Anti-GLP1R antibody-tethered drug conjugates containing GLP1 peptide mimetics and uses thereof

Abstract

The present invention provides antibody-tethered drug conjugates (ATDCs) and compositions thereof that target, for example, the Glucagon-like peptide 1 receptor (GLP1R) and are useful for treating various diseases, for example diabetes. Methods of making such ATDCs are also provided, along with methods of their use.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 319,175, filed March 11, 2022, which is incorporated by reference in its entirety.

[0002] Field of Disclosure The present disclosure relates to antibody-tethered drug conjugates, pharmaceutical compositions, and methods of using same to treat GLP1R-related diseases. [Background technology]

[0003] Diabetes is a chronic disease of abnormal glucose metabolism. It is estimated that 425 million people worldwide are living with diabetes. Global antidiabetic medications include insulin, DPP-4 inhibitors, and glucagon-like peptide 1 receptor (GLP1R) agonists, but in the majority of patients, the combined treatments fail to achieve the goal of managing hyperglycemia and risk factors for cardiovascular disease.

[0004] The glucagon-like peptide 1 receptor (GLP1R) is the receptor for glucagon-like peptide 1 (GLP1) and is expressed in pancreatic β-cells. GLP1R is also expressed in the brain and functions in the control of appetite, memory, and learning. GLP1R is a member of the secretin family (class B) of G protein-coupled receptors (GPCRs). Upon binding of its ligand GLP1, GLP1R initiates a downstream signaling cascade via Gαs G proteins that elevate intracellular cyclic AMP (cAMP) levels leading to transcriptional regulation of genes (Donnelly 2011). Activation of GLP1R results in increased insulin synthesis and insulin release.

[0005] GLP1R and GLP1 are well-validated targets in obesity and type 2 diabetes. Commercially available GLP1R agonists increase insulin secretion, thereby lowering blood glucose levels, but require weekly or more frequent dosing.

[0006] Thus, there is a need in the art for GLP1R agonists that have long duration and good safety. In certain embodiments, the present disclosure meets this need and provides other advantages.

[0007] The preceding discussion has been presented solely to provide a better understanding of the nature of the problems facing the art and should not be construed as an admission of prior art in any manner, nor should the citation of any reference herein be construed as an admission that such reference constitutes "prior art" to the instant application. Summary of the Invention

[0008] Various non-limiting aspects and embodiments of the disclosure are described below.

[0009] The present invention relates to a compound of formula (A): BA-(LP) m (A) or a pharma- ceutically acceptable salt thereof, wherein: The BA is an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, and the antibody or antigen-binding fragment thereof can be, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) an antibody or antigen-binding fragment thereof that binds to the same epitope of GLP1R as the antibody or fragment of (i); L is a non-cleavable linker, Optionally, the heavy chain immunoglobulin of the BA does not include a C-terminal lysine or lysine and glycine; P is

[0010] [ka] A payload having a structure selected from the group consisting of:

[0011] [ka] is the point where the payload attaches to L, X 1 H,

[0012] [ka] is selected from X 2 teeth,

[0013] [ka] is selected from X 3 is a bond, -(CH 2 ) 2-6 -NH-, -(CH 2 ) 2-6 -Tr-, and -(CH 2 ) 2-6 -Tr-(CH 2 ) 1-6 -NH, where Tr is a triazole moiety; n is 0 or 1, X 4 is -NH 2 , -OH, and -N(H)(phenyl); X 5 -OH, -NH 2 , -NH-OH, and

[0014] [ka] is selected from X 6 represents H, -OH, -CH at each occurrence. 3 , and -CH 2 OH, X 7 H,

[0015] [ka] is selected from X 8 H, -OH, -NH2 , and

[0016] [ka] is selected from Ar is

[0017] [ka] is selected from X 9 is -NH 2 ,

[0018] [ka] is selected from and m is an integer of 1 to 4, or a pharma- ceutically acceptable salt thereof.

[0019] The present invention also relates to a compound of formula (I): BA-LP (I) or a pharma- ceutically acceptable salt thereof, wherein: The BA is an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, and the antibody or antigen-binding fragment thereof can be, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) an antibody or antigen-binding fragment thereof that binds to the same epitope of GLP1R as the antibody or fragment of (i); L is a non-cleavable linker, Optionally, the heavy chain immunoglobulin of the BA does not include a C-terminal lysine or lysine and glycine; P is

[0020] [ka] A payload having a structure selected from the group consisting of:

[0021] [ka] is the point where payload P attaches to L, X 1 H,

[0022] [ka] is selected from X 2 teeth,

[0023] [ka] is selected from X 3 is -(CH 2 ) 2-6 -NH- and -(CH 2 ) 2-6 -Tr-, where Tr is a triazole moiety; n is 0 or 1, X 4 is selected from H and phenyl; X 5 -OH, -NH 2 , -NH-OH, and

[0024] [ka] is selected from X 6 represents H, -OH, -CH at each occurrence. 3 , and -CH 2 OH, X 7 H,

[0025] [ka] is selected from X 8 is H, -OH, -NH 2 , and

[0026] [ka] The present invention provides ATDC, or a pharma- ceutically acceptable salt thereof, selected from:

[0027] In some embodiments of the invention, the BA of the ATDC is an antibody that specifically binds to GLP1R, or an antigen-binding fragment thereof, which is antibody 5A10, 9A10, AB9433-I, h38C2, PA5-111834, NLS1205, MAB2814, EPR21819, or glutazumab.

[0028] In some embodiments, the linker L is attached to one or both heavy chains of the BA. In some embodiments, the linker L is attached to one or both heavy chain variable domains of the BA. In some embodiments, the linker L is attached to one or both light chains of the BA. In some embodiments, the linker L is attached to one or both light chain variable domains of the BA.

[0029] In some embodiments of the present invention, the linker L is linked to the BA via a glutamine residue of the BA. In some embodiments, the glutamine residue is introduced into the N-terminus of one or both heavy chains of the BA. In some embodiments of the present invention, the glutamine residue is introduced into the N-terminus of one or both light chains of the BA. In some embodiments of the present invention, the glutamine residue is naturally present in the CH2 domain or CH3 domain of the BA. In some embodiments of the present invention, the glutamine residue is introduced into the BA by modifying one or more amino acids. In some embodiments of the present invention, the glutamine residue is Q295 or N297Q.

[0030] In some embodiments of the invention, the linker L is attached to the BA via a lysine residue.

[0031] In some embodiments, the heavy chain immunoglobulin of the BA does not contain a C-terminal lysine or lysine and glycine. In some embodiments, the heavy chain immunoglobulin of the BA does not contain a C-terminal lysine. In some embodiments, the heavy chain immunoglobulin does not contain a C-terminal lysine and glycine. Heavy chain immunoglobulins that do not contain a C-terminal lysine and glycine also refer to heavy chain immunoglobulins that do not contain lysine or glycine at the C-terminus.

[0032] In some embodiments of the invention, the antibody or antigen-binding fragment thereof is aglycosylated. In some embodiments of the invention, the antibody or antigen-binding fragment thereof is deglycosylated. In some embodiments of the invention, the antigen-binding fragment is a Fab fragment.

[0033] In one embodiment of the present invention, m is 1. In one embodiment, m is an integer from 2 to 4. In one embodiment of the present invention, m is 2.

[0034] In some embodiments of the invention, more than one LP is attached to the BA, hi some embodiments, two LPs are attached to the BA.

[0035] In some embodiments, the linker L has the formula (L'): -La-Y-Lp- (L') wherein La is a first linker covalently attached to BA; Y is a triazole-containing group; L p is absent or is a second linker covalently attached to P, and if Lp is absent then Y is also absent.

[0036] In some embodiments, Y is

[0037] [ka] wherein Q is C or N.

[0038] In some embodiments of the invention, Lp is 1 to 36 -CH 2 CH 2 The PEG segment comprises a polyethylene glycol (PEG) segment having an O-(EG) unit. In some embodiments of the invention, the PEG segment comprises between 2 and 30 EG units. In some embodiments of the invention, the PEG segment comprises between 4 and 24 EG units. In some embodiments of the invention, the PEG segment comprises 4 EG units, 8 EG units, or 12 EG units, or 24 EG units. In some embodiments of the invention, the PEG segment comprises 4 EG units. In some embodiments, the PEG segment comprises 8 EG units.

[0039] In some embodiments, Y-Lp is

[0040] [ka] or a triazole positional isomer thereof, where p is an integer from 1 to 36.

[0041] In some embodiments of the invention, Lp comprises one or more amino acids selected from glycine, serine, glutamic acid, alanine, valine, and proline, and combinations thereof. In some embodiments, Lp comprises 1-10 glycines. In some embodiments, Lp comprises 1-6 serines. In some embodiments of the invention, Lp comprises 1-10 glycines and 1-6 serines. In some embodiments of the invention, Lp comprises 4 glycines and 1 serine. In some embodiments of the invention, Lp comprises Gly-Gly-Gly-Gly-Ser (Gly-Gly-Gly-Gly-Ser). 4 S) (SEQ ID NO: 1), Ser-Gly-Gly-Gly-Gly (SG 4 ) (SEQ ID NO: 2), and Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser (G 4 SG 4 S) (SEQ ID NO:3).

[0042] In some embodiments of the invention, Lp comprises a PEG segment having 1-36 EG units in combination with one or more amino acids selected from glycine, serine, glutamic acid, alanine, valine, and proline, and combinations thereof. In some embodiments of the invention, the serine residue comprises a carbohydrate group. In some embodiments of the invention, the serine residue comprises a glucose group.

[0043] In some embodiments of the invention, Lp is

[0044] [ka] wherein Y is a triazole-containing group, P is a payload, Rc is selected from H and glucose, g is an integer from 1 to 10, and s is an integer from 0 to 4.

[0045] In some embodiments, Y-Lp is

[0046] [ka]

[0047] [ka] or a triazole positional isomer thereof.

[0048] In some embodiments of the present invention, La is 1 to 36 -CH 2 CH 2 In some embodiments of the invention, the PEG segment comprises 4 EG units, 8 EG units, or 12 EG units, or 24 EG units. In some embodiments, the PEG segment comprises 8 EG units. In some embodiments of the invention, La is

[0049] [ka] The compound has a structure selected from the group consisting of:

[0050] In some embodiments of the invention, La comprises one or more amino acids selected from glycine, threonine, serine, glutamine, glutamic acid, alanine, valine, leucine, and proline, and combinations thereof. In some embodiments of the invention, La comprises 1-10 glycines and 1-6 serines. In some embodiments of the invention, La comprises 4 glycines and 1 serine. In some embodiments of the invention, La comprises Gly-Gly-Gly-Gly-Ser (Gly-Gly-Gly-Gly-Ser). 4 S), Ser-Gly-Gly-Gly-Gly (SG 4 ), Gly-Gly-Ser-Gly-Gly-Ser-Gly-Gly(G 2 SG 2 SG 2 ), and Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly (G 4 SG 4 ).

[0051] In some embodiments of the invention, La comprises a PEG segment having 1-36 EG units in combination with one or more amino acids selected from glycine, threonine, serine, glutamine, glutamic acid, alanine, valine, leucine, and proline, and combinations thereof.

[0052] [ka] is selected from the group consisting of:

[0053] In some embodiments of the present invention, La is -(CH 2 ) 2-24In some embodiments, La comprises a -(CH 2 ) 2-24 La comprises a combination of a -chain, a PEG segment having 1 to 36 EG units, and one or more amino acids selected from glycine, threonine, serine, glutamine, glutamic acid, alanine, valine, leucine, and proline, and combinations thereof.

[0054] [ka] is selected from the group consisting of:

[0055] In various embodiments of the present invention, P is

[0056] [ka] It has the structure:

[0057] In some embodiments of the present invention, X 1 is H and X 2 teeth,

[0058] [ka] and X 3 is -(CH 2 ) 2-6 -NH- and -(CH 2 ) 2-6 -Tr-, where Tr is a triazole moiety, n is 1, and X 4 is H.

[0059] In some embodiments of the present invention, X 1 teeth,

[0060] [ka] and X 2 teeth,

[0061] [ka] and X 3 is -(CH 2 ) 2-6 -NH-, n is 1, and X 4 is H and X 5 -OH, -NH 2 , -NH-OH, and

[0062] [ka] is selected from.

[0063] In some embodiments of the present invention, X 1 teeth,

[0064] [ka] and X 2 teeth,

[0065] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, n is 1, and X 4 is H.

[0066] In some embodiments of the present invention, X 1 teeth,

[0067] [ka] and X 2 teeth,

[0068] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, n is 1, and X4 is H and X 6 independently at each occurrence, H and -CH 2 OH, X 7 is H.

[0069] In some embodiments of the present invention, X 1 teeth,

[0070] [ka] and X 2 teeth,

[0071] [ka] and X 3 Ha-(CH 2 ) 2-6 -Tr-, where Tr is a triazole moiety, n is 1, and X 4 is H and X 5 teeth,

[0072] [ka] It is.

[0073] In some embodiments of the present invention, X 1 teeth,

[0074] [ka] and X 2 teeth,

[0075] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, n is 1, and X 4 is H and X 6 independently at each occurrence, H and -CH 3Selected from X 7 teeth,

[0076] [ka] and X 8 Ha-NH 2 It is.

[0077] In some embodiments of the present invention, X 1 teeth,

[0078] [ka] and X 2 teeth,

[0079] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, n is 1, and X 4 is H and X 8 is H.

[0080] In some embodiments of the present invention, X 1 teeth,

[0081] [ka] and X 2 teeth,

[0082] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, n is 1, and X 4 is H and X 6 is H at each occurrence, and X 7 teeth

[0083] [ka] and X 8 is H.

[0084] In some embodiments of the present invention, X 1 teeth,

[0085] [ka] and X 2 teeth,

[0086] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, n is 1, and X 4 is H and X 6 independently at each occurrence, H and -CH 3 Selected from X 7 teeth,

[0087] [ka] and X 8 teeth,

[0088] [ka] It is.

[0089] In some embodiments of the present invention, X 1 teeth,

[0090] [ka] and X 2 teeth,

[0091] [ka] and X 3Ha-(CH 2 ) 2-6 -NH-, n is 1, and X 4 is H.

[0092] In some embodiments of the present invention, X 1 teeth,

[0093] [ka] and X 2 teeth,

[0094] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, n is 1, and X 4 is H.

[0095] In some embodiments of the present invention, X 1 teeth,

[0096] [ka] and X 2 teeth,

[0097] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, n is 1, and X 4 is H and X 6 independently at each occurrence, H and -CH 3 Selected from X 7 teeth,

[0098] [ka] It is.

[0099] In some embodiments of the present invention, X 1 is H and X 2 teeth,

[0100] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, n is 1, and X 4 is H.

[0101] In some embodiments of the present invention, X 1 teeth,

[0102] [ka] and X 2 teeth,

[0103] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, n is 1, and X 4 is H and X 5 teeth,

[0104] [ka] It is.

[0105] In some embodiments of the present invention, X 1 teeth,

[0106] [ka] and X 2 teeth,

[0107] [ka] and X 3Ha-(CH 2 ) 2-6 -NH-, n is 0, and X 4 is phenyl, and X 5 teeth,

[0108] [ka] It is.

[0109] In some embodiments of the present invention, X 1 teeth,

[0110] [ka] and X 2 teeth,

[0111] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, n is 1, and X 4 is phenyl, and X 5 teeth,

[0112] [ka] It is.

[0113] In various embodiments of the present invention, P is

[0114] [ka] It has the structure:

[0115] In some embodiments of the present invention, X 1 teeth,

[0116] [ka] and X 2teeth,

[0117] [ka] and X 3 Ha-(CH 2 ) 2-6 -NH-, X 4 is H and X 5 teeth,

[0118] [ka] It is.

[0119] In various embodiments of the present invention, P is

[0120] [ka]

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] [ka] The compound has a structure selected from the group consisting of:

[0127] In various embodiments of the invention, the ATDC of the invention has a plasma half-life of greater than 7 days.

[0128] In various embodiments of the present invention, the ATDCs of the present invention do not bind to G protein-coupled receptors (GPCRs) other than GLP1R.

[0129] In another aspect of the invention, there is provided herein a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof, or an ATDC, wherein at least about 80% of the antibody or antigen-binding fragment thereof, or the ATDC does not contain a C-terminal lysine, or lysine and glycine, in any heavy chain.

[0130] In some embodiments, the antibody or antigen-binding fragment thereof or the ATDC does not contain a C-terminal lysine. In some embodiments, the antibody or antigen-binding fragment thereof or the ATDC does not contain a C-terminal lysine and glycine.

[0131] In one embodiment of the invention, the pharmaceutical composition comprises an antibody or antigen-binding fragment thereof, or an ATDC, wherein at least about 90% of the antibody or antigen-binding fragment thereof or the ATDC does not contain a C-terminal lysine or lysine and glycine in any heavy chain.

[0132] In one embodiment of the invention, the pharmaceutical composition comprises an antibody or antigen-binding fragment thereof, or an ATDC, wherein about 90% of the antibody or antigen-binding fragment thereof, or the ATDC does not contain a C-terminal lysine or lysine and glycine in any heavy chain.

[0133] In one embodiment of the invention, the pharmaceutical composition comprises an antibody or antigen-binding fragment thereof, or an ATDC, wherein at least about 95% of the antibody or antigen-binding fragment thereof or the ATDC does not contain a C-terminal lysine or lysine and glycine in any heavy chain.

[0134] In one embodiment of the invention, the pharmaceutical composition comprises an antibody or antigen-binding fragment thereof, or an ATDC, wherein at least about 99% of the antibody or antigen-binding fragment thereof or the ATDC does not contain a C-terminal lysine or lysine and glycine in any heavy chain.

[0135] In one embodiment of the invention, the aforementioned heavy chain immunoglobulin that does not contain a C-terminal lysine comprises the amino acid sequence set forth in SEQ ID NO: 414 or 416 or a variant thereof.

[0136] In one embodiment of the invention, the pharmaceutical composition comprises an antibody or antigen-binding fragment thereof, or an ATDC, wherein less than about 20% of the antibody or antigen-binding fragment or ATDC comprises a C-terminal lysine or lysine and glycine in at least one heavy chain.

[0137] In one embodiment of the invention, the pharmaceutical composition comprises an antibody or antigen-binding fragment thereof, or an ATDC, wherein less than about 10% of the antibodies or antigen-binding fragments or ATDCs comprise a C-terminal lysine or lysine and glycine in at least one heavy chain.

[0138] In one embodiment of the invention, the pharmaceutical composition comprises antibodies or antigen-binding fragments thereof, or ATDCs, wherein about 10% of the antibodies or antigen-binding fragments or ATDCs comprise a C-terminal lysine or lysine and glycine in at least one heavy chain.

[0139] In one embodiment of the invention, the pharmaceutical composition comprises an antibody or antigen-binding fragment thereof, or an ATDC, wherein less than about 5% of the antibodies or antigen-binding fragments or ATDCs comprise a C-terminal lysine or lysine and glycine in at least one heavy chain.

[0140] In one embodiment of the invention, the pharmaceutical composition comprises an antibody or antigen-binding fragment thereof, or an ATDC, wherein less than about 1% of the antibodies or antigen-binding fragments or ATDCs comprise a C-terminal lysine or lysine and glycine in at least one heavy chain.

[0141] In one embodiment of the invention, the pharmaceutical composition comprises antibodies or antigen-binding fragments thereof, or ATDCs, wherein about 10% of the antibodies or antigen-binding fragments or ATDCs comprise a C-terminal lysine or lysine and glycine in at least one heavy chain.

[0142] In one embodiment of the invention, at least one heavy chain comprising a C-terminal lysine or lysine and glycine as described above comprises an amino acid sequence set forth in SEQ ID NO: 42, 62, 82, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof.

[0143] In some embodiments of the invention, at least one heavy chain comprising said C-terminal lysine comprises the amino acid sequence set forth in SEQ ID NO:82.

[0144] In another aspect of the invention, there is provided herein a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, or ATDC, and a pharma- ceutically acceptable carrier.

[0145] In another aspect of the invention, there is provided herein a pharmaceutical dosage form comprising an antibody or antigen-binding fragment thereof or an ATDC as described herein.

[0146] In one embodiment of the invention, an antibody or antigen-binding fragment thereof that specifically binds to GLP1R (e.g., a BA of ATDC as described herein) has (a) at least 90% amino acid sequence identity to an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411. and / or (b) a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413. In some embodiments, the heavy chain immunoglobulin does not include a C-terminal lysine or lysine and glycine.

[0147] In one embodiment of the invention, an antibody or antigen-binding fragment thereof that specifically binds to GLP1R (e.g., a BA of the ATDC described herein) is (a) set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411. CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or variable region thereof comprising an amino acid sequence, and at least one amino acid sequence as set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411. (b) a heavy chain immunoglobulin or a variable region thereof, comprising an amino acid sequence having 90% amino acid sequence identity thereto; and (b) a light chain immunoglobulin or a variable region thereof, comprising an amino acid sequence set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, and a light chain immunoglobulin or variable region thereof comprising L1, CDR-L2, and CDR-L3, and at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413. In some embodiments, the heavy chain immunoglobulin comprisesIn one embodiment of the present invention, an antibody or antigen-binding fragment thereof that specifically binds to GLP1R (e.g., BA of the ATDC described herein) comprises: (i) a CDR-H1 comprising an amino acid sequence set forth in SEQ ID NO:28 or a variant thereof, a CDR-H2 comprising an amino acid sequence set forth in SEQ ID NO:30 or a variant thereof, a CDR-H3 comprising an amino acid sequence set forth in SEQ ID NO:32 or a variant thereof, (ii) a CDR-H1 comprising an amino acid sequence set forth in SEQ ID NO:48 or a variant thereof, a CDR-H2 comprising an amino acid sequence set forth in SEQ ID NO:50 or a variant thereof, a CDR-H3 comprising an amino acid sequence set forth in SEQ ID NO:52 or a variant thereof, (iii) a CDR-H1 comprising an amino acid sequence set forth in SEQ ID NO:68 or a variant thereof, a CDR-H2 comprising an amino acid sequence set forth in SEQ ID NO:70 or a variant thereof, a CDR-H3 comprising an amino acid sequence set forth in SEQ ID NO:72 or a variant thereof, (iv) a CDR-H1 comprising an amino acid sequence set forth in SEQ ID NO:88 or a variant thereof, a CDR-H2 comprising an amino acid sequence set forth in SEQ ID NO:90 or a variant thereof. CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 92 or a variant thereof; (v) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 108 or a variant thereof; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 110 or a variant thereof; CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 112 or a variant thereof; (vi) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 128 or a variant thereof; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 130 or a variant thereof; CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 132 or a variant thereof; (vii) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 148 or a variant thereof; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 150 or a variant thereof; CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 152 or a variant thereof; (viii) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 168 or a variant thereof; CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 170 or a variant thereof;(ix) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 189 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 191 or a variant thereof, CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 193 or a variant thereof, (x) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 209 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 211 or a variant thereof, CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 213 or a variant thereof, (xi) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 229 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a variant thereof, CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 233 or a variant thereof, (xii) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 249 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 251 or a variant thereof, CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 253 or a variant thereof (xiii) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 277 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 279 or a variant thereof, CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 281 or a variant thereof, (xiv) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 297 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 299 or a variant thereof, CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 301 or a variant thereof, (xv) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 317 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 319 or a variant thereof, CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 321 or a variant thereof, (xvi) CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 337 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 339 or a variant thereof, CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 341 or a variant thereof,(xvii) a heavy chain immunoglobulin or a variable region thereof, comprising: a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 357 or a variant thereof, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 359 or a variant thereof, a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 361 or a variant thereof, and / or (xviii) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 377 or a variant thereof, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 379 or a variant thereof, a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 381 or a variant thereof, (xix) a heavy chain immunoglobulin or a variable region thereof, comprising: a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 397 or a variant thereof, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 399 or a variant thereof, a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 401 or a variant thereof, and / or (a) a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 36 or a variant thereof, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 38 or a variant thereof, a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 40 (b) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 56 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 58 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 60 or a variant thereof, (c) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 76 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 78 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 80 or a variant thereof, (d) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 96 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 98 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 100 or a variant thereof, (e) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 116 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 118 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 120 or a variant thereof,(f) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 136 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 138 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 140 or a variant thereof, (g) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 156 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 158 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 160 or a variant thereof, (h) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 176 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 178 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 180 or a variant thereof, (i) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 197 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 199 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 201 or a variant thereof, (j) the amino acid sequence set forth in SEQ ID NO: 217 or a variant thereof, CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 219 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 221 or a variant thereof, (k) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 237 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 239 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 241 or a variant thereof, (l) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 257 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 259 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 261 or a variant thereof, (m) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 285 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 287 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 289 or a variant thereof, (n) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 305 or a variant thereof,CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 307 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 309 or a variant thereof, (o) CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 325 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 327 or a variant thereof, CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 329 or a variant thereof, (p) a sequence, The light chain immunoglobulin or its variable region includes a light chain immunoglobulin or its variable region, comprising: (q) CDR-L1 comprising an amino acid sequence as set forth in SEQ ID NO: 365 or a variant thereof; (r) CDR-L1 comprising an amino acid sequence as set forth in SEQ ID NO: 385 or a variant thereof; (r) CDR-L2 comprising an amino acid sequence as set forth in SEQ ID NO: 387 or a variant thereof; (s) CDR-L1 comprising an amino acid sequence as set forth in SEQ ID NO: 405 or a variant thereof; (s) CDR-L2 comprising an amino acid sequence as set forth in SEQ ID NO: 407 or a variant thereof; and (s) CDR-L3 comprising an amino acid sequence as set forth in SEQ ID NO: 409 or a variant thereof. In one embodiment of the present invention, an antibody or antigen-binding fragment thereof that specifically binds to GLP1R (e.g., BA of the ATDC described herein) is selected from the group consisting of: (1) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 28 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 30 or a variant thereof, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 36 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 38 or a variant thereof, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 40 or a variant thereof; (2) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 48 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 50 or a variant thereof, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 52, and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 36 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 38 or a variant thereof, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 40 or a variant thereof; (3) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1 having an amino acid sequence as set forth in SEQ ID NO: 68 or a variant thereof, CDR-H2 having an amino acid sequence as set forth in SEQ ID NO: 70 or a variant thereof, and CDR-H3 having an amino acid sequence as set forth in SEQ ID NO: 72, and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 having an amino acid sequence as set forth in SEQ ID NO: 76 or a variant thereof, CDR-L2 having an amino acid sequence as set forth in SEQ ID NO: 78 or a variant thereof, and CDR-L3 having an amino acid sequence as set forth in SEQ ID NO: 80 or a variant thereof; (4) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1 having an amino acid sequence as set forth in SEQ ID NO: 88 or a variant thereof, CDR-H2 having an amino acid sequence as set forth in SEQ ID NO: 90 or a variant thereof, and CDR-H3 having an amino acid sequence as set forth in SEQ ID NO: 92;and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 having the amino acid sequence set forth in SEQ ID NO: 96 or a variant thereof, CDR-L2 having the amino acid sequence set forth in SEQ ID NO: 98 or a variant thereof, and CDR-L3 having the amino acid sequence set forth in SEQ ID NO: 100 or a variant thereof; (5) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 108 or a variant thereof, CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 110 or a variant thereof, and CDR-H3 having the amino acid sequence set forth in SEQ ID NO: 112, and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 having the amino acid sequence set forth in SEQ ID NO: 116 or a variant thereof, CDR-L2 having the amino acid sequence set forth in SEQ ID NO: 118 or a variant thereof, and CDR-L3 having the amino acid sequence set forth in SEQ ID NO: 120 or a variant thereof; (6) a CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 128 or a variant thereof, CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 130 or a variant thereof, and CDR-L3 having the amino acid sequence set forth in SEQ ID NO: 133 or a variant thereof; 2, and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 having an amino acid sequence as set forth in SEQ ID NO: 136 or a variant thereof, CDR-L2 having an amino acid sequence as set forth in SEQ ID NO: 138 or a variant thereof, and CDR-L3 having an amino acid sequence as set forth in SEQ ID NO: 140 or a variant thereof; (7) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1 having an amino acid sequence as set forth in SEQ ID NO: 148 or a variant thereof, CDR-H2 having an amino acid sequence as set forth in SEQ ID NO: 150 or a variant thereof, and CDR-H3 having an amino acid sequence as set forth in SEQ ID NO: 152, and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 having an amino acid sequence as set forth in SEQ ID NO: 156 or a variant thereof, CDR-L2 having an amino acid sequence as set forth in SEQ ID NO: 158 or a variant thereof, and CDR-L3 having an amino acid sequence as set forth in SEQ ID NO: 160 or a variant thereof; (8) a CDR-H1 having an amino acid sequence as set forth in SEQ ID NO: 168 or a variant thereof;A heavy chain immunoglobulin or a variable region thereof, comprising CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 170 or a variant thereof, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 172, and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 176 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 178 or a variant thereof, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 180 or a variant thereof; (9) A heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 189 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 191 or a variant thereof, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 193 or a variant thereof, and a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 197 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 199 or a variant thereof, and CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 201 or a variant thereof. 3, (10) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 209 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 211 or a variant thereof, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 213 or a variant thereof, and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 217 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 219 or a variant thereof, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 221 or a variant thereof, (11) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 229 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a variant thereof, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 233 or a variant thereof, and CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 237 or a variant thereof,(12) a light chain immunoglobulin or a variable region thereof, comprising CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 239 or a variant thereof, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 241 or a variant thereof; (13) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 249 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 251 or a variant thereof, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 253 or a variant thereof, and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 257 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 259 or a variant thereof, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 261 or a variant thereof; (14) a light chain immunoglobulin or a variable region thereof, comprising CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 277 or a variant thereof, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 279 or a variant thereof, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 281 or a variant thereof; A light chain immunoglobulin or a variable region thereof, comprising a heavy chain immunoglobulin or a variable region thereof, including CDR-H3, and a CDR-L1 having an amino acid sequence set forth in SEQ ID NO: 285 or a variant thereof, a CDR-L2 having an amino acid sequence set forth in SEQ ID NO: 287 or a variant thereof, and a CDR-L3 having an amino acid sequence set forth in SEQ ID NO: 289 or a variant thereof; (14) A heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1 having an amino acid sequence set forth in SEQ ID NO: 297 or a variant thereof, a CDR-H2 having an amino acid sequence set forth in SEQ ID NO: 299 or a variant thereof, and a CDR-H3 having an amino acid sequence set forth in SEQ ID NO: 301 or a variant thereof, and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 having an amino acid sequence set forth in SEQ ID NO: 305 or a variant thereof, a CDR-L2 having an amino acid sequence set forth in SEQ ID NO: 307 or a variant thereof, and a CDR-L3 having an amino acid sequence set forth in SEQ ID NO: 309 or a variant thereof; (15) A CDR-H1 having an amino acid sequence set forth in SEQ ID NO: 317 or a variant thereof;(16) A heavy chain immunoglobulin or a variable region thereof, comprising a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 319 or a variant thereof, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 321 or a variant thereof, and a light chain immunoglobulin or a variable region thereof, comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 325 or a variant thereof, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 327 or a variant thereof, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 329 or a variant thereof; (17) A heavy chain immunoglobulin or a variable region thereof, comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 337 or a variant thereof, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 339 or a variant thereof, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 341 or a variant thereof, and a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 345 or a variant thereof, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 347 or a variant thereof, and a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 349 or a variant thereof. (17) A light chain immunoglobulin or a variable region thereof, comprising a CDR-H1 having an amino acid sequence as set forth in SEQ ID NO: 357 or a variant thereof, a CDR-H2 having an amino acid sequence as set forth in SEQ ID NO: 359 or a variant thereof, and a CDR-H3 having an amino acid sequence as set forth in SEQ ID NO: 361 or a variant thereof, and a light chain immunoglobulin or a variable region thereof, comprising a CDR-L1 having an amino acid sequence as set forth in SEQ ID NO: 365 or a variant thereof, a CDR-L2 having an amino acid sequence as set forth in SEQ ID NO: 367 or a variant thereof, and a CDR-L3 having an amino acid sequence as set forth in SEQ ID NO: 369 or a variant thereof; (18) A heavy chain immunoglobulin or a variable region thereof, comprising a CDR-H1 having an amino acid sequence as set forth in SEQ ID NO: 377 or a variant thereof, a CDR-H2 having an amino acid sequence as set forth in SEQ ID NO: 379 or a variant thereof, and a CDR-H3 having an amino acid sequence as set forth in SEQ ID NO: 381 or a variant thereof, and a CDR-L1 having an amino acid sequence as set forth in SEQ ID NO: 385 or a variant thereof;A light chain immunoglobulin or a variable region thereof, comprising CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 387 or a variant thereof, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 389 or a variant thereof; or (19) a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 397 or a variant thereof, the amino acid sequence set forth in SEQ ID NO: 399; and a light chain immunoglobulin or a variable region thereof, comprising CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 405 or a variant thereof, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 407 or a variant thereof, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 409 or a variant thereof. In one embodiment of the invention, an antibody or antigen-binding fragment thereof that specifically binds to GLP1R (e.g., a BA of ATDC as described herein) has (a) an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411. or a variant thereof, and / or (b) a light chain immunoglobulin or a variable region thereof comprising the amino acid sequence set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof. In some embodiments, the heavy chain immunoglobulin does not include a C-terminal lysine or lysine and glycine. In one embodiment of the invention, an antibody or antigen-binding fragment thereof that specifically binds to GLP1R (e.g., a BA of the ATDC described herein) comprises: (a) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 26 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 34; (b) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 46 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 54; (c) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 66 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 74; (d) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 86 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 94; (e) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 106 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 114; (f) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 126 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 134, (g) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 146 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 154, (h) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 166 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 174, (i) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 187 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 195, (j) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 207 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 215, (k) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 227 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 235, (l) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 247 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 255,(m) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 275 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 283; (n) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 295 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 303; (o) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 315 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 323; (p) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 335 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 340; No. 343, (q) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 355 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 363, (r) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 375 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 383, and / or (s) a heavy chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 395 and a light chain immunoglobulin variable region comprising the amino acid sequence set forth in SEQ ID NO: 403. In one embodiment of the invention, an antibody or antigen-binding fragment thereof that specifically binds to GLP1R (e.g., a BA of the ATDC described herein) is selected from the group consisting of: (a) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 42 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 44; (b) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 62 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 64; (c) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 82 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 84; (d) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 102 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 104; (e) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 122 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 124; (f) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 142 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 144;(g) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 162 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 164; (h) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 182 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 184; (i) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 203 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 205; (j) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 223 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 225; (k) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 243 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 245; (l) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 263 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 265; (m) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 267 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 269; (n) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 271 and The present invention includes a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 273, (o) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 291 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 293, (p) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 311 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 313, (q) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 331 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 333, (r) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 351 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 353, (s) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 371 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 373, (t) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 391 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 393, or (u) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 411 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 413.The present invention provides an antibody-tethered drug conjugate comprising a glucagon-like peptide-1 receptor (GLP1R) targeting antibody or antigen-binding fragment thereof, the GLP1R targeting antibody or antigen-binding fragment thereof comprising: (a) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 42 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 44; (b) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 62 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 64; (c) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 82 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 84; (d) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 102 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 104; (e) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 122 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 124; (f) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 142 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 144; (g) an immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 162. (h) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 182 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 184; (i) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 203 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 205; (j) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 223 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 225; (k) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 243 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 245; (l) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 263 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 265; (m) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 267 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 269; (n) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 271 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 273;(o) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 291 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 293; (p) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 311 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 313; (q) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 331 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 333; (r) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 351 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 353; (s) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 371 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 373; (t) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 391 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 393, (u) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 411 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 413, (v) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 414 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 84, or (w) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 416 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 84, and the structure of the linker payload conjugated to amino acid 3 (Gln) of SEQ ID NO: 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413 is

[0148] [ka] wherein:

[0149] [ka] is the attachment of amino acids 1-6 (LLQGSG (included in the structure above)) to amino acid 7 of SEQ ID NO: 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413. In some embodiments, the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0150] The present invention provides an antibody-tethered drug conjugate comprising a glucagon-like peptide-1 receptor (GLP1R) targeting antibody or antigen-binding fragment thereof, the GLP1R targeting antibody or antigen-binding fragment thereof comprising: (a) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 42 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 44; (b) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 62 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 64; (c) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 82 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 84; (d) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 102 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 104; (e) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 122 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 124; (f) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 142 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 144; (g) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 162 and a light ... (h) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 182 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 184; (i) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 203 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 205; (j) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 223 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 225; (k) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 243 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 245; (l) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 263 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 265; (m) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 267 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 269; (n) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 271 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 273.(o) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 291 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 293; (p) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 311 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 313; (q) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 331 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 333; (r) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 351 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 353; (s) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 371 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 373; (t) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 391 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 393, (u) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 411 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 413, (v) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 414 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 84, or (w) a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 416 and a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 84, and the structure of the linker payload conjugated to amino acid 3 (Gln) of SEQ ID NO: 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413 is

[0151] [ka] wherein:

[0152] [ka] is the attachment of amino acids 1-6 (LLQGSG (included in the structure above)) to amino acid 7 of SEQ ID NO: 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413. In some embodiments, the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0153] The present invention also provides an antibody-tethered drug conjugate (ATDC) comprising an antibody or antigen-binding fragment thereof that specifically binds to GLP1R and a payload conjugated to one or both of two immunoglobulin heavy chains or variable regions thereof, and / or one or both of two immunoglobulin light chains or variable regions thereof, the ATDC comprising:

[0154] [ka] The compound is characterized by the structure: An immunoglobulin is an immunoglobulin chain of an antibody or a fragment thereof (e.g., a light chain immunoglobulin), The linker is a linker as discussed herein, CapAib is 3-((2-(1H-imidazol-5-yl)ethyl)amino)-2,2-dimethyl-3-oxopropanoic acid; E * is (S)-2-amino-3-(2H-tetrazol-5-yl)propanoic acid, G is glycine, T is threonine F * is (S)-2-amino-3-(2-fluorophenyl)-2-methylpropanoic acid, S is serine, D is aspartate, AA2 is (S)-2-amino-3-(4'-(4-(4-(25-amino-2,5,8,11,14,17,20,23-octaoxapentacosyl)-1H-1,2,3-triazol-1-yl)butoxy)-2'-ethyl-[1,1'-biphenyl]-4-yl)propanoic acid [AA2 includes a linker]; AA1 = (S)-2-amino-5-(3,5-dimethylphenyl)pentanamide.

[0155] [ka] The structure of, for example, GT or CapAib-E * which indicates that these residues are linked by a bond, e.g., a peptide bond. In one embodiment of the invention, the antibody or fragment comprises a Qtag on both of the immunoglobulin light chains, the Qtag comprising the amino acid sequence LLQGSG (SEQ ID NO: 18). 2 A linker having the general structure H 2 N-linker payload), for example, as shown in the following reaction diagram:

[0156] [ka] According to the method described above, the side chain -C(=O)-NH is converted to NH through a transglutaminase reaction. 2 Qtag may be conjugated to the side chain group of glutamine (Gln) in * H 2 NLP is -NH 2 is a linker payload having a group. This reaction may also be referred to as aminylation. Aminylation refers to the process in which, for example, a primary amine of a linker payload is covalently attached to a peptide-bound glutamine residue by a transglutaminase. When a transglutaminase is in the vicinity of a peptide Gln residue and an available primary amine substrate (e.g., a linker payload with a primary amine, such as M3190) is present, the enzyme catalyzes the incorporation of a primary amino group into the glutamine, resulting in the formation of a gamma-glutamyl-amine bond. The result of such a reaction may be referred to herein as an "aminylation product." An aminylation product may be the product of the catalysis of two molecules by a transglutaminase enzyme, although not necessarily in phase. For example, an aminylation product may be the result of a chemical synthesis that does not use a transglutaminase enzyme. See Lai et al., Tissue transglutaminase (TG2) and mitochondrial function and dysfunction, Frontiers in Bioscience-Landmark. 2017.22(7); pp. 1114-1137.

[0157] The invention also provides methods for administering GLP1R to a cell (e.g., within a subject or in vivo) for delivery of a payload (e.g., L11, L30, or L32) with an ATDC of any of the embodiments described herein (e.g., REGN7990, REGN9268, REGN15869, REGN18121, REGN18123, REGN8070, REGN8072, REGN9267, REGN7988, REGN5619, REGN7989, REGN8069, REGN8071, REGN9426, REGN5203, REGN5204, REGN5617, REGN5619, REGN7987, REGN9270, REGN9278, REGN9279, or REGN9280, e.g., the linker payload is LP11, LP30, or LP32). The present invention provides a method for selectively targeting a cell on a surface in vitro, the method comprising contacting the cell with an ATDC. In one embodiment of the invention, the method comprises administering the ATDC or a pharmaceutical composition thereof to a subject in whose body the cell is present. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is a pancreatic cell, a brain cell, a cardiac cell, a vascular tissue cell, a kidney cell, an adipose tissue cell, a liver cell, or a muscle cell.

[0158] The invention provides a method of improving GLP1R activity in a subject in need thereof, comprising administering to the subject an effective amount of an ATDC of any of the embodiments described herein (e.g., REGN7990, REGN9268, REGN15869, REGN18121, REGN18123, REGN8070, REGN8072, REGN9267, REGN7988, REGN5619, REGN7989, REGN8069, REGN8071, REGN9426, REGN5203, REGN5204, REGN5617, REGN5619, REGN7987, REGN9270, REGN9278, REGN9279, or REGN9280, e.g., wherein the linker payload is LP11, LP30, or LP32), a composition described herein, or a dosage form described herein. In one embodiment of the invention, the subject suffers from a GLP1R-related disease (eg, obesity and / or diabetes (type 1 or type 2)).

[0159] In another aspect herein, there is provided a method of lowering blood glucose levels in a subject in need thereof, comprising administering to the subject an effective amount of an ATDC of any of the embodiments described herein (e.g., REGN7990, REGN9268, REGN15869, REGN18121, REGN18123, REGN8070, REGN8072, REGN9267, REGN7988, REGN5619, REGN7989, REGN8069, REGN8071, REGN9426, REGN5203, REGN5204, REGN5617, REGN5619, REGN7987, REGN9270, REGN9278, REGN9279, or REGN9280, e.g., the linker payload is LP11, LP30, or LP32), a composition described herein, or a dosage form described herein. In one embodiment of the invention, the subject suffers from a GLP1R-related disease (eg, obesity and / or diabetes (type 1 or type 2)).

[0160] In another aspect herein, there is provided a method of reducing weight in an individual in need thereof, comprising administering to the individual an effective amount of an ATDC of any of the embodiments described herein (e.g., REGN7990, REGN9268, REGN15869, REGN18121, REGN18123, REGN8070, REGN8072, REGN9267, REGN7988, REGN5619, REGN7989, REGN8069, REGN8071, REGN9426, REGN5203, REGN5204, REGN5617, REGN5619, REGN7987, REGN9270, REGN9278, REGN9279, or REGN9280, e.g., the linker payload is LP11, LP30, or LP32), a composition described herein, or a dosage form described herein. In one embodiment of the invention, the subject suffers from a GLP1R-related disease (eg, obesity and / or diabetes (type 1 or type 2)).

[0161]

[0023] In another aspect herein, there is provided a method of treating a GLP1R-related disease in a subject in need thereof, comprising administering to said subject an ATDC of any of the embodiments described herein (e.g., REGN7990, REGN9268, REGN15869, REGN18121, REGN18123, REGN8070, REGN8072, REGN9267, REGN7988, REGN5619, REGN7989 ... The method includes administering to a subject an effective amount of 069, REGN8071, REGN9426, REGN5203, REGN5204, REGN5617, REGN5619, REGN7987, REGN9270, REGN9278, REGN9279, or REGN9280, e.g., the linker payload is LP11, LP30, or LP32), a composition described herein, or a dosage form described herein. In some embodiments, the GLP1R-related disease is type II diabetes, obesity, liver disease, coronary artery disease, or kidney disease. In some embodiments, the GLP1R-related disease is type II diabetes and / or obesity.

[0162] In various embodiments of any of the methods described herein, the compositions or dosage forms of the disclosure (e.g., REGN7990, REGN9268, REGN15869, REGN18121, REGN18123, REGN8070, REGN8072, REGN9267, REGN7988, REGN5619, REGN7989, REGN8069, REGN8071, REGN9426, REGN5203, REGN5204, REGN5617, REGN5619, REGN7987, REGN9270, REGN9278, REGN9279, or REGN9280, e.g., the linker payload is LP11, LP30, or LP32) are administered subcutaneously, intravenously, intradermally, intraperitoneally, or intramuscularly.

[0163] In another aspect herein, a compound of formula (A): BA-(LP) m (A) 1. A method for producing an ATDC as described herein, comprising the steps of: a) contacting a BA containing at least m glutamine residues Gln with at least m equivalents of a compound LP in the presence of a transglutaminase; b) isolating the produced ATDC of formula (A), wherein BA is an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, and the antibody or antigen-binding fragment thereof can be, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) an antibody or antigen-binding fragment thereof that binds to the same epitope of GLP1R as the antibody or fragment of (i); Optionally, a method is provided in which the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0164] In another aspect herein, a compound of formula (I): BA-LP (I) 1. A method for producing an ATDC as described herein, comprising the steps of: a) contacting a BA containing at least one glutamine residue Gln with a compound LP in the presence of a transglutaminase; b) isolating the produced ATDC of formula (I), wherein BA is an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, and the antibody or antigen-binding fragment thereof can be, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) an antibody or antigen-binding fragment thereof that binds to the same epitope of GLP1R as the antibody or fragment of (i); Optionally, a method is provided in which the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0165] In another aspect herein, a compound of formula (A): BA-(LP) m (A) wherein the linker L is of the formula (L'): -La-Y-Lp- (L') wherein La is a first linker covalently attached to BA; Y is a triazole-containing group; L p is a second linker covalently attached to P, and the method further comprises: a) contacting a BA containing at least m glutamine residues Gln with a first linker La containing an azide or alkyne moiety in the presence of a transglutaminase; b) contacting the product of step a) with at least m equivalents of a compound Lp-P, wherein the second linker Lp comprises an azide or alkyne moiety, and La and Lp are capable of reacting to produce a triazole; and c) isolating the produced ATDC of formula (A), wherein BA is an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, and the antibody or antigen-binding fragment thereof can be, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) an antibody or antigen-binding fragment thereof that binds to the same epitope of GLP1R as the antibody or fragment of (i); Optionally, a method is provided in which the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0166] In another aspect herein, a compound of formula (I): BA-LP (I) A method for producing an ATDC as described herein having a structure of -La-Y-Lp- (L') wherein La is a first linker covalently attached to BA; Y is a triazole-containing group; L p is a second linker covalently attached to P, and the method further comprises: a) contacting a BA containing at least one glutamine residue Gln with a first linker La containing an azide or alkyne moiety in the presence of a transglutaminase; b) contacting the product of step a) with a compound Lp-P, where the second linker Lp comprises an azide or alkyne moiety, and La and Lp are capable of reacting to produce a triazole; and c) isolating the produced ATDC of formula (I), wherein BA is an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, and the antibody or antigen-binding fragment thereof can be, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) an antibody or antigen-binding fragment thereof that binds to the same epitope of GLP1R as the antibody or fragment of (i); Optionally, a method is provided in which the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0167] In another aspect herein, there is provided an ATDC or a pharma- ceutically acceptable salt thereof comprising an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, the antibody or antigen-binding fragment thereof being, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) an antibody or fragment of (i) that binds to the same epitope of GLP1R and is linked, for example by a linker, to any of the following formulas: (P-IB), (P-IIB), and (P-IIIB):

[0168] [ka] wherein: X 1 H,

[0169] [ka] is selected from X2 teeth,

[0170] [ka] is selected from X 3 -CH 3 , -(CH 2 ) 2-6 -NH 2 , -(CH 2 ) 2-6 -N 3 , and -(CH 2 ) 2-6 -Tr-(CH 2 ) 1-6 -NH 2 where Tr is a triazole moiety; n is 0 or 1, X 4 is -NH 2 , -OH, and -N(H)(phenyl); X 5 -OH, -NH 2 , -NH-OH, and

[0171] [ka] is selected from X 6 represents H, -OH, -CH at each occurrence. 3 , and -CH 2 OH, X 7 H,

[0172] [ka] is selected from X 8 is H, -OH, -NH 2 , and

[0173] [ka] is selected from Ar is

[0174] [ka] is selected from X 9 is -NH 2 ,

[0175] [ka] is selected from m is an integer from 1 to 4; Optionally, ATDC or a pharma- ceutically acceptable salt thereof is provided, wherein the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0176] In another aspect of the invention, there is provided herein an ATDC or a pharma- ceutically acceptable salt thereof comprising an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, the antibody or antigen-binding fragment being, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) (i) binds to the same epitope of GLP1R as the antibody or fragment thereof and is, for example, linked by a linker, represented by the formula (II)

[0177] [ka] and wherein the antibody or antigen-binding fragment thereof is conjugated to a compound having the structure: During the ceremony, X 1 H,

[0178] [ka] is selected from X 2 teeth,

[0179] [ka] is selected from X 3 is -(CH 2 ) 2-6 -NH 2 , -(CH 2 ) 2-6 -N 3 , and -CH 3 Selected from X 3 Ga-CH 3 When n is 1, Ra in at least one occurrence is -(CH 2 ) 2-6 -NH 2 and -(CH 2 ) 2-6 -N 3 is selected from n is 0 or 1, m is an integer from 0 to 3; Ra independently represents, at each occurrence, -CH 3 , -(CH 2 ) 2-6 -NH 2 , and -(CH 2 ) 2-6 -N 3 is selected from X 4 is selected from H and phenyl; X 5 -OH, -NH 2 , -NH-OH, and

[0180] [ka] is selected from X 6 represents H, -OH, -CH at each occurrence. 3 , and -CH 2 OH, X 7 H,

[0181] [ka] is selected from X 8 is H, -OH, -NH 2 , and

[0182] [ka] is selected from Optionally, ATDC or a pharma- ceutically acceptable salt thereof is provided, wherein the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0183] In some embodiments, P (payload) is, in the ATDC described herein,

[0184] [ka]

[0185] [ka]

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] [ka]

[0190] [ka] having a structure selected from the group consisting of: For example, such P (payload) is conjugated to an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, the antibody or antigen-binding fragment thereof being, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) an antibody or antigen-binding fragment thereof that binds to the same epitope of GLP1R as the antibody or fragment of (i); Optionally, the heavy chain immunoglobulin does not contain a C-terminal lysine or a lysine and a glycine.

[0191] In another aspect of the invention, there is provided herein an ATDC or a pharma- ceutically acceptable salt thereof comprising an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, the antibody or antigen-binding fragment being, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) (i) binds to the same epitope of GLP1R as the antibody or fragment thereof and has the formula (C):

[0192] [ka] wherein: L p does not exist, or

[0193] [ka] Carbamate group; Cyclodextrin; 1 to 36 -CH 2 CH 2 Polyethylene glycol (PEG) segments with O-(EG) units; -(CH 2 ) 2-24 a linker comprising one or more of: a -chain; a triazole; one or more amino acids selected from glycine, serine, glutamic acid, alanine, valine, and proline, and combinations thereof; Q is -NH 2 , -N 3 ,

[0194] [ka] and A is C or N; X 1 H,

[0195] [ka] is selected from X 2 teeth,

[0196] [ka] is selected from X 3 is -CH 3 , -(CH 2 ) 2-6 -NH 2 , -(CH 2 ) 2-6 -N 3 , and -(CH 2 ) 2-6 -Tr-(CH 2 ) 1-6 -NH 2 where Tr is a triazole moiety; n is 0 or 1, X4 is -NH 2 , -OH, and -N(H)(phenyl); X 5 -OH, -NH 2 , -NH-OH, and

[0197] [ka] is selected from X 6 represents H, -OH, -CH at each occurrence. 3 , and -CH 2 OH, X 7 H,

[0198] [ka] is selected from X 8 H, -OH, -NH 2 , and

[0199] [ka] is selected from Ar is

[0200] [ka] is selected from X 9 is -NH 2 ,

[0201] [ka] is selected from m is an integer from 1 to 4; Optionally, ATDC or a pharma- ceutically acceptable salt thereof is provided, wherein the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0202] In another aspect herein, there is provided an ATDC or a pharma- ceutically acceptable salt thereof comprising an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, the antibody or antigen-binding fragment thereof being, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) The antibody or fragment of (i) binds to the same epitope of GLP1R as the antibody or fragment of (i) and has the formula (III):

[0203] [ka] wherein: L p does not exist, or

[0204] [ka] Carbamate group; Cyclodextrin; 1 to 36 -CH 2 CH 2 a polyethylene glycol (PEG) segment having an O-(EG) unit; a linker comprising one or more of the following amino acids: glycine, serine, glutamic acid, alanine, valine, and proline, and combinations thereof; Q is -N 3 ,

[0205] [ka] and A is C or N; X 1 H,

[0206] [ka] is selected from X 2 teeth,

[0207] [ka] is selected from X 3 is -(CH 2 ) 2-6 -NH 2 , -(CH 2 ) 2-6 -N 3 , and -CH 3 Selected from X 3 Ga-CH 3 When n is 1, Ra in at least one occurrence is -(CH 2 ) 2-6 -NH 2 and -(CH 2 ) 2-6 -N 3 is selected from n is 0 or 1, Ra independently at each occurrence is H, -CH 3 , -(CH 2 ) 2-6 -NH 2 , and -(CH 2 ) 2-6 -N 3 is selected from X 4 is selected from H and phenyl; X 5 -OH, -NH 2 , -NH-OH, and

[0208] [ka] is selected from X 6 represents H, -OH, -CH at each occurrence. 3 , and -CH 2 OH, X 7 H,

[0209] [ka] is selected from X 8 is H, -OH, -NH 2 , and

[0210] [ka] is selected from Optionally, ATDC or a pharma- ceutically acceptable salt thereof is provided, wherein the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0211] The present invention relates to an ATDC or a pharma- ceutically acceptable salt thereof comprising an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, the antibody or antigen-binding fragment being, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) binds to the same epitope of GLP1R as the antibody or fragment of (i);

[0212] [ka]

[0213] [ka]

[0214] [ka]

[0215] [ka]

[0216] [ka]

[0217] [ka]

[0218] [ka]

[0219] [ka]

[0220] [ka]

[0221] [ka]

[0222] [ka] and wherein the antibody or antigen-binding fragment thereof is conjugated to a compound having a structure selected from the group consisting of: Optionally, ATDC or a pharma- ceutically acceptable salt thereof is provided, wherein the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0223] The present invention relates to an ATDC or a pharma- ceutically acceptable salt thereof comprising an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, the antibody or antigen-binding fragment being, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) binds to the same epitope of GLP1R as the antibody or fragment of (i), optionally via a linker;

[0224] [ka]

[0225] [ka]

[0226] [ka]

[0227] [ka]

[0228] [ka]

[0229] [ka]

[0230] [ka] and wherein the antibody or antigen-binding fragment thereof is conjugated to a payload having a structure selected from the group consisting of: Optionally, the heavy chain immunoglobulin comprises ATDC, or a pharma- ceutically acceptable salt thereof, which does not contain a C-terminal lysine or lysine and glycine.

[0231] In yet another aspect herein, there is provided an ATDC or a pharma- ceutically acceptable salt thereof comprising an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, the antibody or antigen-binding fragment being, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) binds to the same epitope of GLP1R as the antibody or fragment of (i);

[0232] [ka] wherein:

[0233] [ka] is the point at which the payload is attached to the antibody or antigen-binding fragment thereof, either directly or via a linker; Optionally, ATDC or a pharma- ceutically acceptable salt thereof is provided, wherein the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0234] In one embodiment, the payload on the ATDC comprises an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, the antibody or antigen-binding fragment thereof being, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) binds to the same epitope of GLP1R as the antibody or fragment of (i);

[0235] [ka] and wherein the antibody or antigen-binding fragment thereof has the structure: Optionally, the heavy chain immunoglobulin is the payload, which does not include a C-terminal lysine or lysine and glycine.

[0236] In yet another aspect herein, an ATDC is provided that comprises a GLP1R-targeting antibody or antigen-binding fragment thereof that specifically binds to the Glucagon-like peptide-1 receptor (GLP1R), wherein the antibody or antigen-binding fragment thereof is, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) binds to the same epitope of GLP1R as the antibody or fragment of (i);

[0237] [ka] and wherein the linker payload has the structure:

[0238] [ka] is the point of attachment of the linker payload to the antibody or antigen-binding fragment thereof, Optionally, an ATDC is provided in which the heavy chain immunoglobulin does not contain a C-terminal lysine or lysine and glycine.

[0239] In one embodiment of the invention, a linker payload of the ATDC comprises an antibody or antigen-binding fragment thereof that specifically binds to GLP1R, the antibody or antigen-binding fragment thereof being, for example, (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) binds to the same epitope of GLP1R as the antibody or fragment of (i);

[0240] [ka] and wherein the antibody or antigen-binding fragment thereof has the structure: Optionally, the heavy chain immunoglobulin is a linker payload that does not contain a C-terminal lysine or lysine and glycine.

[0241] These and other aspects of the present disclosure will become apparent to those skilled in the art after reading the following detailed description of the disclosure, including the appended claims. [Brief description of the drawings]

[0242] [Figure 1A] Schematic representation of an exemplary antibody-tethered drug conjugate (ATDC) design and its mechanism of action. [Figure 1B] 1 is a schematic representation of conventional antibody drug conjugate (ADC) design and its mechanism of action. [Diagram 2] FIG. 1 shows a model of an antibody-tethered drug conjugate with the antibody attached to the extracellular domain (ECD) and the payload attached to the transmembrane domain (TMD). [Figure 3A]Schematic diagram of GLP1(7-36)amide (SEQ ID NO:4). The numbers above the sequence correspond to the amino acid positions in the proglucagon propeptide. The arrows between positions 8 and 9 indicate the dipeptidyl peptidase-4 (DPP-IV) cleavage site. The arrows between positions 9 and 10, 11 and 12, 15 and 16, 17 and 18, 18 and 19, 27 and 28, 28 and 29, and 31 and 32 indicate the neutral endopeptidase (NEP) cleavage site. The dashed arrows between positions 30 and 31, and 32 and 33 indicate the cleavage site by an unknown endoprotease. The residues at positions 7, 10, 13, 15, 28, and 29 are amino acids that, when substituted, reduce GLP1R binding and cAMP production. Residues at positions 9, 12, 32, and 36 are amino acids that, when substituted, reduce GLP1R binding. [Figure 3B] 1 shows the structure of GLP1R bound to GLP1 (Protein Data Bank ID: 3IOL). References to this structure can be found in Nature 2017 by Zhang et al., JBC 2019 by Chepurny et al., Pharmacological reviews 2016 by De Graaf et al., and Manandhar and Ahn Journal of Medical Chemistry 2014, each of which is incorporated herein by reference in its entirety. [Figure 4A] FIG. 1 shows the sequence and structure of GLP1 peptidomimetic peptide 5 (SEQ ID NO: 5). Numbers above the sequence correspond to amino acid positions in the proglucagon propeptide. [Figure 4B]FIG. 1 shows the superimposed structures of GLP1R bound to peptide 5 (Protein Data Bank ID: 5NX2) and GLP1 bound to GLP1 (Protein Data Bank ID: 3IOL) using GLP1R in 5NX2 as a template. Reference for the 5NX2 structure can be found in Jazayeri A et al., Nature 546:254-258 (2017), which is incorporated herein by reference in its entirety. [Figure 5-1] Figure 1 shows a synthetic scheme for making the GLP1 peptidomimetic payload of the present disclosure. A solid-phase peptide synthesis was established on the resin, which efficiently produced the payload of the present disclosure with good yield. Additional GLP1R peptidomimetic payloads were produced by systematic R1 / R2 / R3 modification. [Figure 5-2] Figure 1 shows a synthetic scheme for making the GLP1 peptidomimetic payload of the present disclosure. A solid-phase peptide synthesis was established on the resin, which efficiently produced the payload of the present disclosure with good yield. Additional GLP1R peptidomimetic payloads were produced by systematic R1 / R2 / R3 modification. [Figure 6A] FIG. 1 demonstrates that the GLP1R peptidomimetic payloads of the present disclosure showed no activity in relevant GPCR bioassays. [Figure 6B] FIG. 1 demonstrates that the GLP1R peptidomimetic payloads of the present disclosure showed no activity in relevant GPCR bioassays. [Figure 6C] FIG. 1 demonstrates that the GLP1R peptidomimetic payloads of the present disclosure showed no activity in relevant GPCR bioassays. [Figure 6D] FIG. 1 demonstrates that the GLP1R peptidomimetic payloads of the present disclosure showed no activity in relevant GPCR bioassays. [Figure 7A] FIG. 1 shows that the shorter linker GLP1R ATDC showed greater potency than the control ATDC. [Figure 7B-1]FIG. 1 shows that the shorter linker GLP1R ATDC showed greater potency than the control ATDC. [Figure 7B-2] FIG. 1 shows that the shorter linker GLP1R ATDC showed greater potency than the control ATDC. [Figure 8] FIG. 1 shows that the main linker payload exhibits an optimal in vitro ADME profile, no in vitro cardiotoxicity and possible mutagenicity, and its ATDC is highly stable in plasma. [Figure 9A] FIG. 1 shows two methods for conjugating a linker payload to an antibody of the disclosure. [Figure 9B] Figure 1 shows a representative hydrophobic interaction chromatography (HIC) graph of the loading profile of anti-GLP1R ATDC drugs. HIC was used for conjugation potential screening to triage the order of ATDCs that showed low conjugation yields, low DAR, high aggregation, and poor Biacore binding. [Figure 10-1] Figure 1 shows CRE-dependent luciferase reporter activity by anti-GLP1R ATDC. Anti-GLP1R ATDC showed better in vitro potency than isotype control ATDC. Unconjugated mAb did not activate hGLP1R cells (not shown). ATDC did not activate glucagon-like peptide-2 receptor (GLP2R), glucagon receptor (GCGR), or gastric inhibitory polypeptide receptor (GIPR) (not shown). [Figure 10-2] Figure 1 shows CRE-dependent luciferase reporter activity by anti-GLP1R ATDC. Anti-GLP1R ATDC showed better in vitro potency than isotype control ATDC. Unconjugated mAb did not activate hGLP1R cells (not shown). ATDC did not activate glucagon-like peptide-2 receptor (GLP2R), glucagon receptor (GCGR), or gastric inhibitory polypeptide receptor (GIPR) (not shown). [Figure 11A]Figure 1 shows cyclic AMP response element (CRE)-dependent luciferase reporter activity by anti-GLP1R ATDC in the presence of unconjugated anti-GLP1R antibody. It can be seen that unconjugated anti-GLP1R mAb concentrations below 10 nM did not affect anti-GLP1R ATDC activity. 100 nM unconjugated anti-GLP1R mAb reduced anti-GLP1R ATDC titer by 3.8-fold. The assay was performed by first adding unconjugated anti-GLP1R mAb, followed immediately by anti-GLP1R ATDC, and incubating for 4 hours. [Figure 11B] FIG. 11B shows data corresponding to the graph in FIG. 11A. [Figure 12] 1 is a schematic diagram of an exemplary GLP1R Q-tag mAb-GLP1R agonist conjugate of the present disclosure. [Figure 13-1] FIG. 1 shows a general synthetic scheme for preparing GLP1 peptide mimetics according to the present disclosure. [Figure 13-2] FIG. 1 shows a general synthetic scheme for preparing GLP1 peptide mimetics according to the present disclosure. [Figure 13-3] FIG. 1 shows a general synthetic scheme for preparing GLP1 peptide mimetics according to the present disclosure. [Figure 14-1] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P1 and P8 according to the present disclosure. [Figure 14-2] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P1 and P8 according to the present disclosure. [Figure 15-1] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P2 and P9 according to the present disclosure. [Figure 15-2] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P2 and P9 according to the present disclosure. [Figure 16-1]FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P3, P4, P5, P6, P7, P11, P13, P14, P15, P16, and P17 according to the present disclosure. [Figure 16-2] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P3, P4, P5, P6, P7, P11, P13, P14, P15, P16, and P17 according to the present disclosure. [Figure 17A-1] FIG. 1 shows the sequence of solid supported synthesis of GLP1 peptidomimetic payloads P10, P12, P18, P19, P25, P26, P27, P28, P29, P30, P31, P36, P37, and P38 according to the present disclosure. [Figure 17A-2] FIG. 1 shows the sequence of solid supported synthesis of GLP1 peptidomimetic payloads P10, P12, P18, P19, P25, P26, P27, P28, P29, P30, P31, P36, P37, and P38 according to the present disclosure. [Figure 17B-1] FIG. 1 shows the sequence of solid supported synthesis of GLP1 peptidomimetic payloads P10, P12, P18, P19, P25, P26, P27, P28, P29, P30, P31, P36, P37, and P38 according to the present disclosure. [Figure 17B-2] FIG. 1 shows the sequence of solid supported synthesis of GLP1 peptidomimetic payloads P10, P12, P18, P19, P25, P26, P27, P28, P29, P30, P31, P36, P37, and P38 according to the present disclosure. [Figure 18-1] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P20 and P21 according to the present disclosure. [Figure 18-2] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P20 and P21 according to the present disclosure. [Figure 19-1] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P22 and P23 according to the present disclosure. [Figure 19-2]FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P22 and P23 according to the present disclosure. [Figure 20] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payload P24 according to the present disclosure. [Figure 21-1] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P32, P33, P34, and P35 according to the present disclosure. [Figure 21-2] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payloads P32, P33, P34, and P35 according to the present disclosure. [Figure 22-1] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payload P39 according to the present disclosure. [Figure 22-2] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payload P39 according to the present disclosure. [Figure 23-1] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payload P40 according to the present disclosure. [Figure 23-2] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payload P40 according to the present disclosure. [Figure 24-1] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payload P41 according to the present disclosure. [Figure 24-2] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payload P41 according to the present disclosure. [Figure 25-1] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payload P42 according to the present disclosure. [Figure 25-2] FIG. 1 shows the sequence of solid-supported synthesis of GLP1 peptidomimetic payload P42 according to the present disclosure. [Figure 26] FIG. 1 shows synthetic routes for the preparation of linker payloads LP1, LP2, LP3, LP4, and LP5 according to the present disclosure. [Figure 27]FIG. 1 shows a synthetic route for the preparation of linker payloads LP6 and LP7 according to the present disclosure. [Figure 28] FIG. 1 shows synthetic routes for the preparation of linker payloads LP8, LP9, LP10, and LP11 according to the present disclosure. [Figure 29] FIG. 1 shows a synthetic route for the preparation of linker payload LP12 according to the present disclosure. [Diagram 30] FIG. 1 shows a synthetic route for the preparation of linker payloads LP13 and LP14 according to the present disclosure. [Diagram 31] FIG. 1 shows a synthetic route for the preparation of linker payloads LP15 and LP18 according to the present disclosure. [Figure 32-1] FIG. 1 shows a synthetic route for the preparation of linker payload LP17 according to the present disclosure. [Figure 32-2] FIG. 1 shows a synthetic route for the preparation of linker payload LP17 according to the present disclosure. [Diagram 33] FIG. 1 shows a synthetic route for the preparation of linker payloads LP18 and LP20 according to the present disclosure. [Figure 34-1] FIG. 1 shows a synthetic route for the preparation of linker payload LP19 according to the present disclosure. [Figure 34-2] FIG. 1 shows a synthetic route for the preparation of linker payload LP19 according to the present disclosure. [Diagram 35] FIG. 1 shows a synthetic route for the preparation of linker payload LP21 according to the present disclosure. [Figure 36-1] FIG. 1 shows a synthetic route for the preparation of linker payload LP22 according to the present disclosure. [Figure 36-2] FIG. 1 shows a synthetic route for the preparation of linker payload LP22 according to the present disclosure. [Figure 37-1] FIG. 1 shows a synthetic route for the preparation of linker payload LP23 according to the present disclosure. [Figure 37-2] FIG. 1 shows a synthetic route for the preparation of linker payload LP23 according to the present disclosure. [Figure 38]FIG. 1 shows a synthetic route for the preparation of linker payload LP24 according to the present disclosure. [Figure 39] FIG. 1 shows a synthetic route for the preparation of linker payload LP25 according to the present disclosure. [Diagram 40] FIG. 1 shows a synthetic route for the preparation of linker payload LP26 according to the present disclosure. [Figure 41-1] FIG. 1 shows a synthetic route for the preparation of linker payloads LP27 and LP28 according to the present disclosure. [Figure 41-2] FIG. 1 shows a synthetic route for the preparation of linker payloads LP27 and LP28 according to the present disclosure. [Figure 42-1] FIG. 1 shows a synthetic route for the preparation of linker payload LP29 according to the present disclosure. [Figure 42-2] FIG. 1 shows a synthetic route for the preparation of linker payload LP29 according to the present disclosure. [Diagram 43] FIG. 1 shows a synthetic route for the preparation of linker payload LP30 according to the present disclosure. [Diagram 44] FIG. 1 shows a synthetic route for the preparation of linker payload LP31 according to the present disclosure. [Diagram 45] FIG. 1 shows a synthetic route for the preparation of linker payload LP32 according to the present disclosure. [Figure 46-1] FIG. 1 shows a synthetic route for the preparation of linker payload LP33 according to the present disclosure. [Figure 46-2] FIG. 1 shows a synthetic route for the preparation of linker payload LP33 according to the present disclosure. [Figure 47-1] FIG. 1 shows a synthetic route for the preparation of linker payload LP34 according to the present disclosure. [Figure 47-2] FIG. 1 shows a synthetic route for the preparation of linker payload LP34 according to the present disclosure. [Figure 48] FIG. 1 shows a synthetic route for the preparation of linker payload LP35 according to the present disclosure. [Figure 49-1]FIG. 1 shows synthetic routes for the preparation of linker payloads LP36, LP37, LP38, LP39, LP40, and LP41 according to the present disclosure. [Figure 49-2] FIG. 1 shows synthetic routes for the preparation of linker payloads LP36, LP37, LP38, LP39, LP40, and LP41 according to the present disclosure. [Figure 49-3] FIG. 1 shows synthetic routes for the preparation of linker payloads LP36, LP37, LP38, LP39, LP40, and LP41 according to the present disclosure. [Figure 49-4] FIG. 1 shows synthetic routes for the preparation of linker payloads LP36, LP37, LP38, LP39, LP40, and LP41 according to the present disclosure. [Figure 50-1] FIG. 1 shows a synthetic route for the preparation of linker payload LP42 according to the present disclosure. [Figure 50-2] FIG. 1 shows a synthetic route for the preparation of linker payload LP42 according to the present disclosure. [Figure 51-1] FIG. 1 shows a synthetic route for the preparation of linker payload LP43 according to the present disclosure. [Figure 51-2] FIG. 1 shows a synthetic route for the preparation of linker payload LP43 according to the present disclosure. [Figure 52-1] FIG. 1 shows a synthetic route for the preparation of linker payload LP44 according to the present disclosure. [Figure 52-2] FIG. 1 shows a synthetic route for the preparation of linker payload LP44 according to the present disclosure. [Figure 53-1] FIG. 1 shows a synthetic route for the preparation of linker payload LP45 according to the present disclosure. [Figure 53-2] FIG. 1 shows a synthetic route for the preparation of linker payload LP45 according to the present disclosure. [Figure 54] FIG. 1 is a schematic diagram of a general two-step conjugation procedure for the preparation of site-specific antibody drug conjugates. [Figure 55]FIG. 1 is a schematic diagram of a general one-step conjugation procedure for the preparation of site-specific antibody drug conjugates. [Figure 56] Figure 1 shows the commander voltage protocol for electrophysiology testing. From a holding potential of -80mV, the voltage was first stepped to -50mV for 80ms to eliminate leak currents, then to +20mV for 4800ms to open hERG channels. The voltage was then stepped back to -50mV for 5000ms to generate a "rebound" or tail current, which was measured and collected for data analysis. Finally, the voltage was stepped back at the holding potential (-80mV, 1000ms). The voltage command protocol was repeated every 20 seconds and was performed continuously throughout the test (vehicle control and test compound). [Figure 57] FIG. 1 shows the in vitro stability of anti-GLP1R mAB2-LP11 by incubation at 37° C. in mouse, monkey and human plasma for 7 days. [Figure 58] FIG. 1 shows the effect of GLP1R ATDC on the rate of body weight change in obese GLP1R humanized mice. [Figure 59] FIG. 1 shows the effect of GLP1R ATDC on blood glucose levels in obese GLP1R humanized mice. [Figure 60] 1 is a schematic diagram of a GLP1R ATDC according to an exemplary embodiment of the present disclosure. Such ATDCs form part of the present invention, including those in which the antibody is REGN15869, REGN18121, or REGN18123. [Figure 61]1 is a diagram of an anti-GLP1R antibody appended via a glutamine residue (Q) in the Qtag (LLQGSG (SEQ ID NO: 18)) on each LCVR with a linker payload (LP) that is M3190. The bond between the glutamine side chain and the linker is shown, and the bond between the N-terminal LCVR residue and the C-terminal Qtag glycine is shown. ]=point of attachment of the antibody Qtag Gln to the linker of M3190. Such ATDCs form part of the invention, including those in which the antibody is REGN15869, REGN18121, or REGN18123. [Figure 62-1] Comparison of GLP1 (top) and ATDC (bottom) comprising an anti-GLP1R antibody with a LLQGSG (SEQ ID NO: 18) Qtag and conjugated to a linker payload that is M3190. E* is (S)-2-amino-3-(2H-tetrazol-5-yl)propanoic acid, F* is (S)-2-amino-3-(2-fluorophenyl)-2-methylpropanoic acid, cap-Aib is 3-((2-(1H-imidazol-5-yl)ethyl)amino)-2,2-dimethyl-3-oxopropanoic acid, AA2 is (S)-2-amino-3-(4'-(4-(4-(25-amino-2,5,8,11,14,17,20,23-octaoxapentacosyl)-1H-1,2,3-triazol-1-yl)butoxy)-2'-ethyl-[1,1'-biphenyl]-4-yl)propanoic acid [AA2 contains a linker], and AA1 = (S)-2-amino-5-(3,5-dimethylphenyl)pentanamide. Such ATDCs form part of the present invention, including those in which the antibody is REGN15869, REGN18121, or REGN18123. [Figure 62-2]Comparison of GLP1 (top) and ATDC (bottom) comprising an anti-GLP1R antibody with a LLQGSG (SEQ ID NO: 18) Qtag and conjugated to a linker payload that is M3190. E* is (S)-2-amino-3-(2H-tetrazol-5-yl)propanoic acid, F* is (S)-2-amino-3-(2-fluorophenyl)-2-methylpropanoic acid, cap-Aib is 3-((2-(1H-imidazol-5-yl)ethyl)amino)-2,2-dimethyl-3-oxopropanoic acid, AA2 is (S)-2-amino-3-(4'-(4-(4-(25-amino-2,5,8,11,14,17,20,23-octaoxapentacosyl)-1H-1,2,3-triazol-1-yl)butoxy)-2'-ethyl-[1,1'-biphenyl]-4-yl)propanoic acid [AA2 contains a linker], and AA1 = (S)-2-amino-5-(3,5-dimethylphenyl)pentanamide. Such ATDCs form part of the present invention, including those in which the antibody is REGN15869, REGN18121, or REGN18123. [Figure 62-3] Comparison of GLP1 (top) and ATDC (bottom) comprising an anti-GLP1R antibody with a LLQGSG (SEQ ID NO: 18) Qtag and conjugated to a linker payload that is M3190. E* is (S)-2-amino-3-(2H-tetrazol-5-yl)propanoic acid, F* is (S)-2-amino-3-(2-fluorophenyl)-2-methylpropanoic acid, cap-Aib is 3-((2-(1H-imidazol-5-yl)ethyl)amino)-2,2-dimethyl-3-oxopropanoic acid, AA2 is (S)-2-amino-3-(4'-(4-(4-(25-amino-2,5,8,11,14,17,20,23-octaoxapentacosyl)-1H-1,2,3-triazol-1-yl)butoxy)-2'-ethyl-[1,1'-biphenyl]-4-yl)propanoic acid [AA2 contains a linker], and AA1 = (S)-2-amino-5-(3,5-dimethylphenyl)pentanamide. Such ATDCs form part of the present invention, including those in which the antibody is REGN15869, REGN18121, or REGN18123. [Figure 63] CryoEM reconstruction of the GLP-1R / REGN9268 / M3190 complex and epitopes. (A) shows the CryoEM reconstruction of REGN9268-M3190 Fab bound to GLP-1R / G ("tethered" complex). (B) shows the CryoEM reconstruction of REGN9268 Fab bound to GLP1R / G / M3190 ("untethered" complex). G protein density is not present in (B) because the map was calculated from local refinement performed after subtraction of the G protein signal. The positions of GLP-1R domains and complex components are labeled in (A), (B), and (C), and c shows a close-up of the REGN9268 / GLP-1R interface. GLP-1R contact residues (within 4 Å of REGN9268) are shown as sticks and labeled. [Figure 64] Figure 1 shows the cryoEM reconstruction of the GLP-1R / REGN15869 / M3190 complex and epitopes. (A) shows the cryoEM reconstruction of REGN15869-M3190 Fab bound to GLP-1R / G ("tethered" complex). (B) shows the cryoEM reconstruction of REGN15869 Fab bound to GLP1R / G / M3190 ("untethered" complex). The positions of GLP-1R domains and complex components are labeled in (A), (B), and (C), and (C) shows a close-up of the REGN15869 / GLP-1R interface. GLP-1R contact residues (within 4A of REGN15869) are shown as sticks and labeled.

[0243] The drawings in this application are related to the drawings in WO2022056494 (International Application PCT / US2021 / 050337), which are incorporated herein by reference. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0244] The present disclosure provides, in some aspects, an antibody drug conjugate that specifically binds to the glucagon-like peptide 1 receptor (GLP1R) protein. As described in the Background section above, GLP1R and its ligand, GLP1, are highly validated targets for obesity and type 2 diabetes. However, no direct agonist antibodies have been identified in the treatment of type 2 diabetes. Single peptides with agonist activity on GLP1R are effective therapeutics for glucose control and weight loss, but in-line peptide antibody fusions are prone to proteolysis. In certain embodiments of the present disclosure, an antibody drug conjugate was generated that combines an antibody or antigen-binding fragment thereof that specifically targets the extracellular domain of GLP1R with a GLP1 peptidomimetic that functionally activates GLP1R. In certain embodiments, the antibody drug conjugate of the present disclosure has a longer drug duration with equal or greater efficacy in weight loss and glucose reduction and minimal off-target side effects.

[0245] Although detailed embodiments of the present disclosure are disclosed herein, it should be understood that the disclosed embodiments are merely illustrative of the present disclosure, which may be embodied in various forms. In addition, each example given in connection with various embodiments of the present disclosure is intended to be illustrative and not limiting. Therefore, the specific structural and functional details disclosed herein should not be interpreted as limiting, but merely as representative basic principles for teaching those skilled in the art how to utilize the present disclosure in various ways.

[0246] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0247] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes one or more methods, and / or steps of the kind described herein and / or that will become apparent to those skilled in the art upon reading this disclosure.

[0248] As used herein, "subject" or "patient" or "individual" or "animal" refers to humans, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.), and experimental animal models of disease (e.g., mice, rats). In a preferred embodiment, the subject is a human.

[0249] The phrase "pharmaceutical acceptable salt" used in connection with the compositions of the present disclosure refers to any salt suitable for administration to a patient. Suitable salts include, but are not limited to, those disclosed in "Pharmaceutical Salts" by Berge et al., J.Pharm.Sci., 1977, 66:1, which is incorporated herein by reference. Examples of salts include, but are not limited to, acid-derived, base-derived, organic, inorganic, amine, and alkali metal or alkaline earth metal salts, including, but not limited to, calcium salt, magnesium salt, potassium salt, sodium salt, hydrochloride, hydrobromide salt, sulfate salt, nitrate salt, phosphate salt, acetate salt, propionate salt, glycolate salt, pyruvate salt, oxalate salt, maleate salt, malonate salt, succinate salt, fumarate salt, tartrate salt, citrate salt, benzoate salt, cinnamate salt, mandelate salt, methanesulfonate salt, ethanesulfonate salt, p-toluenesulfonate salt, salicylate salt, etc. In some examples, the payload described herein comprises a tertiary amine, and the nitrogen atom in the tertiary amine is the atom to which the payload is attached to the linker or linker spacer.In such examples, the attachment of the payload to the tertiary amine results in a quaternary amine in the linker-payload molecule.The positive charge of the quaternary amine can be balanced by a counterion (e.g., chloro, bromo, iodo, or any other suitable charged moiety, such as those described herein).

[0250] Ranges can be expressed herein as from "about" or "approximately" one particular value and / or to "about" or "approximately" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value.

[0251] "Comprising" or "containing" or "including" means that at least the specified compounds, elements, particles, or method steps are present in a composition or substance or method, but does not exclude the presence of other compounds, materials, particles, or method steps, even if those other compounds, materials, particles, or method steps have the same function as the one specified.

[0252] Compounds of the present disclosure, such as payloads and linker payloads, include those generally described herein, and are further exemplified by classes, subclasses, and species disclosed herein.As used herein, the following definitions shall apply unless otherwise specified.For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed.In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the contents of which are incorporated herein by reference in their entirety.

[0253] As used herein, the term "alkyl" is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl group has about 1 to 20 carbon atoms in its backbone (e.g., C for straight chain). 1 -C 20 , C for branched chain 2 -C 20), alternatively having about 1-10 carbon atoms, or about 1-6 carbon atoms. In some embodiments, cycloalkyl rings have from about 3-10 carbon atoms in their ring structure, and such rings may be monocyclic or bicyclic rings, alternatively having about 5, about 6, or about 7 carbons in the ring structure. In some embodiments, alkyl groups can be lower alkyl groups, which contain 1-4 carbon atoms (e.g., C for straight chain lower alkyl). 1 -C 4 ).

[0254] As used herein, the term "alkenyl" refers to an alkyl group, as used herein, having one or more double bonds.

[0255] As used herein, the term "alkynyl" refers to an alkyl group, as used herein, having one or more triple bonds.

[0256] The term "heteroatom" includes one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic ring).

[0257] The term "halogen" means F, Cl, Br, or I, and the term "halide" refers to a halogen group or substituent, i.e., -F, -Cl, -Br, or -I.

[0258] An "adduct," e.g., a "Diels-Alder adduct," in this disclosure, encompasses any moiety that comprises the product of an addition reaction, e.g., a Diels-Alder reaction, independent of the synthetic steps employed to produce the moiety.

[0259] The term "covalent bond" refers to the formation of a covalent bond, i.e., a chemical bond involving the sharing of one or more electron pairs between two atoms. Covalent bonds may include a variety of interactions, including, but not limited to, σ bonds, π bonds, metal-metal bonds, agostic interactions, bent bonds, and three-center two-electron bonds. When a first group is said to be "capable of covalent bonding" to a second group, this means that the first group is capable of forming a covalent bond with the second group, either directly or indirectly, for example, through the use of a catalyst, or under certain reaction conditions. Non-limiting examples of groups that are capable of covalent bonding to each other include, for example, amines and carboxylic acids (forming amide bonds), dienes and dienophiles (via the Diels-Alder reaction), maleimides and thiols (forming thiomaleimides), and azides and alkynes (forming triazoles via a 1,3-cycloaddition reaction).

[0260] As described herein, the compounds of the present disclosure (e.g., payloads and linker payloads) may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means replacing one or more hydrogens of the specified moiety with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds.

[0261] As used herein, the term "stable" refers to a compound that is not substantially altered when subjected to conditions that permit its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0262] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the disclosure.

[0263] Unless otherwise indicated, the cycloadducts depicted herein, e.g., the products of cycloaddition reactions, e.g., azide-acetylene cycloaddition reactions or Diels-Alder reactions, include all regioisomers, i.e., structural isomers that differ only in the position of functional groups or substituents. As an example, the following structure:

[0264] [ka] represents triazole positional isomers that differ only in the position of the substituents on the triazole ring. Triazole positional isomers have the following structures:

[0265] [ka] It may be represented by:

[0266] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0267] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 11 C or 13 C or 14 Compounds having the present structures except for the replacement of a carbon with a C-rich carbon are within the scope of this disclosure.

[0268] It should also be understood that a reference to one or more method steps does not exclude the presence of additional or intervening method steps that are explicitly identified. Similarly, it should also be understood that a reference to one or more components in a device or system does not exclude the presence of additional or intervening components that are explicitly identified.

[0269] Unless otherwise specified, all crystalline forms of the compounds of the present disclosure, and their salts, are also within the scope of the present disclosure.The compounds of the present disclosure may be isolated in various amorphous and crystalline forms, including, but not limited to, anhydrous, hydrated, non-solvated, or solvated forms.Exemplary hydrates include hemihydrate, monohydrate, dihydrate, and the like.In some embodiments, the compounds of the present disclosure are in anhydrous or non-solvated states."Anhydrous" means that the crystalline form of the compound does not essentially contain bound water in the crystal lattice structure, i.e., the compound does not form crystalline hydrates.

[0270] As used herein, "crystal form" is meant to refer to a particular lattice configuration of a crystalline substance. Different crystal forms of the same substance typically have different crystal lattices (e.g., unit cells), which contribute to the various physical properties that are characteristic of each of the crystal forms. In some cases, different lattice configurations differ in water or solvent content. Different crystal lattices can be distinguished by solid-state characterization methods such as X-ray powder diffraction (PXRD). Other characterization methods, such as, for example, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption measurement (DVS), and solid-state NMR, can further help distinguish crystal forms, as well as determine stability and solvent / water content.

[0271] Crystalline forms of a substance include both solvated (e.g., hydrated) and non-solvated (e.g., anhydrous) forms. Hydrated forms are crystalline forms that contain water within the crystal lattice. Hydrated forms can be stoichiometric hydrates, where water is present within the lattice at a certain water / molecule ratio for hemihydrates, monohydrates, dihydrates, etc. Hydrated forms can also be non-stoichiometric, where the water content varies and is dependent on external conditions such as humidity.

[0272] In some embodiments, the compounds of the present disclosure are substantially isolated. "Substantially isolated" means that a particular compound is at least partially isolated from impurities. For example, in some embodiments, the compounds of the present disclosure contain less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5% impurities. Impurities generally include those that are not substantially isolated compounds, including, for example, other crystal forms and other substances.

[0273] Certain groups, moieties, substituents, and atoms are represented by wavy lines. The wavy lines can cross or cap one or more bonds. The wavy lines indicate the atom to which the group, moiety, substituent, or atom is attached. For example,

[0274] [ka] The phenyl group substituted with a propyl group, represented by the following structure:

[0275] [ka] has.

[0276] The term "GLP1R" refers to glucagon-like peptide 1 receptor, including recombinant GLP1R protein or fragments thereof. GLP1R has a sequence of 463 residues. Donnelly, Br J Pharmacol, 166(1):27-41(2011). Glucagon-like peptide 1 (GLP1) is a 31 amino acid peptide hormone released from intestinal L-cells after nutrient ingestion. Binding of GLP1 to GLP1R enhances glucose-induced insulin secretion from pancreatic β-cells, increases insulin expression, inhibits β-cell apoptosis, promotes β-cell neogenesis, reduces glucagon secretion, delays gastric emptying, promotes satiety, and increases peripheral glucose disappearance.

[0277] Antibody-tethered drug conjugate (ATDC) or antibody-drug conjugate (ADC) refers to an antibody or antigen-binding fragment thereof tethered to a payload (e.g., a GLP1 peptidomimetic) with or without a linker.Antibody-payload conjugate refers to an antibody or fragment linked to a payload, while antibody-linker-payload conjugate refers to an antibody or fragment conjugated to a payload via a linker.Antibody or antigen-binding fragment thereof referred to herein includes embodiments in which the aforementioned antibody or fragment is conjugated to a payload or linker-payload.

[0278] Anti-GLP1R antigen binding proteins and conjugates The present invention provides antigen binding proteins, such as antibodies and antigen-binding fragments thereof that specifically bind to GLP1R, which can be conjugated to a payload by a linker (linker payload) (e.g., REGN7990, REGN9268, REGN15869, REGN18121, REGN18123, REGN8070, REGN8072, REGN9267, REGN7988, REGN5619, REGN7989, REGN8069, REGN8071, REGN9426, REGN5203, REGN5204, REGN5617, REGN5619, REGN7987, REGN9270, REGN9278, REGN9279, or REGN9280, e.g., the linker payload is LP11, LP30, or LP32). In one embodiment of the invention, the payload-tethered anti-GLP1R antibody or antigen-binding fragment thereof has the following structure: BA-(LP) m (A), BA-LP (I) wherein BA is an anti-GLP1R antibody or antigen-binding fragment thereof, the anti-GLP1R antibody or antigen-binding fragment thereof being (i) a heavy chain immunoglobulin or a variable region thereof, comprising CDR-H1, CDR-H2, and CDR-H3 of a heavy chain immunoglobulin or a variable region thereof comprising an amino acid sequence set forth in SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or a variant thereof; and / or a light chain immunoglobulin or a variable region thereof comprising CDR-L1, CDR-L2, and CDR-L3 of a light chain immunoglobulin or a variable region thereof comprising an amino acid sequence as set forth in SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or a variant thereof; (ii) an antibody or antigen-binding fragment thereof that competes with the antibody or fragment of (i) for binding to GLP1R; and / or (iii) an antibody or antigen-binding fragment thereof that binds to the same epitope of GLP1R as the antibody or fragment of (i); L is a non-cleavable linker, P is a payload (e.g., a drug payload such as a GLP1 peptidomimetic); m is 1, 2, 3, or 4. See, for example, ATDC in FIG.

[0279] Antibodies or antigen-binding fragments thereof or conjugates thereof that specifically bind to GLP1R may be referred to as "anti-GLP1R." Anti-GLP1R antibodies and antigen-binding fragments thereof have a K DOr it refers to antibodies and fragments that bind to GLP1R with greater affinity.

[0280] As used herein, an "agonist" antibody or antigen-binding fragment thereof (e.g., ATDC) is an antibody or fragment that increases or enhances at least one biological activity of GLP1R. Such increase or enhancement can be mediated by the antibody itself, or the payload or linker payload of ATDC. For example, an agonist antibody or fragment can induce stimulation of the adenylate cyclase pathway, which leads to increased synthesis of cyclic AMP and insulin release when the cell is a mammalian pancreatic β cell. Other biological activities of GLP1R can be cAMP-dependent activation of protein kinase A (PKA) and / or cAMP-regulated guanine nucleotide exchange factor 2 (Epac2). An agonist antibody or fragment can also reduce glucose levels or reduce body weight after administration to a subject in need of administration.

[0281] A "neutral" antibody or "neutral" binder, with respect to an anti-GLP1R antibody or antigen-binding fragment thereof, refers to an antibody or fragment that binds to GLP1R but does not significantly activate a biological activity of GLP1R (e.g., stimulation of the adenylate cyclase pathway).

[0282] All amino acid abbreviations used in this disclosure are those accepted by the U.S. Patent and Trademark Office as defined in 37 CFR §1.822(B)(J).

[0283] The term "protein" or "polypeptide" refers to any polymer of amino acids having amino acids covalently linked through peptide bonds. "Proteins" include biological drug proteins, recombinant proteins used in research or therapy, trap proteins and other Fc fusion proteins, chimeric proteins, antibodies, monoclonal antibodies, human antibodies, bispecific antibodies, antibody fragments, nanobodies, recombinant antibody chimeras, scFv fusion proteins, cytokines, chemokines, peptide hormones, and the like. Proteins can be produced using recombinant cell-based production systems, such as insect baculovirus systems, yeast systems (e.g., Pichia sp. strains, such as Pichia pastoris), and mammalian systems (e.g., CHO cells and CHO derivatives, such as CHO-K1 cells).

[0284] Polynucleotides include DNA and RNA.

[0285] "GLP1R" refers to human GLP1R unless specifically designated as a non-human species, e.g., "mouse GLP1R", "monkey GLP1R", etc.

[0286] The amino acid sequence of an antibody or antigen-binding fragment thereof can be numbered using any numbering scheme known in the art, including those described in Kabat et al. (the "Kabat" numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (the "Chothia" numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 262:732-745 (the "Contact" numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (the "IMGT" numbering scheme); and Honegge and Pluckthun, J. Mol. Biol., 2001, 309:657-70 (the "AHo" numbering scheme). In one embodiment of the invention, the CDRs of the heavy or light chain immunoglobulin of the anti-GLP1R antibody or antigen-binding fragment thereof (e.g., REGN7990, REGN9268, REGN15869, REGN18121, REGN18123, REGN8070, REGN8072, REGN9267, REGN7988, REGN5619, REGN7989, REGN8069, REGN8071, REGN9426, REGN5203, REGN5204, REGN5617, REGN5619, REGN7987, REGN9270, REGN9278, REGN9279, or REGN9280, e.g., the linker payload is LP11, LP30, or LP32) are as defined by Kabat, Chohia, Contact, IMGT, or AHo.

[0287] The anti-GLP1R antibodies and antigen-binding fragments of the invention may be glutaminyl-modified. For example, the term "glutaminyl-modified" antibody refers to an antibody having at least one covalent bond from a glutamine side chain (from the glutamine (Q) residue in LLQGSG (SEQ ID NO: 18)) to a primary amine compound (e.g., payload or linker payload) of the disclosure (e.g., REGN7990, REGN9268, REGN15869, REGN18121, REGN18123, REGN8070, REGN8071, REGN8072, REGN8073, REGN8074, REGN8075, REGN8076, REGN8077, REGN8078, REGN8079, REGN9268, REGN15869, REGN18121, REGN18123 ...9, REGN8079, REGN9268, REGN15869, REGN18121, REGN18123, REGN8079, REGN8079, 2, REGN9267, REGN7988, REGN5619, REGN7989, REGN8069, REGN8071, REGN9426, REGN5203, REGN5204, REGN5617, REGN5619, REGN7987, REGN9270, REGN9278, REGN9279, or REGN9280, for example, the linker payload is LP11, LP30, or LP32). In certain embodiments of the present invention, the primary amine compound is linked via the amide bond on the glutamine side chain. In certain embodiments of the present invention, the glutamine is endogenous glutamine. In other embodiments of the present invention, the glutamine is endogenous glutamine that is made reactive by polypeptide modification (e.g., deletion, insertion, substitution, or mutation of amino acids on the polypeptide). In further embodiments of the invention, the glutamine is a polypeptide modified with an acyl donor glutamine-containing tag (eg, a glutamine-containing peptide tag, a Q tag, or a TGase recognition tag).

[0288] Transglutaminase (TGase) is an enzyme that catalyzes the transamidation of recognition sequences on other glutamines ("Q-tags" or "Qtags" or "TGase recognition tags"), such as glutamine (Q) residues in the heavy chain of IgG, thereby facilitating site-specific modification. In one embodiment of the invention, an antibody or antigen-binding fragment thereof is modified to include a TGase recognition tag. Suitable TGase recognition tags include those described herein. In one embodiment of the invention, the TGase is a microbial transglutaminase, such as Streptomyces transglutaminase. Sarafeddinov, A Novel Transglutaminase Substrate from Streptomyces mobaraensis Inhibiting Papain-Like Cysteine ​​Proteases”, J. Microbiol. Biotechnol. 2011, 21:617-26. In one embodiment of the present invention, transglutaminase attaches an amine to glutamine (Gln, Q) (e.g., in a Qtag having the amino acid sequence LLQGSG (SEQ ID NO: 18)) via the following reaction scheme: Gln(C=O)NH 2 +RNH 2 →Gln(C=O)NHR+NH 3 ;For example, RNH 2 H 2 N-((CH 2 ) 2 -O) n - Including.

[0289] The term "TGase recognition tag" refers to a sequence of amino acids that includes an acceptor glutamine residue, which, when introduced (e.g., added) into a polypeptide sequence under suitable conditions, is recognized by TGase and results in cross-linking by TGase through a reaction between an amino acid side chain within the sequence of amino acids and a reactive partner. The recognition tag may be a peptide sequence that does not naturally occur in a polypeptide that includes the TGase recognition tag. In some embodiments of the invention, the TGase recognition tag includes at least one Gln. In some embodiments of the invention, the TGase recognition tag includes the amino acid sequence XXQX, where X is any amino acid (e.g., the conventional amino acids Leu, Ala, Gly, Ser, Val, Phe, Tyr, His, Arg, Asn, Glu, Asp, Cys, Met, Pro, Thr, Lys, or Trp, or a non-conventional amino acid). In some embodiments, the acyl donor glutamine-containing tag comprises an amino acid sequence selected from the group consisting of LLQGG (SEQ ID NO:6), LLQG (SEQ ID NO:7), LSLSQG (SEQ ID NO:8), GGGLLQGG (SEQ ID NO:9), GLLQG (SEQ ID NO:10), LLQ,GSPLAQSHGG (SEQ ID NO:11), GLLQGGG (SEQ ID NO:12), GLLQGG (SEQ ID NO:13), GLLQ (SEQ ID NO:14), LLQLLQGA (SEQ ID NO:15), LLQGA (SEQ ID NO:16), LLQYQGA (SEQ ID NO:17), LLQGSG (SEQ ID NO:18), LLQYQG (SEQ ID NO:19), LLQLLQG (SEQ ID NO:20), SLLQG (SEQ ID NO:21), LLQLQ (SEQ ID NO:22), LLQLLQ (SEQ ID NO:23), LLQGSGSG (SEQ ID NO:185), and LLQGR (SEQ ID NO:24). See, for example, WO 2012 / 059882 and U.S. Pat. No. 10,842,881, the entire contents of which are incorporated by reference herein.

[0290] In certain embodiments, the antibody or antigen-binding fragment thereof is modified to contain a Q-tag at the N-terminus of one or both of the antibody or fragment light chains. In certain embodiments, the antibody or fragment thereof is modified to contain a Q-tag at the N-terminus of both antibody light chains.

[0291] In certain embodiments, the antibody or antigen-binding fragment thereof is modified to contain a Q-tag at the N-terminus of one or both of the antibody or antigen-binding fragment heavy chains. In certain embodiments, the antibody or antigen-binding fragment thereof is modified to contain a Q-tag at the N-terminus of both antibody heavy chains.

[0292] In certain embodiments, the antibody or antigen-binding fragment thereof is modified to contain a Q tag at the C-terminus of one or both of the antibody or antigen-binding fragment light chains. In certain embodiments, the antibody or antigen-binding fragment thereof is modified to contain a Q tag at the C-terminus of both antibody light chains.

[0293] In certain embodiments, the antibody or antigen-binding fragment thereof is modified to contain a Q tag at the C-terminus of one or both of the antibody or antigen-binding fragment heavy chains. In certain embodiments, the antibody or antigen-binding fragment thereof is modified to contain a Q tag at the C-terminus of both antibody heavy chains.

[0294] The term "antibody" refers to an immunoglobulin molecule that includes four polypeptide chains, two heavy chains (HC) and two light chains (LC), interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). Preferably, the antibody is in the form of IgG (e.g., IgG1, IgG2, IgG3, or IgG4, or variants thereof, such as IgG4 with S228P mutation), with two heavy chains and two light chains interconnected by disulfide bonds to form a Y-shaped tetramer. See Silva et al., The S228P Mutation Prevents in Vivo and in Vitro IgG4 Fab-arm Exchange as Demonstrated using a Combination of Novel Quantitative Immunoassays and Physiological Matrix Preparation, THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL.290, NO.9, pp. 5462-5469 (2015). In one embodiment of the invention, the antibody or antigen-binding fragment thereof is IgA, IgD, IgE, IgM, IgA1, or IgA2 (or a variant thereof). The antibody may be conjugated to a payload, for example, by a linker.

[0295] The antibody or antigen-binding fragment thereof can be in any form known to those skilled in the art. In certain embodiments, the antibody or fragment comprises a light chain. In certain embodiments, the light chain is a kappa light chain. In certain embodiments, the light chain is a lambda light chain.

[0296] Each heavy chain comprises a heavy chain variable region (referred to herein as HCVR or V H Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L and a light chain constant region (e.g., a human light chain constant region). H Area and V LThe regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with a number of conserved regions, termed framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged in the following order from amino terminus to carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of the antibody (or the antigen-binding portion thereof) can be identical to the human germline sequence or can be naturally or artificially modified. An amino acid consensus sequence can be defined based on a comparative analysis of two or more CDRs.

[0297] Antigen-binding fragments of antibodies that specifically bind to GLP1R are also part of the present invention. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived, for example, from antibody molecules using any suitable standard technique, such as proteolytic or recombinant genetic engineering techniques, involving the manipulation and expression of DNA encoding the variable domains of the antibody and optionally the constant domains of the antibody. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to place one or more variable and / or constant domains in a suitable configuration, or to introduce codons, generate cysteine ​​residues, modify, add, or delete amino acids. Antigen-binding fragments can be conjugated to payloads, for example, by linkers.

[0298] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments, (ii) F(ab') 2Antigen-binding fragments include (iii) Fd fragments, (iv) Fv fragments, (v) single chain Fv (scFv) or scFv-Fc molecules, (vi) dAb fragments, and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable regions (e.g., isolated complementarity determining regions (CDRs) such as CDR3 peptides) of an antibody or restricted FR3-CDR3-FR4 peptides. In some embodiments of the present invention, the antibody fragment is a Fab' fragment. Other engineered molecules such as domain-specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also encompassed by the term "antigen-binding fragment" as used herein.

[0299] An antigen-binding fragment of an antibody contains at least one variable domain. The variable domain can be of any size or amino acid composition and generally contains at least one CDR adjacent to or in frame with one or more framework sequences. L V related to domain H For antigen-binding fragments containing domains, V H Domains and V L The domains can be positioned relative to each other in any suitable configuration. For example, the variable region is a dimer and the V H -V H , V H -V L , or V L -V L It may contain dimers.

[0300] Alternatively, the antigen-binding fragment of the antibody may be a monomeric V H Domain or V L It may contain domains.

[0301] Antigen-binding fragments of antibodies can contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that can be found in antigen-binding fragments of antibodies herein include: (i) V H -C H 1, (ii) V H -C H 2. (iii) V H -C H 3. (iv) V H -C H 1-C H 2. (V)V H -C H 1-C H 2-C H 3. (vi) V H -C H 2-C H 3. (vii) V H -C L , (viii) V L -C H 1, (ix) V L -C H 2. (x)V L -C H 3. (xi) V L -C H 1-C H 2. (xii) V L -C H 1-C H 2-C H 3. (xiii) V L -C H 2-C H 3, and (xiv) V L -C L In any configuration of variable and constant domains, including any of the exemplary configurations listed herein, the variable and constant domains may be directly linked to each other or may be linked by a full or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule.

[0302] Furthermore, antigen-binding fragments of the antibodies herein may be in non-covalent association with each other and / or with one or more monomeric V H Domain or V L The domains may be associated (e.g., by disulfide bonds) to comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed herein.

[0303] As with antibodies, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies can contain at least two different variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use in conjunction with the antigen-binding fragments of antibodies herein using routine techniques available in the art.

[0304] In certain embodiments, the antibody herein, for example, anti-GLP1R antibody, is a human antibody. As used herein, the term "human antibody" is intended to include antibodies with variable and constant regions derived from human germline immunoglobulin sequences. The human antibody herein may, for example, in the CDRs, particularly CDR3, contain amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, are grafted onto human framework sequences.

[0305] In one embodiment of the invention, the antibody is a monoclonal antibody. In one embodiment of the invention, the antibody is a polyclonal antibody. In one embodiment of the invention, the antibody is a chimeric antibody. In one embodiment of the invention, the antibody is a humanized antibody.

[0306] The antibodies and antigen-binding fragments may in some embodiments be recombinant human antibodies and antigen-binding fragments. As used herein, the term "recombinant" antibodies is intended to include antibodies prepared, expressed, generated, or isolated by recombinant means. For example, recombinant antibodies include antibodies expressed using a recombinant expression vector transfected into a host cell (e.g., Chinese hamster ovary cell) and, optionally, isolated from the host cell and / or the culture medium in which the host cell is grown. Recombinant antibodies include antibodies isolated from a recombinant combinatorial human antibody library, antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, generated, or isolated by any other means including splicing of human immunoglobulin gene sequences to other DNA sequences. Such human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, when animals transgenic for human Ig sequences are used) to thereby modify the V H Area and V L The amino acid sequence of the region is H Array and V L Although derived from and related to a sequence, it may not naturally occur within the human antibody germline repertoire in vivo.

[0307] The antibodies and antigen-binding fragments herein may be isolated or purified antibodies. As used herein, an "isolated" or "purified" antibody refers to an antibody that is identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody" for the purposes of this specification. In addition, an antibody that is partially or completely removed from the recombinant host cell in which it is produced is "isolated". For example, an antibody that has been purified from at least one component of a reaction or reaction sequence is an "isolated" or "purified" antibody. An isolated antibody also includes an antibody in situ in a recombinant cell. An isolated antibody includes an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0308] The antibodies and antigen-binding fragments disclosed herein may contain one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains, as compared to the corresponding germline sequences from which the antibodies are derived. Such mutations can be easily ascertained by comparing the amino acid sequences disclosed herein with germline sequences available, for example, from public antibody sequence databases. The present specification includes antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, in which one or more amino acids in one or more framework and / or CDR regions are mutated to the corresponding one or more residues in the germline sequence from which the antibodies are derived, or to the corresponding residues in another human germline sequence, or to conservative amino acid substitutions of the corresponding germline residues (such sequence changes are collectively referred to herein as "germline mutations"). Starting from a given heavy and light chain variable region sequence, one skilled in the art can easily produce a large number of antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and / or CDR residues in the VH and / or VL domains are mutated back to the residues found in the germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the germline sequence from which they were derived, for example only the mutated residues found within the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only the mutated residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residue in a different germline sequence (i.e., a different germline sequence from the germline sequence from which the antibody was originally derived).

[0309] Furthermore, the antibodies and antigen-binding fragments herein can contain any combination of two or more germline mutations in the framework and / or CDR regions, for example, certain individual residues are mutated to the corresponding residues of a particular germline sequence, while certain other residues that differ from the germline sequence of origin are maintained or mutated to the corresponding residues of a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or stimulatory biological properties (as the case may be), reduced immunogenicity, improved drug-to-antibody ratio (DAR) of antibody drug conjugates, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the scope of the present specification.

[0310] The present invention includes anti-GLP1R antibodies and antigen-binding fragments thereof that are aglycosylated (e.g., conjugated to a payload, e.g., by a linker). The term "aglycosylated" antibodies and antigen-binding fragments includes antibodies or fragments that do not contain glycosylation sequences that may interfere with transglutamination reactions, e.g., antibodies that do not have a sugar group at N297 on one or more heavy chains. In certain embodiments, the antibody heavy chain has an N297 mutation. The antibody is mutated to never have an asparagine residue at position 297 according to the EU numbering scheme disclosed by Kabat et al. In certain embodiments, the antibody heavy chain has an N297Q mutation or an N297D mutation. Such antibodies can be prepared by site-directed mutagenesis to remove or disable glycosylation sequences, or to insert a glutamine residue at a site away from any glycosylation-interfering sites or other interfering structures. Such antibodies can also be isolated from natural or artificial sources. Aglycosylated antibodies also include antibodies and fragments that contain T299 or S298P or other mutations, or combinations of mutations resulting from the lack of glycosylation. An aglycosylated antibody or antigen-binding fragment thereof may be completely devoid of glycosylation, for example after expression in a bacterial host cell.

[0311] The present invention includes deglycosylated anti-GLP1R antibodies and antigen-binding fragments thereof (e.g., conjugated to a payload, e.g., by a linker). The term "deglycosylated" antibody or antigen-binding fragment thereof refers to an antibody or fragment from which sugar groups have been removed to facilitate transglutaminase-mediated conjugation. Sugars include, but are not limited to, N-linked oligosaccharides. In some embodiments, deglycosylation is performed at the N297 residue. In some embodiments, removal of sugar groups is achieved enzymatically via PNGase.

[0312] The term "epitope" refers to an antigenic determinant (e.g., of GLP1R) that interacts with a specific antigen-binding site in the variable region of an antibody or antigen-binding fragment thereof, known as the paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions on the antigen and have different biological effects. Epitopes may be structural or linear. Structural epitopes are generated by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are epitopes generated by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes may include sugar, phosphoryl, or sulfonyl moieties on the antigen.

[0313] The term "conjugated" protein, antibody, or antigen-binding fragment, as used herein, refers to a protein, antibody, or fragment that is covalently bound to one or more chemical moieties. The chemical moieties can include the amine compounds of the present disclosure. Linkers (L) and payloads (P) suitable for use in the present disclosure are described in detail herein.

[0314] The term "drug to antibody ratio" or (DAR) is the average number of therapeutic moieties, e.g., drugs, that are conjugated to a binding agent (e.g., an antibody or antigen-binding fragment thereof) of the disclosure.

[0315] The term "linker-antibody ratio" or (LAR) (also written in lower case) is, in some embodiments, the average number of reactive primary amine compounds conjugated to a binding agent of the present disclosure. Such binding agents, such as antibodies or antigen-binding fragments thereof, can be conjugated, for example, with a suitable azide- or alkyne-containing primary amine compound. The resulting binding agent is functionalized with an azide or alkyne, but can later be reacted with the corresponding azide- or alkyne-containing therapeutic moiety via a 1,3-cycloaddition reaction.

[0316] The phrase "reaction pH" refers to the pH of the reaction after all reaction components or reactants have been added.

[0317] Immunoglobulin chains (e.g., REGN7990, REGN9268, REGN15869, REGN18121, REGN18123, REGN8070, REGN8072, REGN9267, REGN7988, REGN5619, REGN7989, REGN8069, REGN8071, REGN9426, REGN5203, REGN5204, REGN5617, REGN5619, REGN7987, REGN9270, REGN9278, REGN9279, or REGN9280 V as described herein H , V L"Variants" of polypeptides such as the amino acid sequences of SEQ ID NOs: 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 414, 416, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 172, 173, 174, 175, 176, 177, 178, 179, 180, 1 2, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239 , 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355 , 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 407, 409, 411, or 413) and at least about 70 to 99.9% (e.g., 70, 72, 74, 75, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9%) refers to polypeptides containing amino acid sequences that are identical or similar, and when the comparison is performed by the BLAST algorithm, the parameters of the algorithm are selected to maximize the match between the respective sequences over the entire length of the respective reference sequences (e.g., expectation threshold: 10, word size: 3, maximum match within query: 0, BLOSUM 62 matrix, gap cost: presence 11, extension 1, conditional compositional score matrix adjustment).

[0318] "Variant" polypeptides include those having the same or similar structure as the reference amino acid sequences described herein (e.g., SEQ ID NOs: 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 415, 417, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244 , 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 3 58, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, ​​384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, or 412) and at least about 70-99.9% (e.g., 70, 72, 74, 75, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, 99.9%) identical, and where the comparison is performed by the BLAST algorithm, the parameters of the algorithm are selected to maximize the match between the respective sequences over the entire length of the respective reference sequences (e.g., expectation threshold: 10, word size: 28, maximum match within query: 0, match / mismatch score: 1, -2, gap cost: linear).

[0319] The following references relate to the BLAST algorithm, which is often used for sequence analysis: BLAST ALGORITHMS: Altschul et al. (2005) FEBS J. 272(20):5101-5109; Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403-410; Gish, W. et al. (1993) Nature Genet. 3:266-272; Madden, T. L. et al. (1996) Meth. Enzymol. 266:131-141; Altschul, S. F. et al. (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J. et al. (1997) Genome Res.7:649-656, Wootton, JC et al. (1993) Comput.Chem.17:149-163, Hancock, JM et al. (1994) Comput.Appl.Biosci.10:67-70, ALIGNMENT SCORING SYSTEMS: Dayhoff, MO et al. "A model of evolutionary change in proteins." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. MODayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC, Schwartz, RM et al. "Matrices for detecting distant relationships." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3.” MO Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, SF, (1991) J. Mol. Biol. 219: pp. 555-565; States, DJ et al. (1991) Methods 3: pp. 66-70; Henikoff, S. et al. (1992) Proc. Natl. Acad. Sci. USA 89: pp. 10915-10919; Altschul, SF et al. (1993) J. Mol. Evol.36:290-300 pages, ALIGNMENT STATISTICS: Karlin, S. et al. (1990) Proc. Natl. Acad. Sci. USA 87: 2264-2268 pages, Karlin, S. et al. (1993) Proc. Natl. Acad. Sci. USA 90:5873~5877, Dembo, A. et al. (1994) Ann. Prob. 22:2022~2039, and Altschul, SF "Evaluating the statistical significance of multiple distinct local alignments." in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1~14, Plenum, NY. .

[0320] Anti-GLP1R antigen binding proteins, such as antibodies and antigen binding fragments thereof of the invention, in one embodiment of the invention comprise a heavy chain immunoglobulin or variable region thereof having at least 70% (e.g., 80%, 85%, 90%, 95%, 99%) amino acid sequence identity to SEQ ID NO: 26, 46, 66, 86, 106, 126, 146, 166, 42, 62, 82, 414, 416, 102, 122, 142, 162, or 182, and / or a light chain immunoglobulin or variable region thereof having at least 70% (e.g., 80%, 85%, 90%, 95%, 99%) amino acid sequence identity to SEQ ID NO: 34, 54, 74, 94, 114, 134, 154, 174, 44, 64, 84, 104, 124, 144, 164, or 184.

[0321] Additionally, variants of the polypeptides can be those having the amino acid sequences described herein (e.g., SEQ ID NOs: 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 414, 416, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 172, 173, 174, 175, 176, 177, 178, 179, 18 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) mutations, such as missense mutations (e.g., conservative substitutions), non-sense mutations, deletions, or insertions. For example, the present invention provides immunoglobulin light chains (i.e., V L ) variants, and / or immunoglobulin heavy chains (i.e., V HIn one embodiment of the invention, the anti-GLP1R antibody or antigen-binding fragment thereof includes an immunoglobulin light chain variant comprising CDR-L1, CDR-L2, and CDR-L3, in which one or more (e.g., one, two, or three) of such CDRs have one or more of the above-mentioned mutations (e.g., conservative substitutions), and / or an immunoglobulin heavy chain variant comprising CDR-H1, CDR-H2, and CDR-H3, in which one or more (e.g., one, two, or three) of such CDRs have one or more of the above-mentioned mutations (e.g., conservative substitutions).

[0322]

[0023] Embodiments of the invention also include antigen binding proteins, such as anti-GLP1R antibodies and antigen binding fragments thereof, which include immunoglobulin VH and VL, or HC and LC, which include variant amino acid sequences having 70% or more (e.g., 80%, 85%, 90%, 95%, 97%, or 99%) overall amino acid sequence identity or similarity to the corresponding VH, VL, HC, or LC amino acid sequences specifically described herein, but the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 of such immunoglobulins are not variant and include the amino acid sequences specifically described herein. Thus, in such embodiments, the CDRs of the variant antigen binding proteins themselves are not variant.

[0323] For example, "conservatively modified variants" or "conservative substitutions" of immunoglobulin chains described herein refer to variants in which there is one or more substitutions of amino acids in a polypeptide with other amino acids having similar properties (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone organization, and rigidity, etc.). Such changes can be frequently made without significantly impairing the biological activity of the antibody or fragment. Those skilled in the art will recognize that single amino acid substitutions in non-essential regions of a polypeptide generally do not significantly alter biological activity (see, for example, Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th Ed.)). Moreover, substitutions of structurally or functionally similar amino acids are unlikely to significantly impair biological activity. The present invention includes anti-GLP1R antigen binding proteins comprising such conservatively modified variant immunoglobulin chains.

[0324] Examples of groups of amino acids with side chains with similar chemical properties include: 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartate and glutamate, and 7) sulfur-containing side chains: cysteine ​​and methionine. Preferred conservative amino acid substitution groups are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative substitution is any change for which the PAM250 log-likelihood matrix value disclosed in Gonnet et al. (1992) Science 256:1443 45 is positive.

[0325] The immunoglobulin chains of the anti-GLP1R antibodies and antigen-binding fragments of the invention are summarized in Tables A and B below.

[0326] [Table 1-1]

[0327] [Table 1-2]

[0328] [Table 2] REGN9268 Heavy chain variable region (HCVR; V H )-Nucleotide sequence GAAGTGCAACTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CATCTTCAGTAGATATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATGAGTAGTA ATAGTAAAAACACATACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAAAACTCACTGTTT CTGCAAATGAACACCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGCGAGAGATGGATACACCCTCAGGGCTTTTGA TATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA (SEQ ID NO: 25) Heavy chain variable region (HCVR; V H )-Amino acid sequence EVQLVESGGGLVKPGGSLRLSCAAS GFIFSRYS MNWVRQAPGKGLEWVSS MSSNSKNT YYADSVKGRFTISRDNAKNSLF LQMNTLRAEDTAVYYC ARDGYTLRAFDI WGQGTMVTVSS (SEQ ID NO: 26) CDR-H1-nucleotide sequence GGA TTC ATC TTC AGT AGA TAT AGC (SEQ ID NO: 27) CDR-H1-amino acid sequence GFIFSRYS (SEQ ID NO:28) CDR-H2-nucleotide sequence ATG AGT AGT AAT AGT AAA AAC ACA (SEQ ID NO: 29) CDR-H2-amino acid sequence MSSNSKNT (SEQ ID NO: 30) CDR-H3-nucleotide sequence GCG AGA GAT GGA TAC ACC CTC AGG GCT TTT GAT ATC (SEQ ID NO: 31) CDR-H3-amino acid sequence ARDGYTLRAFDI (SEQ ID NO: 32) Light chain variable region (LCVR; V L )-Nucleotide sequence GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTCTGTCTCCAGGGGAAAGAGACACCCTCTCCTGCAGGGCCAGTCA GAGTATTGCCGGCAGATACGTAGCCTGGTACCAGCAGAAACCTGGCCAGGCACCCAGACTCCTCATCTACGGTGCATCCA GCAGGGCCACTGGCATCCCAGACAGATTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAG CCTGAAGATTTTGCAGTGTATTACTGTCAGCATATGGTAGCTCACCTTGGACGTTCGGCCAAGGGACCAAAGGTGGAAAT CAAA (SEQ ID NO: 33) Light chain variable region (LCVR; V L )-Amino acid sequence EIVLTQSPGTLSLSPGERDTLSCRAS QSIAGRY VAWYQQKPGQAPRLLIY GAS SRATGIPDRFSGSGSGTDFTLTISRLE PEDFAVYYC QQYGSSPWT FGQGTKVEIK (SEQ ID NO:34) CDR-L1-nucleotide sequence CAG AGT ATT GCC GGC AGA TAC (SEQ ID NO: 35) CDR-L1-amino acid sequence QSIAGRY (SEQ ID NO:36) CDR-L2-nucleotide sequence GGT GCA TCC (SEQ ID NO: 37) CDR-L2-amino acid sequence GAS (SEQ ID NO: 38) CDR-L3-nucleotide sequence CAG CAA TAT GGT AGC TCA CCT TGG ACG (SEQ ID NO: 39) CDR-L3-amino acid sequence QQYGSSPWT (SEQ ID NO: 40) Heavy chain (HC)-nucleotide sequence GAAGTGCAACTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CATCTTCAGTAGATATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATGAGTAGTA ATAGTAAAAACACATACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAAAACTCACTGTTT CTGCAAATGAACACCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGCGAGAGATGGATACACCCTCAGGGCTTTTGA TATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCT CCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGT GGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGG ACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTC CTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCA GGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGC AGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGC AAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGT GTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCA GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGAT GCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 41) Heavy chain amino acid sequence EVQLVESGGGLVKPGGSLRLSCAASGFIFSRYSMNWVRQAPGKGLEWVSSMSSNSKNTYYADSVKGRFTISRDNAKNSLF LQMNTLRAEDTAVYYCARDGYTLRAFDIWGQGTMVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKGLPSSIEKTISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 42) Light chain (LC)-nucleotide sequence TTACTTCAGGGATCTGGTGAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTCTGTCTCCAGGGGAAAGAGACACCCT CTCCTGCAGGGCCAGTCAGAGTATTGCCGGCAGATACGTAGCCTGGTACCAGCAGAAACCTGGCCAGGCACCCAGACTCC TCATCTACGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGATTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTC ACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCATATGGTAGCTCACCTTGGACGTTCGGCCA AGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGAC GCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAA AGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 43) Light chain (LC)-amino acid sequence LLQGSG EIVLTQSPGTLSLSPGERDTLSCRASQSIAGRYVAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTL TISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:44) REGN7990 Heavy chain variable region (HCVR; V H )-Nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTCTCAGCTATTACGGGTA GTGGTGGCAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGCCTTATAGCACCTCGTCCGATGGG CTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 45) Heavy chain variable region (HCVR; V H )-Amino acid sequence EVQLVESGGGLVQPGGSLRLSCAAS GFTFSSYA MSWVRQAPGKGLEWVSA ISGSGGST YYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYC AKGLIAPRPMGFDY WGQGTLVTVSS (SEQ ID NO: 46) CDR-H1-nucleotide sequence GGA TTC ACC TTT AGC AGC TAT GCC (SEQ ID NO: 47) CDR-H1-amino acid sequence GFTFSSYA (SEQ ID NO: 48) CDR-H2-nucleotide sequence ATT AGC GGT AGT GGT GGC AGC ACA (SEQ ID NO: 49) CDR-H2-amino acid sequence ISGSGGST (SEQ ID NO:50) CDR-H3-nucleotide sequence GCG AAA GGC CTT ATA GCA CCT CGT CCG ATG GGC TTT GAC TAC (SEQ ID NO: 51) CDR-H3-amino acid sequence AKGLIAPRPMGFDY (SEQ ID NO:52) Light chain variable region (LCVR; V L )-Nucleotide sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCA GGGTATTAACAGCTGGTTAGCCTGGTATCAGCAGAAACCTGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAAGATTTTGCAACTTACTATTGTCACCAGGCTGACAGTTTCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAA A (SEQ ID NO:53) Light chain variable region (LCVR; V L )-Amino acid sequence DIQMTQSPSSVSASVGDRVTITCRAS QGINSW LAWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYC HQADSFPYT FGQGTKLEIK (SEQ ID NO:54) CDR-L1-nucleotide sequence CAG GGT ATT AAC AGC TGG (SEQ ID NO: 55) CDR-L1-amino acid sequence QGINSW (SEQ ID NO:56) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 57) CDR-L2-amino acid sequence AAS (SEQ ID NO:58) CDR-L3-nucleotide sequence CAC CAG GCT GAC AGT TTC CCG TAC ACT (SEQ ID NO: 59) CDR-L3-amino acid sequence HQADSFPYT (SEQ ID NO: 60) Heavy chain - nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTCTCAGCTATTAGCGGTA GTGGTGGCAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGCCTTATAGCACCTCGTCCGATGGG CTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGC CCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTG TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG CAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCA AGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCA GTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGT GAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGG AGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTAC AAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCC ACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT ACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTC CGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA(SEQ ID NO: 61) Heavy chain - Amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCAKGLIAPRPMGFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 62) Light chain - nucleotide sequence CTGCTGCAAGGCTCTGGCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCAT CACTTGTCGGGCGAGTCAGGGTATTAACAGCTGGTTAGCCTGGTATCAGCAGAAACCTGGGAAAGCCCCTAAGCTCCTGA TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACC ATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCACCAGGCTGACAGTTTCCCGTACACTTTTGGCCAGGG GACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 63) Light chain amino acid sequence LLQGSG DIQMTQSPSSVSASVGDRVTITCRASQGINSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCHQADSFPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 64) RAIN15869 Heavy chain variable region (HCVR; V H )-Nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTCTCAGCTATTACGGGTA GTGGTGGCAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGCCTTATAGCACCTCGTCCGATGGG CTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 65) Heavy chain variable region (HCVR; V H )-Amino acid sequence EVQLVESGGGLVQPGGSLRLSCAAS GFTFSSYA MSWVRQAPGKGLEWVSA ISGSGGSTYYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYC AKGLIAPRPMGFDY WGQGTLVTVSS (SEQ ID NO: 66) CDR-H1-nucleotide sequence GGA TTC ACC TTT AGC AGC TAT GCC (SEQ ID NO: 67) CDR-H1-amino acid sequence GFTFSSYA (SEQ ID NO: 68) CDR-H2-nucleotide sequence ATT AGC GGT AGT GGT GGC AGC ACA (SEQ ID NO: 69) CDR-H2-amino acid sequence ISGSGGST (SEQ ID NO: 70) CDR-H3-nucleotide sequence GCG AAA GGC CTT ATA GCA CCT CGT CCG ATG GGC TTT GAC TAC (SEQ ID NO: 71) CDR-H3-amino acid sequence AKGLIAPRPMGFDY (SEQ ID NO:72) Light chain variable region (LCVR; V L )-Nucleotide sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCA GGGTATTAACAGCTGGTTAGCCTGGTATCAGCAGAAACCTGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAAGATTTTGCAACTTACTATTGTCACCAGGCTGACAGTTTCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAA A (SEQ ID NO:73) Light chain variable region (LCVR; V L )-Amino acid sequence DIQMTQSPSSVSASVGDRVTITCRAS QGINSW LAWYQQKPGKAPKLLIY AAS SLESGVPSRFSGSGSGTDFTLTISSLQP EDFATYYC HQADSFPYT FGQGTKLEIK (SEQ ID NO:74) CDR-L1-nucleotide sequence CAG GGT ATT AAC AGC TGG (SEQ ID NO: 75) CDR-L1-amino acid sequence QGINSW (SEQ ID NO:76) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 77) CDR-L2-amino acid sequence AAS (SEQ ID NO: 78) CDR-L3-nucleotide sequence CAC CAG GCT GAC AGT TTC CCG TAC ACT (SEQ ID NO: 79) CDR-L3-amino acid sequence HQADSFPYT (sequence number 80) Heavy chain - nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTCTCAGCTATTACGGGTA GTGGTGGCAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGCCTTATAGCACCTCGTCCGATGGG CTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGC CCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTG TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG CAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCA AGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCA GTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGT GAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGG AGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTAC AAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCC ACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT ACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTC CGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 81) Heavy chain amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCAKGLIAPRPMGFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 82) Light chain - nucleotide sequence CTGCTGCAAGGCTCTGGCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCAT CACTTGTCGGGCGAGTCAGGGTATTAACAGCTGGTTAGCCTGGTATCAGCAGAAACCTGGGAAAGCCCCTAAGCTCCTGA TCTATGCTGCATCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACC ATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCACCAGGCTGACAGTTTCCCGTACACTTTTGGCCAGG GACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 83) Light chain amino acid sequence LLQGSG DIQMTQSPSSVSASVGDRVTITCRASQGINSWLAWYQQKPGKAPKLLIYAASSLESGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCHQADSFPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 84) RAIN18121 Heavy chain variable region (HCVR; V H )-Nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTCTCAGCTATTACGGGTA GTGGTGGCAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGCCTTATAGCACCTCGTCCGATGGG CTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 65) Heavy chain variable region (HCVR; V H )-Amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCAKGLIAPRPMGFDYWGQGTLVTVSS (SEQ ID NO: 66) CDR-H1-nucleotide sequence GGA TTC ACC TTT AGC AGC TAT GCC (SEQ ID NO: 67) CDR-H1-amino acid sequence GFTFSSYA (SEQ ID NO: 68) CDR-H2-nucleotide sequence ATT AGC GGT AGT GGT GGC AGC ACA (SEQ ID NO: 69) CDR-H2-amino acid sequence ISGSGGST (SEQ ID NO: 70) CDR-H3-nucleotide sequence GCG AAA GGC CTT ATA GCA CCT CGT CCG ATG GGC TTT GAC TAC (SEQ ID NO: 71) CDR-H3-amino acid sequence AKGLIAPRPMGFDY (SEQ ID NO:72) Light chain variable region (LCVR; V L )-Nucleotide sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCA GGGTATTAACAGCTGGTTAGCCTGGTATCAGCAGAAACCTGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAAGATTTTGCAACTTACTATTGTCACCAGGCTGACAGTTTCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAA A (SEQ ID NO:73) Light chain variable region (LCVR; V L )-Amino acid sequence DIQMTQSPSSVSASVGDRVTITCRASQGINSWLAWYQQKPGKAPKLLIYAASSLESGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCHQADSFPYTFGQGTKLEIK (SEQ ID NO: 74) CDR-L1-nucleotide sequence CAG GGT ATT AAC AGC TGG (SEQ ID NO: 75) CDR-L1-amino acid sequence QGINSW (SEQ ID NO:76) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 77) CDR-L2-amino acid sequence AAS (SEQ ID NO: 78) CDR-L3-nucleotide sequence CAC CAG GCT GAC AGT TTC CCG TAC ACT (SEQ ID NO: 79) CDR-L3-amino acid sequence H Q A D S F P Y T (SEQ ID NO: 80) Heavy chain - nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTCTCAGCTATTAGCGGTA GTGGTGGCAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGCCTTATAGCACCTCGTCCGATGGG CTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGC CCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTG TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG CAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCA AGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCA GTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGT GAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGG AGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTAC AAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCC ACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT ACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTC CGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAA(SEQ ID NO: 415) Heavy chain - Amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCAKGLIAPRPMGFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 414) Light chain - nucleotide sequence CTGCTGCAAGGCTCTGGCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCAT CACTTGTCGGGCGAGTCAGGGTATTAACAGCTGGTTAGCCTGGTATCAGCAGAAACCTGGGAAAGCCCCTAAGCTCCTGA TCTATGCTGCATCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACC ATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCACCAGGCTGACAGTTTCCCGTACACTTTTGGCCAGGG GACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 83) Light chain - amino acid sequence LLQGSG DIQMTQSPSSVSASVGDRVTITCRASQGINSWLAWYQQKPGKAPKLLIYAASSLESGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCHQADSFPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 84) RAIN18123 Heavy chain variable region (HCVR; V H )-Nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTCTCAGCTATTACGGGTA GTGGTGGCAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGCCTTATAGCACCTCGTCCGATGGG CTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 65) Heavy chain variable region (HCVR; V H )-Amino acid sequence EVQLVESGGGLVQPGGSLRLSCAAS GFTFSSYA MSWVRQAPGKGLEWVSA ISGSGGST YYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYC AKGLIAPRPMGFDY WGQGTLVTVSS (SEQ ID NO: 66) CDR-H1-nucleotide sequence GGA TTC ACC TTT AGC AGC TAT GCC (SEQ ID NO: 67) CDR-H1-amino acid sequence GFTFSSYA (SEQ ID NO: 68) CDR-H2-nucleotide sequence ATT AGC GGT AGT GGT GGC AGC ACA (SEQ ID NO: 69) CDR-H2-amino acid sequence ISGSGGST (SEQ ID NO: 70) CDR-H3-nucleotide sequence GCG AAA GGC CTT ATA GCA CCT CGT CCG ATG GGC TTT GAC TAC (SEQ ID NO: 71) CDR-H3-amino acid sequence AKGLIAPRPMGFDY (SEQ ID NO:72) Light chain variable region (LCVR; V L )-Nucleotide sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCA GGGTATTAACAGCTGGTTAGCCTGGTATCAGCAGAAACCTGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAAGATTTTGCAACTTACTATTGTCACCAGGCTGACAGTTTCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAA A (SEQ ID NO:73) Light chain variable region (LCVR; V L )-Amino acid sequence DIQMTQSPSSVSASVGDRVTITCRAS QGINSW LAWYQQKPGKAPKLLIY AAS SLESGVPSRFSGSGSGTDFTLTISSLQP EDFATYYC HQADSFPYTFGQGTKLEIK (SEQ ID NO:74) CDR-L1-nucleotide sequence CAG GGT ATT AAC AGC TGG (SEQ ID NO: 75) CDR-L1-amino acid sequence QGINSW (SEQ ID NO:76) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 77) CDR-L2-amino acid sequence AAS (SEQ ID NO: 78) CDR-L3-nucleotide sequence CAC CAG GCT GAC AGT TTC CCG TAC ACT (SEQ ID NO: 79) CDR-L3-amino acid sequence HQADSFPYT (sequence number 80) Heavy chain - nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTCTCAGCTATTACGGGTA GTGGTGGCAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGCCTTATAGCACCTCGTCCGATGGG CTTTGACTACTGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGC CCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTG TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG CAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCA AGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCA GTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGT GAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGG AGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTAC AAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCC ACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT ACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTC CGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGT (SEQ ID NO: 417) Heavy chain amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCAKGLIAPRPMGFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSL (SEQ ID NO: 416) Light chain - nucleotide sequence CTGCTGCAAGGCTCTGGCGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCAT CACTTGTCGGGCGAGTCAGGGTATTAACAGCTGGTTAGCCTGGTATCAGCAGAAACCTGGGAAAGCCCCTAAGCTCCTGA TCTATGCTGCATCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACC ATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCACCAGGCTGACAGTTTCCCGTACACTTTTGGCCAGG GACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 83) Light chain amino acid sequence LLQGSG DIQMTQSPSSVSASVGDRVTITCRASQGINSWLAWYQQKPGKAPKLLIYAASSLESGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCHQADSFPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 84) REGN8070 Heavy chain variable region (HCVR,V H )-Nucleotide sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGGCCAGCCTGGGAGGTCCCTGAGACTGTCCTGTGCAGCCTCTGGATT CACCTTCAGCAGGAATGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTCATATCATATG ATGGAAGTAATAAACACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGGAAATGAACAGCCTGAGAGTTGAGGACACGGCTGTGTATTATTGTGCGAAAGGGGGGATTCCTTTTGACTACTGGGG CCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 85) Heavy chain variable region (HCVR,V H )-Amino acid sequence QVQLVESGGGVGQPGRSLRLSCAAS GFTFSRNA MHWVRQAPGKGLEWVAV ISYDGSNK HYADSVKGRFTISRDNSKNTLY LEMNSLRVEDTAVYYC AKGGIPFDY WGQGTLVTVSS (SEQ ID NO: 86) CDR-H1-nucleotide sequence GGA TTC ACC TTC AGC AGG AAT GCC (SEQ ID NO: 87) CDR-H1-amino acid sequence GFTFSRNA (SEQ ID NO: 88) CDR-H2-nucleotide sequence ATA TCA TAT GAT GGA AGT AAT AAA (SEQ ID NO: 89) CDR-H2-amino acid sequence ISYDGSNK (SEQ ID NO: 90) CDR-H3-nucleotide sequence GCG AAA GGG GGG ATT CCT TTT GAC TAC (SEQ ID NO: 91) CDR-H3-amino acid sequence AKGGIPFDY (SEQ ID NO: 92) Light chain variable region (LCVR,V L )-Nucleotide sequence GATATTGTGATGACCCAGTCTCCACTCTCCTCACCTGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCA AAGCCTCGTACACTTTGATGGAAACACCTACTTGAGTTGGCTTCACCAGAGGCCAGGCCAGCCTCCAAGACTCCTAATTT ATAAGATTTCTAACCGCTTCTCTGGGGTCCCAGACAGATTCAGTGGCAGTGGGGCAGGGACAGATTTCACACTGAAAATC AGCAGGGTGGAACCTGAAGATGTCGGGGTTTATTACTGCATGCATGCTACACAATTTCCGTACACTTTTGGCCAGGGGAC CAAGCTGGAGATCAAA (SEQ ID NO: 93) Light chain variable region (LCVR,V L )-Amino acid sequence DIVMTQSPLSSPVTLGQPASISCRSS QSLVHFDGNTY LSWLHQRPGQPPRLLIY KIS NRFSGVPDRFSGSGAGTDFTLKI SRVEPEDVGVYYC MHATQFPYT FGQGTKLEIK (SEQ ID NO: 94) CDR-L1-nucleotide sequence CAA AGC CTC GTA CAC TTT GAT GGA AAC ACC TAC (SEQ ID NO: 95) CDR-L1-amino acid sequence QSLVHFDGNTY (SEQ ID NO:96) CDR-L2-nucleotide sequence AAG ATT TCT (SEQ ID NO: 97) CDR-L2-amino acid sequence KIS (SEQ ID NO: 98) CDR-L3-nucleotide sequence ATG CAT GCT ACA CAA TTT CCG TAC ACT (SEQ ID NO: 99) CDR-L3-amino acid sequence MHATQFPYT (SEQ ID NO: 100) Heavy chain (HC)-nucleotide sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGGCCAGCCTGGGAGGTCCCTGAGACTGTCCTGTGCAGCCTCTGGATT CACCTTCAGCAGGAATGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTCATATCATATG ATGGAAGTAATAAACACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGGAAATGAACAGCCTGAGAGTTGAGGACACGGCTGTGTATTATTGTGCGAAAGGGGGGATTCCTTTTGACTACTGGGG CCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCA CCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGT GCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCC CCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCC CGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACA GCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCC AACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCT GCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCG CCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTC TTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGC TCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 101) Heavy chain - Amino acid sequence QVQLVESGGGVGQPGRSLRLSCAASGFTFSRNAMHWVRQAPGKGLEWVAVISYDGSNKHYADSVKGRFTISRDNSKNTLY LEMNSLRVEDTAVYYCAKGGIPFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSF FLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 102) Light chain (LC) - nucleotide sequence CTGCTGCAAGGCTCTGGCGATATTGTGATGACCCAGTCTCCACTCTCCTCACCTGTCACCCTTGGACAGCCGGCCTCCAT CTCCTGCAGGTCTAGTCAAAGCCTCGTACACTTTGATGGAAACACCTACTTGAGTTGGCTTCACCAGAGGCCAGGCCAGC CTCCAAGACTCCTAATTTATAAGATTTCTAACCGCTTCTCTGGGGTCCCAGACAGATTCAGTGGCAGTGGGGCAGGGACA GATTTCACACTGAAAATCAGCAGGGTGGAACCTGAAGATGTCGGGGTTTATTACTGCATGCATGCTACACAATTTCCGTA CACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATG AGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAG GTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAG CAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCT CGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 103) Light chain (LC) - amino acid sequence LLQGSG DIVMTQSPLSSPVTLGQPASISCRSSQSLVHFDGNTYLSWLHQRPGQPPRLLIYKISNRFSGVPDRFSGSGAGT DFTLKISRVEPEDVGVYYCMHATQFPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 104) REGN8072 Heavy chain variable region (HCVR,V H )-Nucleotide sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGCGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CGCCTTCAGTAGGTCTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATG ATGGAAGTAATAAATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACACCCTGAGAGCTGAGGACACGGCTCTTTATTACTGTGCGAAAATGTATACAACTATGGACTCTTTTGA CTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 105) Heavy chain variable region (HCVR,V H )-Amino acid sequence QVQLVESGGGVVQPARSLRLSCAAS GFAFSRSA MHWVRQAPGKGLEWVAV ISYDGSNK YYTDSVKGRFTISRDNSKNTLY LQMNTLRAEDTALYYC AKMYTTMDSFDY WGQGTLVTVSS (SEQ ID NO: 106) CDR-H1-nucleotide sequence GGA TTC GCC TTC AGT AGG TCT GCC (SEQ ID NO: 107) CDR-H1-amino acid sequence GFAFSRSA (SEQ ID NO: 108) CDR-H2-nucleotide sequence ATA TCA TAT GAT GGA AGT AAT AAA (SEQ ID NO: 109) CDR-H2-amino acid sequence ISYDGSNK (SEQ ID NO: 110) CDR-H3-nucleotide sequence GCG AAA ATG TAT ACA ACT ATG GAC TCT TTT GAC TAC (SEQ ID NO: 111) CDR-H3-amino acid sequence AKMYTTMDSFDY (SEQ ID NO: 112) Light chain variable region (LCVR,V L )-Nucleotide sequence GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCTGGGCCAGTCA GGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCACTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCT GAAGATTTTGCACTTTATTACTGTCAACAGCTTAATAGTTACCCTCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAA A (SEQ ID NO: 113) Light chain variable region (LCVR,V L )-Amino acid sequence DIQLTQSPSFLSASVGDRVTITCWAS QGISSY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTEFTLTISSLQP EDFALYYC QQLNSYPRT FGQGTKVEIK (SEQ ID NO: 114) CDR-L1-nucleotide sequence CAG GGC ATT AGC AGT TAT (SEQ ID NO: 115) CDR-L1-amino acid sequence QGISSY (sequence number 116) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 117) CDR-L2-amino acid sequence AAS (SEQ ID NO: 118) CDR-L3-nucleotide sequence CAA CAG CTT AAT AGT TAC CCT CGG ACG (SEQ ID NO: 119) CDR-L3-amino acid sequence QQLNSYPRT (SEQ ID NO: 120) Heavy chain (HC)-nucleotide sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGCGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CGCCTTCAGTAGGTCTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATG ATGGAAGTAATAAATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACACCCTGAGAGCTGAGGACACGGCTCTTTATTACTGTGCGAAAATGTATACAACTATGGACTCTTTTGA CTACTGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCT CCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCGGAACCGGTGACGGTGTCGTGG AACTCAGGCGCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGT GGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGG ACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTC CTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCA GGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGC AGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGC AAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGT GTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCA GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGAT GCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA(SEQ ID NO:121) Heavy chain - Amino acid sequence QVQLVESGGGVVQPARSLRLSCAASGFAFSRSAMHWVRQAPGKGLEWVAVISYDGSNKYYTDSVKGRFTISRDNSKNTLY LQMNTLRAEDTALYYCAKMYTTMDSFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKGLPSSIEKTISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 122) Light chain (LC)-nucleotide sequence CTGCTGCAAGGCTCTGGCGACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT CACTTGCTGGGCCAGTCAGGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTGA TCTATGCTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACA ATCAGCAGCCTGCAGCCTGAAGATTTTGCACTTTATTACTGTCAACAGCTTAATAGTTACCCTCGGACGTTCGGCCAAGG GACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 123) Light chain (LC)-amino acid sequence LLQGSG DIQLTQSPSFLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTEFTLT ISSLQPEDFALYYCQQLNSYPRTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 124) REGN9267 Heavy chain variable region (HCVR,V H )-Nucleotide sequence GAAGTGCAACTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CATCTTCAGTAGATATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCCATGAGTAGTA ATAGTAAAAACACATACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAAAACTCACTGTTT CTGCAAATGAACACCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGCGAGAGATGGATACACCCTCAGGGCTTTTGA TATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA (SEQ ID NO: 125) Heavy chain variable region (HCVR,V H )-Amino acid sequence EVQLVESGGGLVKPGGSLRLSCAAS GFIFSRYS MNWVRQAPGKGLEWVSS MSSNSKNT YYADSVKGRFTISRDNAKNSLF LQMNTLRAEDTAVYYC ARDGYTLRAFDI WGQGTMVTVSS (SEQ ID NO: 126) CDR-H1-nucleotide sequence GGA TTC ATC TTC AGT AGA TAT AGC (SEQ ID NO: 127) CDR-H1-amino acid sequence GFIFSRYS (SEQ ID NO: 128) CDR-H2-nucleotide sequence ATG AGT AGT AAT AGT AAA AAC ACA (SEQ ID NO: 129) CDR-H2-amino acid sequence MSSNSKNT (SEQ ID NO: 130) CDR-H3-nucleotide sequence GCG AGA GAT GGA TAC ACC CTC AGG GCT TTT GAT ATC (SEQ ID NO: 131) CDR-H3-amino acid sequence ARDGYTLRAFDI (SEQ ID NO: 132) Light chain variable region (LCVR,V L )-Nucleotide sequence GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTCTGTCTCCAGGGGAAAGAGACACCCTCTCCTGCAGGGCCAGTCA GAGTATTGCCGGCAGATACGTAGCCTGGTACCAGCAGAAACCTGGCCAGGCACCCAGACTCCTCATCTACGGTGCATCCA GCAGGGCCACTGGCATCCCAGACAGATTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAG CCTGAAGATTTTGCAGTGTATTACTGTCAGCATATGGTAGCTCACCTTGGACGTTCGGCCAAGGGACCAAAGGTGGAAAT CAAA (SEQ ID NO: 133) Light chain variable region (LCVR,V L )-Amino acid sequence EIVLTQSPGTLSLSPGERDTLSCRAS QSIAGRY VAWYQQKPGQAPRLLIY GAS SRATGIPDRFSGSGSGTDFTLTISRLE PEDFAVYYC QQYGSSPWT FGQGTKVEIK (SEQ ID NO: 134) CDR-L1-nucleotide sequence CAG AGT ATT GCC GGC AGA TAC (SEQ ID NO: 135) CDR-L1-amino acid sequence QSIAGRY (SEQ ID NO: 136) CDR-L2-nucleotide sequence GGT GCA TCC (SEQ ID NO: 137) CDR-L2-amino acid sequence GAS (SEQ ID NO: 138) CDR-L3-nucleotide sequence CAG CAA TAT GGT AGC TCA CCT TGG ACG (SEQ ID NO: 139) CDR-L3-amino acid sequence QQYGSSPWT (SEQ ID NO: 140) Heavy chain (HC)-nucleotide sequence TTACTTCAGGGATCTGGTGAAGTGCAACTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTC CTGTGCAGCCTCTGGATTCATCTTCAGTAGATATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG TCTCATCCATGAGTAGTAATAGTAAAAACACATACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAGAGACAAC GCCAAAAACTCACTGTTTCTGCAAATGAACACCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGCGAGAGATGGATA CACCCTCAGGGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCT TCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGC CCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTG GGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGT GGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAAC GGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCA GCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGG TCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 141) Heavy chain amino acid sequence LLQGSG EVQLVESGGGLVKPGGSLRLSCAASGFIFSRYSMNWVRQAPGKGLEWVSSMSSNSKNTYYADSVKGRFTISRDN AKNSLFLQMNTLRAEDTAVYYCARDGYTLRAFDIWGQGTMVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 142) Light chain (LC)-nucleotide sequence GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTCTGTCTCCAGGGGAAAGAGACACCCTCTCCTGCAGGGCCAGTCA GAGTATTGCCGGCAGATACGTAGCCTGGTACCAGCAGAAACCTGGCCAGGCACCCAGACTCCTCATCTACGGTGCATCCA GCAGGGCCACTGGCATCCCAGACAGATTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAG CCTGAAGATTTTGCAGTGTATTACTGTCAGCAATATGGTAGCTCACCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAAT CAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTG TGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTA CGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTAG (SEQ ID NO: 143) Light chain (LC)-amino acid sequence EIVLTQSPGTLSLSPGERDTLSCRASQSIAGRYVAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLE PEDFAVYYCQQYGSSPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 144) REGN7988 Heavy chain variable region (HCVR,V H )-Nucleotide sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATT CACCTTCAGTGGCTATGGCATACACTGGGTCCGCCAGGCTCCAGGCAAGGGACTGGTGTGGGTGGCAGTTATATGGTATG ATGGAAGTTTTAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAGATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGTGATAGCAGCTCGTCCGGACGGTA CTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 145) Heavy chain variable region (HCVR,V H )-Amino acid sequence QVQLVESGGGVVQPGRSLRLSCAAS GFTFSGYG IHWVRQAPGKGLVWVAV IWYDGSFK YYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYC ARGDSSSSGRYYYYGMDV WGQGTTVTVSS (SEQ ID NO: 146) CDR-H1-nucleotide sequence GGA TTC ACC TTC AGT GGC TAT GGC (SEQ ID NO: 147) CDR-H1-amino acid sequence GFTFSGYG (SEQ ID NO: 148) CDR-H2-nucleotide sequence ATA TGG TAT GAT GGA AGT TTT AAA (SEQ ID NO: 149) CDR-H2-amino acid sequence IWYDGSFK (sequence number 150) CDR-H3-nucleotide sequence GCG AGA GGT GAT AGC AGC TCG TCC GGA CGG TAC TAC TAC TAC GGT ATG GAC GTC (SEQ ID NO: 151) CDR-H3-amino acid sequence ARGDSSSSGRYYYYGMDV (SEQ ID NO: 152) Light chain variable region (LCVR,V L )-Nucleotide sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCA GGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGACAGCCCCTAAGCGCCTGATCTTTGCTGCATCCAGTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCT GAAGATTTTGCGACTTATTACTGTCTACAGCATAATAATTACCCTCCCACTTTCGGCGGAGGGACCAAGGTGGAGATCAA A (SEQ ID NO: 153) Light chain variable region (LCVR,V L )-Amino acid sequence DIQMTQSPSSLSASVGDRVTITCRAS QGIRND LGWYQQKPGTAPKRLIF AAS SLQSGVPSRFSGSGSGTEFTLTISSLQP EDFATYYC LQHNNYPPT FGGGTKVEIK (SEQ ID NO: 154) CDR-L1-nucleotide sequence CAG GGC ATT AGA AAT GAT (SEQ ID NO: 155) CDR-L1-amino acid sequence QGIRND (SEQ ID NO: 156) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 157) CDR-L2-amino acid sequence AAS (SEQ ID NO: 158) CDR-L3-nucleotide sequence CTA CAG CAT AAT AAT TAC CCT CCC ACT (SEQ ID NO: 159) CDR-L3-amino acid sequence LQHNNYPPT (SEQ ID NO: 160) Heavy chain (HC)-nucleotide sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATT CACCTTCAGTGGCTATGGCATACACTGGGTCCGCCAGGCTCCAGGCAAGGGACTGGTGTGGGTGGCAGTTATATGGTATG ATGGAAGTTTTAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAGATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGTGATAGCAGCTCGTCCGGACGGTA CTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCT TCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGC CCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTG GGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGT GGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAAC GGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCA GCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGG TCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA(SEQ ID NO: 161) Heavy chain - Amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSGYGIHWVRQAPGKGLVWVAVIWYDGSFKYYADSVKGRFTISRDNSKNTLY <h2 style=";text-align:left;direction:ltr">LQMNSLRAEDTAVYYCARGDSSSSGRYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 162) Light chain (LC)-nucleotide sequence CTGCTGCAAGGCTCTGGCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT CACTTGCCGGGCAAGTCAGGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGACAGCCCCTAAGCGCCTGA TCTTTGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACA ATCAGCAGCCTGCAGCCTGAAGATTTTGCGACTTATTACTGTCTACAGCATAATAATTACCCTCCCACTTTCGGCGGAGG GACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 163) Light chain (LC)-amino acid sequence LLQGSG <h2 style=";text-align:left;direction:ltr"> DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGTAPKRLIFAASSLQSGVPSRFSGSGSGTEFTLT <h2 style=";text-align:left;direction:ltr"> ISSLQPEDFATYYCLQHNNYPPTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 164) <h2 style=";text-align:left;direction:ltr"> REGN5619 Heavy chain variable region (HCVR,V H )-Nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAAAACTCTCCTGTGCAGCCTCTGGGTT CACCTTCATGGCTCTGCTATGCACTGGGTCCGCCAGGCTTCCGGGAAAGGGCTGGAGTGGGTTGCCGTATTACAAGCA AAGCTAACAGTTACGCGACAGCATATGATGCGTCGGTGAAAGGCAGGTTCACCATCTCCAGAGATGATTCAAAGAACACG GCGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTATTACTGTACTAGGCAACGATTTTTGGAGTTTTT ATTCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 165) Heavy chain variable region (HCVR,V H)-Amino acid sequence EVQLVESGGGLVQPGGSLKLSCAAS <h2 style=";text-align:left;direction:ltr"> GFTFSGSA MHWVRQASGKGLEWVGR <h2 style=";text-align:left;direction:ltr"> ITSKANSYAT AYDASVKGRFTISRDDSKNT AYLQMNSLKTEDTAVYYC <h2 style=";text-align:left;direction:ltr"> TRQRFLEFLFLDY WGQGTLVTVSS (SEQ ID NO: 166) CDR-H1-nucleotide sequence GGG TTC ACC TTC AGT GGC TCT GCT (SEQ ID NO: 167) CDR-H1-amino acid sequence GFTFSGSA (SEQ ID NO: 168) CDR-H2-nucleotide sequence ATT ACA AGC AAA GCT AAC AGT TAC GCG ACA (SEQ ID NO: 169) CDR-H2-amino acid sequence ITSKANSYAT (SEQ ID NO: 170) CDR-H3-nucleotide sequence ACT AGG CAA CGA TTT TTG GAG TTT TTA TTC CTT GAC TAC (SEQ ID NO: 171) CDR-H3-amino acid sequence TRQRFLEFLFLDY (SEQ ID NO: 172) Light chain variable region (LCVR,V L )-Nucleotide sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCA GAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCT GAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCGGATCACCTTCGGCCAAGGGACACGACTGGAGAT TAAA (SEQ ID NO: 173) Light chain variable region (LCVR,V L )-Amino acid sequence DIQMTQSPSSLSASVGDRVTITCRAS <h2 style=";text-align:left;direction:ltr"> QSISSY LNWYQQKPGKAPKLLIY <h2 style=";text-align:left;direction:ltr"> AAS SLQSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYC <h2 style=";text-align:left;direction:ltr"> QQSYSTPPIT FGQGTRLEIK (SEQ ID NO: 174) CDR-L1-nucleotide sequence CAG AGC ATT AGC AGC TAT (SEQ ID NO: 175) CDR-L1-amino acid sequence QSISSY (SEQ ID NO: 176) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 177) CDR-L2-amino acid sequence AAS (SEQ ID NO: 178) CDR-L3-nucleotide sequence CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC (SEQ ID NO: 179) CDR-L3-amino acid sequence QQSYSTPPIT (sequence number 180) Heavy chain (HC)-nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAAAACTCTCCTGTGCAGCCTCTGGGTT CACCTTCATGGCTCTGCTATGCACTGGGTCCGCCAGGCTTCCGGGAAAGGGCTGGAGTGGGTTGCCGTATTACAAGCA AAGCTAACAGTTACGCGACAGCATATGATGCGTCGGTGAAAGGCAGGTTCACCATCTCCAGAGATGATTCAAAGAACACG GCGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTATTACTGTACTAGGCAACGATTTTTGGAGTTTTT ATTCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG CGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCT CAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACA CCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCA TCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGA CGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGC GGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAG TACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCT TCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG GACTCCGACGGCTCCTTCTTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATG CTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 181) Heavy chain amino acid sequence <h2 style=";text-align:left;direction:ltr"> EVQLVESGGGLVQPGGSLKLSCAASGFTFSGSAMHWVRQASGKGLEWVGRITSKANSYATAYDASVKGRFTISRDDSKNT <h2 style=";text-align:left;direction:ltr"> AYLQMNSLKTEDTAVYYCTRQRFLEFLFLDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 182) Light chain (LC)-nucleotide sequence CTGCTGCAAGGCTCTGGCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT CACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACC ATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCA AGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGAC GCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAA AGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 183) Light chain (LC) - Amino acid sequence LLQGSG <h2 style=";text-align:left;direction:ltr"> DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLT <h2 style=";text-align:left;direction:ltr"> ISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 184) <h2 style=";text-align:left;direction:ltr"> REGN7989 Heavy chain variable region (HCVR,V H )-Nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGGTCTCAGCTATTACGGGTA GTGGTGGCAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGCCTTATAGCACCTCGTCCGATGGG CTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 186) Heavy chain variable region (HCVR,V H )-Amino acid sequence EVQLVESGGGLVQPGGSLRLSCAAS <h2 style=";text-align:left;direction:ltr"> GFTFSSYA MSWVRQAPGKGLEWVSA <h2 style=";text-align:left;direction:ltr"> ISGSGGST YYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYC <h2 style=";text-align:left;direction:ltr"> AKGLIAPRPMGFDY WGQGTLVTVSS (SEQ ID NO: 187) CDR-H1-nucleotide sequence GGA TTC ACC TTT AGC AGC TAT GCC (SEQ ID NO: 188) CDR-H1-amino acid sequence GFTFSSYA (SEQ ID NO: 189) CDR-H2-nucleotide sequence ATT AGC GGT AGT GGT GGC AGC ACA (SEQ ID NO: 190) CDR-H2-amino acid sequence ISGSGGST (SEQ ID NO: 191) CDR-H3-nucleotide sequence GCG AAA GGC CTT ATA GCA CCT CGT CCG ATG GGC TTT GAC TAC (SEQ ID NO: 192) CDR-H3-amino acid sequence AKGLIAPRPMGFDY (SEQ ID NO: 193) Light chain variable region (LCVR,V L )-Nucleotide sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCA GGGTATTAACAGCTGGTTAGCCTGGTATCAGCAGAAACCTGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAAGATTTTGCAACTTACTATTGTCACCAGGCTGACAGTTTCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAA A (SEQ ID NO: 194) Light chain variable region (LCVR,V L )-Amino acid sequence DIQMTQSPSSVSASVGDRVTITCRAS <h2 style=";text-align:left;direction:ltr"> QGINSW LAWYQQKPGKAPKLLIY <h2 style=";text-align:left;direction:ltr"> AAS SLQSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYC <h2 style=";text-align:left;direction:ltr"> HQADSFPYT FGQGTKLEIK (SEQ ID NO: 195) CDR-L1-nucleotide sequence CAG GGT ATT AAC AGC TGG (SEQ ID NO: 196) CDR-L1-amino acid sequence QGINSW (sequence number 197) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 198) CDR-L2-amino acid sequence AAS (SEQ ID NO: 199) CDR-L3-nucleotide sequence CAC CAG GCT GAC AGT TTC CCG TAC ACT (SEQ ID NO: 200) CDR-L3-amino acid sequence HQADSFPYT (sequence number 201) Heavy chain (HC)-nucleotide sequence CTGCTGCAAGGCTCTGGCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTC CTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGG TCTCAGCTATTAGCGGTAGTGGTGGCAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAAT TCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGCCTTAT AGCACCTCGTCCGATGGGCTTTGACTACTGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCAT CGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTC CCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTC AGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATC ACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAG TTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCAC GTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATG CCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGG CTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACC ACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGG GAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTA AATGA (SEQ ID NO: 202) Heavy chain - Amino acid sequence LLQGSG <h2 style=";text-align:left;direction:ltr"> EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDN <h2 style=";text-align:left;direction:ltr"> SKNTLYLQMNSLRAEDTAVYYCAKGLIARPMGFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPE FLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 203) Light chain (LC)-nucleotide sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCA GGGTATTAACAGCTGGTTAGCCTGGTATCAGCAGAAACCTGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCT GAAGATTTTGCAACTTACTATTGTCACCAGGCTGACAGTTTCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAA ACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGT GCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGA GAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTTAG (SEQ ID NO: 204) Light chain (LC)-amino acid sequence <h2 style=";text-align:left;direction:ltr"> DIQMTQSPSSVSASVGDRVTITCRASQGINSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQP <h2 style=";text-align:left;direction:ltr"> EDFATYYCHQADSFPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 205) <h2 style=";text-align:left;direction:ltr"> REGN8069 Heavy chain variable region (HCVR,V H )-Nucleotide sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGGCCAGCCTGGGAGGTCCCTGAGACTGTCCTGTGCAGCCTCTGGATT CACCTTCAGCAGGAATGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTCATATCATATG ATGGAAGTAATAAACACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGGAAATGAACAGCCTGAGAGTTGAGGACACGGCTGTGTATTATTGTGCGAAAGGGGGGATTCCTTTTGACTACTGGGG CCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 206) Heavy chain variable region (HCVR,V H )-Amino acid sequence VQLVESGGGVGQPGRSLRLSCAAS <h2 style=";text-align:left;direction:ltr"> GFTFSRNA MHWVRQAPGKGLEWVAV <h2 style=";text-align:left;direction:ltr"> ISYDGSNK HYADSVKGRFTISRDNSKNTLY LEMNSLRVEDTAVYYC <h2 style=";text-align:left;direction:ltr"> AKGGIPFDY WGQGTLVTVSS (SEQ ID NO: 207) CDR-H1-nucleotide sequence GGA TTC ACC TTC AGC AGG AAT GCC (SEQ ID NO: 208) CDR-H1-amino acid sequence GFTFSRNA; (SEQ ID NO: 209) CDR-H2-nucleotide sequence ATA TCA TAT GAT GGA AGT AAT AAA (SEQ ID NO: 210) CDR-H2-amino acid sequence ISYDGSNK; (SEQ ID NO: 211) CDR-H3-nucleotide sequence GCG AAA GGG GGG ATT CCT TTT GAC TAC (SEQ ID NO: 212) CDR-H3-amino acid sequence AKGGIPFDY; (SEQ ID NO: 213) Light chain variable region (LCVR,V L )-Nucleotide sequence GATATTGTGATGACCCAGTCTCCACTCTCCTCACCTGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCA AAGCCTCGTACACTTTGATGGAAACACCTACTTGAGTTGGCTTCACCAGAGGCCAGGCCAGCCTCCAAGACTCCTAATTT ATAAGATTTCTAACCGCTTCTCTGGGGTCCCAGACAGATTCAGTGGCAGTGGGGCAGGGACAGATTTCACACTGAAAATC AGCAGGGTGGAACCTGAAGATGTCGGGGTTTATTACTGCATGCATGCTACACAATTTCCGTACACTTTTGGCCAGGGGAC CAAGCTGGAGATCAAA (SEQ ID NO: 214) Light chain variable region (LCVR,V L )-Amino acid sequence DIVMTQSPLSSPVTLGQPASISCRSS <h2 style=";text-align:left;direction:ltr"> QSLVHFDGNTY LSWLHQRPGQPPRLLIY <h2 style=";text-align:left;direction:ltr"> KIS NRFSGVPDRFSGSGAGTDFTLKI SRVEPEDVGVYYC <h2 style=";text-align:left;direction:ltr"> MHATQFPYT FGQGTKLEIK (SEQ ID NO: 215) CDR-L1-nucleotide sequence CAA AGC CTC GTA CAC TTT GAT GGA AAC ACC TAC (SEQ ID NO: 216) CDR-L1-amino acid sequence QSLVHFDGNTY (SEQ ID NO: 217) CDR-L2-nucleotide sequence AAG ATT TCT (SEQ ID NO: 218) CDR-L2-amino acid sequence KIS (SEQ ID NO: 219) CDR-L3-nucleotide sequence ATG CAT GCT ACA CAA TTT CCG TAC ACT (SEQ ID NO: 220) CDR-L3-amino acid sequence MHATQFPYT (SEQ ID NO: 221) Heavy chain (HC)-nucleotide sequence CTGCTGCAAGGCTCTGGCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGGCCAGCCTGGGAGGTCCCTGAGACTGTC CTGTGCAGCCTCTGGATTCACCTTCAGCAGGAATGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG TGGCAGTCATATCATATGATGGAAGTAATAAACACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAT TCCAAGAACACGCTGTATCTGGAAATGAACAGCCTGAGAGTTGAGGACACGGCTGTGTATTATTGTGCGAAAGGGGGGAT TCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG CGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCT CAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACA CCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCA TCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGA CGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGC GGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAG TACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCT TCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG GACTCCGACGGCTCCTTCTTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATG CTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 222) Heavy chain amino acid sequence LLQGSG <h2 style=";text-align:left;direction:ltr"> QVQLVESGGGVGQPGRSLRLSCAASGFFTFSRNAMHWVRQAPGKGLEWVAVISYDGSNKHYADSVKGRFTISRDN <h2 style=";text-align:left;direction:ltr"> SKNTLYLEMNSLRVEDTAVYYCAKGGIPFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 223) Light chain (LC)-nucleotide sequence GATATTGTGATGACCCAGTCTCCACTCTCCTCACCTGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCA AAGCCTCGTACACTTTGATGGAAACACCTACTTGAGTTGGCTTCACCAGAGGCCAGGCCAGCCTCCAAGACTCCTAATTT ATAAGATTTCTAACCGCTTCTCTGGGGTCCCAGACAGATTCAGTGGCAGTGGGGCAGGGACAGATTTCACACTGAAAATC AGCAGGGTGGAACCTGAAGATGTCGGGGTTTATTACTGCATGCATGCTACACAATTTCCGTACACTTTTGGCCAGGGGAC CAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAA TCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAG CAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCT TCAACAGGGGAGAGTGTTAG (SEQ ID NO: 224) Light chain (LC) - Amino acid sequence <h2 style=";text-align:left;direction:ltr"> DIVMTQSPLSSPVTLGQPASISCRSSQSLVHFDGNTYLSWLHQRPGQPPRLLIYKISNRFSGVPDRFSGSGAGTDFTLKI SRVEPEDVGVYYCMHATQFPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 225) REGN8071 Heavy chain variable region (HCVR,V H )-Nucleotide sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGCGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CGCCTTCAGTAGGTCTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATG ATGGAAGTAATAAATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAAATGAACACCCTGAGAGCTGAGGACACGGCTCTTTATTACTGTGCGAAAATGTATACAACTATGGACTCTTTTGA CTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 226) Heavy chain variable region (HCVR,V H )-Amino acid sequence QVQLVESGGGVVQPARSLRLSCAAS GFAFSRSA MHWVRQAPGKGLEWVAV ISYDGSNK YYTDSVKGRFTISRDNSKNTLY LQMNTLRAEDTALYYC AKMYTTMDSFDY WGQGTLVTVSS (SEQ ID NO: 227) CDR-H1-nucleotide sequence GGA TTC GCC TTC AGT AGG TCT GCC (SEQ ID NO: 228) CDR-H1-amino acid sequence GFAFSRSA (SEQ ID NO: 229) CDR-H2-nucleotide sequence ATA TCA TAT GAT GGA AGT AAT AAA (SEQ ID NO: 230) CDR-H2-amino acid sequence ISYDGSNK (SEQ ID NO: 231) CDR-H3-nucleotide sequence GCG AAA ATG TAT ACA ACT ATG GAC TCT TTT GAC TAC (SEQ ID NO: 232) CDR-H3-amino acid sequence AKMYTTMDSFDY (SEQ ID NO: 233) Light chain variable region (LCVR,V L )-Nucleotide sequence GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCTGGGCCAGTCA GGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCACTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCT GAAGATTTTGCACTTTATTACTGTCAACAGCTTAATAGTTACCCTCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAA A (SEQ ID NO: 234) Light chain variable region (LCVR,V L )-Amino acid sequence DIQLTQSPSFLSASVGDRVTITCWAS QGISSY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTEFTLTISSLQP EDFALYYC QQLNSYPRT FGQGTKVEIK (SEQ ID NO: 235) CDR-L1-nucleotide sequence CAG GGC ATT AGC AGT TAT (SEQ ID NO: 236) CDR-L1-amino acid sequence QGISSY (sequence number 237) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 238) CDR-L2-amino acid sequence AAS (SEQ ID NO: 239) CDR-L3-nucleotide sequence CAA CAG CTT AAT AGT TAC CCT CGG ACG (SEQ ID NO: 240) CDR-L3-amino acid sequence QQLNSYPRT (SEQ ID NO: 241) Heavy chain (HC)-nucleotide sequence CTGCTGCAAGGCTCTGGCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGCGAGGTCCCTGAGACTCTC CTGTGCAGCCTCTGGATTCGCCTTCAGTAGGTCTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG TGGCAGTTATATCATATGATGGAAGTAATAAATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAT TCCAAGAACACGCTGTATCTGCAAATGAACACCCTGAGAGCTGAGGACACGGCTCTTTATTACTGTGCGAAAATGTATAC AACTATGGACTCTTTTGACTACTGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCT TCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA CCGGTGACGGTGTCGTGGAACTCAGGCGCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGC CCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTG GGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGT GGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAAC GGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCA GCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGG TCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGT CTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA(SEQ ID NO: 242) Heavy chain - Amino acid sequence LLQGSG QVQLVESGGGVVQPARSLRLSCAASGFAFSRSAMHWVRQAPGKGLEWVAVISYDGSNKYYTDSVKGRFTISRDN SKNTLYLQMNTLRAEDTALYYCAKMYTTMDSFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 243) Light chain (LC)-nucleotide sequence GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCTGGGCCAGTCA GGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCACTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCT GAAGATTTTGCACTTTATTACTGTCAACAGCTTAATAGTTACCCTCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAA ACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGT GCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGA GAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTTAG (SEQ ID NO: 244) Light chain (LC)-amino acid sequence DIQLTQSPSFLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTEFTLTISSLQP EDFALYYCQQLNSYPRTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 245) REGN9426 Heavy chain variable region (HCVR,V H )-Nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAAAACTCTCCTGTGCAGCCTCTGGGTT CACCTTCATGGCTCTGCTATGCACTGGGTCCGCCAGGCTTCCGGGAAAGGGCTGGAGTGGGTTGCCGTATTACAAGCA AAGCTAACAGTTACGCGACAGCATATGATGCGTCGGTGAAAGGCAGGTTCACCATCTCCAGAGATGATTCAAAGAACACG GCGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTATTACTGTACTAGGCAACGATTTTTGGAGTTTTT ATTCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 246) Heavy chain variable region (HCVR,V H )-Amino acid sequence EVQLVESGGGLVQPGGSLKLSCAAS GFTFSGSA MHWVRQASGKGLEWVGR ITSKANSYAT AYDASVKGRFTISRDDSKNT AYLQMNSLKTEDTAVYYC TRQRFLEFLFLDY WGQGTLVTVSS (SEQ ID NO: 247) CDR-H1-nucleotide sequence GGG TTC ACC TTC AGT GGC TCT GCT; (SEQ ID NO: 248) CDR-H1-amino acid sequence GFTFSGSA (SEQ ID NO: 249) CDR-H2-nucleotide sequence ATT ACA AGC AAA GCT AAC AGT TAC GCG ACA (SEQ ID NO: 250) CDR-H2-amino acid sequence ITSKANSYAT (sequence number 251) CDR-H3-nucleotide sequence ACT AGG CAA CGA TTT TTG GAG TTT TTA TTC CTT GAC TAC; (SEQ ID NO: 252) CDR-H3-amino acid sequence TRQRFLEFLFLDY (SEQ ID NO: 253) Light chain variable region (LCVR,V L )-Nucleotide sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCA GAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCT GAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCGGATCACCTTCGGCCAAGGGACACGACTGGAGAT TAAA (SEQ ID NO: 254) Light chain variable region (LCVR,V L )-Amino acid sequence DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYC QQSYSTPPIT FGQGTRLEIK (SEQ ID NO: 255) CDR-L1-nucleotide sequence CAG AGC ATT AGC AGC TAT (SEQ ID NO: 256) CDR-L1-amino acid sequence QSISSY (sequence number 257) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 258) CDR-L2-amino acid sequence AAS (SEQ ID NO: 259) CDR-L3-nucleotide sequence CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC (SEQ ID NO: 260) CDR-L3-amino acid sequence QQSYSTPPIT (sequence number 261) Heavy chain (HC)-nucleotide sequence CTGCTGCAAGGCTCTGGCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAAACTCTC CTGTGCAGCCTCTGGGTTCACCTTCATGGCTCTGCTATGCACTGGGTCCGCCAGGCTTCCGGGAAAGGGCTGGAGTGGG TTGGCCGTATTACAAGCAAAGCTAACAGTTACGCGACAGCATATGATGCGTCGGTGAAAGGCAGGTTCACCATCTCCAGA GATGATTCAAAGAACACGGCGTATCTGCAAATGAACAGCCTGAAACCGAGGACACGGCCGTGTATTACTGTACTTAGGCA ACGATTTTTGGAGTTTTTATTCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCC CATCGGTCTTCCCCCTGGCCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTAC TTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTCACAGTC CTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAG ATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCT GAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGT CACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATA ATGCCAAGACAAAGCCGCGGGAGGACAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC TGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGC CAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGA CCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGA GGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGG GTAAATGA (SEQ ID NO: 262) Heavy chain amino acid sequence LLQGSG EVQLVESGGGLVQPGGSLKLSCAASGFTFSGSAMHWVRQASGKGLEWVGRITSKANSYATAYDASVKGRFTISR DDSKNTAYLQMNSLKTEDTAVYYCTRQRFLEFLFLDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAP EFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 263) Light chain (LC)-nucleotide sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCA GAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCT GAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGAT TAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTG TGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTA CGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTAG (SEQ ID NO: 264) Light chain (LC) - Amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYCQQSYSTPPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 265) REGN5203 Heavy chain (HC)-nucleotide sequence TTACTTCAGGGATCTGGTCAAGTTACTCTTAAAGAATCTGGTCCTGGAATTCTTCAACCTTCTCAAACTCTTTCTCTTAC TTGTTCTTTTTCTGGTTTTTCTCTTTCTACTTCTGGTACTGGTGTTGGTTGGATTCGTCAACCTTCTGGTAAAGGTCTTG AATGGCTTTCTCATATTTGGTGGGATGATGTTAAACGTTATAATCCTGCTCTTAAATCTCGTCTTACTATTTCTCGTGAT ACTTCTTATTCTCAAGTTTTTCTTCGTATTGCTTCTGTTGATACTGCTGATACTGCTACTTATTATTGTGCTCGTATTCT TGATGGTACTGGTCCTATGGATTATTGGGGTCAAGGTACTTCTGTTACTGTTTCTTCTGCCTCCACCAAGGGCCCATCGG TCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC GAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGG ACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACA AGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTC CTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTG CGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTG AACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGG GCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCC TGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACG CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAA TGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAAT GA (SEQ ID NO: 266) Heavy chain - Amino acid sequence LLQGSGQVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGTGVGWIRQPSGKGLEWLSHIWWDDVKRYNPALKSRLTISRD TSYSQVFLRIASVDTADTATYYCARILDGTGPMDYWGQGTSVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 267) Light chain (LC)-nucleotide sequence CAAATTGTTCTTACTCAATCTCTGCTATTATGTCTGCTAGCCCTGGTGAAAAAGTTACTATGACTTGTTCTGCTTCTTC TCGTGTTACTTATATGCATTGGTATCAACAACGTTCTGGTACTTCTCCTAAACGTTGGATTTATGATACTTCTAAACTTG CTTCTGGTGTTCCTGCTCGTTTTTCTGGTTCTGGTTCTGGTACTTCTTATTCTCTTACTATTTCTTCTATGGAAGCTGAA GATGCTGCTACTTATTATTGTCAACAATGGGGTAATAATCCTCAATATACTTTTGGTGGTGGTACTCGTCTTGAAATTAA ACGTCGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTG TGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTA CGAGAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTAG (SEQ ID NO: 268) Light chain (LC)-amino acid sequence QIVLTQSPAIMSASPGEKVTMTCSASSRVTYMHWYQQRSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAE DAATYYCQQWGNNPQYTFGGGTRLEIKRRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 269) REGN5204 Heavy chain (HC)-nucleotide sequence CAAGTTACTCTTAAAGAATCTGGTCCTGGAATTCTTCAACCTTCTCAAACTCTTTTCTCTTACTTGTTCTTTTTCTGGTTT TTCTCTTTCTACTTCTGGTACTGGTGTTGGTTGGATTCGTCAACCTTCTGGTAAAGGTCTTGAATGGCTTTCTCATATTT GGTGGGATGATGTTAAACGTTATAATCCTGCTCTTAAATCTCGTCTTACTATTTCTCGTGATACTTCTTATTCTCAAGTT TTTCTTCGTATTGCTTCTGTTGATACTGCTGATACTGCTACTTATTATTGTGCTCGTATTCTTGATGGTACTGGTCCTAT GGATTATTGGGGTCAAGGTACTTCTGTTACTGTTTCTTCTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCT GCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG TGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAG CGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGG TGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAG CCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAG TGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACA GGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACC CCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCC GACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 270) Heavy chain amino acid sequence QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGTGVGWIRQPSGKGLEWLSHIWWDDVKRYNPALKSRLTISRDTSYSQV FLRIASVDTADTATYYCARILDGTGPMDYWGQGTSVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 271) Light chain (LC)-nucleotide sequence TTACTTCAGGGATCTGGTCAAATTGTTCTTACTCAATCTCTGCTATTATGTCTGCTAGCCCTGGTGAAAAAGTTACTAT GACTTGTTCTGCTTCTTCTCGTGTTACTTATATGCATTGGTATCAACAACGTTCTGGTACTTCTCCTAAACGTTGGATTT ATGATACTTCTAAACTTGCTTCTGGTGTTCCTGCTCGTTTTCTGGTTCTGGTTCTGGTACTTCTTATTCTCTTACTATT TCTTCTATGGAAGCTGAAGATGCTGCTACTTATTATTGTCAACAATGGGGTAATAATCCTCAATATACTTTTGGTGGTGG TACTCGTCTTGAAATTAAACGTCGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGAC GCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAA AGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 272) Light chain (LC)-amino acid sequence LLQGSGQIVLTQSPAIMSASPGEKVTMTCSASSRVTYMHWYQQRSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTI SSMEAEDATYYCQQWGNNPQYTFGGGTRLEIKRRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 273) REGN5617 Heavy chain variable region (HCVR, VH) - nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CACCTTCTCTAGGTACTGGATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGCAAG ATGGCAGTGGGAAAAACTATGTGGACTCTGTGATGGGCCGATACACCATCTCCAGAGACAACGCCAAGAACTCACTGTAT CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGATGGATAGCACCAGATTTCCCCGGTAT GGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 274) Heavy chain variable region (HCVR, VH)-amino acid sequence EVQLVESGGGLVQPGGSLRLSCAAS GFTFSRYW MTWVRQAPGKGLEWVAN IKQDGSGK NYVDSVMGRYTISRDNAKNSLY LQMNSLRAEDTAVYYC ARWIAPDFPGMDV WGQGTTVTVSS (sequence number 275) CDR-H1-nucleotide sequence GGA TTC ACC TTC TCT AGG TAC TGG (SEQ ID NO: 276) CDR-H1-amino acid sequence GFTFSRYW (sequence number 277) CDR-H2-nucleotide sequence ATA AAG CAA GAT GGC AGT GGG AAA (SEQ ID NO: 278) CDR-H2-amino acid sequence IKQDGSGK (SEQ ID NO: 279) CDR-H3-nucleotide sequence GCG AGA TGG ATA GCA CCA GAT TTC CCC GGT ATG GAC GTC (SEQ ID NO: 280) CDR-H3-amino acid sequence ARWIAPDFPGMDV (SEQ ID NO: 281) Light chain variable region (LCVR,V L )-Nucleotide sequence GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCTGGGCCAGTCA GGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCACTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCT GCAGATTTTGCAACTTATTACTGTCAACAGCTTAATAGTTACCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAA A (SEQ ID NO: 282) Light chain variable region (LCVR,V L )-Amino acid sequence DIQLTQSPSFLSASVGDRVTITCWAS QGISSY LAWYQQKPGKAPKLLIY AAS TLQSGVPSRFSGSGSGTEFTLTISSLQP ADFATYYC QQLNSYPLT FGGGTKVEIK (SEQ ID NO: 283) CDR-L1-nucleotide sequence CAG GGC ATT AGC AGT TAT (SEQ ID NO: 284) CDR-L1-amino acid sequence QGISSY (sequence number 285) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 286) CDR-L2 - Amino Acid Sequence A A S (SEQ ID NO: 287) CDR-L3 - Nucleotide Sequence CAA CAG CTT AAT AGT TAC CCG CTC ACT (SEQ ID NO: 288) CDR-L3 - Amino Acid Sequence Q Q L N S Y P L T (SEQ ID NO: 289) Heavy Chain (HC) - Nucleotide Sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATT CACCTTCTCTAGGTACTGGATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGCAAG ATGGCAGTGGGAAAAACTATGTGGACTCTGTGATGGGCCGATACACCATCTCCAGAGACAACGCCAAGAACTCACTGTAT CTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGATGGATAGCACCAGATTTCCCCGGTAT GGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCT GCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCG TGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAG CGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGG TGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAG CCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAG TGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACA GGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACC CCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCC GACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA(SEQ ID NO: 290) Heavy chain - Amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMTWVRQAPGKGLEWVANIKQDGSGKNYVDSVMGRYTISRDNAKNSLY LQMNSLRAEDTAVYYCARWIAPDFPGMDVWGQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 291) Light chain (LC)-nucleotide sequence CTGCTGCAAGGCTCTGGCGACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT CACTTGCTGGGCCAGTCAGGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAAACCAGGAAAAGCCCCTAAGCTCCTGA TCTATGCTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACA ATCAGCAGCCTGCAGCCTGCAGATTTTGCAACTTATTACTGTCAACAGCTTAATAGTTACCCGCTCACTTTCGGCGGAGG GACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTG GAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 292) Light chain (LC)-amino acid sequence LLQGSG DIQLTQSPSFLSASVGDRVTITCWASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTEFTLT ISSLQPADFATYYCQQLNSYPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 293) REGN5619 Heavy chain variable region (HCVR, VH) - nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAAAACTCTCCTGTGCAGCCTCTGGGTT CACCTTCATGGCTCTGCTATGCACTGGGTCCGCCAGGCTTCCGGGAAAGGGCTGGAGTGGGTTGCCGTATTACAAGCA AAGCTAACAGTTACGCGACAGCATATGATGCGTCGGTGAAAGGCAGGTTCACCATCTCCAGAGATGATTCAAAGAACACG GCGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTATTACTGTACTAGGCAACGATTTTTGGAGTTTTT ATTCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 294) Heavy chain variable region (HCVR, VH)-amino acid sequence EVQLVESGGGLVQPGGSLKLSCAAS GFTFSGSA MHWVRQASGKGLEWVGR ITSKANSYAT AYDASVKGRFTISRDDSKNT AYLQMNSLKTEDTAVYYC TRQRFLEFLFLDY WGQGTLVTVSS (SEQ ID NO: 295) CDR-H1-nucleotide sequence GGG TTC ACC TTC AGT GGC TCT GCT (SEQ ID NO: 296) CDR-H1-amino acid sequence GFTFSGSA (SEQ ID NO: 297) CDR-H2-nucleotide sequence ATT ACA AGC AAA GCT AAC AGT TAC GCG ACA (SEQ ID NO: 298) CDR-H2-amino acid sequence ITSKANSYAT (sequence number 299) CDR-H3-nucleotide sequence ACT AGG CAA CGA TTT TTG GAG TTT TTA TTC CTT GAC TAC (SEQ ID NO: 300) CDR-H3-amino acid sequence TRQRFLEFLFLDY (SEQ ID NO: 301) Light chain variable region (LCVR,V L )-Nucleotide sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCA GAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCT GAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCGGATCACCTTCGGCCAAGGGACACGACTGGAGAT TAAA (SEQ ID NO: 302) Light chain variable region (LCVR,V L )-Amino acid sequence DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQP EDFATYYC QQSYSTPPIT FGQGTRLEIK (SEQ ID NO: 303) CDR-L1-nucleotide sequence CAG AGC ATT AGC AGC TAT (SEQ ID NO: 304) CDR-L1-amino acid sequence QSISSY (sequence number 305) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 306) CDR-L2-amino acid sequence AAS (SEQ ID NO: 307) CDR-L3-nucleotide sequence CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC; (SEQ ID NO: 308) CDR-L3-amino acid sequence QQSYSTPPIT (sequence number 309) Heavy chain (HC)-nucleotide sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAAAACTCTCCTGTGCAGCCTCTGGGTT CACCTTCATGGCTCTGCTATGCACTGGGTCCGCCAGGCTTCCGGGAAAGGGCTGGAGTGGGTTGCCGTATTACAAGCA AAGCTAACAGTTACGCGACAGCATATGATGCGTCGGTGAAAGGCAGGTTCACCATCTCCAGAGATGATTCAAAGAACACG GCGTATCTGCAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTATTACTGTACTAGGCAACGATTTTTGGAGTTTTT ATTCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG CGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCT CAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACA CCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCA TCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGA CGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGC GGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAG TACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCT TCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG GACTCCGACGGCTCCTTCTTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATG CTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 310) Heavy chain amino acid sequence EVQLVESGGGLVQPGGSLKLSCAASGFTFSGSAMHWVRQASGKGLEWVGRITSKANSYATAYDASVKGRFTISRDDSKNT AYLQMNSLKTEDTAVYYCTRQRFLEFLFLDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 311) Light chain (LC)-nucleotide sequence CTGCTGCAAGGCTCTGGCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCAT CACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACC ATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCA AGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGAC GCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAA AGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 312) Light chain (LC) - Amino acid sequence LLQGSG DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 313) REGN7987 Heavy chain variable region (HCVR,V H )-Nucleotide sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATT CACCTTCAGTGGCTATGGCATACACTGGGTCCGCCAGGCTCCAGGCAAGGGACTGGTGTGGGTGGCAGTTATATGGTATG ATGGAAGTTTTAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT CTGCAGATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGTGATAGCAGCTCGTCCGGACGGTA CTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 314) Heavy chain variable region (HCVR,V H )-Amino acid sequence QVQLVESGGGVVQPGRSLRLSCAAS GFTFSGYG IHWVRQAPGKGLVWVAV IWYDGSFK YYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYC ARGDSSSSGRYYYYGMDV WGQGTTVTVSS; (SEQ ID NO: 315) CDR-H1-nucleotide sequence GA TTC ACC TTC AGT GGC TAT GGC (SEQ ID NO: 316) CDR-H1-amino acid sequence GFTFSGYG (SEQ ID NO: 317) CDR-H2-nucleotide sequence ATA TGG TAT GAT GGA AGT TTT AAA (SEQ ID NO: 318) CDR-H2-amino acid sequence IWYDGSFK (sequence number 319) CDR-H3-nucleotide sequence GCG AGA GGT GAT AGC AGC TCG TCC GGA CGG TAC TAC TAC TAC GGT ATG GAC GTC (SEQ ID NO: 320) CDR-H3-amino acid sequence ARGDSSSSGRYYYYGMDV (SEQ ID NO: 321) Light chain variable region (LCVR, VL) - nucleotide sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCA GGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGACAGCCCCTAAGCGCCTGATCTTTGCTGCATCCAGTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCT GAAGATTTTGCGACTTATTACTGTCTACAGCATAATAATTACCCTCCCACTTTCGGCGGAGGGACCAAGGTGGAGATCAA A (SEQ ID NO: 322) Light chain variable region (LCVR, VL)-amino acid sequence DIQMTQSPSSLSASVGDRVTITCRAS QGIRND LGWYQQKPGTAPKRLIF AAS SLQSGVPSRFSGSGSGTEFTLTISSLQP EDFATYYC LQHNNYPPT FGGGTKVEIK (SEQ ID NO: 323) CDR-L1-nucleotide sequence CAG GGC ATT AGA AAT GAT (SEQ ID NO: 324) CDR-L1-amino acid sequence QGIRND (SEQ ID NO: 325) CDR-L2-nucleotide sequence GCT GCA TCC (SEQ ID NO: 326) CDR-L2-amino acid sequence AAS (SEQ ID NO: 327) CDR-L3-nucleotide sequence CTA CAG CAT AAT AAT TAC CCT CCC ACT (SEQ ID NO: 328) CDR-L3-amino acid sequence LQHNNYPPT (SEQ ID NO: 329) Heavy chain (HC)-nucleotide sequence CTGCTGCAAGGCTCTGGCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTC CTGTGCAGCGTCTGGATTCACCTTCAGTGGCTATGGCATACACTGGGTCCGCCAGGCTCCAGGCAAGGGACTGGTGTGGG TGGCAGTTATATGGTATGATGGAAGTTTTAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAAT TCCAAGAACACGCTGTATCTGCAGATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGTGATAG CAGCTCGTCCGGACGGTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCA CCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTC AAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCTGACCAGCGGCGTGCACACCTTCCCGGCTGT CCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCT GCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGC CCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGAC CCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGG AGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTG CACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCAT CTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAAC AACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAG GTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCC TGTCTCTGGGTAAATGA (SEQ ID NO: 330) Heavy chain - Amino acid sequence LLQGSG QVQLVESGGGVVQPGRSLRLSCAASGFTFSGYGIHWVRQAPGKGLVWVAVIWYDGSFKYYADSVKGRFTISRDN SKNTLYLQMNSLRAEDTAVYYCARGDSSSSGRYYYYGMDVWGQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPC PAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 331) Light chain (LC)-nucleotide sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCA GGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGACAGCCCCTAAGCGCCTGATCTTTGCTGCATCCAGTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCT GAAGATTTTGCGACTTATTACTGTCTACAGCATAATAATTACCCTCCCACTTTCGGCGGAGGGACCAAGGTGGAGATCAA ACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGT GCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGA GAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTTAG; (SEQ ID NO: 332) Light chain (LC)-amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGTAPKRLIFAASSLQSGVPSRFSGSGSGTEFTLTISSLQP EDFATYYCLQHNNYPPTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 333) REGN9270 Heavy chain variable region (HCVR,V H )-Nucleotide sequence CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATGGTGG GTCTTCAGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCCAGGAAAGGGGCTGGAGTGGATTGGGGAAATCAATCATG CTGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAATCACCATATCAGTGGACACGTCCAAGAACCAGTTCTCCCTG AAGCTGAGTTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGAGGATGGTACTATGGTTCGGGGAGTTATCA CCGAAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 334) Heavy chain variable region (HCVR,V H )-Amino acid sequence QVQLQQWGAGLLKPSETLSLTCAVY GGSFSGYY WSWIRQPPGKGLEWIGE INHAGST NYNPSLKSRITISVDTSKNQFSL KLSSVTAADTAVYYC ARGWYYGSGSYHRNWFDP WGQGTLVTVSS (SEQ ID NO: 335) CDR-H1-nucleotide sequence GGT GGG TCC TTC AGT GGT TAC TAC (SEQ ID NO: 336) CDR-H1-amino acid sequence GGSFSGYY (SEQ ID NO: 337) CDR-H2-nucleotide sequence ATC AAT CAT GCT GGA AGC ACC (SEQ ID NO: 338) CDR-H2-amino acid sequence INHAGST (SEQ ID NO: 339) CDR-H3-nucleotide sequence GCG AGA GGA TGG TAC TAT GGT TCG GGG AGT TAT CAC CGA AAC TGG TTC GAC CCC (SEQ ID NO: 340) CDR-H3-amino acid sequence ARGWYYGSGSYHRNWFDP (SEQ ID NO: 341) Light chain variable region (LCVR,V L )-Nucleotide sequence GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCA GAGTGTTTATTACAGCTACTTAGCCTGGTATCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCA ACAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAG CCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAACTCACCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAAT CAAA (SEQ ID NO: 342) Light chain variable region (LCVR,V L )-Amino acid sequence EIVLTQSPGTLSLSPGERATLSCRAS QSVYYSY LAWYQQKPGQAPRLLIY GAS NRATGIPDRFSGSGSGTDFTLTISRLE PEDFAVYYC QQYGNSPWT FGQGTKVEIK (SEQ ID NO: 343) CDR-L1-nucleotide sequence CAG AGT GTT TAT TAC AGC TAC (SEQ ID NO: 344) CDR-L1-amino acid sequence QSVYYSY (SEQ ID NO: 345) CDR-L2-nucleotide sequence GGT GCA TCC (SEQ ID NO: 346) CDR-L2-amino acid sequence GAS (SEQ ID NO: 347) CDR-L3-nucleotide sequence CAG CAG TAT GGT AAC TCA CCT TGG ACG (SEQ ID NO: 348) CDR-L3-amino acid sequence QQYGNSPWT (SEQ ID NO: 349) Heavy chain (HC)-nucleotide sequence TTACTTCAGGGATCTGGTCAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCAC CTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCCAGGAAAGGGGCTGGAGTGGA TTGGGGAAATCAATCATGCTGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAATCACCATATCAGTGGACACGTCC AAGAACCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGAGGATGGTACTA TGGTTCGGGGAGTTATCACCGAAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCA AGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAG GACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCT ACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCA ACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCA GCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCC TGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGG TGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTC CAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCA GCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAAC TACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTG GCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGT CTCTGGGTAAATGA(SEQ ID NO: 350) Heavy chain - Amino acid sequence LLQGSG QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHAGSTNYNPSLKSRITISVDTS KNQFSLKLSSVTAADTAVYYCARGWYYGSGSYHRNWFDPWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 351) Light chain (LC)-nucleotide sequence GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCA GAGTGTTTATTACAGCTACTTAGCCTGGTATCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCA ACAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAG CCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAACTCACCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAAT CAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTG TGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTA CGAGAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTAG (SEQ ID NO: 352) Light chain (LC)-amino acid sequence EIVLTQSPGTLSLSPGERATLSCRASQSVYYSYLAWYQQKPGQAPRLLIYGASNRATGIPDRFSGSGSGTDFTLTISRLE PEDFAVYYCQQYGNSPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 353) REGN9278 Heavy chain variable region (HCVR,V H )-Nucleotide sequence CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATGGTGG GTCTTCAGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCCAGGAAAGGGGCTGGAGTGGATTGGGGAAATCAATCATG CTGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAATCACCATATCAGTGGACACGTCCAAGAACCAGTTCTCCCTG AAGCTGAGTTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGAGGATGGTACTATGGTTCGGGGAGTTATCA CCGAAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 354) Heavy chain variable region (HCVR,V H )-Amino acid sequence QVQLQQWGAGLLKPSETLSLTCAVY GGSFSGYY WSWIRQPPGKGLEWIGE INHAGST NYNPSLKSRITISVDTSKNQFSL KLSSVTAADTAVYYC ARGWYYGSGSYHRNWFDP WGQGTLVTVSS (SEQ ID NO: 355) CDR-H1-nucleotide sequence GGT GGG TCC TTC AGT GGT TAC TAC (SEQ ID NO: 356) CDR-H1-amino acid sequence GGSFSGYY (SEQ ID NO: 357) CDR-H2-nucleotide sequence ATC AAT CAT GCT GGA AGC ACC (SEQ ID NO: 358) CDR-H2-amino acid sequence INHAGST (SEQ ID NO: 359) CDR-H3-nucleotide sequence GCG AGA GGA TGG TAC TAT GGT TCG GGG AGT TAT CAC CGA AAC TGG TTC GAC CCC (SEQ ID NO: 360) CDR-H3-amino acid sequence ARGWYYGSGSYHRNWFDP (SEQ ID NO: 361) Light chain variable region (LCVR,V L )-Nucleotide sequence GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCA GAGTGTTTATTACAGCTACTTAGCCTGGTATCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCA ACAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAG CCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAACTCACCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAAT CAAA (SEQ ID NO: 362) Light chain variable region (LCVR,V L )-Amino acid sequence EIVLTQSPGTLSLSPGERATLSCRAS QSVYYSY LAWYQQKPGQAPRLLIY GAS NRATGIPDRFSGSGSGTDFTLTISRLE PEDFAVYYC QQYGNSPWT FGQGTKVEIK (sequence number 363) CDR-L1-nucleotide sequence CAG AGT GTT TAT TAC AGC TAC (SEQ ID NO: 364) CDR-L1-amino acid sequence QSVYYSY (sequence number 365) CDR-L2-nucleotide sequence GGT GCA TCC (SEQ ID NO: 366) CDR-L2-amino acid sequence GAS (SEQ ID NO: 367) CDR-L3-nucleotide sequence CAG CAG TAT GGT AAC TCA CCT TGG ACG (SEQ ID NO: 368) CDR-L3-amino acid sequence QQYGNSPWT (SEQ ID NO: 369) Heavy chain (HC)-nucleotide sequence CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATGGTGG GTCTTCAGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCCAGGAAAGGGGCTGGAGTGGATTGGGGAAATCAATCATG CTGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAATCACCATATCAGTGGACACGTCCAAGAACCAGTTCTCCCTG AAGCTGAGTTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGAGGATGGTACTATGGTTCGGGGAGTTATCA CCGAAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCC CCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG GTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTA CTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCA GCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGG GGACCATCAGTTCTTCCTGTTCCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGT GGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAAGTTCAACTGGTACGTGGATGGCTGGAGGTGCATAATGCCAAGACAA AGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGC AAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCC CCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCA AAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCC GTGCTGGACTCCGACGCTCCTTCTTCCTTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTT CTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 370) Heavy chain amino acid sequence QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHAGSTNYNPSLKSRITISVDTSKNQFSL KLSSVTAADTAVYYCARGWYYGSGSYHRNWFDPWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 371) Light chain (LC)-nucleotide sequence TTACTTCAGGGATCTGGTGAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCT CTCCTGCAGGGCCAGTCAGAGTGTTTATTACAGCTACTTAGCCTGGTATCAGCAGAAACCTGGCCAGGCTCCCAGGCTCC TCATCTATGGTGCATCCAACAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTC ACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAACTCACCTTGGACGTTCGGCCA AGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGAC GCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAA AGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 372) Light chain (LC)-amino acid sequence LLQGSG EIVLTQSPGTLSLSPGERATLSCRASQSVYYSYLAWYQQKPGQAPRLLIYGASNRATGIPDRFSGSGSGTDFTL TISRLEPEDFAVYYCQQYGNSPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 373) REGN9279 Heavy chain variable region (HCVR,V H )-Nucleotide sequence GAAGTGCAGGTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATT CACCTTTGATGATTATGCCATGTTTTGGGTCCGGCAAGGTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGA ATAGTGGTAGCATAGGCTATGCGGACTCTGTAAAGGGCCGCTTCACCACCTCCAGAGACAACGCCAAGAACTCCCTATAT TTACAAATGAACAGTCTGAGAACTGAAGACACGGCCTTGTATTACTGTGCAAAAGATTATCGACCCCGTAGTGGGAACCA CTATAACAACTACGGTATGGACGTCTGGGGCCCAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 374) Heavy chain variable region (HCVR,V H )-Amino acid sequence EVQVVESGGGLVQPGRSLRLSCTAS GFTFDDYA MFWVRQGPGKGLEWVSG ISWNSGSI GYADSVKGRFTTSRDNAKNSLY LQMNSLRTEDTALYYC AKDYRPRSGNHYNNYGMDV WGPGTTVTVSS (SEQ ID NO: 375) CDR-H1-nucleotide sequence GGA TTC ACC TTT GAT GAT TAT GCC (SEQ ID NO: 376) CDR-H1-amino acid sequence GFTFDDYA (SEQ ID NO: 377) CDR-H2-nucleotide sequence ATT AGT TGG AAT AGT GGT AGC ATA (SEQ ID NO: 378) CDR-H2-amino acid sequence ISWNSGSI (sequence number 379) CDR-H3-nucleotide sequence GCA AAA GAT TAT CGA CCC CGT AGT GGG AAC CAC TAT AAC AAC TAC GGT ATG GAC GTC (SEQ ID NO: 380) CDR-H3-amino acid sequence AKDYRPRSGNHYNNYGMDV (SEQ ID NO: 381) Light chain variable region (LCVR,V L )-Nucleotide sequence GAGATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCA GAGTTTTCGCGGCAACTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTATGGTGCATCCA GCAGGGCCACTGGCATCCCAGACAGGTTCAGGGGCAGTGGGTCTGGGACAGACTTCACGCTCACCATCAGCAGACTGGAG CCTGAGGATTTTGCAGTATATTACTGTCACCAGTATGGTAGGTCACCTTGGACGTTCGGCCAAGGGACCAAAGGTGGAAAT CAAA (SEQ ID NO: 382) Light chain variable region (LCVR,V L )-Amino acid sequence EIVLTQSPGTLSLSPGERATLSCRAS QSFRGNY LAWYQQKPGQAPRLLIY GAS SRATGIPDRFRGSGSGTDFTLTISRLE PEDFAVYYC HQYGRSPWT FGQGTKVEIK (SEQ ID NO: 383) CDR-L1-nucleotide sequence CAG AGT TTT CGC GGC AAC TAC (SEQ ID NO: 384) CDR-L1-amino acid sequence QSFRGNY (SEQ ID NO: 385) CDR-L2-nucleotide sequence GGT GCA TCC (SEQ ID NO: 386) CDR-L2-amino acid sequence GAS (SEQ ID NO: 387) CDR-L3-nucleotide sequence CAC CAG TAT GGT AGG TCA CCT TGG ACG (SEQ ID NO: 388) CDR-L3-amino acid sequence HQYGRSPWT (SEQ ID NO: 389) Heavy chain (HC)-nucleotide sequence TTACTTCAGGGATCTGGTGAAGTGCAGGTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTC CTGTACAGCCTCTGGATTCACCTTTGATGATTATGCCATGTTTTGGGTCCGGCAAGGTCCAGGGAAGGGCCTGGAGTGGG TCTCAGGTATTAGTTGGAATAGTGGTAGCATAGGCTATGCGGACTCTGTAAAGGGCCGCTTCACCACCTCCAGAGACAAC GCCAAGAACTCCCTATATTTACAAATGAACAGTCTGAGAACTGAAGACACGGCCTTGTATTACTGTGCAAAAGATTATCG ACCCCGTAGTGGGAACCACTATAACAACTACGGTATGGACGTCTGGGGCCCAGGGACCACGGTCACCGTCTCCTCAGCCT CCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGC TGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACA CCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCC TGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCG GACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCG TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTC CTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAAC CATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACC AGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAG CAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCT CCCTGTCTCTGGGTAAATGA(SEQ ID NO: 390) Heavy chain - Amino acid sequence LLQGSG EVQVVESGGGLVQPGRSLRLSCTASGFTFDDYAMFWVRQGPGKGLEWVSGISWNSGSIGYADSVKGRFTTSRDN AKNSLYLQMNSLRTEDTALYYCAKDYRPRSGNHYNNYGMDVWGPGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPP CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 391) Light chain (LC)-nucleotide sequence GAGATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCA GAGTTTTCGCGGCAACTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTATGGTGCATCCA GCAGGGCCACTGGCATCCCAGACAGGTTCAGGGGCAGTGGGTCTGGGACAGACTTCACGCTCACCATCAGCAGACTGGAG CCTGAGGATTTTGCAGTATATTACTGTCACCAGTATGGTAGGTCACCTTGGACGTTCGGCCAAGGGACCAAAGGTGGAAAT CAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTG TGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTA CGAGAAACACAAAGTCCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTAG (SEQ ID NO: 392) Light chain (LC)-amino acid sequence EIVLTQSPGTLSLSPGERATLSCRASQSFRGNYLAWYQQKPGQAPRLLIYGASSRATGIPDRFRGSGSGTDFTLTISRLE PEDFAVYYCHQYGRSPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 393) REGN9280 Heavy chain variable region (HCVR,V H )-Nucleotide sequence GAAGTGCAGGTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATT CACCTTTGATGATTATGCCATGTTTTGGGTCCGGCAAGGTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGA ATAGTGGTAGCATAGGCTATGCGGACTCTGTAAAGGGCCGCTTCACCACCTCCAGAGACAACGCCAAGAACTCCCTATAT TTACAAATGAACAGTCTGAGAACTGAAGACACGGCCTTGTATTACTGTGCAAAAGATTATCGACCCCGTAGTGGGAACCA CTATAACAACTACGGTATGGACGTCTGGGGCCCAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 394) Heavy chain variable region (HCVR,V H )-Amino acid sequence EVQVVESGGGLVQPGRSLRLSCTAS GFTFDDYA MFWVRQGPGKGLEWVSG ISWNSGSI GYADSVKGRFTTSRDNAKNSLY LQMNSLRTEDTALYYC AKDYRPRSGNHYNNYGMDV WGPGTTVTVSS (sequence number 395) CDR-H1-nucleotide sequence GGA TTC ACC TTT GAT GAT TAT GCC (SEQ ID NO: 396) CDR-H1-amino acid sequence GFTFDDYA (SEQ ID NO: 397) CDR-H2-nucleotide sequence ATT AGT TGG AAT AGT GGT AGC ATA (SEQ ID NO: 398) CDR-H2-amino acid sequence ISWNSGSI (sequence number 399) CDR-H3-nucleotide sequence GCA AAA GAT TAT CGA CCC CGT AGT GGG AAC CAC TAT AAC AAC TAC GGT ATG GAC GTC (SEQ ID NO: 400) CDR-H3-amino acid sequence AKDYRPRSGNHYNNYGMDV (SEQ ID NO: 401) Light chain variable region (LCVR,V L )-Nucleotide sequence GAGATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCA GAGTTTTCGCGGCAACTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTATGGTGCATCCA GCAGGGCCACTGGCATCCCAGACAGGTTCAGGGGCAGTGGGTCTGGGACAGACTTCACGCTCACCATCAGCAGACTGGAG CCTGAGGATTTTGCAGTATATTACTGTCACCAGTATGGTAGGTCACCTTGGACGTTCGGCCAAGGGACCAAAGGTGGAAAT CAAA (SEQ ID NO: 402) Light chain variable region (LCVR,V L )-Amino acid sequence EIVLTQSPGTLSLSPGERATLSCRAS QSFRGNY LAWYQQKPGQAPRLLIY GAS SRATGIPDRFRGSGSGTDFTLTISRLE PEDFAVYYC HQYGRSPWT FGQGTKVEIK (sequence number 403) CDR-L1-nucleotide sequence CAG AGT...

Claims

1. Formula (A): BA-(L-P) ｍ (A) An antibody-tethered drug conjugate having the structure of the formula, or a pharmaceutically acceptable salt thereof, wherein, BA is an antibody or its antigen-binding fragment that specifically binds to the glucagon-like peptide-1 receptor (GLP1R), and the antibody or its antigen-binding fragment is (i) Heavy chain immunoglobulin or its variable region containing CDR-H1, CDR-H2, and CDR-H3 of the heavy chain immunoglobulin or its variable region containing the amino acid sequence or variant of the heavy chain immunoglobulin or its variable region described in SEQ ID NOs: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, Furthermore / or including light chain immunoglobulin or its variable region CDR-L1, CDR-L2, and CDR-L3, which include the amino acid sequence or variant thereof described in SEQ ID NOs: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, (ii) an antibody or antigen-binding fragment that competes with the antibody or antigen-binding fragment of (i) for binding to GLP1R, and / or (iii) An antibody or antigen-binding fragment that binds to the same GLP1R epitope as the antibody or antigen-binding fragment of (i), L is an inseparable linker, Optionally, the heavy chain immunoglobulin of BA does not contain C-terminal lysine, or lysine and glycine. Optionally, the light chain immunoglobulin and / or heavy chain immunoglobulin of the BA comprises an N-terminal Qtag conjugated to the non-cleavable linker. P is, 【Chemistry 1】 A payload having a structure selected from the group consisting of, in the formula, 【Chemistry 2】 This is the point where the payload is coupled to L. X １ H, 【Transformation 3】 Selected from, X ２ teeth, 【Chemistry 4】 Selected from, X ３ is selected from the group consisting of a bond, -(CH ２ ), ２－６ -NH-, -(CH ２ ), ２－６ -Tr-, and -(CH ２ ), ２－６ -Tr-(CH ２ ), １－６ -NH-, where Tr is a triazole moiety, n is either 0 or 1, X ４ is, -NH ２ Selected from -OH and -N(H)(phenyl), X ５ is -OH, -NH ２ , -NH-OH, and 【Transformation 5】 Selected from, X ６ These appear independently as H, -OH, and -CH when they appear. ３ , and -CH ２ Selected from OH, X ７ H, 【Transformation 6】 Selected from, X ８ H, -OH, -NH ２ , and 【Transformation 7】 Selected from, Ar is, 【Transformation 8】 Selected from, X ９ is, -NH ２ , 【Chemistry 9】 Selected from, m is an integer between 1 and 4, wherein the antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof.

2. Equation (I): BA-L-P (I) It has the structure, and in the formula, P is, 【Chemistry 10】 A payload having a structure selected from the group consisting of, in the formula, 【Chemistry 11】 This is the point where the payload is coupled to L. X １ H, 【Chemistry 12】 Selected from, X ２ teeth, 【Chemistry 13】 Selected from, X ３ is, -(CH ２ ) ２－６ -NH- and -(CH ２ ) ２－６ -Tr- is selected, where Tr is the triazole moiety. n is either 0 or 1, X4 is selected from -NH2, -OH, and -N(H)(phenyl), X4a is selected from H and phenyl, X ５ is -OH, -NH ２ , -NH-OH, and 【Chemistry 14】 Selected from, X ６ These appear independently as H, -OH, and -CH when they appear. ３ , and -CH ２ Selected from OH, X ７ H, 【Chemistry 15】 Selected from, X ８ H, -OH, -NH ２ , and 【Chemistry 16】 Selected from, The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the light chain immunoglobulin optionally comprises an N-terminal Qtag.

3. P is, 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 The antibody-attached drug conjugate according to claim 1, wherein the payload has a structure selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

4. P is 【Chemistry 24】 The payload has the structure, in the formula, 【Chemistry 25】 The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the payload binds directly or via a linker to the antibody or its antigen-binding fragment.

5. The aforementioned payload, 【Chemistry 26】 An antibody-attached drug conjugate according to claim 4, having the structure of the above, or a pharmaceutically acceptable salt thereof. 【Request Item 6】 【Chemistry 27】 A linker payload having the structure, in the formula, 【Chemistry 28】 The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the linker payload binds to the Qtag of the antibody or its antibody-antigen-binding fragment.

7. The aforementioned linker payload 【Chemistry 29】 An antibody-attached drug conjugate according to claim 6, having the structure of the above, or a pharmaceutically acceptable salt thereof.

8. The antibody or its antigen-binding fragment (a) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 42 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 44 (b) Heavy chain immunoglobulins containing the amino acid sequence described in SEQ ID NO: 62 and light chain immunoglobulins containing the amino acid sequence described in SEQ ID NO: 64 (c) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 82 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 84 (d) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 102 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 104 (e) Heavy chain immunoglobulins containing the amino acid sequence described in SEQ ID NO: 122 and light chain immunoglobulins containing the amino acid sequence described in SEQ ID NO: 124 (f) Heavy chain immunoglobulins containing the amino acid sequence described in SEQ ID NO: 142 and light chain immunoglobulins containing the amino acid sequence described in SEQ ID NO: 144 (g) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 162 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 164 (h) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 182 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 184 (i) Heavy chain immunoglobulins containing the amino acid sequence described in SEQ ID NO: 203 and light chain immunoglobulins containing the amino acid sequence described in SEQ ID NO: 205 (j) Heavy chain immunoglobulins containing the amino acid sequence described in SEQ ID NO: 223 and light chain immunoglobulins containing the amino acid sequence described in SEQ ID NO: 225 (k) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 243 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 245 (l) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 263 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 265 (m) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 267 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 269 (n) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 271 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 273 (o) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 291 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 293 (p) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 311 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 313 (q) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 331 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 333, (r) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 351 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 353 (s) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 371 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 373 (t) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 391 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 393 (u) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 411 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 413 (v) Heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 414 and light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 84, or (w) comprises a heavy chain immunoglobulin containing the amino acid sequence described in SEQ ID NO: 416 and a light chain immunoglobulin containing the amino acid sequence described in SEQ ID NO:

84. Optionally, the heavy chain immunoglobulin does not contain C-terminal lysine, or lysine and glycine. The structure of the linker payload, which is conjugated via amino acid 3 (Gln) to amino acids 1-6 (LLQGSG) of sequence numbers 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, is 【Transformation 30】 It is expressed by, in the formula, 【Chemistry 31】 The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein amino acids 1-6 (LLQGSG) bind to amino acid 7 of sequence numbers 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413.

9. An isolated antibody or its antigen-binding fragment that specifically binds to a glucagon-like peptide-1 receptor (GLP1R), (i) Heavy chain immunoglobulin or its variable region containing CDR-H1, CDR-H2, and CDR-H3 of the heavy chain immunoglobulin or its variable region containing the amino acid sequence or variant of the heavy chain immunoglobulin or its variable region described in SEQ ID NOs: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, and / or A light chain immunoglobulin or its variable region comprising CDR-L1, CDR-L2, and CDR-L3, which include the amino acid sequence or variant described in SEQ ID NOs. 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, wherein the light chain immunoglobulin or its variable region comprises CDR-L1, CDR-L2, and CDR-L3, wherein the light chain immunoglobulin optionally lacks the N-terminal residue LLQGSG (SEQ ID NO. 18), (ii) an antibody or antigen-binding fragment that competes with the antibody or antigen-binding fragment of (i) for binding to GLP1R, and / or (iii) An antibody or antigen-binding fragment that binds to the same GLP1R epitope as the antibody or antigen-binding fragment of (i), Optionally, the heavy chain immunoglobulin does not contain C-terminal lysine, or lysine and glycine. An isolated antibody or antigen-binding fragment thereof, optionally conjugated to a payload or linker payload.

10. The linker L is (i) bonded to one or both heavy chains of BA, (ii) Bound to one or both heavy chain variable domains of BA, (iii) bonded to one or both of the light chains of BA, (iv) Binding to one or both light chain variable domains of the BA, (v) Binding to BA via glutamine residues, and / or (vi) The antibody-tethered drug conjugate according to claim 1 or a pharmaceutically acceptable salt thereof, which is conjugated to BA via a lysine residue.

11. The glutamine residue in (v) is (i) Introduced at the N-terminus of one or both heavy chains of the BA, (ii) Introduced at the N-terminus of one or both of the light chains of the BA, (iii) Naturally present in the CH2 domain or CH3 domain of the BA, (iv) Introduced into the BA by modifying one or more amino acids, and / or (i) an antibody-tethered drug conjugate according to claim 10, which is Q295 or mutates from N297 to Q297 (N297Q), or a pharmaceutically acceptable salt thereof.

12. The antibody-attached drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the antibody or its antigen-binding fragment is aglycosylated or deglycosylated.

13. The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the antigen-binding fragment is a Fab fragment.

14. The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein m is 1 or 2.

15. The linker L is of formula (L'): -La-Y-Lp- (L') It has the structure, and in the formula, La is a first linker covalently bonded to BA, Y is a triazole-containing group, The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein Lp is absent or is a second linker covalently bonded to P, and if Lp is absent, Y is also absent.

16. Y-Lp does not exist, or 【Chemistry 32】 The antibody-attached drug conjugate according to claim 15, having a structure selected from the group consisting of, or a triazole positional isomer thereof, wherein p is an integer from 1 to 36.

17. Y is 【Transformation 33】 The antibody-attached drug conjugate according to claim 15, having a structure selected from the group consisting of, where Q is C or N, wherein Q is C or N.

18. The antibody-attached drug conjugate or a pharmaceutically acceptable salt thereof according to any one of Claim 15, wherein Lp comprises a polyethylene glycol (PEG) segment having 1 to 36 -CH2CH2O-(EG) units, and / or Lp comprises one or more amino acids selected from glycine, serine, glutamic acid, alanine, valine, and proline, and combinations thereof.

19. The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 18, wherein the PEG segment comprises four EG units, or eight EG units, or twelve EG units, or twenty-four EG units.

20. The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 18, wherein Lp comprises 1 to 10 glycine molecules and / or 1 to 6 serine molecules.

21. The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 20, wherein Lp is selected from the group consisting of Gly-Gly-Gly-Gly-Ser(G4S) (SEQ ID NO: 1), Ser-Gly-Gly-Gly-Gly(SG4) (SEQ ID NO: 2), and Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser(G4S-G4S) (SEQ ID NO: 3).

22. The Lp is 【Transformation 34】 Having a structure selected from the group consisting of, The antibody-attached drug conjugate or a pharmaceutically acceptable salt thereof according to claim 15, wherein Y is a triazole-containing group, P is a payload, Rc is selected from H and glucose, g is an integer from 1 to 10, and s is an integer from 0 to 4.

23. Y-Lp is 【Chemistry 35】 【Transformation 36】 An antibody-attached drug conjugate according to claim 15, having a structure selected from the group consisting of, or a triazole positional isomer thereof, or a pharmaceutically acceptable salt thereof.

24. The antibody-attached drug conjugate or a pharmaceutically acceptable salt thereof according to claim 15, wherein La comprises a polyethylene glycol (PEG) segment having 1 to 36 -CH2CH2O-(EG) units, and / or La comprises one or more amino acids selected from glycine, threonine, serine, glutamine, glutamic acid, alanine, valine, leucine, and proline, and combinations thereof, and / or La comprises a -(CH2)2-24- chain.

25. The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 24, wherein the PEG segment comprises four EG units, or eight EG units, or twelve EG units, or twenty-four EG units.

26. The La is, 【Chemistry 37】 An antibody-attached drug conjugate according to claim 15, having a structure selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

27. ​​The antibody-tethered drug conjugate according to claim 24, wherein La comprises 1 to 10 glycine molecules and 1 to 6 serine molecules, or a pharmaceutically acceptable salt thereof.

28. The antibody-attached drug conjugate or a pharmaceutically acceptable salt thereof according to claim 27, wherein La is selected from the group consisting of Gly-Gly-Gly-Gly-Ser(G4S) (SEQ ID NO: 1), Ser-Gly-Gly-Gly-Gly(SG4) (SEQ ID NO: 2), Gly-Gly-Ser-Gly-Gly-Ser-Gly-Gly(G2S-G2S-G2), and Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly(G4S-G4) (SEQ ID NO: 3).

29. The La is 【Transformation 38】 An antibody-tethered drug conjugate according to claim 24, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

30. The P is 【Chemistry 39】 An antibody-attached drug conjugate according to claim 1, having the structure of the above, or a pharmaceutically acceptable salt thereof.

31. (i) X1 is H, and X2 is 【Chemistry 40】 X3 is selected from -(CH2)2-6-NH- and -(CH2)2-6-Tr-, where Tr is the triazole moiety, n is 1, and X4a is H. (ii) X 1 is, 【Chemistry 41】 And X 2 is, 【Chemistry 42】 And X3 is -(CH2)2-6-NH-, n is 1, X4a is H, and X5 is -OH, -NH2, -NH-OH, and 【Chemistry 43】 Selected from, (iii) X 1 is, 【Chemistry 44】 And X 2 is, 【Chemistry 45】 And X 3 is -(CH 2) 2-6 -NH-, n is 1, and X 4a is H, (iv) X 1 is, 【Chemistry 46】 And X 2 is, 【Chemistry 47】 And X3 is -(CH2)2-6-NH-, n is 1, X4a is H, X6 is independently selected from H and -CH2OH at each occurrence, and X7 is H. (v) X 1 is, 【Chemistry 48】 And X 2 is, 【Chemistry 49】 And X3 is -(CH2)2-6-Tr-, where Tr is the triazole portion, n is 1, X4a is H, and X5 is, [Transformation 50] And, (vi) X 1 is, 【Chemistry 51】 And X 2 is, 【Chemistry 52】 And X 3 is -(CH 2) 2-6 -NH-, n is 1, X 4a is H, X 6 is independently selected from H and -CH 3 at each occurrence, and X 7 is 【Chemistry 53】 And X 8 is -NH 2, (vii) X 1 is, 【Chemistry 54】 And X 2 is, 【Transformation 55】 And X 3 is -(CH 2) 2-6 -NH-, n is 1, X 4a is H, X 8 is H, (viiii) X 1 is, 【Transformation 56】 And X 2 is, 【Chemistry 57】 And X 3 is -(CH 2) 2-6 -NH-, n is 1, X 4a is H, X 6 is H in each instance, and X 7 is, 【Transformation 58】 And X 8 is H, (ix)X 1 is, 【Chemistry 59】 And X 2 is, 【Transformation 60】 And X 3 is -(CH 2) 2-6 -NH-, n is 1, X 4a is H, X 6 is independently selected from H and -CH 3 at each occurrence, and X 7 is 【Chemistry 61】 And X 8 is, 【Transformation 62】 And, (x)X 1 is, 【Transformation 63】 And X 2 is, 【Chemistry 64】 And X 3 is -(CH 2) 2-6 -NH-, n is 1, and X 4a is H, (xi)X 1 is, 【Transformation 65】 And X 2 is, 【Chemical 66】 And X 3 is -(CH 2) 2-6 -NH-, n is 1, and X 4a is H, (xi)X 1 is, 【Transformation 67】 And X 2 is, 【Transformation 68】 And X 3 is -(CH 2) 2-6 -NH-, n is 1, X 4a is H, X 6 is independently selected from H and -CH 3 at each occurrence, and X 7 is 【Transformation 69】 And, (xiii) X 1 is H, and X 2 is, 【Transformation 70】 And X 3 is -(CH 2) 2-6 -NH-, n is 1, and X 4a is H, (xiv)X 1 is, 【Chemistry 71】 And X 2 is, 【Chemistry 72】 And X 3 is -(CH 2) 2-6 -NH-, n is 1, X 4a is H, and X 5 is, 【Transformation 73】 And, (xv)X 1 is, 【Chemistry 74】 And X 2 is, 【Chemistry 75】 And X3 is -(CH2)2-6-NH-, n is 0, X4a is phenyl, and X5 is, 【Transformation 76】 And, (xvi)X 1 is, 【Chemical 77】 And X 2 is, 【Transformation 78】 And X3 is -(CH2)2-6-NH-, n is 1, X4a is phenyl, and X5 is 【Chemistry 79】 is, or (xvii)X 1 is, 【Chemistry 80】 And X 2 is, 【Chemistry 81】 And X 3 is -(CH 2) 2-6 -NH-, X 4a is H, and X 5 is, 【Chemistry 82】 The antibody-tethered drug conjugate according to claim 2 or a pharmaceutically acceptable salt thereof.

32. The P is, 【Chemistry 83】 【Chemical 84】 【Chemical 85】 【Chemical 86】 【Chemistry 87】 【Chemical 88】 【Chemical 89】 An antibody-attached drug conjugate according to claim 1, having a structure selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

33. The antibody-tethered drug conjugate according to claim 1, which has a half-life in plasma longer than 7 days and / or does not bind to G protein-binding receptors (GPCRs) other than GLP1R, or a pharmaceutically acceptable salt thereof.

34. A payload conjugated to a linker conjugated to one or both of two immunoglobulin heavy chains or their variable regions in an antibody or its antigen-binding fragment, [Chemical 90] It has the structure, and in the formula, Immunoglobulin is the immunoglobulin chain of the antibody or antigen-binding fragment, CapAib is 3-((2-(1H-imidazole-5-yl)ethyl)amino)-2,2-dimethyl-3-oxopropanoic acid, E* is (S)-2-amino-3-(2H-tetrazole-5-yl)propanoic acid, G stands for glycine, T is threonine, F* is (S)-2-amino-3-(2-fluorophenyl)-2-methylpropanoic acid, S is serine, D is aspartate, AA2 is (S)-2-amino-3-(4'-(4-(4-(25-amino-2,5,8,11,14,17,20,23-octaoxapentacosyl)-1H-1,2,3-triazole-1-yl)butoxy)-2'-ethyl-[1,1'-biphenyl]-4-yl)propanoic acid [AA2 contains a linker], The antibody-tethered drug conjugate according to claim 1, wherein AA1 = (S)-2-amino-5-(3,5-dimethylphenyl)pentanamide, or a pharmaceutically acceptable salt thereof.

35. The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the linker is optionally conjugated by the Qtag to the immunoglobulin heavy chain and / or the immunoglobulin light chain or its variable region via a glutamine (Q) residue of the Qtag.

36. The Qtag is an amino acid sequence LLQGG (SEQ ID NO: 6), LLQG (SEQ ID NO: 7), LSLSQG (SEQ ID NO: 8), GGGLLQGG (SEQ ID NO: 9), GLLQG (SEQ ID NO: 10), LLQ,GSPLAQSHGG (SEQ ID NO: 11), GLLQGGG (SEQ ID NO: 12), GLLQGG (SEQ ID NO: 13), GLLQ (SEQ ID NO: 14), LLQLLQGA (SEQ ID NO: 15), LLQGA (SEQ ID NO: 16), LL An antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 35, comprising QYQGA (SEQ ID NO: 17), LLQGSG (SEQ ID NO: 18), LLQYQG (SEQ ID NO: 19), LLQLLQG (SEQ ID NO: 20), SLLQG (SEQ ID NO: 21), LLQLQ (SEQ ID NO: 22), LLQLLQ (SEQ ID NO: 23), LLQGSGSG (SEQ ID NO: 185), and / or LLQGR (SEQ ID NO: 24).

37. (a) Heavy chain immunoglobulin or its variable region is an amino acid sequence described in SEQ ID NOs: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, or SEQ ID NO: 26 , comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequences described in 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, and / or (b) Light chain immunoglobulin or its variable region is an amino acid sequence described in SEQ ID NOs: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, or SEQ ID NOs: 34, 54, 74, 94, 114, 1 An antibody-attached drug conjugate according to claim 1 or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence having at least 90% sequence identity with the amino acid sequences described in 34, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413.

38. The heavy chain immunoglobulin or its variable region (i) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 28 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 30 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 32 or a variant thereof, (ii) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 48 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 50 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 52 or a variant thereof, (iii) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 68 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 70 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 72 or a variant thereof, (iv) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 88 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 90 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 92 or a variant thereof, (v) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 108 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 110 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 112 or a variant thereof, (vi) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 128 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 130 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 132 or a variant thereof, (vii) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 148 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 150 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 152 or a variant thereof, (viiii) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 168 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 170 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 172 or a variant thereof, (ix) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 189 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 191 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 193 or a variant thereof, (x) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 209 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 211 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 213 or a variant thereof, (xi) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 229 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 231 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 233 or a variant thereof, (xi) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 249 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 251 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 253 or a variant thereof, (xiii) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 277 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 279 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 281 or a variant thereof, (xiv) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 297 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 299 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 301 or a variant thereof, (xv) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 317 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 319 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 321 or a variant thereof, (xvi) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 337 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 339 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 341 or a variant thereof, (xvii) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 357 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 359 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 361 or a variant thereof, and / or (xviiii) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 377 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 379 or a variant thereof, CDR-H3 containing the amino acid sequence described in SEQ ID NO: 381 or a variant thereof, (xix) CDR-H1 containing the amino acid sequence described in SEQ ID NO: 397 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 399 or a variant thereof, and CDR-H3 containing the amino acid sequence described in SEQ ID NO: 401 or a variant thereof. Furthermore / or The light chain immunoglobulin or its variable region (a) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 36 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 38 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 40 or a variant thereof, (b) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 56 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 58 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 60 or a variant thereof, (c) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 76 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 78 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 80 or a variant thereof, (d) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 96 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 98 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 100 or a variant thereof, (e) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 116 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 118 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 120 or a variant thereof, (f) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 136 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 138 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 140 or a variant thereof, (g) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 156 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 158 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 160 or a variant thereof, (h) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 176 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 178 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 180 or a variant thereof, (i) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 197 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 199 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 201 or a variant thereof, (j) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 217 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 219 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 221 or a variant thereof, (k) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 237 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 239 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 241 or a variant thereof, (l) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 257 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 259 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 261 or a variant thereof, (m) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 285 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 287 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 289 or a variant thereof, (n) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 305 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 307 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 309 or a variant thereof, (o) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 325 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 327 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 329 or a variant thereof, (p) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 345 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 347 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 349 or a variant thereof, (q) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 365 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 367 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 369 or a variant thereof, (r) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 385 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 387 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 389 or a variant thereof, and / or (s) CDR-L1 containing the amino acid sequence described in SEQ ID NO: 405 or a variant thereof, CDR-L2 containing the amino acid sequence described in SEQ ID NO: 407 or a variant thereof, CDR-L3 containing the amino acid sequence described in SEQ ID NO: 409 or a variant thereof, The antibody-tethered drug conjugate according to claim 1 or a pharmaceutically acceptable salt thereof.

39. (1) The heavy chain immunoglobulin or its variable region comprises CDR-H1 comprising the amino acid sequence described in SEQ ID NO: 28 or a variant thereof, CDR-H2 comprising the amino acid sequence described in SEQ ID NO: 30 or a variant thereof, and CDR-H3 comprising the amino acid sequence described in SEQ ID NO: 32, The light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 36, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 38, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

40. (2) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence described in SEQ ID NO: 48 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 50 or a variant thereof, and CDR-H3 containing the amino acid sequence described in SEQ ID NO: 52, The light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 56, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 58, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

60. (3) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence described in SEQ ID NO: 68 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 70 or a variant thereof, and CDR-H3 containing the amino acid sequence described in SEQ ID NO: 72, The light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 76, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 78, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

80. (4) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence described in SEQ ID NO: 88 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 90 or a variant thereof, and CDR-H3 containing the amino acid sequence described in SEQ ID NO: 92, The light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 96, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 98, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

100. (5) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence described in SEQ ID NO: 108 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 110 or a variant thereof, and CDR-H3 containing the amino acid sequence described in SEQ ID NO: 112, The light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 116, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 118, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

120. (6) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence described in SEQ ID NO: 128 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 130 or a variant thereof, and CDR-H3 containing the amino acid sequence described in SEQ ID NO: 132, The light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 136, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 138, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

140. (7) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence described in SEQ ID NO: 148 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 150 or a variant thereof, and CDR-H3 containing the amino acid sequence described in SEQ ID NO: 152, The light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 156, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 158, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

160. (8) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence described in SEQ ID NO: 168 or a variant thereof, CDR-H2 containing the amino acid sequence described in SEQ ID NO: 170 or a variant thereof, and CDR-H3 containing the amino acid sequence described in SEQ ID NO:

172. The light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 176, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 178, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

180. (9) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 189, CDR-H2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 191, CDR-H3 containing the amino acid sequence or variant thereof described in SEQ ID NO: 193, and the light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 197, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 199, CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO: 201, (10) The heavy chain immunoglobulin or its variable region comprises CDR-H1 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 209, CDR-H2 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 211, and CDR-H3 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 213, and the light chain immunoglobulin or its variable region comprises CDR-L1 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 217, CDR-L2 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 219, and CDR-L3 comprising the amino acid sequence or variant thereof described in SEQ ID NO:

221. (11) The heavy chain immunoglobulin or its variable region comprises CDR-H1 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 229, CDR-H2 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 231, CDR-H3 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 233, and the light chain immunoglobulin or its variable region comprises CDR-L1 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 237, CDR-L2 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 239, CDR-L3 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 241, (12) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 249, CDR-H2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 251, and CDR-H3 containing the amino acid sequence or variant thereof described in SEQ ID NO: 253, and the light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 257, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 259, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

261. (13) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 277, CDR-H2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 279, and CDR-H3 containing the amino acid sequence or variant thereof described in SEQ ID NO: 281, and the light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 285, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 287, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

289. (14) The heavy chain immunoglobulin or its variable region comprises CDR-H1 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 297, CDR-H2 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 299, CDR-H3 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 301, and the light chain immunoglobulin or its variable region comprises CDR-L1 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 305, CDR-L2 comprising the amino acid sequence or variant thereof described in SEQ ID NO: 307, and CDR-L3 comprising the amino acid sequence or variant thereof described in SEQ ID NO:

309. (15) The heavy chain immunoglobulin or its variable region comprises CDR-H1 comprising the amino acid sequence described in SEQ ID NO: 317 or a variant thereof, CDR-H2 comprising the amino acid sequence described in SEQ ID NO: 319 or a variant thereof, CDR-H3 comprising the amino acid sequence described in SEQ ID NO: 321 or a variant thereof, and the light chain immunoglobulin or its variable region comprises CDR-L1 comprising the amino acid sequence described in SEQ ID NO: 325 or a variant thereof, CDR-L2 comprising the amino acid sequence described in SEQ ID NO: 327 or a variant thereof, CDR-L3 comprising the amino acid sequence described in SEQ ID NO: 329 or a variant thereof, (16) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 337, CDR-H2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 339, and CDR-H3 containing the amino acid sequence or variant thereof described in SEQ ID NO: 341, and the light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 345, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 347, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

349. (17) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 357, CDR-H2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 359, and CDR-H3 containing the amino acid sequence or variant thereof described in SEQ ID NO: 361, and the light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 365, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 367, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

369. (18) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 377, CDR-H2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 379, CDR-H3 containing the amino acid sequence or variant thereof described in SEQ ID NO: 381, and the light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 385, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 387, CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO: 389, or (19) The heavy chain immunoglobulin or its variable region comprises CDR-H1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 397, CDR-H2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 399, and CDR-H3 containing the amino acid sequence or variant thereof described in SEQ ID NO: 401, and the light chain immunoglobulin or its variable region comprises CDR-L1 containing the amino acid sequence or variant thereof described in SEQ ID NO: 405, CDR-L2 containing the amino acid sequence or variant thereof described in SEQ ID NO: 407, and CDR-L3 containing the amino acid sequence or variant thereof described in SEQ ID NO:

409. The antibody-tethered drug conjugate according to claim 1 or a pharmaceutically acceptable salt thereof.

40. (a) The heavy chain immunoglobulin variable region is an amino acid sequence EVQLVESGGGLLVKPGGSLRLSCAASGFIFSRYSMNWVRQAPGKGLEWVSSMSSNSKNTYYADSVKGRFTISRDNAKNSLFLQMNTLRAEDTAVYYCARDGYTLRAAFDIWGQGTMVTVSS (Sequence ID) 26) The light chain immunoglobulin variable region includes the amino acid sequence EIVLTQSPGTLSLSSPGERDTLSCRASQSIAGRYVAWYQQKPGQAPRRLLIYGASSRATGIPDRFSGSGSGTDFTLTTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 34), (b) The heavy chain immunoglobulin variable region is the amino acid sequence EVQLVESGGGLLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLIAAPRPMGFDYWGQGTLVTVSS (sequence) Number 46) is included, and the light chain immunoglobulin variable region includes the amino acid sequence DIQMTQSPSSVSASVGDRVTITCRASQGINSWLAWYQQKPGKAAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQADSFPYTFGQGTKLEIK (Sequence ID 54), (c) The heavy chain immunoglobulin variable region is the amino acid sequence EVQLVESGGGLLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLIAPRPMGFDYWGQGTLVTVSS (sequence) The variable region of the light chain immunoglobulin (number 66) contains the amino acid sequence DIQMTQSPSSVSASVGDRVTITCRASQGINSWLAWYQQKPGKAAPKLLIYAASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQADSFPYTFGQGTKLEIK (Sequence ID 74), (d) The heavy chain immunoglobulin variable region is the amino acid sequence QVQLVESGGGGVGQPGRSLRLSCAASGFTFFSRNAMHWVRQAPGKGLEWVAVISYDGSNKHYADSVKGRFTISRDNSKNTLYLEMNSLRVEDTAVYYCAKGGGIPFDYWGQGTLVTVSS (SEQ ID NO: 86) The light chain immunoglobulin variable region contains the amino acid sequence DIVMTQSPLSSPVTLGQPASISCRSSQSLLVHFDGNTYLSWLHQRPGQPPRLLLIYKISNRFSGVPDRFSGGSGAGTDFFTLKISRVEPEDVGVYYCMHATQFPYTFGQGTKLEIK (SEQ ID NO: 94), (e) The heavy chain immunoglobulin variable region is the amino acid sequence QVQLVESGGGGVVQPARSLRLLSCAASGFAFSRSSAMHWVRQAPGKGLEWVAVISYDGSNKYYYTDSVKGRFTISRDNSKNTLYLQMNTLRAEDTALYYYCAKMYTTTMDSFDYWGQGTLVTVSS (Sequence ID) 106) contains, and the light chain immunoglobulin variable region contains the amino acid sequence DIQLTQSPSFLSASVGDRVTITCWASQGISSYLAWYQQKPGKAAPKLLLIYAASTLQSGVPSRFSGSGSGTEFLTISSLQPEDFALYYCQQLNSYPRTFGQGTKVEIK (SEQ ID NO: 114), (f) The heavy chain immunoglobulin variable region is the amino acid sequence EVQLVESGGGLLVKPGGSLRLSCAASGFIFSRYSMNWVRQAPGKGLEWVSSMSSNSKNTYYADSVKGRFTISRDNAKNSLFLQMNTLRAEDTAVYYCARDGYTLRAAFDIWGQGTMVTVSS (Sequence ID 1) 26) The light chain immunoglobulin variable region includes the amino acid sequence EIVLTQSPGTLSLSPGERDTLSCRASQSIAGRYVAWYQQKPGQAPRRLLIYGASSRATGIPDRFSGSGSGTDFTLTTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 134), (g) The heavy chain immunoglobulin variable region is the amino acid sequence QVQLVESGGGGVVQPGRSLRLSCAASGFTFSGYGIHWVRQAPGKGLVWVAVIWYDGSFKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGDSSSSSGRYYYYYGMDVWGQGTTVTVSS (distributed The light chain immunoglobulin variable region includes the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGTAPKRLIFAASSLQSGVPSRFSGSGSGTEFFTLTISSLQPEDFATYYCLQHNNYPPTFGGGTKVEIK (SEQ ID NO: 154), (h) The heavy chain immunoglobulin variable region is the amino acid sequence EVQLVESGGGLVQPGGSLKLSCAASGFTFSGSAMHWVRQASGKGLEWVGRITSKANSYATAYDASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRQRFLEFLFLDYWGQGTLVTVSS (sequence number) (Sequence No. 166) contains, and the light chain immunoglobulin variable region contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPPITFGQGTRLEIK (Sequence No. 174), (i) The heavy chain immunoglobulin variable region is the amino acid sequence EVQLVESGGGLLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLIAAPRPMGFDYWGQGTLVTVSS (sequence number) (Sequence No. 187) contains, and the light chain immunoglobulin variable region contains the amino acid sequence DIQMTQSPSSVSASVGDRVTITCRASQGINSWLAWYQQKPGKAAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQADSFPYTFGQGTKLEIK (Sequence No. 195), (j) The heavy chain immunoglobulin variable region is the amino acid sequence QVQLVESGGGGVGQPGRSLRLSCAASGFTFFSRNAMHWVRQAPGKGLEWVAVISYDGSNKHYADSVKGRFTISRDNSKNTLYLEMNSLRVEDTAVYYCAKGGGIPFDYWGQGTLVTVSS (SEQ ID NO: 207) The light chain immunoglobulin variable region contains the amino acid sequence DIVMTQSPLSSPVTLGQPASISCRSSQSLLVHFDGNTYLSWLHQRPGQPPRLLLIYKISNRFSGVPDRFSGGSGAGTDFFTLKISRVEPEDVGVYYCMHATQFPYTFGQGTKLEIK (SEQ ID NO: 215), (k) The heavy chain immunoglobulin variable region is the amino acid sequence QVQLVESGGGGVVQPARSLRLLSCAASGFAFSRSSAMHWVRQAPGKGLEWVAVISYDGSNKYYYTDSVKGRFTISRDNSKNTLYLQMNTLRAEDTALYYYCAKMYTTTMDSFDYWGQGTLVTVSS (Sequence ID) 227) contains, and the light chain immunoglobulin variable region contains the amino acid sequence DIQLTQSPSFLSASVGDRVTITCWASQGISSYLAWYQQKPGKAAPKLLLIYAASTLQSGVPSRFSGSGSGTEFFTLTISSLQPEDFALYYCQQLNSYPRTFGQGTKVEIK (SEQ ID NO: 235), (l) The heavy chain immunoglobulin variable region is the amino acid sequence EVQLVESGGGLLVQPGGSLKLSCAASGFTFSGSAMHWVRQASGKGLEWVGRITSKANSYATAYDASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRQRFLEFLFLDYWGQGTLVTVSS (sequence number) (Sequence No. 247) contains, and the light chain immunoglobulin variable region contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAAPKLLIYAASSLQSGVPPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPPITFGQGTRLEIK (Sequence No. 255), (m) Heavy chain immunoglobulin variable region is amino acid sequence EVQLVESGGGLLVQPGGSLRLSCAASGFTFSRYWMTWVRQAPGKGLEWVANIKQDGSGKNYVDSVMGRYTISRDNAKNSLYLQMNSLRAEDTAVYYCARWIAPDFPGMDVWGQGTTVTVSS (Sequence ID) 275) contains, and the light chain immunoglobulin variable region contains the amino acid sequence DIQLTQSPSFLSASSVGDRVTITCWASQGISSYLAWYQQKPGKAAPKLLLIYAASTLQSGVPSRFSGSGSGTEFLTISSLQPADFATYYCQQLNSYPLTFGGGTKVEIK (SEQ ID NO: 283), (n) The heavy chain immunoglobulin variable region is the amino acid sequence EVQLVESGGGLVQPGGSLKLSCAASGFTFSGSAMHWVRQASGKGLEWVGRITSKANSYATAYDASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRQRFLEFLFLDYWGQGTLVTVSS (sequence number) (Sequence No. 295) contains, and the light chain immunoglobulin variable region contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAAPKLLIYAASSLQSGVPPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPPITFGQGTRLEIK (Sequence No. 303), (o) The heavy chain immunoglobulin variable region is the amino acid sequence QVQLVESGGGGVVQPGRSLRLSCAASGFTFSGYGIHWVRQAPGKGLVWVAVIWYDGSFKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGDSSSSSGRYYYYYGMDVWGQGTTVTVSS (distributed The light chain immunoglobulin variable region includes the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGTAPKRLIFAASSLQSGVPSRFSGSGSGTEFFTLTISSLQPEDFATYYCLQHNNYPPTFGGGTKVEIK (SEQ ID NO: 323), (p) The heavy chain immunoglobulin variable region is the amino acid sequence QVQLQQWGAGLLKPSETLSLTCAVYGGGSFSGYYYWSWIRQPPGKGLEWIGEINHAGSTNYNPSLKSRITISSVDTSKNQFSLKLSSVTAADTAVYYCARGWYYGSGSSYHRNWFDPWGQGTLVTVSS (sequence) The variable region of the light chain immunoglobulin (number 335) includes the amino acid sequence EIVLTQSPGTLSLSPGERATLSCRASQSVYYSYLAWYQQKPGQAPRRLLIYGASNRATGIPDRFSGSGSGTDFTLTISRREPEDFAVYYCQQYGNSPWTFGQGTKVEIK (Sequence ID 343), (q) The variable region of heavy chain immunoglobulin is the amino acid sequence QVQLQQWGAGLLKPSETLSLTCAVYGGGSFSGYYYWSWIRQPPGKGLEWIGEINHAGSTNYNPSLKSRITISVDTSKNQFSLKLSSVTAADTAVYYCARGWYYGSGSYHRNWFDPWGQGTLVTVSS (sequence) The variable region of the light chain immunoglobulin (number 355) contains the amino acid sequence EIVLTQSPGTLSLSSPGERATLSCRASQSVYYSYLAWYQQKPGQAPRRLLIYGASNRATGIPDRFSGSGSGTDFTLTISRREPEDFAVYYCQQYGNSPWTFGQGTKVEIK (Sequence ID 363), (r) The heavy chain immunoglobulin variable region is the amino acid sequence EVQVVESGGGGLVQPGRSLRLSCTASGFTFDDYAMFWVRQGPGKGLEWVSGISWNSGSIGYADSVKGRFTTSRDNAKNSLYLQMNSLRTEDTALYYCAKDYRPRSGNHYNNYGMDVWGPGTTVTVSS (SEQ ID NO: 3) 75) comprising, and the light chain immunoglobulin variable region comprising the amino acid sequence EIVLTQSPGTLSLSSPGERATLSCRASQSFRGNYLAWYQQKPGQAPRRLLIYGASSRATGIPDRRFRGGSGSGTDFTLTISRRLEPEDFAVYYCHQYGRSPWTFGQGTKVEIK (SEQ ID NO: 383), and / or (s) The heavy chain immunoglobulin variable region is the amino acid sequence EVQVVESGGGGLVQPGRSLRLSCTASGFTFDDYAMFWVRQGPGKGLEWVSGISWNSGSIGYADSVKGRFTTSRDNAKNSLYLQMNSLRTEDTALYYCAKDYRPRSGNHYNNYGMDVWGPGTTVTVSS (distribution The light chain immunoglobulin variable region includes the amino acid sequence EIVLTQSPGTLSLSSPGERATLSCRASQSFRGNYLAWYQQKPGQAPRRLLIYGASSRATGIPDRRFRGGSGSGTDFTLTISRREPEDFAVYYCHQYGRSPWTFGQGTKVEIK (SEQ ID NO: 403), The antibody-tethered drug conjugate according to claim 1 or a pharmaceutically acceptable salt thereof.

41. (a) Heavy chain immunoglobulin having the amino acid sequence EVQLVESGGGLLVKPGGSLRLSCAASGFIFSRYSMNWVRQAPGKGLEWVSSMSSNSKNTYYADSVKGRFTISRDNAKNSLFLQMNTLRAEDTAVYYCARDGYTLRAAFDIWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 42), and the light chain immunoglobulin contains the amino acid sequence LLQGSGEIVLTQSPGTLSLSSPGERDTLSCRASQSIAGRYVAWYQQKPGQAP Includes RLLIYGASSRATGIPDRFSGSGSGTDFTLTTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 44), (b) Heavy chain immunoglobulins have the amino acid sequence EVQLVESGGGLLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLIAPRPMGFDYWGQGTLVTVSSASASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 62), and the light chain immunoglobulin contains the amino acid sequence LLQGSGDIQMTQSPSSVSASVGGDRVTITCRASQGINSWLAWYQQKPGKA Includes PKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQADSFPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 64), (c) Heavy chain immunoglobulins have the amino acid sequence EVQLVESGGGLLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLIAPRPMGFDYWGQGTLVTVSSASASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 82), and the light chain immunoglobulin contains the amino acid sequence LLQGSGDIQMTQSPSSVSASVGGDRVTITCRASQGINSWLAWYQQKPGKA Includes PKLLIYAASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQADSFPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 84), (d) Heavy chain immunoglobulins have the amino acid sequence QVQLVESGGGGVGQPGRSLRLSCAASGFTFSRNAMHWVRQAPGKGLEWVAVISYDGSNKHYADSVKGRFTISRDNSKNTLYLEEMNSLRVEDTAVYYCAKGGIPFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTP EVTCVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVY TLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 102), and the light chain immunoglobulin contains the amino acid sequence LLQGSGDIVMTQSPLSSPVTTLGQPASISCRSSQSLVHFDGNTYLSWLHQRPGQPP Includes RLLIYKISNRFSGVPDRFSGSGAGGTDFTLKISRVEPEDVGVYYCMHATQFPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCCLLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 104), (e) Heavy chain immunoglobulins have the amino acid sequence QVQLVESGGGGVVQPARSLRLLSCAASGFAFSRSSAMHWVRQAPGKGLEWVAVISYDGSNKYYYTDSVKGRFTISRDNSKNTLYLQMNTLRAEDTALYYYCAKMYTTTMDSFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 122), and the light chain immunoglobulin contains the amino acid sequence LLQGSGDIQLTQSPSFLSASVGGDRVTITCWASQGISSYLAWYQQKPGKAP Includes KLLIYAASTLQSGVPPSRFSGSGSGTEFLTISSLQPEDFALYYCQQLNSYPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 124), (f) Heavy chain immunoglobulins have the amino acid sequence LLQGSGEVQLVESGGGLLVKPGGSLRLSCAASGFIFSRYSMNWVRQAPGKGLEWVSSMSSNSKNTYYADSVKGRFTISRDNAKNSLFLQMNTLRAEDTAVYYCARDGYTLRAAFDIWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 142), and the light chain immunoglobulin contains the amino acid sequence EIVLTQSPGTLSLSSPGERDTLSCRASQSIAGRYVAWYQQKPGQAP Includes RLLIYGASSRATGIPDRFSGSGSGTDFTLTTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 144), (g) Heavy chain immunoglobulin has the amino acid sequence QVQLVESGGGGVVQPGRSLRLSCAASGFTFSGYGIHWVRQAPGKGLVWVAVIWYDGSFKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGDSSSSSGRYYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 162) contains light chain immunoglobulin with the amino acid sequence LLQGSGDIQMTQSPSSLSASSVGDRVTITCRASQGIRNDLGWYQQKPGTA Includes PKRLIFAASSLQSGVPSRFSGSGSGTEFLTISSLQPEDFATYYCLQHNNYPPTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 164), (h) Heavy chain immunoglobulins have the amino acid sequence EVQLVESGGGLVQPGGSLKLSCAASGFTFSGSAMHWVRQASGKGLEWVGRITSKANSYATAYDASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRQRFLEFLFLDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR The light chain immunoglobulin contains the amino acid sequence LLQGSGDIQMTQSPSSLSASVGDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 182), and the light chain immunoglobulin contains the amino acid sequence LLQGSGDIQMTQSPSSLSASSVGDRVTITCRASQSISSYLNWYQQKPGKAP Includes KLLIYAASSLQSGVPPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 184), (i) Heavy chain immunoglobulins have the amino acid sequence LLQGSGEVQLVESGGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLIAPRPMGFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 203), and the light chain immunoglobulin contains the amino acid sequence DIQMTQSPSSVSASVGDRVTITCRASQGINSWLAWYQQKPGKAP Includes KLLIYAASSLQSGVPPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQADSFPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 205), (j) Heavy chain immunoglobulins have the amino acid sequence LLQGSGQVQLVESGGGGVGQPGRSLRLSCAASGFTFFSRNAMHWVRQAPGKGLEWVAVISYDGSNKHYADSVKGRFTISRDNSKNTLYLEMNSLRVEDTAVYYCAKGGIPFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFPPKPKDTL MISRTPEVTCVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 223), and the light chain immunoglobulin contains the amino acid sequence DIVMTQSPLSSPVTLGQPASISCRSSQSLVHFDGNTYLSWLHQRPGQPP Includes RLLIYKISNRFSGVPDRFSGSGAGGTDFTLKISRVEPEDVGVYYCMHATQFPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCCLLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 225), (k) Heavy chain immunoglobulins have the amino acid sequence LLQGSGQVQLVESGGGGVVQPARSLRLLSCAASGFAFSRSSAMHWVRQAPGKGLEWVAVISYDGSNKYYYTDSVKGRFTISRDNSKNTLYLQMNTLRAEDTALYYYCAKMYTTTMDSFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 243), and the light chain immunoglobulin contains the amino acid sequence DIQLTQSPSFLSASVGGDRVTITCWASQGISSYLAWYQQKPGKAP Includes KLLIYAASTLQSGVPPSRFSGSGSGTEFLTISSLQPEDFALYYCQQLNSYPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 245), (l) Heavy chain immunoglobulins have the amino acid sequence LLQGSGEVQLVESGGGGLVQPGGSLKLSCAASGFTFSGSAMHWVRQASGKGLEWVGRITSKANSYATAYDASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRQRFLEFLFLDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISK AKGQPREPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 263), and the light chain immunoglobulin contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAP Includes KLLIYAASSLQSGVPPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 265), (m) Heavy chain immunoglobulin has the amino acid sequence LLQGSGQVTLKESGPPGILQPSQTLSLTCCSFSGFSLLSTSGTGVGWIRQPSGKGLEWLSHIWWDDVKRYNPALKSRLTISRDSYSQVFLRIASSVDTADTATYYCARILDGTGPPMDYWGQGTSVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPKP KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKA KGQPREPQVYTLPPPSQEEEMTKNQVSLTCLLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 267), and the light chain immunoglobulin contains the amino acid sequence QIVLTQSPAIMSASPGEKVTMTCSASASSRVTYMHWYQQRSGTSPKR Includes WIYDTSKLASGVPPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWGNNPQYTFGGGTRLEIKRRRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 269), (n) Heavy chain immunoglobulin has the amino acid sequence QVTLKESGPGILQPSQTLSLTCCSFSGFSLLSTSGTGVGWIRQPSGKGLEWLSHIWWDDVKRYNPALKSRLTISRDSYSQVFLRIASSVDTATADTATYYCARILDGTGPPMDYWGQGTSVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFPPKPKDTLMI SRTPEVTCVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (Sequence ID 271) contains light chain immunoglobulin with the amino acid sequence LLQGSGQIVLTQSPAIMSASPGEKVTMTCSASASSRVTYMHWYQQQRSGTSPKR Includes WIYDTSKLASGVPPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWGNNPQYTFGGGTRLEIKRRRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 273), (o) Heavy chain immunoglobulins have the amino acid sequence EVQLVESGGGLLVQPGGSLRLSCAASGFTFSRYWMTWVRQAPGKGLEWVANIKQDGSGKNYVDSVMGRYTISRDNAKNSLYLQMNSLRAEDTAVYYCARWIAPDFPGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFPPKPKDTLMI SRTPEVTCVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (Sequence ID 291), and the light chain immunoglobulin contains the amino acid sequence LLQGSGDIQLTQSPSFLSASVGGDRVTITCWASQGISSYLAWYQQKPGKAP Includes KLLIYAASTLQSGVPPSRFSGSGSGTEFLTISSLQPADFATYYCQQLNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 293), (p) Heavy chain immunoglobulins have the amino acid sequence EVQLVESGGGLVQPGGSLKLSCAASGFTFSGSAMHWVRQASGKGLEWVGRITSKANSYATAYDASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRQRFLEFLFLDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 311), and the light chain immunoglobulin contains the amino acid sequence LLQGSGDIQMTQSPSSLSASSVGDRVTITCRASQSISSYLNWYQQKPGKAP Includes KLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 313), (q) Heavy chain immunoglobulin has the amino acid sequence LLQGSGQVQLVESGGGGVVQPGRSLRLSCAASGFTFSGYGIHWVRQAPGKGLVWVAVIWYDGSFKYYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGDSSSSGRYYYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI The light chain immunoglobulin contains SKAKGQPREPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 331), and the amino acid sequence DIQMTQSPSSLSASVGDRVTITCCRASQGIRNDLGWYQQKPGTA Includes PKRLIFAASSLQSGVPSRFSGSGSGTEFLTISSLQPEDFATYYCLQHNNYPPTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 333), (r) Heavy chain immunoglobulin has the amino acid sequence LLQGSGQVQLQQWGAGLLKPSETLSLTCAVYGGGSFSGYYYWSWIRQPPGKGLEWIGEINHAGSTNYNPSLKSRITISSVDTSKNQFSLKLSSVTAADTAVYYCARGWYYGSGSSYHRNWFDPWGQGTLVTVSSASTKGPSVFPPLAPCSRSTSESTAAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTIS The light chain immunoglobulin contains the amino acid sequence EIVLTQSPGTLSLSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 351), and the light chain immunoglobulin contains the amino acid sequence EIVLTQSPGTLSLSSPGERATLSCRASQSVYYSYLAWYQQKPGQA Includes PRLLIYGASNRATGIPDRFSGSGSGTDFTLTTISRLEPEDFAVYYCQQYGNSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 353), (s) Heavy chain immunoglobulin has the amino acid sequence QVQLQQWGAGLLKPSETLSLTCAVYGGGSFSGYYYWSWIRQPPGKGLEWIGEINHAGSTNYNPSLKSRITISVDTSKNQFSLKLSSVTAADTAVYYCARGWYYGSGSSYHRNWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTL MISRTPEVTCVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 371), and the light chain immunoglobulin contains the amino acid sequence LLQGSGEIVLTQSPGTLSLSSPGERAATLSCRASQSVYYSYLAWYQQKPGQA Includes PRLLIYGASNRATGIPDRFSGSGSGTDFTLTTISRLEPEDFAVYYCQQYGNSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 373), (t) Heavy chain immunoglobulin has the amino acid sequence LLQGSGEVQVVESGGGLLVQPGRSLRLSCTASGFTFDDDYAMFWVRQGPGKGLEWVSGISWNSGSIGYADSVKGRFTTSRDNAKNSLYLQMNSLRTEDTALYYYCAKDYRPRSGNHYNNYGMMDVWGPGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI SKAKGQPREPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 391), and the light chain immunoglobulin contains the amino acid sequence EIVLTQSPGTLSLSSPGERATLSCRASQSFRGNYLAWYQQKPGQ Includes APRLLLIYGASSRATGIPDRRFRGGSGSGTDFTLTTISRLEPEDFAVYYCHQYGRSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 393), (u) Heavy chain immunoglobulins have the amino acid sequence EVQVVESGGGGLVQPGRSLRLSCTASGFTFDDDYAMFWVRQGPGKGLEWVSSGISWNSGSIGYADSVKGRFTTSRDNAKNSLYLQMNSLRTEDTALYYYCAKDYRPRSGNHYNNYGMDVWGPGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLGK (SEQ ID NO: 411), and the light chain immunoglobulin contains the amino acid sequence LLQGSGEIVLTQSPGTLSLSSPGERAATLSCRASQSFRGNYLAWYQQKPGQ APRLLIYGASSRATGIPDRRFRGGSGSGTDFTLTTISRLEPEDFAVYYCHQYGRSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 413) (v) Heavy chain immunoglobulins have the amino acid sequence EVQLVESGGGLLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSAISGSGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLIAPRPMGFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFPPKPKDTLMI SRTPEVTCVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSLSLG (SEQ ID NO: 414) contains light chain immunoglobulin with the amino acid sequence LLQGSGDIQMTQSPSSVSASVGDRVVTITCRASQGINSWLAWYQQKPGKAPKL Includes LIYAASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQADSFPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (SEQ ID NO: 84), or (c) Heavy chain immunoglobulins have the amino acid sequence EVQLVESGGGLLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLIAPRPMGFDYWGQGTLVTVSSASASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPPAPEFLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQP REPQVYTLPPPSQEEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTTVDKSRWQEGNVFSSCSVMHEALHNHYTQKSLSLSSLL (SEQ ID NO: 416), and the light chain immunoglobulin contains the amino acid sequence LLQGSGDIQMTQSPSSVSASVGGDRVTITCRASQGINSWLAWYQQKPGKAP KLLIYAASSLESGVPPSRFGSGSGSGTDFTLTISSLQPEDFATYYCHQADSFPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEEC (Sequence ID 84) The antibody-tethered drug conjugate according to claim 1 or a pharmaceutically acceptable salt thereof.

42. (a) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 82, and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 84 (b) an immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 414, and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 84, (c) an immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 416, and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 84, or (d) comprising an immunoglobulin heavy chain containing the amino acid sequence of SEQ ID NO: 42 and an immunoglobulin light chain containing the amino acid sequence of SEQ ID NO: 44, the linker payload is 【Chemistry 91】 The antibody-tethered drug conjugate or a pharmaceutically acceptable salt thereof according to claim 6, represented by the structure of the formula, where ] is the point on which the linker payload binds to amino acid 3 (Gln) of SEQ ID NO: 44 or 84.

43. A pharmaceutical composition comprising an antibody-tethered drug conjugate according to any one of claims 1 to 8 and 10 to 42, wherein at least about 80% of the antibody-tethered drug conjugate does not contain C-terminal lysine, or lysine and glycine, in any of its heavy chains.

44. The pharmaceutical composition according to claim 43, wherein the heavy chain immunoglobulin, which does not contain C-terminal lysine, comprises the amino acid sequence or a variant thereof described in SEQ ID NO: 414 or 416.

45. The pharmaceutical composition according to claim 43, wherein less than 20% of the antibody or its antigen-binding fragment, or the antibody-tethered drug conjugate, contains C-terminal lysine in at least one heavy chain.

46. The pharmaceutical composition according to claim 45, wherein the at least one heavy chain containing C-terminal lysine comprises an amino acid sequence or variant thereof as described in SEQ ID NOs: 42, 62, 82, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411.

47. A pharmaceutical composition comprising an antibody-tethered drug conjugate according to any one of claims 1 to 8 and 10 to 42, and a pharmaceutically acceptable carrier.

48. A pharmaceutical dosage form comprising an antibody-tethered drug conjugate according to any one of claims 1 to 8 and 10 to 42.

49. A vial or injection device comprising an antibody-tethered drug conjugate according to any one of claims 1 to 8 and 10 to 42.

50. Use of an antibody-tethered drug conjugate according to any one of claims 1 to 8 and 10 to 42 in the manufacture of a drug for selectively targeting GLP1R on the surface of cells in the body or in vitro.

51. Use of an antibody-tethered drug conjugate according to any one of claims 1 to 8 and 10 to 42 in the manufacture of a drug for improving GLP1R activity, lowering blood glucose levels, lowering body weight, or treating GLP1R-related diseases in subjects requiring treatment of GLP1R-related diseases.

52. Formula (A): BA-(LP) m (A) A method for producing an antibody-attached drug conjugate according to claim 1 having the structure thereof or a pharmaceutically acceptable salt thereof, a) A step of contacting BA containing at least m glutamine residues (Gln) with at least m equivalents of compound L-P in the presence of transglutaminase, b) a step of isolating the compound of formula (A) produced, The aforementioned BA is, (i) Heavy chain immunoglobulin or its variable region containing CDR-H1, CDR-H2, and CDR-H3 of the heavy chain immunoglobulin or its variable region containing the amino acid sequence or variant of the heavy chain immunoglobulin or its variable region described in SEQ ID NOs: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, 395, 42, 62, 82, 414, 416, 102, 122, 142, 162, 182, 203, 223, 243, 263, 267, 271, 291, 311, 331, 351, 371, 391, or 411, Furthermore / or including light chain immunoglobulin or its variable region CDR-L1, CDR-L2, and CDR-L3, which include the amino acid sequence or variant thereof described in SEQ ID NOs: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, 403, 44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 269, 273, 293, 313, 333, 353, 373, 393, or 413, (ii) An antibody or antigen-binding fragment that competes with the antibody or antigen-binding fragment of (i) for binding to GLP1R, (iii) An antibody or antigen-binding fragment that binds to the same GLP1R epitope as the antibody or antigen-binding fragment of (i), A method wherein the heavy chain immunoglobulin is optionally free of C-terminal lysine, or free of lysine and glycine.

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