Kostelny et al., 1992, J. Immunol. 148:1547-1553. The two binding sites of a dual-specific antigen-binding protein or antibody bind to two distinct epitopes, which may reside on the same or different protein targets.

[0059] When used in relation to antigen-binding proteins (e.g., antibodies), the term “competition” means competition between antigen-binding proteins, as determined by assays in which one antigen-binding protein (e.g., an antibody or an immunofunctional fragment thereof) blocks or inhibits, under test, the specific binding of a reference antigen-binding protein to a common antigen (e.g., GIPR or a fragment thereof). Many types of competitive binding assays can be used, for example, solid-phase direct or indirect radioimmunoassays (RIAs), solid-phase direct or indirect enzyme immunoassays (EIAs), sandwich competitive assays (see, e.g., Stahli et al., 1983, Methods in Enzymology 9:242-253); solid-phase direct biotin-avidin EIA (see, e.g., Kirkland et al., 1986, J.Immunol. 137:3614-3619); solid-phase direct labeling assays, solid-phase direct labeling sandwich assays (see, e.g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid-phase direct labeling RIA with I-125 labeling (see, e.g., Morel et al., 1988, Molec.Immunol. 25:7-15); solid-phase direct biotin-avidin EIA (see, e.g., Cheung, et al., 1990, Virology). See 176:546-552); and directly labeled RIA (see Moldenhauer et al., 1990, Scand. J. Immunol. 32:77-82). Typically, such assays use purified antigen bound to a solid surface or cells containing either such antigen, an unlabeled test antigen-binding protein, and a labeled reference antigen-binding protein. Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test antigen-binding protein. Typically, the test antigen-binding protein is present in excess. Further details on methods for determining competitive binding are provided in the examples herein.Typically, when there is an excess of competing antigen-binding proteins, these proteins inhibit the specific binding of the reference antigen-binding protein to the common antigen by at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. In some cases, binding is inhibited by at least 80%, 85%, 90%, 95%, or 97% or more.

[0060] The term "antigen" refers to a molecule or part of a molecule that has the ability to be bound by a selective binder, such as an antigen-binding protein (including an antibody), and that can be used in an animal to produce an antibody capable of binding to that antigen. An antigen may have one or more epitopes that have the ability to interact with different antigen-binding proteins, such as antibodies.

[0061] The term "epitope" refers to a part of a molecule that is bound by an antigen-binding protein (e.g., an antibody). The term includes any determinant that has the ability to specifically bind to an antigen-binding protein, such as an antibody. Epitopes can be continuous or discontinuous (discontinuous) (for example, in a polypeptide, amino acid residues that are not continuous in the polypeptide sequence but are linked within the molecule are bound by the antigen-binding protein). A structural epitope is one that is present in the three-dimensional structure of an active protein but not in a denatured protein. In certain embodiments, an epitope may be mimicry in that it contains a three-dimensional structure similar to the epitope used to generate the antigen-binding protein, but does not contain, or contains only some of, the amino acid residues found in that epitope used to generate the antigen-binding protein. Epitopes are most commonly found in proteins, but in some examples they can be found in other types of molecules, such as nucleic acids. Epitope determinants may include chemically active surface groupings of a molecule, such as amino acids, sugar side chains, phosphate groups, or sulfonyl groups, and may possess specific three-dimensional structural properties and / or specific charge properties. Generally, antigen-binding proteins specific to a particular target antigen preferentially recognize epitopes present on the target antigen in complex mixtures of proteins and / or macromolecules.

[0062] As used herein, “substantially pure” means that the described molecular species is the dominant species present, i.e., more abundant on a molar basis than any other individual species in the same mixture. In certain embodiments, a substantially pure molecule is a composition containing at least 50% (on a molar basis) of all polymer species in which the species of interest is present. In other embodiments, a substantially pure composition comprises at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of all polymer species present in the composition. In other embodiments, the species of interest is purified to a substantially homogeneous state, and no impurities in the composition can be detected by conventional detection methods, so that the composition consists of a single detectable polymer species.

[0063] The term “treating” refers to any sign of success in treating or improving an injury, condition, or state, which may include any objective or subjective parameters such as reduction, remission, or reduction of symptoms or improved patient tolerance of the injury, condition, or state; slowing of the rate of exacerbation or decline; reduction of debilitation at the endpoint of exacerbation; or improvement of the patient’s physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. For example, certain methods given herein treat Cushing’s syndrome well by lowering cortisol levels and / or improving the symptoms associated with Cushing’s syndrome. Cushing’s syndrome may be ACTH-dependent as a result of a pituitary tumor that produces excessive ACTH in the pituitary gland, stimulating the adrenal gland to produce excessive cortisol. Other types of tumors, including tumors in the lungs, pancreas, and thyroid gland, may also produce ACTH, resulting in the production of excessive cortisol. Furthermore, tumors in the adrenal glands can also cause excessive cortisol production. In food-dependent Cushing's syndrome, the consumption of dietary foods leads to the normal release of GIP from the gut, which in turn promotes excessive cortisol production through GIPR expression in adrenal cortical adenomas (JCI Insight. 2017; 2(18): e92184).

[0064] An “effective dose” is generally a sufficient amount to reduce the severity and / or frequency of symptoms, eliminate symptoms and / or their underlying causes, prevent the onset of symptoms and / or their underlying causes, and / or improve or repair damage resulting from or associated with the disease state (e.g., Cushing’s syndrome). In some embodiments, an effective dose is a therapeutic effective dose or a prophylactic effective dose. A “therapeutic effective dose” is a sufficient amount to treat a disease state (e.g., atherosclerosis) or symptoms, in particular a condition or symptom associated with the disease state, or a sufficient amount to prevent, stop, delay or improve the progression of the disease state or any other undesirable symptoms associated with the disease, by any means. A “prophylactic effective dose” is a quantity of a pharmaceutical composition that, when administered to a subject, will have the intended prophylactic effect, such prophylactic effect being, for example, prevention or delay of the onset (or recurrence) of a disease state, or a reduction in the likelihood of the onset (or recurrence) of a disease state or associated symptoms. A complete therapeutic or prophylactic effect may not necessarily occur with a single dose, but may occur only after a series of doses have been administered. Therefore, a therapeutic or prophylactic effective dose can be administered in one or more doses.

[0065] As used herein, the terms “therapeutic effective dose” and “therapeutic effective amount” mean the amount of GIPR-binding protein that elicits a biological or pharmacokinetic response in a tissue system, animal or human being being explored by a researcher, physician or other clinician, including the alleviation or improvement of symptoms of a disease or disorder under treatment, i.e., the amount of GIPR-binding protein that supports one or more desired biological or pharmacokinetic responses at an observable level, such as a reduction in cortisol levels.

[0066] The terms "polynucleotide" or "nucleic acid" include both single-stranded and double-stranded nucleotide polymers. The nucleotides constituting a polynucleotide may be ribonucleotides, deoxyribonucleotides, or modified forms of either type of nucleotide. Modifications include base modifications such as bromouridine and inosine derivatives, ribose modifications such as 2',3'-dideoxyribose, and modifications of internucleotide bonds such as phosphorothioates, phosphorodioates, phosphoroselenoates, phosphorodyselenoates, phosphoranilothioates, phosphoroaniladates, and phosphoramidates.

[0067] The term "oligonucleotide" refers to a polynucleotide containing 200 or fewer nucleotides. In some embodiments, oligonucleotides are 10 to 60 nucleotides long. In other embodiments, oligonucleotides are 12, 13, 14, 15, 16, 17, 18, 19, or 20 to 40 nucleotides long. Oligonucleotides may be single-stranded or double-stranded for use, for example, in the construction of mutant genes. Oligonucleotides may be sense oligonucleotides or antisense oligonucleotides. Oligonucleotides may include labels, including radiolabeling, fluorescent labeling, hapten, or antigenic labeling for detection assays. Oligonucleotides may be used, for example, as PCR primers, cloning primers, or hybridization probes.

[0068] "Isolated nucleic acid molecule" means DNA or RNA of genomic, mRNA, cDNA, or synthetic origin, or any combination thereof, wherein the isolated polynucleotide does not contain all or some of the naturally occurring polynucleotides, or is ligated to polynucleotides that are not naturally ligated. For the purposes of this disclosure, "nucleic acid molecule containing" a particular nucleotide sequence should be understood not to include an intact chromosome. An isolated nucleic acid molecule "containing" a particular nucleic acid sequence may, in addition to that particular sequence, contain up to 10 or even up to 20 other sequences encoding proteins or parts thereof, or may contain regulatory sequences that control the expression of the coding region of the described nucleic acid sequence in a manipulatively ligated manner, and / or may contain vector sequences.

[0069] Unless otherwise specified, the left end of any single-stranded polynucleotide sequence discussed herein is the 5' end, and the left direction of a double-stranded polynucleotide sequence is called the 5' direction. The direction of addition from 5' to 3' of a nascent RNA transcript is called the transcription direction; the sequence region on the DNA strand that has the same sequence as the RNA transcript on the 5' side of the 5' end of the RNA transcript is called the “upstream sequence”; and the sequence region on the DNA strand that has the same sequence as the RNA transcript on the 3' side of the 3' end of the RNA transcript is called the “downstream sequence.”

[0070] The term “regulatory sequence” refers to a polynucleotide sequence that can influence the expression and processing of the coding sequence to which it is ligated. The properties of such a regulatory sequence may depend on the host organism. In certain embodiments, a regulatory sequence for prokaryotes may include a promoter, a ribosome binding site, and a transcription termination sequence. For example, a regulatory sequence for eukaryotes may include a promoter containing one or more recognition sites for a transcription factor, a transcription enhancer sequence, and a transcription termination sequence. A “regulatory sequence” may also include a leader sequence and / or a fusion partner sequence.

[0071] The term "vector" refers to any molecule or entity (e.g., nucleic acid, plasmid, bacteriophage, or virus) used to introduce protein-coding information into a host cell.

[0072] The terms “expression vector” or “expression construct” refer to a vector containing nucleic acid sequences suitable for transforming host cells and which induce and / or control the expression of one or more heterogeneous coding regions that are manipulatively ligated thereto (in cooperation with the host cell). An expression construct may, but is not limited to, include sequences that affect or control transcription, translation, and, if introns are present, affect RNA splicing of manipulatively ligated coding regions thereto.

[0073] As used herein, “operably ligated” means that the components to which this term applies are in a relationship that enables them to perform their intrinsic function under appropriate conditions. For example, a regulatory sequence “operably ligated” to a protein-coding sequence in a vector is ligated thereto such that the expression of the protein-coding sequence is achieved under conditions compatible with the transcriptional activity of the regulatory sequence.

[0074] The term "host cell" refers to a cell that has been transformed with a nucleic acid sequence to express the target gene. This term includes offspring of a parent cell, regardless of whether they are morphologically or genetically identical to the original parent cell, as long as the target gene is present.

[0075] The terms “polypeptide” and “protein” are used interchangeably herein to refer to polymers of amino acid residues. These terms also apply to amino acid polymers in which one or more amino acid residues are analogs or mimetic versions of corresponding naturally occurring amino acids, as well as to naturally occurring amino acid polymers. These terms may also include amino acid polymers modified, for example, by the addition of carbohydrate residues to form glycoproteins, or by phosphorylation. Polypeptides and proteins include molecules that can be produced by naturally occurring and non-recombinant cells, or by genetically engineered or recombinant cells, and which have the amino acid sequence of a naturally occurring protein, or molecules that have the deletion, addition, and / or substitution of one or more amino acids from the native sequence. Specifically, the terms “polypeptide” and “protein” include sequences of GIPR antigen-binding proteins, antibodies, or antigen-binding proteins that have the deletion, addition, and / or substitution of one or more amino acids. The term “polypeptide fragment” refers to a polypeptide having an amino-terminus deletion, a carboxyl-terminus deletion, and / or an internal deletion compared to a full-length protein. Such fragments may also include modified amino acids compared to a full-length protein. In certain embodiments, the fragments are approximately 5 to 500 amino acids long. For example, the fragments may have amino acid lengths of at least 5, 6, 8, 10, 14, 20, 50, 70, 100, 110, 150, 200, 250, 300, 350, 400, or 450. Useful polypeptide fragments include immunologically functional fragments of antibodies that contain a binding domain.

[0076] The term “isolated protein” means that the protein in question (1) does not contain at least some other proteins that would normally be expected to be found with it, (2) substantially does not contain other proteins from the same source, such as the same species, (3) is expressed by cells of a different species, (4) has at least about 50 percent of the polynucleotides, lipids, carbohydrates or other substances that would naturally accompany it removed, (5) is manipulably bound (by covalent or non-covalent interactions) to polypeptides that would not naturally accompany it, or (6) does not occur naturally. Generally, “isolated protein” constitutes at least about 5%, at least about 10%, at least about 25%, or at least about 50% of a given sample. Such isolated protein may be encoded by genomic DNA, cDNA, mRNA, or other RNA of synthetic origin, or any combination thereof. Preferably, the isolated protein is substantially free of proteins or polypeptides or other contaminants found in its natural environment that would interfere with its therapeutic, diagnostic, preventive, research, or other use.

[0077] A "variant" of a polypeptide (e.g., an antigen-binding protein such as an antibody) contains an amino acid sequence in which one or more amino acid residues are inserted, deleted, and / or substituted compared to another polypeptide sequence. Variants include fusion proteins.

[0078] A polypeptide "derivative" is a polypeptide (e.g., an antigen-binding protein such as an antibody) that has been chemically modified in some way different from a variant by insertion, deletion, or substitution, for example, by complexing with another chemical moiety.

[0079] As used herein in relation to biological materials such as polypeptides, nucleic acids, and host cells, the term “natural” refers to materials found in nature.

[0080] As used herein, the terms "subject" or "patient" may refer to any mammal. In typical embodiments, the subject or patient is a human.

[0081] As disclosed herein, the GIPR polypeptides described herein can be manipulated and / or prepared using standard molecular biological methodologies. In various examples, the nucleic acid sequence encoding GIPR may include all or part of SEQ ID NOs: 1, 3, or 5, and can be isolated and / or amplified from genomic DNA or cDNA using appropriate oligonucleotide primers. The primers can be designed based on the nucleic acid and amino acid sequences provided herein, according to standard (RT)-PCR amplification techniques. The amplified GIPR nucleic acid can then be cloned into an appropriate vector and characterized by DNA sequencing analysis.

[0082] Oligonucleotides for use as probes in the isolation or amplification of all or part of the GIPR sequences provided herein can be designed and produced using standard synthesis techniques, such as automated DNA synthesizers, or isolated from longer DNA sequences.

[0083] The 466 amino acid sequence of human GIPR is (Volz et al., FEBS Lett. 373:23-29 (1995); NCBI reference sequence NP_0001555): [ka] And, DNA sequence (NCBI reference sequence NM_000164): [ka] [ka] It is coded by.

[0084] The predicted human GIPR A430 amino acid isoform (isoform X1) based on automated computer analysis is given by the sequence (NCBI reference sequence XP_005258790): [ka] It has, DNA sequence: [ka] It is coded by.

[0085] The 493 amino acid isoforms of human GIPR produced by alternative splicing are given by the sequence (Gremlich et al., Diabetes 44:1202-8(1995); UniProtKB sequence identification number P48546-2): [ka] It has, DNA sequence: [ka] It is coded by.

[0086] The 460-amino acid sequence of mouse GIPR is (NCBI Reference Sequence: NP_001074284; uniprotKB / Swiss-Prot Q0P543-1); see Vassilatis et al., PNAS USA 2003, 100:4903-4908.

[0087] [ka] And, DNA sequence (NCBI reference sequence NM_001080815): [ka] It is coded by.

[0088] The 230 amino acid isoforms of mouse GIPR produced by alternative splicing are given by the sequence (Gerhard et al., Genome Res, 14:2121-2127 (2004); NCBI reference sequence AAI20674): [ka] It has, DNA sequence: [ka] It is coded by.

[0089] As described herein, the term “GIPR polypeptide” encompasses natural GIPR polypeptide sequences, such as the human amino acid sequences SEQ ID NOs. 3141, 3143, or 3145. However, the term “GIPR polypeptide” also encompasses polypeptides containing amino acid sequences that differ by one or more amino acids from the amino acid sequences of natural GIPR polypeptide sequences, such as SEQ ID NOs. 3141, 3143, or 3145, and as a result, the sequence is at least 85% identical to SEQ ID NOs. 3141, 3143, or 3145. GIPR polypeptides can be prepared using natural or non-natural amino acids by introducing one or more amino acid substitutions, either conserved or non-conserved, at specific positions in the GIPR polypeptide.

[0090] "Conservative amino acid substitution" may include substituting a native amino acid residue (i.e., a residue found at a given position in the wild-type GIPR polypeptide sequence) with a non-native residue (i.e., a residue not found at a given position in the wild-type GIPR polypeptide sequence), thereby resulting in little to no effect on the polarity or charge of the amino acid residue at that position. Conservative amino acid substitution also typically includes non-natural amino acid residues incorporated by chemical peptide synthesis rather than by synthesis in a biological system. These include peptide mimetic compounds and other forms in which the amino acid moiety is reversed or inverted.

[0091] Natural residues can be classified into classes based on the following common side-chain characteristics: (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr; (3) Acidic: Asp, Glu; (4) Basicity: Asn, Gln, His, Lys, Arg; (5) Residues that affect chain orientation: Gly, Pro; and (6) Aromatic: Trp, Tyr, Phe.

[0092] Further groups of amino acids can also be formulated using the principles described, for example, Creighton (1984) PROTEINS: STRUCTURE AND MOLECULAR PROPERTIES (2nd Ed. 1993), WH Freeman and Company. In some cases, it may be useful to further characterize substitutions based on two or more such properties (for example, substitutions at "less polar" residues such as thr residues can be highly conserved substitutions in appropriate circumstances).

[0093] A conservative permutation may involve exchanging one member of such a class for another member of the same class. A non-conservative permutation may involve exchanging one member of such a class for a member of another class.

[0094] Synthetic amino acid residues, rare amino acid residues, or modified amino acid residues known to have similar physiological and chemical properties to those in the above classifications may be used to "conservatively" substitute specific amino acid residues in a sequence. For example, a D-Arg residue may substitute for a typical L-Arg residue. In some cases, a particular substitution may be described in relation to two or more of the above classes (for example, a substitution in a small hydrophobic residue means the substitution of one amino acid in a residue found in both of the above classes, or in another synthetic, rare, or modified residue known in the art to have similar physiological and chemical properties to such a residue that satisfies both definitions).

[0095] Nucleic acid sequences encoding GIPR polypeptides provided herein include those that are degenerate in relation to SEQ ID NOs. 3141, 3143, or 3145, and those that encode polypeptide variants of SEQ ID NOs. 3141, 3143, or 3145, derived from other aspects of the present disclosure.

[0096] To express the GIPR nucleic acid sequences provided herein, a suitable coding sequence, for example, SEQ ID NOs. 3141, 3143, or 3145, can be cloned into a suitable vector according to standard cloning and expression techniques known in the art, and after introduction into a suitable host, the sequence can be expressed to produce the encoded polypeptide (for example, as described in Sambrook, J., Fritsh, EF, and Maniatis, T. Molecular Cloning: A Laboratory Manual 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989). The present invention also relates to such vectors containing the nucleic acid sequences according to the present invention.

[0097] A “vector” refers to a delivery vehicle that (a) promotes the expression of a nucleic acid sequence encoding a polypeptide, (b) promotes the production of a polypeptide therefrom, (c) promotes the gene transfer / transformation of target cells using it, (d) promotes the replication of a nucleic acid sequence, (e) promotes the stability of a nucleic acid, (f) promotes the detection of nucleic acids and / or transformed / transformed cells, and / or (g) otherwise confers a beneficial biological and / or physiological function to the nucleic acid encoding the polypeptide. A vector can be any suitable vector, including chromosomal vectors, non-chromosomal vectors, and synthetic nucleic acid vectors (nucleic acid sequences containing a suitable set of expression regulatory elements). Examples of such vectors include derivatives of SV40, bacterial plasmids, phage DNA, baculoviruses, yeast plasmids, vectors derived from combinations of plasmids and phage DNA, and viral nucleic acid (RNA or DNA) vectors.

[0098] Recombinant expression vectors can be designed to express the GIPR protein in prokaryotic cells (e.g., Escherichia coli) or eukaryotic cells (e.g., insect cells, yeast cells, or mammalian cells using baculovirus expression vectors). In one embodiment, the host cell is a non-human mammalian host cell. Typical host cells include those typically used for cloning and expression, such as Escherichia coli strains TOP10F', TOP10, DH10B, DH5a, HB101, W3110, BL21(DE3) and BL21(DE3)pLysS, BLUESCRIPT (Stratagene), mammalian cell lines CHO, CHO-K1, HEK293, 293-EBNA, pIN vector (Van Heeke & Schuster, J. Biol. Chem. 264:5503-5509 (1989); pET vector (Novagen, Madison) Examples include Wis.). Alternatively, recombinant expression vectors can be transcribed and translated in vitro using, for example, a T7 promoter regulatory sequence, T7 polymerase, and an in vitro translation system. The vector preferably contains a promoter upstream of the cloning site containing the nucleic acid sequence encoding the polypeptide. Examples of switchable promoters include the lac promoter, T7 promoter, trc promoter, tac promoter, and trp promoter.

[0099] Accordingly, vectors comprising nucleic acid sequences encoding GIPR and promoting the expression of recombinant GIPR are provided herein. In various embodiments, the vectors include operably linked nucleotide sequences that regulate GIPR expression. The vectors may include, or be linked to, some suitable promoters, enhancers, and other expression-promoting elements. Examples of such elements include potent expression promoters (e.g., human CMV IE promoter / enhancer, RSV promoter, SV40 promoter, SL3-3 promoter, MMTV promoter, or HIV LTR promoter, EF1 alpha promoter, CAG promoter), effective poly(A) termination sequences, replication origins for plasmid products in Escherichia coli (E. coli), antibiotic resistance genes as selection markers, and / or convenient cloning sites (e.g., polylinkers). The vectors may also include inductive promoters as opposed to constitutive promoters such as CMV IE. In one embodiment, nucleic acids are provided comprising sequences encoding a GIPR polypeptide that are operably linked to a tissue-specific promoter that promotes the expression of the sequence in tissues associated with cortisol secretion or production.

[0100] In another aspect of this disclosure, a host cell comprising the GIPR nucleic acid and vector disclosed herein is provided. In various embodiments, the vector or nucleic acid is incorporated into the host cell genome, and in other embodiments, the vector or nucleic acid is extrachromosomal.

[0101] Recombinant cells such as yeast, bacteria (e.g., Escherichia coli (E. coli)), and mammalian cells (e.g., immortalized mammalian cells) are provided, containing such nucleic acids, vectors, or combinations thereof. In various embodiments, cells are provided that contain non-integrated nucleic acids such as plasmids, cosmids, phagemids, or linear expression elements, containing coding sequences for the expression of GIPR polypeptides.

[0102] Vectors containing nucleic acid sequences encoding GIPR polypeptides provided herein can be introduced into host cells by transformation or gene transfer. Methods for transforming cells with expression vectors are well known.

[0103] The nucleic acid encoding GIPR can be positioned and / or delivered to a host cell or host animal via a viral vector. Any suitable viral vector having this capability can be used. The viral vector may contain any number of viral polynucleotides, either alone or in combination with one or more viral proteins that facilitate the delivery, replication, and / or expression of the nucleic acid of the present invention in a desired host cell. The viral vector may be a polynucleotide containing all or part of the viral genome, a viral protein / nucleic acid complex, a virus-like particle (VLP), or an intact viral particle containing viral nucleic acid and GIPR polypeptide-coding nucleic acid. The viral particle viral vector may contain wild-type viral particles or modified viral particles. The viral vector may be a vector that requires the presence of another vector or wild-type virus for replication and / or expression, such as an adenovirus vector amplicon (for example, the viral vector may be a helper-dependent virus). Typically, such viral vectors consist of wild-type viral particles or viral particles whose protein and / or nucleic acid content has been modified to increase the transgene capacity or to facilitate the transduction and / or expression of nucleic acids (an example of such vectors is the herpesvirus / AAV amplicon). Typically, viral vectors are similar to and / or derived from viruses that normally infect humans. Suitable viral vector particles in this regard include, for example, adenovirus vector particles (including any virus of the family Adenoviridae or any virus derived from a virus of the family Adenoviridae), adeno-associated virus vector particles (AAV vector particles), or other parvovirus and parvovirus vector particles, papillomavirus vector particles, flavivirus vectors, alphavirus vectors, herpesvirus vectors, poxvirus vectors, and retrovirus vectors (including lentivirus vectors).

[0104] The GIPR polypeptide expressed as described herein can be isolated using standard protein purification methods. The GIPR polypeptide can be isolated from cells that naturally express it, or from cells that have been engineered to express GIPR, such as cells that do not naturally express GIPR.

[0105] Protein purification methods, as well as related materials and reagents, that may be used to isolate GIPR polypeptides are known in the art. Further purification methods that may be useful for isolating GIPR polypeptides can be found in references such as Bootcov MR, 1997, Proc. Natl. Acad. Sci. USA 94:11514-9, Fairlie WD, 2000, Gene 254:67-76.

[0106] Antagonist antigen-binding proteins that bind to GIPR, including human GIPR (hGIPR), are provided herein. In one embodiment, human GIPR has a sequence such as that shown in SEQ ID NO: 3141. In another embodiment, human GIPR has a sequence such as that shown in SEQ ID NO: 3143. In yet another embodiment, human GIPR has a sequence such as that shown in SEQ ID NO: 3145.

[0107] The antigen-binding proteins provided are polypeptides into which one or more complementarity-determining regions (CDRs) described herein are incorporated and / or linked. In some antigen-binding proteins, the CDR is incorporated into a “framework” region, which aligns the orientation of the CDR, resulting in the achievement of the appropriate antigen-binding properties of the CDR. The specific antigen-binding proteins described herein are antibodies or derived from antibodies. In other antigen-binding proteins, the CDR sequence is incorporated into a different type of protein backbone. Various structures are further described below.

[0108] The antigen-binding proteins disclosed herein have various uses. For example, they are useful in specific binding assays, affinity purification of GIPR, and screening assays for identifying other antagonists of GIPR activity. Other applications of antigen-binding proteins include, for example, screening assays for diagnosing diseases or conditions associated with GIPR and determining the presence or absence of GIPR. Given that the provided antigen-binding proteins are antagonists, GIPR antigen-binding proteins are valuable in therapeutic methods useful for reducing cortisol levels. Therefore, these antigen-binding proteins are useful in the treatment and prevention of Cushing's syndrome.

[0109] A variety of selective conjugates useful for modulating GIPR activity are provided. These agents include, for example, antigen-binding proteins containing an antigen-binding domain (e.g., scFv, domain antibodies, and polypeptides having an antigen-binding region) that specifically bind to GIPR polypeptides, particularly human GIPR. Some of these agents are useful, for example, for promoting GIPR activity and can activate one or more GIPR-related activities.

[0110] Generally, the antigen-binding proteins provided typically contain one or more CDRs described herein (e.g., 1, 2, 3, 4, 5, or 6). In some cases, the antigen-binding protein comprises (a) a polypeptide structure and (b) one or more CDRs inserted into and / or linked to the polypeptide structure. The polypeptide structure can take on a variety of different forms. For example, the polypeptide structure may be or contain a framework of a naturally occurring antibody or a fragment or variant thereof, or it may be entirely synthetic. Examples of various polypeptide structures are further described below.

[0111] In certain embodiments, the polypeptide structure of the antigen-binding protein is an antibody or derived from an antibody. Accordingly, examples of the specific antigen-binding proteins provided include, but are not limited to, monoclonal antibodies, bispecific antibodies, domain antibodies such as minibodies and Nanobodies®, synthetic antibodies (which may be referred to herein as “antibody mimes”), chimeric antibodies, humanized antibodies, human antibodies, antibody fusions, and parts or fragments thereof of each. In some cases, the antigen-binding protein is an immunological fragment of a complete antibody (e.g., Fab, Fab', F(ab')2). In other cases, the antigen-binding protein is an scFv using a CDR derived from the antibody of the present invention.

[0112] Antigen-binding proteins provided herein specifically bind to human GIPR. In certain embodiments, the antigen-binding protein specifically binds to human GIPR containing or comprising the amino acid sequence of SEQ ID NO: 3141. In certain embodiments, the antigen-binding protein specifically binds to human GIPR containing or comprising the amino acid sequence of SEQ ID NO: 3143. In certain embodiments, the antigen-binding protein specifically binds to human GIPR containing or comprising the amino acid sequence of SEQ ID NO: 3145.

[0113] The antigen-binding proteins provided are antagonists and typically possess the following characteristics: the ability to reduce cortisol levels resulting from GIP stimulation (endogenous or exogenous).

[0114] In one embodiment, the GIPR antigen-binding protein has one or more of the following activities: (a) When coupled to human GIPR and consequently measured, for example, via surface plasma resonance or coupled equilibrium exclusion techniques, the KD is ≤200 nM, ≤150 nM, ≤100 nM, ≤50 nM, ≤10 nM, ≤5 nM, ≤2 nM, or ≤1 nM. (b) Its half-life in human serum is at least 3 days.

[0115] Some of the antigen-binding proteins provided have an association rate (ka) for GIPR of at least 10 4 / Mx sec, at least 10 5 / Mx sec or at least 10 6 / Mx sec. The dissociation rate (dissociation rate or off-rate) of the specific antigen-binding proteins provided is slow. Some antigen-binding proteins have a kd (dissociation rate) of, for example, 1x10 -2 s -1 or 1x10 -3 s -1 or 1x10 -4 s -1 or 1x10 -5 s -1 In certain embodiments, the antigen-binding protein has a KD (equilibrium binding affinity) of less than 25 pM, less than 50 pM, less than 100 pM, less than 500 pM, less than 1 nM, less than 5 nM, less than 10 nM, less than 25 nM or less than 50 nM.

[0116] In another aspect, antigen-binding proteins are provided that have a half-life of at least 1 day in vitro or in vivo (e.g., when administered to a human subject). In one embodiment, the antigen-binding protein has a half-life of at least 3 days. In various other embodiments, the antigen-binding protein has a half-life of 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50 or 60 days or more. In another embodiment, the antigen-binding protein is derivatized or modified such that its half-life is increased compared to an undenatured or unmodified antibody. In another embodiment, the antigen-binding protein contains a point mutation to increase serum half-life. Further details regarding such variants and derivatized forms are provided below.

[0117] Some of the antigen-binding proteins offered typically have structures associated with naturally occurring antibodies. These antibody structural units typically consist of one or more tetramers, each composed of two identical caplets of polypeptide chains, although some mammalian species also produce antibodies with only a single heavy chain. In a typical antibody, each pair or caplet contains one full-length "light" chain (approximately 25 kDa in certain embodiments) and one full-length "heavy" chain (approximately 50–70 kDa in certain embodiments). Each individual immunoglobulin chain is composed of several "immunoglobulin domains," each consisting of approximately 90–110 amino acids and exhibiting a characteristic folding pattern. These domains are the basic units upon which antibody polypeptides are constructed. The amino-terminus of each chain typically contains a variable domain responsible for antigen recognition. The carboxy-terminus is evolutionarily more conserved than the other end of the chain and is called the "constant region" or "C region." Human light chains are generally classified into kappa and lambda light chains, each containing one variable domain and one constant domain. Heavy chains are typically classified into muon, delta, gamma, alpha, or epsilon chains, each defining the antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subtypes, including but not limited to IgG1, IgG2, IgG3, and IgG4. The IgM subtype includes IgM and IgM2. The IgA subtype includes IgA1 and IgA2. In humans, the IgA and IgD isotypes contain four heavy chains and four light chains, the IgG and IgE isotypes contain two heavy chains and two light chains, and the IgM isotype contains five heavy chains and five light chains. The C region of the heavy chain typically contains one or more domains that can perform effector functions. The number of heavy chain constant domains depends on the isotype. For example, the IgG heavy chain contains three C-domains, each known as CH1, CH2, and CH3. The provided antibody may have any of these isotypes and subtypes.In certain embodiments, the GIPR antibody is of the IgG1, IgG2, or IgG4 subtype. The terms “GIPR antibody” and “anti-GIPR antibody” are used interchangeably throughout this application and the drawings. Both terms refer to an antibody that binds to GIPR.

[0118] In the full-length light and heavy chains, the variable and constant regions are linked by "J" regions of approximately 12 or more amino acids, and the heavy chain also contains "D" regions of approximately 10 or more amino acids. See, for example, Fundamental Immunology, 2nd ed., Ch.7 (Paul, W., ed.) 1989, New York: Raven Press (which is incorporated herein by reference in its entirety for all purposes). The variable region of each light / heavy chain pair typically forms an antigen-binding site.

[0119] In the antibodies provided herein, the variable regions of the immunoglobulin chains generally exhibit an identical overall structure, including a relatively conserved framework region (FR) linked by three hypervariable regions (often referred to as “complementarity-determining regions” or CDRs). The CDRs derived from the two chains of each heavy / light chain pair described above are typically aligned by the framework region to form a structure that specifically binds to a particular epitope on the GIPR. From the N-terminus to the C-terminus, both the natural light and heavy chain variable regions typically follow the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. A numbering scheme has been devised to assign numbers to the amino acids occupying positions in each of these domains. This numbering system is defined in Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Md.) or Chothia & Lesk, 1987, J.Mol.Biol.196:901-917; Chothia et al., 1989, Nature 342:878-883.

[0120] The sequence information of the specific antibodies prepared and identified as described in the following examples is summarized in Tables 1 and 6. Accordingly, in one embodiment, the antigen-binding protein is an antibody having a CDR, variable domain, and light and heavy chain sequences as identified in one of the rows in Table 1 or Table 6.

[0121] Sequence numbers are assigned to the variable light chain, variable heavy chain, light chain, heavy chain, CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 sequences of the antibody and fragments of the present invention, as shown in Tables 1 and 6. Sequence numbers are also assigned to the polynucleotides encoding the variable light chain, variable heavy chain, light chain, heavy chain, CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 sequences of the antibody and fragments of the present invention, as shown in Tables 2 and 7. The antigen-binding proteins of the present invention can be identified by sequence numbers, but can also be identified by construct names (e.g., 2C2.005) or identifier numbers (e.g., iPS:336175). The antigen-binding proteins identified in Tables 1 to 10 below can be classified into families based on their construct names. For example, the "4B1 family" includes constructs 4B1, 4B1.010, 4B1.011, 4B1.012, 4B1.013, 4B1.014, 4B1.015, and 4B1.016.

[0122] Various light chain variable regions and heavy chain variable regions provided herein are shown in Tables 3 and 8. Each of these variable regions can be linked to a heavy chain or light chain constant region to form the heavy chain and light chain of a complete antibody, respectively. Furthermore, each of the heavy chain and light chain sequences thus produced can be combined to form the structure of a complete antibody.

[0123] [Table 1]

[0124] [Table 2]

[0125] Table 3

[0126] Table 4

[0127] Table 5

[0128] Table 6

[0129] Table 7

[0130] Table 8

[0131] Table 9

[0132] Table 10

[0133] Table 11

[0134] Table 12

[0135] Table 13

[0136] Table 14

[0137] Table 15

[0138] Table 16

[0139] Table 17

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[0240] Table 118

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[0245]

Table 123

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[0681] In one embodiment, the antibody or a fragment thereof includes a light chain variable region containing a sequence selected from the group consisting of SEQ ID NOs: 1 to 157. In one embodiment, the antibody or a fragment thereof includes a heavy chain variable region containing a sequence selected from the group consisting of SEQ ID NOs: 158 to 314. In one embodiment, the antibody or a fragment thereof includes a light chain variable region containing a sequence selected from the group consisting of SEQ ID NOs: 1 to 157, and a heavy chain variable region containing a sequence selected from the group consisting of SEQ ID NOs: 158 to 314. In one embodiment, the antibody or fragment thereof includes a light chain variable region containing SEQ ID NO: 1 and a heavy chain variable region containing SEQ ID NO: 158; a light chain variable region containing SEQ ID NO: 2 and a heavy chain variable region containing SEQ ID NO: 159; a light chain variable region containing SEQ ID NO: 3 and a heavy chain variable region containing SEQ ID NO: 160; a light chain variable region containing SEQ ID NO: 4 and a heavy chain variable region containing SEQ ID NO: 161; a light chain variable region containing SEQ ID NO: 5 and a heavy chain variable region containing SEQ ID NO: 162; a light chain variable region containing SEQ ID NO: 6 and a heavy chain variable region containing SEQ ID NO: 163; a light chain variable region containing SEQ ID NO: 7 and a heavy chain variable region containing SEQ ID NO: 164; a light chain variable region containing SEQ ID NO: 8 and a heavy chain variable region containing SEQ ID NO: 165; a light chain variable region containing SEQ ID NO: 9 and a heavy chain variable region containing SEQ ID NO: 166; a light chain variable region containing SEQ ID NO: 10 and a heavy chain variable region containing SEQ ID NO: 167; a light chain variable region containing SEQ ID NO: 11 and a heavy chain variable region containing SEQ ID NO: 168; and a light chain variable region containing SEQ ID NO: 12. Variable region and heavy chain variable region including SEQ ID NO: 169; light chain variable region including SEQ ID NO: 13 and heavy chain variable region including SEQ ID NO: 170; light chain variable region including SEQ ID NO: 14 and heavy chain variable region including SEQ ID NO: 171; light chain variable region including SEQ ID NO: 15 and heavy chain variable region including SEQ ID NO: 172; light chain variable region including SEQ ID NO: 16 and heavy chain variable region including SEQ ID NO: 173; light chain variable region including SEQ ID NO: 17 and heavy chain variable region including SEQ ID NO: 174; light chain variable region including SEQ ID NO: 18 and heavy chain variable region including SEQ ID NO: 175; light chain variable region including SEQ ID NO: 19 and heavy chain variable region including SEQ ID NO: 176; light chain variable region including SEQ ID NO: 20 and heavy chain variable region including SEQ ID NO: 177; light chain variable region including SEQ ID NO: 21 and heavy chain variable region including SEQ ID NO: 178; light chain variable region including SEQ ID NO: 22 and heavy chain variable region including SEQ ID NO: 179; light chain variable region including SEQ ID NO: 23 and heavy chain variable region including SEQ ID NO: 180;Light chain variable region including SEQ ID NO: 24 and heavy chain variable region including SEQ ID NO: 181; Light chain variable region including SEQ ID NO: 25 and heavy chain variable region including SEQ ID NO: 182; Light chain variable region including SEQ ID NO: 26 and heavy chain variable region including SEQ ID NO: 183; Light chain variable region including SEQ ID NO: 27 and heavy chain variable region including SEQ ID NO: 184; Light chain variable region including SEQ ID NO: 28 and heavy chain variable region including SEQ ID NO: 185; Light chain variable region including SEQ ID NO: 29 and heavy chain variable region including SEQ ID NO: 186; Light chain variable region including SEQ ID NO: 30 and heavy chain variable region including SEQ ID NO: 187; including SEQ ID NO: 31 Light chain variable region and heavy chain variable region including SEQ ID NO: 188; Light chain variable region including SEQ ID NO: 32 and heavy chain variable region including SEQ ID NO: 189; Light chain variable region including SEQ ID NO: 33 and heavy chain variable region including SEQ ID NO: 190; Light chain variable region including SEQ ID NO: 34 and heavy chain variable region including SEQ ID NO: 191; Light chain variable region including SEQ ID NO: 35 and heavy chain variable region including SEQ ID NO: 192; Light chain variable region including SEQ ID NO: 36 and heavy chain variable region including SEQ ID NO: 193; Light chain variable region including SEQ ID NO: 37 and heavy chain variable region including SEQ ID NO: 194; Light chain variable region including SEQ ID NO: 38 and Heavy chain variable region containing SEQ ID NO: 195; light chain variable region containing SEQ ID NO: 39 and heavy chain variable region containing SEQ ID NO: 196; light chain variable region containing SEQ ID NO: 40 and heavy chain variable region containing SEQ ID NO: 197; light chain variable region containing SEQ ID NO: 41 and heavy chain variable region containing SEQ ID NO: 198; light chain variable region containing SEQ ID NO: 42 and heavy chain variable region containing SEQ ID NO: 199; light chain variable region containing SEQ ID NO: 43 and heavy chain variable region containing SEQ ID NO: 200; light chain variable region containing SEQ ID NO: 44 and heavy chain variable region containing SEQ ID NO: 201; light chain variable region containing SEQ ID NO: 45 and SEQ ID NO: 202 Includes heavy chain variable region; light chain variable region including SEQ ID NO: 46 and heavy chain variable region including SEQ ID NO: 203; light chain variable region including SEQ ID NO: 47 and heavy chain variable region including SEQ ID NO: 204; light chain variable region including SEQ ID NO: 48 and heavy chain variable region including SEQ ID NO: 205; light chain variable region including SEQ ID NO: 49 and heavy chain variable region including SEQ ID NO: 206; light chain variable region including SEQ ID NO: 50 and heavy chain variable region including SEQ ID NO: 207; light chain variable region including SEQ ID NO: 51 and heavy chain variable region including SEQ ID NO: 208; light chain variable region including SEQ ID NO: 52 and heavy chain variable region including SEQ ID NO: 209;Light chain variable region including SEQ ID NO: 53 and heavy chain variable region including SEQ ID NO: 210; Light chain variable region including SEQ ID NO: 54 and heavy chain variable region including SEQ ID NO: 211; Light chain variable region including SEQ ID NO: 55 and heavy chain variable region including SEQ ID NO: 212; Light chain variable region including SEQ ID NO: 56 and heavy chain variable region including SEQ ID NO: 213; Light chain variable region including SEQ ID NO: 57 and heavy chain variable region including SEQ ID NO: 214; Light chain variable region including SEQ ID NO: 58 and heavy chain variable region including SEQ ID NO: 215; Light chain variable region including SEQ ID NO: 59 and heavy chain variable region including SEQ ID NO: 216; including SEQ ID NO: 60 Light chain variable region and heavy chain variable region including SEQ ID NO: 217; Light chain variable region including SEQ ID NO: 61 and heavy chain variable region including SEQ ID NO: 218; Light chain variable region including SEQ ID NO: 62 and heavy chain variable region including SEQ ID NO: 219; Light chain variable region including SEQ ID NO: 63 and heavy chain variable region including SEQ ID NO: 220; Light chain variable region including SEQ ID NO: 64 and heavy chain variable region including SEQ ID NO: 221; Light chain variable region including SEQ ID NO: 65 and heavy chain variable region including SEQ ID NO: 222; Light chain variable region including SEQ ID NO: 66 and heavy chain variable region including SEQ ID NO: 223; Light chain variable region including SEQ ID NO: 67 and Heavy chain variable region including SEQ ID NO: 224; light chain variable region including SEQ ID NO: 68 and heavy chain variable region including SEQ ID NO: 225; light chain variable region including SEQ ID NO: 69 and heavy chain variable region including SEQ ID NO: 226; light chain variable region including SEQ ID NO: 70 and heavy chain variable region including SEQ ID NO: 227; light chain variable region including SEQ ID NO: 71 and heavy chain variable region including SEQ ID NO: 228; light chain variable region including SEQ ID NO: 72 and heavy chain variable region including SEQ ID NO: 229; light chain variable region including SEQ ID NO: 73 and heavy chain variable region including SEQ ID NO: 230; light chain variable region including SEQ ID NO: 74 and SEQ ID NO: 231 Including heavy chain variable region; light chain variable region including SEQ ID NO: 75 and heavy chain variable region including SEQ ID NO: 232; light chain variable region including SEQ ID NO: 76 and heavy chain variable region including SEQ ID NO: 233; light chain variable region including SEQ ID NO: 77 and heavy chain variable region including SEQ ID NO: 234; light chain variable region including SEQ ID NO: 78 and heavy chain variable region including SEQ ID NO: 235; light chain variable region including SEQ ID NO: 79 and heavy chain variable region including SEQ ID NO: 236; light chain variable region including SEQ ID NO: 80 and heavy chain variable region including SEQ ID NO: 237; light chain variable region including SEQ ID NO: 81 and heavy chain variable region including SEQ ID NO: 238;Light chain variable region including SEQ ID NO: 82 and heavy chain variable region including SEQ ID NO: 239; Light chain variable region including SEQ ID NO: 83 and heavy chain variable region including SEQ ID NO: 240; Light chain variable region including SEQ ID NO: 84 and heavy chain variable region including SEQ ID NO: 241; Light chain variable region including SEQ ID NO: 85 and heavy chain variable region including SEQ ID NO: 242; Light chain variable region including SEQ ID NO: 86 and heavy chain variable region including SEQ ID NO: 243; Light chain variable region including SEQ ID NO: 87 and heavy chain variable region including SEQ ID NO: 244; Light chain variable region including SEQ ID NO: 88 and heavy chain variable region including SEQ ID NO: 245; Light chain including SEQ ID NO: 89 Variable region and heavy chain variable region including SEQ ID NO: 246; light chain variable region including SEQ ID NO: 90 and heavy chain variable region including SEQ ID NO: 247; light chain variable region including SEQ ID NO: 91 and heavy chain variable region including SEQ ID NO: 248; light chain variable region including SEQ ID NO: 92 and heavy chain variable region including SEQ ID NO: 249; light chain variable region including SEQ ID NO: 93 and heavy chain variable region including SEQ ID NO: 250; light chain variable region including SEQ ID NO: 94 and heavy chain variable region including SEQ ID NO: 251; light chain variable region including SEQ ID NO: 95 and heavy chain variable region including SEQ ID NO: 252; light chain variable region including SEQ ID NO: 96 and SEQ ID NO: 2 Heavy chain variable region including 53; light chain variable region including SEQ ID NO: 97 and heavy chain variable region including SEQ ID NO: 254; light chain variable region including SEQ ID NO: 98 and heavy chain variable region including SEQ ID NO: 255; light chain variable region including SEQ ID NO: 99 and heavy chain variable region including SEQ ID NO: 256; light chain variable region including SEQ ID NO: 100 and heavy chain variable region including SEQ ID NO: 257; light chain variable region including SEQ ID NO: 101 and heavy chain variable region including SEQ ID NO: 258; light chain variable region including SEQ ID NO: 102 and heavy chain variable region including SEQ ID NO: 259; light chain variable region including SEQ ID NO: 103 and heavy chain variable region including SEQ ID NO: 260 Variable region; light chain variable region including SEQ ID NO: 104 and heavy chain variable region including SEQ ID NO: 261; light chain variable region including SEQ ID NO: 105 and heavy chain variable region including SEQ ID NO: 262; light chain variable region including SEQ ID NO: 106 and heavy chain variable region including SEQ ID NO: 263; light chain variable region including SEQ ID NO: 107 and heavy chain variable region including SEQ ID NO: 264; light chain variable region including SEQ ID NO: 108 and heavy chain variable region including SEQ ID NO: 265; light chain variable region including SEQ ID NO: 109 and heavy chain variable region including SEQ ID NO: 266; light chain variable region including SEQ ID NO: 110 and heavy chain variable region including SEQ ID NO: 267;Light chain variable region containing SEQ ID NO: 111 and heavy chain variable region containing SEQ ID NO: 268; Light chain variable region containing SEQ ID NO: 112 and heavy chain variable region containing SEQ ID NO: 269; Light chain variable region containing SEQ ID NO: 113 and heavy chain variable region containing SEQ ID NO: 270; Light chain variable region containing SEQ ID NO: 114 and heavy chain variable region containing SEQ ID NO: 271; Light chain variable region containing SEQ ID NO: 115 and heavy chain variable region containing SEQ ID NO: 272; Light chain variable region containing SEQ ID NO: 116 and heavy chain variable region containing SEQ ID NO: 273; Light chain variable region containing SEQ ID NO: 117 and heavy chain variable region containing SEQ ID NO: 274; Light chain variable region containing SEQ ID NO: 118 and heavy chain variable region containing SEQ ID NO: 275; Light chain variable region containing SEQ ID NO: 119 and heavy chain variable region containing SEQ ID NO: 276; Light chain variable region containing SEQ ID NO: 120 and heavy chain variable region containing SEQ ID NO: 277; Light chain variable region containing SEQ ID NO: 121 and heavy chain variable region containing SEQ ID NO: 278; Light chain variable region containing SEQ ID NO: 122 and heavy chain variable region containing SEQ ID NO: 279; Light chain variable region containing SEQ ID NO: 123 and heavy chain variable region containing SEQ ID NO: 280; Light chain variable region containing SEQ ID NO: 124 and heavy chain variable region containing SEQ ID NO: 281; Light chain variable region containing SEQ ID NO: 125 and heavy chain variable region containing SEQ ID NO: 282; Light chain variable region containing SEQ ID NO: 126 and heavy chain variable region containing SEQ ID NO: 283; Light chain variable region containing SEQ ID NO: 127 and heavy chain variable region containing SEQ ID NO: 284; Light chain variable region containing SEQ ID NO: 128 and heavy chain variable region containing SEQ ID NO: 285; Light chain variable region containing SEQ ID NO: 129 and heavy chain variable region containing SEQ ID NO: 286; Light chain variable region containing SEQ ID NO: 130 and heavy chain variable region containing SEQ ID NO: 287; Light chain variable region containing SEQ ID NO: 131 and heavy chain variable region containing SEQ ID NO: 288; Light chain variable region containing SEQ ID NO: 132 and heavy chain variable region containing SEQ ID NO: 289; Light chain variable region containing SEQ ID NO: 133 and heavy chain variable region containing SEQ ID NO: 290; Light chain variable region containing SEQ ID NO: 134 and heavy chain variable region containing SEQ ID NO: 291; Light chain variable region containing SEQ ID NO: 135 and heavy chain variable region containing SEQ ID NO: 292; Light chain variable region containing SEQ ID NO: 136 and heavy chain variable region containing SEQ ID NO: 293; Light chain variable region containing SEQ ID NO: 137 and heavy chain variable region containing SEQ ID NO: 294; Light chain variable region containing SEQ ID NO: 138 and heavy chain variable region containing SEQ ID NO: 295;Light chain variable region containing SEQ ID NO: 139 and heavy chain variable region containing SEQ ID NO: 296; Light chain variable region containing SEQ ID NO: 140 and heavy chain variable region containing SEQ ID NO: 297; Light chain variable region containing SEQ ID NO: 141 and heavy chain variable region containing SEQ ID NO: 298; Light chain variable region containing SEQ ID NO: 142 and heavy chain variable region containing SEQ ID NO: 299; Light chain variable region containing SEQ ID NO: 143 and heavy chain variable region containing SEQ ID NO: 300; ; Light chain variable region including SEQ ID NO: 144 and heavy chain variable region including SEQ ID NO: 301; Light chain variable region including SEQ ID NO: 145 and heavy chain variable region including SEQ ID NO: 302; Light chain variable region including SEQ ID NO: 146 and heavy chain variable region including SEQ ID NO: 303; Light chain variable region including SEQ ID NO: 147 and heavy chain variable region including SEQ ID NO: 304; Light chain variable region including SEQ ID NO: 148 and heavy chain variable region including SEQ ID NO: 305; Light chain variable region including SEQ ID NO: 149 and heavy chain variable region including SEQ ID NO: 306; Light chain variable region including SEQ ID NO: 150 and heavy chain variable region including SEQ ID NO: 307; Light chain variable region including SEQ ID NO: 151 and This includes combinations of light chain variable regions and heavy chain variable regions selected from the group consisting of: a heavy chain variable region including sequence number 308; a light chain variable region including sequence number 152 and a heavy chain variable region including sequence number 309; a light chain variable region including sequence number 153 and a heavy chain variable region including sequence number 310; a light chain variable region including sequence number 154 and a heavy chain variable region including sequence number 311; a light chain variable region including sequence number 155 and a heavy chain variable region including sequence number 312; a light chain variable region including sequence number 156 and a heavy chain variable region including sequence number 313; a light chain variable region including sequence number 157 and a heavy chain variable region including sequence number 314.

[0682] In one embodiment, the antibody or fragment thereof includes a light chain variable region encoded by a polynucleotide selected from the group consisting of SEQ ID NOs: 1571 to 1727. In one embodiment, the antibody or fragment thereof includes a heavy chain variable region encoded by a polynucleotide selected from the group consisting of SEQ ID NOs: 1728 to 1884. In one embodiment, the antibody or fragment thereof includes a light chain variable region encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NOs: 1571 to 1727, and a heavy chain variable region encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NOs: 1728 to 1884. In one embodiment, the antibody or fragment thereof comprises a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1571 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1728; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1572 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1729; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1573 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1730; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1574 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1731; and a polynucleotide sequence encoded by a polynucleotide sequence including SEQ ID NO: 1575. A light chain variable region and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1732; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1576 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1733; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1577 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1734; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1578 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1735; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1579 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1736;Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1580 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1737; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1581 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1738; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1582 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1739; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1583 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1740; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1584 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1741; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1585 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1742; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1586 and The heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1743; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1587 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1744; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1588 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1745; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1589 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1746; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1590 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1747; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1591 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1748; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1592 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1749;Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1593 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1750; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1594 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1751; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1595 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1752; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1596 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1753; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1597 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1754; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1598 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1755; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1599 and The heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1756; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1600 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1757; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1601 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1758; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1602 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1759; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1603 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1760; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1604 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1761; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1605 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1762;Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1606 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1763; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1607 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1764; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1608 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1765; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1609 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1766; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1610 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1767; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1611 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1768; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1612 and The heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1769; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1613 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1770; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1614 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1771; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1615 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1772; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1616 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1773; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1617 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1774; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1618 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1775;Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1619 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1776; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1620 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1777; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1621 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1778; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1622 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1779; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1623 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1780; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1624 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1781; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1625 and The heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1782; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1626 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1783; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1627 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1784; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1628 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1785; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1629 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1786; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1630 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1787; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1631 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1788;Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1632 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1789; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1633 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1790; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1634 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1791; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1635; A variable region and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1792; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1636 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1793; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1637 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1794; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1638 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1795; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1639 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1796; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1640 and a heavy chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1797; a light chain variable region encoded by a polynucleotide sequence including SEQ ID NO: 1641 and a polynucleotide sequence including SEQ ID NO: 1798 Heavy chain variable region encoded by rheotide sequence; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1642 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1799; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1643 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1800; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1644 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1801; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1645 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1802; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1646 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1803; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1647 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1804;Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1648 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1805; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1649 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1806; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1650 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1807; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1651 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1808; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1652 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1809; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1653 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1810; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1654 and The heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1811; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1655 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1812; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1656 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1813; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1657 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1814; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1658 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1815; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1659 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1816; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1660 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1817;Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1661 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1818; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1662 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1819; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1663 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1820; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1664 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1821; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1665 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1822; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1666 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1823; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1667 and The heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1824; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1668 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1825; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1669 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1826; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1670 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1827; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1671 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1828; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1672 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1829; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1673 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1830;Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1674 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1831; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1675 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1832; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1676 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1833; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1677 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1834; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1678 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1835; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1679 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1836; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1680 and The heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1837; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1681 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1838; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1682 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1839; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1683 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1840; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1684 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1841; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1685 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1842; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1686 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1843;Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1687 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1844; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1688 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1845; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1689 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1846; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1690 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1847; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1691 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1848; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1692 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1849; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1693 and The heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1850; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1694 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1851; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1695 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1852; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1696 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1853; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1697 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1854; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1698 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1855; the light chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1699 and the heavy chain variable region encoded by the polynucleotide sequence containing SEQ ID NO: 1856;Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1700 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1857; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1701 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1858; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1702 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1859; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1703 and polynucleotide sequence containing SEQ ID NO: 1860; Heavy chain variable region encoded by rheotide sequence; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1704 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1861; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1705 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1862; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1706 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1863; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1707 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1864; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1708 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1865; light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1709 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1866; polynucleotide sequence containing SEQ ID NO: 1710 A light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1867; a light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1711 and a heavy chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1868; a light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1712 and a heavy chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1869; a light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1713 and a heavy chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1870; a light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1714 and a heavy chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1871; a light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1715 and a heavy chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1872; a light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1716 and a heavy chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1873;Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1717 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1874; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1718 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1875; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1719 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1876; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1720 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1877; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1721 and heavy chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1878; Light chain variable region encoded by polynucleotide sequence containing SEQ ID NO: 1722 and polynucleotide sequence containing SEQ ID NO: 1879 This includes combinations of light and heavy chain variable regions selected from the group consisting of: a heavy chain variable region encoded by a nucleotide sequence; a light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1723 and a heavy chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1880; a light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1724 and a heavy chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1881; a light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1725 and a heavy chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1882; a light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1726 and a heavy chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1883; a light chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1727 and a heavy chain variable region encoded by a polynucleotide sequence containing SEQ ID NO: 1884.

[0683] Some antigen-binding proteins contain variable light chain domains and variable heavy chain domains, as listed in one of the rows for one of the antibodies listed in Tables 3 and 8. In some cases, the antigen-binding protein contains two identical variable light chain domains and two identical variable heavy chain domains from one of the antibodies listed in Tables 3 and 8. Some of the antigen-binding proteins provided contain variable light chain domains and variable heavy chain domains as listed in one of the rows for one of the antibodies listed in Tables 3 and 8, with the exception that one or both of the domains differ from the sequences identified in those tables by only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, each such sequence difference being independently either a deletion, insertion, or substitution of a single amino acid, resulting in a change of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids or less compared to the variable domain sequences identified in Tables 3 and 8. In one embodiment, the antigen-binding protein contains the variable region sequences from Tables 3 and 8, but with a deletion of the N-terminal methionine. Other antigen-binding proteins also contain variable light chain domains and variable heavy chain domains, as listed in one of the rows for one of the antibodies listed in Tables 3 and 8, with the exception that one or both of the domains differ from the sequences specified in those tables in that the heavy chain variable domain and / or light chain variable domain contain or consist of an amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the heavy chain variable domain sequence or light chain variable domain sequence amino acid sequence specified in Tables 3 and 8.

[0684] In another embodiment, the antigen-binding protein consists solely of variable light chain domains or variable heavy chain domains from the antibodies listed in Tables 3 and 8. In yet another embodiment, the antigen-binding protein contains two or more identical variable heavy chain domains or two or more identical variable light chain domains from those listed in Tables 3 and 8. Such domain antibodies may be fused or linked together via linkers as described in more detail below. The half-life of the domain antibodies may be extended by fusion with or linkage to one or more molecules (e.g., PEG or albumin).

[0685] Other antigen-binding proteins provided are variants of antibodies formed by combinations of heavy and light chains shown in Tables 3 and 8, each containing a light and / or heavy chain having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of the chains. In some cases, such antibodies contain at least one heavy chain and one light chain, while in other cases, the variant form contains two identical light chains and two identical heavy chains.

[0686] Various combinations of heavy chain variable regions can be combined with any of the various combinations of light chain variable regions.

[0687] In further embodiments, the isolated antigen-binding proteins provided herein are human antibodies comprising sequences as shown in Tables 3 and 8, and being of the IgG1-, IgG2-, IgG3-, or IgG4- type.

[0688] The antigen-binding proteins disclosed herein are polypeptides into which one or more CDRs are implanted, inserted, and / or ligated. An antigen-binding protein may have one, two, three, four, five, or six CDRs. Thus, an antigen-binding protein may, for example, have one heavy-chain CDR1 ("CDRH1") and / or one heavy-chain CDR2 ("CDRH2") and / or one heavy-chain CDR3 ("CDRH3") and / or one light-chain CDR1 ("CDRL1") and / or one light-chain CDR2 ("CDRL2") and / or one light-chain CDR3 ("CDRL3"). Some antigen-binding proteins contain both CDRH3 and CDRL3. Specific light-chain and heavy-chain CDRs are identified in Tables 4A and 4B and Tables 9A and 9B, respectively.

[0689] The complementarity-determining regions (CDRs) and framework regions (FRs) of a given antibody can be identified using the system described by Kabat et al. in Sequences of Proteins of Immunological Interest, 5th Ed., US Dept. of Health and Human Services, PHS, NIH, NIH Publication no. 91-3242, 1991. The specific antibodies disclosed herein contain one or more amino acid sequences that are identical to, or substantially identical to, one or more amino acid sequences of the CDRs given in Tables 4A and 4B and Tables 9A and 9B. Such CDRs are identified using the system described by Kabat et al.

[0690] The structure and properties of CDRs contained in naturally occurring antibodies are described above. Briefly, in conventional antibodies, CDRs are embedded within a framework of variable regions of the heavy and light chains that constitute the region responsible for antigen binding and recognition. The variable region contains at least three heavy or light chain CDRs, as seen above (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Public Health Service NIH, Bethesda, MD; Chothia and Lesk, 1987, J.Mol.Biol.196:901-917; Chothia et al., 1989, Nature 342:877-883), and they are located within a framework region (referred to as framework regions 1-4, FR1, FR2, FR3, and FR4, as seen above in Kabat et al., 1991; also see Chothia and Lesk, 1987). However, the CDRs provided herein can not only be used to define the antigen-binding domain of conventional antibody structures, but can also be embedded in various other polypeptide structures described herein.

[0691] In one embodiment, the antibody or fragment thereof includes CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3. In one embodiment, the antibody or fragment thereof includes CDRL1 containing a sequence selected from the group consisting of SEQ ID NOs. 629 to 785. In one embodiment, the antibody or fragment thereof includes CDRL2 containing a sequence selected from the group consisting of SEQ ID NOs. 786 to 942. In one embodiment, the antibody or fragment thereof includes CDRL3 containing a sequence selected from the group consisting of SEQ ID NOs. 943 to 1099. In one embodiment, the antibody or fragment thereof includes CDRH1 containing a sequence selected from the group consisting of SEQ ID NOs. 1100 to 1256. In one embodiment, the antibody or fragment thereof includes CDRH2 containing a sequence selected from the group consisting of SEQ ID NOs. 1257 to 1413. In one embodiment, the antibody or fragment thereof includes CDRH3 containing a sequence selected from the group consisting of SEQ ID NOs. 1414 to 1570. In one embodiment, the antibody or its fragment comprises CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, each of which is sequence number 629, 786, 943, 1100, 1257, and 1414; 630, 787, 944, 1101, 1258, and 1415; 631, 788, 945, 1102, 1259, and 1416; 632, 789, 946, sequence number 946, sequence number 632, 789, 946, sequence number 946, sequence number 945, sequence number 1102, 1259, and 1416; sequence number 632, 789, 946, sequence number 946, sequence number 946. Sequence ID 1103, Sequence ID 1260 and Sequence ID 1417; Sequence ID 633, Sequence ID 790, Sequence ID 947, Sequence ID 1104, Sequence ID 1261 and Sequence ID 1418; Sequence ID 634, Sequence ID 791, Sequence ID 948, Sequence ID 1105, Sequence ID 1262 and Sequence ID 1419; Sequence ID 635, Sequence ID 792, Sequence ID 949, Sequence ID 1106, Sequence ID 1263 and Sequence ID 1420; Sequence ID 636, Sequence ID 793, Sequence ID 950, Sequence ID 1107, Sequence ID 1264 and Sequence ID 1421; Sequence ID 637, Sequence ID 794, Sequence ID 951, Sequence ID 1108, Sequence ID 1265 and Sequence ID 1422;SEQ ID NOs: 638, 795, 952, 1109, 1266 and 1423; SEQ ID NOs: 639, 796, 953, 1110, 1267 and 1424; SEQ ID NOs: 640, 797, 954, 1111, 1268 and 1425; SEQ ID NOs: 641, 798, 955, 1112, 1269 and 1426; SEQ ID NOs: 642, 799, 956, 1113, 12 70 and SEQ ID NO: 1427; SEQ ID NO: 643, SEQ ID NO: 800, SEQ ID NO: 957, SEQ ID NO: 1114, SEQ ID NO: 1271 and SEQ ID NO: 1428; SEQ ID NO: 644, SEQ ID NO: 801, SEQ ID NO: 958, SEQ ID NO: 1115, SEQ ID NO: 1272 and SEQ ID NO: 1429; SEQ ID NO: 645, SEQ ID NO: 802, SEQ ID NO: 959, SEQ ID NO: 1116, SEQ ID NO: 1273 and SEQ ID NO: 1430; SEQ ID NO: 646, SEQ ID NO: 803, SEQ ID NO: 960, SEQ ID NO: 1117, SEQ ID NO: 1274 and SEQ ID NO: 1431; SEQ ID NO: 647, SEQ ID NO: 804, SEQ ID NO: 961, SEQ ID NO: Array Number 1118, SEQ ID NO: 1275 and SEQ ID NO: 1432; SEQ ID NO: 648, SEQ ID NO: 805, SEQ ID NO: 962, SEQ ID NO: 1119, SEQ ID NO: 1276 and SEQ ID NO: 1433; SEQ ID NO: 649, SEQ ID NO: 806, SEQ ID NO: 963, SEQ ID NO: 1120, SEQ ID NO: 1277 and SEQ ID NO: 1434; SEQ ID NO: 650, SEQ ID NO: 807, SEQ ID NO: 964, SEQ ID NO: 1121, SEQ ID NO: 1278 and SEQ ID NO: 1435; SEQ ID NO: 651, SEQ ID NO: 808, SEQ ID NO: 965, SEQ ID NO: 1122, SEQ ID NO: 1279 and SEQ ID NO: 1436; SEQ ID NO: 652, SEQ ID NO: 8 09, SEQ ID NO: 966, SEQ ID NO: 1123, SEQ ID NO: 1280 and SEQ ID NO: 1437; SEQ ID NO: 653, SEQ ID NO: 810, SEQ ID NO: 967, SEQ ID NO: 1124, SEQ ID NO: 1281 and SEQ ID NO: 1438; SEQ ID NO: 654, SEQ ID NO: 811, SEQ ID NO: 968, SEQ ID NO: 1125, SEQ ID NO: 1282 and SEQ ID NO: 1439; SEQ ID NO: 655, SEQ ID NO: 812, SEQ ID NO: 969, SEQ ID NO: 1126, SEQ ID NO: 1283 and SEQ ID NO: 1440; SEQ ID NO: 656, SEQ ID NO: 813, SEQ ID NO: 970, SEQ ID NO: 1127, SEQ ID NO: 1284 and SEQ ID NO: 1441;SEQ ID NOs: 657, 814, 971, 1128, 1285 and 1442; SEQ ID NOs: 658, 815, 972, 1129, 1286 and 1443; SEQ ID NOs: 659, 816, 973, 1130, 1287 and 1444; SEQ ID NOs: 660, 817, 974, 1131, 1288 and 1445; SEQ ID NOs: 661, 818, 975, 1132, 12 89 and SEQ ID NO: 1446; SEQ ID NO: 662, SEQ ID NO: 819, SEQ ID NO: 976, SEQ ID NO: 1133, SEQ ID NO: 1290 and SEQ ID NO: 1447; SEQ ID NO: 663, SEQ ID NO: 820, SEQ ID NO: 977, SEQ ID NO: 1134, SEQ ID NO: 1291 and SEQ ID NO: 1448; SEQ ID NO: 664, SEQ ID NO: 821, SEQ ID NO: 978, SEQ ID NO: 1135, SEQ ID NO: 1292 and SEQ ID NO: 1449; SEQ ID NO: 665, SEQ ID NO: 822, SEQ ID NO: 979, SEQ ID NO: 1136, SEQ ID NO: 1293 and SEQ ID NO: 1450; SEQ ID NO: 666, SEQ ID NO: 823, SEQ ID NO: 980, SEQ ID NO: 1446; SEQ ID NO: 662, SEQ ID NO: 819, SEQ ID NO: 976, SEQ ID NO: 1133, SEQ ID NO: 1290 and SEQ ID NO: 1447; SEQ ID NO: 663, SEQ ID NO: 821, SEQ ID NO: 978, SEQ ID NO: 1136, SEQ ID NO: 1293 and SEQ ID NO: 1450; SEQ ID NO: 666, SEQ ID NO: 823, SEQ ID NO: 980, SEQ ID NO: 1446; SEQ ID NO: 662, SEQ ID NO: 819, SEQ ID NO: 976, SEQ ID NO: Number 1137, Sequence ID 1294 and Sequence ID 1451; Sequence ID 667, Sequence ID 824, Sequence ID 981, Sequence ID 1138, Sequence ID 1295 and Sequence ID 1452; Sequence ID 668, Sequence ID 825, Sequence ID 982, Sequence ID 1139, Sequence ID 1296 and Sequence ID 1453; Sequence ID 669, Sequence ID 826, Sequence ID 983, Sequence ID 1140, Sequence ID 1297 and Sequence ID 1454; Sequence ID 670, Sequence ID 827, Sequence ID 984, Sequence ID 1141, Sequence ID 1298 and Sequence ID 1455; Sequence ID 671, Sequence ID 8 28, SEQ ID NO: 985, SEQ ID NO: 1142, SEQ ID NO: 1299 and SEQ ID NO: 1456; SEQ ID NO: 672, SEQ ID NO: 829, SEQ ID NO: 986, SEQ ID NO: 1143, SEQ ID NO: 1300 and SEQ ID NO: 1457; SEQ ID NO: 673, SEQ ID NO: 830, SEQ ID NO: 987, SEQ ID NO: 1144, SEQ ID NO: 1301 and SEQ ID NO: 1458; SEQ ID NO: 674, SEQ ID NO: 831, SEQ ID NO: 988, SEQ ID NO: 1145, SEQ ID NO: 1302 and SEQ ID NO: 1459; SEQ ID NO: 675, SEQ ID NO: 832, SEQ ID NO: 989, SEQ ID NO: 1146, SEQ ID NO: 1303 and SEQ ID NO: 1460;SEQ ID NOs: 676, 833, 990, 1147, 1304 and 1461; SEQ ID NOs: 677, 834, 991, 1148, 1305 and 1462; SEQ ID NOs: 678, 835, 992, 1149, 1306 and 1463; SEQ ID NOs: 679, 836, 993, 1150, 1307 and 1464; SEQ ID NOs: 680, 837, 994, 1151 and 1308 and SEQ ID NO: 1465; SEQ ID NO: 681, SEQ ID NO: 838, SEQ ID NO: 995, SEQ ID NO: 1152, SEQ ID NO: 1309 and SEQ ID NO: 1466; SEQ ID NO: 682, SEQ ID NO: 839, SEQ ID NO: 996, SEQ ID NO: 1153, SEQ ID NO: 1310 and SEQ ID NO: 1467; SEQ ID NO: 683, SEQ ID NO: 840, SEQ ID NO: 997, SEQ ID NO: 1154, SEQ ID NO: 1311 and SEQ ID NO: 1468; SEQ ID NO: 684, SEQ ID NO: 841, SEQ ID NO: 998, SEQ ID NO: 1155, SEQ ID NO: 1312 and SEQ ID NO: 1469; SEQ ID NO: 685, SEQ ID NO: 842, SEQ ID NO: 999, SEQ ID NO: 11 56, SEQ ID NOs. 1313 and 1470; SEQ ID NOs. 686, 843, 1000, 1157, 1314 and 1471; SEQ ID NOs. 687, 844, 1001, 1158, 1315 and 1472; SEQ ID NOs. 688, 845, 1002, 1159, 1316 and 1473; SEQ ID NOs. 689, 846, 1003, 1160, 1317 and 1474; SEQ ID NOs. 690, 847 , SEQ ID NOs. 1004, 1161, 1318 and 1475; SEQ ID NOs. 691, 848, 1005, 1162, 1319 and 1476; SEQ ID NOs. 692, 849, 1006, 1163, 1320 and 1477; SEQ ID NOs. 693, 850, 1007, 1164, 1321 and 1478; SEQ ID NOs. 694, 851, 1008, 1165, 1322 and 1479;SEQ ID NOs: 695, 852, 1009, 1166, 1323 and 1480; SEQ ID NOs: 696, 853, 1010, 1167, 1324 and 1481; SEQ ID NOs: 697, 854, 1011, 1168, 1325 and 1482; SEQ ID NOs: 698, 855, 1012, 1169, 1326 and 1483; SEQ ID NOs: 699, 856, 1013, Column number 1170, sequence number 1327 and sequence number 1484; sequence number 700, sequence number 857, sequence number 1014, sequence number 1171, sequence number 1328 and sequence number 1485; sequence number 701, sequence number 858, sequence number 1015, sequence number 1172, sequence number 1329 and sequence number 1486; sequence number 702, sequence number 859, sequence number 1016, sequence number 1173, sequence number 1330 and sequence number 1487; sequence number 703, sequence number 860, sequence number 1017, sequence number 1174, sequence number 1331 and sequence number 1488; SEQ ID NOs: 704, 861, 1018, 1175, 1332 and 1489; SEQ ID NOs: 705, 862, 1019, 1176, 1333 and 1490; SEQ ID NOs: 706, 863, 1020, 1177, 1334 and 1491; SEQ ID NOs: 707, 864, 1021, 1178, 1335 and 1492; SEQ ID NOs: 708, 865, 1022, Column number 1179, sequence number 1336 and sequence number 1493; sequence number 709, sequence number 866, sequence number 1023, sequence number 1180, sequence number 1337 and sequence number 1494; sequence number 710, sequence number 867, sequence number 1024, sequence number 1181, sequence number 1338 and sequence number 1495; sequence number 711, sequence number 868, sequence number 1025, sequence number 1182, sequence number 1339 and sequence number 1496; sequence number 712, sequence number 869, sequence number 1026, sequence number 1183, sequence number 1340 and sequence number 1497;SEQ ID NOs: 713, 870, 1027, 1184, 1341 and 1498; SEQ ID NOs: 714, 871, 1028, 1185, 1342 and 1499; SEQ ID NOs: 715, 872, 1029, 1186, 1343 and 1500; SEQ ID NOs: 716, 873, 1030, 1187, 1344 and 1501; SEQ ID NOs: 717, distribution; Column number 874, SEQ ID NO: 1031, SEQ ID NO: 1188, SEQ ID NO: 1345 and SEQ ID NO: 1502; SEQ ID NO: 718, SEQ ID NO: 875, SEQ ID NO: 1032, SEQ ID NO: 1189, SEQ ID NO: 1346 and SEQ ID NO: 1503; SEQ ID NO: 719, SEQ ID NO: 876, SEQ ID NO: 1033, SEQ ID NO: 1190, SEQ ID NO: 1347 and SEQ ID NO: 1504; SEQ ID NO: 720, SEQ ID NO: 877, SEQ ID NO: 1034, SEQ ID NO: 1191, SEQ ID NO: 1348 and SEQ ID NO: 1505; SEQ ID NO: 721, SEQ ID NO: 878, SEQ ID NO: 1035, SEQ ID NO: 1192, SEQ ID NO: 1349 and sequence Number 1506; Sequence IDs 722, 879, 1036, 1193, 1350 and 1507; Sequence IDs 723, 880, 1037, 1194, 1351 and 1508; Sequence IDs 724, 881, 1038, 1195, 1352 and 1509; Sequence IDs 725, 882, 1039, 1196, 1353 and 1510; Sequence IDs 726, 883, 1040, 11 97, SEQ ID NOs. 1354 and 1511; SEQ ID NOs. 727, 884, 1041, 1198, 1355 and 1512; SEQ ID NOs. 728, 885, 1042, 1199, 1356 and 1513; SEQ ID NOs. 729, 886, 1043, 1200, 1357 and 1514; SEQ ID NOs. 730, 887, 1044, 1201, 1358 and 1515; SEQ ID NOs. 731, 888 , SEQ ID NOs. 1045, 1202, 1359 and 1516; SEQ ID NOs. 732, 889, 1046, 1203, 1360 and 1517; SEQ ID NOs. 733, 890, 1047, 1204, 1361 and 1518; SEQ ID NOs. 734, 891, 1048, 1205, 1362 and 1519; SEQ ID NOs. 735, 892, 1049, 1206, 1363 and 1520;SEQ ID NOs: 736, 893, 1050, 1207, 1364 and 1521; SEQ ID NOs: 737, 894, 1051, 1208, 1365 and 1522; SEQ ID NOs: 738, 895, 1052, 1209, 1366 and 1523; SEQ ID NOs: 739, 896, 1053, 1210, 1367 and 1524; SEQ ID NOs: 740, 897, 1054, Column number 1211, sequence number 1368 and sequence number 1525; sequence number 741, sequence number 898, sequence number 1055, sequence number 1212, sequence number 1369 and sequence number 1526; sequence number 742, sequence number 899, sequence number 1056, sequence number 1213, sequence number 1370 and sequence number 1527; sequence number 743, sequence number 900, sequence number 1057, sequence number 1214, sequence number 1371 and sequence number 1528; sequence number 744, sequence number 901, sequence number 1058, sequence number 1215, sequence number 1372 and sequence number 1529; SEQ ID NOs: 745, 902, 1059, 1216, 1373 and 1530; SEQ ID NOs: 746, 903, 1060, 1217, 1374 and 1531; SEQ ID NOs: 747, 904, 1061, 1218, 1375 and 1532; SEQ ID NOs: 748, 905, 1062, 1219, 1376 and 1533; SEQ ID NOs: 749, 906, 1063, Column number 1220, sequence number 1377 and sequence number 1534; sequence number 750, sequence number 907, sequence number 1064, sequence number 1221, sequence number 1378 and sequence number 1535; sequence number 751, sequence number 908, sequence number 1065, sequence number 1222, sequence number 1379 and sequence number 1536; sequence number 752, sequence number 909, sequence number 1066, sequence number 1223, sequence number 1380 and sequence number 1537; sequence number 753, sequence number 910, sequence number 1067, sequence number 1224, sequence number 1381 and sequence number 1538;SEQ ID NOs: 754, 911, 1068, 1225, 1382 and 1539; SEQ ID NOs: 755, 912, 1069, 1226, 1383 and 1540; SEQ ID NOs: 756, 913, 1070, 1227, 1384 and 1541; SEQ ID NOs: 757, 914, 1071, 1228, 1385 and 1542; SEQ ID NOs: 758, 915, 1072, Column number 1229, sequence number 1386 and sequence number 1543; sequence number 759, sequence number 916, sequence number 1073, sequence number 1230, sequence number 1387 and sequence number 1544; sequence number 760, sequence number 917, sequence number 1074, sequence number 1231, sequence number 1388 and sequence number 1545; sequence number 761, sequence number 918, sequence number 1075, sequence number 1232, sequence number 1389 and sequence number 1546; sequence number 762, sequence number 919, sequence number 1076, sequence number 1233, sequence number 1390 and sequence number 1547; SEQ ID NOs: 763, 920, 1077, 1234, 1391 and 1548; SEQ ID NOs: 764, 921, 1078, 1235, 1392 and 1549; SEQ ID NOs: 765, 922, 1079, 1236, 1393 and 1550; SEQ ID NOs: 766, 923, 1080, 1237, 1394 and 1551; SEQ ID NOs: 767, 924, 1081, Column number 1238, sequence number 1395 and sequence number 1552; sequence number 768, sequence number 925, sequence number 1082, sequence number 1239, sequence number 1396 and sequence number 1553; sequence number 769, sequence number 926, sequence number 1083, sequence number 1240, sequence number 1397 and sequence number 1554; sequence number 770, sequence number 927, sequence number 1084, sequence number 1241, sequence number 1398 and sequence number 1555; sequence number 771, sequence number 928, sequence number 1085, sequence number 1242, sequence number 1399 and sequence number 1556;SEQ ID NOs: 772, 929, 1086, 1243, 1400 and 1557; SEQ ID NOs: 773, 930, 1087, 1244, 1401 and 1558; SEQ ID NOs: 774, 931, 1088, 1245, 1402 and 1559; SEQ ID NOs: 775, 932, 1089, 1246, 1403 and 1560; SEQ ID NOs: 776, 933, 1090, 1247, 1404 and 1561; SEQ ID NOs: 777, 934, 1091, 1248, 1405 and 1562; SEQ ID NOs: 778, 935, 1092, 1249, 1406 and 1563; SEQ ID NOs: 779, Includes sequences selected from the group consisting of sequence number 936, sequence number 1093, sequence number 1250, sequence number 1407 and sequence number 1564; sequence number 780, sequence number 937, sequence number 1094, sequence number 1251, sequence number 1408 and sequence number 1565; sequence number 781, sequence number 938, sequence number 1095, sequence number 1252, sequence number 1409 and sequence number 1566; sequence number 782, sequence number 939, sequence number 1096, sequence number 1253, sequence number 1410 and sequence number 1567; sequence number 783, sequence number 940, sequence number 1097, sequence number 1254, sequence number 1411 and sequence number 1568; sequence number 784, sequence number 941, sequence number 1098, sequence number 1255, sequence number 1412 and sequence number 1569; and sequence number 785, sequence number 942, sequence number 1099, sequence number 1256, sequence number 1413 and sequence number 1570.

[0692] In one embodiment, the antibody or fragment thereof includes CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, which are encoded by polynucleotides. In one embodiment, the antibody or fragment thereof includes CDRL1, which is encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NOs. 2199 to 2355. In one embodiment, the antibody or fragment thereof includes CDRL2, which is encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NOs. 2356 to 2512. In one embodiment, the antibody or fragment thereof includes CDRL3, which is encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NOs. 2513 to 2669. In one embodiment, the antibody or fragment thereof includes CDRH1, which is encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NOs. 2700 to 2826. In one embodiment, the antibody or fragment thereof includes CDRH2, which is encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NOs. 2827 to 2983. In one embodiment, the antibody or fragment thereof contains CDRH3 encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NOs: 2984 to 3140. In one embodiment, the antibody or fragment thereof contains CDRL1, CDRL2, CDRL3, CDRH1, CDRH2 and CDRH3, each of which CDRL1, CDRL2, CDRL3, CDRH1, CDRH2 and CDRH3 respectively corresponds to SEQ ID NOs: 2199, 2356, 2513, 2670, 2827 and 2984; SEQ ID NOs: 2200, 2357, 2514, 2671, 2828 and 2985; SEQ ID NOs: 2201, 2358, 2515, SEQ ID NOs 2672, SEQ ID NOs. 2829 and 2986; SEQ ID NOs. 2202, 2359, 2516, 2673, 2830 and 2987; SEQ ID NOs. 2203, 2360, 2517, 2674, 2831 and 2988; SEQ ID NOs. 2204, 2361, 2518, 2675, 2832 and 2989; SEQ ID NOs. 2205, 2362, 2519, 2676, 2833 and 2990;Sequence IDs 2206, 2363, 2520, 2677, 2834 and 2991; Sequence IDs 2207, 2364, 2521, 2678, 2835 and 2992; Sequence IDs 2208, 2365, 2522, 2679, 2836 and 2993; Sequence IDs 2209, 2366, 2523, 2680, 2837 and 2994; Sequence IDs 2210, 2367, 2524, Sequence IDs 2681, 2838, and 2995; Sequence IDs 2211, 2368, 2525, 2682, 2839, and 2996; Sequence IDs 2212, 2369, 2526, 2683, 2840, and 2997; Sequence IDs 2213, 2370, 2527, 2684, 2841, and 2998; Sequence IDs 2214, 2371, 2528, 2685, 2842, and 2999; Sequence IDs 2215, 2372, 2529, 2686, 2843 and 3000; Sequence IDs 2216, 2373, 2530, 2687, 2844 and 3001; Sequence IDs 2217, 2374, 2531, 2688, 2845 and 3002; Sequence IDs 2218, 2375, 2532, 2689, 2846 and 3003; Sequence IDs 2219, 2376, 2533, Sequence IDs 2690, 2847 and 3004; Sequence IDs 2220, 2377, 2534, 2691, 2848 and 3005; Sequence IDs 2221, 2378, 2535, 2692, 2849 and 3006; Sequence IDs 2222, 2379, 2536, 2693, 2850 and 3007; Sequence IDs 2223, 2380, 2537, 2694, 2851 and 3008;Sequence IDs 2224, 2381, 2538, 2695, 2852 and 3009; Sequence IDs 2225, 2382, 2539, 2696, 2853 and 3010; Sequence IDs 2226, 2383, 2540, 2697, 2854 and 3011; Sequence IDs 2227, 2384, 2541, 2698, 2855 and 3012; Sequence IDs 2228, 2385, 2542, Sequence IDs 2699, 2856 and 3013; Sequence IDs 2229, 2386, 2543, 2700, 2857 and 3014; Sequence IDs 2230, 2387, 2544, 2701, 2858 and 3015; Sequence IDs 2231, 2388, 2545, 2702, 2859 and 3016; Sequence IDs 2232, 2389, 2546, 2703, 2860 and 3017; Sequence IDs 2233, 2390, 2547, 2704, 2861 and 3018; Sequence IDs 2234, 2391, 2548, 2705, 2862 and 3019; Sequence IDs 2235, 2392, 2549, 2706, 2863 and 3020; Sequence IDs 2236, 2393, 2550, 2707, 2864 and 3021; ​​Sequence IDs 2237, 2394, 2551, Sequence IDs 2708, 2865 and 3022; Sequence IDs 2238, 2395, 2552, 2709, 2866 and 3023; Sequence IDs 2239, 2396, 2553, 2710, 2867 and 3024; Sequence IDs 2240, 2397, 2554, 2711, 2868 and 3025; Sequence IDs 2241, 2398, 2555, 2712, 2869 and 3026;Sequence IDs 2242, 2399, 2556, 2713, 2870 and 3027; Sequence IDs 2243, 2400, 2557, 2714, 2871 and 3028; Sequence IDs 2244, 2401, 2558, 2715, 2872 and 3029; Sequence IDs 2245, 2402, 2559, 2716, 2873 and 3030; Sequence IDs 2246, 2403, 2560, Sequence IDs 2717, 2874, and 3031; Sequence IDs 2247, 2404, 2561, 2718, 2875, and 3032; Sequence IDs 2248, 2405, 2562, 2719, 2876, and 3033; Sequence IDs 2249, 2406, 2563, 2720, 2877, and 3034; Sequence IDs 2250, 2407, 2564, 2721, 2878, and 3035; Sequence IDs 2251, 2408, 2565, 2722, 2879 and 3036; Sequence IDs 2252, 2409, 2566, 2723, 2880 and 3037; Sequence IDs 2253, 2410, 2567, 2724, 2881 and 3038; Sequence IDs 2254, 2411, 2568, 2725, 2882 and 3039; Sequence IDs 2255, 2412, 2569, Sequence IDs 2726, 2883 and 3040; Sequence IDs 2256, 2413, 2570, 2727, 2884 and 3041; Sequence IDs 2257, 2414, 2571, 2728, 2885 and 3042; Sequence IDs 2258, 2415, 2572, 2729, 2886 and 3043; Sequence IDs 2259, 2416, 2573, 2730, 2887 and 3044;SEQ ID NOs: 2260, 2417, 2574, 2731, 2888 and 3045; SEQ ID NOs: 2261, 2418, 2575, 2732, 2889 and 3046; SEQ ID NOs: 2262, 2419, 2576, 2733, 2890 and 3047; SEQ ID NOs: 2263, 2420, 2577, 2734, 2891 and 3048; SEQ ID NOs: 2264, 2421, 2578, Sequence IDs 2735, 2892 and 3049; Sequence IDs 2265, 2422, 2579, 2736, 2893 and 3050; Sequence IDs 2266, 2423, 2580, 2737, 2894 and 3051; Sequence IDs 2267, 2424, 2581, 2738, 2895 and 3052; Sequence IDs 2268, 2425, 2582, 2739, 2896 and 3053; Sequence IDs 2269, 2426, 2583, 2740, 2897 and 3054; Sequence IDs 2270, 2427, 2584, 2741, 2898 and 3055; Sequence IDs 2271, 2428, 2585, 2742, 2899 and 3056; Sequence IDs 2272, 2429, 2586, 2743, 2900 and 3057; Sequence IDs 2273, 2430, 2587, Sequence IDs 2744, 2901 and 3058; Sequence IDs 2274, 2431, 2588, 2745, 2902 and 3059; Sequence IDs 2275, 2432, 2589, 2746, 2903 and 3060; Sequence IDs 2276, 2433, 2590, 2747, 2904 and 3061; Sequence IDs 2277, 2434, 2591, 2748, 2905 and 3062;Sequence IDs 2278, 2435, 2592, 2749, 2906 and 3063; Sequence IDs 2279, 2436, 2593, 2750, 2907 and 3064; Sequence IDs 2280, 2437, 2594, 2751, 2908 and 3065; ;Sequence IDs 2281, 2438, 2595, 2752, 2909 and 3066;Sequence IDs 2282, 2439, 2596, 2753, 2910 and 3067;Sequence IDs 2283, 2440, 2597, 2754, 2911 and 3068;Sequence IDs 2284, 2441, 2598, 2755, 2912 and 3069;Sequence IDs 2285, 2442, 2599 , SEQ ID NOs. 2756, 2913 and 3070; SEQ ID NOs. 2286, 2443, 2600, 2757, 2914 and 3071; SEQ ID NOs. 2287, 2444, 2601, 2758, 2915 and 3072; SEQ ID NOs. 2288, 2445, 2602, 2759, 2916 and 3073; SEQ ID NOs. 2289, 2446, 2603, 2760, 2917 and 3074 ;Sequence IDs 2290, 2447, 2604, 2761, 2918 and 3075;Sequence IDs 2291, 2448, 2605, 2762, 2919 and 3076;Sequence IDs 2292, 2449, 2606, 2763, 2920 and 3077;Sequence IDs 2293, 2450, 2607, 2764, 2921 and 3078;Sequence IDs 2294, 2451, 2608, Sequence IDs 2765, 2922, and 3079; Sequence IDs 2295, 2452, 2609, 2766, 2923, and 3080; Sequence IDs 2296, 2453, 2610, 2767, 2924, and 3081; Sequence IDs 2297, 2454, 2611, 2768, 2925, and 3082; Sequence IDs 2298, 2455, 2612, 2769, 2926, and 3083;SEQ ID NOs: 2299, 2456, 2613, 2770, 2927 and 3084; SEQ ID NOs: 2300, 2457, 2614, 2771, 2928 and 3085; SEQ ID NOs: 2301, 2458, 2615, 2772, 2929 and 3086; SEQ ID NOs: 2302, 2459, 2616, 2773, 2930 and 3087; SEQ ID NOs: 2303, 2460, 2617, Sequence IDs 2774, 2931 and 3088; Sequence IDs 2304, 2461, 2618, 2775, 2932 and 3089; Sequence IDs 2305, 2462, 2619, 2776, 2933 and 3090; Sequence IDs 2306, 2463, 2620, 2777, 2934 and 3091; Sequence IDs 2307, 2464, 2621, 2778, 2935 and 3092; SEQ ID NOs: 2308, 2465, 2622, 2779, 2936 and 3093; SEQ ID NOs: 2309, 2466, 2623, 2780, 2937 and 3094; SEQ ID NOs: 2310, 2467, 2624, 2781, 2938 and 3095; SEQ ID NOs: 2311, 2468, 2625, 2782, 2939 and 3096; SEQ ID NOs: 2312, 2469, 2626, SEQ ID NOs: 2783, 2940 and 3097; SEQ ID NOs: 2313, 2470, 2627, 2784, 2941 and 3098; SEQ ID NOs: 2314, 2471, 2628, 2785, 2942 and 3099; SEQ ID NOs: 2315, 2472, 2629, 2786, 2943 and 3100; SEQ ID NOs: 2316, 2473, 2630, 2787, 2944 and 3101;SEQ ID NOs: 2317, 2474, 2631, 2788, 2945 and 3102; SEQ ID NOs: 2318, 2475, 2632, 2789, 2946 and 3103; SEQ ID NOs: 2319, 2476, 2633, 2790, 2947 and 3104; SEQ ID NOs: 2320, 2477, 2634, 2791, 2948 and 3105; SEQ ID NOs: 2321, 2478, 2635, Sequence IDs 2792, 2949 and 3106; Sequence IDs 2322, 2479, 2636, 2793, 2950 and 3107; Sequence IDs 2323, 2480, 2637, 2794, 2951 and 3108; Sequence IDs 2324, 2481, 2638, 2795, 2952 and 3109; Sequence IDs 2325, 2482, 2639, 2796, 2953 and 3110; SEQ ID NOs: 2326, 2483, 2640, 2797, 2954 and 3111; SEQ ID NOs: 2327, 2484, 2641, 2798, 2955 and 3112; SEQ ID NOs: 2328, 2485, 2642, 2799, 2956 and 3113; SEQ ID NOs: 2329, 2486, 2643, 2800, 2957 and 3114; SEQ ID NOs: 2330, 2487, 2644, Sequence IDs 2801, 2958, and 3115; Sequence IDs 2331, 2488, 2645, 2802, 2959, and 3116; Sequence IDs 2332, 2489, 2646, 2803, 2960, and 3117; Sequence IDs 2333, 2490, 2647, 2804, 2961, and 3118; Sequence IDs 2334, 2491, 2648, 2805, 2962, and 3119;SEQ ID NOs: 2335, 2492, 2649, 2806, 2963 and 3120; SEQ ID NOs: 2336, 2493, 2650, 2807, 2964 and 3121; SEQ ID NOs: 2337, 2494, 2651, 2808, 2965 and 3122; SEQ ID NOs: 2338, 2495, 2652, 2809, 2966 and 3123; SEQ ID NOs: 2339, 2496, 2653, Sequence IDs 2810, 2967, and 3124; Sequence IDs 2340, 2497, 2654, 2811, 2968, and 3125; Sequence IDs 2341, 2498, 2655, 2812, 2969, and 3126; Sequence IDs 2342, 2499, 2656, 2813, 2970, and 3127; Sequence IDs 2343, 2500, 2657, 2814, 2971, and 3128; Sequence IDs 2344, 2501, 2658, 2815, 2972 ​​and 3129; Sequence IDs 2345, 2502, 2659, 2816, 2973 and 3130; Sequence IDs 2346, 2503, 2660, 2817, 2974 and 3131; Sequence IDs 2347, 2504, 2661, 2818, 2975 and 3132; Sequence IDs 2348, 2505, 2662, Sequence IDs 2819, 2976, and 3133; Sequence IDs 2349, 2506, 2663, 2820, 2977, and 3134; Sequence IDs 2350, 2507, 2664, 2821, 2978, and 3135; Sequence IDs 2351, 2508, 2665, 2822, 2979, and 3136; Sequence IDs 2352, 2509, 2666, 2823, 2980, and 3137;The sequences are coded by sequences selected from the group consisting of SEQ ID NOs: 2353, 2510, 2667, 2824, 2981, and 3138; SEQ ID NOs: 2354, 2511, 2668, 2825, 2982, and 3139; and SEQ ID NOs: 2355, 2512, 2669, 2826, 2983, and 3140.

[0693] In another embodiment, the antigen-binding protein comprises variant forms of one, two, three, four, five, or six CDRs listed in Tables 4A and 4B or Tables 9A and 9B, each having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the CDR sequences listed in Tables 4A and 4B or Tables 9A and 9B. Some antigen-binding proteins comprise one, two, three, four, five, or six CDRs listed in Tables 4A and 4B or Tables 9A and 9B, each or collectively differing from the CDRs listed in this table by one, two, three, four, or five or fewer amino acids.

[0694] In various other embodiments, the antigen-binding protein is derived from such an antibody. For example, in one embodiment, the antigen-binding protein comprises all 1, 2, 3, 4, 5, or 6 CDRs listed in one of the rows for any particular antibody listed in Tables 4A and 4B and Tables 9A and 9B. In another embodiment, the antigen-binding protein comprises variant forms of 1, 2, 3, 4, 5, or 6 CDRs listed in one of the rows for antibodies in Tables 4A and 4B and Tables 9A and 9B, each CDR having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the CDR sequences listed in Tables 4A and 4B and Tables 9A and 9B. Some antigen-binding proteins contain one, two, three, four, five, or six CDRs listed in one of the columns of Tables 4A and 4B and Tables 9A and 9B, each differing from the CDRs listed in those tables by one, two, three, four, or five or fewer amino acids. In another embodiment, the antigen-binding protein contains all six CDRs listed in the rows of Tables 4A and 4B and Tables 9A and 9B, with the total number of amino acid changes from the CDRs being one, two, three, four, or five or fewer amino acids.

[0695] In one embodiment, the antibody or fragment thereof includes a light chain containing a sequence selected from the group consisting of SEQ ID NOs: 472 to 628. In one embodiment, the antibody or fragment thereof includes a heavy chain containing a sequence selected from the group consisting of SEQ ID NOs: 472 to 628. In one embodiment, the antibody or functional fragment thereof includes a light chain containing a sequence selected from the group consisting of SEQ ID NOs: 472 to 628, and a heavy chain containing a sequence selected from the group consisting of SEQ ID NOs: 472 to 628. In one embodiment, the antibody or its fragments include a light chain containing SEQ ID NO: 315 and a heavy chain containing SEQ ID NO: 472; a light chain containing SEQ ID NO: 316 and a heavy chain containing SEQ ID NO: 473; a light chain containing SEQ ID NO: 317 and a heavy chain containing SEQ ID NO: 474; a light chain containing SEQ ID NO: 318 and a heavy chain containing SEQ ID NO: 475; a light chain containing SEQ ID NO: 319 and a heavy chain containing SEQ ID NO: 476; a light chain containing SEQ ID NO: 320 and a heavy chain containing SEQ ID NO: 477; a light chain containing SEQ ID NO: 321 and a heavy chain containing SEQ ID NO: 478; a light chain containing SEQ ID NO: 322 and a heavy chain containing SEQ ID NO: 479; a light chain containing SEQ ID NO: 323 and a heavy chain containing SEQ ID NO: 480; a light chain containing SEQ ID NO: 324 and a heavy chain containing SEQ ID NO: 481; a light chain containing SEQ ID NO: 325 and a heavy chain containing SEQ ID NO: 482; a light chain containing SEQ ID NO: 326 and a heavy chain containing SEQ ID NO: 483; a light chain containing SEQ ID NO: 327 and a heavy chain containing SEQ ID NO: 484; a light chain containing SEQ ID NO: 328 and a heavy chain containing SEQ ID NO: 485; SEQ ID NO: Light chain containing 329 and heavy chain containing SEQ ID NO: 486; Light chain containing SEQ ID NO: 330 and heavy chain containing SEQ ID NO: 487; Light chain containing SEQ ID NO: 331 and heavy chain containing SEQ ID NO: 488; Light chain containing SEQ ID NO: 332 and heavy chain containing SEQ ID NO: 489; Light chain containing SEQ ID NO: 333 and heavy chain containing SEQ ID NO: 490; Light chain containing SEQ ID NO: 334 and heavy chain containing SEQ ID NO: 491; Light chain containing SEQ ID NO: 335 and heavy chain containing SEQ ID NO: 492; Light chain containing SEQ ID NO: 336 and heavy chain containing SEQ ID NO: 493; Light chain containing SEQ ID NO: 337 and heavy chain containing SEQ ID NO: 494; Light chain containing SEQ ID NO: 338 and heavy chain containing SEQ ID NO: 495; Light chain containing SEQ ID NO: 339 and heavy chain containing SEQ ID NO: 496; Light chain containing SEQ ID NO: 340 and heavy chain containing SEQ ID NO: 497; Light chain containing SEQ ID NO: 341 and heavy chain containing SEQ ID NO: 498; Light chain containing SEQ ID NO: 342 and heavy chain containing SEQ ID NO: 499; Light chain containing SEQ ID NO: 343 and heavy chain containing SEQ ID NO: 500;Light chain containing SEQ ID NO: 344 and heavy chain containing SEQ ID NO: 501; Light chain containing SEQ ID NO: 345 and heavy chain containing SEQ ID NO: 502; Light chain containing SEQ ID NO: 346 and heavy chain containing SEQ ID NO: 503; Light chain containing SEQ ID NO: 347 and heavy chain containing SEQ ID NO: 504; Light chain containing SEQ ID NO: 348 and heavy chain containing SEQ ID NO: 505; Light chain containing SEQ ID NO: 349 and heavy chain containing SEQ ID NO: 506; Light chain containing SEQ ID NO: 350 and heavy chain containing SEQ ID NO: 507; Light chain containing SEQ ID NO: 351 and heavy chain containing SEQ ID NO: 508; Light chain containing SEQ ID NO: 352 and heavy chain containing SEQ ID NO: 509; SEQ ID NO: 35 Light chain containing 3 and heavy chain containing SEQ ID NO: 510; Light chain containing SEQ ID NO: 354 and heavy chain containing SEQ ID NO: 511; Light chain containing SEQ ID NO: 355 and heavy chain containing SEQ ID NO: 512; Light chain containing SEQ ID NO: 356 and heavy chain containing SEQ ID NO: 513; Light chain containing SEQ ID NO: 357 and heavy chain containing SEQ ID NO: 514; Light chain containing SEQ ID NO: 358 and heavy chain containing SEQ ID NO: 515; Light chain containing SEQ ID NO: 359 and heavy chain containing SEQ ID NO: 516; Light chain containing SEQ ID NO: 360 and heavy chain containing SEQ ID NO: 517; Light chain containing SEQ ID NO: 361 and heavy chain containing SEQ ID NO: 518; Light chain containing SEQ ID NO: 362 and Heavy chain containing SEQ ID NO: 519; light chain containing SEQ ID NO: 363 and heavy chain containing SEQ ID NO: 520; light chain containing SEQ ID NO: 364 and heavy chain containing SEQ ID NO: 521; light chain containing SEQ ID NO: 365 and heavy chain containing SEQ ID NO: 522; light chain containing SEQ ID NO: 366 and heavy chain containing SEQ ID NO: 523; light chain containing SEQ ID NO: 367 and heavy chain containing SEQ ID NO: 524; light chain containing SEQ ID NO: 368 and heavy chain containing SEQ ID NO: 525; light chain containing SEQ ID NO: 369 and heavy chain containing SEQ ID NO: 526; light chain containing SEQ ID NO: 370 and heavy chain containing SEQ ID NO: 527; light chain containing SEQ ID NO: 371 and SEQ ID NO: 52 Heavy chain containing 8; light chain containing SEQ ID NO: 372 and heavy chain containing SEQ ID NO: 529; light chain containing SEQ ID NO: 373 and heavy chain containing SEQ ID NO: 530; light chain containing SEQ ID NO: 374 and heavy chain containing SEQ ID NO: 531; light chain containing SEQ ID NO: 375 and heavy chain containing SEQ ID NO: 532; light chain containing SEQ ID NO: 376 and heavy chain containing SEQ ID NO: 533; light chain containing SEQ ID NO: 377 and heavy chain containing SEQ ID NO: 534; light chain containing SEQ ID NO: 378 and heavy chain containing SEQ ID NO: 535; light chain containing SEQ ID NO: 379 and heavy chain containing SEQ ID NO: 536; light chain containing SEQ ID NO: 380 and heavy chain containing SEQ ID NO: 537;Light chain containing SEQ ID NO: 381 and heavy chain containing SEQ ID NO: 538; Light chain containing SEQ ID NO: 382 and heavy chain containing SEQ ID NO: 539; Light chain containing SEQ ID NO: 383 and heavy chain containing SEQ ID NO: 540; Light chain containing SEQ ID NO: 384 and heavy chain containing SEQ ID NO: 541; Light chain containing SEQ ID NO: 385 and heavy chain containing SEQ ID NO: 542; Light chain containing SEQ ID NO: 386 and heavy chain containing SEQ ID NO: 543; Light chain containing SEQ ID NO: 387 and heavy chain containing SEQ ID NO: 544; Light chain containing SEQ ID NO: 388 and heavy chain containing SEQ ID NO: 545; Light chain containing SEQ ID NO: 389 and heavy chain containing SEQ ID NO: 546; SEQ ID NO: 39 Light chain containing 0 and heavy chain containing SEQ ID NO: 547; Light chain containing SEQ ID NO: 391 and heavy chain containing SEQ ID NO: 548; Light chain containing SEQ ID NO: 392 and heavy chain containing SEQ ID NO: 549; Light chain containing SEQ ID NO: 393 and heavy chain containing SEQ ID NO: 550; Light chain containing SEQ ID NO: 394 and heavy chain containing SEQ ID NO: 551; Light chain containing SEQ ID NO: 395 and heavy chain containing SEQ ID NO: 552; Light chain containing SEQ ID NO: 396 and heavy chain containing SEQ ID NO: 553; Light chain containing SEQ ID NO: 397 and heavy chain containing SEQ ID NO: 554; Light chain containing SEQ ID NO: 398 and heavy chain containing SEQ ID NO: 555; Light chain containing SEQ ID NO: 399 and Heavy chain containing SEQ ID NO: 556; light chain containing SEQ ID NO: 400 and heavy chain containing SEQ ID NO: 557; light chain containing SEQ ID NO: 401 and heavy chain containing SEQ ID NO: 558; light chain containing SEQ ID NO: 402 and heavy chain containing SEQ ID NO: 559; light chain containing SEQ ID NO: 403 and heavy chain containing SEQ ID NO: 560; light chain containing SEQ ID NO: 404 and heavy chain containing SEQ ID NO: 561; light chain containing SEQ ID NO: 405 and heavy chain containing SEQ ID NO: 562; light chain containing SEQ ID NO: 406 and heavy chain containing SEQ ID NO: 563; light chain containing SEQ ID NO: 407 and heavy chain containing SEQ ID NO: 564; light chain containing SEQ ID NO: 408 and SEQ ID NO: 56 Heavy chain containing 5; light chain containing SEQ ID NO: 409 and heavy chain containing SEQ ID NO: 566; light chain containing SEQ ID NO: 410 and heavy chain containing SEQ ID NO: 567; light chain containing SEQ ID NO: 411 and heavy chain containing SEQ ID NO: 568; light chain containing SEQ ID NO: 412 and heavy chain containing SEQ ID NO: 569; light chain containing SEQ ID NO: 413 and heavy chain containing SEQ ID NO: 570; light chain containing SEQ ID NO: 414 and heavy chain containing SEQ ID NO: 571; light chain containing SEQ ID NO: 415 and heavy chain containing SEQ ID NO: 572; light chain containing SEQ ID NO: 416 and heavy chain containing SEQ ID NO: 573; light chain containing SEQ ID NO: 417 and heavy chain containing SEQ ID NO: 574;Light chain containing SEQ ID NO: 418 and heavy chain containing SEQ ID NO: 575; Light chain containing SEQ ID NO: 419 and heavy chain containing SEQ ID NO: 576; Light chain containing SEQ ID NO: 420 and heavy chain containing SEQ ID NO: 577; Light chain containing SEQ ID NO: 421 and heavy chain containing SEQ ID NO: 578; Light chain containing SEQ ID NO: 422 and heavy chain containing SEQ ID NO: 579; Light chain containing SEQ ID NO: 423 and heavy chain containing SEQ ID NO: 580; Light chain containing SEQ ID NO: 424 and heavy chain containing SEQ ID NO: 581; Light chain containing SEQ ID NO: 425 and heavy chain containing SEQ ID NO: 582; Light chain containing SEQ ID NO: 426 and heavy chain containing SEQ ID NO: 583; SEQ ID NO: 42 Light chain containing 7 and heavy chain containing SEQ ID NO: 584; Light chain containing SEQ ID NO: 428 and heavy chain containing SEQ ID NO: 585; Light chain containing SEQ ID NO: 429 and heavy chain containing SEQ ID NO: 586; Light chain containing SEQ ID NO: 430 and heavy chain containing SEQ ID NO: 587; Light chain containing SEQ ID NO: 431 and heavy chain containing SEQ ID NO: 588; Light chain containing SEQ ID NO: 432 and heavy chain containing SEQ ID NO: 589; Light chain containing SEQ ID NO: 433 and heavy chain containing SEQ ID NO: 590; Light chain containing SEQ ID NO: 434 and heavy chain containing SEQ ID NO: 591; Light chain containing SEQ ID NO: 435 and heavy chain containing SEQ ID NO: 592; Light chain containing SEQ ID NO: 436 and Heavy chain containing SEQ ID NO: 593; light chain containing SEQ ID NO: 437 and heavy chain containing SEQ ID NO: 594; light chain containing SEQ ID NO: 438 and heavy chain containing SEQ ID NO: 595; light chain containing SEQ ID NO: 439 and heavy chain containing SEQ ID NO: 596; light chain containing SEQ ID NO: 440 and heavy chain containing SEQ ID NO: 597; light chain containing SEQ ID NO: 441 and heavy chain containing SEQ ID NO: 598; light chain containing SEQ ID NO: 442 and heavy chain containing SEQ ID NO: 599; light chain containing SEQ ID NO: 443 and heavy chain containing SEQ ID NO: 600; light chain containing SEQ ID NO: 444 and heavy chain containing SEQ ID NO: 601; light chain containing SEQ ID NO: 445 and SEQ ID NO: 60 Heavy chain containing 2; light chain containing SEQ ID NO: 446 and heavy chain containing SEQ ID NO: 603; light chain containing SEQ ID NO: 447 and heavy chain containing SEQ ID NO: 604; light chain containing SEQ ID NO: 448 and heavy chain containing SEQ ID NO: 605; light chain containing SEQ ID NO: 449 and heavy chain containing SEQ ID NO: 606; light chain containing SEQ ID NO: 450 and heavy chain containing SEQ ID NO: 607; light chain containing SEQ ID NO: 451 and heavy chain containing SEQ ID NO: 608; light chain containing SEQ ID NO: 452 and heavy chain containing SEQ ID NO: 609; light chain containing SEQ ID NO: 453 and heavy chain containing SEQ ID NO: 610; light chain containing SEQ ID NO: 454 and heavy chain containing SEQ ID NO: 611;Light chain containing SEQ ID NO: 455 and heavy chain containing SEQ ID NO: 612; Light chain containing SEQ ID NO: 456 and heavy chain containing SEQ ID NO: 613; Light chain containing SEQ ID NO: 457 and heavy chain containing SEQ ID NO: 614; Light chain containing SEQ ID NO: 458 and heavy chain containing SEQ ID NO: 615; Light chain containing SEQ ID NO: 459 and heavy chain containing SEQ ID NO: 616; Light chain containing SEQ ID NO: 460 and heavy chain containing SEQ ID NO: 617; Light chain containing SEQ ID NO: 461 and heavy chain containing SEQ ID NO: 618; Light chain containing SEQ ID NO: 462 and heavy chain containing SEQ ID NO: 619; Light chain containing SEQ ID NO: 463 and heavy chain containing SEQ ID NO: 620; This includes combinations of light and heavy chains selected from the group consisting of: a light chain containing sequence number 464 and a heavy chain containing sequence number 621; a light chain containing sequence number 465 and a heavy chain containing sequence number 622; a light chain containing sequence number 466 and a heavy chain containing sequence number 623; a light chain containing sequence number 467 and a heavy chain containing sequence number 624; a light chain containing sequence number 468 and a heavy chain containing sequence number 625; a light chain containing sequence number 469 and a heavy chain containing sequence number 626; a light chain containing sequence number 470 and a heavy chain containing sequence number 627; and a light chain containing sequence number 471 and a heavy chain containing sequence number 628.

[0696] In one embodiment, the antibody or fragment thereof includes a light chain encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NOs. 1885 to 2014. In one embodiment, the antibody or fragment thereof includes a heavy chain encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NOs. 2042 to 2198. In one embodiment, the antibody or fragment thereof includes a light chain encoded by a polynucleotide sequence selected from the group consisting of SEQ ID NOs. 1885 to 2014, and a heavy chain containing a sequence selected from the group consisting of SEQ ID NOs. 2042 to 2198. In one embodiment, the antibody or fragment thereof comprises a light chain encoded by a polynucleotide sequence including SEQ ID NO: 1885 and a heavy chain encoded by a polynucleotide sequence including SEQ ID NO: 2042; a light chain encoded by a polynucleotide sequence including SEQ ID NO: 1886 and a heavy chain encoded by a polynucleotide sequence including SEQ ID NO: 2043; a light chain encoded by a polynucleotide sequence including SEQ ID NO: 1887 and a heavy chain encoded by a polynucleotide sequence including SEQ ID NO: 2044; a light chain encoded by a polynucleotide sequence including SEQ ID NO: 1888 and a heavy chain encoded by a polynucleotide sequence including SEQ ID NO: 2045; a light chain encoded by a polynucleotide sequence including SEQ ID NO: 1889 and a heavy chain encoded by a polynucleotide sequence including SEQ ID NO: 2046; and a polynucleotide sequence including SEQ ID NO: 1890. A light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2047 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 1891 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2048; a light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1892 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2049; a light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1893 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2050; a light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1894 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2051; a light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1895 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2052;Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1896 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2053; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1897 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2054; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1898 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2055; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1899 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2056; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1900 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2057; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1901 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2058; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1902 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2059; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1903 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2060; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1904 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2061; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1905 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2062; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1906 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2063; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1907 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2064; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1908 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2065; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1909 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2066;Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1910 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2067; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1911 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2068; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1912 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2069; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1913 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2070; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1914 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2071; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1915 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2072; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1916 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2073; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1917 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2074; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1918 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2075; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1919 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2076; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1920 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2077; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1921 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2078; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1922 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2079; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1923 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2080;Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1924 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2081; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1925 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2082; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1926 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2083; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1927 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2084; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1928 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2085; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1929 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2086; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1930 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2087; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1931 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2088; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1932 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2089; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1933 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2090; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1934 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2091; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1935 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2092; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1936 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2093; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1937 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2094;Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1938 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2095; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1939 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2096; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1940 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2097; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1941 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2098; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1942 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2099; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1943 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2100; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1944 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2101; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1945 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2102; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1946 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2103; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1947 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2104; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1948 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2105; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1949 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2106; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1950 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2107; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1951 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2108;Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1952 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2109; light chain encoded by polynucleotide sequence containing SEQ ID NO: 1953 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2110; light chain encoded by polynucleotide sequence containing SEQ ID NO: 1954 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2111; light chain encoded by polynucleotide sequence containing SEQ ID NO: 1955 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2112; light chain encoded by polynucleotide sequence containing SEQ ID NO: 1956 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2113; light chain encoded by polynucleotide sequence containing SEQ ID NO: 1957 and; Heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2114; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1958 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2115; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1959 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2116; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1960 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2117; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1961 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2118; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1962 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2119; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1963 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2120; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1964 and polynucleotide sequence containing SEQ ID NO: 2121 Heavy chain encoded by an Otid sequence; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1965 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2122; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1966 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2123; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1967 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2124; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1968 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2125; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1969 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2126; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1970 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2127; light chain encoded by a polynucleotide sequence containing SEQ ID NO: 1971 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2128;Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1972 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2129; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1973 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2130; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1974 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2131; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1975 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2132; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1976 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2133; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1977 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2134; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1978 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2135; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1979 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2136; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1980 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2137; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1981 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2138; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1982 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2139; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1983 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2140; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1984 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2141; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1985 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2142;Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1986 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2143; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1987 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2144; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1988 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2145; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1989 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2146; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1990 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2147; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1991 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2148; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1992 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2149; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1993 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2150; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1994 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2151; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1995 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2152; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1996 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2153; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1997 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2154; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1998 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2155; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 1999 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2156;Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2000 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2157; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2001 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2158; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2002 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2159; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2003 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2160; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2004 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2161; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2005 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2162; Light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2006 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2163; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2007 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2164; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2008 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2165; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2009 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2166; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2010 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2167; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2011 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2168; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2012 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2169; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2013 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2170;Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2014 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2171; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2015 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2172; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2016 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2173; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2017 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2174; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2018 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2175; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2019 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2176; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2020 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2177; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2021 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2178; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2022 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2179; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2023 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2180; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2024 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2181; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2025 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2182; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2026 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2183; Light chain encoded by polynucleotide sequence containing SEQ ID NO: 2027 and heavy chain encoded by polynucleotide sequence containing SEQ ID NO: 2184;Light chain encoded by a polynucleotide sequence containing SEQ ID NO. 2028 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO. 2185; light chain encoded by a polynucleotide sequence containing SEQ ID NO. 2029 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO. 2186; light chain encoded by a polynucleotide sequence containing SEQ ID NO. 2030 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO. 2187; light chain encoded by a polynucleotide sequence containing SEQ ID NO. 2031 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO. 2188; light chain encoded by a polynucleotide sequence containing SEQ ID NO. 2032 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO. 2189; light chain encoded by a polynucleotide sequence containing SEQ ID NO. 2033 and heavy chain encoded by a polynucleotide sequence containing SEQ ID NO. 2190; A heavy chain; a light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2034 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2191; a light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2035 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2192; a light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2036 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2193; a light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2037 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2194; a polynucleotide sequence containing SEQ ID NO: 2038 The combination includes a light chain variable region and a heavy chain variable region selected from the group consisting of: a light chain encoded by an Otid sequence and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2195; a light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2039 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2196; a light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2040 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2197; and a light chain encoded by a polynucleotide sequence containing SEQ ID NO: 2041 and a heavy chain encoded by a polynucleotide sequence containing SEQ ID NO: 2198.

[0697] In another embodiment, the antigen-binding protein includes a full-length light chain and a full-length heavy chain as listed in one of the rows for one of the antibodies listed in Table 5 or Table 10. Some antigen-binding proteins provided include a full-length light chain and a full-length heavy chain as listed in one of the rows for one of the antibodies listed in Table 5 or Table 10, with the exception that one or both of these chains differ from the sequence identified in that table by only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, each such sequence difference independently being either a deletion, insertion, or substitution of a single amino acid, and as a result of such deletion, insertion, and / or substitution, one, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acids are altered compared to the full-length sequence identified in Table 5 or Table 10. In one embodiment, the antigen-binding protein includes a full-length light chain and / or full-length heavy chain from Table 5 or Table 10, but lacks N-terminal methionine. In another embodiment, the antigen-binding protein includes a full-length light chain and / or full-length heavy chain from Table 5 or Table 10, but lacks C-terminal lysine. Other antigen-binding proteins also include a full-length light chain and / or full-length heavy chain as listed in one of the rows for one of the antibodies listed in Table 5 or Table 10, with the exception that one or both of these chains differ from the sequences specified in Table 5 or Table 10 in that the light chain and / or heavy chain contain or consist of an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the light chain or heavy chain sequence specified in Table 5 or Table 10.

[0698] In another embodiment, the antigen-binding protein consists solely of light-chain polypeptides or heavy-chain polypeptides as shown in Table 5 or Table 10.

[0699] In yet another embodiment, the antigen-binding protein containing the CDR, variable domain and / or full-length sequence listed in Tables 3, 4A, 4B, 5, 8, 9A, 9B and 10 is a monoclonal antibody, chimeric antibody, humanized antibody, human antibody, multispecific antibody, or an antibody fragment thereof. In yet another embodiment, the antibody fragment of the isolated antigen-binding protein provided herein is a Fab fragment, Fab' fragment, F(ab')2 fragment, Fv fragment, diabody, or scFv based on an antibody having a sequence such as those listed in Table 5 or Table 10.

[0700] In yet another embodiment, the isolated antigen-binding proteins provided in Table 5 or Table 10 may be coupled to a labeling group and may compete for binding to GIPR with one of the isolated antigen-binding proteins provided herein.

[0701] In another embodiment, an antigen-binding protein is provided that competes with one of the exemplary antibodies or functional fragments above for specific binding to human GIPR (e.g., SEQ ID NO: 3141). Such an antigen-binding protein may bind to the same epitope as one of the antigen-binding proteins described herein, or may bind to a duplicate epitope. Antigen-binding proteins and fragments that compete with the exemplary antigen-binding proteins are expected to exhibit similar functional properties. The exemplary antigen-binding proteins and fragments include those having heavy and light chains, variable region domains and CDRs, as shown in Tables 3, 4A, 4B, 5, 8, 9A, 9B and 10. Thus, as a specific example, the antigen-binding proteins provided include those that compete with antibodies having the following: All six CDRs listed for any antibody listed in Tables 4A and 4B or Tables 9A and 9B; VH and VL listed for any antibody listed in Table 3 or Table 8; or Two light chains and two heavy chains, as specified for any antibody listed in Table 5 or Table 10.

[0702] The antigen-binding proteins provided include monoclonal antibodies that bind to GIPR. Monoclonal antibodies can be produced, for example, by immortalizing spleen cells isolated from transgenic animals after completion of an immunization schedule, using any technique known in the art. Spleen cells can be immortalized, for example, by fusing spleen cells with myeloma cells to produce hybridomas, using any technique known in the art. Myeloma cells for use in the fusion procedure to produce hybridomas are preferably non-antibody-producing, highly efficient at fusion, and lack enzymes that prevent them from growing in certain selective media that support the proliferation of only the desired fusion cells (hybridoms). Examples of cell lines suitable for use in mouse fusion include Sp-20, P3-X63 / Ag8, P3-X63-Ag8.653, NS1 / 1.Ag4 1, Sp210-Ag14, FO, NSO / U, MPC-11, MPC11-X45-GTG1.7, and S194 / 5XXO Bul. Examples of cell lines used in rat fusion include R210.RCY3, Y3-Ag1.2.3, IR983F, and 4B210. Other cell lines useful for cell fusion include U-266, GM1500-GRG2, LICR-LON-HMy2, and UC729-6.

[0703] In some cases, hybridoma cell lines are produced by immunizing animals (e.g., transgenic animals possessing human immunoglobulin sequences) with a GIPR immunogen, recovering spleen cells from the immunized animals, creating hybridoma cells by fusing the recovered spleen cells to a myeloma cell line, establishing a hybridoma cell line from the hybridoma cells, and identifying a hybridoma cell line that produces antibodies binding to the GIPR polypeptide. Such hybridoma cell lines and the anti-GIPR monoclonal antibodies they produce are embodiments of the present invention.

[0704] Monoclonal antibodies secreted by hybridoma cell lines can be purified using any technique known in the art. Further screening of hybridomas or mAbs may identify mAbs with specific properties, such as the ability to enhance GIPR activity.

[0705] Chimeric antibodies and humanized antibodies based on the aforementioned sequences are also provided. Monoclonal antibodies for use as therapeutic agents can be modified in various ways before use. One example is a chimeric antibody, which is an antibody consisting of protein segments derived from different antibodies that are covalently linked to produce a functional immunoglobulin light chain or immunoglobulin heavy chain or an immunofunctional portion thereof. Generally, a portion of the heavy chain and / or light chain is identical or homologous to a corresponding sequence in an antibody from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to a corresponding sequence in an antibody from a different species or belonging to a different antibody class or subclass. For methods relating to chimeric antibodies, see, for example, U.S. Patent No. 4,816,567; and Morrison et al., 1985, Proc. Natl. Acad. Sci. USA 81:6851-6855 (these documents are incorporated herein by reference). CDR porting is described, for example, in U.S. Patent Nos. 6,180,370, 5,693,762, 5,693,761, 5,585,089, and 5,530,101.

[0706] Generally, the goal of creating chimeric antibodies is to create a chimera in which the number of amino acids derived from the intended patient species is maximized. One example is a "CDR-implanted" antibody, which contains one or more complementarity-determining regions (CDRs) derived from a specific species or belonging to a specific antibody class or subclass, while the remainder of the antibody chain is identical or homologous to the corresponding sequence in an antibody derived from a different species or belonging to a different antibody class or subclass. In human use, variable regions or selected CDRs derived from rodent antibodies are often implanted into human antibodies, thereby replacing the naturally occurring variable regions or CDRs of the human antibody.

[0707] One useful type of chimeric antibody is the "humanized" antibody. Generally, humanized antibodies are produced from monoclonal antibodies originally produced in non-human animals. Typically, certain amino acid residues in this monoclonal antibody, derived from the non-antigen recognition portion of the antibody, are modified to be homologous to the corresponding residues in the corresponding isotype of the human antibody. Humanization can be carried out using various methods, for example, by substituting the corresponding region of the human antibody with at least a portion of the rodent variable region (see, e.g., U.S. Patents No. 5,585,089 and 5,693,762; Jones et al., 1986, Nature 321:522-525; Riechmann et al., 1988, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-1536).

[0708] In one embodiment, the CDRs of the light chain variable region and heavy chain variable region of the antibody provided herein are transplanted into a framework region (FR) derived from an antibody of the same or different lineage. For example, the heavy chain variable region and the light chain variable region V H 1. V H 2, V H 3, V H 4. V H 5, V H 6, V H 7, V H 8, V H 9, VH 10, V H 11, V H 12 and / or V L 1 and V L The CDR of 2 can be transplanted into a consensus human FR. To create a consensus human FR, several FRs derived from human heavy or light chain amino acid sequences can be aligned to identify the consensus amino acid sequence. In other embodiments, the heavy or light chain FRs disclosed herein are exchanged with FRs derived from different heavy or light chains. In one embodiment, rare amino acids in the heavy and light chain FRs of the GIPR antibody are not exchanged, and the rest of the FR amino acids are exchanged. A “rare amino acid” is a specific amino acid that is located in a position where it is not normally found in the FR. Alternatively, a variable region to be transplanted from one heavy or light chain may be used with a constant region different from the constant region of that particular heavy or light chain, as disclosed herein. In other embodiments, the variable region to be transplanted is part of a single-chain Fv antibody.

[0709] In certain embodiments, hybrid antibodies can be produced by using a constant region derived from a non-human species together with a human variable region.

[0710] Fully human GIPR antibodies are also provided. Methods are available for producing fully human antibodies ("fully human antibodies") that are specific to a given antigen without exposing humans to the antigen. One specific means provided for carrying out the production of fully human antibodies is the "humanization" of the mouse humoral immune system. Introducing a human immunoglobulin (Ig) locus into a mouse in which the endogenous Ig gene has been inactivated is one means of producing fully human monoclonal antibodies (mAbs) in a mouse, an animal that can be immunized to some desired antigen. Using fully human antibodies can minimize immunogenic and allergic responses that may occur when a mouse mAb or mouse-derived mAb is administered to a human as a therapeutic agent.

[0711] Fully human antibodies can be produced by immunizing transgenic animals (usually mice) that lack endogenous immunoglobulin production and are capable of producing a repertoire of human antibodies. Antigens for this purpose typically consist of six or more consecutive amino acids and are selectively conjugated to a carrier such as a hapten. See, for example, Jakobovits et al., 1993, Proc. Natl. Acad. Sci. USA 90:2551-2555; Jakobovits et al., 1993, Nature 362:255-258; and Bruggermann et al., 1993, Year in Immunol. 7:33. In one example of such a method, the transgenic animal is produced by deactivating the endogenous mouse immunoglobulin loci encoding the heavy and light chains of immunoglobulin in mice and inserting a large fragment of human genomic DNA containing loci encoding human heavy and light chain proteins into the mouse genome. Next, partially modified animals having less complement than the complete complement of the human immunoglobulin locus are crossbred to obtain animals possessing all the desired immunosystem modifications. Upon administration of the immunogen, these transgenic animals produce antibodies that are immunospecific to the immunogen but have a human amino acid sequence, including the variable region, rather than a mouse amino acid sequence. For further details of such methods, see, for example, International Publication Nos. 96 / 33735 and 94 / 02602. Further methods relating to transgenic mice for the production of human antibodies are described in U.S. Patent Nos. 5,545,807, 6,713,610, 6,673,986, 6,162,963, 5,545,807, 6,300,129, 6,255,458, 5,877,397, 5,874,299, and 5,545,806, International Publication Nos. 91 / 10741 and 90 / 04036, and European Patent Nos. 546073B1 and 546073A1.

[0712] The transgenic mice described above, referred to herein as "HuMab" mice, contain a minilocus of human immunoglobulin genes encoding unreorganized immunoglobulin sequences of human heavy chains ([mu] and [gamma]) and [kappa] light chains, along with targeted mutations that inactivate endogenous [mu] and [kappa] chain loci (Lonberg et al., 1994, Nature 368:856-859). Consequently, mice exhibit reduced expression of mouse IgM or [kappa], and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutations to produce high-affinity human IgG [kappa] monoclonal antibodies (Lonberg et al., above; Lonberg and Huszar, 1995, Intern. Rev. Immunol. 13:65-93; Harding and Lonberg, 1995, Ann. NY Acad. Sci. 764:536-546). HuMab mouse preparation was performed by Taylor et al.,1992,Nucleic Acids Research 20:6287-6295;Chen et al.,1993,International Immunology 5:647-656;Tuaillon et al.,1994,J.Immunol.152:2912-2920;Lonberg et al.,1994,Nature 368:856-859;Lonberg,1994,Handbook of Exp.Pharmacology 113:49-101;Taylor et al.,1994,International Immunology 6:579-591;Lonberg and Huszar,1995,Intern.Rev.Immunol.13:65-93;Harding and Lonberg, 1995, Ann.NY This is described in detail in Acad.Sci.764:536-546; Fishwild et al., 1996, Nature Biotechnology 14:845-851, and these documents are incorporated herein by reference in their entirety for all purposes.Furthermore, please refer to U.S. Patent Nos. 5,545,806, 5,569,825, 5,625,126, 5,633,425, 5,789,650, 5,877,397, 5,661,016, 5,814,318, 5,874,299 and 5,770,429, as well as U.S. Patent No. 5,545,807, International Publication No. 93 / 1227, International Publication No. 92 / 22646, and International Publication No. 92 / 03918 (all of their disclosures are incorporated herein by reference in their entirety for all purposes). Techniques utilizing the production of human antibodies in these transgenic mice are also disclosed in International Publication No. 98 / 24893 and Mendez et al., 1997, Nature Genetics 15:146-156, which are incorporated herein by reference. For example, transgenic mouse lines HCo7 and HCo12 can be used to produce human monoclonal antibodies against GIPR. Further details regarding the production of human antibodies using transgenic mice are provided below.

[0713] By using hybridoma technology, antigen-specific human mAbs with desired specificity can be generated and selected from transgenic mice such as those mentioned above. Such antibodies can be cloned and expressed using appropriate vectors and host cells, or the antibodies can be recovered from cultured hybridoma cells.

[0714] Fully human antibodies may also be derived from phage display libraries (as disclosed in Hoogenboom et al., 1991, J.Mol. Biol. 227:381; and Marks et al., 1991, J.Mol. Biol. 222:581). Phage display techniques mimic immunoselection through the presentation of an antibody repertoire on the surface of filamentous bacteriophages and subsequent selection of the phages by their binding to a selected antigen. One such technique is described in International Publication No. 99 / 10494 (incorporated herein by reference).

[0715] GIPR-binding proteins may also be variants, mimetic compounds, derivatives, or oligomers based on the structure of GIPR antigen-binding proteins having the CDR, variable region, and / or full-length chain described above.

[0716] In one embodiment, for example, the antigen-binding protein is a variant form of the antigen-binding protein disclosed above. For example, some antigen-binding proteins have one or more conserved amino acid substitutions in one or more of the heavy chain or light chain, variable region or CDR.

[0717] Naturally occurring amino acids can be classified into the following classes based on their common side-chain characteristics: 1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; 2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; 3) Acidic: Asp, Glu; 4) Basicity: His, Lys, Arg; 5) Residues that affect chain orientation: Gly, Pro; and 6) Aromatics: Trp, Tyr, Phe.

[0718] Conservative amino acid substitutions can involve the exchange of one member of a particular class with another member of the same class. Conservative amino acid substitutions can also include non-natural amino acid residues, which are generally incorporated through chemical peptide synthesis rather than synthesis in biological systems. These include peptide mimes and other forms in which the amino acid moieties are reversed or inverted.

[0719] Non-conservative substitutions may involve the exchange of a member of one of the above classes with a member of another class. Such substituted residues may be introduced into a region homologous to that of a human antibody in the antibody, or into a region that is not homologous to that of the molecule.

[0720] According to certain embodiments, when implementing such modifications, the hydroxyl index of amino acids may be taken into consideration. The hydroxyl profile of a protein is calculated by assigning a numerical value ("hydroxyl index") to each amino acid and then iterating and averaging these values ​​along the peptide chain. Each amino acid is assigned a hydroxyl index based on its hydrophobic and charge properties. These are isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine / cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamic acid (-3.5); glutamine (-3.5); aspartic acid (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).

[0721] The importance of hydroxyl profiles in conferring interactive biological functions to proteins is well understood in the art (see, for example, Kyte et al., 1982, J.Mol.Biol.157:105-131). Certain amino acids are known to be able to substitute for other amino acids with similar hydroxyl indices or hydroxyl scores while still retaining similar biological activity. In certain embodiments, when modifications are made based on the hydroxyl index, substitutions of amino acids with a hydroxyl index of ±2 are included. In some embodiments, substitutions of ±1 are included, and in others, substitutions of ±0.5 are included.

[0722] It is understood in the Art that similar amino acid substitutions can be efficiently performed based on hydrophilicity, and in particular, that the resulting biologically functional proteins or peptides may be intended for use in immunological embodiments, as in this case. In certain embodiments, the local maximum mean hydrophilicity of a protein is governed by the hydrophilicity of its adjacent amino acids, which correlates with its immunogenicity and antigen-binding or immunogenicity, i.e., the biological properties of the protein.

[0723] The following hydrophilic values ​​are assigned to these amino acid residues: arginine (+3.0); lysine (+3.0); aspartic acid (+3.0±1); glutamic acid (+3.0±1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5±1); alanine (-0.5); histidine (-0.5); cysteine ​​(-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); and tryptophan (-3.4). In certain embodiments, when modifications based on similar hydrophilic values ​​are implemented, substitutions of amino acids with a hydrophilic value within ±2 are included. In other embodiments, those within ±1 are included, and in yet another embodiment, those within ±0.5 are included. In some cases, epitopes can be identified from the primary amino acid sequence based on their hydrophilicity. These regions are also called "epitope core regions."

[0724] Table 11 shows exemplary conservative amino acid substitutions. [Table 559]

[0725] Those skilled in the art will be able to determine preferred variants of the polypeptides described herein using well-known techniques. Those skilled in the art will be able to identify preferred regions of the molecule that can be modified without impairing activity by targeting regions considered not important to activity. Those skilled in the art will also be able to identify conserved residues and portions of molecules among similar polypeptides. In further embodiments, regions that may be important to biological activity or structure can also be subjected to conserved amino acid substitution without impairing biological activity or adversely affecting the polypeptide structure.

[0726] Furthermore, those skilled in the art can evaluate structure-function tests to identify residues important for activity or structure in similar polypeptides. By considering such comparisons, the importance of amino acid residues in a protein corresponding to amino acid residues important for activity or structure in similar proteins can be predicted. Those skilled in the art can select chemically similar amino acid substitutions for such predicted important amino acid residues.

[0727] Those skilled in the art can also analyze the three-dimensional structure and the amino acid sequence of similar polypeptides. By considering such information, those skilled in the art can predict the alignment of amino acid residues of an antibody with respect to its three-dimensional structure. Since amino acid residues predicted to be present on the protein surface may be involved in important interactions with other molecules, those skilled in the art can select such residues so as not to undergo radical changes. Furthermore, those skilled in the art can construct test variants containing a single amino acid substitution at each desired amino acid residue. These variants can then be screened using assays for GIPR activity, thus providing information on which amino acids can be modified and which should not. In other words, based on information gathered from such routine experiments, those skilled in the art can easily determine amino acid positions where further substitutions, either alone or in combination with other mutations, should be avoided.

[0728] Many scientific publications deal with secondary structure prediction. See Moult, 1996, Curr. Op. in Biotech. 7:422-427; Chou et al., 1974, Biochem. 13:222-245; Chou et al., 1974, Biochemistry 113:211-222; Chou et al., 1978, Adv. Enzymol. Relat. Areas Mol. Biol. 47:45-148; Chou et al., 1979, Ann. Rev. Biochem. 47:251-276; and Chou et al., 1979, Biophys. J. 26:367-384. Furthermore, computer programs are now available to assist in secondary structure prediction. One method of secondary structure prediction is based on homology modeling. For example, two polypeptides or proteins with more than 30% sequence identity or more than 40% similarity may have similar structural topologies. Recent improvements in protein databases (PDBs) have enhanced the predictability of secondary structures, including the latent number of folds within polypeptide or protein structures. (See Holm et al., 1999, Nucl. Acid. Res. 27:244-247. (Brenner et al., 1997, Curr. Op. Struct. Biol. 7:369-376)) It has been suggested that the number of folds present in a given polypeptide or protein is limited, and that the accuracy of structural prediction will dramatically improve once a definitive number of structures are elucidated.

[0729] Further methods for predicting secondary structure include "threading" (Jones, 1997, Curr. Opin. Struct. Biol. 7:377-387; Sippl et al., 1996, Structure 4:15-19), "profile analysis" (Bowie et al., 1991, Science 253:164-170; Gribskov et al., 1990, Meth. Enzym. 183:146-159; Gribskov et al., 1987, Proc. Nat. Acad. Sci. 84:4355-4358), and "evolutionary linkage" (Holm, 1999, see above; and Brenner, 1997, see above).

[0730] In some embodiments, amino acid substitutions are made to: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for protein complex formation, (4) alter ligand or antigen binding affinity, and / or (4) confer or modify other physiological or functional properties to such polypeptides. For example, one or more amino acid substitutions (conservative amino acid substitutions in certain embodiments) may be carried out in the natural sequence. Substitutions may be carried out in antibody moieties located outside domains that form intermolecular contact sites. In such embodiments, conservative amino acid substitutions that do not substantially alter the structural properties of the parent sequence (e.g., one or more replacement amino acids that do not impair the secondary structure that characterizes the parent or native antigen-binding protein) may be used. Examples of polypeptide secondary and tertiary structures recognized in the art are described in Proteins, Structures and Molecular Principles (Creighton, Ed.), 1984, WH New York: Freeman and Company; Introduction to Protein Structure (Branden and Tooze, eds.), 1991, New York: Garland Publishing; and Thornton et al., 1991, Nature 354:105, which are incorporated herein by reference, respectively.

[0731] Further preferred antibody variants include cysteine ​​variants, in which one or more cysteine ​​residues in the parental or native amino acid sequence are deleted or substituted with another amino acid (e.g., serine). Cysteine ​​variants are particularly useful when the antibody must be refolded into a biologically active conformation. The number of cysteine ​​residues in a cysteine ​​variant may be fewer than that of the native antibody, and is typically a number that further minimizes interactions arising from unpaired cysteine.

[0732] The disclosed heavy and light chains, variable region domains, and CDRs can be used to prepare polypeptides containing antigen-binding regions capable of specifically binding to GIPR. For example, one or more CDR1s can be covalently or noncovalently incorporated into a molecule (e.g., a polypeptide) to prepare an immunoadhesive. The CDR can be incorporated into the immunoadhesive as part of a larger polypeptide chain, covalently linked to another polypeptide chain, or noncovalently incorporated into the immunoadhesive. The CDR enables the immunoadhesive to specifically bind to a particular antigen of interest (e.g., a GIPR polypeptide or its epitope).

[0733] Mimics based on the variable region domains and CDRs described herein (e.g., "peptide mimics" or "peptide analogs") are also provided. These analogs may be peptides, non-peptides, or combinations of peptide and non-peptide regions. (Fauchere, 1986, Adv. Drug Res. 15:29; Veber and Freidinger, 1985, TINS ​​p.392; and Evans et al., 1987, J. Med. Chem. 30:1229 - these are incorporated herein by reference for all purposes). Peptide mimics structurally similar to therapeutically useful peptides may be used to produce similar therapeutic or prophylactic effects. Such compounds are often developed with the assistance of computerized molecular modeling. Generally, peptide mimes are proteins that are structurally similar to antibodies exhibiting desired biological activity, such as the ability to specifically bind GIPR, but have one or more peptide links that can be optionally replaced by links selected from the following by methods known in the art: -CH2NH-, -CH2S-, -CH2-CH2-, -CH-CH-(cis and trans), -COCH2-, -CH(OH)CH2-, and -CH2SO-. In certain embodiments, one or more amino acids in the consensus sequence may be systematically substituted with identical D-amino acids (e.g., D-lysine instead of L-lysine) to produce proteins with improved stability. Furthermore, restrictive peptides containing the consensus sequence or substantially identical variations of the consensus sequence can be produced by methods known in the art (Rizo and Gierasch, 1992, Ann. Rev. Biochem. 61:387, incorporated herein by reference), for example, by adding internal cysteine ​​residues capable of forming intramolecular disulfide crosslinks that cyclize the peptide.

[0734] Derivatives of antigen-binding proteins described herein are also provided. Derivatized antigen-binding proteins may include any molecule or substance that confers desired properties to an antibody or fragment, such as an increased half-life for a particular application. Derivatized antigen-binding proteins may include, for example, a detectable (or labeled) moiety (e.g., a radioactive molecule, a colorimetric molecule, an antigenic molecule, or an enzyme molecule, a detectable bead (such as a magnetic or high-electron-density (e.g., gold) bead), or a molecule that binds to another molecule (e.g., biotin or streptavidin)), a therapeutic or diagnostic moiety (e.g., a radioactive moiety, a cytotoxic moiety, or a pharmaceutically active moiety), or a molecule that improves the stability of the antigen-binding protein for a particular application (e.g., administration to a subject such as a human subject, or other in vivo or in vitro use). Examples of molecules that can be used for the derivatization of antigen-binding proteins include albumin (e.g., human serum albumin) and polyethylene glycol (PEG). Albumin-linked and PEGylated derivatives of antigen-binding proteins can be prepared using techniques well known in the art. Certain antigen-binding proteins include PEGylated single-chain polypeptides as described herein. In one embodiment, the antigen-binding protein is complexed with or otherwise linked to transthyretin (TTR) or a TTR variant. TTR or TTR variants may be chemically modified with a chemical selected from the group consisting of, for example, dextran, poly(n-vinylpyrrolidone), polyethylene glycol, propropylene glycol homopolymer, polypropylene oxide / ethylene oxide copolymer, polyoxyethylated polyol, and polyvinyl alcohol.

[0735] Other derivatives include covalent or aggregated complexes of the GIPR antigen-binding protein with other proteins or polypeptides, such as those resulting from the expression of recombinant fusion proteins containing heterologous polypeptides fused to the N-terminus or C-terminus of the GIPR antigen-binding protein. For example, the complexed peptide may be a heterologous signal (or leader) polypeptide, such as a yeast alpha factor leader, or a peptide such as an epitope tag. Fusion proteins containing the GIPR antigen-binding protein may include peptides (e.g., poly-His) added to facilitate the purification or identification of the GIPR antigen-binding protein. The GIPR antigen-binding protein can also be linked to FLAG peptides as described in Hopp et al., 1988, Bio / Technology 6:1204; and U.S. Patent No. 5,011,912. FLAG peptides enable rapid assays by providing highly antigenic epitopes to which specific monoclonal antibodies (mAbs) reversibly bind, and facilitate the purification of the expressed recombinant protein. Reagents useful for preparing fusion proteins in which a given polypeptide is fused with a FLAG peptide are commercially available (Sigma, St. Louis, MO).

[0736] In some embodiments, the antigen-binding protein includes one or more labels. The terms “labeling group” or “label” mean any detectable label. Suitable labeling groups include: radioisotopes or radionuclides (e.g., 3 H, 14 C, 15 N, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131I) Examples of labels include, but are not limited to, fluorescent groups (e.g., FITC, rhodamine, lanthanide phosphors), enzyme groups (e.g., horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase), chemiluminescent groups, biotinyl groups, or predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites to secondary antibodies, metal-binding domains, epitope tags). In some embodiments, the labeling group is coupled to the antigen-binding protein via spacer arms of varying lengths to reduce potential steric hindrance. Various methods for labeling proteins are known in the art and can be used as appropriate.

[0737] The term "effector group" refers to any group that is coupled to an antigen-binding protein and acts as a cytotoxic substance. Examples of suitable effector groups include radioisotopes or radionuclides (e.g., 3 H, 14 C, 15 N, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I) Other suitable groups include toxins, therapeutic groups, or chemotherapy groups. Examples of suitable groups include calicheamicin, auristatin, geldanamycin, and mytansin. In some embodiments, the effector group is coupled to the antigen-binding protein via spacer arms of varying lengths to reduce potential steric hindrance.

[0738] Generally, labels are classified into various classes depending on the assay in which they are to be detected: a) isotopic labels which may be radioactive or heavy isotopes; b) magnetic labels (e.g., magnetic particles); c) redox active moieties; d) optical dyes; enzymatic groups (e.g., horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase); e) biotinylated groups; and f) predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal-binding domains, epitope tags, etc.). In some embodiments, the labeling group is coupled to the antigen-binding protein via spacer arms of varying lengths to reduce potential steric hindrance. Various methods for labeling proteins are known in the art.

[0739] Certain labels contain optical dyes, which include, but are not limited to, chromophores, phosphors, and fluorophores, the latter of which are often specific. Fluorophores may be "small molecule" phosphors or protein phosphors.

[0740] "Fluorescent labeling" refers to any molecule that can be detected through its unique fluorescent properties. Suitable fluorescent labels include fluorescein, rhodamine, tetramethylrhodamine, eosin, erythrosine, coumarin, methyl-coumarin, pyrene, malachite green, stilbene, Lucifer Yellow, Cascade Blue J, Texas Red, IAEDANS, EDANS, BODIPY FL, LC Red 640, Cy 5, Cy 5.5, LC Red 705, Oregon green, Alexa-Fluor dyes (Alexa Fluor 350, Alexa Fluor 430, Alexa Fluor 488, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, Alexa Fluor 680), Cascade Blue, Cascade Yellow, and R-phycoerythrin (PE) (Molecular Probes, Eugene, OR), FITC, rhodamine, and Texas Examples of suitable optical dyes, including but not limited to Red (Pierce, Rockford, IL), Cy5, Cy5.5, and Cy7 (Amersham Life Science, Pittsburgh, PA), are provided below. Suitable optical dyes, including fluorophores, are described in the Molecular Probes Handbook by Richard P. Haugland, which is explicitly incorporated herein by reference.

[0741] Suitable protein-based fluorescent labels also include green fluorescent proteins containing GFP (Chalfie et al., 1994, Science 263:802-805) and EGFP (Clontech Labs., Inc., Genbank acceptance number U55762) from species of sea urchin (Renilla), broad-winged sea pen (Ptilosarcus), or jellyfish (Aequorea), blue fluorescent protein (BFP, Quantum Biotechnologies, Inc., Quebec, Canada; Stauber, 1998, Biotechniques 24:462-471; Heim et al., 1996, Curr. Biol. 6:178-182), enhanced yellow fluorescent protein (EYFP, Clontech Labs., Inc.), and luciferase (Ichiki et al. al., 1993, J.Immunol. 150:5408-5417), β-galactosidase (Nolan et al.) Other examples include, but are not limited to, al., 1988, Proc. Natl. Acad. Sci. USA 85:2603-2607) and sea urchin (International Publication Nos. 92 / 15673, 95 / 07463, 98 / 14605, 98 / 26277, 99 / 49019, U.S. Patent Nos. 5292658, 5418155, 5683888, 5741668, 5777079, 5804387, 5874304, 5876995, and 5925558).

[0742] Nucleic acids encoding antigen-binding proteins or parts thereof as described herein are also provided, such nucleic acids include nucleic acids encoding one or both chains of an antibody, or fragments, derivatives, mutant proteins or variants thereof; polynucleotides encoding only heavy chain variable regions or CDRs; polynucleotides sufficient for use as hybrid-forming probes, PCR primers or sequencing primers for identification, analysis, mutagenesis, or amplification of polynucleotides encoding polypeptides; antisense nucleic acids for inhibiting polynucleotide expression; and complementary sequences thereof. Nucleic acids can be of any length. Nucleic acids can have nucleotide lengths of, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 750, 1,000, 1,500, 3,000, 5,000 or more, and / or may contain one or more further sequences, such as regulatory sequences, and / or may be part of a longer nucleic acid, such as a vector. Nucleic acids can be single-stranded or double-stranded and may include RNA and / or DNA nucleotides, as well as their artificial variants (e.g., peptide nucleic acids). Complete heavy-chain and light-chain sequences can be formed by adding any of the variable regions provided herein to such constant-chain regions. However, it should be understood that these constant-chain region sequences are provided only as specific examples. In some embodiments, the variable region array is concatenated with other constant region arrays known in the art.

[0743] Nucleic acids encoding specific antigen-binding proteins or parts thereof (e.g., full-length antibodies, heavy or light chains, variable domains, or CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, or CDRL3) can be isolated from B cells of mice immunized with GIPR or its immunogenic fragments. The nucleic acids can be isolated by conventional procedures such as polymerase chain reaction (PCR). Phage display is another example of a known technique by which derivatives of antibodies and other antigen-binding proteins can be prepared. In one approach, polypeptides that are components of the antigen-binding protein of interest are expressed in some suitable recombinant expression system, and the expressed polypeptides can then associate to form the antigen-binding protein.

[0744] One embodiment further provides nucleic acids that hybridize with other nucleic acids under specific hybridization conditions. Methods for hybridizing nucleic acids are well known in the art. See, for example, Current Protocols in Molecular Biology, John Wiley & Sons, NY (1989), 6.3.1-6.3.6. As defined herein, moderately stringent hybridization conditions include a pre-washing solution containing 5x sodium chloride / sodium citrate (SSC), 0.5% SDS, 1.0 mM EDTA (pH 8.0), a hybridization buffer of about 50% formamide and 6x SSC, and a hybridization temperature of about 55°C (or other similar hybridization solutions such as one containing about 50% formamide at a hybridization temperature of 42°C), and washing conditions of 60°C with 0.5x SSC and 0.1% SDS. Under stringent hybridization conditions, hybridization is performed in 6xSSC at 45°C, followed by one or more washes in 0.1xSSC, 0.2% SDS at 68°C. Furthermore, those skilled in the art can manipulate the hybridization conditions and / or washing conditions to improve or reduce the stringency of hybridization such that nucleic acids containing nucleotide sequences that are at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to each other typically still hybridize with each other.

[0745] Basic parameters influencing the selection of hybrid formation conditions and guidelines for devising appropriate conditions are shown, for example, by Sambrook, Fritsch, and Maniatis (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, above; and Current Protocols in Molecular Biology, 1995, Ausubel et al., eds., John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4), and can be readily determined by those skilled in the art, for example, based on nucleic acid length and / or base composition.

[0746] Mutations can be introduced into nucleic acids, thereby altering the amino acid sequence of the polypeptide encoded by that nucleic acid (e.g., an antibody or antibody derivative). Mutations can be introduced using any technique known in the art. In one embodiment, for example, a site-directed mutagenesis protocol is used to modify one or more specific amino acid residues. In another embodiment, for example, a random mutagenesis protocol is used to modify one or more randomly selected residues. Whatever the method, the mutant polypeptide can be expressed and screened for desired properties.

[0747] Mutations can be introduced into nucleic acids without significantly altering the biological activity of the polypeptide they encode. For example, nucleotide substitutions can be performed that result in amino acid substitutions at non-essential amino acid residue positions. Alternatively, one or more mutations can be introduced into nucleic acids that selectively alter the biological activity of the polypeptide they encode. For example, mutations can quantitatively or qualitatively alter biological activity. Examples of quantitative alterations include increasing, decreasing, or eliminating activity. Examples of qualitative alterations include changing the antigen specificity of an antibody. In one embodiment, the amino acid sequence can be modified by mutating a nucleic acid encoding any of the antigen-binding proteins described herein using molecular biological techniques that are well established in the art.

[0748] In another embodiment, nucleic acid molecules suitable for use as primers or hybrid-forming probes for detecting nucleic acid sequences are provided. The nucleic acid molecule may comprise only a portion of a nucleic acid sequence encoding a full-length polypeptide, for example, a fragment that can be used as a probe or primer, or a fragment encoding the active portion of the polypeptide.

[0749] Nucleic acid sequence-based probes can be used to detect nucleic acids or similar nucleic acids, such as transcripts encoding polypeptides. Probes may include labeling groups such as radioisotopes, fluorescent compounds, enzymes, or enzyme cofactors. Such probes can be used to identify cells expressing polypeptides.

[0750] Another embodiment provides a vector containing nucleic acids encoding a polypeptide or a portion thereof (e.g., a fragment containing one or more CDRs or one or more variable region domains). Examples of vectors include, but are not limited to, plasmids, viral vectors, non-episomal mammalian vectors, and expression vectors, such as recombinant expression vectors. Recombinant expression vectors may contain nucleic acids in a form suitable for expression in host cells. Recombinant expression vectors include one or more regulatory sequences selected based on the host cells to be used for expression, such regulatory sequences being manipulably linked to the nucleic acid sequence to be expressed. Regulatory sequences may induce constitutive expression of a nucleotide sequence in many types of host cells (e.g., SV40 early gene enhancer, Roussarcoma virus promoter, and cytomegalovirus promoter), or induce expression of a nucleotide sequence only in specific host cells (e.g., tissue-specific regulatory sequences, Voss et al., 1986, Trends Biochem. Sci. 11:287, Maniatis et al., 1987, Science). See 236:1237 (this document is incorporated herein by reference in its entirety), as well as those that induce inducible expression of nucleotide sequences in response to specific treatments or conditions (e.g., metallothionin promoters in mammalian cells, and tet-responsive and / or streptomycin-responsive promoters in both prokaryotes and eukaryotes (see the same document)). Those skilled in the art will understand that the design of expression vectors may depend on factors such as the selection of host cells to be transformed and the desired level of protein expression. Expression vectors can be introduced into host cells to produce proteins or peptides, including fusion proteins or peptides encoded by the nucleic acids described herein.

[0751] In another embodiment, a host cell into which a recombinant expression vector has been introduced is provided. The host cell may be any prokaryotic cell (e.g., Escherichia coli (E. coli)) or eukaryotic cell (e.g., yeast cell, insect cell, or mammalian cell (e.g., CHO cell)). The vector DNA can be introduced into the prokaryotic or eukaryotic cell by conventional transformation or gene transfer techniques. In the case of stable translocation of mammalian cells, it is known that, depending on the expression vector and gene transfer technique used, the foreign DNA can be incorporated into the genome of only a small number of cells. To identify and select these incorporates, a gene encoding a selectable marker (e.g., for antibiotic resistance) is generally introduced into the host cell along with the target gene. Preferred selectable markers include those that confer resistance to drugs such as G418, hygromycin, and methotrexate. Cells into which the introduced nucleic acid has been stably translocated can be identified, among several methods, particularly by drug selection (e.g., cells into which the selectable marker gene has been incorporated survive, while other cells die).

[0752] Expression systems and constructs in the form of plasmids, expression vectors, transcriptions or expression cassettes, comprising at least one of the above-mentioned polynucleotides, as well as host cells comprising such expression systems or constructs, are also provided herein.

[0753] The antigen-binding proteins provided herein can be prepared by any of many conventional techniques. For example, the GIPR antigen-binding protein can be produced by a recombinant expression system using any technique known in the art. See, for example, Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses, Kennet et al. (eds.), Plenum Press, New York (1980); and Antibodies: A Laboratory Manual, Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1988).

[0754] Antigen-binding proteins can be expressed in hybridoma cell lines (for example, specifically, antibodies can be expressed in hybridomas) or non-hybridoma cell lines. Expression constructs encoding antibodies can be used to transform mammalian host cells, insect host cells, or microbial host cells. Transformation can be carried out using any known method for introducing polynucleotides into host cells, including, for example, methods of packaging polynucleotides into viruses or bacteriophages using gene transfer procedures known in the art, as exemplified by U.S. Patents No. 4,399,216, 4,912,040, 4,740,461, and 4,959,455, and then transducing the host cells with the construct. The optimal transformation procedure used depends on the type of host cell being transformed. Methods for introducing heterologous polynucleotides into mammalian cells are well known in this art and include, but are not limited to, dextran-mediated gene transfer, calcium phosphate precipitation, polybren-mediated gene transfer, protoplast fusion, electroporation, polynucleotide encapsulation in liposomes, mixing of nucleic acids with positively charged lipids, and direct microinjection of DNA into the nucleus.

[0755] A recombinant expression construct generally comprises a nucleic acid molecule encoding a polypeptide that includes one or more of the following: one or more CDRs provided herein; a light chain constant region; a light chain variable region; a heavy chain constant region (e.g., C H 1. C H 2 and / or C H 3) and / or another scaffold region of the GIPR antigen-binding protein. These nucleic acid sequences are inserted into a suitable expression vector using standard ligation techniques. In one embodiment, the heavy or light chain constant region is added to the C-terminus of an anti-GIPR specific heavy or light chain variable region and ligated into the expression vector. The vector is typically selected to be functional in the specific host cell in which it is used (i.e., the vector is compatible with the host's cellular mechanisms and can enable gene amplification and / or expression). In some embodiments, vectors are used that utilize protein-protein interaction detection methods using a protein reporter such as dihydrofolate reductase (see, for example, U.S. Patent No. 6,270,964, which is incorporated herein by reference). Suitable expression vectors can be purchased, for example, from Invitrogen Life Technologies or BD Biosciences (formerly "Clontech"). Other useful vectors for cloning and expressing antibodies and fragments are described in Bianchi and McGrew, 2003, Biotech. Biotechnol. Bioeng. 84:439-44 (this document is incorporated herein by reference). Further suitable expression vectors are discussed, for example, in Methods Enzymol., vol. 185 (DV Goeddel, ed.), 1990, New York: Academic Press.

[0756] Typically, expression vectors used in any host cell contain sequences for plasmid maintenance and sequences for cloning and expression of exogenous nucleotide sequences. These sequences, collectively called “adjacent sequences,” typically in certain embodiments include the following nucleotide sequences: a promoter, one or more enhancer sequences, an origin of replication, a transcription termination sequence, a complete intron sequence containing donor and acceptor splice sites, a sequence encoding a leader sequence for polypeptide secretion, a ribosome binding site, a polyadenylation sequence, a polylinker region for inserting the nucleic acid encoding the polypeptide to be expressed, and one or more selectable marker elements. Each of these sequences is discussed below.

[0757] Optionally, the vector may contain an oligonucleotide molecule located at the 5' or 3' end of a sequence encoding a "tag," i.e., the sequence encoding the GIPR antigen-binding protein. Such oligonucleotide sequences may encode polyHis (e.g., hexaHis) or another "tag" such as FLAG®, HA (influenza virus hemagglutinin), or myc, for which commercially available antibodies exist. This tag is typically fused to the polypeptide during polypeptide expression and can be useful as a means for affinity purification or detection of the GIPR antigen-binding protein from host cells. Affinity purification can be achieved, for example, by column chromatography using an antibody against the tag as an affinity matrix. Optionally, the tag can then be removed from the purified GIPR antigen-binding protein by various means, such as using a specific peptidase for cleavage.

[0758] Adjacent sequences can be homogeneous (i.e., derived from the same species and / or strain as the host cell), heterogeneous (i.e., derived from a species other than the host cell species or strain), hybrid (i.e., a combination of adjacent sequences from multiple origins), synthetic, or native. Therefore, the source of an adjacent sequence may be some prokaryote or eukaryote, some vertebrate or invertebrate, or some plant, provided that the adjacent sequence is functional in the host cell mechanism and can be activated by the host cell mechanism.

[0759] Useful flanking sequences in a vector can be obtained by any of several methods well known in the art. Typically, useful flanking sequences as used herein have been previously identified by mapping and / or restriction endonuclease digestion and can therefore be isolated from a suitable tissue source using a suitable restriction endonuclease. In some cases, the entire nucleotide sequence of the flanking sequence may be known. In this case, the flanking sequence can be synthesized using the methods described herein for nucleic acid synthesis or cloning.

[0760] Whether all or only some of the adjacent sequences are known, adjacent sequences can be obtained by polymerase chain reaction (PCR) and / or by screening a genomic library with suitable probes such as oligonucleotides and / or adjacent sequence fragments from the same or a different species. If the adjacent sequences are unknown, DNA fragments containing adjacent sequences can be isolated from larger DNA fragments that may contain, for example, coding sequences or even one or more other genes. Isolation can be achieved by preparing suitable DNA fragments by digestion with restriction endonucleases, followed by isolation using agarose gel purification, Qiagen® column chromatography (Chatsworth, CA), or other methods known to those skilled in the art. The selection of suitable enzymes for achieving this purpose will be readily apparent to those skilled in the art.

[0761] The origin of replication is typically a component of commercially available prokaryotic expression vectors, and this origin assists in the amplification of the vector in host cells. If the selected vector does not contain the origin of replication site, it can be chemically synthesized based on a known sequence and ligated into the vector. For example, the origin of replication derived from plasmid pBR322 (New England Biolabs, Beverly, MA) is suitable for most Gram-negative bacteria, and various viral origins (e.g., SV40, polyoma, adenovirus, varicella-stomatitis virus (VSV), or papillomavirus, e.g., HPV or BPV) are useful for cloning vectors in mammalian cells. In general, elements of the origin of replication are not necessary for mammalian expression vectors (for example, the SV40 origin is often used simply because it also contains a viral initial promoter).

[0762] Transcription termination sequences are typically located 3' to the end of the polypeptide encoding region and serve to terminate transcription. In prokaryotic cells, transcription termination sequences are usually GC-rich fragments followed by polyT sequences. These sequences can be readily cloned from libraries or even commercially purchased as part of vectors, while they can also be readily synthesized using nucleic acid synthesis methods such as those described herein.

[0763] Selection marker genes encode proteins essential for the survival and proliferation of host cells grown in a selection medium. Typical selection marker genes encode (a) proteins that confer resistance to antibiotics or other toxins, such as ampicillin, tetracycline, or kanamycin, in prokaryotic host cells; (b) proteins that compensate for deficiencies in the cellular nutritional requirements; or (c) proteins that supply essential nutrients unavailable from complex or defining media. Specific selectable markers include kanamycin resistance genes, ampicillin resistance genes, and tetracycline resistance genes. Conveniently, neomycin resistance genes can also be used for selection in both prokaryotic and eukaryotic host cells.

[0764] Other selectable genes can be used to amplify the expressed genes. Amplification is the process by which genes required for the production of proteins important for proliferation or cell survival are repeated in tandem within the chromosomes of recombinant cells in successive generations. Examples of suitable selectable markers for mammalian cells include the dihydrofolate reductase (DHFR) gene and the promoter resthymidine kinase gene. Mammalian cell transformants are placed under selective pressure so that only those transformants are uniquely adapted to survive by the selectable gene present in the vector. Selective pressure is applied by culturing the transformed cells under conditions of continuously increasing the concentration of the selective drug in the culture medium, thereby amplifying both the selectable gene and the DNA encoding another gene, such as an antigen-binding protein that binds to the GIPR polypeptide. As a result, the amount of polypeptides, such as antigen-binding proteins, synthesized from the amplified DNA increases.

[0765] The ribosome binding site is typically required for mRNA translation initiation and is characterized by a Shine-Dalgarno sequence (prokaryotes) or a Kozak sequence (eukaryotes). This element is typically located at the 3' end of the promoter and at the 5' end of the coding sequence of the polypeptide to be expressed.

[0766] In some cases, such as when glycosylation is desired in eukaryotic host cell expression systems, various pre-sequences or pro-sequences can be manipulated to improve glycosylation or yield. For example, the peptidase cleavage site of a particular signal peptide can be modified, or a pro-sequence can be added, which can also affect glycosylation. The final protein product may have one or more additional amino acids that were not completely removed during expression and remain at a -1 position (relative to the first amino acid of the mature protein). For example, the final protein product may have one or two amino acid residues found at the peptidase cleavage site, attached to the amino terminus. Alternatively, by using several enzymatic cleavage sites, if the enzyme cleaves such regions within the mature polypeptide, the desired polypeptide may be produced in a slightly truncated form.

[0767] Expression and cloning typically involve a promoter that is recognized by the host organism and manipulably ligated to a molecule encoding the GIPR antigen-binding protein. The promoter is a non-transcriptional sequence located upstream (i.e., at the 5' end) of the start codon of a structural gene (generally within approximately 100–1000 bp) and controls the transcription of that structural gene. Traditionally, promoters are classified into two classes: inductive promoters and constitutive promoters. Inductive promoters initiate an increase in transcription levels from DNA under their control in response to changes in culture conditions such as the presence or absence of nutrients or changes in temperature. Constitutive promoters, on the other hand, transcribe the gene to which they manipulably ligate uniformly, i.e., with little or no control over gene expression. Numerous promoters recognized by various potential host cells are well known. By extracting the promoter from the source DNA by restriction enzyme digestion and inserting the desired promoter sequence into a vector, the appropriate promoter is manipulably ligated to the DNA encoding the heavy or light chain containing the GIPR antigen-binding protein.

[0768] Suitable promoters for use with yeast hosts are also well known in the art. Advantageously, yeast enhancers are used in conjunction with yeast promoters. Promoters suitable for use in mammalian host cells are well known, and such promoters include, but are not limited to, those derived from the genomes of viruses such as polyomaviruses, fowlpox virus, adenoviruses (such as adenovirus type 2), bovine papillomavirus, aerovirus, cytomegalovirus, retroviruses, hepatitis B virus, and simian virus 40 (SV40). Other suitable mammalian promoters include, for example, heterologous mammalian promoters such as heat shock promoters and actin promoters.

[0769] Enhancer sequences can be inserted into vectors to increase transcription by higher eukaryotes of DNA encoding the light or heavy chain containing the GIPR antigen-binding protein. Enhancers are cis-acting elements of DNA, typically about 10–300 bp long, that act on promoters to increase transcription. Enhancers are found relatively independently of direction and position, at both the 5' and 3' ends of the transcription unit. Several enhancer sequences are known to be available from mammalian genes (e.g., globin, elastase, albumin, alpha-fetoprotein, and insulin). However, viral enhancers are typically used. The SV40 enhancer, cytomegalovirus initial promoter enhancer, polyoma enhancer, and adenovirus enhancer, known in the art, are exemplary enhancing elements for eukaryotic promoter activation. Enhancers can be located in a vector either at the 5' or 3' end of the coding sequence, but are typically placed at the 5' end of the promoter. Sequences encoding appropriate native or heterologous signal sequences (leader sequences or signal peptides) can be incorporated into expression vectors to promote extracellular antibody secretion. The choice of signal peptide or leader depends on the type of host cell in which antibody production is to be induced, and heterologous signal sequences may replace native signal sequences. Examples of signal peptides that function in mammalian host cells include: the interleukin-7 (IL-7) signal sequence described in U.S. Patent No. 4,965,195; the signal sequence for the interleukin-2 receptor described in Cosman et al., 1984, Nature 312:768; the interleukin-4 receptor signal peptide described in European Patent No. 0367566; the type I interleukin-1 receptor signal peptide described in U.S. Patent No. 4,968,607; and the type II interleukin-1 receptor signal peptide described in European Patent No. 0460846.

[0770] In one embodiment, the leader sequence includes sequence number 3157 (MDMRVPAQLL GLLLLWLRGA RC), which is coded by sequence number 3158 (atggacatga gagtgcctgc acagctgctg ggcctgctgc tgctgtggct gagaggcgcc agatgc). In another embodiment, the leader sequence includes sequence number 3159 (MAWALLLLTL LTQGTGSWA), which is coded by sequence number 3160 (atggcctggg ctctgctgct cctcaccctc ctcactcagg gcacagggtc ctgggcc).

[0771] The expression vector provided may be constructed from a starting vector, such as a commercially available vector. Such a vector may or may not contain all of the desired adjacent sequences. If one or more of the adjacent sequences described herein are not initially present in the vector, they may be obtained individually and ligated into the vector. The methods used to obtain each adjacent sequence are well known to those skilled in the art.

[0772] After constructing a vector and inserting a light chain, heavy chain, or nucleic acid molecule encoding both light and heavy chains containing the GIPR antigen-binding sequence into the appropriate site in the vector, the completed vector may be inserted into a suitable host cell for amplification and / or polypeptide expression. Transformation of the host cell into a select host cell for the expression vector of the antigen-binding protein can be achieved by well-known methods, including gene transfer, infection, calcium phosphate coprecipitation, electroporation, microinjection, lipofection, DEAE-dextran-mediated gene transfer, or other known techniques. The method of selection depends in part on the type of host cell to be used. Such methods and other suitable methods are well-known to those skilled in the art and are shown, for example, in Sambrook et al., 2001.

[0773] When cultured under appropriate conditions, host cells synthesize antigen-binding proteins, which can then be recovered from the culture medium (if the host cell secretes it into the medium) or directly from the host cell producing it (if it is not secreted). The selection of appropriate host cells depends on various factors, including the desired expression level, polypeptide modifications (such as glycosylation or phosphorylation) that are desirable or essential for activity, and the ease of folding into biologically active molecules.

[0774] Mammalian cell lines available as hosts for expression are well known in the art, and such mammalian cell lines include, but are not limited to, immortalized cell lines available from the American Type Culture Collection (ATCC), including, but not limited to, Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and many other cell lines. In certain embodiments, cell lines may be selected by determining which cell lines express and constitutively produce antigen-binding proteins with GIPR binding properties at high levels. In other embodiments, cell lines derived from B cell lineages that do not produce antibodies of their own but have the ability to produce and secrete heterologous antibodies may be selected.

[0775] In one embodiment, the present invention relates to antigen-binding proteins produced by cells expressing one or more polynucleotides specified in Tables 2, 3, 4, 5, 7, 8, 9, and 10.

[0776] In one embodiment, the GIPR-binding protein is administered for long-term treatment. In another embodiment, the binding protein is administered for emergency treatment.

[0777] Pharmaceutical compositions comprising GIPR antigen-binding proteins are also provided and may be used in any preventive and therapeutic methods disclosed herein. In one embodiment, therapeutically effective amounts of one or more antigen-binding proteins and pharmaceutically acceptable diluents, carriers, solubilizers, emulsifiers, preservatives and / or adjuvants are also provided. Acceptable formulation materials are non-toxic to the recipient at the dosage and concentration used.

[0778] In certain embodiments, the pharmaceutical composition may contain formulation materials for modifying, maintaining, or preserving the composition's properties, such as pH, osmotic pressure, viscosity, transparency, color, isotonicity, odor, sterility, stability, dissolution rate or release rate, absorption, or permeability. In such embodiments, suitable formulation materials include: amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (such as boric acid, bicarbonate, tris-HCl, citric acid, phosphoric acid, or other organic acids); fillers (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose, or dextrin); proteins (such as serum albumin, gelatin, or immunoglobulin); colorants, flavorings, and diluents; emulsifiers; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; and salt-forming ions. Examples of active ingredients include: (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (such as glycerin, propylene glycol, or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as Pluronic acid, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate, Triton, tromethamine, lecithin, cholesterol, tyroxapol, etc.); stability enhancers (such as sucrose or sorbitol); tonicity enhancers (such as alkali metal halides, preferably sodium chloride or potassium chloride, mannitol, or sorbitol); delivery vehicles; diluents; excipients and / or pharmaceutical adjuvants.REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition, (ARGenrmo, ed.), 1990, Mack Publishing Company, provides further details and options regarding suitable agents that may be incorporated into this pharmaceutical composition.

[0779] In certain embodiments, the optimal pharmaceutical composition is determined by those skilled in the art, for example, depending on the intended route of administration, method of delivery, and desired dose. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES above. In certain embodiments, such a composition may affect the physical state, stability, in vivo release rate, and in vivo efflux rate of the antigen-binding protein of disclosure. In certain embodiments, the main vehicle or carrier in the pharmaceutical composition may actually be either aqueous or non-aqueous. For example, a suitable vehicle or carrier may be water or saline for injection. In certain embodiments, the GIPR antigen-binding protein composition may be prepared for storage in the form of a lyophilized cake or aqueous solution by mixing a selective composition of desired purity with an optional formulation agent (REMINGTON'S PHARMACEUTICAL SCIENCES above). Furthermore, in certain embodiments, the GIPR antigen-binding protein may be formulated as a lyophilized product using a suitable excipient such as sucrose.

[0780] This pharmaceutical composition may be selected for parenteral delivery. Alternatively, this composition may be selected for inhalation or for delivery through the gastrointestinal tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the scope of the art.

[0781] The components of the formulation are preferably present at the administration site in an acceptable concentration. In certain embodiments, a buffer is used to maintain the composition at a physiological pH or slightly lower, typically within a pH range of about 5 to about 8.

[0782] When parenteral administration is intended, the therapeutic composition may be provided in the form of a pyrogenically-free, parenterally acceptable aqueous solution containing the desired human GIPR antigen-binding protein in a pharmaceutically acceptable vehicle. A particularly suitable medium for parenteral injection is sterile distilled water in which the GIPR antigen-binding protein is formulated as a properly preserved sterile isotonic solution. In certain embodiments, the preparation may involve formulating the desired molecule with a drug, such as injectable microspheres, biodegradable particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads, or liposomes, which can achieve controlled or sustained release of the product that can be delivered via depot injection. In certain embodiments, hyaluronic acid, which has the effect of increasing the duration of action in circulation, may also be used. In certain embodiments, an implantable drug delivery device may be used to introduce the desired antigen-binding protein.

[0783] Certain pharmaceutical compositions may be formulated for inhalation. In some embodiments, the GIPR antigen-binding protein is formulated as a dry, inhalable powder. In certain embodiments, the GIPR antigen-binding protein inhalation solution may also be formulated with a spray for aerosol delivery. In certain embodiments, the solution may be sprayed. Methods of pulmonary administration and formulation are further described in International Patent Application PCT / US Patent Application Publication No. 94 / 001875, which is incorporated by reference and describes the pulmonary delivery of chemically modified proteins. Some formulations may be administered orally. GIPR antigen-binding proteins administered in this manner may be formulated with or without carriers conventionally used in formulations of solid dosage forms such as tablets and capsules. In certain embodiments, capsules may be designed so that the active portion of the formulation is released when bioavailability is maximized and pre-systemic degradation is minimized in the gastrointestinal tract. Further agents may be included to enhance the absorption of the GIPR antigen-binding protein. Diluents, flavoring agents, low-melting-point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrants, and binders may also be used.

[0784] Some pharmaceutical compositions contain an effective amount of one or more GIPR antigen-binding proteins in a mixture, along with non-toxic excipients suitable for tablet production. Solutions can be prepared in unit dosage forms by dissolving the tablets in sterile water or another suitable vehicle. Suitable excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate or sodium bicarbonate, lactose or calcium phosphate; binders such as starch, gelatin or acacia; or lubricants such as magnesium stearate, stearic acid or talc.

[0785] Further pharmaceutical compositions, including formulations containing GIPR-binding proteins in sustained or controlled delivery formulations, will be apparent to those skilled in the art. Various other sustained or controlled delivery means, such as liposome carriers, biodegradable microparticles or porous beads, and techniques for formulating depot injections are also known to those skilled in the art. See, for example, International Application PCT / US93 / 00829, incorporated by reference, which describes the controlled release of porous polymer microparticles for delivering pharmaceutical compositions. Sustained-release preparations may include a semipermeable polymer matrix in the form of a molded article, e.g., a film or microcapsules. The sustained-release matrix includes polyester, hydrogel, polylactide (disclosed in U.S. Patent No. 3,773,919 and European Patent Application Publication No. 058481, respectively, incorporated by reference), L-glutamic acid and gamma-ethyl-L-glutamate copolymer (Sidman et al., 1983, Biopolymers 2:547-556), poly(2-hydroxyethyl-inethacrylate) (Langer et al., 1981, J. Biomed. Mater. Res. 15:167-277 and Langer, 1982, Chem. Tech. 12:98-105), ethylene vinyl acetate (Langer et al. The sustained-release composition may also include liposomes (as described above) (e.g., 1981) or poly-D(-)-3-hydroxybutyrate (European Patent Application Publication No. 133,988). The sustained-release composition may also include liposomes which may be prepared by any of several methods known in the art. See, for example, Eppstein et al., 1985, Proc. Natl. Acad. Sci. USA 82:3688-3692; European Patent Application Publication No. 036,676; No. 088,046 and No. 143,949, which are incorporated by reference.

[0786] Pharmaceutical compositions used for in vivo administration are typically provided as sterile preparations. Sterilization can be achieved by filtration through a sterile filtration membrane. When the composition is freeze-dried, sterilization using this method can be performed either before or after freeze-drying and reconstitution. Compositions for parenteral administration can be stored in freeze-dried form or in solution. Parenteral compositions are generally placed in containers with a sterile access port, such as intravenous solution bags or vials with a stopper that can be penetrated by a subcutaneous needle.

[0787] In certain formulations, the concentration of antigen-binding protein is at least 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, or 150 mg / mL. In one embodiment, the pharmaceutical composition comprises antigen-binding protein, a buffer, and polysorbate. In other embodiments, the pharmaceutical composition comprises antigen-binding protein, a buffer, sucrose, and polysorbate. An example of a pharmaceutical composition is one containing 50-100 mg / mL of antigen-binding protein, 5-20 mM sodium acetate, 5-10% w / v sucrose, and 0.002-0.008% w / v polysorbate. Certain compositions, for example, contain 65-75 mg / mL of antigen-binding protein, 8-10% w / v sucrose, and 0.005-0.006% w / v polysorbate in a 9-11 mM sodium acetate buffer. The pH of certain such formulations is in the range of 4.5-6. The pH of other formulations is 5.0-5.5 (e.g., pH 5.0, 5.2, or 5.4).

[0788] Once formulated, the pharmaceutical composition may be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, crystal, or as a dehydrated or lyophilized powder. Such formulations may be stored in a form ready for immediate use or in a form that is reconstituted before administration (e.g., lyophilized). Kits for obtaining single-dose dosing units are also provided. Certain kits contain a first container with a dry protein and a second container with an aqueous formulation. In certain embodiments, kits are provided that include pre-filled syringes having single and multi-chambers (e.g., liquid syringes and lyosyringes). The therapeutically effective amount of the GIPR antigen-binding protein-containing pharmaceutical composition to be used depends, for example, on the nature and purpose of the treatment. Those skilled in the art will understand that the appropriate dose level for a treatment will vary in part depending on the molecule being delivered, the indication for which the GIPR antigen-binding protein is used, the route of administration, and the patient's physique (weight, body surface or organ size) and / or condition (age and overall health). In certain embodiments, clinicians may set the dosage and modify the route of administration to obtain the optimal therapeutic effect.

[0789] The frequency of administration depends on the pharmacokinetic parameters of the specific GIPR antigen-binding protein in the formulation used. Typically, clinicians administer the composition until the desired effect is achieved. Thus, the composition may be administered as a single dose, or as two or more doses (which may or may not contain the desired molecule in the same amount) over a period of time, or as a continuous infusion via an implantable device or catheter. The appropriate dose can be determined using appropriate dose-response data. In certain embodiments, the antigen-binding protein may be administered to the patient over a long period of time. In certain embodiments, the antigen-binding protein may be administered every two weeks, every month, every two months, every three months, every four months, every five months, or every six months.

[0790] The administration route of the pharmaceutical composition follows known methods, such as oral administration, intravenous administration, intraperitoneal administration, intracerebral (intraparenchymal) administration, intraventricular administration, intramuscular administration, intraocular administration, intraarterial administration, intraportal administration, or intrafocal administration by injection, by continuous release system, or by implantable device. In certain embodiments, the composition may be administered by bolus injection, by continuous infusion, or by implantable device.

[0791] The composition can be administered topically via implantation of a membrane, sponge, or other suitable material on which the desired molecule is adsorbed or encapsulated. In certain embodiments, if an implantation device is used, this device can be implanted in any suitable tissue or organ, and the delivery of the desired molecule may be via diffusion, sustained-release bolus, or continuous administration.

[0792] It may also be desirable to use the GIPR antigen-binding protein pharmaceutical composition in accordance with the disclosed ex vivo. In such cases, cells, tissues, or organs removed from a patient are exposed to the GIPR antigen-binding protein pharmaceutical composition, and subsequently, the cells, tissues, and / or organs are transplanted back into the patient.

[0793] Physicians may be able to select appropriate treatment indicators and target lipid levels according to the individual profile of a particular patient. One widely accepted standard that guides the treatment of hyperlipidemia is the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of the High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report, National Institutes of Health, NIH Publication No. 02-5215 (2002), the print publication of which is incorporated herein by reference in its entirety.

[0794] The efficacy of a particular dose can be evaluated by reference to biomarkers or by improvement of specific physiological parameters. Examples of appropriate biomarkers include the ratio of free cholesterol to plasma lipids, the ratio of free cholesterol to membrane proteins, the ratio of phosphatidylcholine to sphingomyelin, or HDL-C levels.

[0795] This specification also provides compositions comprising a GIPR antigen-binding protein and one or more further therapeutic agents, as well as methods for administering such agents concurrently or sequentially with the GIPR antigen-binding protein for use in the preventive and therapeutic methods disclosed herein. One or more further agents may be formulated or administered concurrently with the GIPR antigen-binding protein. In general, therapeutic methods, compositions, and compounds can also be used in combination with other therapeutic agents in the treatment of various disease conditions, together with the further agents administered concurrently.

[0796] Diagnostic applications provided herein include the use of antigen-binding proteins to detect GIPR expression. Examples of methods useful in detecting the presence of GIPR include immunoassays such as enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA).

[0797] For diagnostic purposes, antigen-binding proteins are typically labeled with a detectable labeling group. Suitable labeling groups include: radioisotopes or radionuclides (e.g., 3 H, 14 C, 15 N, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131I) The labeling group may be, but is not limited to, a fluorescent group (e.g., FITC, rhodamine, lanthanide phosphor), an enzyme group (e.g., horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase), a chemiluminescent group, a biotinyl group, or a predetermined polypeptide epitope recognized by a secondary reporter (e.g., a leucine zipper pair sequence, a binding site for a secondary antibody, a metal-binding domain, an epitope tag). In some embodiments, the labeling group is coupled to the antigen-binding protein via spacer arms of varying lengths to reduce potential steric hindrance. Various methods for labeling proteins are known in the art and may be used.

[0798] In some embodiments, GIPR antigen-binding proteins are isolated and measured using techniques known in the art. See, for example, Harlow and Lane, 1988, Antibodies: A Laboratory Manual, New York: Cold Spring Harbor (ed. 1991 and periodic supplements); John E. Coligan, ed., 1993, Current Protocols In Immunology New York: John Wiley & Sons.

[0799] Another aspect of this disclosure provides the detection of the presence of a test molecule that competes with a provided antigen-binding protein for binding to GIPR. One example of such an assay involves detecting the amount of free antigen-binding protein in a solution containing a certain amount of GIPR, in or out of the presence of the test molecule. An increase in the amount of free antigen-binding protein (i.e., antigen-binding protein not bound to GIPR) indicates that the test molecule has the ability to compete with the antigen-binding protein for GIPR binding. In one embodiment, the antigen-binding protein is labeled with a labeling group. Alternatively, the test molecule is labeled, and the amount of free test molecule is monitored in and out of the presence of the antigen-binding protein.

[0800] In application, Cushing's syndrome may be treated in patients requiring treatment for Cushing's syndrome by administering a therapeutically effective dose of GIPR-binding protein. Administration may be carried out as described herein, including by IV injection, intraperitoneal (IP) injection, subcutaneous injection, intramuscular injection, or orally in the form of tablets or liquid formulations. Depending on the situation, the therapeutically effective or preferred dose of GIPR-binding protein may be determined by the clinician. The therapeutically effective dose of GIPR-binding protein depends, among many other factors, including the administration schedule, the unit dose of the drug being administered, whether the GIPR-binding protein is administered in combination with other therapeutic agents, and the recipient's immune status and health. As used herein, the term “therapeutically effective dose” means the amount of GIPR-binding protein that elicits a biological or medical response in a tissue system, animal or human being being explored by researchers, physicians or other clinicians, including the reduction or improvement of symptoms of the disease or disorder being treated; i.e., the amount of GIPR-binding protein that supports one or more desired biological or medical responses at an observable level, such responses being, for example, a decrease in cortisol levels.

[0801] It should be noted that the therapeutically effective dose of GIPR-binding protein may vary depending on the desired outcome. Therefore, for example, in situations where lower cortisol levels are indicated, the dose of GIPR-binding protein will be higher than the dose required to achieve relatively high cortisol levels. Conversely, in situations where higher cortisol levels are indicated, the dose of GIPR-binding protein will be lower than the dose required to achieve relatively high cortisol levels.

[0802] In various embodiments, the subjects are humans with cortisol levels of 50–100 μg / day or higher, who may be treated with GIPR-binding protein.

[0803] In one embodiment, the method of the present disclosure includes first measuring the baseline level of cortisol in a subject. Subsequently, a pharmaceutical composition containing GIPR-binding protein is administered to the subject. After a desired period, the cortisol level in the subject is measured again. Next, these two levels may be compared to determine the relative change in cortisol levels in the subject. Depending on the result of the comparison, another dose of the pharmaceutical composition containing GIPR-binding protein may be administered to achieve a desired cortisol level.

[0804] It should be noted that pharmaceutical compositions containing GIPR-binding proteins may be administered co-administered with other compounds. The uniqueness and properties of compounds administered co-administered with GIPR-binding proteins depend on the nature of the medical condition being treated or improved.

[0805] Kits for carrying out the disclosed methods are also provided. Such kits may include pharmaceutical compositions such as those described herein, which include nucleic acids encoding peptides or proteins provided herein, vectors and cells containing such nucleic acids, and compounds containing such nucleic acids, and such may be provided in sterile containers. Optionally, instructions on how to use the provided pharmaceutical compositions in the treatment of Cushing's syndrome may also be included, or such instructions may be made available to patients or healthcare providers.

[0806] In one embodiment, the kit comprises (a) a pharmaceutical composition containing a therapeutically effective amount of GIPR-binding protein, and (b) one or more containers for the pharmaceutical composition. Such a kit may also include instructions for its use, which may be tailored to suit the specific cortisol-related disorder during treatment. The instructions may describe the use and properties of the materials provided in the kit. In certain embodiments, the kit includes instructions for a patient to carry out an administration for the treatment of Cushing's syndrome.

[0807] Instructions may be printed on a material such as paper or plastic, and may be present in the kit as a package insert, such as on the label of the kit container or its components (e.g., accompanying the packaging). In other embodiments, instructions may exist as an electronically stored data file on a suitable computer-readable storage medium, such as a CD-ROM or diskette. In yet another embodiment, the actual instructions may not be present in the kit, but means for obtaining the instructions from a remote source, such as the internet, are provided. An example of this embodiment is a kit that includes a web address where the instruct...

Claims

1. A method for treating a subject with a disorder associated with elevated cortisol levels, comprising administering to the subject a therapeutically effective amount of an antigen-binding protein that specifically binds to a protein having an amino acid sequence having at least 90% amino acid sequence identity with respect to the amino acid sequence of GIPR.

2. The method according to claim 1, wherein the disorder is Cushing's syndrome.

3. The method according to any one of claims 1 to 2, wherein the antigen-binding protein specifically binds to a human gastric suppressor peptide receptor (GIPR) polypeptide.

4. The method according to claim 3, wherein the human GIPR has a sequence that includes a sequence selected from the group consisting of SEQ ID NO: 3141, SEQ ID NO: 3143, and SEQ ID NO: 3145.

5. The method according to claim 4, wherein the antigen-binding protein is a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or an antibody fragment thereof.

6. The method according to claim 5, wherein the antibody fragment is a Fab fragment, a Fab' fragment, or an F(ab')2 fragment.

7. The method according to claim 6, wherein the antigen-binding protein is a human antibody.

8. The method according to claim 6, wherein the antigen-binding protein is a monoclonal antibody.

9. The method according to claim 6, wherein the antigen-binding protein is of the IgG1, IgG2, IgG3, or IgG4 type.

10. The method according to claim 9, wherein the antigen-binding protein is of the IgG1 or IgG2 type.

11. The method according to claim 6, wherein the antigen-binding protein is coupled to a labeling group.

12. The method according to claim 6, wherein the antigen-binding protein inhibits the binding of GIP to the extracellular portion of human GIPR.

13. The method according to claim 6, wherein the antigen-binding protein is an antibody or a fragment thereof, and the antibody comprises CDRL1, CDRL2, CDRL3, CDRH1, CDRH2 and CDRH3, wherein CDRL1 comprises a sequence selected from the group consisting of SEQ ID NOs: 629 to 785; CDRL2 comprises a sequence selected from the group consisting of SEQ ID NOs: 786 to 942; CDRL3 comprises a sequence selected from the group consisting of SEQ ID NOs: 943 to 1099; CDRH1 comprises a sequence selected from the group consisting of SEQ ID NOs: 1100 to 1256; CDRH2 comprises a sequence selected from the group consisting of SEQ ID NOs: 1257 to 1413; and CDRH3 comprises a sequence selected from the group consisting of SEQ ID NOs: 1414 to 1570.

14. The antigen-binding protein is an antibody or a fragment thereof, and the antibody comprises CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, with each of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 corresponding to SEQ ID NOs: 629, 786, 943, 1100, 1257, and 1414; SEQ ID NOs: 630, 787, 944, 1101, 1258, and 1415; SEQ ID NOs: 631, 788, 945, and 110 2. Sequence IDs 1259 and 1416; Sequence IDs 632, 789, 946, 1103, 1260 and 1417; Sequence IDs 633, 790, 947, 1104, 1261 and 1418; Sequence IDs 634, 791, 948, 1105, 1262 and 1419; Sequence IDs 635, 792, 949, 1106, 1263 and 1420; Sequence IDs 636, 793, 9 50, Sequence ID 1107, Sequence ID 1264 and Sequence ID 1421; Sequence ID 637, Sequence ID 794, Sequence ID 951, Sequence ID 1108, Sequence ID 1265 and Sequence ID 1422; Sequence ID 638, Sequence ID 795, Sequence ID 952, Sequence ID 1109, Sequence ID 1266 and Sequence ID 1423; Sequence ID 639, Sequence ID 796, Sequence ID 953, Sequence ID 1110, Sequence ID 1267 and Sequence ID 1424; Sequence ID 640, Sequence ID 797, Sequence ID 954, Sequence ID 1111, Sequence ID 1268 and Sequence ID 1425; Sequence ID 641, Sequence ID Sequence ID 798, Sequence ID 955, Sequence ID 1112, Sequence ID 1269 and Sequence ID 1426; Sequence ID 642, Sequence ID 799, Sequence ID 956, Sequence ID 1113, Sequence ID 1270 and Sequence ID 1427; Sequence ID 643, Sequence ID 800, Sequence ID 957, Sequence ID 1114, Sequence ID 1271 and Sequence ID 1428; Sequence ID 644, Sequence ID 801, Sequence ID 958, Sequence ID 1115, Sequence ID 1272 and Sequence ID 1429; Sequence ID 645, Sequence ID 802, Sequence ID 959, Sequence ID 1116, Sequence ID 1273 and Sequence ID 1430;Sequence IDs 646, 803, 960, 1117, 1274 and 1431; Sequence IDs 647, 804, 961, 1118, 1275 and 1432; Sequence IDs 648, 805, 962, 1119, 1276 and 1433; Sequence IDs 649, 806, 963, 1120, 1277 and 1434; Sequence IDs 650, 807, 964, 1121, 12 78 and SEQ ID NO: 1435; SEQ ID NO: 651, SEQ ID NO: 808, SEQ ID NO: 965, SEQ ID NO: 1122, SEQ ID NO: 1279 and SEQ ID NO: 1436; SEQ ID NO: 652, SEQ ID NO: 809, SEQ ID NO: 966, SEQ ID NO: 1123, SEQ ID NO: 1280 and SEQ ID NO: 1437; SEQ ID NO: 653, SEQ ID NO: 810, SEQ ID NO: 967, SEQ ID NO: 1124, SEQ ID NO: 1281 and SEQ ID NO: 1438; SEQ ID NO: 654, SEQ ID NO: 811, SEQ ID NO: 968, SEQ ID NO: 1125, SEQ ID NO: 1282 and SEQ ID NO: 1439; SEQ ID NO: 655, SEQ ID NO: 812, SEQ ID NO: 969, sequence Number 1126, Sequence ID 1283 and Sequence ID 1440; Sequence ID 656, Sequence ID 813, Sequence ID 970, Sequence ID 1127, Sequence ID 1284 and Sequence ID 1441; Sequence ID 657, Sequence ID 814, Sequence ID 971, Sequence ID 1128, Sequence ID 1285 and Sequence ID 1442; Sequence ID 658, Sequence ID 815, Sequence ID 972, Sequence ID 1129, Sequence ID 1286 and Sequence ID 1443; Sequence ID 659, Sequence ID 816, Sequence ID 973, Sequence ID 1130, Sequence ID 1287 and Sequence ID 1444; Sequence ID 660, Sequence ID 8 17, SEQ ID NO: 974, SEQ ID NO: 1131, SEQ ID NO: 1288 and SEQ ID NO: 1445; SEQ ID NO: 661, SEQ ID NO: 818, SEQ ID NO: 975, SEQ ID NO: 1132, SEQ ID NO: 1289 and SEQ ID NO: 1446; SEQ ID NO: 662, SEQ ID NO: 819, SEQ ID NO: 976, SEQ ID NO: 1133, SEQ ID NO: 1290 and SEQ ID NO: 1447; SEQ ID NO: 663, SEQ ID NO: 820, SEQ ID NO: 977, SEQ ID NO: 1134, SEQ ID NO: 1291 and SEQ ID NO: 1448; SEQ ID NO: 664, SEQ ID NO: 821, SEQ ID NO: 978, SEQ ID NO: 1135, SEQ ID NO: 1292 and SEQ ID NO: 1449;Sequence IDs 665, 822, 979, 1136, 1293 and 1450; Sequence IDs 666, 823, 980, 1137, 1294 and 1451; Sequence IDs 667, 824, 981, 1138, 1295 and 1452; Sequence IDs 668, 825, 982, 1139, 1296 and 1453; Sequence IDs 669, 826, 983, 1140, 12 97 and SEQ ID NO: 1454; SEQ ID NO: 670, SEQ ID NO: 827, SEQ ID NO: 984, SEQ ID NO: 1141, SEQ ID NO: 1298 and SEQ ID NO: 1455; SEQ ID NO: 671, SEQ ID NO: 828, SEQ ID NO: 985, SEQ ID NO: 1142, SEQ ID NO: 1299 and SEQ ID NO: 1456; SEQ ID NO: 672, SEQ ID NO: 829, SEQ ID NO: 986, SEQ ID NO: 1143, SEQ ID NO: 1300 and SEQ ID NO: 1457; SEQ ID NO: 673, SEQ ID NO: 830, SEQ ID NO: 987, SEQ ID NO: 1144, SEQ ID NO: 1301 and SEQ ID NO: 1458; SEQ ID NO: 674, SEQ ID NO: 831, SEQ ID NO: 988, sequence Number 1145, Sequence ID 1302 and Sequence ID 1459; Sequence ID 675, Sequence ID 832, Sequence ID 989, Sequence ID 1146, Sequence ID 1303 and Sequence ID 1460; Sequence ID 676, Sequence ID 833, Sequence ID 990, Sequence ID 1147, Sequence ID 1304 and Sequence ID 1461; Sequence ID 677, Sequence ID 834, Sequence ID 991, Sequence ID 1148, Sequence ID 1305 and Sequence ID 1462; Sequence ID 678, Sequence ID 835, Sequence ID 992, Sequence ID 1149, Sequence ID 1306 and Sequence ID 1463; Sequence ID 679, Sequence ID 8 36, SEQ ID NO: 993, SEQ ID NO: 1150, SEQ ID NO: 1307 and SEQ ID NO: 1464; SEQ ID NO: 680, SEQ ID NO: 837, SEQ ID NO: 994, SEQ ID NO: 1151, SEQ ID NO: 1308 and SEQ ID NO: 1465; SEQ ID NO: 681, SEQ ID NO: 838, SEQ ID NO: 995, SEQ ID NO: 1152, SEQ ID NO: 1309 and SEQ ID NO: 1466; SEQ ID NO: 682, SEQ ID NO: 839, SEQ ID NO: 996, SEQ ID NO: 1153, SEQ ID NO: 1310 and SEQ ID NO: 1467; SEQ ID NO: 683, SEQ ID NO: 840, SEQ ID NO: 997, SEQ ID NO: 1154, SEQ ID NO: 1311 and SEQ ID NO: 1468;Sequence IDs 684, 841, 998, 1155, 1312 and 1469; Sequence IDs 685, 842, 999, 1156, 1313 and 1470; Sequence IDs 686, 843, 1000, 1157, 1314 and 1471; Sequence IDs 687, 844, 1001, 1158, 1315 and 1472; Sequence IDs 688, 845, 1002, sequence number Sequence ID 1159, Sequence ID 1316 and Sequence ID 1473; Sequence ID 689, Sequence ID 846, Sequence ID 1003, Sequence ID 1160, Sequence ID 1317 and Sequence ID 1474; Sequence ID 690, Sequence ID 847, Sequence ID 1004, Sequence ID 1161, Sequence ID 1318 and Sequence ID 1475; Sequence ID 691, Sequence ID 848, Sequence ID 1005, Sequence ID 1162, Sequence ID 1319 and Sequence ID 1476; Sequence ID 692, Sequence ID 849, Sequence ID 1006, Sequence ID 1163, Sequence ID 1320 and Sequence ID 1477; Distribution Column number 693, SEQ ID NO: 850, SEQ ID NO: 1007, SEQ ID NO: 1164, SEQ ID NO: 1321 and SEQ ID NO: 1478; SEQ ID NO: 694, SEQ ID NO: 851, SEQ ID NO: 1008, SEQ ID NO: 1165, SEQ ID NO: 1322 and SEQ ID NO: 1479; SEQ ID NO: 695, SEQ ID NO: 852, SEQ ID NO: 1009, SEQ ID NO: 1166, SEQ ID NO: 1323 and SEQ ID NO: 1480; SEQ ID NO: 696, SEQ ID NO: 853, SEQ ID NO: 1010, SEQ ID NO: 1167, SEQ ID NO: 1324 and SEQ ID NO: 1481; SEQ ID NO: 697, SEQ ID NO: 854, SEQ ID NO: 1011, Array Number 1168, Sequence ID 1325 and Sequence ID 1482; Sequence ID 698, Sequence ID 855, Sequence ID 1012, Sequence ID 1169, Sequence ID 1326 and Sequence ID 1483; Sequence ID 699, Sequence ID 856, Sequence ID 1013, Sequence ID 1170, Sequence ID 1327 and Sequence ID 1484; Sequence ID 700, Sequence ID 857, Sequence ID 1014, Sequence ID 1171, Sequence ID 1328 and Sequence ID 1485; Sequence ID 701, Sequence ID 858, Sequence ID 1015, Sequence ID 1172, Sequence ID 1329 and Sequence ID 1486;Sequence IDs 702, 859, 1016, 1173, 1330 and 1487; Sequence IDs 703, 860, 1017, 1174, 1331 and 1488; Sequence IDs 704, 861, 1018, 1175, 1332 and 1489; Sequence IDs 705, 862, 1019, 1176, 1333 and 1490; Sequence IDs 706, 863, 1020, Column number 1177, sequence number 1334 and sequence number 1491; sequence number 707, sequence number 864, sequence number 1021, sequence number 1178, sequence number 1335 and sequence number 1492; sequence number 708, sequence number 865, sequence number 1022, sequence number 1179, sequence number 1336 and sequence number 1493; sequence number 709, sequence number 866, sequence number 1023, sequence number 1180, sequence number 1337 and sequence number 1494; sequence number 710, sequence number 867, sequence number 1024, sequence number 1181, sequence number 1338 and sequence number 1495; Sequence IDs 711, 868, 1025, 1182, 1339 and 1496; Sequence IDs 712, 869, 1026, 1183, 1340 and 1497; Sequence IDs 713, 870, 1027, 1184, 1341 and 1498; Sequence IDs 714, 871, 1028, 1185, 1342 and 1499; Sequence IDs 715, 872, 1029, Column number 1186, sequence number 1343 and sequence number 1500; sequence number 716, sequence number 873, sequence number 1030, sequence number 1187, sequence number 1344 and sequence number 1501; sequence number 717, sequence number 874, sequence number 1031, sequence number 1188, sequence number 1345 and sequence number 1502; sequence number 718, sequence number 875, sequence number 1032, sequence number 1189, sequence number 1346 and sequence number 1503; sequence number 719, sequence number 876, sequence number 1033, sequence number 1190, sequence number 1347 and sequence number 1504;Sequence IDs 720, 877, 1034, 1191, 1348 and 1505; Sequence IDs 721, 878, 1035, 1192, 1349 and 1506; Sequence IDs 722, 879, 1036, 1193, 1350 and 1507; Sequence IDs 723, 880, 1037, 1194, 1351 and 1508; Sequence IDs 724, 881, 1038, sequence number; Sequence ID 1195, Sequence ID 1352 and Sequence ID 1509; Sequence ID 725, Sequence ID 882, Sequence ID 1039, Sequence ID 1196, Sequence ID 1353 and Sequence ID 1510; Sequence ID 726, Sequence ID 883, Sequence ID 1040, Sequence ID 1197, Sequence ID 1354 and Sequence ID 1511; Sequence ID 727, Sequence ID 884, Sequence ID 1041, Sequence ID 1198, Sequence ID 1355 and Sequence ID 1512; Sequence ID 728, Sequence ID 885, Sequence ID 1042, Sequence ID 1199, Sequence ID 1356 and Sequence ID 1513; Sequence ID 729 , SEQ ID NOs. 886, 1043, 1200, 1357 and 1514; SEQ ID NOs. 730, 887, 1044, 1201, 1358 and 1515; SEQ ID NOs. 731, 888, 1045, 1202, 1359 and 1516; SEQ ID NOs. 732, 889, 1046, 1203, 1360 and 1517; SEQ ID NOs. 733, 890, 1047, 1204, 13 61 and SEQ ID NO: 1518; SEQ ID NO: 734, SEQ ID NO: 891, SEQ ID NO: 1048, SEQ ID NO: 1205, SEQ ID NO: 1362 and SEQ ID NO: 1519; SEQ ID NO: 735, SEQ ID NO: 892, SEQ ID NO: 1049, SEQ ID NO: 1206, SEQ ID NO: 1363 and SEQ ID NO: 1520; SEQ ID NO: 736, SEQ ID NO: 893, SEQ ID NO: 1050, SEQ ID NO: 1207, SEQ ID NO: 1364 and SEQ ID NO: 1521; SEQ ID NO: 737, SEQ ID NO: 894, SEQ ID NO: 1051, SEQ ID NO: 1208, SEQ ID NO: 1365 and SEQ ID NO: 1522; SEQ ID NO: 738, SEQ ID NO: 895, SEQ ID NO: 1052, SEQ ID NO: 1209, SEQ ID NO: 1366 and SEQ ID NO: 1523; SEQ ID NO: 739, SEQ ID NO: 896, SEQ ID NO: 1053, SEQ ID NO: 1210, SEQ ID NO: 1367 and SEQ ID NO: 1524; SEQ ID NO: 740, SEQ ID NO: 897, SEQ ID NO: 1054, SEQ ID NO: 1211, SEQ ID NO: 1368 and SEQ ID NO: 1525; SEQ ID NO: 741, SEQ ID NO: 898, SEQ ID NO: 1055, SEQ ID NO: 1212, SEQ ID NO: 1369 and SEQ ID NO: 1526; SEQ ID NO: 742, SEQ ID NO: 899, SEQ ID NO: 1056, SEQ ID NO: 1213, SEQ ID NO: 1370 and SEQ ID NO: 1527;Sequence IDs 743, 900, 1057, 1214, 1371 and 1528; Sequence IDs 744, 901, 1058, 1215, 1372 and 1529; Sequence IDs 745, 902, 1059, 1216, 1373 and 1530; Sequence IDs 746, 903, 1060, 1217, 1374 and 1531; Sequence IDs 747, 904, 1061, Column number 1218, sequence number 1375 and sequence number 1532; sequence number 748, sequence number 905, sequence number 1062, sequence number 1219, sequence number 1376 and sequence number 1533; sequence number 749, sequence number 906, sequence number 1063, sequence number 1220, sequence number 1377 and sequence number 1534; sequence number 750, sequence number 907, sequence number 1064, sequence number 1221, sequence number 1378 and sequence number 1535; sequence number 751, sequence number 908, sequence number 1065, sequence number 1222, sequence number 1379 and sequence number 1536; Sequence IDs 752, 909, 1066, 1223, 1380 and 1537; Sequence IDs 753, 910, 1067, 1224, 1381 and 1538; Sequence IDs 754, 911, 1068, 1225, 1382 and 1539; Sequence IDs 755, 912, 1069, 1226, 1383 and 1540; Sequence IDs 756, 913, 1070, Column number 1227, sequence number 1384 and sequence number 1541; sequence number 757, sequence number 914, sequence number 1071, sequence number 1228, sequence number 1385 and sequence number 1542; sequence number 758, sequence number 915, sequence number 1072, sequence number 1229, sequence number 1386 and sequence number 1543; sequence number 759, sequence number 916, sequence number 1073, sequence number 1230, sequence number 1387 and sequence number 1544; sequence number 760, sequence number 917, sequence number 1074, sequence number 1231, sequence number 1388 and sequence number 1545;Sequence IDs 761, 918, 1075, 1232, 1389 and 1546; Sequence IDs 762, 919, 1076, 1233, 1390 and 1547; Sequence IDs 763, 920, 1077, 1234, 1391 and 1548; Sequence IDs 764, 921, 1078, 1235, 1392 and 1549; Sequence IDs 765, 922, 1079, Column number 1236, sequence number 1393 and sequence number 1550; sequence number 766, sequence number 923, sequence number 1080, sequence number 1237, sequence number 1394 and sequence number 1551; sequence number 767, sequence number 924, sequence number 1081, sequence number 1238, sequence number 1395 and sequence number 1552; sequence number 768, sequence number 925, sequence number 1082, sequence number 1239, sequence number 1396 and sequence number 1553; sequence number 769, sequence number 926, sequence number 1083, sequence number 1240, sequence number 1397 and sequence number 1554; Sequence IDs 770, 927, 1084, 1241, 1398 and 1555; Sequence IDs 771, 928, 1085, 1242, 1399 and 1556; Sequence IDs 772, 929, 1086, 1243, 1400 and 1557; Sequence IDs 773, 930, 1087, 1244, 1401 and 1558; Sequence IDs 774, 931, 1088, Column number 1245, sequence number 1402 and sequence number 1559; sequence number 775, sequence number 932, sequence number 1089, sequence number 1246, sequence number 1403 and sequence number 1560; sequence number 776, sequence number 933, sequence number 1090, sequence number 1247, sequence number 1404 and sequence number 1561; sequence number 777, sequence number 934, sequence number 1091, sequence number 1248, sequence number 1405 and sequence number 1562; sequence number 778, sequence number 935, sequence number 1092, sequence number 1249, sequence number 1406 and sequence number 1563;Sequence IDs 779, 936, 1093, 1250, 1407 and 1564; Sequence IDs 780, 937, 1094, 1251, 1408 and 1565; Sequence IDs 781, 938, 1095, 1252, 1409 and 1566; Sequence IDs 782, 939, 1096, 1253 and 141 The method according to claim 6, comprising an array selected from the group consisting of 0 and SEQ ID NO: 1567; SEQ ID NO: 783, 940, 1097, 1254, 1411, and 1568; SEQ ID NO: 784, 941, 1098, 1255, 1412, and 1569; and SEQ ID NO: 785, 942, 1099, 1256, 1413, and 1570.

15. The method according to claim 6, wherein the antigen-binding protein is an antibody or a fragment thereof, and the antibody or fragment thereof comprises a light chain variable region containing a sequence selected from the group consisting of SEQ ID NOs: 1 to 157, and a heavy chain variable region containing a sequence selected from the group consisting of SEQ ID NOs: 158 to 314.

16. The antigen-binding protein is an antibody or a fragment thereof, and the antibody or fragment thereof comprises: a light chain variable region containing SEQ ID NO: 1 and a heavy chain variable region containing SEQ ID NO: 158; a light chain variable region containing SEQ ID NO: 2 and a heavy chain variable region containing SEQ ID NO: 159; a light chain variable region containing SEQ ID NO: 3 and a heavy chain variable region containing SEQ ID NO: 160; a light chain variable region containing SEQ ID NO: 4 and a heavy chain variable region containing SEQ ID NO: 161; a light chain variable region containing SEQ ID NO: 5 and a heavy chain variable region containing SEQ ID NO: 162; a light chain variable region containing SEQ ID NO: 6 and a heavy chain variable region containing SEQ ID NO: 163; and a light chain variable region containing SEQ ID NO:

7. Variable region and heavy chain variable region including sequence number 164; light chain variable region including sequence number 8 and heavy chain variable region including sequence number 165; light chain variable region including sequence number 9 and heavy chain variable region including sequence number 166; light chain variable region including sequence number 10 and heavy chain variable region including sequence number 167; light chain variable region including sequence number 11 and heavy chain variable region including sequence number 168; light chain variable region including sequence number 12 and heavy chain variable region including sequence number 169; light chain variable region including sequence number 13 and heavy chain variable region including sequence number 170; light chain variable region including sequence number 14 and sequence number Heavy chain variable region including sequence number 171; light chain variable region including sequence number 15 and heavy chain variable region including sequence number 172; light chain variable region including sequence number 16 and heavy chain variable region including sequence number 173; light chain variable region including sequence number 17 and heavy chain variable region including sequence number 174; light chain variable region including sequence number 18 and heavy chain variable region including sequence number 175; light chain variable region including sequence number 19 and heavy chain variable region including sequence number 176; light chain variable region including sequence number 20 and heavy chain variable region including sequence number 177; light chain variable region including sequence number 21 and sequence number 178 Heavy chain variable region; light chain variable region including SEQ ID NO: 22 and heavy chain variable region including SEQ ID NO: 179; light chain variable region including SEQ ID NO: 23 and heavy chain variable region including SEQ ID NO: 180; light chain variable region including SEQ ID NO: 24 and heavy chain variable region including SEQ ID NO: 181; light chain variable region including SEQ ID NO: 25 and heavy chain variable region including SEQ ID NO: 182; light chain variable region including SEQ ID NO: 26 and heavy chain variable region including SEQ ID NO: 183; light chain variable region including SEQ ID NO: 27 and heavy chain variable region including SEQ ID NO: 184; light chain variable region including SEQ ID NO: 28 and heavy chain variable region including SEQ ID NO: 185;Light chain variable region including SEQ ID NO: 29 and heavy chain variable region including SEQ ID NO: 186; Light chain variable region including SEQ ID NO: 30 and heavy chain variable region including SEQ ID NO: 187; Light chain variable region including SEQ ID NO: 31 and heavy chain variable region including SEQ ID NO: 188; Light chain variable region including SEQ ID NO: 32 and heavy chain variable region including SEQ ID NO: 189; Light chain variable region including SEQ ID NO: 33 and heavy chain variable region including SEQ ID NO: 190; Light chain variable region including SEQ ID NO: 34 and heavy chain variable region including SEQ ID NO: 191; Light chain variable region including SEQ ID NO: 35 and heavy chain variable region including SEQ ID NO: 192; including SEQ ID NO: 36 A light chain variable region and a heavy chain variable region including SEQ ID NO: 193; a light chain variable region including SEQ ID NO: 37 and a heavy chain variable region including SEQ ID NO: 194; a light chain variable region including SEQ ID NO: 38 and a heavy chain variable region including SEQ ID NO: 195; a light chain variable region including SEQ ID NO: 39 and a heavy chain variable region including SEQ ID NO: 196; a light chain variable region including SEQ ID NO: 40 and a heavy chain variable region including SEQ ID NO: 197; a light chain variable region including SEQ ID NO: 41 and a heavy chain variable region including SEQ ID NO: 198; a light chain variable region including SEQ ID NO: 42 and a heavy chain variable region including SEQ ID NO: 199; a light chain variable region including SEQ ID NO: 43 and Heavy chain variable region including SEQ ID NO: 200; light chain variable region including SEQ ID NO: 44 and heavy chain variable region including SEQ ID NO: 201; light chain variable region including SEQ ID NO: 45 and heavy chain variable region including SEQ ID NO: 202; light chain variable region including SEQ ID NO: 46 and heavy chain variable region including SEQ ID NO: 203; light chain variable region including SEQ ID NO: 47 and heavy chain variable region including SEQ ID NO: 204; light chain variable region including SEQ ID NO: 48 and heavy chain variable region including SEQ ID NO: 205; light chain variable region including SEQ ID NO: 49 and heavy chain variable region including SEQ ID NO: 206; light chain variable region including SEQ ID NO: 50 and SEQ ID NO: 207 Including heavy chain variable region; light chain variable region including SEQ ID NO: 51 and heavy chain variable region including SEQ ID NO: 208; light chain variable region including SEQ ID NO: 52 and heavy chain variable region including SEQ ID NO: 209; light chain variable region including SEQ ID NO: 53 and heavy chain variable region including SEQ ID NO: 210; light chain variable region including SEQ ID NO: 54 and heavy chain variable region including SEQ ID NO: 211; light chain variable region including SEQ ID NO: 55 and heavy chain variable region including SEQ ID NO: 212; light chain variable region including SEQ ID NO: 56 and heavy chain variable region including SEQ ID NO: 213; light chain variable region including SEQ ID NO: 57 and heavy chain variable region including SEQ ID NO: 214;Light chain variable region including SEQ ID NO: 58 and heavy chain variable region including SEQ ID NO: 215; Light chain variable region including SEQ ID NO: 59 and heavy chain variable region including SEQ ID NO: 216; Light chain variable region including SEQ ID NO: 60 and heavy chain variable region including SEQ ID NO: 217; Light chain variable region including SEQ ID NO: 61 and heavy chain variable region including SEQ ID NO: 218; Light chain variable region including SEQ ID NO: 62 and heavy chain variable region including SEQ ID NO: 219; Light chain variable region including SEQ ID NO: 63 and heavy chain variable region including SEQ ID NO: 220; Light chain variable region including SEQ ID NO: 64 and heavy chain variable region including SEQ ID NO: 221; including SEQ ID NO: 65 A light chain variable region and a heavy chain variable region including SEQ ID NO: 222; a light chain variable region including SEQ ID NO: 66 and a heavy chain variable region including SEQ ID NO: 223; a light chain variable region including SEQ ID NO: 67 and a heavy chain variable region including SEQ ID NO: 224; a light chain variable region including SEQ ID NO: 68 and a heavy chain variable region including SEQ ID NO: 225; a light chain variable region including SEQ ID NO: 69 and a heavy chain variable region including SEQ ID NO: 226; a light chain variable region including SEQ ID NO: 70 and a heavy chain variable region including SEQ ID NO: 227; a light chain variable region including SEQ ID NO: 71 and a heavy chain variable region including SEQ ID NO: 228; a light chain variable region including SEQ ID NO: 72 and Heavy chain variable region including SEQ ID NO: 229; light chain variable region including SEQ ID NO: 73 and heavy chain variable region including SEQ ID NO: 230; light chain variable region including SEQ ID NO: 74 and heavy chain variable region including SEQ ID NO: 231; light chain variable region including SEQ ID NO: 75 and heavy chain variable region including SEQ ID NO: 232; light chain variable region including SEQ ID NO: 76 and heavy chain variable region including SEQ ID NO: 233; light chain variable region including SEQ ID NO: 77 and heavy chain variable region including SEQ ID NO: 234; light chain variable region including SEQ ID NO: 78 and heavy chain variable region including SEQ ID NO: 235; light chain variable region including SEQ ID NO: 79 and SEQ ID NO: 236 Including heavy chain variable region; light chain variable region including SEQ ID NO: 80 and heavy chain variable region including SEQ ID NO: 237; light chain variable region including SEQ ID NO: 81 and heavy chain variable region including SEQ ID NO: 238; light chain variable region including SEQ ID NO: 82 and heavy chain variable region including SEQ ID NO: 239; light chain variable region including SEQ ID NO: 83 and heavy chain variable region including SEQ ID NO: 240; light chain variable region including SEQ ID NO: 84 and heavy chain variable region including SEQ ID NO: 241; light chain variable region including SEQ ID NO: 85 and heavy chain variable region including SEQ ID NO: 242; light chain variable region including SEQ ID NO: 86 and heavy chain variable region including SEQ ID NO: 243;Light chain variable region containing SEQ ID NO: 87 and heavy chain variable region containing SEQ ID NO: 244; Light chain variable region containing SEQ ID NO: 88 and heavy chain variable region containing SEQ ID NO: 245; Light chain variable region containing SEQ ID NO: 89 and heavy chain variable region containing SEQ ID NO: 246; Light chain variable region containing SEQ ID NO: 90 and heavy chain variable region containing SEQ ID NO: 247; Light chain variable region containing SEQ ID NO: 91 and heavy chain variable region containing SEQ ID NO: 248; Light chain variable region containing SEQ ID NO: 92 and heavy chain variable region containing SEQ ID NO: 249; Light chain variable region containing SEQ ID NO: 93 and heavy chain variable region containing SEQ ID NO: 250; Sequence number Light chain variable region including number 94 and heavy chain variable region including sequence number 251; light chain variable region including sequence number 95 and heavy chain variable region including sequence number 252; light chain variable region including sequence number 96 and heavy chain variable region including sequence number 253; light chain variable region including sequence number 97 and heavy chain variable region including sequence number 254; light chain variable region including sequence number 98 and heavy chain variable region including sequence number 255; light chain variable region including sequence number 99 and heavy chain variable region including sequence number 256; light chain variable region including sequence number 100 and heavy chain variable region including sequence number 257; sequence number 10 Light chain variable region containing 1 and heavy chain variable region containing SEQ ID NO: 258; Light chain variable region containing SEQ ID NO: 102 and heavy chain variable region containing SEQ ID NO: 259; Light chain variable region containing SEQ ID NO: 103 and heavy chain variable region containing SEQ ID NO: 260; Light chain variable region containing SEQ ID NO: 104 and heavy chain variable region containing SEQ ID NO: 261; Light chain variable region containing SEQ ID NO: 105 and heavy chain variable region containing SEQ ID NO: 262; Light chain variable region containing SEQ ID NO: 106 and heavy chain variable region containing SEQ ID NO: 263; Light chain variable region containing SEQ ID NO: 107 and heavy chain variable region containing SEQ ID NO: 264; Sequence number Light chain variable region including sequence number 108 and heavy chain variable region including sequence number 265; light chain variable region including sequence number 109 and heavy chain variable region including sequence number 266; light chain variable region including sequence number 110 and heavy chain variable region including sequence number 267; light chain variable region including sequence number 111 and heavy chain variable region including sequence number 268; light chain variable region including sequence number 112 and heavy chain variable region including sequence number 269; light chain variable region including sequence number 113 and heavy chain variable region including sequence number 270; light chain variable region including sequence number 114 and heavy chain variable region including sequence number 271;Light chain variable region including SEQ ID NO: 115 and heavy chain variable region including SEQ ID NO: 272; Light chain variable region including SEQ ID NO: 116 and heavy chain variable region including SEQ ID NO: 273; Light chain variable region including SEQ ID NO: 117 and heavy chain variable region including SEQ ID NO: 274; Light chain variable region including SEQ ID NO: 118 and heavy chain variable region including SEQ ID NO: 275; Light chain variable region including SEQ ID NO: 119 and heavy chain variable region including SEQ ID NO: 276; Light chain variable region including SEQ ID NO: 120 and heavy chain variable region including SEQ ID NO: 277; Light chain variable region including SEQ ID NO: 121 and heavy chain variable region including SEQ ID NO: 278; Light chain variable region including SEQ ID NO: 122 and heavy chain variable region including SEQ ID NO: 279; Light chain variable region including SEQ ID NO: 123 and heavy chain variable region including SEQ ID NO: 280; Light chain variable region including SEQ ID NO: 124 and heavy chain variable region including SEQ ID NO: 281; Light chain variable region including SEQ ID NO: 125 and heavy chain variable region including SEQ ID NO: 282; Light chain variable region including SEQ ID NO: 126 and heavy chain variable region including SEQ ID NO: 283; Light chain variable region including SEQ ID NO: 127 and heavy chain variable region including SEQ ID NO: 284; Light chain variable region including SEQ ID NO: 128 and heavy chain variable region including SEQ ID NO: 285; Light chain variable region including SEQ ID NO: 129 and heavy chain variable region including SEQ ID NO: 286; Light chain variable region including SEQ ID NO: 130 and heavy chain variable region including SEQ ID NO: 287; Light chain variable region including SEQ ID NO: 131 and heavy chain variable region including SEQ ID NO: 288; Light chain variable region including SEQ ID NO: 132 and heavy chain variable region including SEQ ID NO: 289; Light chain variable region including SEQ ID NO: 133 and heavy chain variable region including SEQ ID NO: 290; Light chain variable region including SEQ ID NO: 134 and heavy chain variable region including SEQ ID NO: 291; Light chain variable region including SEQ ID NO: 135 and heavy chain variable region including SEQ ID NO: 292; Light chain variable region including SEQ ID NO: 136 and heavy chain variable region including SEQ ID NO: 293; Light chain variable region including SEQ ID NO: 137 and heavy chain variable region including SEQ ID NO: 294; Light chain variable region including SEQ ID NO: 138 and heavy chain variable region including SEQ ID NO: 295; Light chain variable region including SEQ ID NO: 139 and heavy chain variable region including SEQ ID NO: 296; Light chain variable region including SEQ ID NO: 140 and heavy chain variable region including SEQ ID NO: 297; Light chain variable region including SEQ ID NO: 141 and heavy chain variable region including SEQ ID NO: 298; Light chain variable region including SEQ ID NO: 142 and heavy chain variable region including SEQ ID NO: 299;Light chain variable region containing SEQ ID NO: 143 and heavy chain variable region containing SEQ ID NO: 300; Light chain variable region containing SEQ ID NO: 144 and heavy chain variable region containing SEQ ID NO: 301; Light chain variable region containing SEQ ID NO: 145 and heavy chain variable region containing SEQ ID NO: 302; Light chain variable region containing SEQ ID NO: 146 and heavy chain variable region containing SEQ ID NO: 303; Light chain variable region containing SEQ ID NO: 147 and heavy chain variable region containing SEQ ID NO: 304; Light chain variable region containing SEQ ID NO: 148 and heavy chain variable region containing SEQ ID NO: 305; Light chain containing SEQ ID NO: 149; The method according to claim 6, comprising a combination of a light chain variable region and a heavy chain variable region selected from the group consisting of: a variable region and a heavy chain variable region including sequence number 306; a light chain variable region including sequence number 150 and a heavy chain variable region including sequence number 307; a light chain variable region including sequence number 151 and a heavy chain variable region including sequence number 308; a light chain variable region including sequence number 152 and a heavy chain variable region including sequence number 309; a light chain variable region including sequence number 153 and a heavy chain variable region including sequence number 310; a light chain variable region including sequence number 154 and a heavy chain variable region including sequence number 311; a light chain variable region including sequence number 155 and a heavy chain variable region including sequence number 312; a light chain variable region including sequence number 156 and a heavy chain variable region including sequence number 313; and a light chain variable region including sequence number 157 and a heavy chain variable region including sequence number 314.

17. The isolated antigen-binding protein according to claim 21, wherein the antigen-binding protein is an antibody, and the antibody comprises a light chain containing a sequence selected from the group consisting of SEQ ID NOs: 472 to 628, and a heavy chain containing a sequence selected from the group consisting of SEQ ID NOs: 472 to 628.

18. The antigen-binding protein is an antibody, and the antibody contains a light chain containing SEQ ID NO: 315 and a heavy chain containing SEQ ID NO: 472; a light chain containing SEQ ID NO: 316 and a heavy chain containing SEQ ID NO: 473; a light chain containing SEQ ID NO: 317 and a heavy chain containing SEQ ID NO: 474; a light chain containing SEQ ID NO: 318 and a heavy chain containing SEQ ID NO: 475; a light chain containing SEQ ID NO: 319 and a heavy chain containing SEQ ID NO: 476; a light chain containing SEQ ID NO: 320 and a heavy chain containing SEQ ID NO: 477; a light chain containing SEQ ID NO: 321 and a heavy chain containing SEQ ID NO: 478; a light chain containing SEQ ID NO: 322 and a heavy chain containing SEQ ID NO: 479; and SEQ ID NO:

323. Light chain and heavy chain containing SEQ ID NO: 480; Light chain containing SEQ ID NO: 324 and heavy chain containing SEQ ID NO: 481; Light chain containing SEQ ID NO: 325 and heavy chain containing SEQ ID NO: 482; Light chain containing SEQ ID NO: 326 and heavy chain containing SEQ ID NO: 483; Light chain containing SEQ ID NO: 327 and heavy chain containing SEQ ID NO: 484; Light chain containing SEQ ID NO: 328 and heavy chain containing SEQ ID NO: 485; Light chain containing SEQ ID NO: 329 and heavy chain containing SEQ ID NO: 486; Light chain containing SEQ ID NO: 330 and heavy chain containing SEQ ID NO: 487; Light chain containing SEQ ID NO: 331 and heavy chain containing SEQ ID NO: 488; Light chain containing SEQ ID NO: 332 and Heavy chain containing sequence number 489; light chain containing sequence number 333 and heavy chain containing sequence number 490; light chain containing sequence number 334 and heavy chain containing sequence number 491; light chain containing sequence number 335 and heavy chain containing sequence number 492; light chain containing sequence number 336 and heavy chain containing sequence number 493; light chain containing sequence number 337 and heavy chain containing sequence number 494; light chain containing sequence number 338 and heavy chain containing sequence number 495; light chain containing sequence number 339 and heavy chain containing sequence number 496; light chain containing sequence number 340 and heavy chain containing sequence number 497; light chain containing sequence number 341 and sequence number 498 Heavy chain containing; light chain containing SEQ ID NO: 342 and heavy chain containing SEQ ID NO: 499; light chain containing SEQ ID NO: 343 and heavy chain containing SEQ ID NO: 500; light chain containing SEQ ID NO: 344 and heavy chain containing SEQ ID NO: 501; light chain containing SEQ ID NO: 345 and heavy chain containing SEQ ID NO: 502; light chain containing SEQ ID NO: 346 and heavy chain containing SEQ ID NO: 503; light chain containing SEQ ID NO: 347 and heavy chain containing SEQ ID NO: 504; light chain containing SEQ ID NO: 348 and heavy chain containing SEQ ID NO: 505; light chain containing SEQ ID NO: 349 and heavy chain containing SEQ ID NO: 506; light chain containing SEQ ID NO: 350 and heavy chain containing SEQ ID NO: 507;Light chain containing SEQ ID NO: 351 and heavy chain containing SEQ ID NO: 508; Light chain containing SEQ ID NO: 352 and heavy chain containing SEQ ID NO: 509; Light chain containing SEQ ID NO: 353 and heavy chain containing SEQ ID NO: 510; Light chain containing SEQ ID NO: 354 and heavy chain containing SEQ ID NO: 511; Light chain containing SEQ ID NO: 355 and heavy chain containing SEQ ID NO: 512; Light chain containing SEQ ID NO: 356 and heavy chain containing SEQ ID NO: 513; Light chain containing SEQ ID NO: 357 and heavy chain containing SEQ ID NO: 514; Light chain containing SEQ ID NO: 358 and heavy chain containing SEQ ID NO: 515; Light chain containing SEQ ID NO: 359 and heavy chain containing SEQ ID NO: 516; SEQ ID NO: 36 Light chain containing 0 and heavy chain containing SEQ ID NO: 517; Light chain containing SEQ ID NO: 361 and heavy chain containing SEQ ID NO: 518; Light chain containing SEQ ID NO: 362 and heavy chain containing SEQ ID NO: 519; Light chain containing SEQ ID NO: 363 and heavy chain containing SEQ ID NO: 520; Light chain containing SEQ ID NO: 364 and heavy chain containing SEQ ID NO: 521; Light chain containing SEQ ID NO: 365 and heavy chain containing SEQ ID NO: 522; Light chain containing SEQ ID NO: 366 and heavy chain containing SEQ ID NO: 523; Light chain containing SEQ ID NO: 367 and heavy chain containing SEQ ID NO: 524; Light chain containing SEQ ID NO: 368 and heavy chain containing SEQ ID NO: 525; Light chain containing SEQ ID NO: 369 and Heavy chain containing SEQ ID NO: 526; light chain containing SEQ ID NO: 370 and heavy chain containing SEQ ID NO: 527; light chain containing SEQ ID NO: 371 and heavy chain containing SEQ ID NO: 528; light chain containing SEQ ID NO: 372 and heavy chain containing SEQ ID NO: 529; light chain containing SEQ ID NO: 373 and heavy chain containing SEQ ID NO: 530; light chain containing SEQ ID NO: 374 and heavy chain containing SEQ ID NO: 531; light chain containing SEQ ID NO: 375 and heavy chain containing SEQ ID NO: 532; light chain containing SEQ ID NO: 376 and heavy chain containing SEQ ID NO: 533; light chain containing SEQ ID NO: 377 and heavy chain containing SEQ ID NO: 534; light chain containing SEQ ID NO: 378 and SEQ ID NO: 53 Heavy chain containing 5; light chain containing SEQ ID NO: 379 and heavy chain containing SEQ ID NO: 536; light chain containing SEQ ID NO: 380 and heavy chain containing SEQ ID NO: 537; light chain containing SEQ ID NO: 381 and heavy chain containing SEQ ID NO: 538; light chain containing SEQ ID NO: 382 and heavy chain containing SEQ ID NO: 539; light chain containing SEQ ID NO: 383 and heavy chain containing SEQ ID NO: 540; light chain containing SEQ ID NO: 384 and heavy chain containing SEQ ID NO: 541; light chain containing SEQ ID NO: 385 and heavy chain containing SEQ ID NO: 542; light chain containing SEQ ID NO: 386 and heavy chain containing SEQ ID NO: 543; light chain containing SEQ ID NO: 387 and heavy chain containing SEQ ID NO: 544;Light chain containing SEQ ID NO: 388 and heavy chain containing SEQ ID NO: 545; Light chain containing SEQ ID NO: 389 and heavy chain containing SEQ ID NO: 546; Light chain containing SEQ ID NO: 390 and heavy chain containing SEQ ID NO: 547; Light chain containing SEQ ID NO: 391 and heavy chain containing SEQ ID NO: 548; Light chain containing SEQ ID NO: 392 and heavy chain containing SEQ ID NO: 549; Light chain containing SEQ ID NO: 393 and heavy chain containing SEQ ID NO: 550; Light chain containing SEQ ID NO: 394 and heavy chain containing SEQ ID NO: 551; Light chain containing SEQ ID NO: 395 and heavy chain containing SEQ ID NO: 552; Light chain containing SEQ ID NO: 396 and heavy chain containing SEQ ID NO: 553; SEQ ID NO: 39 Light chain containing 7 and heavy chain containing SEQ ID NO: 554; Light chain containing SEQ ID NO: 398 and heavy chain containing SEQ ID NO: 555; Light chain containing SEQ ID NO: 399 and heavy chain containing SEQ ID NO: 556; Light chain containing SEQ ID NO: 400 and heavy chain containing SEQ ID NO: 557; Light chain containing SEQ ID NO: 401 and heavy chain containing SEQ ID NO: 558; Light chain containing SEQ ID NO: 402 and heavy chain containing SEQ ID NO: 559; Light chain containing SEQ ID NO: 403 and heavy chain containing SEQ ID NO: 560; Light chain containing SEQ ID NO: 404 and heavy chain containing SEQ ID NO: 561; Light chain containing SEQ ID NO: 405 and heavy chain containing SEQ ID NO: 562; Light chain containing SEQ ID NO: 406 and Heavy chain containing SEQ ID NO: 563; light chain containing SEQ ID NO: 407 and heavy chain containing SEQ ID NO: 564; light chain containing SEQ ID NO: 408 and heavy chain containing SEQ ID NO: 565; light chain containing SEQ ID NO: 409 and heavy chain containing SEQ ID NO: 566; light chain containing SEQ ID NO: 410 and heavy chain containing SEQ ID NO: 567; light chain containing SEQ ID NO: 411 and heavy chain containing SEQ ID NO: 568; light chain containing SEQ ID NO: 412 and heavy chain containing SEQ ID NO: 569; light chain containing SEQ ID NO: 413 and heavy chain containing SEQ ID NO: 570; light chain containing SEQ ID NO: 414 and heavy chain containing SEQ ID NO: 571; light chain containing SEQ ID NO: 415 and SEQ ID NO: 57 Heavy chain containing 2; light chain containing SEQ ID NO: 416 and heavy chain containing SEQ ID NO: 573; light chain containing SEQ ID NO: 417 and heavy chain containing SEQ ID NO: 574; light chain containing SEQ ID NO: 418 and heavy chain containing SEQ ID NO: 575; light chain containing SEQ ID NO: 419 and heavy chain containing SEQ ID NO: 576; light chain containing SEQ ID NO: 420 and heavy chain containing SEQ ID NO: 577; light chain containing SEQ ID NO: 421 and heavy chain containing SEQ ID NO: 578; light chain containing SEQ ID NO: 422 and heavy chain containing SEQ ID NO: 579; light chain containing SEQ ID NO: 423 and heavy chain containing SEQ ID NO: 580; light chain containing SEQ ID NO: 424 and heavy chain containing SEQ ID NO: 581;Light chain containing SEQ ID NO: 425 and heavy chain containing SEQ ID NO: 582; Light chain containing SEQ ID NO: 426 and heavy chain containing SEQ ID NO: 583; Light chain containing SEQ ID NO: 427 and heavy chain containing SEQ ID NO: 584; Light chain containing SEQ ID NO: 428 and heavy chain containing SEQ ID NO: 585; Light chain containing SEQ ID NO: 429 and heavy chain containing SEQ ID NO: 586; Light chain containing SEQ ID NO: 430 and heavy chain containing SEQ ID NO: 587; Light chain containing SEQ ID NO: 431 and heavy chain containing SEQ ID NO: 588; Light chain containing SEQ ID NO: 432 and heavy chain containing SEQ ID NO: 589; Light chain containing SEQ ID NO: 433 and heavy chain containing SEQ ID NO: 590; SEQ ID NO: 43 Light chain containing 4 and heavy chain containing SEQ ID NO: 591; Light chain containing SEQ ID NO: 435 and heavy chain containing SEQ ID NO: 592; Light chain containing SEQ ID NO: 436 and heavy chain containing SEQ ID NO: 593; Light chain containing SEQ ID NO: 437 and heavy chain containing SEQ ID NO: 594; Light chain containing SEQ ID NO: 438 and heavy chain containing SEQ ID NO: 595; Light chain containing SEQ ID NO: 439 and heavy chain containing SEQ ID NO: 596; Light chain containing SEQ ID NO: 440 and heavy chain containing SEQ ID NO: 597; Light chain containing SEQ ID NO: 441 and heavy chain containing SEQ ID NO: 598; Light chain containing SEQ ID NO: 442 and heavy chain containing SEQ ID NO: 599; Light chain containing SEQ ID NO: 443 and Heavy chain containing SEQ ID NO: 600; light chain containing SEQ ID NO: 444 and heavy chain containing SEQ ID NO: 601; light chain containing SEQ ID NO: 445 and heavy chain containing SEQ ID NO: 602; light chain containing SEQ ID NO: 446 and heavy chain containing SEQ ID NO: 603; light chain containing SEQ ID NO: 447 and heavy chain containing SEQ ID NO: 604; light chain containing SEQ ID NO: 448 and heavy chain containing SEQ ID NO: 605; light chain containing SEQ ID NO: 449 and heavy chain containing SEQ ID NO: 606; light chain containing SEQ ID NO: 450 and heavy chain containing SEQ ID NO: 607; light chain containing SEQ ID NO: 451 and heavy chain containing SEQ ID NO: 608; light chain containing SEQ ID NO: 452 and SEQ ID NO: 60 Heavy chain containing 9; light chain containing SEQ ID NO: 453 and heavy chain containing SEQ ID NO: 610; light chain containing SEQ ID NO: 454 and heavy chain containing SEQ ID NO: 611; light chain containing SEQ ID NO: 455 and heavy chain containing SEQ ID NO: 612; light chain containing SEQ ID NO: 456 and heavy chain containing SEQ ID NO: 613; light chain containing SEQ ID NO: 457 and heavy chain containing SEQ ID NO: 614; light chain containing SEQ ID NO: 458 and heavy chain containing SEQ ID NO: 615; light chain containing SEQ ID NO: 459 and heavy chain containing SEQ ID NO: 616; light chain containing SEQ ID NO: 460 and heavy chain containing SEQ ID NO: 617; light chain containing SEQ ID NO: 461 and heavy chain containing SEQ ID NO: 618;The method according to claim 6, comprising a combination of light and heavy chains selected from the group consisting of: a light chain containing SEQ ID NO: 462 and a heavy chain containing SEQ ID NO: 619; a light chain containing SEQ ID NO: 463 and a heavy chain containing SEQ ID NO: 620; a light chain containing SEQ ID NO: 464 and a heavy chain containing SEQ ID NO: 621; a light chain containing SEQ ID NO: 465 and a heavy chain containing SEQ ID NO: 622; a light chain containing SEQ ID NO: 466 and a heavy chain containing SEQ ID NO: 623; a light chain containing SEQ ID NO: 467 and a heavy chain containing SEQ ID NO: 624; a light chain containing SEQ ID NO: 468 and a heavy chain containing SEQ ID NO: 625; a light chain containing SEQ ID NO: 469 and a heavy chain containing SEQ ID NO: 626; a light chain containing SEQ ID NO: 470 and a heavy chain containing SEQ ID NO: 627; and a light chain containing SEQ ID NO: 471 and a heavy chain containing SEQ ID NO:

628.

19. The antigen-binding protein is an antibody or a fragment thereof, and the antibody comprises CDRL1, CDRL2, CDRL3, CDRH1, CDRH2 and CDRH3, and the CDRL1 is sequence numbers a4, a10, a16, a22, a28, a34, a40, a46, a52, a58, a64, a70, a76, a82, a88, a94, a100, a106, a112, a118, a124, a130, a136, a142, a148, a154, a160, a166, a172, a178, a184, a190, a196, a202, a208, a214, a220, a226, a232, a238, a244, a250, a256, a262, a268, a2 74, a280, a286, a292, a298, a304, a310, a316, a322, a328, a334, a340, a346, a352, a358, a1290, a1300, a1310, a1320, a The CDRL2 includes sequences selected from the group consisting of 1330, a1340, and a1350; and the CDRL2 includes sequences a5, a11, a17, a23, a29, a35, a41, a47, a53, a59, a65, a71, a77, a83, a89, a95, a101, a107, a113, a119, a125, a131, a137, a143, a149, a155, a161, a167, a173, a179, a185, a191, a197 , comprising an array selected from the group consisting of a203, a209, a215, a221, a227, a233, a239, a245, a251, a257, a263, a269, a275, a281, a287, a293, a299, a305, a311, a317, a323, a329, a335, a341, a347, a353, a359, a1291, a1301, a1311, a1321, a1331, a1341 and a1351;The aforementioned CDRL3 is the destination numbers a6, a12, a18, a24, a30, a36, a42, a48, a54, a60, a66, a72, a78, a84, a90, a96, a102, a108, a114, a120, a126, a132, a138, a144, a150, a156, a162, a168, a174, a180, a186, a192, a198, a204, a210, a216, a222, a The CDRH1 includes an array selected from the group consisting of 228, a234, a240, a246, a252, a258, a264, a270, a276, a282, a288, a294, a300, a306, a312, a318, a324, a330, a336, a342, a348, a354, a360, a1292, a1302, a1312, a1322, a1332, a1342 and a1352; and the CDRH1 includes an array selected from the group consisting of 228, a234, a240, a246, a252, a258, a264, a270, a276, a282, a288, a294, a300, a306, a312, a318, a324, a330, a336, a342, a348, a354, a360, a1292, a1302, a1312, a1322, a1332, a1342 and a1352. , Sequence numbers a364, a370, a376, a382, a388, a394, a400, a406, a412, a418, a424, a430, a436, a442, a448, a454, a460, a466, a472, a478, a484, a490, a496, a502, a508, a514, a520, a526, a532, a538, a544, a550, a556, a562, a568, a5 The sequence includes a sequence selected from the group consisting of 74, a580, a586, a592, a598, a604, a610, a616, a622, a628, a634, a640, a646, a652, a658, a664, a670, a676, a682, a688, a694, a700, a706, a712, a718, a1293, a1303, a1313, a1323, a1333, a1343 and a1353;The aforementioned CDRH2 corresponds to the arrival numbers a365, a371, a377, a383, a389, a395, a401, a407, a413, a419, a425, a431, a437, a443, a449, a455, a461, a467, a473, a479, a485, a491, a497, a503, a509, a515, a521, a527, a533, a539, a545, a551, a557, a563, a56 9, comprising an array selected from the group consisting of a575, a581, a587, a593, a599, a605, a611, a617, a623, a629, a635, a641, a647, a653, a659, a665, a671, a677, a683, a689, a695, a701, a707, a713, a719, a1294, a1304, a1314, a1324, a1334, a1344 and a1354; The aforementioned CDRH3 corresponds to sequence numbers a366, a372, a378, a384, a390, a396, a402, a408, a414, a420, a426, a432, a438, a444, a450, a456, a462, a468, a474, a480, a486, a492, a498, a504, a510, a516, a522, a528, a534, a540, a546, a552, a558, a564, a570 , comprising an array selected from the group consisting of a576, a582, a588, a594, a600, a606, a612, a618, a624, a630, a636, a642, a648, a654, a660, a666, a672, a678, a684, a690, a696, a702, a708, a714, a720, a1295, a1305, a1315, a1325, a1335, a1345 and a1355; The isolated antigen-binding protein according to claim 6.

20. The antigen-binding protein is an antibody or a fragment thereof, and the antibody comprises CDRL1, CDRL2, CDRL3, CDRH1, CDRH2 and CDRH3, with each CDRL1, CDRL2, CDRL3, CDRH1, CDRH2 and CDRH3 corresponding to SEQ ID NOs: a4, a5, a6, a364, a365 and a366; a10, a11, a12, a370, a371 and a372; a16, a17, a18, a376, Column number a377 and sequence number a378; sequence number a22, sequence number a23, sequence number a24, sequence number a382, sequence number a383 and sequence number a384; sequence number a28, sequence number a29, sequence number a30, sequence number a388, sequence number a389 and sequence number a390; sequence number a34, sequence number a35, sequence number a36, sequence number a394, sequence number a395 and sequence number a396; sequence number a40, sequence number a41, sequence number a42, sequence number a400, sequence number a401 and sequence number a402; sequence number a46, sequence number a47, sequence number a48, Sequence IDs a406, a407 and a408; Sequence IDs a52, a53, a54, a412, a413 and a414; Sequence IDs a58, a59, a60, a418, a419 and a420; Sequence IDs a64, a65, a66, a424, a425 and a426; Sequence IDs a70, a71, a72, a430, a431 and a432; Sequence IDs a76, a 77, Sequence ID a78, Sequence ID a436, Sequence ID a437 and Sequence ID a438; Sequence ID a82, Sequence ID a83, Sequence ID a84, Sequence ID a442, Sequence ID a443 and Sequence ID a444; Sequence ID a88, Sequence ID a89, Sequence ID a90, Sequence ID a448, Sequence ID a449 and Sequence ID a450; Sequence ID a94, Sequence ID a95, Sequence ID a96, Sequence ID a454, Sequence ID a455 and Sequence ID a456; Sequence ID a100, Sequence ID a101, Sequence ID a102, Sequence ID a460, Sequence ID a461 and Sequence ID a462;Sequence ID a106, sequence ID a107, sequence ID a108, sequence ID a466, sequence ID a467 and sequence ID a468; sequence ID a112, sequence ID a113, sequence ID a114, sequence ID a472, sequence ID a473 and sequence ID a474; sequence ID a118, sequence ID a119, sequence ID a120, sequence ID a478, sequence ID a479 and sequence ID a480; sequence ID a124, sequence ID a125, sequence ID a126, sequence ID a484, sequence ID a485 and sequence ID a486; sequence ID a130, sequence ID a131, sequence ID a132, Sequence IDs a490, a491 and a492; sequence IDs a136, a137, a138, a496, a497 and a498; sequence IDs a142, a143, a144, a502, a503 and a504; sequence IDs a148, a149, a150, a508, a509 and a510; sequence IDs a154, a155, a156, a514, a515 and a516; Sequence IDs a160, a161, a162, a520, a521 and a522; sequence IDs a166, a167, a168, a526, a527 and a528; sequence IDs a172, a173, a174, a532, a533 and a534; sequence IDs a178, a179, a180, a538, a539 and a540; sequence IDs a184, a185, a186, Sequence IDs a544, a545 and a546; sequence IDs a190, a191, a192, a550, a551 and a552; sequence IDs a196, a197, a198, a556, a557 and a558; sequence IDs a202, a203, a204, a562, a563 and a564; sequence IDs a208, a209, a210, a568, a569 and a570;Sequence IDs a214, a215, a216, a574, a575 and a576; sequence IDs a220, a221, a222, a580, a581 and a582; sequence IDs a226, a227, a228, a586, a587 and a588; sequence IDs a232, a233, a234, a592, a593 and a594; sequence IDs a238, a239, a240, Sequence IDs a598, a599 and a600; sequence IDs a244, a245, a246, a604, a605 and a606; sequence IDs a250, a251, a252, a610, a611 and a612; sequence IDs a256, a257, a258, a616, a617 and a618, a262, a263, a264, a622, a623 and a624; Sequence IDs a268, a269, a270, a628, a629 and a630; sequence IDs a274, a275, a276, a634, a635 and a636; sequence IDs a280, a281, a282, a640, a641 and a642; sequence IDs a286, a287, a288, a646, a647 and a648; sequence IDs a292, a293, a294, Sequence IDs a652, a653, and a654; Sequence IDs a298, a299, a300, a658, a659, and a660; Sequence IDs a304, a305, a306, a664, a665, and a666; Sequence IDs a310, a311, a312, a670, a671, and a672; Sequence IDs a316, a317, a318, a676, a677, and a678;Sequence IDs a322, a323, a324, a682, a683 and a684; sequence IDs a328, a329, a330, a688, a689 and a690; sequence IDs a334, a335, a336, a694, a695 and a696; sequence IDs a340, a341, a342, a700, a701 and a70 2; Sequence IDs a346, a347, a348, a706, a707 and a708; Sequence IDs a352, a353, a354, a712, a713 and a714; Sequence IDs a358, a359, a360, a718, a719 and a720; Sequence IDs a1290, a1291, a1292, a1293, a1294 and Column number a1295; Sequence numbers a1300, a1301, a1302, a1303, a1304 and a1305; Sequence numbers a1310, a1311, a1312, a1313, a1314 and a1315; Sequence numbers a1320, a1321, a1322, a1323, a1324 and a1325; Sequence numbers a1330, a1331, a1333 32, SEQ ID NO: a1333, a1334 and a1335; SEQ ID NO: a1340, a1341, a1342, a1343, a1344 and a1345; SEQ ID NO: a1350, a1351, a1352, a1353, a1354 and a1355; and SEQ ID NO: a1360, a1361, a1362, a1363, a1364 and a1365; The isolated antigen-binding protein according to claim 6, comprising a sequence selected from the group consisting of the following.

21. The antigen-binding protein is an antibody or a fragment thereof, and the antibody or fragment thereof is sequence numbers a723, a727, a731, a735, a739, a743, a747, a751, a755, a759, a763, a767, a771, a775, a779, a783, a787, a791, a795, a799, a803, a807, a811, a815, a819, a823, a827, a831, a835, a839, a843, a847, a851 A light chain containing a sequence selected from the group consisting of a855, a859, a863, a867, a871, a875, a879, a883, a887, a891, a895, a899, a903, a907, a911, a915, a919, a923, a927, a931, a935, a939, a943, a947, a951, a955, a959, a1286, a1296, a1306, a1316, a1326, a1336, a1346 and a1356. The variable region and sequence numbers a724, a728, a732, a736, a740, a744, a748, a752, a756, a760, a764, a768, a772, a776, a780, a784, a788, a792, a796, a800, a804, a808, a812, a816, a820, a824, a828, a832, a836, a840, a844, a848, a852, a856, a860, a864, a868, a872, a876, An isolated antigen-binding protein according to claim 6, comprising a heavy chain variable region containing a sequence selected from the group consisting of a880, a884, a888, a892, a896, a900, a904, a908, a912, a916, a920, a924, a928, a932, a936, a940, a944, a948, a952, a956, a960, a1287, a1297, a1307, a1317, a1327, a1337, a1347, and a1357.

22. The antigen-binding protein is an antibody or a fragment thereof, and the antibody or fragment thereof comprises a light chain variable region containing SEQ ID NO: a723 and a heavy chain variable region containing SEQ ID NO: a724; a light chain variable region containing SEQ ID NO: a727 and a heavy chain variable region containing SEQ ID NO: a728; a light chain variable region containing SEQ ID NO: a731 and a heavy chain variable region containing SEQ ID NO: a732; a light chain variable region containing SEQ ID NO: a735 and a heavy chain variable region containing SEQ ID NO: a736; a light chain variable region containing SEQ ID NO: a739 and a heavy chain variable region containing SEQ ID NO: a740; a light chain variable region containing SEQ ID NO: a743 and a heavy chain variable region containing SEQ ID NO: a744 Including heavy chain variable region; light chain variable region including SEQ ID NO: a747 and heavy chain variable region including SEQ ID NO: a748; light chain variable region including SEQ ID NO: a751 and heavy chain variable region including SEQ ID NO: a752; light chain variable region including SEQ ID NO: a755 and heavy chain variable region including SEQ ID NO: a756; light chain variable region including SEQ ID NO: a759 and heavy chain variable region including SEQ ID NO: a760; light chain variable region including SEQ ID NO: a763 and heavy chain variable region including SEQ ID NO: a764; light chain variable region including SEQ ID NO: a767 and heavy chain variable region including SEQ ID NO: a768; light chain variable region including SEQ ID NO: a771 and Heavy chain variable region containing SEQ ID NO: a772; light chain variable region containing SEQ ID NO: a775 and heavy chain variable region containing SEQ ID NO: a776; light chain variable region containing SEQ ID NO: a779 and heavy chain variable region containing SEQ ID NO: a780; light chain variable region containing SEQ ID NO: a783 and heavy chain variable region containing SEQ ID NO: a784; light chain variable region containing SEQ ID NO: a787 and heavy chain variable region containing SEQ ID NO: a788; light chain variable region containing SEQ ID NO: a791 and heavy chain variable region containing SEQ ID NO: a792; light chain variable region containing SEQ ID NO: a795 and heavy chain variable region containing SEQ ID NO: a796; SEQ ID NO: a799 A light chain variable region including sequence number a800 and a heavy chain variable region including sequence number a803 and a heavy chain variable region including sequence number a804; a light chain variable region including sequence number a807 and a heavy chain variable region including sequence number a808; a light chain variable region including sequence number a811 and a heavy chain variable region including sequence number a812; a light chain variable region including sequence number a815 and a heavy chain variable region including sequence number a816; a light chain variable region including sequence number a819 and a heavy chain variable region including sequence number a820; a light chain variable region including sequence number a823 and a heavy chain variable region including sequence number a824;Light chain variable region containing sequence number a827 and heavy chain variable region containing sequence number a828; light chain variable region containing sequence number a831 and heavy chain variable region containing sequence number a832; light chain variable region containing sequence number a835 and heavy chain variable region containing sequence number a836; light chain variable region containing sequence number a839 and heavy chain variable region containing sequence number a840; light chain variable region containing sequence number a843 and heavy chain variable region containing sequence number a844; light chain variable region containing sequence number a847 and heavy chain variable region containing sequence number a848; light chain variable region containing sequence number a851 and sequence number a852 Including heavy chain variable region; light chain variable region including SEQ ID NO: a855 and heavy chain variable region including SEQ ID NO: a856; light chain variable region including SEQ ID NO: a859 and heavy chain variable region including SEQ ID NO: a860; light chain variable region including SEQ ID NO: a863 and heavy chain variable region including SEQ ID NO: a864; light chain variable region including SEQ ID NO: a867 and heavy chain variable region including SEQ ID NO: a868; light chain variable region including SEQ ID NO: a871 and heavy chain variable region including SEQ ID NO: a872; and light chain variable region including SEQ ID NO: a875 and heavy chain variable region including SEQ ID NO: a876; light chain variable region including SEQ ID NO: a879 and heavy chain variable region including sequence number a880; light chain variable region including sequence number a883 and heavy chain variable region including sequence number a884; light chain variable region including sequence number a887 and heavy chain variable region including sequence number a888; light chain variable region including sequence number a891 and heavy chain variable region including sequence number a892; light chain variable region including sequence number a895 and heavy chain variable region including sequence number a896; light chain variable region including sequence number a899 and heavy chain variable region including sequence number a900; light chain variable region including sequence number a903 and heavy chain variable region including sequence number a904; sequence number a907 Light chain variable region including a908; light chain variable region including a911 and heavy chain variable region including a912; light chain variable region including a915 and heavy chain variable region including a916; light chain variable region including a919 and heavy chain variable region including a920; light chain variable region including a923 and heavy chain variable region including a924; light chain variable region including a927 and heavy chain variable region including a928; light chain variable region including a931 and heavy chain variable region including a932;Light chain variable region containing SEQ ID NO: a935 and heavy chain variable region containing SEQ ID NO: a936; Light chain variable region containing SEQ ID NO: a939 and heavy chain variable region containing SEQ ID NO: a940; Light chain variable region containing SEQ ID NO: a943 and heavy chain variable region containing SEQ ID NO: a944; Light chain variable region containing SEQ ID NO: a947 and heavy chain variable region containing SEQ ID NO: a948; Light chain variable region containing SEQ ID NO: a951 and heavy chain variable region containing SEQ ID NO: a952; Light chain variable region containing SEQ ID NO: a955 and heavy chain variable region containing SEQ ID NO: a956; Light chain variable region containing SEQ ID NO: a959 and heavy chain variable region containing SEQ ID NO: a960; Light chain variable region containing SEQ ID NO: a1286 and SEQ ID NO: a1 Heavy chain variable region including 287; light chain variable region including SEQ ID NO: a1296 and heavy chain variable region including SEQ ID NO: a1297; light chain variable region including SEQ ID NO: a1306 and heavy chain variable region including SEQ ID NO: a1307; light chain variable region including SEQ ID NO: a1316 and heavy chain variable region including SEQ ID NO: a1317; light chain variable region including SEQ ID NO: a1326 and heavy chain variable region including SEQ ID NO: a1327; light chain variable region including SEQ ID NO: a1336 and heavy chain variable region including SEQ ID NO: a1337; light chain variable region including SEQ ID NO: a1346 and heavy chain variable region including SEQ ID NO: a1347; light chain variable region including SEQ ID NO: a1356 and heavy chain variable region including SEQ ID NO: a1357; The isolated antigen-binding protein according to claim 6, comprising a combination of a light chain variable region and a heavy chain variable region selected from the group consisting of the following.

23. The antigen-binding protein is an antibody, and the antibody is sequence numbers a963, a967, a971, a975, a979, a983, a987, a991, a995, a999, a1003, a1007, a1011, a1015, a1019, a1023, a1027, a1031, a1035, a1039, a1043, a1047, a1051, a1055, a1059, a1063 , a1067, a1071, a1075, a1079, a1083, a1087, a1091, a1095, a1099, a1103, a1107, a1111, a1115, a1119, a1 123, a1127, a1131, a1135, a1139, a1143, a1147, a1151, a1155, a1159, a1163, a1167, a1171, a1175, a1179 A light chain containing a sequence selected from the group consisting of 1183, a1187, a1191, a1195, a1199, a1288, a1298, a1308, a1318, a1328, a1338, a1348 and a1358, and sequence numbers a964, a968, a972, a976, a980, a984, a988, a992, a996, a1000, a1004, a1008, a1012, a1016, a1020, a1024, a1028, a1032, a103 6, a1040, a1044, a1048, a1052, a1056, a1060, a1064, a1068, a1072, a1076, a1080, a 1084, a1088, a1092, a1096, a1100, a1104, a1108, a1112, a1116, a1120, a1124, a11 28, a1132, a1136, a1140, a1144, a1148, a1152, a1156, a1160, a1164, a1168, a1172, The isolated antigen-binding protein according to claim 6, comprising a heavy chain containing a sequence selected from the group consisting of a1176, a1180, a1184, a1188, a1192, a1196, a1200, a1289, a1299, a1309, a1319, a1329, a1339, a1349 and a1359.

24. The antigen-binding protein is an antibody, and the antibody comprises a light chain containing SEQ ID NO: a963 and a heavy chain containing SEQ ID NO: a964; a light chain containing SEQ ID NO: a967 and a heavy chain containing SEQ ID NO: a968; a light chain containing SEQ ID NO: a971 and a heavy chain containing SEQ ID NO: a972; a light chain containing SEQ ID NO: a975 and a heavy chain containing SEQ ID NO: a976; a light chain containing SEQ ID NO: a979 and a heavy chain containing SEQ ID NO: a980; a light chain containing SEQ ID NO: a983 and a heavy chain containing SEQ ID NO: a984; a light chain containing SEQ ID NO: a987 and a heavy chain containing SEQ ID NO: a988; a light chain containing SEQ ID NO: a991 and a heavy chain containing SEQ ID NO: a99 Heavy chain containing 2; light chain containing SEQ ID NO: a995 and heavy chain containing SEQ ID NO: a996; light chain containing SEQ ID NO: a999 and heavy chain containing SEQ ID NO: a1000; light chain containing SEQ ID NO: a1003 and heavy chain containing SEQ ID NO: a1004; light chain containing SEQ ID NO: a1007 and heavy chain containing SEQ ID NO: a1008; light chain containing SEQ ID NO: a1011 and heavy chain containing SEQ ID NO: a1012; light chain containing SEQ ID NO: a1015 and heavy chain containing SEQ ID NO: a1016; light chain containing SEQ ID NO: a1019 and heavy chain containing SEQ ID NO: a1020; light chain containing SEQ ID NO: a1023 and containing SEQ ID NO: a1024 Heavy chain; light chain containing SEQ ID NO: a1027 and heavy chain containing SEQ ID NO: a1028; light chain containing SEQ ID NO: a1031 and heavy chain containing SEQ ID NO: a1032; light chain containing SEQ ID NO: a1035 and heavy chain containing SEQ ID NO: a1036; light chain containing SEQ ID NO: a1039 and heavy chain containing SEQ ID NO: a1040; light chain containing SEQ ID NO: a1043 and heavy chain containing SEQ ID NO: a1044; light chain containing SEQ ID NO: a1047 and heavy chain containing SEQ ID NO: a1048; light chain containing SEQ ID NO: a1051 and heavy chain containing SEQ ID NO: a1052; light chain containing SEQ ID NO: a1055 and heavy chain containing SEQ ID NO: a1056 Chain; light chain containing sequence number a1059 and heavy chain containing sequence number a1060; light chain containing sequence number a1063 and heavy chain containing sequence number a1064; light chain containing sequence number a1067 and heavy chain containing sequence number a1068; light chain containing sequence number a1071 and heavy chain containing sequence number a1072; light chain containing sequence number a1075 and heavy chain containing sequence number a1076; light chain containing sequence number a1079 and heavy chain containing sequence number a1080; light chain containing sequence number a1083 and heavy chain containing sequence number a1084; light chain containing sequence number a1087 and heavy chain containing sequence number a1088;Light chain containing sequence number a1091 and heavy chain containing sequence number a1092; light chain containing sequence number a1095 and heavy chain containing sequence number a1096; light chain containing sequence number a1099 and heavy chain containing sequence number a1100; light chain containing sequence number a1103 and heavy chain containing sequence number a1104; light chain containing sequence number a1107 and heavy chain containing sequence number a1108; light chain containing sequence number a1111 and heavy chain containing sequence number a1112; light chain containing sequence number a1115 and heavy chain containing sequence number a1116; light chain containing sequence number a1119 and heavy chain containing sequence number a1120; Light chain containing sequence number a1123 and heavy chain containing sequence number a1124; light chain containing sequence number a1127 and heavy chain containing sequence number a1128; light chain containing sequence number a1131 and heavy chain containing sequence number a1132; light chain containing sequence number a1135 and heavy chain containing sequence number a1136; light chain containing sequence number a1139 and heavy chain containing sequence number a1140; light chain containing sequence number a1143 and heavy chain containing sequence number a1144; light chain containing sequence number a1147 and heavy chain containing sequence number a1148; light chain containing sequence number a1151 and heavy chain containing sequence number a1152; Light chain containing sequence number a1155 and heavy chain containing sequence number a1156; light chain containing sequence number a1159 and heavy chain containing sequence number a1160; light chain containing sequence number a1163 and heavy chain containing sequence number a1164; light chain containing sequence number a1167 and heavy chain containing sequence number a1168; light chain containing sequence number a1171 and heavy chain containing sequence number a1172; light chain containing sequence number a1175 and heavy chain containing sequence number a1176; light chain containing sequence number a1179 and heavy chain containing sequence number a1180; light chain containing sequence number a1183 and heavy chain containing sequence number a1184; Light chain containing sequence number a1187 and heavy chain containing sequence number a1188; light chain containing sequence number a1191 and heavy chain containing sequence number a1192; light chain containing sequence number a1195 and heavy chain containing sequence number a1196; light chain containing sequence number a1199 and heavy chain containing sequence number a1200; light chain containing sequence number a1288 and heavy chain containing sequence number a1289; light chain containing sequence number a1298 and heavy chain containing sequence number a1299; light chain containing sequence number a1308 and heavy chain containing sequence number a1309; light chain containing sequence number a1318 and heavy chain containing sequence number a1319;Light chain containing SEQ ID NO: a1328 and heavy chain containing SEQ ID NO: a1329; Light chain containing SEQ ID NO: a1338 and heavy chain containing SEQ ID NO: a1339; Light chain containing SEQ ID NO: a1348 and heavy chain containing SEQ ID NO: a1349; Light chain containing SEQ ID NO: a1358 and heavy chain containing SEQ ID NO: a1359; The isolated antigen-binding protein according to claim 6, comprising a combination of light chains and heavy chains selected from the group consisting of the following.

Images