p75 neurotrophin receptor (p75 NTR ) binding proteins and p75 NTR mediated nervous system delivery
Patent Information
- Application Number
- CN202580018932.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2024-07-17
- Filing Date
- 2025-01-10
- Publication Date
- 2026-10-27
Smart Images
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Abstract
Description
[0001] Cross-references to related applications
[0002] This patent application claims the benefit of U.S. Provisional Application No. 63 / 619,934, filed January 11, 2024, and U.S. Provisional Application No. 63 / 672,471, filed July 17, 2024, the disclosures of which are incorporated herein by reference in their entirety for all purposes.
[0003] sequence list
[0004] This application contains a sequence list electronically submitted in XML file format, and is incorporated herein by reference in its entirety. The XML copy was created on January 6, 2025, named 250298_000780_SL.xml, and has a size of 741,077 bytes. Technical Field
[0005] This invention relates to the p75 neurotrophic factor receptor (p75). NTR Antigen-binding proteins and protein-drug conjugates, wherein the protein-drug conjugates contain p75 conjugated to the molecular cargo. NTR Antigen-binding proteins, and methods for treating diseases using such antigen-binding proteins and protein-drug conjugates. Background Technology
[0006] Developing drug delivery methods to improve the safety and efficacy of neurotherapies is an increasingly important and evolving field. Overcoming the blood-brain barrier (BBB) has always been a challenge in delivering therapeutic drugs to the brain. While the peripheral nervous system (PNS) does not have a BBB, appropriately delivering therapeutic drugs to cells of interest within the PNS has been very challenging. Safe and effective neurotherapies also require appropriate pharmacokinetic / pharmacodynamic (PK / PD) properties of the therapeutic drug in the neural tissue of interest, as well as limited potential effects on other neural regions. Furthermore, the options for achieving retrograde targeting for therapeutic drug delivery are limited.
[0007] Effectively delivering therapeutic drugs to the nervous system may offer potential treatment opportunities for chronic pain and itching symptoms, as well as other previously incurable conditions such as spinal cord degeneration, amyotrophic lateral sclerosis (ALS), and neurodegenerative diseases such as Alzheimer's disease (AD). Summary of the Invention
[0008] As mentioned in the background section above, there is an unmet need in the art to develop effective means for delivering therapeutic drugs to the nervous system of a subject, such as to the peripheral nervous system (PNS). This application provides compositions and methods to address this need, as well as other related needs.
[0009] In one respect, this article provides a method for interaction with the p75 neurotrophic factor receptor (p75). NTR The antigen-binding protein that binds to the antigen, wherein the antigen-binding protein shows less than 50% of human p75 NTR The inhibitory effect of the extracellular domains of p75 on the activity of p75. NTR The activity of its extracellular domain blocks human nerve growth factor (NGF)-dependent human tropomyosin receptor kinase A (TrkA) signaling, as measured in cell-based assays.
[0010] In some implementations, the cell-based assay includes the following steps:
[0011] a) In the presence of the antigen-binding protein, human p75 NTR The soluble extracellular domains of [the substance] were incubated with mature human NGF, optionally with human p75. NTR The extracellular domain of IgG fuses with the Fc domain of IgG;
[0012] b) Incubate the mixture from step (a) with a population of recombinant mammalian cells stably expressing TrkA and a serum response element fused with a luciferase reporter.
[0013] c) Measure the luciferase activity from the mixture in step (b) in relative luminescent units (RLU); and
[0014] d) Calculate the inhibition percentage using the following formula:
[0015]
[0016] Among them, RLU 可溶性p75 Using non-binding p75 NTR The RLU values of antigen-binding proteins in cells treated under the same conditions, and the RLU NGF Using only mature human NGF in the absence of p75 NTR The RLU value of cells treated with soluble extracellular domains.
[0017] In some embodiments, the antigen-binding protein comprises:
[0018] (1) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 529 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 537 or a variant thereof;
[0019] (2) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 549 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 557 or a variant thereof;
[0020] (3) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 569 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 577 or a variant thereof;
[0021] (4) HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR containing the amino acid sequence shown in SEQ ID NO: 589 or a variant thereof; and LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR containing the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof; and / or
[0022] (5) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 609 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof.
[0023] In some embodiments, the antigen-binding protein comprises:
[0024] (1) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 531 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 533 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 535 or a variant thereof; and / or
[0025] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 539 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 541 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 543 or a variant thereof;
[0026] (2) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 551 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 553 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 555 or a variant thereof; and / or
[0027] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 559 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 561 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 563 or a variant thereof;
[0028] (3) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 571 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 573 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 575 or a variant thereof; and / or
[0029] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 579 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 581 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 583 or a variant thereof;
[0030] (4) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 591 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 593 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 595 or a variant thereof; and / or
[0031] LCVR comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 599 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 601 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 603 or a variant thereof; and / or
[0032] (5) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 611 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 613 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 615 or a variant thereof; and / or
[0033] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 599 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 601 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 603 or a variant thereof.
[0034] In some embodiments, the antigen-binding protein comprises:
[0035] (1) HCVR, comprising the amino acid sequence shown in SEQ ID NO: 529 or a variant thereof; and LCVR, comprising the amino acid sequence shown in SEQ ID NO: 537 or a variant thereof;
[0036] (2) HCVR, comprising the amino acid sequence shown in SEQ ID NO: 549 or a variant thereof; and LCVR, comprising the amino acid sequence shown in SEQ ID NO: 557 or a variant thereof;
[0037] (3) HCVR, comprising the amino acid sequence shown in SEQ ID NO: 569 or a variant thereof; and LCVR, comprising the amino acid sequence shown in SEQ ID NO: 577 or a variant thereof;
[0038] (4) HCVR, comprising the amino acid sequence shown in SEQ ID NO: 589 or a variant thereof; and LCVR, comprising the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof; and / or
[0039] (5) HCVR, which contains the amino acid sequence shown in SEQ ID NO: 609 or a variant thereof; and LCVR, which contains the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof.
[0040] In some embodiments, the antigen-binding protein comprises:
[0041] (1) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 545 or a variant thereof and a light chain comprising the amino acid sequence shown in SEQ ID NO: 547 or a variant thereof;
[0042] (2) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 565 or a variant thereof and a light chain comprising the amino acid sequence shown in SEQ ID NO: 567 or a variant thereof;
[0043] (3) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 585 or a variant thereof and a light chain comprising the amino acid sequence shown in SEQ ID NO: 587 or a variant thereof;
[0044] (4) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 605 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 607 or a variant thereof; and / or
[0045] (5) A heavy chain containing the amino acid sequence shown in SEQ ID NO: 617 or a variant thereof and a light chain containing the amino acid sequence shown in SEQ ID NO: 607 or a variant thereof.
[0046] In one respect, this article provides a method for interaction with the p75 neurotrophic factor receptor (p75). NTR The antigen-binding protein that binds includes:
[0047] (i) HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR containing the amino acid sequence shown in SEQ ID NO: 2, 22, 42, 58, 78, 98, 116, 136, 155, 173, 189, 207, 227, 245, 261, 279, 297, 315, 331, 349, 369, 387, 401, 417, 427, 437, 445, 455, 465, 475, 484, 493, 503, 513, 519, 529, 549, 569, 589, or 609, or a variant thereof; and / or
[0048] (ii) LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR containing the amino acid sequence shown in SEQ ID NO: 10, 30, 50, 66, 86, 106, 124, 144, 162, 179, 197, 215, 235, 251, 269, 287, 304, 323, 339, 357, 377, 391, 409, 537, 557, 577, or 597, or a variant thereof.
[0049] In some embodiments, the antigen-binding protein comprises:
[0050] (1) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 2 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 10 or a variant thereof;
[0051] (2) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof;
[0052] (3) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 42 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof;
[0053] (4) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 58 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 66 or a variant thereof;
[0054] (5) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof;
[0055] (6) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 98 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 106 or a variant thereof;
[0056] (7) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 116 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 124 or a variant thereof;
[0057] (8) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof;
[0058] (9) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 155 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 162 or a variant thereof;
[0059] (10) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 173 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 179 or a variant thereof;
[0060] (11) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 189 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 197 or a variant thereof;
[0061] (12) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 207 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 215 or a variant thereof;
[0062] (13) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 227 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 235 or a variant thereof;
[0063] (14) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 245 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 251 or a variant thereof;
[0064] (15) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof;
[0065] (16) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 279 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 287 or a variant thereof;
[0066] (17) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 297 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 304 or a variant thereof;
[0067] (18) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 315 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 323 or a variant thereof;
[0068] (19) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 331 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 339 or a variant thereof;
[0069] (20) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 349 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 357 or a variant thereof;
[0070] (21) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof;
[0071] (22) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 387 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 391 or a variant thereof;
[0072] (23) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 401 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0073] (24) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 417 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0074] (25) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequence shown in SEQ ID NO: 427 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0075] (26) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 437 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0076] (27) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 445 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0077] (28) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 455 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0078] (29) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 465 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0079] (30) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 475 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0080] (31) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0081] (32) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 493 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0082] (33) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 503 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0083] (34) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 513 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0084] (35) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 519 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0085] (36) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequence shown in SEQ ID NO: 529 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequence shown in SEQ ID NO: 537 or a variant thereof;
[0086] (37) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 549 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 557 or a variant thereof;
[0087] (38) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 569 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 577 or a variant thereof;
[0088] (39) HCVRs comprising HCDR1, HCDR2, and HCDR3 of the amino acid sequence shown in SEQ ID NO: 589 or a variant thereof; and LCVRs comprising LCDR1, LCDR2, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof; and / or
[0089] (40) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 609 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof.
[0090] In some embodiments, the antigen-binding protein comprises:
[0091] (1) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 2 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 10 or a variant thereof;
[0092] (2) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof;
[0093] (3) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 42 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof;
[0094] (4) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 58 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 66 or a variant thereof;
[0095] (5) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof;
[0096] (6) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 98 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 106 or a variant thereof;
[0097] (7) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 116 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 124 or a variant thereof;
[0098] (8) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof;
[0099] (9) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 155 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 162 or a variant thereof;
[0100] (10) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 173 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 179 or a variant thereof;
[0101] (11) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 207 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 215 or a variant thereof;
[0102] (12) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 245 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 251 or a variant thereof;
[0103] (13) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 279 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 287 or a variant thereof;
[0104] (14) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 297 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 304 or a variant thereof;
[0105] (15) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 315 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 323 or a variant thereof;
[0106] (16) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 349 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 357 or a variant thereof;
[0107] (17) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 387 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 391 or a variant thereof;
[0108] (18) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 417 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0109] (19) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 427 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0110] (20) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 437 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0111] (21) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 445 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0112] (22) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 455 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0113] (23) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 465 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0114] (24) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 475 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0115] (25) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 493 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0116] (26) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 503 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0117] (27) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 513 or a variant thereof; and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; and / or
[0118] (28) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 519 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
[0119] In some embodiments, the antigen-binding protein comprises:
[0120] (1) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 189 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 197 or a variant thereof;
[0121] (2) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 227 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 235 or a variant thereof;
[0122] (3) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof;
[0123] (4) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 331 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 339 or a variant thereof;
[0124] (5) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof;
[0125] (6) HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR containing the amino acid sequence shown in SEQ ID NO: 401 or a variant thereof; and LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; and / or
[0126] (7) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
[0127] In some embodiments, the antigen-binding protein comprises:
[0128] (1) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof;
[0129] (2) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof;
[0130] (3) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof;
[0131] (4) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof;
[0132] (5) HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof; and LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof; and / or
[0133] (6) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
[0134] In some embodiments, the antigen-binding protein comprises:
[0135] (1) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 4 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 6 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 8 or a variant thereof; and
[0136] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 16 or a variant thereof;
[0137] (2) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 24 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 26 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof; and
[0138] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 32 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 36 or a variant thereof;
[0139] (3) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 44 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 46 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof; and
[0140] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 52 or a variant thereof;
[0141] (4) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 60 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 62 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 64 or a variant thereof; and
[0142] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 68 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 72 or a variant thereof;
[0143] (5) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 80 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 82 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 84 or a variant thereof; and
[0144] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 88 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 92 or a variant thereof;
[0145] (6) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 102 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 104 or a variant thereof; and
[0146] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 108 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 110 or a variant thereof;
[0147] (7) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 118 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 120 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 122 or a variant thereof; and
[0148] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 126 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 130 or a variant thereof;
[0149] (8) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 140 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 142 or a variant thereof; and
[0150] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 146 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 149 or a variant thereof;
[0151] (9) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 158 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 160 or a variant thereof; and
[0152] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 164 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 167 or a variant thereof;
[0153] (10) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 175 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 177 or a variant thereof; and
[0154] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 181 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 183 or a variant thereof;
[0155] (11) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 191 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 193 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 195 or a variant thereof; and
[0156] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 199 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 201 or a variant thereof;
[0157] (12) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 209 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 211 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 213 or a variant thereof; and
[0158] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 217 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 219 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 221 or a variant thereof;
[0159] (13) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 229 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 231 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 233 or a variant thereof; and
[0160] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 239 or a variant thereof;
[0161] (14) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 247 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 249 or a variant thereof; and
[0162] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 253 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 255 or a variant thereof;
[0163] (15) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 263 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 265 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 267 or a variant thereof; and
[0164] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 271 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 273 or a variant thereof;
[0165] (16) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 281 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 283 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 285 or a variant thereof; and
[0166] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 289 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 291 or a variant thereof;
[0167] (17) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 299 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 193 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 302 or a variant thereof; and
[0168] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 307 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 309 or a variant thereof;
[0169] (18) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 317 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 321 or a variant thereof; and
[0170] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 325 or a variant thereof;
[0171] (19) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 333 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 335 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 337 or a variant thereof; and
[0172] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 341 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 343 or a variant thereof;
[0173] (20) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 351 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 353 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 355 or a variant thereof; and
[0174] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 359 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 361 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 363 or a variant thereof;
[0175] (21) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 371 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 373 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 375 or a variant thereof; and
[0176] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 379 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 381 or a variant thereof;
[0177] (22) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 389 or a variant thereof; and
[0178] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 393 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 361 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 395 or a variant thereof;
[0179] (23) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 403 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 405 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 407 or a variant thereof; and
[0180] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0181] (24) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 419 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 421 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 423 or a variant thereof; and
[0182] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0183] (25) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 429 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 431 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 433 or a variant thereof; and
[0184] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0185] (26) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 191 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 335 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 441 or a variant thereof; and
[0186] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0187] (27) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 447 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 449 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 451 or a variant thereof; and
[0188] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0189] (28) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 457 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 459 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 461 or a variant thereof; and
[0190] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0191] (29) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 467 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 469 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 471 or a variant thereof; and
[0192] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0193] (30) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 477 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 158 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 480 or a variant thereof; and
[0194] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0195] (31) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 486 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 283 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 489 or a variant thereof; and
[0196] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0197] (32) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 495 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 497 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 499 or a variant thereof; and
[0198] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0199] (33) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 505 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 507 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 509 or a variant thereof; and
[0200] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0201] (34) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 515 or a variant thereof; and
[0202] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0203] (35) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 521 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 523 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 525 or a variant thereof; and
[0204] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0205] (36) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 531 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 533 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 535 or a variant thereof; and
[0206] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 539 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 541 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 543 or a variant thereof;
[0207] (37) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 551 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 553 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 555 or a variant thereof; and
[0208] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 559 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 561 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 563 or a variant thereof;
[0209] (38) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 571 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 573 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 575 or a variant thereof; and
[0210] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 579 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 581 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 583 or a variant thereof;
[0211] (39) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 591 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 593 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 595 or a variant thereof; and
[0212] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 599 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 601 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 603 or a variant thereof;
[0213] (40) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 611 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 613 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 615 or a variant thereof; and / or
[0214] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 599 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 601 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 603 or a variant thereof.
[0215] In some embodiments, the antigen-binding protein comprises:
[0216] (1) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 4 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 6 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 8 or a variant thereof; and / or
[0217] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 16 or a variant thereof;
[0218] (2) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 24 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 26 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof; and / or
[0219] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 32 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 36 or a variant thereof;
[0220] (3) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 44 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 46 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof; and / or
[0221] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 52 or a variant thereof;
[0222] (4) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 60 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 62 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 64 or a variant thereof; and / or
[0223] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 68 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 72 or a variant thereof;
[0224] (5) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 80 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 82 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 84 or a variant thereof; and / or
[0225] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 88 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 92 or a variant thereof;
[0226] (6) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 102 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 104 or a variant thereof; and / or
[0227] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 108 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 110 or a variant thereof;
[0228] (7) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 118 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 120 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 122 or a variant thereof; and / or
[0229] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 126 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 130 or a variant thereof;
[0230] (8) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 140 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 142 or a variant thereof; and / or
[0231] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 146 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 149 or a variant thereof;
[0232] (9) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 158 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 160 or a variant thereof; and / or
[0233] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 164 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 167 or a variant thereof;
[0234] (10) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 175 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 177 or a variant thereof; and / or
[0235] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 181 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 183 or a variant thereof;
[0236] (11) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 209 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 211 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 213 or a variant thereof; and / or
[0237] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 217 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 219 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 221 or a variant thereof;
[0238] (12) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 247 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 249 or a variant thereof; and / or
[0239] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 253 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 255 or a variant thereof;
[0240] (13) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 281 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 283 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 285 or a variant thereof; and / or
[0241] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 289 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 291 or a variant thereof;
[0242] (14) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 299 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 193 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 302 or a variant thereof; and / or
[0243] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 307 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 309 or a variant thereof;
[0244] (15) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 317 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 321 or a variant thereof; and / or
[0245] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 325 or a variant thereof;
[0246] (16) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 351 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 353 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 355 or a variant thereof; and / or
[0247] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 359 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 361 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 363 or a variant thereof;
[0248] (17) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 389 or a variant thereof; and / or
[0249] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 393 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 361 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 395 or a variant thereof;
[0250] (18) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 419 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 421 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 423 or a variant thereof; and / or
[0251] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0252] (19) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 429 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 431 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 433 or a variant thereof; and / or
[0253] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0254] (20) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 191 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 335 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 441 or a variant thereof; and / or
[0255] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0256] (21) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 447 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 449 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 451 or a variant thereof; and / or
[0257] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0258] (22) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 457 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 459 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 461 or a variant thereof; and / or
[0259] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0260] (23) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 467 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 469 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 471 or a variant thereof; and / or
[0261] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0262] (24) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 477 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 158 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 480 or a variant thereof; and / or
[0263] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0264] (25) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 495 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 497 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 499 or a variant thereof; and / or
[0265] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0266] (26) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 505 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 507 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 509 or a variant thereof; and / or
[0267] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof;
[0268] (27) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 515 or a variant thereof; and / or
[0269] LCVR comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; and / or
[0270] (28) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 521 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 523 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 525 or a variant thereof; and / or
[0271] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof.
[0272] In some embodiments, the antigen-binding protein comprises:
[0273] (1) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 191 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 193 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 195 or a variant thereof; and / or
[0274] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 199 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 201 or a variant thereof;
[0275] (2) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 229 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 231 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 233 or a variant thereof; and / or
[0276] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 239 or a variant thereof;
[0277] (3) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 263 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 265 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 267 or a variant thereof; and / or
[0278] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 271 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 273 or a variant thereof;
[0279] (4) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 333 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 335 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 337 or a variant thereof; and / or
[0280] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 341 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 343 or a variant thereof;
[0281] (5) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 371 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 373 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 375 or a variant thereof; and / or
[0282] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 379 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 381 or a variant thereof;
[0283] (6) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 403 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 405 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 407 or a variant thereof; and / or
[0284] LCVR comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; and / or
[0285] (7) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 486 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 283 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 489 or a variant thereof; and / or
[0286] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof.
[0287] In some embodiments, the antigen-binding protein comprises:
[0288] (1) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 24 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 26 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof; and / or
[0289] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 32 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 36 or a variant thereof;
[0290] (2) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 80 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 82 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 84 or a variant thereof; and / or
[0291] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 88 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 92 or a variant thereof;
[0292] (3) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 140 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 142 or a variant thereof; and / or
[0293] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 146 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 149 or a variant thereof;
[0294] (4) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 263 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 265 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 267 or a variant thereof; and / or
[0295] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 271 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 273 or a variant thereof;
[0296] (5) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 371 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 373 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 375 or a variant thereof; and / or
[0297] LCVR comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 379 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 381 or a variant thereof; and / or
[0298] (6) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 486 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 283 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 489 or a variant thereof; and / or
[0299] LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof.
[0300] In some embodiments, the antigen-binding protein comprises:
[0301] (1) An HCVR containing the amino acid sequence shown in SEQ ID NO: 2 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 10 or a variant thereof;
[0302] (2) An HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof;
[0303] (3) An HCVR containing the amino acid sequence shown in SEQ ID NO: 42 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof;
[0304] (4) An HCVR containing the amino acid sequence shown in SEQ ID NO: 58 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 66 or a variant thereof;
[0305] (5) An HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof;
[0306] (6) An HCVR containing the amino acid sequence shown in SEQ ID NO: 98 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 106 or a variant thereof;
[0307] (7) An HCVR containing the amino acid sequence shown in SEQ ID NO: 116 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 124 or a variant thereof;
[0308] (8) An HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof;
[0309] (9) An HCVR containing the amino acid sequence shown in SEQ ID NO: 155 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 162 or a variant thereof;
[0310] (10) An HCVR containing the amino acid sequence shown in SEQ ID NO: 173 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 179 or a variant thereof;
[0311] (11) An HCVR containing the amino acid sequence shown in SEQ ID NO: 189 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 197 or a variant thereof;
[0312] (12) An HCVR containing the amino acid sequence shown in SEQ ID NO: 207 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 215 or a variant thereof;
[0313] (13) An HCVR containing the amino acid sequence shown in SEQ ID NO: 227 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 235 or a variant thereof;
[0314] (14) An HCVR containing the amino acid sequence shown in SEQ ID NO: 245 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 251 or a variant thereof;
[0315] (15) An HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof;
[0316] (16) An HCVR containing the amino acid sequence shown in SEQ ID NO: 279 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 287 or a variant thereof;
[0317] (17) An HCVR containing the amino acid sequence shown in SEQ ID NO: 297 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 304 or a variant thereof;
[0318] (18) An HCVR containing the amino acid sequence shown in SEQ ID NO: 315 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 323 or a variant thereof;
[0319] (19) An HCVR containing the amino acid sequence shown in SEQ ID NO: 331 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 339 or a variant thereof;
[0320] (20) An HCVR containing the amino acid sequence shown in SEQ ID NO: 349 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 357 or a variant thereof;
[0321] (21) An HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof;
[0322] (22) An HCVR containing the amino acid sequence shown in SEQ ID NO: 387 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 391 or a variant thereof;
[0323] (23) An HCVR containing the amino acid sequence shown in SEQ ID NO: 401 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0324] (24) An HCVR containing the amino acid sequence shown in SEQ ID NO: 417 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0325] (25) An HCVR containing the amino acid sequence shown in SEQ ID NO: 427 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0326] (26) An HCVR containing the amino acid sequence shown in SEQ ID NO: 437 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0327] (27) An HCVR containing the amino acid sequence shown in SEQ ID NO: 445 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0328] (28) An HCVR containing the amino acid sequence shown in SEQ ID NO: 455 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0329] (29) An HCVR containing the amino acid sequence shown in SEQ ID NO: 465 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0330] (30) An HCVR containing the amino acid sequence shown in SEQ ID NO: 475 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0331] (31) An HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0332] (32) An HCVR containing the amino acid sequence shown in SEQ ID NO: 493 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0333] (33) An HCVR containing the amino acid sequence shown in SEQ ID NO: 503 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0334] (34) An HCVR containing the amino acid sequence shown in SEQ ID NO: 513 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0335] (35) An HCVR containing the amino acid sequence shown in SEQ ID NO: 519 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0336] (36) An HCVR containing the amino acid sequence shown in SEQ ID NO: 529 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 537 or a variant thereof;
[0337] (37) An HCVR containing the amino acid sequence shown in SEQ ID NO: 549 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 557 or a variant thereof;
[0338] (38) An HCVR containing the amino acid sequence shown in SEQ ID NO: 569 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 577 or a variant thereof;
[0339] (39) HCVR containing the amino acid sequence shown in SEQ ID NO: 589 or a variant thereof, and LCVR containing the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof, and / or
[0340] (40) An HCVR containing the amino acid sequence shown in SEQ ID NO: 609 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof.
[0341] In some embodiments, the antigen-binding protein comprises:
[0342] (1) An HCVR containing the amino acid sequence shown in SEQ ID NO: 2 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 10 or a variant thereof;
[0343] (2) An HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof;
[0344] (3) An HCVR containing the amino acid sequence shown in SEQ ID NO: 42 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof;
[0345] (4) An HCVR containing the amino acid sequence shown in SEQ ID NO: 58 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 66 or a variant thereof;
[0346] (5) An HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof;
[0347] (6) An HCVR containing the amino acid sequence shown in SEQ ID NO: 98 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 106 or a variant thereof;
[0348] (7) An HCVR containing the amino acid sequence shown in SEQ ID NO: 116 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 124 or a variant thereof;
[0349] (8) An HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof;
[0350] (9) An HCVR containing the amino acid sequence shown in SEQ ID NO: 155 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 162 or a variant thereof;
[0351] (10) An HCVR containing the amino acid sequence shown in SEQ ID NO: 173 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 179 or a variant thereof;
[0352] (11) An HCVR containing the amino acid sequence shown in SEQ ID NO: 207 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 215 or a variant thereof;
[0353] (12) An HCVR containing the amino acid sequence shown in SEQ ID NO: 245 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 251 or a variant thereof;
[0354] (13) An HCVR containing the amino acid sequence shown in SEQ ID NO: 279 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 287 or a variant thereof;
[0355] (14) An HCVR containing the amino acid sequence shown in SEQ ID NO: 297 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 304 or a variant thereof;
[0356] (15) An HCVR containing the amino acid sequence shown in SEQ ID NO: 315 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 323 or a variant thereof;
[0357] (16) An HCVR containing the amino acid sequence shown in SEQ ID NO: 349 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 357 or a variant thereof;
[0358] (17) An HCVR containing the amino acid sequence shown in SEQ ID NO: 387 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 391 or a variant thereof;
[0359] (18) An HCVR containing the amino acid sequence shown in SEQ ID NO: 417 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0360] (19) An HCVR containing the amino acid sequence shown in SEQ ID NO: 427 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0361] (20) An HCVR containing the amino acid sequence shown in SEQ ID NO: 437 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0362] (21) An HCVR containing the amino acid sequence shown in SEQ ID NO: 445 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0363] (22) An HCVR containing the amino acid sequence shown in SEQ ID NO: 455 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0364] (23) An HCVR containing the amino acid sequence shown in SEQ ID NO: 465 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0365] (24) An HCVR containing the amino acid sequence shown in SEQ ID NO: 475 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0366] (25) An HCVR containing the amino acid sequence shown in SEQ ID NO: 493 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0367] (26) An HCVR containing the amino acid sequence shown in SEQ ID NO: 503 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof;
[0368] (27) An HCVR containing the amino acid sequence shown in SEQ ID NO: 513 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof, and / or
[0369] (28) An HCVR containing the amino acid sequence shown in SEQ ID NO: 519 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
[0370] In some embodiments, the antigen-binding protein comprises:
[0371] (1) An HCVR containing the amino acid sequence shown in SEQ ID NO: 189 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 197 or a variant thereof;
[0372] (2) An HCVR containing the amino acid sequence shown in SEQ ID NO: 227 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 235 or a variant thereof;
[0373] (3) An HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof;
[0374] (4) An HCVR containing the amino acid sequence shown in SEQ ID NO: 331 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 339 or a variant thereof;
[0375] (5) HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof, and LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof;
[0376] (6) An HCVR containing the amino acid sequence shown in SEQ ID NO: 401 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof, and / or
[0377] (7) An HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
[0378] In some embodiments, the antigen-binding protein comprises:
[0379] (1) An HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof;
[0380] (2) An HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof;
[0381] (3) An HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof;
[0382] (4) An HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof;
[0383] (5) HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof, and LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof, and / or
[0384] (6) An HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
[0385] In some embodiments, the antigen-binding protein comprises:
[0386] (1) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 18 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 20 or a variant thereof;
[0387] (2) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 38 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 40 or a variant thereof;
[0388] (3) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 54 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 56 or a variant thereof;
[0389] (4) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 74 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 76 or a variant thereof;
[0390] (5) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 94 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 96 or a variant thereof;
[0391] (6) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 112 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 114 or a variant thereof;
[0392] (7) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 132 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 134 or a variant thereof;
[0393] (8) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 151 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 153 or a variant thereof;
[0394] (9) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 169 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 171 or a variant thereof;
[0395] (10) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 185 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 187 or a variant thereof;
[0396] (11) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 203 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 205 or a variant thereof;
[0397] (12) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 223 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 225 or a variant thereof;
[0398] (13) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 241 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 243 or a variant thereof;
[0399] (14) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 257 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 259 or a variant thereof;
[0400] (15) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 275 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 277 or a variant thereof;
[0401] (16) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 293 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 295 or a variant thereof;
[0402] (17) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 311 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 313 or a variant thereof;
[0403] (18) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 327 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 329 or a variant thereof;
[0404] (19) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 345 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 347 or a variant thereof;
[0405] (20) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 365 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 367 or a variant thereof;
[0406] (21) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 383 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 385 or a variant thereof;
[0407] (22) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 397 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 399 or a variant thereof;
[0408] (23) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 413 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0409] (24) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 425 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0410] (25) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 435 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0411] (26) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 443 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0412] (27) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 453 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0413] (28) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 463 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0414] (29) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 473 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0415] (30) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 482 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0416] (31) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 491 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0417] (32) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 501 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0418] (33) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 511 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0419] (34) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 517 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0420] (35) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 527 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0421] (36) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 545 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 547 or a variant thereof;
[0422] (37) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 565 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 567 or a variant thereof;
[0423] (38) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 585 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 587 or a variant thereof;
[0424] (39) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 605 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 607 or a variant thereof; and / or
[0425] (40) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 617 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 607 or a variant thereof.
[0426] In some embodiments, the antigen-binding protein comprises:
[0427] (1) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 18 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 20 or a variant thereof;
[0428] (2) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 38 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 40 or a variant thereof;
[0429] (3) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 54 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 56 or a variant thereof;
[0430] (4) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 74 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 76 or a variant thereof;
[0431] (5) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 94 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 96 or a variant thereof;
[0432] (6) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 112 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 114 or a variant thereof;
[0433] (7) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 132 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 134 or a variant thereof;
[0434] (8) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 151 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 153 or a variant thereof;
[0435] (9) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 169 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 171 or a variant thereof;
[0436] (10) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 185 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 187 or a variant thereof;
[0437] (11) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 223 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 225 or a variant thereof;
[0438] (12) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 257 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 259 or a variant thereof;
[0439] (13) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 293 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 295 or a variant thereof;
[0440] (14) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 311 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 313 or a variant thereof;
[0441] (15) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 327 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 329 or a variant thereof;
[0442] (16) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 365 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 367 or a variant thereof;
[0443] (17) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 397 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 399 or a variant thereof;
[0444] (18) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 425 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0445] (19) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 435 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0446] (20) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 443 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0447] (21) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 453 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0448] (22) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 463 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0449] (23) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 473 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0450] (24) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 482 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0451] (25) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 501 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0452] (26) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 511 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof;
[0453] (27) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 517 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; and / or
[0454] (28) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 527 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof.
[0455] In some embodiments, the antigen-binding protein comprises:
[0456] (1) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 203 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 205 or a variant thereof;
[0457] (2) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 241 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 243 or a variant thereof;
[0458] (3) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 275 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 277 or a variant thereof;
[0459] (4) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 345 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 347 or a variant thereof;
[0460] (5) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 383 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 385 or a variant thereof;
[0461] (6) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 413 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; and / or
[0462] (7) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 491 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof.
[0463] In some embodiments, the antigen-binding protein comprises:
[0464] (1) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 38 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 40 or a variant thereof;
[0465] (2) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 94 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 96 or a variant thereof;
[0466] (3) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 151 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 153 or a variant thereof;
[0467] (4) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 275 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 277 or a variant thereof;
[0468] (5) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 383 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 385 or a variant thereof; and / or
[0469] (6) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 491 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof.
[0470] In some embodiments, the antigen-binding protein blocks the binding of human neurotrophic factor receptor mouse Fc dimer (human p75-mFc) to human neurotrophic factor 3 (hNT-3) by at least about 50%.
[0471] In some embodiments, the antigen-binding protein blocks less than about 50% of the binding of human neurotrophic factor receptor mouse Fc dimer (human p75-mFc) to human neurotrophic factor 3 (hNT-3).
[0472] On the other hand, this article provides an antigen-binding protein that binds to an antibody containing the HCVR / LCVR amino acid sequence pair as described in Table 1-1 at p75. NTR The same tabletop on.
[0473] On the other hand, this article provides an antigen-binding protein that competitively binds to p75 against antibodies containing the HCVR / LCVR amino acid sequence pairs as described in Table 1-1. NTR .
[0474] In some embodiments, the antigen-binding protein comprises an antibody or an antigen-binding fragment thereof.
[0475] In some embodiments, the antigen-binding protein is selected from humanized antibodies or their antigen-binding fragments, human antibodies or their antigen-binding fragments, murine antibodies or their antigen-binding fragments, chimeric antibodies or their antigen-binding fragments, monovalent Fab', bivalent Fab2, F(ab)'3 fragments, single-chain variable fragments (scFv), biscFv, (scFv)2, double-chain antibodies, microantibodies, nanoantibodies, triple-chain antibodies, quadruple-chain antibodies, disulfide-stabilized Fv proteins (dsFv), single-domain antibodies (sdAb), Ig NAR, single-chain antibodies, bispecific antibodies or their binding fragments, bispecific T-cell adaptors (BiTE), trispecific antibodies or their chemically modified derivatives.
[0476] In one embodiment, the antigen-binding protein comprises an antigen-binding region fragment (Fab).
[0477] In one embodiment, the antigen-binding protein comprises a single-stranded variable fragment (scFv).
[0478] In one embodiment, the scFv includes variable regions arranged from the N-terminus to the C-terminus in the following direction: HCVR-LCVR.
[0479] In one embodiment, the scFv includes variable regions arranged from the N-terminus to the C-terminus in the following direction: LCVR-HCVR.
[0480] In some implementations, the variable regions in the scFv are connected via connectors.
[0481] In one embodiment, the adapter is a peptide adapter.
[0482] In one embodiment, the peptide linker is -(GGGGS). n -(SEQ ID NO: 668), where n is any integer selected from 1 to 10.
[0483] In some embodiments, the antigen-binding protein binds to human p75. NTR Combine.
[0484] In one embodiment, the antigen-binding protein uses K D Approximately 1×10 -9 M or stronger affinity with people p75 NTR Combine.
[0485] On the other hand, this article provides an isolated polynucleotide encoding an antigen-binding protein as described herein.
[0486] On the other hand, this article provides a vector comprising isolated polynucleotides as described herein.
[0487] On the other hand, this article provides a host cell comprising an antigen-binding protein as described herein, an isolated polynucleotide as described herein, or a vector as described herein.
[0488] In one embodiment, the host cell is a Chinese hamster ovary (CHO) cell.
[0489] On the other hand, this article provides a protein-drug conjugate containing a protein-drug conjugate that interacts with the p75 neurotrophic factor receptor (p75). NTR Antigen-binding proteins that bind to and conjugate with molecular cargo.
[0490] In some embodiments, the antigen-binding protein of the protein-drug conjugate comprises an antigen-binding protein as described herein.
[0491] In one embodiment, the antigen-binding protein and the molecular cargo are coupled via a connector.
[0492] In some embodiments, the molecular cargo comprises polynucleotide molecules, polypeptide molecules, carriers, or small molecules.
[0493] In one embodiment, the molecular cargo comprises polynucleotide molecules.
[0494] In some embodiments, the polynucleotide molecule is an interfering nucleic acid molecule, guide RNA, ribozyme, aptamer, mixer, multimer, or mRNA.
[0495] In one embodiment, the interfering nucleic acid molecule is siRNA, shRNA, miRNA, antisense oligonucleotide, or gapmer.
[0496] In one embodiment, the interfering nucleic acid molecule is siRNA.
[0497] In one embodiment, the siRNA comprises a positive strand of 21 nucleotides in length.
[0498] In one embodiment, the siRNA comprises an antisense strand of 23 nucleotides in length.
[0499] In some embodiments, the siRNA contains two phosphate thioester bonds at the first and second nucleotide internucleotide bonds at the 5' end of the positive strand.
[0500] In some embodiments, the siRNA contains two phosphate thioester bonds at the first and second nucleotide internucleotide bonds at the 3' and / or 5' ends of the antisense strand.
[0501] In one embodiment, the interfering nucleic acid molecule is an antisense oligonucleotide.
[0502] In one embodiment, the polynucleotide molecule is guide RNA.
[0503] In some implementations, the polynucleotide molecule targets genes or gene products associated with pain, itching, or neurological disorders or impairments.
[0504] In some embodiments, the gene or gene product associated with pain, itching, or neurological disorders or disturbances is a voltage-gated sodium channel Nav1.7, a voltage-gated sodium channel Nav1.8, a voltage-gated sodium channel Nav1.9, a voltage-gated sodium channel Nav1.6, a tropomyosin receptor kinase A (TrkA), a tropomyosin receptor kinase C (TRKC), an acid-sensitive ion channel subunit 1 (ASIC1), an acid-sensitive ion channel subunit 3 (ASIC3), a transient receptor potential vanillic acid isoform 1 (TRPV1), a transient receptor potential vanillic acid isoform 4 (TRPV4), a transient receptor potential cation channel subfamily A member 1 (TRPA1), or a transient receptor potential cation channel subfamily M member 8 (TRPA1). PM8), fatty acid amide hydrolase (FAAH), piezoelectric mechanosensitive ion channel component 1 (PIEZO1), piezoelectric mechanosensitive ion channel component 2 (PIEZO2), enkephalin, RET proto-oncogene (RET), interleukin-4 receptor (IL4R), interleukin-13 receptor (IL13R), interleukin-31 receptor (IL31R), interleukin-6 receptor α (IL6Ra), glycoprotein 130 (gp130), ion transport regulator 2 containing FXYD domain (FXYD2), P2X purine receptor 3 (P2X3), calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase activating peptide (PACAP), or interleukin-6 (IL6).
[0505] In some embodiments, the polynucleotide molecule comprises one or more modified nucleotides.
[0506] In some embodiments, the molecular cargo comprises polypeptide molecules.
[0507] In some embodiments, the polypeptide molecule is an enzyme, a neuroprotective molecule, or a compound with p75. NTR Antigen-binding proteins that bind to targets other than those mentioned above.
[0508] In some implementations, the polypeptide molecule is associated with pain, itching, or neurological disorders or impairments.
[0509] In some embodiments, the polypeptide molecule is a neurotrophic factor, an antibody or antibody fragment, an antibody receptor fusion protein, or a cytokine signaling inhibitor.
[0510] In some implementations, protein-drug conjugates are used to treat or prevent pain, itching, or neurological disorders or impairments.
[0511] In some implementations, the pain is peripheral chronic pain, chronic neuropathic pain, somatic pain, chronic postoperative pain, small fiber peripheral neuropathy, chemotherapy-induced neuropathy, painful diabetic neuropathy, postherpetic neuralgia, osteoarthritis, back pain, arthralgia, trigeminal neuralgia, trigeminal neuralgia, temporomandibular joint pain, migraine, autonomic dysfunction, or myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS).
[0512] In one embodiment, the chronic neuropathic pain is trigeminal neuralgia or trigeminal neuropathy.
[0513] In one implementation, the itching is chronic itching.
[0514] In some implementations, the neurological disease or disorder is a neurodegenerative disease or disorder, a neurodevelopmental disease or disorder, a physical injury, a neuropsychiatric disease or disorder, or a nervous system cancer.
[0515] In one implementation, the neurodegenerative disease or disorder is Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).
[0516] In one implementation, the physical injury is traumatic brain injury, spinal cord injury, stroke, or cerebral edema.
[0517] In one implementation, the nervous system cancer is a brain cancer or a peripheral nerve cancer.
[0518] In one embodiment, the pain, itching, or neurological disorder or impairment is associated with sensory neurons, dorsal root ganglion cells, or trigeminal ganglion cells or populations thereof.
[0519] In some embodiments, the molecular cargo includes a carrier.
[0520] In some implementations, the carrier is a lipid-based carrier.
[0521] In some embodiments, the lipid-based carrier is a lipid nanoparticle (LNP), liposome, lipid-like substance, or lipid complex.
[0522] In one embodiment, the lipid-based carrier is LNP.
[0523] In some embodiments, the LNP also comprises polynucleotide molecules and / or polypeptide molecules.
[0524] In some implementations, the LNP comprises one or more components of a gene editing system.
[0525] In some implementations, the LNP includes:
[0526] (a) A Cas nuclease or a nucleic acid encoding the Cas nuclease, and / or
[0527] (b) Guide RNA or one or more DNAs encoding the guide RNA.
[0528] In one embodiment, the Cas nuclease is the Cas9 protein.
[0529] In some embodiments, the Cas9 protein is derived from Streptococcus pyogenes. (Streptococcus pyogenes Cas9 protein, Staphylococcus aureus ( Staphylococcus aureus Cas9 protein, Campylobacter jejuni ( Campylobacter jejuni Cas9 protein, Streptococcus thermophilus ( Streptococcus thermophilus Cas9 protein or Neisseria meningitidis ( Neisseria meningitidis Cas9 protein.
[0530] In some implementations, the nucleic acid encoding the Cas nuclease is codon-optimized for expression in mammalian cells.
[0531] In one embodiment, the nucleic acid encoding the Cas nuclease is codon-optimized for expression in human cells.
[0532] In one embodiment, the nucleic acid encoding the Cas nuclease is mRNA.
[0533] In one implementation, the guide RNA is a single-stranded guide RNA (sgRNA).
[0534] In some implementations, the LNP comprises a zinc finger nuclease (ZFN) or a transcription activator-like effector nuclease (TALEN).
[0535] In some embodiments, the LNP comprises cationic lipids, neutral lipids, accessory lipids, occult lipids, or any combination thereof.
[0536] In one embodiment, the neutral lipid is distearate phosphatidylcholine (DSPC).
[0537] In one embodiment, the auxiliary lipid is cholesterol.
[0538] In one embodiment, the stealth lipid is PEG2k-DMG.
[0539] On the other hand, this document provides pharmaceutical compositions comprising an antigen-binding protein as described herein, a separated polynucleotide as described herein, a carrier or protein-drug conjugate as described herein, and a pharmaceutically acceptable loading agent.
[0540] On the other hand, this document provides a composition or kit comprising an antigen-binding protein as described herein, an isolated polynucleotide as described herein, a carrier as described herein, a protein-drug conjugate as described herein, or a pharmaceutical composition as described herein, and further therapeutic agents.
[0541] On the other hand, this article provides a complex comprising a receptor for human p75 neurotrophic factor (p75). NTR (peptide-bound antigen-binding proteins as described herein or protein-drug conjugates as described herein)
[0542] On the other hand, this document provides a method for preparing an antigen-binding protein as described herein, the method comprising culturing host cells containing a polynucleotide encoding the antigen-binding protein in a culture medium under conditions favorable to the expression of the antigen-binding protein.
[0543] In some embodiments, the method for preparing the antigen-binding protein as described herein includes the steps of:
[0544] (a) Introducing the polynucleotide into a host cell;
[0545] (b) The host cells are cultured under conditions that favor the expression of the antigen-binding protein;
[0546] (c) Optionally, the antigen-binding protein is isolated from the culture medium and / or the host cells; and
[0547] (d) Optionally, the antigen-binding protein is conjugated to the molecular cargo.
[0548] On the other hand, this article provides an antigen-binding protein that is generated or obtainable by the methods described herein.
[0549] On the other hand, this article provides a method for preparing protein-drug conjugates as described herein, comprising:
[0550] (a) Contacting the antigen-binding protein with the molecular cargo under conditions conducive to the conjugation of the antigen-binding protein with the molecular cargo; and
[0551] (b) Optionally, the protein-drug conjugate produced in step (a) is separated.
[0552] On the other hand, this document provides a method for preparing protein-drug conjugates as described herein, wherein the molecular cargo comprises a polypeptide molecule, including:
[0553] (a) Culturing host cells containing a polynucleotide encoding the protein-drug conjugate under conditions that allow for the expression of the protein-drug conjugate; and
[0554] (b) Optionally, the protein-drug conjugate produced in step (a) is separated.
[0555] On the other hand, this document provides a protein-drug conjugate that is generated or obtainable according to the methods described herein.
[0556] On the other hand, this document provides a container or injection device comprising an antigen-binding protein as described herein, a separated polynucleotide as described herein, a carrier as described herein, or a protein-drug conjugate as described herein.
[0557] On the other hand, this document provides a method for administering an antigen-binding protein, a isolated polynucleotide, a carrier, or a protein-drug conjugate as described herein to a subject, the method comprising introducing the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate into the subject.
[0558] In some implementations, the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is introduced into the subject via subcutaneous, intramuscular, or intravenous administration.
[0559] In some embodiments, the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is introduced into the subject via intrathecal, intracisional, intraventricular, or intraparenchymal administration.
[0560] In one embodiment, the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is introduced into the subject via intravitreal administration into the eye.
[0561] On the other hand, this article provides a method for delivering molecular cargo into a subject to express p75. NTR A method for determining the tissue or cell type, the method comprising administering to the subject a protein-drug conjugate as described herein or a pharmaceutical composition as described herein.
[0562] In some implementations, the tissue is the brain, spinal cord, peripheral nervous system, autonomic nervous system, enteric nervous system, or eye.
[0563] In one implementation, the tissue is the brain or spinal cord.
[0564] In one implementation, the cell type is a sensory neuron.
[0565] In one embodiment, the cell type is a dorsal root ganglion cell or a trigeminal ganglion cell.
[0566] In some implementations, the protein-drug conjugate is introduced into the subject via subcutaneous, intramuscular, or intravenous administration.
[0567] In some implementations, the protein-drug conjugate is introduced into the subject via subcutaneous, intrathecal, intracisional, intraventricular, or intraparenchymal administration.
[0568] In one embodiment, the protein-drug conjugate is introduced into the subject via intravitreal administration into the eye.
[0569] In one embodiment, the protein-drug conjugate is introduced into the subject via subcutaneous administration.
[0570] In one embodiment, the protein-drug conjugate is introduced into the subject via intracerebrospinal administration.
[0571] On the other hand, this document provides a method for treating or preventing pain, pruritus, or neurological disorders or impairments in a subject in need, the method comprising administering to the subject an effective amount of an antigen-binding protein, a isolated polynucleotide, a carrier, a protein-drug conjugate, or a pharmaceutical composition as described herein.
[0572] In some embodiments, the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is administered subcutaneously, intramuscularly, or intravenously.
[0573] In some embodiments, the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is introduced into the subject via intrathecal, intracisional, intraventricular, or intraparenchymal administration.
[0574] In one embodiment, the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is introduced into the subject via intravitreal administration into the eye.
[0575] In some implementations, the pain is peripheral chronic pain, chronic neuropathic pain, somatic pain, chronic postoperative pain, small fiber peripheral neuropathy, chemotherapy-induced neuropathy, painful diabetic neuropathy, postherpetic neuralgia, osteoarthritis, back pain, arthralgia, trigeminal neuralgia, trigeminal neuralgia, temporomandibular joint pain, migraine, autonomic dysfunction, or myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS).
[0576] In one embodiment, the chronic neuropathic pain is trigeminal neuralgia or trigeminal neuropathy.
[0577] In one implementation, the itching is chronic itching.
[0578] In some implementations, the neurological disease or disorder is a neurodegenerative disease, a neurodevelopmental disease, chronic neuropathic pain, physical injury, neuropsychiatric disease, or nervous system cancer.
[0579] In one implementation, the neurodegenerative disease or disorder is Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).
[0580] In one implementation, the physical injury is traumatic brain injury, spinal cord injury, stroke, or cerebral edema.
[0581] In one implementation, the nervous system cancer is a brain cancer or a peripheral nerve cancer.
[0582] In some implementations, the pain, itching, or neurological disorder or impairment is associated with sensory neurons, dorsal root ganglion cells, trigeminal ganglion cells, or populations thereof.
[0583] In some implementations, such as the method described herein, additional treatment may be administered to the subject.
[0584] In some implementations, the additional treatment includes administration of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, local anesthetics, capsaicin, Cox-2 inhibitors, antidepressants, anticonvulsants, antiepileptic drugs, opioids, steroids, anticonvulsants, muscle relaxants, triptans, dihydroergotamine, lamiditan, calcitonin gene-related peptide antagonists, antiemetics, beta-blockers, calcium channel blockers, serotonin and norepinephrine reuptake inhibitors (SNRIs), botulinum toxin A, or benzodiazepines, or combinations thereof. Attached Figure Description
[0585] Figure 1 It showed resistance to p75 NTRAntibodies were internalized in isolated dorsal root ganglion (DRG) tissue. In vivo, time-lapse confocal imaging of isolated DRG. Maximum projection of three confocal optical sections 10 μm apart, obtained by administering Alexa 647-conjugated antibody at t=0. [Image showing the effect of applying fluorescently conjugated anti-p75 antibodies.] NTR Axons were labeled within 5 minutes of antibody addition to the culture medium. Internalization into neuronal cell bodies was observed 1–4 hours after antibody addition.
[0586] Figure 2A-2B It showed resistance to p75 NTR Antibodies are internalized in ex vivo DRG tissue. In vivo, time-lapse confocal imaging of ex vivo grown DRG. Maximum projection of three confocal optical sections 10 μm apart is shown after administration of Alexa 647-conjugated antibody at t=0. [Image showing the effect of applying fluorescently conjugated anti-p75 antibodies.] NTR Axons were labeled within 5 minutes of antibody addition to the culture medium. Internalization into neuronal cell bodies was observed 1–4 hours after antibody addition.
[0587] Figures 3A-3F Shows anti-p75 NTR Antibodies were internalized in the DRG after intraplantar injection. The maximum projection of confocal Z-stacked images of the entire DRG collected 5 days after the injection of fluorescently conjugated antibodies into the hindfoot pad. Waist DRG with intraplantar injection of anti-FelD1 (… Figure 3A or anti-p75 NTR REGN14155( Figure 3B or anti-p75 NTR REGN14187( Figure 3C Ipsilateral. Lumbar DRG and intraplantar injection of anti-Fel D1 ( Figure 3D or anti-p75 NTR REGN14155( Figure 3E or anti-p75 NTR REGN14187 contralateral. CT-B labeling of DRG neurons on the same side after injection ( Figures 3A-3C ), but not on the opposite side ( Figure 3D-3F Anti-p75 NTR Antibody uptake was observed in both DRGs. CT-B, cholera toxin subunit B-Alexa 488 ( Figure 3F ).
[0588] Figures 4A-4C Shows anti-p75 NTR The antibody was internalized in the trigeminal ganglion (TG) after intraplantar injection. The maximum projection of a confocal Z-stacked image of the entire trigeminal ganglion was collected 5 days after the injection of the fluorescently conjugated antibody into the hindfoot pad. Transmitted light and fluorescence images of the trigeminal ganglion are from: intraplantar injection of anti-Fel D1 (… Figure 4AIntraplantar injection of anti-p75 NTR REGN14155( Figure 4B Intraplantar injection of anti-p75 NTR REGN14187( Figure 4C ).
[0589] Figures 5A-5F Shows anti-p75 NTR The antibody was internalized in the DRG and TG after intramuscular injection. The maximum projection of the confocal Z-stacked image of the entire DRG was collected 5 days after the injection of the fluorescently conjugated antibody into the gastrocnemius muscle. Waist DRG with intramuscular injection of anti-FelD1 (… Figure 5A Ipsilateral. Lumbar DRG and intramuscular injection of anti-p75. NTR REGN14187( Figure 5B Ipsilateral. Lumbar DRG and intramuscular injection of anti-FelD1 ( Figure 5C (Contralateral) Lumbar DRG and intramuscular injection of anti-p75 NTR REGN14187( Figure 5D Conversely, the trigeminal ganglion of mice injected into the gastrocnemius muscle (Fel D1) Figure 5E Injecting anti-p75 into the gastrocnemius muscle. NTR The trigeminal ganglion of REGN14187 mice ( Figure 5F ). CT-B was used to label DRG neurons on the same side after injection. Figures 5A-5B ), but not on the opposite side ( Figures 5C-5D ) or TG ( Figure 5E-5F Anti-p75 NTR Uptake was observed in both bilateral DRGs and in the trigeminal ganglion. CT-B, cholera toxin subunit B-Alexa 488.
[0590] Figure 6 Anti-p75 was observed 3 days after subcutaneous injection. NTR Antibodies were internalized in all lumbar DRGs. Fluorescent anti-p75 was detected in all lumbar DRGs 3 days after subcutaneous injection of 0.5 mg / kg fluorescently labeled antibody. NTR The A647 fluorescence image of the waist DRG is superimposed on the transmitted light image of the DRG for display.
[0591] Figures 7A-7B Anti-p75 was observed 3 days after subcutaneous injection. NTR Antibody internalization in DRG neurons. 20X confocal single-slice image, magnified 1.5x, allows for visualization of fluorescently labeled anti-p75 in DRG neurons. NTR Intracellular distribution visualization of REGN14187. Spot-like, intracellular anti-p75 was detected in neurons. NTR Antibody.
[0592] Figures 8A-8C Shows anti-p75 NTR The antibody was internalized in DRG neurons expressing peripheral proteins, a marker of peripheral neurons. Subcutaneous injection of anti-p75 was also administered. NTR DRG slices from REGN14187 mice were then stained with anti-peripheral proteins to identify wide-field fluorescence images of neurons.
[0593] Figure 9A-9N Anti-p75 was observed 5 days after subcutaneous injection. NTR The antibody was internalized in the DRG, TG, colon, eye, and sympathetic ganglia. Five days after subcutaneous injection of 0.7 mg / kg fluorescently labeled antibody, TG levels were [data missing]. Figure 9B ), neck DRG ( Figure 9D ), chest DRG ( Figure 9E ) and waist DRG ( Figure 9F Fluorescent anti-p75 was detected in ) NTR Antibody. A647 fluorescence images of TG and DRG are superimposed on the transmitted light image of DRG for display. Figures 9A-9F In the colon ( Figure 9H Fluorescent anti-p75 was detected in ) NTR Antibody. Higher magnification images of colon tissue show fluorescent anti-p75. NTR Antibodies are internalized in the cells of the myenteric plexus. Figure 9I Fluorescent anti-p75 was detected in the eye. NTR Antibody( Figure 9K ).exist Figure 9G-9K The image shows an A647 fluorescence confocal image of colon or eye tissue. In the sympathetic ganglion ( Figure 9M Fluorescent anti-p75 was detected in ) NTR Antibodies. In Figure 9L-9M The image shows a wide-field fluorescence image of A647 on the ventral side of the thoracic spinal cord. Subcutaneous injection of fluorescent anti-Fel D1 did not produce a fluorescence signal in any tissue. Figure 9A , 9C (9G, 9J, and 9L). Anti-p75 was confirmed using co-labeling with neuronal and glial cell markers. NTR Antibodies are internalized in DRG neurons rather than in surrounding satellite glial cells. Figure 9N ).
[0594] Figures 10A-10F The results showed that after subcutaneous injection, anti-p75... NTR Antibodies in the cerebellum ( Figure 10A ), hippocampus ( Figure 10B ),liver( Figure 10C ) and spinal cord ( Figure 10F Not detected in choroid plexus. Following subcutaneous injection, it was detected in choroid plexus ( Figure 10B ),kidney( Figure 10C ) and heart ( Figure 10ELow levels of anti-p75 were detected in the sample. NTR Antibody. Confocal images of the DAPI and A647 channels are shown.
[0595] Figure 11A-11D The results showed that anti-p75 was detected in the choroid plexus after subcutaneous injection. NTR Antibodies. 10X confocal images of sagittal brain sections showed anti-p75 in the choroid plexus 5 days after subcutaneous injection. NTR Antibodies (arrow) are barely detectable or undetectable in other areas of the brain.
[0596] Figure 12A-12D The results showed that low levels of anti-p75 were detected after ICV injection. NTR Antibody. 5X confocal fluorescence images of sagittal brain slices show anti-p75. NTR Low accumulation of specific markers in the ventral and cortical regions ( Figure 12D Anti-Fel D1 () Figure 12B ) and anti-p75 NTR Antibody( Figure 12D All of these were observed to accumulate in the ventricles at the injection site.
[0597] Figures 13A-13D The results showed that the sensory neurons at the injection site were located on the same side as the terminals of the sensory neurons in the beard pad. Figure 13B ) rather than the opposite side ( Figure 13D Alexa-conjugated anti-p75 (Alexa-anti-p75) antibodies were detected in sensory neurons of the trigeminal ganglion, indicating retrograde transport of the fluorescently conjugated antibody from the axonal terminal along the sensory neuron axon to the sensory neuron cell body. Ipsilateral ( Figure 13A ) and the opposite side ( Figure 13C Confocal images of the trigeminal ganglion stained with DAPI.
[0598] Figure 14 The results showed that, compared with the isotype conjugate control, the anti-p75 activity was significantly higher. NTR Intravenous delivery of the antibody-Nav1.7 siRNA conjugate improved the reduction of Scn9a transcripts in the trigeminal ganglion. Humanized Nav1.7 mice were administered two intravenous (IV) injections of 50 mg / kg of anti-p75. NTR Antibody-Nav1.7 siRNA conjugate or isotype antibody conjugate control. Trigeminal ganglia were collected 14 days after the first IV dose for quantitative PCR analysis. Compared with the isotype conjugate control, anti-p75... NTR The antibody conjugate showed an approximately 30% reduction in Nav1.7 mRNA transcripts. Three mice were used in each group.
[0599] Figures 15A-15H The results show that REGN19516 is present in the trigeminal ganglion ( Figure 15D ) and DRG ( Figure 15H Following intravenous injection of REGN anti-p75, fluorescent REGN anti-p75 was observed. NTR Internalization into neurons. Intravenous injection of the fluorescent isotype control antibody REGN1945 did not show labeling in TG or DRG. Figure 15B , 15F ). Detailed Implementation
[0600] This disclosure provides a specific binding to the p75 neurotrophic factor receptor (p75). NTR This disclosure also provides antigen-binding proteins containing specific binding p75 or fragments of its antigen. NTR Protein-drug conjugates, which are antigen-binding proteins of their antigen fragments and conjugate with molecular cargo. For example, such conjugates can be used to deliver molecular cargo to various tissues in the body, such as the peripheral nervous system, the autonomic nervous system (e.g., the sympathetic / parasympathetic nervous system, such as sympathetic ganglia and / or parasympathetic ganglia), the enteric nervous system (e.g., the myenteric plexus), the central nervous system (CNS), and ocular tissues and / or cells, such as sensory neurons (e.g., but not limited to dorsal root ganglion (DRG) cells and / or trigeminal ganglion (TG) cells), sympathetic neurons, parasympathetic neurons, and enteric neurons. In some embodiments, the conjugates described herein can be used to deliver molecular cargo to cells, such as dermal fibers, celiac ganglion cells, Müller glial cells, Leydig cells, ionocytes, dendritic cells, Schwann cells, salivary gland cells, retinal bipolar neurons, basal respiratory cells, basal squamous epithelial cells, etc. The conjugates described herein possess the ability to efficiently deliver molecular cargo to the nervous system, including the peripheral nervous system, brain, and spinal cord, particularly DRG cells (e.g., neurons) and TG cells (e.g., neurons), and therefore can be used to treat pain (e.g., chronic pain, including peripheral chronic pain), pruritus (e.g., chronic pruritus), and neurological disorders and disorders, such as neurodegenerative disorders, neurodevelopmental disorders, and neuropsychiatric disorders. In some embodiments, the conjugates described herein possess the ability to efficiently deliver molecular cargo to peptidoenergetic and non-peptidoenergetic sensory neurons (peripheral proteins) within the DRG. In some embodiments, anti-p75... NTR It can be efficiently taken up by DRG and / or TG cells (e.g., neurons), but is rarely taken up in surrounding tissues and the brain.
[0601] According to this disclosure, molecular biology, microbiology, and recombinant DNA techniques commonly used by those skilled in the art can be employed. These techniques are well explained in the literature. See, e.g., Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (herein referred to as "Sambrook et al., 1989"); DNA Cloning: A Practical Approach, Volumes I and II (ed. DN Glover, 1985); Oligonucleotide Synthesis (ed. MJ Gait, 1984); Nucleic AcidHybridization (BD Hames & SJ Higgins (1985)); Transcription AndTranslation (BD Hames & SJ Higgins (1984)); Animal Cell Culture (RIFreshney (1986)); Immobilized Cells And Enzymes (IRL Press, (1986)); B.Perbal, A Practical Guide To Molecular Cloning (1984); FM Ausubel et al. (Eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994).
[0602] Polynucleotides include DNA and RNA. This disclosure includes any polynucleotide described herein that is operatively linked to a promoter or other expression control sequence.
[0603] The term "p75" NTR "p75" or "p75NTR" refers to the p75 neurotrophic factor receptor. The p75 neurotrophic factor receptor (p75...) NTR p75 belongs to the tumor necrosis factor receptor superfamily (TNFRSF). It is expressed at the peripheral axon terminals. NTR The receptor is known to be retrogradely transported to the cell body, transmitting survival, apoptosis, and differentiation signals to the cell body. Rabies virus binds to p75.NTR The receptor hijacks the reverse transport mechanism to infect neurons. In the presence of TrkA, p75 NTR Enhances NGF signaling and increases survival and differentiation. In the absence of TrkA, NGF interacts with p75. NTR The binding of p75 promotes apoptosis. In many pathological conditions such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and ischemia, p75... NTR Increased expression of p75 is observed in the peripheral nervous system (PNS), such as in sympathetic and sensory neurons. NTR (Qin et al., Journal of Neuroscience Research, 98(10), 1987-1998 (2000); Yamamoto et al., Neurochem Res 21, 929-938 (1996); both of which are cited in full herefor reference), and p75 was found in some subgroups of parasympathetic neurons and some enteric neurons. NTR In non-neural tissues, p75 can be found in mesenchymal cells of multiple organs / structures, including limbs, maxillary pads, teeth, lungs, muscles, testes, retina, pituitary gland, hair follicles, salivary glands, perivascular cells, and meninges. NTR .
[0604] In one implementation, an exemplary person p75 NTRThe protein (NCBI accession number NP_002498.1) contains the following amino acid sequence: MGAGATGRAMDGPRLLLLLLLGVSLGGAKEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRST PPEGSDSTAPSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDNLIPVYCSILAAVVVGLVAYIAFKRWNSCKQNKQGANSRPVNQTPPPEGEKLHSDSGISVDSQSLH DQQPHTQTASGQALKGDGGLYSSLPPAKREEVEKLLNGSAGDTWRHLAGELGYQPEHIDSFTHEACPVRALLASWATQDSATLDALLAALRRIQRADLVESLCSESTATSPV(SEQ ID NO: 669).
[0605] In some implementations, the person described in this article (p. 75) NTR Proteins can be encoded by the following nucleotide sequences:
[0606]
[0607] p75 NTR Protein-binding proteins and protein-drug conjugates
[0608] In one aspect, this disclosure provides an antigen-binding protein that specifically binds to p75NTR.
[0609] Specific binding to p75 NTR The antigen-binding protein can bind to p75 at approximately 25°C. NTR Or its fusion protein, for example, tagged with His6 (SEQ ID NO: 619) and / or myc with, for example, human p75. NTR Or monkey p75 NTR Fusion, for example, in the determination of surface plasmon resonance, having K D Approximately 1×10 -9 M or stronger affinity. Such antigen-binding proteins can be called "anti-p75". NTR ".
[0610] In some implementations, p75 is specifically bound. NTR Antigen-binding proteins may contain antibodies or antigen-binding fragments of antibodies, such as antigen-binding domain fragments (Fab) or single-chain variable fragments (scFv).
[0611] This disclosure also provides p75 NTR Protein-drug conjugates. p75 NTR The protein-drug conjugate may optionally contain a signal peptide that specifically binds to p75. NTR (e.g., human p75) NTR The antigen-binding protein (e.g., an antibody or an antigen-binding fragment of an antibody, such as an antigen-binding region fragment (Fab) or a single-chain variable fragment (scFv)) is linked, and the antigen-binding protein is conjugated to the molecular cargo (optionally via a linker). This is described on p75. NTR Protein-drug conjugates can deliver conjugated molecular cargoes to desired tissues (e.g., neural tissue) and / or desired cell types (e.g., sensory neurons (e.g., but not limited to dorsal root ganglion cells and / or trigeminal ganglion cells)) in vivo. The p75 described herein... NTRNon-limiting examples of cell types to which protein-drug conjugates can deliver conjugated molecular cargo include neurons, Müller glial cells, Leydig cells, ionocytes, dorsal root ganglion (DRG) cells, trigeminal ganglion cells, sympathetic ganglion cells, dermal fibroblasts, retinal cells, myenteric plexus cells, celiac ganglion cells, dendritic cells, Schwann cells, salivary gland cells, retinal bipolar neurons, basal respiratory cells, basal squamous epithelial cells, and oligodendrocytes.
[0612] The term "conjugate" refers to an object in which two substances are covalently or non-covalently linked. The term "covalently linked" refers to the characteristic of at least two molecules being linked together by one or more covalent bonds. In various embodiments, two molecules may be covalently linked together by a single bond (e.g., a disulfide bridge or disulfide bond) acting as a connector between the molecules. In some embodiments, two or more molecules may be covalently linked together by a molecule acting as a connector, which binds the at least two molecules together via multiple covalent bonds. In some embodiments, the connector may be a cleavable connector or an uncleavable connector. In a conjugate, the two substances may be directly linked or linked via a connector. In this disclosure, one of the two substances is an antigen-binding protein, such as an antibody or its antigen-binding fragment, and the other substance is a drug (e.g., a polynucleotide, polypeptide, or liposome or LNP disclosed herein). In this disclosure, the connector may be a cleavable connector or an uncleavable connector. In some embodiments, two polypeptide molecules covalently linked directly or indirectly (e.g., via a connector) may be expressed from a single polynucleotide molecule.
[0613] As used herein, the term "antibody-drug conjugate" or "ADC" refers to a conjugate of an antibody or its antigen-binding fragment with a drug (e.g., a polynucleotide, peptide, liposome, or LNP disclosed herein). By conjugating an antibody or its antigen-binding fragment with a drug (e.g., a polynucleotide, peptide, liposome, or LNP disclosed herein), the drug is endowed with an affinity for the antigen, thereby improving the efficiency of drug delivery to the target site in vivo. As used herein, "antibody-drug conjugate" or "ADC" also encompasses fusion proteins in which an antibody or its antigen-binding fragment is fused to another polypeptide molecule.
[0614] This disclosure includes specific binding to p75. NTR (e.g., human p75) NTR Antibodies and their antigen-binding fragments, such as Fab and scFv.
[0615] As used herein, the term "antibody" refers to an immunoglobulin molecule (e.g., IgG) comprising four polypeptide chains (two heavy chains (HC) and two light chains (LC)) interconnected by disulfide bonds. In one embodiment, each antibody heavy chain (HC) contains a heavy chain variable region ("HCVR" or "V"). H (e.g., SEQ ID NO: 2, 22, 42, 58, 78, 98, 116, 136, 155, 173, 189, 207, 227, 245, 261, 279, 297, 315, 331, 349, 369, 387, 401, 417, 427, 437, 445, 455, 465, 475, 484, 493, 503, 513, 519, 529, 549, 569, 589, 609 or variants thereof) and heavy chain constant regions; and each antibody light chain (LC) contains a light chain variable region (“LCVR” or “V”). L (e.g., SEQ ID NO: 10, 30, 50, 66, 86, 106, 124, 144, 162, 179, 197, 215, 235, 251, 269, 287, 304, 323, 339, 357, 377, 391, 409, 537, 557, 577, 597 or variants thereof) and the light chain constant region (CL). V H and V L The region can be further subdivided into highly variable regions known as complementarity-determining regions (CDRs), interspersed with more conservative regions known as framework regions (FRs). Each V H and V L It contains three CDRs and four FRs.
[0616] In one implementation, the amino acid assignment to each framework or CDR domain in the immunoglobulin is based on the definitions in Sequences of Proteins of Immunological Interest, Kabat et al.; National Institutes of Health, Bethesda, Md.; 5th edition; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia et al., (1987) J Mol. Biol. 196:901-917 or Chothia et al., (1989) Nature 342:878-883. Therefore, this disclosure includes antibody and antigen-binding fragments comprising a CDR of VH and a CDR of VL, wherein VH and VL comprise amino acid sequences as listed herein (see, for example, sequences in Table 1-1 or variants thereof), and wherein the CDR is defined according to Kabat and / or Chothia.
[0617] p75 mentioned in this article NTR The binding protein can be an antigen-binding fragment of an antibody that can optionally be conjugated to molecular cargo. As used herein, the term “antigen-binding portion” or “antigen-binding fragment” of an antibody refers to any sequence of an immunoglobulin molecule (preferably, the complete antibody is IgG) that binds to an antigen but does not contain a complete antibody. Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; and (vi) dAb fragments; which consist of amino acid residues mimicking the hypervariable region of an antibody (e.g., a separated complementarity-determining region (CDR), such as a CDR3 peptide), or a restricted FR3-CDR3-FR4 peptide. As used herein, other engineered molecules (such as domain-specific antibodies, single-domain antibodies, domain-deficient antibodies, chimeric antibodies, CDR-transplanted antibodies, double-chain antibodies, triple-chain antibodies, quadruple-chain antibodies, microantibodies, and small modular immunopharmaceuticals (SMIPs)) are also included in the term “antigen-binding fragment”.
[0618] As mentioned above, p75 in this article NTRThe binding protein can be an scFv (single-chain variable region fragment) optionally conjugated to the molecular cargo. The scFv has heavy chain variable region (VH) and light chain variable region (VL) domains (in any order) preferably linked together by a flexible linker (e.g., a peptide linker). The length of the flexible linker used to connect these two V regions may be important for the proper folding of the polypeptide chain. Previously, it was estimated that the peptide linker must span 3.5 nm (35 Å) between the carboxyl terminus of the variable domain and the amino terminus of the other domain without affecting the ability of the domains to fold and form an intact antigen-binding site (Huston et al., Protein engineering of single-chain Fv analogs and fusion proteins. Methods in Enzymology. 1991; 203:46–88). In one embodiment, the linker comprises an amino acid sequence long enough to separate the variable domains by approximately 3.5 nm.
[0619] In some implementations, p75 is specifically bound. NTR Antigen-binding proteins contain heavy chain variable regions (HCVR or V). H ) and / or light chain variable region (LCVR or V L ).
[0620] In one implementation, p75 is specifically bound. NTR The antigen-binding protein contains anti-p75 NTR The scFv has variable zones arranged as follows: LCVR-HCVR or HCVR-LCVR, where HCVR and LCVR are optionally connected by a connector.
[0621] In some implementations, p75 NTR Protein-drug conjugates contain heavy chain variable regions (HCVR or V). H ) and / or light chain variable region (LCVR or V L ).
[0622] In one implementation, p75 NTR Protein-drug conjugates include anti-p75. NTR The scFv has variable regions arranged as follows: LCVR-HCVR or HCVR-LCVR, wherein HCVR and LCVR are optionally connected by a connector, and the scFv is connected to a molecular cargo, optionally via a connector (e.g., LCVR-(Gly4Ser)3(SEQ ID NO: 623)-HCVR-molecular cargo; or LCVR-(Gly4Ser)3(SEQ ID NO: 623)-HCVR-molecular cargo).
[0623] In some implementations, the p75 described herein NTR The binding protein comprises a monovalent or “single-arm” antibody. As used herein, a monovalent or “single-arm” antibody refers to an immunoglobulin containing a single variable domain. For example, a single-arm antibody may contain a single variable domain within a Fab, wherein the Fab is linked to at least one Fc fragment. In some embodiments, a single-arm antibody comprises: (i) a heavy chain containing a heavy chain constant region and a heavy chain variable region; (ii) a light chain containing a light chain constant region and a light chain variable region; and (iii) a polypeptide containing an Fc fragment or a truncated heavy chain. In some embodiments, the Fc fragment or truncated heavy chain contained in the polypeptide is a “pseudo-Fc,” which refers to an Fc fragment not linked to an antigen-binding domain. The single-arm antibodies described herein may comprise any of the HCVR / LCVR pairs or CDR amino acid sequences listed in Table 1-1 herein. Single-arm antibodies comprising a full-length heavy chain, a full-length light chain, and an additional Fc domain polypeptide can be constructed using standard methods (see, for example, WO2010151792, which is incorporated herein by reference in its entirety), wherein the heavy chain constant region differs from the Fc domain polypeptide by at least two amino acids (e.g., H95R and Y96F according to the IMGT exon numbering system; or H435R and Y436F according to the EU numbering system). Such modifications can be used for the purification of monovalent antibodies (see WO2010151792).
[0624] In one embodiment, the antigen-binding fragment of the antibody will contain at least one variable domain. The variable domain can have any size or amino acid composition and will typically include at least one CDR adjacent to or within a framework having one or more framework sequences. L V associated with the structural domain H In the antigen-binding fragment of the domain, V H and V L Domains can be arranged in any suitable arrangement relative to each other. For example, variable regions can be dimers and contain V. H -V H V H -V L or V L -V L Dimer. Alternatively, the antigen-binding fragment of an antibody may contain a non-covalently bound monomer V. H and / or V L Structural domain.
[0625] In some embodiments, the antigen-binding fragment of the antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found within the antigen-binding fragment of the antibody described herein include: (i) VH -CH1;(ii)V H -CH2;(iii)V H -CH3;(iv)V H -CH1-CH2;(v)V H -CH1-CH2-CH3;(vi)V H -CH2-CH3;(vii)V H -CL;(viii)V L -CH1;(ix)V L -CH2;(x)V L -CH3;(xi)V L -CH1-CH2;(xii)V L -CH1-CH2-CH3;(xiii)V L -CH2-CH3; and (xiv)V L -CL. In any configuration of the variable and constant domains (including any of the exemplary configurations listed above), the variable and constant domains may be directly connected to each other or connected via full or partial hinge or linker regions. Hinge regions may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids, resulting in flexible or semi-flexible connections between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragments of the antibodies described herein may include the domains listed above and / or connected to one or more monomers V. H or V LHomodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations of non-covalently associated domains (e.g., via disulfide bonds). This disclosure includes antigen-binding fragments of antigen-binding proteins (e.g., antibodies) as described herein, such as REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REG N14175; REGN14176; REGN14177; REGN14178; REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517.
[0626] Antigen-binding proteins (e.g., antibodies and antigen-binding fragments) can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding proteins are further discussed herein. This disclosure includes monospecific and multispecific (e.g., bispecific) antigen-binding fragments comprising antigen-binding proteins specifically listed herein (e.g., REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165); One or more variable structural domains of REGN14175; REGN14176; REGN14177; REGN14178; REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517).
[0627] The term "specific binding" or similar terms refers to the formation of a relatively stable antigen-binding complex by an antigen-binding protein (e.g., an antibody or its antigen-binding fragment) under physiological conditions. Specific binding can occur at a rate of approximately 1 × 10⁻⁶. -6 M or a smaller equilibrium dissociation constant (K) D To characterize, for example, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M or 10 -12 M (smaller K) D (Indicating a tighter binding). Methods for determining whether an antigen-binding protein (e.g., an antibody or its antigen-binding fragment) specifically binds to an antigen are known in the art and include, for example, equilibrium dialysis, surface plasmon resonance (e.g., Biacore). TMBiolayer interferometry (e.g., Octet® HTX biosensor), solution affinity ELISA, etc. In some embodiments, specific binding is measured in surface plasmon resonance assays, for example at 25°C or 37°C. Antigen-binding proteins (e.g., antibodies or their antigen-binding fragments) that specifically bind to antigens from one species may or may not have cross-reactivity with other antigens (e.g., orthogonal homologous antigens from another species). This disclosure includes specific binding to p75. NTR Proteins (e.g., human p75) NTR Protein, mouse p75 NTR Protein and / or cynomolgus p75 NTR Antigen-binding proteins (such as p75). NTR "Refers to the specific binding of p75" NTR Antigen-binding proteins (or other molecules), such as antibodies or their antigen-binding fragments.
[0628] "Isolated" antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof), polypeptides, polynucleotides, and mediators are at least partially free of other biological molecules from the cells or cell cultures from which they are produced. Such biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other substances such as cell debris and growth media. Isolated antigen-binding proteins may further be at least partially free of expression system components, such as biological molecules from host cells or their growth media. Generally, the term "isolated" is not intended to mean the complete absence of such biological molecules (e.g., trace or insignificant amounts of impurities may remain), nor does it mean the absence of water, buffers, or salts, or components of pharmaceutical formulations containing antigen-binding proteins (e.g., antibodies or antigen-binding fragments).
[0629] This disclosure includes antigen-binding proteins described herein (e.g., REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN14175; REGN14176; REGN14176; REGN14177; REGN1418; REGN1419; REGN14159; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN14175; REGN14176; REGN14177; REGN14178; REGN14179 ... GN14177; REGN14178; REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517) bind to antigen-binding proteins, such as antibodies or antigen-binding fragments, with the same epitope.
[0630] An antigen is a molecule to which an antibody or an antigen-binding fragment thereof binds, such as a peptide (e.g., p75). NTR Or a fragment thereof (antigen fragment). A specific region on the antigen that an antibody recognizes and binds to is called an epitope. Antigen-binding proteins (e.g., antibodies) that specifically bind to such antigens, as described herein, are part of this disclosure.
[0631] The term "epitope" refers to a specific antigen-binding site of an antigen-binding protein (e.g., a variable region of an antibody called the complementary site) that interacts with an antigen-binding protein (e.g., p75). NTR Epitopes are antigenic determinants. A single antigen may have more than one epitope. Therefore, different antibodies can bind to different regions on an antigen and may have different biological effects. The term "epitaxe" can also refer to the site on an antigen to which B and / or T cells respond and / or the antigenic region to which an antibody binds. Epitopes can be defined as structural or functional. Functional epitopes are typically a subset of structural epitopes and have those residues that directly contribute to the affinity of the interaction. Epitopes can be linear or conformational, i.e., composed of nonlinear amino acids. In some embodiments, epitopes may contain determinants as chemically active surface groups of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and in some embodiments, may have specific three-dimensional structural properties and / or specific charge properties. The epitopes to which the antigen-binding proteins described herein bind may be contained in p75. NTRThe epitopes are located in segments (e.g., their extracellular domains). Antigen-binding proteins (e.g., antibodies) described herein that bind to such epitopes are part of this disclosure.
[0632] Methods for identifying epitopes of antigen-binding proteins (e.g., antibodies, fragments, or peptides) include alanine scanning mutation analysis, peptide blotting (Reineke (2004) Methods Mol. Biol. 248:443-63), peptide cleavage analysis, crystallographic studies, and NMR analysis. Additionally, methods such as epitope excision, epitope extraction, and chemical modification of antigens can be employed (Tomer (2000) Prot. Sci. 9:487-496). Another method that can be used to identify the amino acids within a peptide that interacts with an antigen-binding protein (e.g., antibody, fragment, or peptide) is hydrogen / deuterium exchange detected by mass spectrometry. See, for example, Ehring (1999) Analytical Biochemistry 267:252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A.
[0633] This disclosure includes antigen-binding proteins described herein (e.g., REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN14175; REGN...). 14176; REGN14177; REGN14178; REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517) Competitive combination p75 NTR (For example, p75 discussed in this article) NTR Antigen-binding proteins (e.g., epitopes). As used herein, the term "competition" refers to competition with antigens (e.g., p75). NTRAn antigen-binding protein (e.g., an antibody or its antigen-binding fragment) binds to and inhibits or blocks the binding of another antigen-binding protein (e.g., an antibody or its antigen-binding fragment) to the antigen. Unless otherwise stated, the term also includes competition between two antigen-binding proteins (e.g., antibodies) in two orientations, i.e., a first antibody binds to the antigen and blocks the binding of a second antibody, and vice versa. Thus, in one embodiment, the competition occurs in one such orientation. In some embodiments, the first antigen-binding protein (e.g., an antibody) and the second antigen-binding protein (e.g., an antibody) may bind to the same epitope. Alternatively, the first antigen-binding protein and the second antigen-binding protein (e.g., an antibody) may bind to different but, for example, overlapping or non-overlapping epitopes, wherein the binding of one inhibits or blocks the binding of the second antibody (e.g., via steric hindrance). Competition between antigen-binding proteins (e.g., antibodies) can be measured by methods known in the art (e.g., by real-time label-free biolayer interferometry). Additionally, anti-p75... NTR Binding competition between antigen-binding proteins (e.g., monoclonal antibodies (mAbs)) can be determined using real-time label-free biolayer interferometry on the OctetRED384 biosensor (Pall ForteBio Corp.).
[0634] Typically, the antibody or antigen-binding fragments described herein, modified in some way, retain specificity with p75. NTR The ability to combine, for example, retain its p75 NTR Binding activity of at least 10% (when the activity is expressed on a molar basis) (when compared with a parent antibody). Preferably, the antibody or antigen-binding fragment described herein retains p75 as in the parent antibody. NTR The binding affinity is at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more. It is also intended that the antibody or antigen-binding fragment described herein may contain conserved or non-conserved amino acid substitutions (referred to as “conserved variants” or “functionally conserved variants” of the antibody) that do not significantly alter its biological activity.
[0635] p75 mentioned in this article NTR The binding protein may be a monoclonal antibody or an antigen-binding fragment of a monoclonal antibody that can optionally conjugate to molecular cargo. This disclosure includes monoclonal p75. NTRBinding proteins, such as antibodies and their antigen-binding fragments (e.g., REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN14175; REGN14176; REGN... 14177; REGN14178; REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517), and monoclonal compositions comprising a variety of isolated monoclonal antigen-binding proteins. As used herein, the term “monoclonal antibody” or “mAb” refers to a member of a substantially homogeneous group of antibodies, i.e., antibody molecules comprising this group are identical in amino acid sequence, except for possibly naturally occurring mutations that may be present in trace amounts. The term "multiple" such monoclonal antibodies and fragments in a composition refers to the same (i.e., as discussed above, in the amino acid sequence, except for possibly naturally occurring mutations that may be present in trace amounts) antibodies and fragments at concentrations higher than those that would normally be present in nature (e.g., in the blood of a host organism such as a mouse or human).
[0636] In one implementation, p75 NTR Binding proteins, such as antibodies or antigen-binding fragments (which may optionally be conjugated to molecular cargo), comprise heavy-chain constant domains of, for example, IgA type (e.g., IgA1 or IgA2), IgD type, IgE type, IgG type (e.g., IgG1, IgG2, IgG3, and IgG4), or IgM type. In one embodiment, the antigen-binding protein (e.g., antibody or antigen-binding fragment) comprises, for example, a κ or λ type light-chain constant domain. In one embodiment, V, as listed herein... H Linked to human heavy chain constant domains (e.g., IgG), and as listed herein, V LConnected to constant structural domains (e.g., κ) of human light chains. This disclosure includes variable structural domains (e.g., REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN14175; REGN14176; REGN14148; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN14175; REGN14176; REGN14148; REGN14159; REGN14168 ... 77; REGN14178; REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517) are antigen-binding proteins that are linked to heavy chain and / or light chain constant domains, as shown herein.
[0637] This disclosure includes individuals that can be coupled with molecular cargo (p75). NTR Binding proteins. As used herein, the term "human" antigen-binding protein (such as antibodies or antigen-binding fragments) includes antibodies and fragments having human amino acid sequences, such as antibodies and fragments derived from variable and constant regions of human germline immunoglobulin sequences (whether in human cells or transplanted into non-human cells such as mouse cells). See, for example, U.S. Patent Nos. 8,502,018; 6,596,541 or 5,789,215. The anti-p75 described herein NTRHuman mAbs may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., those in CDRs and, particularly, CDR3) (e.g., mutations introduced through random or site-specific mutagenesis in vitro or through somatic mutations in vivo). However, as used herein, the term "human antibody" is not intended to include mAbs in which a germline CDR sequence derived from another mammalian species (e.g., mouse) has been grafted onto a human FR sequence. The term includes antibodies generated in or recombined in non-human mammals or in the cells of non-human mammals. The term is not intended to include naturally occurring antibodies isolated directly from human subjects. This disclosure includes human antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof, such as REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN141 75; REGN14176; REGN14177; REGN14178; REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517).
[0638] This disclosure includes anti-p75 NTRChimeric antigen-binding proteins, such as antibodies and their antigen-binding fragments (which may optionally be conjugated to molecular cargo), and their methods of use. As used herein, a “chimeric antibody” is an antibody having a variable domain from a first antibody and a constant domain from a second antibody, wherein the first and second antibodies are from different species. (See, for example, US4816567; and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81:6851-6855). This disclosure includes chimeric antibodies that contain the variable domains described herein (e.g., from REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN1417). 5; REGN14176; REGN14177; REGN14178; REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517) and non-human constant structural domains.
[0639] The term "recombination" (p. 75) NTRBinding proteins, such as antibodies or antigen-binding fragments thereof (which may optionally be conjugated to molecular cargo), refer to such molecules that are formed, expressed, isolated, or obtained by techniques or methods known in the art, such as recombinant DNA techniques, which include, for example, DNA splicing and transgenic expression. This term includes antibodies expressed in non-human mammals (including transgenic non-human mammals, e.g., transgenic mice) or cells (e.g., CHO cells) such as cell expression systems or isolated from recombinant human antibody libraries. This disclosure includes recombinant antigen-binding proteins, such as antibodies and antigen-binding fragments described herein (e.g., REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN14165; REGN14166; REGN14167; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN1416 ... 14175; REGN14176; REGN14177; REGN14178; REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517).
[0640] In one embodiment, the antigen-binding fragment of the antibody will contain a fragment smaller than the intact antibody but still specifically binding to the antigen (e.g., p75). NTR The structure may be combined, for example, containing at least one variable domain. The variable domain can have any size or amino acid composition and will typically contain at least one (e.g., three) CDRs adjacent to or within a frame carrying one or more framework sequences. In the presence of V... L V associated with the structural domain H In the antigen-binding fragment of the domain, V H and V L Domains can be arranged in any suitable arrangement relative to each other. For example, variable regions can be dimers and contain V. H -V H V H -V L or V L -V LDimer. Alternatively, the antigen-binding fragment of an antibody may contain a non-covalently bound monomer V. H and / or V L Structural domain.
[0641] In some embodiments, the antigen-binding fragment of the antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found within the antigen-binding fragment of the antibody described herein include: (i) V H -CH1;(ii)V H -CH2;(iii)V H -CH3;(iv)V H -CH1-CH2;(v)V H -CH1-CH2-CH3;(vi)V H -CH2-CH3;(vii)V H -CL;(viii)V L -CH1;(ix)V L -CH2;(x)V L -CH3;(xi)V L -CH1-CH2;(xii)V L -CH1-CH2-CH3;(xiii)V L -CH2-CH3; and (xiv)V L -CL. In any configuration of the variable and constant domains (including any of the exemplary configurations listed above), the variable and constant domains may be directly connected to each other or connected via full or partial hinge or linker regions. Hinge regions may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids, resulting in flexible or semi-flexible connections between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragments of the antibodies described herein may include the domains listed above and / or connected to one or more monomers V. H or V LHomodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations of non-covalently associated domains (e.g., via disulfide bonds). This disclosure includes antigen-binding fragments of antigen-binding proteins (e.g., antibodies) as described herein, such as REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REG N14175; REGN14176; REGN14177; REGN14178; REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517.
[0642] Antigen-binding proteins (e.g., antibodies and antigen-binding fragments) can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding proteins are further discussed herein. This disclosure includes monospecific and multispecific (e.g., bispecific) antigen-binding fragments comprising antigen-binding proteins specifically listed herein (e.g., REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165); One or more variable structural domains of REGN14175; REGN14176; REGN14177; REGN14178; REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517).
[0643] "Variants" of polypeptides, such as immunoglobulin chains (e.g., those containing the amino acid sequences specifically listed herein: REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN14165; REGN14166); REGN14167; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN1416 ... GN14175; REGN14176; REGN14177; REGN14178; REGN14179; REGN14180; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; V HV L SEQ ID NO: 2, 10, 18, 20, 22, 30, 38, 40, 42, 50, 54, 56, 58, 66, 74, 76, 78, 86, 94, 96, 98, 106, 112, 114, 116, 124, 132, 134, 136, 144, 151, 153, 155, 162, 169, 171, 173 179, 185, 187, 189, 197, 203, 205, 207, 215, 223, 225, 227, 235, 241, 243, 245, 251, 257, 259, 261, 269, 275, 277, 279, 287, 293, 295, 297, 304, 311, 313, 3 15, 323, 327, 329, 331, 339, 345, 347, 349, 357, 365, 367, 369, 377, 383, 385, 387, 391, 397, 399, 401, 409, 413, 415, 417, 425, 427, 435, 437, 443, 445, 453 (Any one of 455, 463, 465, 473, 475, 482, 484, 491, 493, 501, 503, 511, 513, 517, 519, 527, 529, 545, 547, 549, 565, 567, 569, 585, 587, 589, 605, 607, 609, or 617) At least approximately 70% to 99.9% (e.g., at least 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%, or 99.9%) of identical or similar amino acid sequences; (wherein the parameters of the algorithm are selected to achieve maximum matching between corresponding sequences across the entire length of the corresponding reference sequence (e.g., expected threshold: 10; word length: 3; maximum number of matches within the query range: 0; BLOSUM) 62 matrix; gap cost: exist 11, extend 1; conditional composition fraction matrix adjustment)), and / or a polypeptide containing the amino acid sequence but having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) mutations (e.g., point mutations, insertions, truncations and / or deletions).
[0644] In addition, variants of the polypeptide may include polypeptides such as immunoglobulin chains (e.g., REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN14 175; REGN14176; REGN14177; REGN14178; REGN14179; REGN14180; REGN14181; GN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; V H V L The polypeptide may contain the amino acid sequence of a reference polypeptide whose amino acid sequence is specifically listed herein, but contains one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) mutations, such as one or more missense mutations (e.g., conserved substitutions), nonsense mutations, deletions, or insertions. See Table 1-1. For example, this disclosure includes p75 containing the following items. NTR Binding protein: An immunoglobulin light chain (or V) containing the amino acid sequence listed in SEQ ID NO: 10 but having one or more of these mutations. L Variants, and / or immunoglobulin heavy chains (or V) containing the amino acid sequence listed in SEQ ID NO:2 but having one or more of these mutations. H (Variation). In one implementation, p75 NTR The binding protein includes the following: immunoglobulin light chain variants containing LCDR1, LCDR2, and LCDR3, wherein one or more of such CDRs (e.g., 1, 2, or 3) have one or more of such mutations (e.g., conserved substitutions); and / or immunoglobulin heavy chain variants containing HCDR1, HCDR2, and HCDR3, wherein one or more of such CDRs (e.g., 1, 2, or 3) have one or more of such mutations (e.g., conserved substitutions).
[0645] The following references relate to the BLAST algorithm commonly used in sequence analysis: BLAST ALGORITHMS: Altschul et al. (2005) FEBS J. 272(20): 5101-5109; Altschul, SF et al. (1990) J. Mol. Biol. 215: 403-410; Gish, W. et al. (1993) Nature Genet. 3: 266-272; Madden, TL et al. (1996) Meth. Enzymol. 266: 131-141; Altschul, SF 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, Supplement 3. MO Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, RM et al., "Matrices for detecting distant relationships." in Atlas of Protein Sequence and Structure, (1978) Vol. 5, Supplement 3. MO Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, D.C.; Altschul, SF, (1991) J. Mol. Biol. 219: 555-565; States, DJ et al., (1991) Methods 3: 66-70; Henikoff, S. et al., (1992) Proc. Natl. Acad. Sci. USA 89: 10915-10919; Altschul, SF et al., (1993) J. Mol. Evol. 36: 290-300; ALIGNMENT STATISTICS: Karlin, S. et al., (1990) Proc. Natl. Acad.Sci.USA 87:2264-2268; 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.
[0646] For example, the “conservatively modified variant” or “conservative substitution” of immunoglobulin chains listed herein refers to a variant in which one or more amino acids in the polypeptide are substituted with other amino acids having similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, ossicular structure, and stiffness). Such changes can generally be made without significantly impairing the biological activity of the antibody or fragment. Those skilled in the art will recognize that, in general, a single amino acid substitution in a non-essential region of a polypeptide does 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 edition). Furthermore, substitutions of structurally or functionally similar amino acids are unlikely to significantly impair biological activity. This disclosure includes p75 of immunoglobulin chains containing such conservedly modified variants. NTR Binding protein.
[0647] Examples of amino acid groups with side chains having 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: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine and methionine. Alternatively, conservative substitutions are any changes with positive values in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443-45.
[0648] Unless otherwise stated, “REGN14148”, “REGN14149”, “REGN14150”, “REGN14151”, “REGN14152”, “REGN14153”, “REGN14154”, “REGN14155”, “REGN14156”, “REGN14157”, “REGN14158”, “REGN14159”, “REGN14160”, “REGN14161”, “REGN14162”, “REGN14163”, “REGN14164”, “REGN14165”, “REGN14175”, “REGN14176” "REGN14177", "REGN14178", "REGN14179", "REGN14180", "REGN14181", "REGN14182", "REGN14183", "REGN14184", "REGN14185", "REGN14186", "REGN14187", "REGN14188", "REGN14189", "REGN14190", "REGN14191", "REGN19513", "REGN19514", "REGN19515", "REGN19516", and "REGN19517" refer to page 75. NTR Binding proteins, such as antibodies and their antigen-binding fragments (including multispecific antigen-binding proteins), which contain the variable region of the immunoglobulin heavy chain (V... H ) and immunoglobulin light chain variable region (V L), which respectively contain the specific entries shown in SEQ ID NO: 2&10; 22&30; 42&50; 58&66; 78&86; 98&106; 116&124; 136&144; 155&162; 173&179; 189&197; 207&215; 227&235; 245&251; 261&269; 279&287; 297&304; 315&323; 331&339; 349&357; 369&377; 387&391; 401&409; 417&409; 427&40 9; 437&409; 445&409; 455&409; 465&409; 475&409; 484&409; 493&409; 503&409; 513&409; 519&409; 529&537; 549&557; 569&577; 589&597; and 609&597 (or any variant thereof); or comprising the immunoglobulin heavy chain (HC) and immunoglobulin light chain (LC), said HC and LC comprising, respectively, as specifically shown in SEQ ID NO: 18&20; 38&40; 54&56; 74&76; 94&96; 112&114; 132&134; 151&153; 169&171; 185&187; 203&205; 223&225; 241&243; 257&259; 275&277; 293&295; 311&313; 327&329; 345&347; 365&367; 383&385; 397&399; 413&415; 425&415; 435&415; Amino acid sequence pairs in 443 & 415; 453 & 415; 463 & 415; 473 & 415; 482 & 415; 491 & 415; 501 & 415; 511 & 415; 517 & 415; 527 & 415; 545 & 547; 565 & 567; 585 & 587; 605 & 607; and 617 & 607 (or any variant thereof); or heavy chains containing their CDRs (HCDR1 (or a variant thereof), HCDR2 (or a variant thereof), and HCDR3 (or a variant thereof)) or V H And / or light chains or V containing their CDRs (LCDR1 (or variants thereof), LCDR2 (or variants thereof), and LCDR3 (or variants thereof)). L In one implementation scheme, V H Linked to the IgG constant heavy chain domain, such as the human IgG constant heavy chain domain (e.g., IgG1 or IgG4 (e.g., containing S228P and / or S108P mutations)) and / or V LConnected to a light chain constant domain, such as a human light chain constant domain (e.g., λ or κ constant light chain domain). Encodes one or more of any such immunoglobulin chains (e.g., V...). H V L Polynucleotides (HC and / or LC) are part of this disclosure.
[0649] The antibody and antigen binding fragments described herein (e.g., REGN14148; REGN14149; REGN14150; REGN14151; REGN14152; REGN14153; REGN14154; REGN14155; REGN14156; REGN14157; REGN14158; REGN14159; REGN14160; REGN14161; REGN14162; REGN14163; REGN14164; REGN14165; REGN14175; REGN14176; REGN14177; REGN14178) REGN14179; REGN14180; REGN14181; REGN14182; REGN14183; REGN14184; REGN14185; REGN14186; REGN14187; REGN14188; REGN14189; REGN14190; REGN14191; REGN19513; REGN19514; REGN19515; REGN19516; or REGN19517) contain immunoglobulin chains comprising the amino acid sequences (and variants thereof) specifically listed herein, as well as cellular and in vitro post-translational modifications to the antibody or fragment. For example, this disclosure includes modifications related to p75. NTR The antibody and its antigen-binding fragment that specifically bind, comprising the heavy chain and / or light chain amino acid sequences listed herein, wherein one or more asparagine, serine and / or threonine residues are glycosylated, one or more asparagine residues are deamidated, one or more residues (e.g., Met, Trp and / or His) are oxidized, the N-terminal glutamine is pyroglutamic acid (pyroE) and / or the C-terminal lysine or other amino acid is deleted.
[0650] This disclosure is on page 75. NTR binding protein or p75 NTR The amino acid sequences of the domains and chains of the protein-drug conjugates are summarized in Table 1-1 below. For example, the anti-p75 molecules including HCVR and LCVR in the molecules listed in Table 1-1... NTRAntibodies and their antigen-binding fragments (e.g., scFv and Fab); or including their CDRs, or including the HC and LC of molecules in Tables 1-1, optionally conjugated with molecular cargo, form part of this disclosure.
[0651] Table 1-1. SEQ ID NO of the amino acid sequences of the domains of the antibody or antigen-binding fragments (e.g., Fab or scFv molecules) or protein-drug conjugates disclosed herein.
[0652]
[0653] The anti-p75 described in this article NTR The amino acid and nucleotide sequences of the domains or chains of the antibody or antigen-binding fragment (e.g., Fab or scFv molecules) or protein-drug conjugate are as described below. p75 of this disclosure encodes... NTR The nucleotide sequences of the amino acid sequences of the domains or chains of the binding protein or protein-drug conjugate are also summarized in Tables 1-2. This disclosure includes any antibody or antigen-binding fragment thereof, including HCVRs and LCVRs having the sequences described below, or HCVRs and LCVRs having their HCDR and LCDR, respectively.
[0654] REGN14148
[0655] HCVR DNA sequence
[0656] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCGGCCTCTGGATTCACCTTTAATAACTATTGGATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGCCAGATGGAAGTGAG AAATCATATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAAATCACTGTTTCTGCAAATGACCAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGCGACGAACTGGGGTTTGACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[0657] (SEQ ID NO: 1)
[0658] HCVR amino acid sequence
[0659] EVQLVESGGGLVQPGGSLRLSCAASGFTFNNYWMSWIRQAPGKGLEWVANIKPDGSEKSYVDSVKGRFTISRDNAKKSLFLQMTSLRAEDTAVYYCATNWGFDWGQGTLVTVSS
[0660] (SEQ ID NO: 2)
[0661] CDR1 DNA sequence
[0662] GGA TTC ACC TTT AAT AAC TAT TGG
[0663] (SEQ ID NO: 3)
[0664] CDR1 amino acid sequence
[0665] GFTFNNYW
[0666] (SEQ ID NO: 4)
[0667] CDR2 DNA sequence
[0668] ATA AAG CCA GAT GGA AGT GAG AAA
[0669] (SEQ ID NO: 5)
[0670] CDR2 amino acid sequence
[0671] IKPDGSEK
[0672] (SEQ ID NO: 6)
[0673] CDR3 DNA sequence
[0674] GCG ACG AAC TGG GGG TTT GAC
[0675] (SEQ ID NO: 7)
[0676] CDR3 amino acid sequence
[0677] ATNWGFD
[0678] (SEQ ID NO: 8)
[0679] LCVR DNA sequence
[0680] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGACAGAGTCACCGTCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTAGGCTGGTTTCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGACTTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGTATAATAGTTACCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
[0681] (SEQ ID NO: 9)
[0682] LCVR amino acid sequence
[0683] DIQMTQSPSSLSASVGDRVTVTCRASQDIRNDLGWFQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYNSYPWTFGQGTKVEIK
[0684] (SEQ ID NO: 10)
[0685] CDR1 DNA sequence
[0686] CAG GAC ATT AGA AAT GAT
[0687] (SEQ ID NO: 11)
[0688] CDR1 amino acid sequence
[0689] Q D I R N D
[0690] (SEQ ID NO: 12)
[0691] CDR2 DNA sequence
[0692] GCT GCA TCC
[0693] (SEQ ID NO: 13)
[0694] CDR2 amino acid sequence
[0695] A A S
[0696] (SEQ ID NO: 14)
[0697] CDR3 DNA sequence
[0698] CTA CAG TAT AAT AGT TAC CCG TGG ACG
[0699] (SEQ ID NO: 15)
[0700] CDR3 amino acid sequence
[0701] LQYNSYPWT
[0702] (SEQ ID NO: 16)
[0703] HC DNA sequence
[0704]
[0705] (SEQ ID NO: 17)
[0706] HC amino acid sequence
[0707] EVQLVESGGGLVQPGGSLRLSCAASGFTFNNYWMSWIRQAPGKGLEWVANIKPDGSEKSYVDSVKGRFTISRDNAKKSLFLQMTSLRAEDTAVYYCATNWGFDWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[0708] (SEQ ID NO: 18)
[0709] LC DNA sequence
[0710] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTGGGAGACAGAGTCACCGTCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTAGGCTGGTTTCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGACTTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGTATAATAGTTACCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[0711] (SEQ ID NO: 19)
[0712] LC amino acid sequence
[0713] DIQMTQSPSSLSASVGDRVTVTCRASQDIRNDLGWFQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYNSYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[0714] (SEQ ID NO: 20)
[0715] REGN14149
[0716] HCVR DNA sequence
[0717] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTACCACCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGCTACTGGTAGTGGCACATACTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGAGAATTCCAAGAACACGCTGTATCTGCAAATGAAAAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGTGAAAGGTCCGTATAGTAACAGCCGGAACGTGGGCTTCCAGCACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA
[0718] (SEQ ID NO: 21)
[0719] HCVR amino acid sequence
[0720] EVQLVESGGGLVQPGGSLRLSCAASGFTFTTYAMSWVRQAPGKGLEWVSAISATGSGTYYADSVKGRFTISRENSKNTLYLQMKSLRAEDTAVYYCVKGPYSNSRNVGFQHWGQGTLVTVSS
[0721] (SEQ ID NO: 22)
[0722] CDR1 DNA sequence
[0723] GGA TTC ACC TTT ACC ACC TAT GCC
[0724] (SEQ ID NO: 23)
[0725] CDR1 amino acid sequence
[0726] G F T F T T Y A
[0727] (SEQ ID NO: 24)
[0728] CDR2 DNA sequence
[0729] ATT AGT GCT ACT GGT AGT GGC ACA
[0730] (SEQ ID NO: 25)
[0731] CDR2 amino acid sequence
[0732] I S A T G S G T
[0733] (SEQ ID NO: 26)
[0734] CDR3 DNA sequence
[0735] GTG AAA GGT CCG TAT AGT AAC AGC CGG AAC GTG GGC TTC CAG CAC
[0736] (SEQ ID NO: 27)
[0737] CDR3 amino acid sequence
[0738] V K G P Y S N S R N V G F Q H
[0739] (SEQ ID NO: 28)
[0740] LCVR DNA sequence
[0741] GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTACATAGTAATGGATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAACTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTTCTGCATGCAACATCTACAAACTCCCATGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
[0742] (SEQ ID NO: 29)
[0743] LCVR amino acid sequence
[0744] DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCMQHLQTPMYTFGQGTKLEIK
[0745] (SEQ ID NO: 30)
[0746] CDR1 DNA sequence
[0747] CAG AGC CTC CTA CAT AGT AAT GGA TAC AAC TAT
[0748] (SEQ ID NO: 31)
[0749] CDR1 amino acid sequence
[0750] QSLLHSNGYNY
[0751] (SEQ ID NO: 32)
[0752] CDR2 DNA sequence
[0753] TTG GGT TCT
[0754] (SEQ ID NO: 33)
[0755] CDR2 amino acid sequence
[0756] LGS
[0757] (SEQ ID NO: 34)
[0758] CDR3 DNA sequence
[0759] ATG CAA CAT CTA CAA ACT CCC ATG TAC ACT
[0760] (SEQ ID NO: 35)
[0761] CDR3 amino acid sequence
[0762] MQHLQTPMYT
[0763] (SEQ ID NO: 36)
[0764] HC DNA sequence
[0765]
[0766] (SEQ ID NO: 37)
[0767] HC amino acid sequence
[0768] EVQLVESGGGLVQPGGSLRLSCAASGFTFTTYAMSWVRQAPGKGLEWVSAISATGSGTYYADSVKGRFTISRENSKNTLYLQMKSLRAEDTAVYYCVKGPYSNSRNVGFQHWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[0769] (SEQ ID NO: 38)
[0770] LC DNA sequence
[0771] GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTACATAGTAATGGATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAACTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTTCTGCATGCAACATCTACAAACTCCCATGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[0772] (SEQ ID NO: 39)
[0773] LC amino acid sequence
[0774] DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCMQHLQTPMYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[0775] (SEQ ID NO: 40)
[0776] REGN14150
[0777] HCVR DNA sequence
[0778] CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAAGTCTCCTGTAAGGCTTCTGGTTACACCTTTAGTAGCCATGGTATCACCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTATAATGGTGACACAAACTATGCACAGAAAGTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGTACAGCCTACATGGAACTGAGGAGCCTGAGATCTGACGACACGGCCGTGTTTTACTGTGCGCGATATAGGGGAATAGTAGGTCGTAATTACAACTACTATGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
[0779] (SEQ ID NO: 41)
[0780] HCVR amino acid sequence
[0781] QVQLVQSGAEVKKPGASVKVSCKASGYTFSSHGITWVRQAPGQGLEWMGWISAYNGDTNYAQKVQGRVTMTTDTSTSTAYMELRSLRSDDTAVFYCARYRGIVGRNYNYYGMDVWGQGTTVTVSS
[0782] (SEQ ID NO: 42)
[0783] CDR1 DNA sequence
[0784] GGT TAC ACC TTT AGT AGC CAT GGT
[0785] (SEQ ID NO: 43)
[0786] CDR1 amino acid sequence
[0787] G Y T F S S H G
[0788] (SEQ ID NO: 44)
[0789] CDR2 DNA sequence
[0790] ATC AGC GCT TAT AAT GGT GAC ACA
[0791] (SEQ ID NO: 45)
[0792] CDR2 amino acid sequence
[0793] I S A Y N G D T
[0794] (SEQ ID NO: 46)
[0795] CDR3 DNA sequence
[0796] GCG CGA TAT AGG GGA ATA GTA GGT CGT AAT TAC AAC TAC TAT GGT ATG GACGTC
[0797] (SEQ ID NO: 47)
[0798] CDR3 amino acid sequence
[0799] A R Y R G I V G R N Y N Y Y G M D V
[0800] (SEQ ID NO: 48)
[0801] LCVR DNA sequence
[0802] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGAGAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATGTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCACCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCCCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
[0803] (SEQ ID NO: 49)
[0804] LCVR amino acid sequence
[0805] DIQMTQSPSSSLSASVGERVTITCRASQDIRNDLGWYQQKPGKAPKRLMYAASSLQSGVPSRFSGSGSGTEFTLTISTLQPEDFATYYCLQHNSYPLTFGGGTKVEIK
[0806] (SEQ ID NO: 50)
[0807] CDR1 DNA sequence
[0808] CAG GAC ATT AGA AAT GAT
[0809] (SEQ ID NO: 11)
[0810] CDR1 amino acid sequence
[0811] QDIRND
[0812] (SEQ ID NO: 12)
[0813] CDR2 DNA sequence
[0814] GCT GCA TCC
[0815] (SEQ ID NO: 13)
[0816] CDR2 amino acid sequence
[0817] AAS
[0818] (SEQ ID NO: 14)
[0819] CDR3 DNA sequence
[0820] CTA CAG CAT AAT AGT TAC CCC CTC ACT
[0821] (SEQ ID NO: 51)
[0822] CDR3 amino acid sequence
[0823] LQHNSYPLT
[0824] (SEQ ID NO: 52)
[0825] HC DNA sequence
[0826]
[0827] (SEQ ID NO: 53)
[0828] HC amino acid sequence
[0829] QVQLVQSGAEVKKPGASVKVSCKASGYTFSSHGITWVRQAPGQGLEWMGWISAYNGDTNYAQKVQGRVTMTTDTSTSTAYMELRSLRSDDTAVFYCARYRGIVGRNYNYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[0830] (SEQ ID NO: 54)
[0831] LC DNA sequence
[0832] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGAGAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATGTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCACCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCCCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[0833] (SEQ ID NO: 55)
[0834] LC amino acid sequence
[0835] DIQMTQSPSSLSASVGERVTITCRASQDIRNDLGWYQQKPGKAPKRLMYAASSLQSGVPSRFSGSGSGTEFTLTISTLQPEDFATYYCLQHNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[0836] (SEQ ID NO: 56)
[0837] REGN14151
[0838] HCVR DNA sequence
[0839] CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCTTCTCCGGGGACAGTGTCTCTAGGAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAAGTGGTATAATGATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCAGACACAGCCAAGAACCAGTTCTCCCTGCAGCTGAAATCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGAGGGGCCCTATTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[0840] (SEQ ID NO: 57)
[0841] HCVR amino acid sequence
[0842] QVQLQQSGPGLVKPSQTLSLTCAFSGDSVSRNSAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTAKNQFSLQLKSVTPEDTAVYYCAREGPYFDYWGQGTLVTVSS
[0843] (SEQ ID NO: 58)
[0844] CDR1 DNA sequence
[0845] GGG GAC AGT GTC TCT AGG AAC AGT GCT GCT
[0846] (SEQ ID NO: 59)
[0847] CDR1 amino acid sequence
[0848] G D S V S R N S A A
[0849] (SEQ ID NO: 60)
[0850] CDR2 DNA sequence
[0851] ACA TAC TAC AGG TCC AAG TGG TAT AAT
[0852] (SEQ ID NO: 61)
[0853] CDR2 amino acid sequence
[0854] TYYRSKWYN
[0855] (SEQ ID NO: 62)
[0856] CDR3 DNA sequence
[0857] GCA AGA GAG GGG CCC TAT TTT GAC TAC
[0858] (SEQ ID NO: 63)
[0859] CDR3 amino acid sequence
[0860] AREGPYFDY
[0861] (SEQ ID NO: 64)
[0862] LCVR DNA sequence
[0863] GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTACACAGCTCCAACAATATGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGTTGCTCATTTACTGGG CATCTACCCGGAAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTTCAGGCTGCTGATGTGGCAGTTTATTACTGTCTGCAATATTATAATACTCCTCGAACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
[0864] (SEQ ID NO: 65)
[0865] LCVR amino acid sequence
[0866] DIVMTQSPDSLAVSLGERATINCKSSQSVLHSSNNMNYLAWYQQKPGQPPKLLIYWASTRKSGVPDRFSGSGSGTDFTLTISSLQAADVAVYYCLQYYNTPRTFGQGTKVEIK
[0867] (SEQ ID NO: 66)
[0868] CDR1 DNA sequence
[0869] CAG AGT GTT TTA CAC AGC TCC AAC AAT ATG AAC TAC
[0870] (SEQ ID NO: 67)
[0871] CDR1 amino acid sequence
[0872] QSVLHSSNNMNY
[0873] (SEQ ID NO: 68)
[0874] CDR2 DNA sequence
[0875] TGG GCA TCT
[0876] (SEQ ID NO: 69)
[0877] CDR2 amino acid sequence
[0878] WAS
[0879] (SEQ ID NO: 70)
[0880] CDR3 DNA sequence
[0881] CTG CAA TAT TAT AAT ACT CCT CGA ACG
[0882] (SEQ ID NO: 71)
[0883] CDR3 amino acid sequence
[0884] LQYYNTPRT
[0885] (SEQ ID NO: 72)
[0886] HC DNA sequence
[0887]
[0888] (SEQ ID NO: 73)
[0889] HC amino acid sequence
[0890] QVQLQQSGPGLVKPSQTLSLTCAFSGDSVSRNSAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTAKNQFSLQLKSVTPEDTAVYYCAREGPYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[0891] (SEQ ID NO: 74)
[0892] LC DNA sequence
[0893] GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTACACAGCTCCAACAATATGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGTTGCTCATTTACTGGGCATCTACCCGGAAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTTCAGGCTGCTGATGTGGCAGTTTATTACTGTCTGCAATATTATAATACTCCTCGAACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[0894] (SEQ ID NO: 75)
[0895] LC amino acid sequence
[0896] DIVMTQSPDSLAVSLGERATINCKSSQSVLHSSNNMNYLAWYQQKPGQPPKLLIYWASTRKSGVPDRFSGSGSGTDFTLTISSLQAADVAVYYCLQYYNTPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[0897] (SEQ ID NO: 76)
[0898] REGN14152
[0899] HCVR DNA sequence
[0900] GAGGTGCAGCTGGTGGAGTCTGAGGGAGGCTGGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATCACCTTTAGCATCTATGCCATGGCCTGGGTCCGCCAGGCTCCAGGGAAGGGACTTGAGTGGGTCTCAACTATTAGTGGTAGTGGTGATTCCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTTTCTGCAAATGAACAGCCTGAGAGCCGTGGACACGGCCATATATTACTGTGCGAAAAGAGGATTTGCAGCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[0901] (SEQ ID NO: 77)
[0902] HCVR amino acid sequence
[0903] EVQLVESEGGWVQPGGSLRLSCAASGITFSIYAMAWVRQAPGKGLEWVSTISGSGDSTYYADSVKGRFTISRDNSKNTLFLQMNSLRAVDTAIYYCAKRGFAAFDYWGQGTLVTVSS
[0904] (SEQ ID NO: 78)
[0905] CDR1 DNA sequence
[0906] GGA ATC ACC TTT AGC ATC TAT GCC
[0907] (SEQ ID NO: 79)
[0908] CDR1 amino acid sequence
[0909] G I T F S I Y A
[0910] (SEQ ID NO: 80)
[0911] CDR2 DNA sequence
[0912] ATT AGT GGT AGT GGT GAT TCC ACA
[0913] (SEQ ID NO: 81)
[0914] CDR2 amino acid sequence
[0915] I S G S G D S T
[0916] (SEQ ID NO: 82)
[0917] CDR3 DNA sequence
[0918] GCG AAA AGA GGA TTT GCA GCT TTT GAC TAC
[0919] (SEQ ID NO: 83)
[0920] CDR3 amino acid sequence
[0921] A K R G F A A F D Y
[0922] (SEQ ID NO: 84)
[0923] LCVR DNA sequence
[0924] GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGTAGGGCCAGTCAGAGTGTTAGCAGCACCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGTCTCCCAGGCTCCTCATCTATGGTGCATCAAACAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCACGTCTGCTCAGTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
[0925] (SEQ ID NO: 85)
[0926] LCVR amino acid sequence
[0927] EIVLTQSPGTLSLSPGERATLSCRASQSVSSTYLAWYQQKPGQSPRLLIYGASNRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSRLLSFGGGTKVEIK
[0928] (SEQ ID NO: 86)
[0929] CDR1 DNA sequence
[0930] CAG AGT GTT AGC AGC ACC TAC
[0931] (SEQ ID NO: 87)
[0932] CDR1 amino acid sequence
[0933] QSVSSTY
[0934] (SEQ ID NO: 88)
[0935] CDR2 DNA sequence
[0936] GGT GCA TCA
[0937] (SEQ ID NO: 89)
[0938] CDR2 amino acid sequence
[0939] GAS
[0940] (SEQ ID NO: 90)
[0941] CDR3 DNA sequence
[0942] CAG CAG TAT GGT AGC TCA CGT CTG CTC AGT
[0943] (SEQ ID NO: 91)
[0944] CDR3 amino acid sequence
[0945] QQYGSSRLLS
[0946] (SEQ ID NO: 92)
[0947] HC DNA sequence
[0948]
[0949] (SEQ ID NO: 93)
[0950] HC amino acid sequence
[0951] EVQLVESEGGWVQPGGSLRLSCAASGITFSIYAMAWVRQAPGKGLEWVSTISGSGDSTYYADSVKGRFTISRDNSKNTLFLQMNSLRAVDTAIYYCAKRGFAAFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[0952] (SEQ ID NO: 94)
[0953] LC DNA sequence
[0954] GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGTAGGGCCAGTCAGAGTGTTAGCAGCACCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGTCTCCCAGGCTCCTCATCTATGGTGCATCAAACAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCACGTCTGCTCAGTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[0955] (SEQ ID NO: 95)
[0956] LC amino acid sequence
[0957] EIVLTQSPGTLSLSPGERATLSCRASQSVSSTYLAWYQQKPGQSPRLLIYGASNRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSRLLSFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[0958] (SEQ ID NO: 96)
[0959] REGN14153
[0960] HCVR DNA sequence
[0961] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTAGTTATGCCATGAACTGGGTCCGCCAGGCTCCAGGGGAGGGCCTGGAGTGGGTCTCAACTTTGACTGGTAGTGGTGGTAGTACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTTTCTGCACATGAGCAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGGTGGAGTGGGATCTACTAAGGTTGTCTACTACGGTTTGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
[0962] (SEQ ID NO: 97)
[0963] HCVR amino acid sequence
[0964] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGEGLEWVSTLTGSGGSTYYADSVKGRFTISRDNSKNTLFLHMSSLRAEDTAVYYCAKGGVGSTKVVYYGLDVWGQGTTVTVSS
[0965] (SEQ ID NO: 98)
[0966] CDR1 DNA sequence
[0967] GGA TTC ACC TTT AGT AGT TAT GCC
[0968] (SEQ ID NO: 99)
[0969] CDR1 amino acid sequence
[0970] G F T F S S Y A
[0971] (SEQ ID NO: 100)
[0972] CDR2 DNA sequence
[0973] TTG ACT GGT AGT GGT GGT AGT ACA
[0974] (SEQ ID NO: 101)
[0975] CDR2 amino acid sequence
[0976] L T G S G G S T
[0977] (SEQ ID NO: 102)
[0978] CDR3 DNA sequence
[0979] GCG AAA GGT GGA GTG GGA TCT ACT AAG GTT GTC TAC TAC GGT TTG GAC GTC
[0980] (SEQ ID NO: 103)
[0981] CDR3 amino acid sequence
[0982] A K G G V G S T K V V Y Y G L D V
[0983] (SEQ ID NO: 104)
[0984] LCVR DNA sequence
[0985] GATATTGTGATGACTCAGTCTCCACTTTCCCTGCCCGTCATCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATCGTAATGGATACAACTTTTTGGATTGGTACCTGCGGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACAAACTCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
[0986] (SEQ ID NO: 105)
[0987] LCVR amino acid sequence
[0988] DIVMTQSPLSLPVIPGEPASISCRSSQSLLHRNGYNFLDWYLRKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPLTFGGGTKVEIK
[0989] (SEQ ID NO: 106)
[0990] CDR1 DNA sequence
[0991] CAG AGC CTC CTG CAT CGT AAT GGA TAC AAC TTT
[0992] (SEQ ID NO: 107)
[0993] CDR1 amino acid sequence
[0994] QSLLHRNGYNF
[0995] (SEQ ID NO: 108)
[0996] CDR2 DNA sequence
[0997] TTG GGT TCT
[0998] (SEQ ID NO: 33)
[0999] CDR2 amino acid sequence
[1000] LGS
[1001] (SEQ ID NO: 34)
[1002] CDR3 DNA sequence
[1003] ATG CAA GCT CTA CAA ACT CCG CTC ACT
[1004] (SEQ ID NO: 109)
[1005] CDR3 amino acid sequence
[1006] MQALQTPLT
[1007] (SEQ ID NO: 110)
[1008] HC DNA sequence
[1009]
[1010] (SEQ ID NO: 111)
[1011] HC amino acid sequence
[1012] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGEGLEWVSTLTGSGGSTYYADSVKGRFTISRDNSKNTLFLHMSSLRAEDTAVYYCAKGGVGSTKVVYYGLDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1013] (SEQ ID NO: 112)
[1014] LC DNA sequence
[1015] GATATTGTGATGACTCAGTCTCCACTTTCCCTGCCCGTCATCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATCGTAATGGATACAACTTTTTGGATTGGTACCTGCGGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGCTCTACAAACTCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1016] (SEQ ID NO: 113)
[1017] LC amino acid sequence
[1018] DIVMTQSPLSLPVIPGEPASISCRSSQSLLHRNGYNFLDWYLRKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1019] (SEQ ID NO: 114)
[1020] REGN14154
[1021] HCVR DNA sequence
[1022] CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACTTGCACTGTCTCGGGTGGCTCCAGCAGCAGAAGTAGTTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGAGTATCTATTATAGTGGGAACACCTACTACAACCCGTCCCTCCAGAGTCGAGTCACCATATCCGTAGACACGTCCAAGAACCAGTTCTCCCTGAAACTGAACTCTGTGACCGCCGCAGACACGGCTGTATTTTATTGTGCGAGACACAAACCTACTACGTGGGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
[1023] (SEQ ID NO: 115)
[1024] HCVR amino acid sequence
[1025] QLQLQESGPGLVKPSETLSLTCTVSGGSSSRSSYYWGWIRQPPGKGLEWIGSIYYSGNTYYNPSLQSRVTISVDTSKNQFSLKLNSVTAADTAVFYCARHKPTTWAFDIWGQGTMVTVSS
[1026] (SEQ ID NO: 116)
[1027] CDR1 DNA sequence
[1028] GGT GGC TCC AGC AGC AGA AGT AGT TAC TAC
[1029] (SEQ ID NO: 117)
[1030] CDR1 amino acid sequence
[1031] G G S S S R S S Y Y
[1032] (SEQ ID NO: 118)
[1033] CDR2 DNA switch
[1034] ATC TAT TAT AGT GGG AAC ACC
[1035] (SEQ ID NO: 119)
[1036] CDR2 switchboard
[1037] IYYSGNT
[1038] (SEQ ID NO: 120)
[1039] CDR3 DNA switch
[1040] GCG AGA CAC AAA CCT ACT ACG TGG GCT TTT GAT ATC
[1041] (SEQ ID NO: 121)
[1042] CDR3 switchboard
[1043] ARHKPTTWAFDI
[1044] (SEQ ID NO: 122)
[1045] LCVR DNA switch
[1046] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATCAGTAGTTGGCCTGGTATCAGCAGAAACCAGGGAAAGTCCCAAAGTTGCTGATCTATAAGGCGTCTAATT TAGAAAGTGGGGTCCCCTCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCGACCTGCAGCCTGATGATTTTGCAAGTTATTACTGCCAACAGTATAGTACTTATTCTCGGACGTTCGGCCGAGGGACCAAGGTGGAGATCAAA
[1047] (SEQ ID NO: 123)
[1048] LCVR amino acid sequence
[1049] DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKVPKLLIYKASNLESGVPSRFSGSGSGTEFTLTISDLQPDDFASYYCQQYSTYSRTFGRGTKVEIK
[1050] (SEQ ID NO: 124)
[1051] CDR1 DNA sequence
[1052] CAG AGT ATC AGT AGT TGG
[1053] (SEQ ID NO: 125)
[1054] CDR1 amino acid sequence
[1055] QSISSW
[1056] (SEQ ID NO: 126)
[1057] CDR2 DNA sequence
[1058] AAG GCG TCT
[1059] (SEQ ID NO: 127)
[1060] CDR2 amino acid sequence
[1061] KAS
[1062] (SEQ ID NO: 128)
[1063] CDR3 DNA sequence
[1064] CAA CAG TAT AGT ACT TAT TCT CGG ACG
[1065] (SEQ ID NO: 129)
[1066] CDR3 amino acid sequence
[1067] QQYSTYSRT
[1068] (SEQ ID NO: 130)
[1069] HC DNA sequence
[1070]
[1071] (SEQ ID NO: 131)
[1072] HC amino acid sequence
[1073] QLQLQESGPGLVKPSETLSLTCTVSGGSSSRSSYYWGWIRQPPGKGLEWIGSIYYSGNTYYNPSLQSRVTISVDTSKNQFSLKLNSVTAADTAVFYCARHKPTTWAFDIWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1074] (SEQ ID NO: 132)
[1075] LC DNA sequence
[1076] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATCAGTAGTTGGTTGGCCTGGTATCAGCAGAAACCAGGGAAAGTCCCAAAGTTGCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTCCCCTCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCGACCTGCAGCCTGATGATTTTGCAAGTTATTACTGCCAACAGTATAGTACTTATTCTCGGACGTTCGGCCGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1077] (SEQ ID NO: 133)
[1078] LC amino acid sequence
[1079] DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKVPKLLIYKASNLESGVPSRFSGSGSGTEFTLTISDLQPDDFASYYCQQYSTYSRTFGRGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1080] (SEQ ID NO: 134)
[1081] REGN14155
[1082] HCVR DNA sequence
[1083] CAGGTTCAGCTGGTGCAGTCTGGAGGTGAGGTGAAGAAGCCTGGGGACTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTATGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGTCTACAGTGGTAAAAAAAACTACGCACGGAAGGTCCAGGACAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGGTGAGGAGCCTGCGATCTGACGACACGGCCATATATTATTGTACAAGAAGGGGAGTGTCTTCGATGGTCGGTGCTTTTGAAATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA
[1084] (SEQ ID NO: 135)
[1085] HCVR amino acid sequence
[1086] QVQLVQSGGEVKKPGDSVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISVYSGKKNYARKVQDRVTMTTDTSTSTAYMEVRSLRSDDTAIYYCTRRGVSSMVGAFEIWGQGTMVTVSS
[1087] (SEQ ID NO: 136)
[1088] CDR1 DNA sequence
[1089] GGT TAC ACC TTT ACC AGC TAT GGT
[1090] (SEQ ID NO: 137)
[1091] CDR1 amino acid sequence
[1092] G Y T F T S Y G
[1093] (SEQ ID NO: 138)
[1094] CDR2 DNA sequence
[1095] ATC AGC GTC TAC AGT GGT AAA AAA
[1096] (SEQ ID NO: 139)
[1097] CDR2 amino acid sequence
[1098] I S V Y S G K K
[1099] (SEQ ID NO: 140)
[1100] CDR3 DNA sequence
[1101] ACA AGA AGG GGA GTG TCT TCG ATG GTC GGT GCT TTT GAA ATC
[1102] (SEQ ID NO: 141)
[1103] CDR3 amino acid sequence
[1104] T R R G V S S M V G A F E I
[1105] (SEQ ID NO: 142)
[1106] LCVR DNA sequence
[1107] GAAATTGTGTTGACGCAGTCTCCAGGCATTCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAAGGCCAGTCAGAGTGTTAGCAACAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGAGCATCTAGTAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTGTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTCTATTACTGTCAGCAGTATGGTAGCTCACCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
[1108] (SEQ ID NO: 143)
[1109] LCVR amino acid sequence
[1110] EIVLTQSPGILSLSPGERATLSCKASQSVSNSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTVTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIK
[1111] (SEQ ID NO: 144)
[1112] CDR1 DNA sequence
[1113] CAG AGT GTT AGC AAC AGC TAC
[1114] (SEQ ID NO: 145)
[1115] CDR1 amino acid sequence
[1116] QSVSNSY
[1117] (SEQ ID NO: 146)
[1118] CDR2 DNA sequence
[1119] GGA GCA TCT
[1120] (SEQ ID NO: 147)
[1121] CDR2 amino acid sequence
[1122] GAS
[1123] (SEQ ID NO: 90)
[1124] CDR3 DNA sequence
[1125] CAG CAG TAT GGT AGC TCA CCG CTC ACT
[1126] (SEQ ID NO: 148)
[1127] CDR3 amino acid sequence
[1128] QQYGSSPLT
[1129] (SEQ ID NO: 149)
[1130] HC DNA sequence
[1131]
[1132] (SEQ ID NO: 150)
[1133] HC amino acid sequence
[1134] QVQLVQSGGEVKKPGDSVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISVYSGKKNYARKVQDRVTMTTDTSTSTAYMEVRSLRSDDTAIYYCTRRGVSSMVGAFEIWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1135] (SEQ ID NO: 151)
[1136] LC DNA sequence
[1137] GAAATTGTGTTGACGCAGTCTCCAGGCATTCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAAGGCCAGTCAGAGTGTTAGCAACAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGAGCATCTAGTAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTGTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTCTATTACTGTCAGCAGTATGGTAGCTCACCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1138] (SEQ ID NO: 152)
[1139] LC amino acid sequence
[1140] EIVLTQSPGILSLSPGERATLSCKASQSVSNSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTVTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1141] (SEQ ID NO: 153)
[1142] REGN14156
[1143] HCVR DNA sequence
[1144] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGAGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAACTATTAGTGGTAGTGGTGGTAACACATACTACGCAGTCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACACTTCCAAGAACACGCTGTATCTGCAAATGAACGGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGACCCTCACCAGTGGCTGGTACCTTTTTGAGTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[1145] (SEQ ID NO: 154)
[1146] HCVR amino acid sequence
[1147] EVQLVESGGGLVQPGESLRLSCAASGFTFSSYAMTWVRQAPGKGLEWVSTISGSGGNTYYAVSVKGRFTISRDTSKNTLYLQMNGLRAEDTAVYYCATLTSGWYLFEYWGQGTLVTVSS
[1148] (SEQ ID NO: 155)
[1149] CDR1 DNA sequence
[1150] GGA TTC ACC TTT AGC AGC TAT GCC
[1151] (SEQ ID NO: 156)
[1152] CDR1 amino acid sequence
[1153] G F T F S S Y A
[1154] (SEQ ID NO: 100)
[1155] CDR2 DNA sequence
[1156] ATT AGT GGT AGT GGT GGT AAC ACA
[1157] (SEQ ID NO: 157)
[1158] CDR2 amino acid sequence
[1159] I S G S G G N T
[1160] (SEQ ID NO: 158)
[1161] CDR3 DNA sequence
[1162] GCG ACC CTC ACC AGT GGC TGG TAC CTT TTT GAG TAC
[1163] (SEQ ID NO: 159)
[1164] CDR3 amino acid sequence
[1165] A T L T S G W Y L F E Y
[1166] (SEQ ID NO: 160)
[1167] LCVR DNA sequence
[1168] GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGGCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTTCTTTGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGAAGCTCACCTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
[1169] (SEQ ID NO: 161)
[1170] LCVR amino acid sequence
[1171] EIVLTQSPGTLSLAPGERATLSCRASQSVSSSFFAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPPWTFGQGTKVEIK
[1172] (SEQ ID NO: 162)
[1173] CDR1 DNA sequence
[1174] CAG AGT GTT AGC AGC AGC TTC
[1175] (SEQ ID NO: 163)
[1176] CDR1 amino acid sequence
[1177] QSVSSSF
[1178] (SEQ ID NO: 164)
[1179] CDR2 DNA sequence
[1180] GGT GCA TCC
[1181] (SEQ ID NO: 165)
[1182] CDR2 amino acid sequence
[1183] GAS
[1184] (SEQ ID NO: 90)
[1185] CDR3 DNA sequence
[1186] CAG CAG TAT GGA AGC TCA CCT CCG TGG ACG
[1187] (SEQ ID NO: 166)
[1188] CDR3 amino acid sequence
[1189] QQYGSSPPWT
[1190] (SEQ ID NO: 167)
[1191] HC DNA sequence
[1192]
[1193] (SEQ ID NO: 168)
[1194] HC amino acid sequence
[1195] EVQLVESGGGLVQPGESLRLSCAASGFTFSSYAMTWVRQAPGKGLEWVSTISGSGGNTYYAVSVKGRFTISRDTSKNTLYLQMNGLRAEDTAVYYCATLTSGWYLFEYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1196] (SEQ ID NO: 169)
[1197] LC DNA sequence
[1198] GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGGCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTTCTTTGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGAAGCTCACCTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1199] (SEQ ID NO: 170)
[1200] LC amino acid sequence
[1201] EIVLTQSPGTLSLAPGERATLSCRASQSVSSSFFAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1202] (SEQ ID NO: 171)
[1203] REGN14157
[1204] HCVR DNA sequence
[1205] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGGTAGTGGTGATAACACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGTCGAGGATACGGCCGTATATTATTGTGCGAAAGAGAAGAGCAGTGGCTGGTACGAATACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[1206] (SEQ ID NO: 172)
[1207] HCVR amino acid sequence
[1208] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGDNTYYADSVKGRFTISRDNSKNTLYLQMNSLRVEDTAVYYCAKEKSSGWYEYWGQGTLVTVSS
[1209] (SEQ ID NO: 173)
[1210] CDR1 DNA sequence
[1211] GGA TTC ACC TTT AGC AGC TAT GCC
[1212] (SEQ ID NO: 156)
[1213] CDR1 amino acid sequence
[1214] G F T F S S Y A
[1215] (SEQ ID NO: 100)
[1216] CDR2 DNA sequence
[1217] ATT AGT GGT AGT GGT GAT AAC ACA
[1218] (SEQ ID NO: 174)
[1219] CDR2 amino acid sequence
[1220] I S G S G D N T
[1221] (SEQ ID NO: 175)
[1222] CDR3 DNA sequence
[1223] GCG AAA GAG AAG AGC AGT GGC TGG TAC GAA TAC
[1224] (SEQ ID NO: 176)
[1225] CDR3 amino acid sequence
[1226] A K E K S S G W Y E Y
[1227] (SEQ ID NO: 177)
[1228] LCVR DNA sequence
[1229] GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGTTCCAACAATAAGAATTACTTAGCTTGGTACCAGCAGAAACCAGGACAGACTCCTAAACTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATTTTATTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
[1230] (SEQ ID NO: 178)
[1231] LCVR amino acid sequence
[1232] DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQTPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYFIPYTFGQGTKLEIK
[1233] (SEQ ID NO: 179)
[1234] CDR1 DNA sequence
[1235] CAG AGT GTT TTA TAC AGT TCC AAC AAT AAG AAT TAC
[1236] (SEQ ID NO: 180)
[1237] CDR1 amino acid sequence
[1238] QSVLYSSNNKNY
[1239] (SEQ ID NO: 181)
[1240] CDR2 DNA sequence
[1241] TGG GCA TCT
[1242] (SEQ ID NO: 69)
[1243] CDR2 amino acid sequence
[1244] WAS
[1245] (SEQ ID NO: 70)
[1246] CDR3 DNA sequence
[1247] CAG CAA TAT TAT TTT ATT CCG TAC ACT
[1248] (SEQ ID NO: 182)
[1249] CDR3 amino acid sequence
[1250] QQYYFIPYT
[1251] (SEQ ID NO: 183)
[1252] HC DNA sequence
[1253]
[1254] (SEQ ID NO: 184)
[1255] HC amino acid sequence
[1256] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGDNTYYADSVKGRFTISRDNSKNTLYLQMNSLRVEDTAVYYCAKEKSSGWYEYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1257] (SEQ ID NO: 185)
[1258] LC DNA sequence
[1259] GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGTTCCAACAATAAGAATTACTTAGCTTGGTACCAGCAGAAACCAGGACAGACTCCTAAACTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATTTTATTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1260] (SEQ ID NO: 186)
[1261] LC amino acid sequence
[1262] DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQTPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYFIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1263] (SEQ ID NO: 187)
[1264] REGN14158
[1265] HCVR DNA sequence
[1266] CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGATGGCAGTTATATCATATGATGGAAGTAACAAATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAGGAACACGCTGTATCTGCAAATGAACAGCCTGAGAACTGAGGACACGGCTGTGTTTTATTGTGCGAAAGAGTCGAGTATAACAGCCCGTCCGAGAGACTACAACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
[1267] (SEQ ID NO: 188)
[1268] HCVR amino acid sequence
[1269] QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYGMHWVRQAPGKGLEWMAVISYDGSNKYYADSVKGRFTISRDNSRNTLYLQMNSLRTEDTAVFYCAKESSITARPRDYNYGMDVWGQGTTVTVSS
[1270] (SEQ ID NO: 189)
[1271] CDR1 DNA sequence
[1272] GGA TTC ACC TTC AGT CAC TAT GGC
[1273] (SEQ ID NO: 190)
[1274] CDR1 amino acid sequence
[1275] G F T F S H Y G
[1276] (SEQ ID NO: 191)
[1277] CDR2 DNA sequence
[1278] ATA TCA TAT GAT GGA AGT AAC AAA
[1279] (SEQ ID NO: 192)
[1280] CDR2 amino acid sequence
[1281] I S Y D G S N K
[1282] (SEQ ID NO: 193)
[1283] CDR3 DNA sequence
[1284] GCG AAA GAG TCG AGT ATA ACA GCC CGT CCG AGA GAC TAC AAC TAC GGT ATGGAC GTC
[1285] (SEQ ID NO: 194)
[1286] CDR3 amino acid sequence
[1287] A K E S S I T A R P R D Y N Y G M D V
[1288] (SEQ ID NO: 195)
[1289] LCVR DNA sequence
[1290] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCGGCTATTTAAATTGGTTTCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTAATCTATGCTGCATCCACTTTGCAAACTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCATCATCAGCAGTCTGCAGCCTGACGATTTTGCAACTTACCACTGTCAACAGAGTTACACTTCCCCTTTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA
[1291] (SEQ ID NO: 196)
[1292] LCVR amino acid sequence
[1293] DIQMTQSPSSSLSASVGDRVTITCRASQSISGYLNWFQQKPGKAPKLLIYAASTLQTGVPSRFSGSGSGTDFTLIISSLQPDDFATYHCQQSYTSPFTFGPGTKVDIK
[1294] (SEQ ID NO: 197)
[1295] CDR1 DNA sequence
[1296] CAG AGC ATT AGC GGC TAT
[1297] (SEQ ID NO: 198)
[1298] CDR1 amino acid sequence
[1299] QSISGY
[1300] (SEQ ID NO: 199)
[1301] CDR2 DNA sequence
[1302] GCT GCA TCC
[1303] (SEQ ID NO: 13)
[1304] CDR2 amino acid sequence
[1305] AAS
[1306] (SEQ ID NO: 14)
[1307] CDR3 DNA sequence
[1308] CAA CAG AGT TAC ACT TCC CCT TTC ACT
[1309] (SEQ ID NO: 200)
[1310] CDR3 amino acid sequence
[1311] QQSYTSPFT
[1312] (SEQ ID NO: 201)
[1313] HC DNA sequence
[1314]
[1315] (SEQ ID NO: 202)
[1316] HC amino acid sequence
[1317] QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYGMHWVRQAPGKGLEWMAVISYDGSNKYYADSVKGRFTISRDNSRNTLYLQMNSLRTEDTAVFYCAKESSITARPRDYNYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1318] (SEQ ID NO: 203)
[1319] LC DNA sequence
[1320] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCGGCTATTTAAATTGGTTTCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTAATCTATGCTGCATCCACTTTGCAAACTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCATCATCAGCAGTCTGCAGCCTGACGATTTTGCAACTTACCACTGTCAACAGAGTTACACTTCCCCTTTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1321] (SEQ ID NO: 204)
[1322] LC amino acid sequence
[1323] DIQMTQSPSSLSASVGDRVTITCRASQSISGYLNWFQQKPGKAPKLLIYAASTLQTGVPSRFSGSGSGTDFTLIISSLQPDDFATYHCQQSYTSPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1324] (SEQ ID NO: 205)
[1325] REGN14159
[1326] HCVR DNA sequence
[1327] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGCACAGCGGGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCGACTATGCCGTGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGGTATTAGCCGTGGTGGTGATTACACGTACTACGCAGACTCCGTGAAGGGCCGGTTCATCATCTCCAGAGACAATTCCAAGAATATGTTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTATTGTGCGAAAAACTGGGGATCACTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[1328] (SEQ ID NO: 206)
[1329] HCVR amino acid sequence
[1330] EVQLVESGGGLAQRGGSLRLSCAASGFTFSDYAVSWVRQAPGKGLEWVSGISRGGDYTYYADSVKGRFIISRDNSKNMLYLQMNSLRAEDTAVYYCAKNWGSLDYWGQGTLVTVSS
[1331] (SEQ ID NO: 207)
[1332] CDR1 DNA sequence
[1333] GGA TTC ACC TTT AGC GAC TAT GCC
[1334] (SEQ ID NO: 208)
[1335] CDR1 amino acid sequence
[1336] G F T F S D Y A
[1337] (SEQ ID NO: 209)
[1338] CDR2 DNA sequence
[1339] ATT AGC CGT GGT GGT GAT TAC ACG
[1340] (SEQ ID NO: 210)
[1341] CDR2 amino acid sequence
[1342] I S R G G D Y T
[1343] (SEQ ID NO: 211)
[1344] CDR3 DNA sequence
[1345] GCG AAA AAC TGG GGA TCA CTT GAC TAC
[1346] (SEQ ID NO: 212)
[1347] CDR3 amino acid sequence
[1348] A K N W G S L D Y
[1349] (SEQ ID NO: 213)
[1350] LCVR DNA sequence
[1351] GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTATGATGCATCCAACAGGGTCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCGAACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
[1352] (SEQ ID NO: 214)
[1353] LCVR amino acid sequence
[1354] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRVTGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPRTFGQGTKLEIK
[1355] (SEQ ID NO: 215)
[1356] CDR1 DNA sequence
[1357] CAG AGT GTT AGC AGC TAC
[1358] (SEQ ID NO: 216)
[1359] CDR1 amino acid sequence
[1360] QSVSSY
[1361] (SEQ ID NO: 217)
[1362] CDR2 DNA sequence
[1363] GAT GCA TCC
[1364] (SEQ ID NO: 218)
[1365] CDR2 amino acid sequence
[1366] DAS
[1367] (SEQ ID NO: 219)
[1368] CDR3 DNA sequence
[1369] CAG CAG CGT AGC AAC TGG CCT CGA ACT
[1370] (SEQ ID NO: 220)
[1371] CDR3 amino acid sequence
[1372] QQRSNWPRT
[1373] (SEQ ID NO: 221)
[1374] HC DNA sequence
[1375]
[1376] (SEQ ID NO: 222)
[1377] HC amino acid sequence
[1378] EVQLVESGGGLAQRGGSLRLSCAASGFTFSDYAVSWVRQAPGKGLEWVSGISRGGDYTYYADSVKGRFIISRDNSKNMLYLQMNSLRAEDTAVYYCAKNWGSLDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1379] (SEQ ID NO: 223)
[1380] LC DNA sequence
[1381] GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTATGATGCATCCAACAGGGTCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCGAACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1382] (SEQ ID NO: 224)
[1383] LC amino acid sequence
[1384] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRVTGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPRTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1385] (SEQ ID NO: 225)
[1386] REGN14160
[1387] HCVR DNA sequence
[1388] CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTTACTATGTCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAATGGGTGACAGTTATATCATATGATGGAACTAAGAAACACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACCTTGTATCTGCAAATGAACAGCCTGAGAGCTGACGACACGGCTGTGTATTACTGTGCGAAAACGCATAGTACGTCATCCAGGGCCGACTACTTCTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
[1389] (SEQ ID NO: 226)
[1390] HCVR amino acid sequence
[1391] QVQLVESGGGVVQPGRSLRLSCAASGFTFSYYVMHWVRQAPGKGLEWVTVISYDGTKKHYADSVKGRFTISRDNSKNTLYLQMNSLRADDTAVYYCAKTHSTSSRADYFYGMDVWGQGTTVTVSS
[1392] (SEQ ID NO: 227)
[1393] CDR1 DNA sequence
[1394] GGA TTC ACC TTC AGT TAC TAT GTC
[1395] (SEQ ID NO: 228)
[1396] CDR1 amino acid sequence
[1397] G F T F S Y Y V
[1398] (SEQ ID NO: 229)
[1399] CDR2 DNA sequence
[1400] ATA TCA TAT GAT GGA ACT AAG AAA
[1401] (SEQ ID NO: 230)
[1402] CDR2 amino acid sequence
[1403] I S Y D G T K K
[1404] (SEQ ID NO: 231)
[1405] CDR3 DNA sequence
[1406] GCG AAA ACG CAT AGT ACG TCA TCC AGG GCC GAC TAC TTC TAC GGT ATG GACGTC
[1407] (SEQ ID NO: 232)
[1408] CDR3 amino acid sequence
[1409] A K T H S T S S R A D Y F Y G M D V
[1410] (SEQ ID NO: 233)
[1411] LCVR DNA sequence
[1412] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTCAGTTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCTCCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
[1413] (SEQ ID NO: 234)
[1414] LCVR amino acid sequence
[1415] DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPQFLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTLLTFGGGTKVEIK
[1416] (SEQ ID NO: 235)
[1417] CDR1 DNA sequence
[1418] CAG AGC ATT AGC AGC TAT
[1419] (SEQ ID NO: 236)
[1420] CDR1 amino acid sequence
[1421] QSISSY
[1422] (SEQ ID NO: 237)
[1423] CDR2 DNA sequence
[1424] GCT GCA TCC
[1425] (SEQ ID NO: 13)
[1426] CDR2 amino acid sequence
[1427] AAS
[1428] (SEQ ID NO: 14)
[1429] CDR3 DNA sequence
[1430] CAA CAG AGT TAC AGT ACC CTC CTC ACT
[1431] (SEQ ID NO: 238)
[1432] CDR3 amino acid sequence
[1433] QQSYSTLLT
[1434] (SEQ ID NO: 239)
[1435] HC DNA sequence
[1436]
[1437] (SEQ ID NO: 240)
[1438] HC amino acid sequence
[1439] QVQLVESGGGVVQPGRSLRLSCAASGFTFSYYVMHWVRQAPGKGLEWVTVISYDGTKKHYADSVKGRFTISRDNSKNTLYLQMNSLRADDTAVYYCAKTHSTSSRADYFYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1440] (SEQ ID NO: 241)
[1441] LC DNA sequence
[1442] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTCAGTTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCTCCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1443] (SEQ ID NO: 242)
[1444] LC amino acid sequence
[1445] DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPQFLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTLLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1446] (SEQ ID NO: 243)
[1447] REGN14161
[1448] HCVR DNA sequence
[1449] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAACTATTAATACTAATGGTGGTAGCACATTCTTCGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCATATATTACTGTGCGAAAGAAAAACGGGGCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
[1450] (SEQ ID NO: 244)
[1451] HCVR amino acid sequence
[1452] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMTWVRQAPGKGLEWVSTINTNGGSTFFADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCAKEKRGGMDVWGQGTTVTVSS
[1453] (SEQ ID NO: 245)
[1454] CDR1 DNA sequence
[1455] GGA TTC ACC TTT AGC AGC TAT GCC
[1456] (SEQ ID NO: 156)
[1457] CDR1 amino acid sequence
[1458] G F T F S S Y A
[1459] (SEQ ID NO: 100)
[1460] CDR2 DNA sequence
[1461] ATT AAT ACT AAT GGT GGT AGC ACA
[1462] (SEQ ID NO: 246)
[1463] CDR2 amino acid sequence
[1464] I N T N G G S T
[1465] (SEQ ID NO: 247)
[1466] CDR3 DNA sequence
[1467] GCG AAA GAA AAA CGG GGC GGT ATG GAC GTC
[1468] (SEQ ID NO: 248)
[1469] CDR3 amino acid sequence
[1470] A K E K R G G M D V
[1471] (SEQ ID NO: 249)
[1472] LCVR DNA sequence
[1473] GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATATGGCTCCAACAAAAAGAACTACTTAGCTTGGTACCAACAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGTAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTACTCTCACGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
[1474] (SEQ ID NO: 250)
[1475] LCVR amino acid sequence
[1476] DIVMTQSPDSLAVSLGERATINCKSSQSVLYGSNKKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTLTWTFGQGTKVEIK
[1477] (SEQ ID NO: 251)
[1478] CDR1 DNA sequence
[1479] CAG AGT GTT TTA TAT GGC TCC AAC AAA AAG AAC TAC
[1480] (SEQ ID NO: 252)
[1481] CDR1 amino acid sequence
[1482] QSVLYGSNKKNY
[1483] (SEQ ID NO: 253)
[1484] CDR2 DNA sequence
[1485] TGG GCA TCT
[1486] (SEQ ID NO: 69)
[1487] CDR2 amino acid sequence
[1488] WAS
[1489] (SEQ ID NO: 70)
[1490] CDR3 DNA sequence
[1491] CAG CAA TAT TAT AGT ACT CTC ACG TGG ACG
[1492] (SEQ ID NO: 254)
[1493] CDR3 amino acid sequence
[1494] QQYYSTLTWT
[1495] (SEQ ID NO: 255)
[1496] HC DNA sequence
[1497]
[1498] (SEQ ID NO: 256)
[1499] HC amino acid sequence
[1500] EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMTWVRQAPGKGLEWVSTINTNGGSTFFADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCAKEKRGGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1501] (SEQ ID NO: 257)
[1502] LC DNA sequence
[1503] GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATATGGCTCCAACAAAAAGAACTACTTAGCTTGGTACCAACAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGTAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTACTCTCACGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1504] (SEQ ID NO: 258)
[1505] LC amino acid sequence
[1506] DIVMTQSPDSLAVSLGERATINCKSSQSVLYGSNKKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTLTWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1507] (SEQ ID NO: 259)
[1508] REGN14162
[1509] HCVR DNA sequence
[1510] CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTTTCTGGTGACTCCATCAGTACTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGAAAGGGACTGGAGTGGATTGGGTTTTTCCATTACAGTGGGAGCAGCAAATACAAGCCCTCCCTCAAGAGTCGAGTCACCATATCACTAGACACGTCCAAGAATCAGTTCTCCCTGAACCTGCGGTCTGTGACCGCTGCGGACACGGCCGTGTATTATTGTGCGAGATTAGGCTGGGGATTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[1511] (SEQ ID NO: 260)
[1512] HCVR amino acid sequence
[1513] QVQLQESGPGLVKPSETLSLTCTVSGDSISTYYWSWIRQPPGKGLEWIGFFHYSGSSKYKPSLKSRVTISLDTSKNQFSLNLRSVTAADTAVYYCARLGWGFDYWGQGTLVTVSS
[1514] (SEQ ID NO: 261)
[1515] CDR1 DNA sequence
[1516] GGT GAC TCC ATC AGT ACT TAC TAC
[1517] (SEQ ID NO: 262)
[1518] CDR1 amino acid sequence
[1519] G D S I S T Y Y
[1520] (SEQ ID NO: 263)
[1521] CDR2 DNA sequence
[1522] TTC CAT TAC AGT GGG AGC AGC
[1523] (SEQ ID NO: 264)
[1524] CDR2 amino acid sequence
[1525] FHYSGSS
[1526] (SEQ ID NO: 265)
[1527] CDR3 DNA sequence
[1528] GCG AGA TTA GGC TGG GGA TTT GAC TAC
[1529] (SEQ ID NO: 266)
[1530] CDR3 amino acid sequence
[1531] ARLGWGFDY
[1532] (SEQ ID NO: 267)
[1533] LCVR DNA sequence
[1534] GAAATTGTGTTGACGCAGTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGC AGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCAGCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA
[1535] (SEQ ID NO: 268)
[1536] LCVR amino acid sequence
[1537] EIVLTQSPGTLSLSPGERATLSCRASQSVSSNYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSAFTFGPGTKVDIK
[1538] (SEQ ID NO: 269)
[1539] CDR1 DNA sequence
[1540] CAG AGT GTT AGC AGC AAC TAC
[1541] (SEQ ID NO: 270)
[1542] CDR1 amino acid sequence
[1543] QSVSSNY
[1544] (SEQ ID NO: 271)
[1545] CDR2 DNA sequence
[1546] GGT GCA TCC
[1547] (SEQ ID NO: 165)
[1548] CDR2 amino acid sequence
[1549] GAS
[1550] (SEQ ID NO: 90)
[1551] CDR3 DNA sequence
[1552] CAG CAG TAT GGT AGC TCA GCA TTC ACT
[1553] (SEQ ID NO: 272)
[1554] CDR3 amino acid sequence
[1555] QQYGSSAFT
[1556] (SEQ ID NO: 273)
[1557] HC DNA sequence
[1558]
[1559] (SEQ ID NO: 274)
[1560] HC amino acid sequence
[1561] QVQLQESGPGLVKPSETLSLTCTVSGDSISTYYWSWIRQPPGKGLEWIGFFHYSGSSKYKPSLKSRVTISLDTSKNQFSLNLRSVTAADTAVYYCARLGWGFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1562] (SEQ ID NO: 275)
[1563] LC DNA sequence
[1564] GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCAGCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1565] (SEQ ID NO: 276)
[1566] LC amino acid sequence
[1567] EIVLTQSPGTLSLSPGERATLSCRASQSVSSNYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSAFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1568] (SEQ ID NO: 277)
[1569] REGN14163
[1570] HCVR DNA sequence
[1571] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTAACTATTGGATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGCAAGATGGAAGTGAGAAGTACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGACGTGGATACACCTATGGCAGCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[1572] (SEQ ID NO: 278)
[1573] HCVR amino acid sequence
[1574] EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMNWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRGYTYGSFDYWGQGTLVTVSS
[1575] (SEQ ID NO: 279)
[1576] CDR1 DNA sequence
[1577] GGA TTC ACC TTT AGT AAC TAT TGG
[1578] (SEQ ID NO: 280)
[1579] CDR1 amino acid sequence
[1580] G F T F S N Y W
[1581] (SEQ ID NO: 281)
[1582] CDR2 DNA switch
[1583] ATA AAG CAA GAT YOU ARE GOING TO BE AWAY
[1584] (SEQ ID NO: 282)
[1585] CDR2 switchboard
[1586] IKQDGSEC
[1587] (SEQ ID NO: 283)
[1588] CDR3 DNA switch
[1589] GCG AGA CGT GGA TAC ACC TAT GGC AGC TTT GAC TAC
[1590] (SEQ ID NO: 284)
[1591] CDR3 switchboard
[1592] ARRGYTYGSFDY
[1593] (SEQ ID NO: 285)
[1594] LCVR DNA switch
[1595] GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGCGTCAGGGTTTTAGCATCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGGTCCTGATCTATGCTGCATCCACTT TGCAGAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTTTTTGTCAACAGGCTAACAGTTTCCCTCCCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA
[1596] (SEQ ID NO: 286)
[1597] LCVR license plate
[1598] DIQMTQSPSSVSASVGDRVTITCRARQGFSIWLAWYQQKPGKAPKVLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPPTFGGGTKVEIK
[1599] (SEQ ID NO: 287)
[1600] CDR1 DNA sequence
[1601] CAG GGT TTT AGC ATC TGG
[1602] (SEQ ID NO: 288)
[1603] CDR1 amino acid sequence
[1604] QGFSIW
[1605] (SEQ ID NO: 289)
[1606] CDR2 DNA sequence
[1607] GCT GCA TCC
[1608] (SEQ ID NO: 13)
[1609] CDR2 amino acid sequence
[1610] AAS
[1611] (SEQ ID NO: 14)
[1612] CDR3 DNA sequence
[1613] CAA CAG GCT AAC AGT TTC CCT CCC ACT
[1614] (SEQ ID NO: 290)
[1615] CDR3 amino acid sequence
[1616] QQANSFPPT
[1617] (SEQ ID NO: 291)
[1618] HC DNA sequence
[1619]
[1620] (SEQ ID NO: 292)
[1621] HC amino acid sequence
[1622] EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMNWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRGYTYGSFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1623] (SEQ ID NO: 293)
[1624] LC DNA sequence
[1625] GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGCGTCAGGGTTTTAGCATCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGGTCCTGATCTATGCTGCATCCACTTTGCAGAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCTCCCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1626] (SEQ ID NO: 294)
[1627] LC amino acid sequence
[1628] DIQMTQSPSSVSASVGDRVTITCRARQGFSIWLAWYQQKPGKAPKVLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPPTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1629] (SEQ ID NO: 295)
[1630] REGN14164
[1631] HCVR DNA sequence
[1632] CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAACTATGGCATGTACTGGGTCCGCCAGGCTCCAGGCAAGGGTCTGGAGTGGGTGTCAATTATATCATATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCAGCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGGTGAGGACACGGCTGTGTATTACTGTGCGAAAGATAGAGGAGCTGGAACTACAGCCTTCCACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
[1633] (SEQ ID NO: 296)
[1634] HCVR amino acid sequence
[1635] QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVSIISYDGSNKYYADSVKGRFTSSRDNSKNTLYLQMNSLRGEDTAVYYCAKDRGAGTTAFHYGMDVWGQGTTVTVSS
[1636] (SEQ ID NO: 297)
[1637] CDR1 DNA sequence
[1638] GGA TTC ACC TTC AGT AAC TAT GGC
[1639] (SEQ ID NO: 298)
[1640] CDR1 amino acid sequence
[1641] G F T F S N Y G
[1642] (SEQ ID NO: 299)
[1643] CDR2 DNA sequence
[1644] ATA TCA TAT GAT GGA AGT AAT AAA
[1645] (SEQ ID NO: 300)
[1646] CDR2 amino acid sequence
[1647] I S Y D G S N K
[1648] (SEQ ID NO: 193)
[1649] CDR3 DNA sequence
[1650] GCG AAA GAT AGA GGA GCT GGA ACT ACA GCC TTC CAC TAC GGT ATG GAC GTC
[1651] (SEQ ID NO: 301)
[1652] CDR3 amino acid sequence
[1653] A K D R G A G T T A F H Y G M D V
[1654] (SEQ ID NO: 302)
[1655] LCVR DNA sequence
[1656] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGTTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGGTCCTGATCTATGCTGCATTCAGTTTGCAAAGTGGGGTCCCTTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTAACTATCAGTAGCCTGCAACCTGAGGATTTCGCAACTTACTATTGTCACCAGACTTATAGTGTTCCTCCGATCACCTTCGGCCAAGGGACCAAGCTGGAGATCAAA
[1657] (SEQ ID NO: 303)
[1658] LCVR amino acid sequence
[1659] DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKVLIYAAFSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQTYSVPPITFGQGTKLEIK
[1660] (SEQ ID NO: 304)
[1661] CDR1 DNA sequence
[1662] CAG AGC ATT AGC AGT TAT
[1663] (SEQ ID NO: 305)
[1664] CDR1 amino acid sequence
[1665] QSISSY
[1666] (SEQ ID NO: 237)
[1667] CDR2 DNA sequence
[1668] GCT GCA TTC
[1669] (SEQ ID NO: 306)
[1670] CDR2 amino acid sequence
[1671] AAF
[1672] (SEQ ID NO: 307)
[1673] CDR3 DNA sequence
[1674] CAC CAG ACT TAT AGT GTT CCT CCG ATC ACC
[1675] (SEQ ID NO: 308)
[1676] CDR3 amino acid sequence
[1677] HQTYSVPPIT
[1678] (SEQ ID NO: 309)
[1679] HC DNA sequence
[1680]
[1681] (SEQ ID NO: 310)
[1682] HC amino acid sequence
[1683] QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMYWVRQAPGKGLEWVSIISYDGSNKYYADSVKGRFTSSRDNSKNTLYLQMNSLRGEDTAVYYCAKDRGAGTTAFHYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1684] (SEQ ID NO: 311)
[1685] LC DNA sequence
[1686] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGTTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGGTCCTGATCTATGCTGCATTCAGTTTGCAAAGTGGGGTCCCTTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTAACTATCAGTAGCCTGCAACCTGAGGATTTCGCAACTTACTATTGTCACCAGACTTATAGTGTTCCTCCGATCACCTTCGGCCAAGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1687] (SEQ ID NO: 312)
[1688] LC amino acid sequence
[1689] DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKVLIYAAFSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQTYSVPPITFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1690] (SEQ ID NO: 313)
[1691] REGN14165
[1692] HCVR DNA sequence
[1693] CAGGTTCAGCTGGTGCAGTCTGGAGGTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAACTATGGAATCAGCTGGATACGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGGTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGACCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTATATTTCTGTGCGAGAGATCGGGGACAACTGGATCGAGGAGGAAACTACTACTTCTACATTATGAGCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
[1694] (SEQ ID NO: 314)
[1695] HCVR amino acid sequence
[1696] QVQLVQSGGEVKKPGASVKVSCKASGYTFTNYGISWIRQAPGQGLEWMGWISAYNGNTNYAQKVQGRVTMTTDTSTTTAYMELRSLRSDDTAVYFCARDRGQLDRGGNYYFYIMSVWGQGTTVTVSS
[1697] (SEQ ID NO: 315)
[1698] CDR1 DNA sequence
[1699] GGT TAC ACC TTT ACC AAC TAT GGA
[1700] (SEQ ID NO: 316)
[1701] CDR1 amino acid sequence
[1702] G Y T F T N Y G
[1703] (SEQ ID NO: 317)
[1704] CDR2 DNA sequence
[1705] ATC AGC GCT TAC AAT GGT AAC ACA
[1706] (SEQ ID NO: 318)
[1707] CDR2 amino acid sequence
[1708] I S A Y N G N T
[1709] (SEQ ID NO: 319)
[1710] CDR3 DNA sequence
[1711] GCG AGA GAT CGG GGA CAA CTG GAT CGA GGA GGA AAC TAC TAC TTC TAC ATTATG AGC GTC
[1712] (SEQ ID NO: 320)
[1713] CDR3 amino acid sequence
[1714] A R D R G Q L D R G G N Y Y F Y I M S V
[1715] (SEQ ID NO: 321)
[1716] LCVR DNA sequence
[1717] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTAATCTATGCTGCATCCAATTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAGTAGTTACCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
[1718] (SEQ ID NO: 322)
[1719] LCVR amino acid sequence
[1720] DIQMTQSPSSSLSASVGDRVTITCRASQDIRNDLGWYQQKPGKAPKRLIYAASNLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHSSYPWTFGQGTKVEIK
[1721] (SEQ ID NO: 323)
[1722] CDR1 DNA sequence
[1723] CAG GAC ATT AGA AAT GAT
[1724] (SEQ ID NO: 11)
[1725] CDR1 amino acid sequence
[1726] QDIRND
[1727] (SEQ ID NO: 12)
[1728] CDR2 DNA sequence
[1729] GCT GCA TCC
[1730] (SEQ ID NO: 13)
[1731] CDR2 amino acid sequence
[1732] AAS
[1733] (SEQ ID NO: 14)
[1734] CDR3 DNA sequence
[1735] CTA CAG CAT AGT AGT TAC CCG TGG ACG
[1736] (SEQ ID NO: 324)
[1737] CDR3 amino acid sequence
[1738] LQHSSYPWT
[1739] (SEQ ID NO: 325)
[1740] HC DNA sequence
[1741]
[1742] (SEQ ID NO: 326)
[1743] HC amino acid sequence
[1744] QVQLVQSGGEVKKPGASVKVSCKASGYTFTNYGISWIRQAPGQGLEWMGWISAYNGNTNYAQKVQGRVTMTTDTSTTTAYMELRSLRSDDTAVYFCARDRGQLDRGGNYYFYIMSVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1745] (SEQ ID NO: 327)
[1746] LC DNA sequence
[1747] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTAATCTATGCTGCATCCAATTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAGTAGTTACCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1748] (SEQ ID NO: 328)
[1749] LC amino acid sequence
[1750] DIQMTQSPSSLSASVGDRVTITCRASQDIRNDLGWYQQKPGKAPKRLIYAASNLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHSSYPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1751] (SEQ ID NO: 329)
[1752] REGN14175
[1753] HCVR DNA sequence
[1754] CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGATTCAGTAGTTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTCATTTCATATGATGGAAGTGATAAATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTTTATATGCAAATGAACAGACTGAAAAGTGAGGACACGGCTGTTTATTATTGTGCGAAAGAGAGAAGTACAGCAGCTCGTCGGGGGGACTACTACGACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
[1755] (SEQ ID NO: 330)
[1756] HCVR amino acid sequence
[1757] QVQLVESGGGVVQPGRSLRLSCAASGFRFSSYGMHWVRQAPGKGLEWVAVISYDGSDKYYADSVKGRFTISRDNSKNTLYMQMNRLKSEDTAVYYCAKERSTAARRGDYYDYGMDVWGQGTTVTVSS
[1758] (SEQ ID NO: 331)
[1759] CDR1 DNA sequence
[1760] GGA TTC AGA TTC AGT AGT TAT GGC
[1761] (SEQ ID NO: 332)
[1762] CDR1 amino acid sequence
[1763] G F R F S S Y G
[1764] (SEQ ID NO: 333)
[1765] CDR2 DNA sequence
[1766] ATT TCA TAT GAT GGA AGT GAT AAA
[1767] (SEQ ID NO: 334)
[1768] CDR2 amino acid sequence
[1769] I S Y D G S D K
[1770] (SEQ ID NO: 335)
[1771] CDR3 DNA sequence
[1772] GCG AAA GAG AGA AGT ACA GCA GCT CGT CGG GGG GAC TAC TAC GAC TAC GGTATG GAC GTC
[1773] (SEQ ID NO: 336)
[1774] CDR3 amino acid sequence
[1775] A K E R S T A A R R G D Y Y D Y G M D V
[1776] (SEQ ID NO: 337)
[1777] LCVR DNA sequence
[1778] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTTTGCATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCACCAGAAACCAGGGAGAGCCCCTAAACTCCTGATCTTTGCTTCATTCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGAACAGATTTCACTCTCACCATCAGCAGTGTGGAACCTGAAGATTTTGCATCTTACTACTGTCAACAGAGTTACAGTACCCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA
[1779] (SEQ ID NO: 338)
[1780] LCVR amino acid sequence
[1781] DIQMTQSPSSLFASVGDRVTITCRASQSISSYLNWYHQKPGRAPKLLIFASFSLQSGVPSRFSGSGSGTDFTLTISSVEPEDFASYYCQQSYSTPFTFGPGTKVDIK
[1782] (SEQ ID NO: 339)
[1783] CDR1 DNA sequence
[1784] CAG AGC ATT AGC AGC TAT
[1785] (SEQ ID NO: 236)
[1786] CDR1 amino acid sequence
[1787] QSISSY
[1788] (SEQ ID NO: 237)
[1789] CDR2 DNA sequence
[1790] GCT TCA TTC
[1791] (SEQ ID NO: 340)
[1792] CDR2 amino acid sequence
[1793] ASF
[1794] (SEQ ID NO: 341)
[1795] CDR3 DNA sequence
[1796] CAA CAG AGT TAC AGT ACC CCA TTC ACT
[1797] (SEQ ID NO: 342)
[1798] CDR3 amino acid sequence
[1799] QQSYSTPFT
[1800] (SEQ ID NO: 343)
[1801] HC DNA sequence
[1802]
[1803] (SEQ ID NO: 344)
[1804] HC amino acid sequence
[1805] QVQLVESGGGVVQPGRSLRLSCAASGFRFSSYGMHWVRQAPGKGLEWVAVISYDGSDKYYADSVKGRFTISRDNSKNTLYMQMNRLKSEDTAVYYCAKERSTAARRGDYYDYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1806] (SEQ ID NO: 345)
[1807] LC DNA sequence
[1808] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTTTGCATCTGTGGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCACCAGAAACCAGGGAGAGCCCCTAAACTCCTGATCTTTGCTTCATTCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGAACAGATTTCACTCTCACCATCAGCAGTGTGGAACCTGAAGATTTTGCATCTTACTACTGTCAACAGAGTTACAGTACCCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1809] (SEQ ID NO: 346)
[1810] LC amino acid sequence
[1811] DIQMTQSPSSLFASVGDRVTITCRASQSISSYLNWYHQKPGRAPKLLIFASFSLQSGVPSRFSGSGSGTDFTLTISSVEPEDFASYYCQQSYSTPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1812] (SEQ ID NO: 347)
[1813] REGN14176
[1814] HCVR DNA sequence
[1815] CAGGTTCAGCTGGTGCAGTCTGGAACTGAGGTGAAGAAGCCTGGGGCCTCAGTGACGGTCTCCTGCAAGGCTTCTGGTTACACTTTTACCAGCTATAGTGTCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACGCTTACAATGGTGACACAAACTATGCACAGAGGTTCCACGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTATATGGACTTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCGGATAAGTGGAACCTTAGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[1816] (SEQ ID NO: 348)
[1817] HCVR amino acid sequence
[1818] QVQLVQSGTEVKKPGASVTVSCKASGYTFTSYSVSWVRQAPGQGLEWMGWINAYNGDTNYAQRFHGRVTMTTDTSTSTAYMDLRSLRSDDTAVYYCARDRISGTLDYWGQGTLVTVSS
[1819] (SEQ ID NO: 349)
[1820] CDR1 DNA sequence
[1821] GGT TAC ACT TTT ACC AGC TAT AGT
[1822] (SEQ ID NO: 350)
[1823] CDR1 amino acid sequence
[1824] G Y T F T S Y S
[1825] (SEQ ID NO: 351)
[1826] CDR2 DNA sequence
[1827] ATC AAC GCT TAC AAT GGT GAC ACA
[1828] (SEQ ID NO: 352)
[1829] CDR2 amino acid sequence
[1830] I N A Y N G D T
[1831] (SEQ ID NO: 353)
[1832] CDR3 DNA sequence
[1833] GCG AGA GAT CGG ATA AGT GGA ACC TTA GAC TAC
[1834] (SEQ ID NO: 354)
[1835] CDR3 amino acid sequence
[1836] A R D R I S G T L D Y
[1837] (SEQ ID NO: 355)
[1838] LCVR DNA sequence
[1839] GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGTCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGTAATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCACGGCGCCTATTTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCATTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGATTTTATTACTGCATGCAAGGTACACACTGGCCTCGGACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
[1840] (SEQ ID NO: 356)
[1841] LCVR amino acid sequence
[1842] DVVMTQSPLSLPVTLGQSASISCRSSQSLVYSNGNTYLNWFQQRPGQSPRRLFYKVSNRDSGVPDRFSGIGSGTDFTLKISRVEAEDVGFYYCMQGTHWPRTFGQGTKLEIK
[1843] (SEQ ID NO: 357)
[1844] CDR1 DNA sequence
[1845] CAA AGC CTC GTA TAC AGT AAT GGA AAC ACC TAC
[1846] (SEQ ID NO: 358)
[1847] CDR1 amino acid sequence
[1848] QSLVYSNGNTY
[1849] (SEQ ID NO: 359)
[1850] CDR2 DNA sequence
[1851] AAG GTT TCT
[1852] (SEQ ID NO: 360)
[1853] CDR2 amino acid sequence
[1854] KVS
[1855] (SEQ ID NO: 361)
[1856] CDR3 DNA sequence
[1857] ATG CAA GGT ACA CAC TGG CCT CGG ACT
[1858] (SEQ ID NO: 362)
[1859] CDR3 amino acid sequence
[1860] MQGTHWPRT
[1861] (SEQ ID NO: 363)
[1862] HC DNA sequence
[1863]
[1864] (SEQ ID NO: 364)
[1865] HC amino acid sequence
[1866] QVQLVQSGTEVKKPGASVTVSCKASGYTFTSYSVSWVRQAPGQGLEWMGWINAYNGDTNYAQRFHGRVTMTTDTSTSTAYMDLRSLRSDDTAVYYCARDRISGTLDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1867] (SEQ ID NO: 365)
[1868] LC DNA sequence
[1869] GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGTCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACAGTAATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCACGGCGCCTATTTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCATTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGATTTTATTACTGCATGCAAGGTACACACTGGCCTCGGACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1870] (SEQ ID NO: 366)
[1871] LC amino acid sequence
[1872] DVVMTQSPLSLPVTLGQSASISCRSSQSLVYSNGNTYLNWFQQRPGQSPRRLFYKVSNRDSGVPDRFSGIGSGTDFTLKISRVEAEDVGFYYCMQGTHWPRTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1873] (SEQ ID NO: 367)
[1874] REGN14177
[1875] HCVR DNA sequence
[1876] CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGCGACTATTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATCAGTAAAAGTGGTACTACCAAATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCAGTGTATCTGCAAATGAACAGTTTGAGAGCCGAGGACACGGCCGTCTATTACTGTGAGAAAAGGGGCAGCTTGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[1877] (SEQ ID NO: 368)
[1878] HCVR amino acid sequence
[1879] QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISKSGTTKYYADSVKGRFTISRDNAKNSVYLQMNSLRAEDTAVYYCEKRGSLGQGTLVTVSS
[1880] (SEQ ID NO: 369)
[1881] CDR1 DNA sequence
[1882] GGA TTC ACC TTC AGC GAC TAT TAC
[1883] (SEQ ID NO: 370)
[1884] CDR1 amino acid sequence
[1885] G F T F S D Y Y
[1886] (SEQ ID NO: 371)
[1887] CDR2 DNA sequence
[1888] ATC AGT AAA AGT GGT ACT ACC AAA
[1889] (SEQ ID NO: 372)
[1890] CDR2 amino acid sequence
[1891] ISKSGTTK
[1892] (SEQ ID NO: 373)
[1893] CDR3 DNA sequence
[1894] GAG AAA AGG GGC AGC
[1895] (SEQ ID NO: 374)
[1896] CDR3 amino acid sequence
[1897] EKRGS
[1898] (SEQ ID NO: 375)
[1899] LCVR DNA sequence
[1900] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAAGTATTTAAATTGGTATCAGCAGAAGCCAGGGAAAGCCCCTAAGCTCCTGATCTACGGTGCATCCTATT TGGAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAGATTTTACTTTTACCATCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTTCTGTCAACAATATGATATTGTCCGGTTCACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
[1901] (SEQ ID NO: 376)
[1902] LCVR amino acid sequence
[1903] DIQMTQSPSSSLSASVGDRVTITCQASQDISKYLNWYQQKPGKAPKLLIYGASYLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQQYDIVRFTFGQGTKLEIK
[1904] (SEQ ID NO: 377)
[1905] CDR1 DNA sequence
[1906] CAG GAC ATT AGC AAG TAT
[1907] (SEQ ID NO: 378)
[1908] CDR1 amino acid sequence
[1909] QDISKY
[1910] (SEQ ID NO: 379)
[1911] CDR2 DNA sequence
[1912] GGT GCA TCC
[1913] (SEQ ID NO: 165)
[1914] CDR2 amino acid sequence
[1915] GAS
[1916] (SEQ ID NO: 90)
[1917] CDR3 DNA sequence
[1918] CAA CAA TAT GAT ATT GTC CGG TTC ACT
[1919] (SEQ ID NO: 380)
[1920] CDR3 amino acid sequence
[1921] QQYDIVRFT
[1922] (SEQ ID NO: 381)
[1923] HC DNA sequence
[1924]
[1925] (SEQ ID NO: 382)
[1926] HC amino acid sequence
[1927] QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISKSGTTKYYADSVKGRFTISRDNAKNSVYLQMNSLRAEDTAVYYCEKRGSLGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1928] (SEQ ID NO: 383)
[1929] LC DNA sequence
[1930] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAAGTATTTAAATTGGTATCAGCAGAAGCCAGGGAAAGCCCCTAAGCTCCTGATCTACGGTGCATCCTATTTGGAAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAGATTTTACTTTTACCATCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTTCTGTCAACAATATGATATTGTCCGGTTCACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1931] (SEQ ID NO: 384)
[1932] LC amino acid sequence
[1933] DIQMTQSPSSLSASVGDRVTITCQASQDISKYLNWYQQKPGKAPKLLIYGASYLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQQYDIVRFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1934] (SEQ ID NO: 385)
[1935] REGN14178
[1936] HCVR DNA sequence
[1937] CAGGTTCAGCTGGTGCAGTCTGGACCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTACCAGCTATGGTTTCAGTTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCGCTTACAATGGTAACACAAACTATGCACAGAAGTTCCAGGACAGAGTCACCATGACCACAGACTCATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTTTATTCCTGTGCGAGAGATCGTGGATTTTGGAGAGCCTATTATGTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[1938] (SEQ ID NO: 386)
[1939] HCVR amino acid sequence
[1940] QVQLVQSGPEVKKPGASVKVSCKASGYTFTSYGFSWVRQAPGQGLEWMGWISAYNGNTNYAQKFQDRVTMTTDSSTSTAYMELRSLRSDDTAVYSCARDRGFWRAYYVFDYWGQGTLVTVSS
[1941] (SEQ ID NO: 387)
[1942] CDR1 DNA sequence
[1943] GGT TAC ACC TTT ACC AGC TAT GGT
[1944] (SEQ ID NO: 137)
[1945] CDR1 amino acid sequence
[1946] G Y T F T S Y G
[1947] (SEQ ID NO: 138)
[1948] CDR2 DNA sequence
[1949] ATC AGC GCT TAC AAT GGT AAC ACA
[1950] (SEQ ID NO: 318)
[1951] CDR2 amino acid sequence
[1952] I S A Y N G N T
[1953] (SEQ ID NO: 319)
[1954] CDR3 DNA sequence
[1955] GCG AGA GAT CGT GGA TTT TGG AGA GCC TAT TAT GTC TTT GAC TAC
[1956] (SEQ ID NO: 388)
[1957] CDR3 amino acid sequence
[1958] A R D R G F W R A Y Y V F D Y
[1959] (SEQ ID NO: 389)
[1960] LCVR DNA sequence
[1961] GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGTACAGTGATGGAAACAACTACTTGAATTGGTTTCAGCGGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTGATCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAATATACACACTGGCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA
[1962] (SEQ ID NO: 390)
[1963] LCVR amino acid sequence
[1964] DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNNYLNWFQRRPGQSPRRLIYKVSDRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQYTHWPYTFGQGTKLEIK
[1965] (SEQ ID NO: 391)
[1966] CDR1 DNA sequence
[1967] CAA AGC CTC GTG TAC AGT GAT GGA AAC AAC TAC
[1968] (SEQ ID NO: 392)
[1969] CDR1 amino acid sequence
[1970] QSLVYSDGNNY
[1971] (SEQ ID NO: 393)
[1972] CDR2 DNA sequence
[1973] AAG GTT TCT
[1974] (SEQ ID NO: 360)
[1975] CDR2 amino acid sequence
[1976] KVS
[1977] (SEQ ID NO: 361)
[1978] CDR3 DNA sequence
[1979] ATG CAA TAT ACA CAC TGG CCG TAC ACT
[1980] (SEQ ID NO: 394)
[1981] CDR3 amino acid sequence
[1982] MQYTHWPYT
[1983] (SEQ ID NO: 395)
[1984] HC DNA sequence
[1985]
[1986] (SEQ ID NO: 396)
[1987] HC amino acid sequence
[1988] QVQLVQSGPEVKKPGASVKVSCKASGYTFTSYGFSWVRQAPGQGLEWMGWISAYNGNTNYAQKFQDRVTMTTDSSTSTAYMELRSLRSDDTAVYSCARDRGFWRAYYVFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[1989] (SEQ ID NO: 397)
[1990] LC DNA sequence
[1991] GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTGTACAGTGATGGAAACAACTACTTGAATTGGTTTCAGCGGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTGATCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAATATACACACTGGCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[1992] (SEQ ID NO: 398)
[1993] LC amino acid sequence
[1994] DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNNYLNWFQRRPGQSPRRLIYKVSDRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQYTHWPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[1995] (SEQ ID NO: 399)
[1996] REGN14179
[1997] HCVR DNA sequence
[1998] GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGCTTATGCCATGCACTGGGTCCGTCAAGTTCCAGGAAAGGGCCTGCAGTGGGTCTCAGGTATTAGTTGGAATAGTGATAATATAGACTATACGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGGACAGTCTGAGAGATGAGGACACGGCCTTGTATTTCTGTGCAAAAGATAGGGTTCGGGGAGTTCGTTACTACTACCACTACGGCATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
[1999] (SEQ ID NO: 400)
[2000] HCVR amino acid sequence
[2001] EVQLVESGGGLVQPGRSLRLSCAASGFTFDAYAMHWVRQVPGKGLQWVSGISWNSDNIDYTDSVKGRFTISRDNAKNSLYLQMDSLRDEDTALYFCAKDRVRGVRYYYHYGMDVWGQGTTVTVSS
[2002] (SEQ ID NO: 401)
[2003] CDR1 DNA sequence
[2004] GGA TTC ACC TTT GAT GCT TAT GCC
[2005] (SEQ ID NO: 402)
[2006] CDR1 amino acid sequence
[2007] G F T F D A Y A
[2008] (SEQ ID NO: 403)
[2009] CDR2 DNA sequence
[2010] ATT AGT TGG AAT AGT GAT AAT ATA
[2011] (SEQ ID NO: 404)
[2012] CDR2 amino acid sequence
[2013] I S W N S D N I
[2014] (SEQ ID NO: 405)
[2015] CDR3 DNA sequence
[2016] GCA AAA GAT AGG GTT CGG GGA GTT CGT TAC TAC TAC CAC TAC GGC ATG GACGTC
[2017] (SEQ ID NO: 406)
[2018] CDR3 amino acid sequence
[2019] A K D R V R G V R Y Y Y H Y G M D V
[2020] (SEQ ID NO: 407)
[2021] LCVR DNA sequence
[2022] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA
[2023] (SEQ ID NO: 408)
[2024] LCVR amino acid sequence
[2025] DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
[2026] (SEQ ID NO: 409)
[2027] CDR1 DNA sequence
[2028] CAG AGC ATT AGC AGC TAT
[2029] (SEQ ID NO: 236)
[2030] CDR1 amino acid sequence
[2031] QSISSY
[2032] (SEQ ID NO: 237)
[2033] CDR2 DNA sequence
[2034] GCT GCA TCC
[2035] (SEQ ID NO: 13)
[2036] CDR2 amino acid sequence
[2037] AAS
[2038] (SEQ ID NO: 14)
[2039] CDR3 DNA sequence
[2040] CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC
[2041] (SEQ ID NO: 410)
[2042] CDR3 amino acid sequence
[2043] QQSYSTPPIT
[2044] (SEQ ID NO: 411)
[2045] HC DNA sequence
[2046]
[2047] (SEQ ID NO: 412)
[2048] HC amino acid sequence
[2049] EVQLVESGGGLVQPGRSLRLSCAASGFTFDAYAMHWVRQVPGKGLQWVSGISWNSDNIDYTDSVKGRFTISRDNAKNSLYLQMDSLRDEDTALYFCAKDRVRGVRYYYHYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[2050] (SEQ ID NO: 413)
[2051] LC DNA sequence
[2052] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[2053] (SEQ ID NO: 414)
[2054] LC amino acid sequence
[2055] DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[2056] (SEQ ID NO: 415)
[2057] REGN14180
[2058] HCVR DNA sequence
[2059] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCTTTAGCAGCTTTGTCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGAGTGGGTCTCAGCTATTCGGGATACTGGTGATAACACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAACCGAGGACACGGCCGTAATTTACTGTGCGAGAGGGGGGAGAACTAGAATTCCGTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[2060] (SEQ ID NO: 416)
[2061] HCVR amino acid sequence
[2062] EVQLVESGGGLVQPGGSLRLSCTASGFTFSSFVMSWVRQAPGKGLEWVSAIRDTGDNTYYADSVKGRFTISRDNSKNTLYLQMNSLRTEDTAVIYCARGGRTRIPFDYWGQGTLVTVSS
[2063] (SEQ ID NO: 417)
[2064] CDR1 DNA sequence
[2065] GGA TTC ACC TTT AGC AGC TTT GTC
[2066] (SEQ ID NO: 418)
[2067] CDR1 amino acid sequence
[2068] G F T F S S F V
[2069] (SEQ ID NO: 419)
[2070] CDR2 DNA sequence
[2071] ATT CGG GAT ACT GGT GAT AAC ACA
[2072] (SEQ ID NO: 420)
[2073] CDR2 amino acid sequence
[2074] I R D T G D N T
[2075] (SEQ ID NO: 421)
[2076] CDR3 DNA sequence
[2077] GCG AGA GGG GGG AGA ACT AGA ATT CCG TTT GAC TAC
[2078] (SEQ ID NO: 422)
[2079] CDR3 amino acid sequence
[2080] A R G G R T R I P F D Y
[2081] (SEQ ID NO: 423)
[2082] LCVR DNA sequence
[2083] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA
[2084] (SEQ ID NO: 408)
[2085] LCVR amino acid sequence
[2086] DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
[2087] (SEQ ID NO: 409)
[2088] CDR1 DNA sequence
[2089] CAG AGC ATT AGC AGC TAT
[2090] (SEQ ID NO: 236)
[2091] CDR1 amino acid sequence
[2092] QSISSY
[2093] (SEQ ID NO: 237)
[2094] CDR2 DNA sequence
[2095] GCT GCA TCC
[2096] (SEQ ID NO: 13)
[2097] CDR2 amino acid sequence
[2098] AAS
[2099] (SEQ ID NO: 14)
[2100] CDR3 DNA sequence
[2101] CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC
[2102] (SEQ ID NO: 410)
[2103] CDR3 amino acid sequence
[2104] QQSYSTPPIT
[2105] (SEQ ID NO: 411)
[2106] HC DNA sequence
[2107]
[2108] (SEQ ID NO: 424)
[2109] HC amino acid sequence
[2110] EVQLVESGGGLVQPGGSLRLSCTASGFTFSSFVMSWVRQAPGKGLEWVSAIRDTGDNTYYADSVKGRFTISRDNSKNTLYLQMNSLRTEDTAVIYCARGGRTRIPFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[2111] (SEQ ID NO: 425)
[2112] LC DNA sequence
[2113] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[2114] (SEQ ID NO: 414)
[2115] LC amino acid sequence
[2116] DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[2117] (SEQ ID NO: 415)
[2118] REGN14181
[2119] HCVR DNA sequence
[2120] CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCATCTTCAGTAACTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAATTATATCTTTTGATGGAAATAATAAATACTATGCAGACTCCGTGAAGCGCCGATTCACCATCTCCAGAGACAATTTCAAGAGCACGCTGTATCTGCAATTGAACAGCCTGACAATTGAGGACACGGCTGTATATTTCTGTGCGAAAGAGTTTAGCAGGCGGAATTTCTTTGACCACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[2121] (SEQ ID NO: 426)
[2122] HCVR amino acid sequence
[2123] QVQLVESGGGVVQPGRSLRLSCAASGFIFSNYGMHWVRQAPGKGLEWVAIISFDGNNKYYADSVKRRFTISRDNFKSTLYLQLNSLTIEDTAVYFCAKEFSRRNFFDHWGQGTLVTVSS
[2124] (SEQ ID NO: 427)
[2125] CDR1 DNA sequence
[2126] GGA TTC ATC TTC AGT AAC TAT GGC
[2127] (SEQ ID NO: 428)
[2128] CDR1 amino acid sequence
[2129] G F I F S N Y G
[2130] (SEQ ID NO: 429)
[2131] CDR2 DNA sequence
[2132] ATA TCT TTT GAT GGA AAT AAT AAA
[2133] (SEQ ID NO: 430)
[2134] CDR2 amino acid sequence
[2135] ISFDGNNK
[2136] (SEQ ID NO: 431)
[2137] CDR3 DNA sequence
[2138] GCG AAA GAG TTT AGC AGG CGG AAT TTC TTT GAC CAC
[2139] (SEQ ID NO: 432)
[2140] CDR3 amino acid sequence
[2141] AKEFSRRNFFDH
[2142] (SEQ ID NO: 433)
[2143] LCVR DNA sequence
[2144] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTG CAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA
[2145] (SEQ ID NO: 408)
[2146] LCVR amino acid sequence
[2147] DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
[2148] (SEQ ID NO: 409)
[2149] CDR1 DNA sequence
[2150] CAG AGC ATT AGC AGC TAT
[2151] (SEQ ID NO: 236)
[2152] CDR1 amino acid sequence
[2153] QSISSY
[2154] (SEQ ID NO: 237)
[2155] CDR2 DNA sequence
[2156] GCT GCA TCC
[2157] (SEQ ID NO: 13)
[2158] CDR2 amino acid sequence
[2159] AAS
[2160] (SEQ ID NO: 14)
[2161] CDR3 DNA sequence
[2162] CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC
[2163] (SEQ ID NO: 410)
[2164] CDR3 amino acid sequence
[2165] QQSYSTPPIT
[2166] (SEQ ID NO: 411)
[2167] HC DNA sequence
[2168]
[2169] (SEQ ID NO: 434)
[2170] HC amino acid sequence
[2171] QVQLVESGGGVVQPGRSLRLSCAASGFIFSNYGMHWVRQAPGKGLEWVAIISFDGNNKYYADSVKRRFTISRDNFKSTLYLQLNSLTIEDTAVYFCAKEFSRRNFFDHWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[2172] (SEQ ID NO: 435)
[2173] LC DNA sequence
[2174] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[2175] (SEQ ID NO: 414)
[2176] LC amino acid sequence
[2177] DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[2178] (SEQ ID NO: 415)
[2179] REGN14182
[2180] HCVR DNA sequence
[2181] CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCATTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGATGGCTATCATCTCATATGACGGAAGTGATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCGAGAACACACTATATCTGCAAATGAGCAGCCTGAGAACTGAAGACACGGCTGTGTATTACTGTGCGAAAGCCAGTATAACTGGAACTTACTACTTCTTCTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA
[2182] (SEQ ID NO: 436)
[2183] HCVR amino acid sequence
[2184] QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYGMHWVRQAPGKGLEWMAIISYDGSDKYYADSVKGRFTISRDNSENTLYLQMSSLRTEDTAVYYCAKASITGTYYFFYGMDVWGQGTTVTVSS
[2185] (SEQ ID NO: 437)
[2186] CDR1 DNA sequence
[2187] GGA TTC ACC TTC AGT CAT TAT GGC
[2188] (SEQ ID NO: 438)
[2189] CDR1 amino acid sequence
[2190] G F T F S H Y G
[2191] (SEQ ID NO: 191)
[2192] CDR2 DNA sequence
[2193] ATC TCA TAT GAC GGA AGT GAT AAA
[2194] (SEQ ID NO: 439)
[2195] CDR2 amino acid sequence
[2196] I S Y D G S D K
[2197] (SEQ ID NO: 335)
[2198] CDR3 DNA sequence
[2199] GCG AAA GCC AGT ATA ACT GGA ACT TAC TAC TTC TTC TAC GGT ATG GAC GTC
[2200] (SEQ ID NO: 440)
[2201] CDR3 amino acid sequence
[2202] A K A S I T G T Y Y F F Y G M D V
[2203] (SEQ ID NO: 441)
[2204] LCVR DNA sequence
[2205] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA
[2206] (SEQ ID NO: 408)
[2207] LCVR amino acid sequence
[2208] DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK
[2209] (SEQ ID NO: 409)
[2210] CDR1 DNA sequence
[2211] CAG AGC ATT AGC AGC TAT
[2212] (SEQ ID NO: 236)
[2213] CDR1 amino acid sequence
[2214] QSISSY
[2215] (SEQ ID NO: 237)
[2216] CDR2 DNA sequence
[2217] GCT GCA TCC
[2218] (SEQ ID NO: 13)
[2219] CDR2 amino acid sequence
[2220] AAS
[2221] (SEQ ID NO: 14)
[2222] CDR3 DNA sequence
[2223] CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC
[2224] (SEQ ID NO: 410)
[2225] CDR3 amino acid sequence
[2226] QQSYSTPPIT
[2227] (SEQ ID NO: 411)
[2228] HC DNA sequence
[2229]
[2230] (SEQ ID NO: 442)
[2231] HC amino acid sequence
[2232] QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYGMHWVRQAPGKGLEWMAIISYDGSDKYYADSVKGRFTISRDNSENTLYLQMSSLRTEDTAVYYCAKASITGTYYFFYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
[2233] (SEQ ID NO: 443)
[2234] LC DNA sequence
[2235] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
[2236] (SEQ ID NO: 414)
[2237] LC amino acid sequence
[2238] DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
[2239] (SEQ ID NO: 415)
[2240] REGN14183
[2241] HCVR DNA sequence
[2242] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGTCTCTGGATTCACCTTTAGCAGCTATGTCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGATAGTGGTGGTAACACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCAGAGAGCCGAGGACACGGCCGTGTATTATTGTGCGAAGGGGGGGCGCAGCAGGTTCCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA
[2243] (SEQ ID NO: 444)
[2244] HCVR amino acid sequence
[2245] EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSYVMSWVRQAPGKGLEWVSAISDSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSQRAEDTAVYYCAKGGRSRFPFDYWGQGTLVTVSS
[2246] (SEQ ID NO: 445)
[2247] CDR1 DNA sequence
[2248] GGA TTC ACC TTT AGC AGC TAT GTC
[2249] (SEQ ID NO: 446)
[2250] CDR1 amino acid sequence
[2251] G F T F S S Y V
[2252] (SEQ ID NO: 447)
[2253] CDR2 DNA sequence
[2254] ATT AGT GAT AGT GGT GGT AAC ACA
[2255] (SEQ ID NO: 448)
[2256] CDR2 amino acid sequence
[2257] ISDSGGNT
[2258] (SEQ ID NO: 449)
[2259] CDR3 DNA sequence
[2260] GCG AAG GGG GGG CGC AGC AGG TTC CCT TTT GAC TAC
[2261] (SEQ ID NO: 450)
[2262] CDR3 amino acid sequence
[2263] AKGGRSRFPFDY
[2264] (SEQ ID NO: 451)
[2265] LCVR DNA sequence
[2266] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTG CAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGC...
Claims
1. A receptor for p75 neurotrophic factor (p75) NTR The antigen-binding protein that binds to the antigen, wherein the antigen-binding protein shows less than 50% of human p75 NTR The inhibitory effect of the extracellular domains of p75 on the activity of p75. NTR The activity of its extracellular domain blocks human nerve growth factor (NGF)-dependent human tropomyosin receptor kinase A (TrkA) signaling, as measured in cell-based assays.
2. The antigen-binding protein according to claim 1, wherein the cell-based assay comprises the following steps: a) In the presence of the antigen-binding protein, human p75 NTR The soluble extracellular domains of [the substance] were incubated with mature human NGF, optionally with human p75. NTR The extracellular domain of IgG fuses with the Fc domain of IgG; b) Incubate the mixture from step (a) with a population of recombinant mammalian cells stably expressing TrkA and a serum response element fused with a luciferase reporter. c) Measure the luciferase activity from the mixture from step (b) in relative luminescent units (RLU); and d) Calculate the inhibition percentage using the following formula: Among them, RLU 可溶性p75 Using non-binding p75 NTR The RLU values of antigen-binding proteins in cells treated under the same conditions, and the RLU NGF Using only mature human NGF in the absence of p75 NTR The RLU value of cells treated with soluble extracellular domains.
3. The antigen-binding protein according to claim 1 or claim 2, comprising: (1) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 529 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 537 or a variant thereof; (2) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 549 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 557 or a variant thereof; (3) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 569 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 577 or a variant thereof; (4) HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR containing the amino acid sequence shown in SEQ ID NO: 589 or a variant thereof; and LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR containing the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof; and / or (5) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 609 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof.
4. The antigen-binding protein according to any one of claims 1-3, comprising: (1) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 531 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 533 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 535 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 539 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 541 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 543 or a variant thereof; (2) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 551 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 553 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 555 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 559 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 561 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 563 or a variant thereof; (3) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 571 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 573 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 575 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 579 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 581 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 583 or a variant thereof; (4) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 591 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 593 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 595 or a variant thereof; and / or LCVR comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 599 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 601 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 603 or a variant thereof; and / or (5) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 611 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 613 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 615 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 599 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 601 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 603 or a variant thereof.
5. The antigen-binding protein according to any one of claims 1-4, comprising: (1) HCVR, comprising the amino acid sequence shown in SEQ ID NO: 529 or a variant thereof; and LCVR, comprising the amino acid sequence shown in SEQ ID NO: 537 or a variant thereof; (2) HCVR, comprising the amino acid sequence shown in SEQ ID NO: 549 or a variant thereof; and LCVR, comprising the amino acid sequence shown in SEQ ID NO: 557 or a variant thereof; (3) HCVR, comprising the amino acid sequence shown in SEQ ID NO: 569 or a variant thereof; and LCVR, comprising the amino acid sequence shown in SEQ ID NO: 577 or a variant thereof; (4) HCVR, comprising the amino acid sequence shown in SEQ ID NO: 589 or a variant thereof; and LCVR, comprising the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof; and / or (5) HCVR, which contains the amino acid sequence shown in SEQ ID NO: 609 or a variant thereof; and LCVR, which contains the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof.
6. The antigen-binding protein according to any one of claims 1-5, comprising: (1) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 545 or a variant thereof and a light chain comprising the amino acid sequence shown in SEQ ID NO: 547 or a variant thereof; (2) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 565 or a variant thereof and a light chain comprising the amino acid sequence shown in SEQ ID NO: 567 or a variant thereof; (3) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 585 or a variant thereof and a light chain comprising the amino acid sequence shown in SEQ ID NO: 587 or a variant thereof; (4) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 605 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 607 or a variant thereof; and / or (5) A heavy chain containing the amino acid sequence shown in SEQ ID NO: 617 or a variant thereof and a light chain containing the amino acid sequence shown in SEQ ID NO: 607 or a variant thereof.
7. A receptor for p75 neurotrophic factor (p75) NTR The antigen-binding protein that binds includes: (i) HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR containing the amino acid sequence shown in SEQ ID NO: 2, 22, 42, 58, 78, 98, 116, 136, 155, 173, 189, 207, 227, 245, 261, 279, 297, 315, 331, 349, 369, 387, 401, 417, 427, 437, 445, 455, 465, 475, 484, 493, 503, 513, 519, 529, 549, 569, 589, or 609, or a variant thereof; and / or (ii) LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR containing the amino acid sequence shown in SEQ ID NO: 10, 30, 50, 66, 86, 106, 124, 144, 162, 179, 197, 215, 235, 251, 269, 287, 304, 323, 339, 357, 377, 391, 409, 537, 557, 577, or 597, or a variant thereof.
8. The antigen-binding protein according to claim 7, comprising: (1) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 2 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 10 or a variant thereof; (2) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof; (3) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 42 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof; (4) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 58 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 66 or a variant thereof; (5) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof; (6) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 98 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 106 or a variant thereof; (7) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 116 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 124 or a variant thereof; (8) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof; (9) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 155 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 162 or a variant thereof; (10) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 173 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 179 or a variant thereof; (11) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 189 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 197 or a variant thereof; (12) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 207 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 215 or a variant thereof; (13) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 227 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 235 or a variant thereof; (14) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 245 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 251 or a variant thereof; (15) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof; (16) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 279 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 287 or a variant thereof; (17) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 297 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 304 or a variant thereof; (18) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 315 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 323 or a variant thereof; (19) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 331 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 339 or a variant thereof; (20) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequence shown in SEQ ID NO: 349 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequence shown in SEQ ID NO: 357 or a variant thereof; (21) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof; (22) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequence shown in SEQ ID NO: 387 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequence shown in SEQ ID NO: 391 or a variant thereof; (23) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 401 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (24) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequence shown in SEQ ID NO: 417 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (25) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequence shown in SEQ ID NO: 427 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (26) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 437 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (27) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 445 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (28) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 455 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (29) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 465 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (30) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 475 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (31) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (32) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 493 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (33) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 503 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (34) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 513 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (35) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 519 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (36) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequence shown in SEQ ID NO: 529 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequence shown in SEQ ID NO: 537 or a variant thereof; (37) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 549 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 557 or a variant thereof; (38) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 569 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 577 or a variant thereof; (39) HCVRs comprising HCDR1, HCDR2, and HCDR3 of the amino acid sequence shown in SEQ ID NO: 589 or a variant thereof; and LCVRs comprising LCDR1, LCDR2, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof; and / or (40) HCVRs comprising HCDR1, HCDR2 and HCDR3 of the HCVR containing the amino acid sequence shown in SEQ ID NO: 609 or a variant thereof; and LCVRs comprising LCDR1, LCDR2 and LCDR3 of the LCVR containing the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof.
9. The antigen-binding protein according to claim 7 or claim 8, comprising: (1) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 2 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 10 or a variant thereof; (2) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof; (3) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 42 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof; (4) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 58 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 66 or a variant thereof; (5) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof; (6) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 98 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 106 or a variant thereof; (7) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 116 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 124 or a variant thereof; (8) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof; (9) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 155 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 162 or a variant thereof; (10) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 173 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 179 or a variant thereof; (11) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 207 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 215 or a variant thereof; (12) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 245 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 251 or a variant thereof; (13) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 279 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 287 or a variant thereof; (14) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 297 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 304 or a variant thereof; (15) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 315 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 323 or a variant thereof; (16) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 349 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 357 or a variant thereof; (17) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 387 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 391 or a variant thereof; (18) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 417 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (19) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 427 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (20) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 437 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (21) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 445 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (22) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 455 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (23) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 465 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (24) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 475 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (25) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 493 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (26) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 503 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (27) HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR containing the amino acid sequence shown in SEQ ID NO: 513 or a variant thereof; and LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; and / or (28) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 519 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
10. The antigen-binding protein according to claim 7 or claim 8, comprising: (1) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 189 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 197 or a variant thereof; (2) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 227 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 235 or a variant thereof; (3) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof; (4) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 331 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 339 or a variant thereof; (5) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof; (6) HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR containing the amino acid sequence shown in SEQ ID NO: 401 or a variant thereof; and LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; and / or (7) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
11. The antigen-binding protein of claim 7 or claim 8, comprising: (1) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof; (2) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof; (3) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof; (4) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof; and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof; (5) HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof; and LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof; and / or (6) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof; and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
12. The antigen-binding protein according to claim 7 or claim 8, comprising: (1) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 4 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 6 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 8 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 16 or a variant thereof; (2) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 24 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 26 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 32 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 36 or a variant thereof; (3) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 44 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 46 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 52 or a variant thereof; (4) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 60 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 62 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 64 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 68 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 72 or a variant thereof; (5) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 80 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 82 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 84 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 88 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 92 or a variant thereof; (6) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 102 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 104 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 108 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 110 or a variant thereof; (7) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 118 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 120 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 122 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 126 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 130 or a variant thereof; (8) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 140 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 142 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 146 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 149 or a variant thereof; (9) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 158 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 160 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 164 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 167 or a variant thereof; (10) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 175 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 177 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 181 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 183 or a variant thereof; (11) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 191 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 193 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 195 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 199 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 201 or a variant thereof; (12) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 209 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 211 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 213 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 217 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 219 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 221 or a variant thereof; (13) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 229 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 231 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 233 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 239 or a variant thereof; (14) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 247 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 249 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 253 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 255 or a variant thereof; (15) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 263 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 265 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 267 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 271 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 273 or a variant thereof; (16) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 281 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 283 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 285 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 289 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 291 or a variant thereof; (17) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 299 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 193 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 302 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 307 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 309 or a variant thereof; (18) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 317 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 321 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 325 or a variant thereof; (19) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 333 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 335 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 337 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 341 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 343 or a variant thereof; (20) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 351 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 353 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 355 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 359 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 361 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 363 or a variant thereof; (21) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 371 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 373 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 375 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 379 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 381 or a variant thereof; (22) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 389 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 393 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 361 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 395 or a variant thereof; (23) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 403 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 405 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 407 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (24) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 419 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 421 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 423 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (25) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 429 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 431 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 433 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (26) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 191 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 335 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 441 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (27) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 447 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 449 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 451 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (28) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 457 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 459 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 461 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (29) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 467 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 469 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 471 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (30) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 477 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 158 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 480 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (31) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 486 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 283 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 489 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (32) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 495 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 497 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 499 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (33) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 505 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 507 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 509 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (34) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 515 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (35) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 521 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 523 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 525 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (36) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 531 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 533 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 535 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 539 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 541 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 543 or a variant thereof; (37) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 551 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 553 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 555 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 559 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 561 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 563 or a variant thereof; (38) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 571 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 573 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 575 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 579 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 581 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 583 or a variant thereof; (39) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 591 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 593 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 595 or a variant thereof; and LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 599 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 601 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 603 or a variant thereof; (40) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 611 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 613 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 615 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 599 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 601 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 603 or a variant thereof.
13. The antigen-binding protein according to any one of claims 7-9, comprising: (1) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 4 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 6 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 8 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 16 or a variant thereof; (2) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 24 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 26 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 32 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 36 or a variant thereof; (3) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 44 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 46 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 48 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 52 or a variant thereof; (4) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 60 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 62 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 64 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 68 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 72 or a variant thereof; (5) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 80 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 82 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 84 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 88 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 92 or a variant thereof; (6) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 102 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 104 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 108 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 110 or a variant thereof; (7) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 118 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 120 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 122 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 126 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 128 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 130 or a variant thereof; (8) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 140 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 142 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 146 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 149 or a variant thereof; (9) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 158 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 160 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 164 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 167 or a variant thereof; (10) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 175 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 177 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 181 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 183 or a variant thereof; (11) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 209 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 211 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 213 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 217 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 219 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 221 or a variant thereof; (12) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 100 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 247 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 249 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 253 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 70 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 255 or a variant thereof; (13) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 281 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 283 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 285 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 289 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 291 or a variant thereof; (14) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 299 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 193 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 302 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 307 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 309 or a variant thereof; (15) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 317 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 321 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 12 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 325 or a variant thereof; (16) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 351 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 353 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 355 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 359 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 361 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 363 or a variant thereof; (17) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 389 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 393 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 361 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 395 or a variant thereof; (18) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 419 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 421 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 423 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (19) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 429 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 431 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 433 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (20) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 191 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 335 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 441 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (21) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 447 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 449 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 451 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (22) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 457 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 459 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 461 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (23) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 467 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 469 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 471 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (24) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 477 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 158 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 480 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (25) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 495 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 497 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 499 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (26) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 505 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 507 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 509 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; (27) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 319 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 515 or a variant thereof; and / or LCVR comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; and / or (28) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 521 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 523 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 525 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof.
14. The antigen-binding protein according to any one of claims 7-8 and 10, comprising: (1) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 191 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 193 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 195 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 199 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 201 or a variant thereof; (2) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 229 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 231 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 233 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 239 or a variant thereof; (3) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 263 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 265 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 267 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 271 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 273 or a variant thereof; (4) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 333 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 335 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 337 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 341 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 343 or a variant thereof; (5) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 371 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 373 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 375 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 379 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 381 or a variant thereof; (6) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 403 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 405 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 407 or a variant thereof; and / or LCVR comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof; and / or (7) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 486 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 283 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 489 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof.
15. The antigen-binding protein of any one of claims 7-8 and 11, comprising: (1) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 24 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 26 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 28 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 32 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 34 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 36 or a variant thereof; (2) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 80 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 82 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 84 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 88 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 92 or a variant thereof; (3) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 138 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 140 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 142 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 146 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 149 or a variant thereof; (4) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 263 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 265 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 267 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 271 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 273 or a variant thereof; (5) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 371 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 373 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 375 or a variant thereof; and / or LCVR comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 379 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 90 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 381 or a variant thereof; and / or (6) HCVR, comprising: HCDR1 containing the amino acid sequence shown in SEQ ID NO: 486 or a variant thereof, HCDR2 containing the amino acid sequence shown in SEQ ID NO: 283 or a variant thereof, and HCDR3 containing the amino acid sequence shown in SEQ ID NO: 489 or a variant thereof; and / or LCVR, comprising: LCDR1 containing the amino acid sequence shown in SEQ ID NO: 237 or a variant thereof, LCDR2 containing the amino acid sequence shown in SEQ ID NO: 14 or a variant thereof, and LCDR3 containing the amino acid sequence shown in SEQ ID NO: 411 or a variant thereof.
16. The antigen-binding protein according to any one of claims 7-8 and 12, comprising: (1) An HCVR containing the amino acid sequence shown in SEQ ID NO: 2 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 10 or a variant thereof; (2) An HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof; (3) An HCVR containing the amino acid sequence shown in SEQ ID NO: 42 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof; (4) An HCVR containing the amino acid sequence shown in SEQ ID NO: 58 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 66 or a variant thereof; (5) An HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof; (6) An HCVR containing the amino acid sequence shown in SEQ ID NO: 98 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 106 or a variant thereof; (7) An HCVR containing the amino acid sequence shown in SEQ ID NO: 116 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 124 or a variant thereof; (8) An HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof; (9) An HCVR containing the amino acid sequence shown in SEQ ID NO: 155 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 162 or a variant thereof; (10) An HCVR containing the amino acid sequence shown in SEQ ID NO: 173 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 179 or a variant thereof; (11) An HCVR containing the amino acid sequence shown in SEQ ID NO: 189 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 197 or a variant thereof; (12) An HCVR containing the amino acid sequence shown in SEQ ID NO: 207 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 215 or a variant thereof; (13) An HCVR containing the amino acid sequence shown in SEQ ID NO: 227 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 235 or a variant thereof; (14) An HCVR containing the amino acid sequence shown in SEQ ID NO: 245 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 251 or a variant thereof; (15) An HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof; (16) An HCVR containing the amino acid sequence shown in SEQ ID NO: 279 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 287 or a variant thereof; (17) An HCVR containing the amino acid sequence shown in SEQ ID NO: 297 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 304 or a variant thereof; (18) An HCVR containing the amino acid sequence shown in SEQ ID NO: 315 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 323 or a variant thereof; (19) An HCVR containing the amino acid sequence shown in SEQ ID NO: 331 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 339 or a variant thereof; (20) An HCVR containing the amino acid sequence shown in SEQ ID NO: 349 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 357 or a variant thereof; (21) An HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof; (22) An HCVR containing the amino acid sequence shown in SEQ ID NO: 387 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 391 or a variant thereof; (23) An HCVR containing the amino acid sequence shown in SEQ ID NO: 401 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (24) An HCVR containing the amino acid sequence shown in SEQ ID NO: 417 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (25) An HCVR containing the amino acid sequence shown in SEQ ID NO: 427 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (26) An HCVR containing the amino acid sequence shown in SEQ ID NO: 437 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (27) An HCVR containing the amino acid sequence shown in SEQ ID NO: 445 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (28) An HCVR containing the amino acid sequence shown in SEQ ID NO: 455 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (29) An HCVR containing the amino acid sequence shown in SEQ ID NO: 465 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (30) An HCVR containing the amino acid sequence shown in SEQ ID NO: 475 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (31) An HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (32) An HCVR containing the amino acid sequence shown in SEQ ID NO: 493 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (33) An HCVR containing the amino acid sequence shown in SEQ ID NO: 503 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (34) An HCVR containing the amino acid sequence shown in SEQ ID NO: 513 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (35) An HCVR containing the amino acid sequence shown in SEQ ID NO: 519 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (36) An HCVR containing the amino acid sequence shown in SEQ ID NO: 529 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 537 or a variant thereof; (37) An HCVR containing the amino acid sequence shown in SEQ ID NO: 549 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 557 or a variant thereof; (38) An HCVR containing the amino acid sequence shown in SEQ ID NO: 569 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 577 or a variant thereof; (39) An HCVR containing the amino acid sequence shown in SEQ ID NO: 589 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof, and / or (40) An HCVR containing the amino acid sequence shown in SEQ ID NO: 609 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 597 or a variant thereof.
17. The antigen-binding protein according to any one of claims 7-9, 12-13, and 16, comprising: (1) An HCVR containing the amino acid sequence shown in SEQ ID NO: 2 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 10 or a variant thereof; (2) An HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof; (3) An HCVR containing the amino acid sequence shown in SEQ ID NO: 42 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 50 or a variant thereof; (4) An HCVR containing the amino acid sequence shown in SEQ ID NO: 58 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 66 or a variant thereof; (5) An HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof; (6) An HCVR containing the amino acid sequence shown in SEQ ID NO: 98 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 106 or a variant thereof; (7) An HCVR containing the amino acid sequence shown in SEQ ID NO: 116 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 124 or a variant thereof; (8) An HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof; (9) An HCVR containing the amino acid sequence shown in SEQ ID NO: 155 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 162 or a variant thereof; (10) An HCVR containing the amino acid sequence shown in SEQ ID NO: 173 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 179 or a variant thereof; (11) An HCVR containing the amino acid sequence shown in SEQ ID NO: 207 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 215 or a variant thereof; (12) An HCVR containing the amino acid sequence shown in SEQ ID NO: 245 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 251 or a variant thereof; (13) An HCVR containing the amino acid sequence shown in SEQ ID NO: 279 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 287 or a variant thereof; (14) An HCVR containing the amino acid sequence shown in SEQ ID NO: 297 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 304 or a variant thereof; (15) An HCVR containing the amino acid sequence shown in SEQ ID NO: 315 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 323 or a variant thereof; (16) An HCVR containing the amino acid sequence shown in SEQ ID NO: 349 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 357 or a variant thereof; (17) An HCVR containing the amino acid sequence shown in SEQ ID NO: 387 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 391 or a variant thereof; (18) An HCVR containing the amino acid sequence shown in SEQ ID NO: 417 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (19) An HCVR containing the amino acid sequence shown in SEQ ID NO: 427 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (20) An HCVR containing the amino acid sequence shown in SEQ ID NO: 437 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (21) An HCVR containing the amino acid sequence shown in SEQ ID NO: 445 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (22) An HCVR containing the amino acid sequence shown in SEQ ID NO: 455 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (23) An HCVR containing the amino acid sequence shown in SEQ ID NO: 465 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (24) An HCVR containing the amino acid sequence shown in SEQ ID NO: 475 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (25) An HCVR containing the amino acid sequence shown in SEQ ID NO: 493 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (26) An HCVR containing the amino acid sequence shown in SEQ ID NO: 503 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof; (27) An HCVR containing the amino acid sequence shown in SEQ ID NO: 513 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof, and / or (28) An HCVR containing the amino acid sequence shown in SEQ ID NO: 519 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
18. The antigen-binding protein according to any one of claims 7-8, 10, 12, 14, and 16, comprising: (1) An HCVR containing the amino acid sequence shown in SEQ ID NO: 189 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 197 or a variant thereof; (2) An HCVR containing the amino acid sequence shown in SEQ ID NO: 227 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 235 or a variant thereof; (3) An HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof; (4) An HCVR containing the amino acid sequence shown in SEQ ID NO: 331 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 339 or a variant thereof; (5) An HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof; (6) An HCVR containing the amino acid sequence shown in SEQ ID NO: 401 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof, and / or (7) An HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
19. The antigen-binding protein of any one of claims 7-8, 11, 12, 15, and 16, comprising: (1) An HCVR containing the amino acid sequence shown in SEQ ID NO: 22 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 30 or a variant thereof; (2) An HCVR containing the amino acid sequence shown in SEQ ID NO: 78 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 86 or a variant thereof; (3) An HCVR containing the amino acid sequence shown in SEQ ID NO: 136 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 144 or a variant thereof; (4) An HCVR containing the amino acid sequence shown in SEQ ID NO: 261 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 269 or a variant thereof; (5) HCVR containing the amino acid sequence shown in SEQ ID NO: 369 or a variant thereof, and LCVR containing the amino acid sequence shown in SEQ ID NO: 377 or a variant thereof, and / or (6) An HCVR containing the amino acid sequence shown in SEQ ID NO: 484 or a variant thereof, and an LCVR containing the amino acid sequence shown in SEQ ID NO: 409 or a variant thereof.
20. The antigen-binding protein of any one of claims 7-8, 12, and 16, comprising: (1) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 18 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 20 or a variant thereof; (2) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 38 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 40 or a variant thereof; (3) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 54 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 56 or a variant thereof; (4) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 74 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 76 or a variant thereof; (5) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 94 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 96 or a variant thereof; (6) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 112 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 114 or a variant thereof; (7) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 132 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 134 or a variant thereof; (8) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 151 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 153 or a variant thereof; (9) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 169 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 171 or a variant thereof; (10) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 185 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 187 or a variant thereof; (11) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 203 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 205 or a variant thereof; (12) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 223 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 225 or a variant thereof; (13) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 241 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 243 or a variant thereof; (14) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 257 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 259 or a variant thereof; (15) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 275 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 277 or a variant thereof; (16) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 293 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 295 or a variant thereof; (17) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 311 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 313 or a variant thereof; (18) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 327 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 329 or a variant thereof; (19) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 345 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 347 or a variant thereof; (20) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 365 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 367 or a variant thereof; (21) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 383 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 385 or a variant thereof; (22) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 397 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 399 or a variant thereof; (23) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 413 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (24) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 425 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (25) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 435 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (26) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 443 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (27) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 453 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (28) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 463 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (29) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 473 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (30) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 482 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (31) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 491 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (32) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 501 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (33) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 511 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (34) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 517 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (35) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 527 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (36) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 545 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 547 or a variant thereof; (37) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 565 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 567 or a variant thereof; (38) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 585 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 587 or a variant thereof; (39) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 605 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 607 or a variant thereof; and / or (40) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 617 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 607 or a variant thereof.
21. The antigen-binding protein according to any one of claims 7-9, 12-13, 16-17, and 20, comprising: (1) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 18 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 20 or a variant thereof; (2) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 38 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 40 or a variant thereof; (3) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 54 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 56 or a variant thereof; (4) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 74 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 76 or a variant thereof; (5) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 94 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 96 or a variant thereof; (6) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 112 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 114 or a variant thereof; (7) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 132 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 134 or a variant thereof; (8) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 151 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 153 or a variant thereof; (9) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 169 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 171 or a variant thereof; (10) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 185 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 187 or a variant thereof; (11) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 223 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 225 or a variant thereof; (12) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 257 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 259 or a variant thereof; (13) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 293 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 295 or a variant thereof; (14) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 311 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 313 or a variant thereof; (15) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 327 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 329 or a variant thereof; (16) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 365 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 367 or a variant thereof; (17) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 397 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 399 or a variant thereof; (18) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 425 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (19) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 435 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (20) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 443 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (21) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 453 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (22) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 463 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (23) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 473 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (24) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 482 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (25) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 501 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (26) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 511 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; (27) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 517 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; and / or (28) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 527 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof.
22. The antigen-binding protein according to any one of claims 7-8, 10, 12, 14, 16, 18, and 20, comprising: (1) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 203 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 205 or a variant thereof; (2) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 241 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 243 or a variant thereof; (3) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 275 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 277 or a variant thereof; (4) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 345 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 347 or a variant thereof; (5) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 383 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 385 or a variant thereof; (6) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 413 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof; and / or (7) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 491 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof.
23. The antigen-binding protein according to any one of claims 7-8, 11, 12, 15, 16, 19, and 20, comprising: (1) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 38 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 40 or a variant thereof; (2) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 94 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 96 or a variant thereof; (3) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 151 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 153 or a variant thereof; (4) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 275 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 277 or a variant thereof; (5) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 383 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 385 or a variant thereof; and / or (6) A heavy chain comprising the amino acid sequence shown in SEQ ID NO: 491 or a variant thereof, and a light chain comprising the amino acid sequence shown in SEQ ID NO: 415 or a variant thereof.
24. The antigen-binding protein according to any one of claims 7-9, 12-13, 16-17 and 20-21, wherein the antigen-binding protein blocks the binding of human neurotrophic factor receptor mouse Fc dimer (human p75-mFc) to human neurotrophic factor 3 (hNT-3) by at least about 50%.
25. The antigen-binding protein according to claims 7-8, 10, 12, 14, 16, 18, 20 and 22, wherein the antigen-binding protein blocks the binding of human neurotrophic factor receptor mouse Fc dimer (human p75-mFc) to human neurotrophic factor 3 (hNT-3) by less than about 50%.
26. An antigen-binding protein that binds to an antibody comprising the HCVR / LCVR amino acid sequence pair as described in Table 1-1 at p75. NTR The same tabletop on.
27. An antigen-binding protein that competitively binds to p75 of an antibody comprising the HCVR / LCVR amino acid sequence pairs as described in Table 1-1. NTR .
28. The antigen-binding protein according to any one of claims 1-27, wherein the antigen-binding protein comprises an antibody or an antigen-binding fragment thereof.
29. The antigen-binding protein according to any one of claims 1-27, wherein the antigen-binding protein is selected from humanized antibodies or their antigen-binding fragments, human antibodies or their antigen-binding fragments, murine antibodies or their antigen-binding fragments, chimeric antibodies or their antigen-binding fragments, monovalent Fab', bivalent Fab2, F(ab)'3 fragments, single-chain variable fragments (scFv), biscFv, (scFv)2, double-chain antibodies, microantibodies, nanoantibodies, triple-chain antibodies, quadruple-chain antibodies, disulfide-stabilized Fv proteins (dsFv), single-domain antibodies (sdAb), Ig NAR, single-chain antibodies, bispecific antibodies or their binding fragments, bispecific T-cell adaptors (BiTE), trispecific antibodies or their chemically modified derivatives.
30. The antigen-binding protein of claim 29, wherein the antigen-binding protein comprises an antigen-binding region fragment (Fab).
31. The antigen-binding protein of claim 29, wherein the antigen-binding protein comprises a single-chain variable fragment (scFv).
32. The antigen-binding protein of claim 31, wherein the scFv comprises variable regions arranged from the N-terminus to the C-terminus in the following orientation: HCVR-LCVR.
33. The antigen-binding protein of claim 31, wherein the scFv comprises variable regions arranged from the N-terminus to the C-terminus in the following orientation: LCVR-HCVR.
34. The antigen-binding protein according to any one of claims 31-33, wherein the variable region in scFv is connected by a linker.
35. The antigen-binding protein of claim 34, wherein the linker is a peptide linker.
36. The antigen-binding protein of claim 35, wherein the peptide linker is -(GGGGS). n -(SEQ ID NO:668), where n is any integer selected from 1 to 10.
37. The antigen-binding protein according to any one of claims 1-36, wherein the antigen-binding protein binds to human p75. NTR Combine.
38. The antigen-binding protein of claim 37, wherein the antigen-binding protein is K D Approximately 1×10 -9 M or stronger affinity with people p75 NTR Combine.
39. An isolated polynucleotide encoding an antigen-binding protein according to any one of claims 1-38.
40. A vector comprising the isolated polynucleotide according to claim 39.
41. A host cell comprising an antigen-binding protein according to any one of claims 1-38, an isolated polynucleotide according to claim 39, or a vector according to claim 40.
42. The host cell according to claim 41 is a Chinese hamster ovary (CHO) cell.
43. A protein-drug conjugate comprising a protein that interacts with the p75 neurotrophic factor receptor (p75). NTR Antigen-binding proteins that bind to and conjugate with molecular cargo.
44. The protein-drug conjugate of claim 43, wherein the antigen-binding protein comprises the antigen-binding protein of any one of claims 1-38.
45. The protein-drug conjugate of claim 43 or 44, wherein the antigen-binding protein and the molecular cargo are conjugated via a linker.
46. The protein-drug conjugate according to any one of claims 43-45, wherein the molecular cargo comprises a polynucleotide molecule, a polypeptide molecule, a carrier, or a small molecule.
47. The protein-drug conjugate of claim 46, wherein the molecular cargo comprises a polynucleotide molecule.
48. The protein-drug conjugate according to claim 47, wherein the polynucleotide molecule is an interfering nucleic acid molecule, guide RNA, ribozyme, aptamer, mixer, polymer, or mRNA.
49. The protein-drug conjugate according to claim 48, wherein the interfering nucleic acid molecule is siRNA, shRNA, miRNA, antisense oligonucleotide, or gapmer.
50. The protein-drug conjugate according to claim 49, wherein the interfering nucleic acid molecule is siRNA.
51. The protein-drug conjugate of claim 50, wherein the siRNA comprises a positive strand of 21 nucleotides in length.
52. The protein-drug conjugate according to claim 50 or claim 51, wherein the siRNA comprises an antisense strand of 23 nucleotides in length.
53. The protein-drug conjugate according to any one of claims 50-52, wherein the siRNA comprises two phosphate thioester bonds at the first and second nucleotide internucleotide bonds at the 5' end of the positive strand.
54. The protein-drug conjugate according to any one of claims 50-53, wherein the siRNA comprises two phosphate thioester bonds at the first and second nucleotide internucleotide bonds at the 3' and / or 5' ends of the antisense strand.
55. The protein-drug conjugate according to claim 49, wherein the interfering nucleic acid molecule is an antisense oligonucleotide.
56. The protein-drug conjugate of claim 48, wherein the polynucleotide molecule is guide RNA.
57. The protein-drug conjugate according to any one of claims 46-56, wherein the polynucleotide molecule targets a gene or gene product associated with pain, itching, or neurological disorders or impairments.
58. The protein-drug conjugate of claim 57, wherein the gene or gene product associated with pain, pruritus, or neurological disorders or disorders is a voltage-gated sodium channel Nav1.7, a voltage-gated sodium channel Nav1.8, a voltage-gated sodium channel Nav1.9, a voltage-gated sodium channel Nav1.6, a tropomyosin receptor kinase A (TrkA), a tropomyosin receptor kinase C (TRKC), an acid-sensitive ion channel subunit 1 (ASIC1), an acid-sensitive ion channel subunit 3 (ASIC3), a transient receptor potential vanillic acid isoform 1 (TRPV1), a transient receptor potential vanillic acid isoform 4 (TRPV4), a transient receptor potential cation channel subfamily A member 1 (TRPA1), or a transient receptor potential cation channel subfamily A member 1. Member M of the group 8 (TRPM8), fatty acid amide hydrolase (FAAH), piezoelectric mechanosensitive ion channel component 1 (PIEZO1), piezoelectric mechanosensitive ion channel component 2 (PIEZO2), enkephalin, RET proto-oncogene (RET), interleukin-4 receptor (IL4R), interleukin-13 receptor (IL13R), interleukin-31 receptor (IL31R), interleukin-6 receptor α (IL6Ra), glycoprotein 130 (gp130), ion transport regulator 2 containing the FXYD domain (FXYD2), P2X purine receptor 3 (P2X3), calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase activating peptide (PACAP), or interleukin-6 (IL6).
59. The protein-drug conjugate according to any one of claims 46-58, wherein the polynucleotide molecule comprises one or more modified nucleotides.
60. The protein-drug conjugate of claim 46, wherein the molecular cargo comprises a polypeptide molecule.
61. The protein-drug conjugate according to claim 60, wherein the polypeptide molecule is an enzyme, a neuroprotective molecule, or a p75-based peptide. NTR Antigen-binding proteins that bind to targets other than those mentioned above.
62. The protein-drug conjugate of claim 60 or claim 61, wherein the polypeptide molecule is associated with pain, itching, or neurological disorders or impairments.
63. The protein-drug conjugate according to claim 62, wherein the polypeptide molecule is a neurotrophic factor, an antibody or antibody fragment, an antibody receptor fusion protein, or a cytokine signaling inhibitor.
64. The protein-drug conjugate according to any one of claims 43-63, for the treatment or prevention of pain, itching, or neurological disorders or disturbances.
65. The protein-drug conjugate according to any one of claims 57-58 and 62-64, wherein the pain is peripheral chronic pain, chronic neuropathic pain, somatic pain, chronic postoperative pain, small fiber peripheral neuropathy, chemotherapy-induced neuropathy, painful diabetic neuropathy, postherpetic neuralgia, osteoarthritis, back pain, arthralgia, trigeminal neuralgia, trigeminal neuralgia, temporomandibular joint pain, migraine, autonomic dysfunction, or myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS).
66. The protein-drug conjugate of claim 65, wherein the chronic neuropathic pain is trigeminal neuralgia or trigeminal neuropathy.
67. The protein-drug conjugate according to any one of claims 57-58 and 62-64, wherein the pruritus is chronic pruritus.
68. The protein-drug conjugate according to any one of claims 57-58 and 62-64, wherein the neurological disease or disorder is a neurodegenerative disease or disorder, a neurodevelopmental disease or disorder, a physical injury, a neuropsychiatric disease or disorder, or a nervous system cancer.
69. The protein-drug conjugate of claim 68, wherein the neurodegenerative disease or disorder is Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).
70. The protein-drug conjugate of claim 68, wherein the physical injury is traumatic brain injury, spinal cord injury, stroke, or cerebral edema.
71. The protein-drug conjugate of claim 68, wherein the nervous system cancer is brain cancer or peripheral nerve cancer.
72. The protein-drug conjugate according to any one of claims 57-71, wherein the pain, itching, or neurological disorder or impairment is associated with sensory neurons, dorsal root ganglion cells, or trigeminal ganglion cells or populations thereof.
73. The protein-drug conjugate of claim 46, wherein the molecular cargo comprises a carrier.
74. The protein-drug conjugate of claim 73, wherein the carrier is a lipid-based carrier.
75. The protein-drug conjugate of claim 74, wherein the lipid-based carrier is a lipid nanoparticle (LNP), liposome, lipid-like substance, or lipid complex.
76. The protein-drug conjugate of claim 75, wherein the lipid-based carrier is LNP.
77. The protein-drug conjugate of claim 76, wherein the LNP further comprises a polynucleotide molecule and / or a polypeptide molecule.
78. The protein-drug conjugate of claim 76 or 77, wherein the LNP comprises one or more components of a gene editing system.
79. The protein-drug conjugate of claim 78, wherein the LNP comprises: (a) A Cas nuclease or a nucleic acid encoding the Cas nuclease, and / or (b) Guide RNA or one or more DNAs encoding the guide RNA.
80. The protein-drug conjugate of claim 79, wherein the Cas nuclease is the Cas9 protein.
81. The protein-drug conjugate of claim 80, wherein the Cas9 protein is derived from Streptococcus pyogenes. (Streptococcus pyogenes Cas9 protein, Staphylococcus aureus ( Staphylococcus aureus Cas9 protein, Campylobacter jejuni ( Campylobacter jejuni Cas9 protein, Streptococcus thermophilus ( Streptococcus thermophilus Cas9 protein or Neisseria meningitidis ( Neisseria meningitidis Cas9 protein.
82. The protein-drug conjugate according to any one of claims 79-81, wherein the nucleic acid encoding the Cas nuclease is codon-optimized for expression in mammalian cells.
83. The protein-drug conjugate of claim 82, wherein the nucleic acid encoding the Cas nuclease is codon-optimized for expression in human cells.
84. The protein-drug conjugate according to any one of claims 79-83, wherein the nucleic acid encoding the Cas nuclease is mRNA.
85. The protein-drug conjugate according to any one of claims 48, 56-59 and 79-84, wherein the guide RNA is a single-stranded guide RNA (sgRNA).
86. The protein-drug conjugate of claim 78, wherein the LNP comprises a zinc finger nuclease (ZFN) or a transcription activator-like effector nuclease (TALEN).
87. The protein-drug conjugate according to any one of claims 76-86, wherein the LNP comprises cationic lipids, neutral lipids, accessory lipids, occult lipids, or any combination thereof.
88. The protein-drug conjugate according to claim 87, wherein the neutral lipid is distearate phosphatidylcholine (DSPC).
89. The protein-drug conjugate of claim 87, wherein the auxiliary lipid is cholesterol.
90. The protein-drug conjugate of claim 87, wherein the occult lipid is PEG2k-DMG.
91. A pharmaceutical composition comprising the antigen-binding protein of any one of claims 1-38, the isolated polynucleotide of claim 39, the carrier of claim 40, or the protein-drug conjugate of any one of claims 43-90, and a pharmaceutically acceptable carrier.
92. A composition or kit comprising the antigen-binding protein of any one of claims 1-38, the isolated polynucleotide of claim 39, the carrier of claim 40, the protein-drug conjugate of any one of claims 43-90, or the pharmaceutical composition of claim 91, and further therapeutic agents.
93. A complex comprising a receptor for human p75 neurotrophic factor (p75). NTR The polypeptide-bound antigen-binding protein of any one of claims 1-38 or the protein-drug conjugate of any one of claims 43-90.
94. A method for preparing an antigen-binding protein according to any one of claims 1-38, the method comprising culturing host cells containing a polynucleotide encoding the antigen-binding protein in a culture medium under conditions favorable to the expression of the antigen-binding protein.
95. The method according to claim 94, the method comprising the steps of: (a) Introducing the polynucleotide into a host cell; (b) The host cells are cultured under conditions that favor the expression of the antigen-binding protein; (c) Optionally, the antigen-binding protein is isolated from the culture medium and / or the host cells; and (d) Optionally, the antigen-binding protein is conjugated to the molecular cargo.
96. An antigen-binding protein, said antigen-binding protein being generated or obtainable by the method of claim 94 or claim 95.
97. A method for preparing the protein-drug conjugate according to any one of claims 43-90, comprising: (a) The antigen-binding protein is brought into contact with the molecular cargo under conditions that facilitate the conjugation of the antigen-binding protein with the molecular cargo; and (b) Optionally, the protein-drug conjugate produced in step (a) is separated.
98. A method for preparing a protein-drug conjugate according to any one of claims 43-90, wherein the molecular cargo comprises a polypeptide molecule, comprising: (a) Culture host cells containing polynucleotides encoding the protein-drug conjugate under conditions that allow expression of the protein-drug conjugate; and (b) Optionally, the protein-drug conjugate produced in step (a) is separated.
99. A protein-drug conjugate, said protein-drug conjugate being produced or obtainable by the method according to claim 97 or claim 98.
100. A container or injection device comprising an antigen-binding protein according to any one of claims 1-38 and 96, an isolated polynucleotide according to claim 39, a carrier according to claim 40, or a protein-drug conjugate according to any one of claims 43-90 and 99.
101. A method of administering the antigen-binding protein of any one of claims 1-38 and 96, the isolated polynucleotide of claim 39, the carrier of claim 40, or the protein-drug conjugate of any one of claims 43-90 and 99 to a subject, the method comprising introducing the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate into the subject.
102. The method of claim 101, wherein the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is introduced into the subject via subcutaneous, intramuscular, or intravenous administration.
103. The method of claim 101, wherein the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is introduced into the subject via intrathecal, intracisional, intraventricular, or intraparenchymal administration.
104. The method of claim 101, wherein the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is introduced into the subject via intravitreal administration into the eye.
105. A method for delivering molecular cargo into a subject to express p75. NTR A method for determining the tissue or cell type, the method comprising administering to the subject the protein-drug conjugate of any one of claims 43-90 and 99 or the pharmaceutical composition of claim 91.
106. The method of claim 105, wherein the tissue is the brain, spinal cord, peripheral nervous system, autonomic nervous system, enteric nervous system, or eye.
107. The method of claim 106, wherein the tissue is the brain or spinal cord.
108. The method of claim 105, wherein the cell type is a sensory neuron.
109. The method of claim 105, wherein the cell type is a dorsal root ganglion cell or a trigeminal ganglion cell.
110. The method according to any one of claims 105-109, wherein the protein-drug conjugate is introduced into the subject via subcutaneous, intramuscular, or intravenous administration.
111. The method according to any one of claims 105-109, wherein the protein-drug conjugate is introduced into the subject via subcutaneous, intrathecal, intracisional, intraventricular, or intraparenchymal administration.
112. The method according to any one of claims 105-109, wherein the protein-drug conjugate is introduced into the subject via intravitreal administration into the eye.
113. The method of claim 107 or claim 110, wherein the protein-drug conjugate is introduced into the subject via subcutaneous administration.
114. The method of claim 107 or claim 111, wherein the protein-drug conjugate is introduced into the subject via intracerebroventricular administration.
115. A method for treating or preventing pain, pruritus, or neurological disorders or impairments in a subject in need, the method comprising administering to the subject an effective amount of the antigen-binding protein of any one of claims 1-38 and 96, the isolated polynucleotide of claim 39, the carrier of claim 40, or the protein-drug conjugate of any one of claims 43-90 and 99, or the pharmaceutical composition of claim 91.
116. The method of claim 115, wherein the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is administered subcutaneously, intramuscularly, or intravenously.
117. The method of claim 115, wherein the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is introduced into the subject via intrathecal, intracisional, intraventricular, or intraparenchymal administration.
118. The method of claim 115, wherein the antigen-binding protein, the polynucleotide, the carrier, or the protein-drug conjugate is introduced into the subject via intravitreal administration into the eye.
119. The method according to any one of claims 115-118, wherein the pain is peripheral chronic pain, chronic neuropathic pain, somatic pain, chronic postoperative pain, small fiber peripheral neuropathy, chemotherapy-induced neuropathy, painful diabetic neuropathy, postherpetic neuralgia, osteoarthritis, back pain, arthralgia, trigeminal neuralgia, trigeminal neuralgia, temporomandibular joint pain, migraine, autonomic dysfunction, or myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS).
120. The method of claim 119, wherein the chronic neuropathic pain is trigeminal neuralgia or trigeminal neuropathy.
121. The method according to any one of claims 115-118, wherein the pruritus is chronic pruritus.
122. The method according to any one of claims 115-118, wherein the neurological disease or disorder is a neurodegenerative disease, a neurodevelopmental disease, chronic neuropathic pain, physical injury, neuropsychiatric disease, or nervous system cancer.
123. The method of claim 122, wherein the neurodegenerative disease or disorder is Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS).
124. The method of claim 122, wherein the physical injury is traumatic brain injury, spinal cord injury, stroke, or cerebral edema.
125. The method of claim 122, wherein the nervous system cancer is brain cancer or peripheral nerve cancer.
126. The method according to any one of claims 115-125, wherein the pain, itching, or neurological disorder or impairment is associated with sensory neurons, dorsal root ganglion cells, trigeminal ganglion cells, or a population thereof.
127. The method according to any one of claims 101-126, the method further comprising administering additional treatment to the subject.
128. The method of claim 127, wherein the additional treatment comprises administration of a nonsteroidal anti-inflammatory drug (NSAID), acetaminophen, a local anesthetic, capsaicin, a Cox-2 inhibitor, an antidepressant, an anticonvulsant, an antiepileptic drug, an opioid, a steroid, an anticonvulsant, a muscle relaxant, a triptan, dihydroergotamine, lamiditan, a calcitonin gene-related peptide antagonist, an antiemetic, a beta-blocker, a calcium channel blocker, a serotonin and norepinephrine reuptake inhibitor (SNRI), botulinum toxin A, or a benzodiazepine, or a combination thereof.
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