Natriuretic peptide receptor 1 antibodies and methods of use

By developing antibodies that can activate NPR1 without ANP, the problem of existing antibodies failing in the absence of ANP is solved, and the potential efficacy improvement in the treatment of heart failure is achieved.

CN119613549APending Publication Date: 2025-03-14NOVARTIS AG
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Patent Information

Application Number
CN202411828892.4
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Priority Date
2019-06-12
Filing Date
2020-06-10
Publication Date
2025-03-14

AI Technical Summary

Technical Problem

Existing antibodies against NPR1 do not have functional activity in the absence of ANP and do not have functional activity in the body, so they cannot effectively treat heart failure.

Method used

Develop antibodies that bind to NPR1 and activate NPR1 in the absence of ANP, including ANP-competitive and ANP-non-competitive antibodies. These antibodies bind to specific epitopes and can stably activate NPR1, mimicking the effects of ANP.

Benefits of technology

In mouse and rat models, these antibodies showed in vivo activity, able to enhance the body's natural system, consolidate existing therapeutic principles, and functionally equivalent to ANP.

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Abstract

The present disclosure relates to anti-natriuretic peptide receptor 1 (NPR1) antibodies, including agonist antibodies capable of activating the NPR1 receptor; a pharmaceutical composition comprising the antibody; and methods of treatment comprising the antibodies.
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Description

[0001] This application is a divisional application of Chinese application No. 202080043331.7, whose application date is June 10, 2020 and whose invention name is “Natriuretic Peptide Receptor 1 Antibodies and Methods of Use”. Background Art

[0002] Heart failure is a major public health problem affecting more than 20 million patients worldwide (Orso et al., 2014, Expert Opin Pharmacother. 15(13):1849-1861) and is associated with high morbidity (Ibebuogu et al., 2011, Circulation. Heart failure 4(2):114-120). Natriuretic Peptide Receptor 1 (NPR1; also known as NPRA) is a receptor guanylate cyclase that is activated by atrial natriuretic peptide (ANP), resulting in a decrease in blood pressure and blood volume (Chen & Burnett, 2006, European Heart Journal Supplements 8 (Supplement E): E18-E25; Ibebuogu et al. 2011, supra; Mani et al. 2015, Bioscience Reports 35(5): e00260). ANP binding induces dimerization and twisting of the receptor, thereby inducing activation of the guanylate cyclase domain and conversion of GTP to cGMP (Misono et al., 2011, The FEBS journal 278(11): 1818-1829). ANP is cleared by NPR3, a natriuretic peptide receptor lacking a guanylate cyclase domain, and is degraded by neutral endopeptidase (NEP) (Chen & Burnett 2006, supra; Schmitt et al., 2003, Clin Sci (Lond). [Clinical Science (London)] 105 (2): 141-160). Certain antibodies against NPR1 (including antibody 5591-IgG) are described, for example, in WO 2010 / 065293. However, these antibodies do not appear to be functionally active in vitro in the absence of ANP and are not functionally active in vivo.

[0003] It has been shown that an increase in ANP may be beneficial for patients with heart failure (heart pumping blood outward) with reduced ejection fraction. See McMurray et al., N. Engl. J. Med. [New England Journal of Medicine]; Vol. 371, No. 11, pp. 993-1004 (2014); and Nougué et al., Eur J Heart Fail. [European Journal of Heart Failure] May 2019; 21(5): 598-605. However, there is a need for longer-acting agents with alternative modes of action to supplement or replace existing therapies. Summary of the invention

[0004] It is demonstrated herein that NPR1 can be activated by using agonistic anti-NPR1 antibodies or antigen-binding fragments thereof. In addition, the present disclosure demonstrates that there are two types of such antibodies. One type binds to NPR1 and competes with ANP binding (but still activates NPR1; hereinafter referred to as "ANP-competitive" anti-NPR1 antibodies), while the second type is able to bind and activate NPR1 without competing with ANP (hereinafter referred to as "ANP-noncompetitive" anti-NPR1 antibodies). Such antibodies (e.g., ANP-noncompetitive anti-NPR1 antibodies) can be used to enhance the body's natural systems and / or consolidate existing therapeutic principles. In addition, it has been found that certain NPR1 agonist antibodies that can activate NPR1 in the absence of ANP are functionally equivalent to ANP.

[0005] The antibodies of the present application have shown in vivo activity in both mice and rats. In addition, the unique epitope binding of the antibodies described herein has been demonstrated using crystal structure data.

[0006] Thus, the present disclosure provides an anti-NPR1 antibody (e.g., a human monoclonal antibody) or an antigen-binding fragment thereof, which (i) binds to natriuretic peptide receptor 1 (NPR1); and (ii) is capable of activating NPR1 in the absence of ANP. Such antibodies are agonistic anti-NPR1 antibodies. In some embodiments of the present invention, the present disclosure also provides an anti-NPR1 antibody or an antigen-binding fragment thereof, which (i) binds to natriuretic peptide receptor 1 (NPR1); and (ii) activates NPR1 in the absence of ANP. In some embodiments of the present invention, the present disclosure also provides an antibody or an antigen-binding fragment thereof, which (i) binds to natriuretic peptide receptor 1 (NPR1); and (ii) is capable of activating NPR1 both in the presence and absence of ANP. Also provided are nucleic acids encoding the antibodies, vectors comprising the nucleic acids, host cells comprising the nucleic acids and / or vectors, and methods of making the antibodies using the nucleic acids, vectors and / or host cells. Also provided are pharmaceutical compositions and combinations comprising the antibodies, nucleic acids, vectors or host cells, and methods of treating using the antibodies, nucleic acids, vectors, host cells or pharmaceutical compositions. Also disclosed herein is the use of the antibody, nucleic acid, vector, host cell or pharmaceutical composition or combination in treating a disease.

[0007] Thus, in one aspect of the invention, provided herein is an isolated antibody or antigen-binding fragment that (i) binds to natriuretic peptide receptor 1 (NPR1); and (ii) is capable of activating NPR1 in the absence of atrial natriuretic peptide (ANP). In some embodiments of the invention, the isolated antibody or antigen-binding fragment does not bind to and / or activate natriuretic peptide receptor 2 (NPR2) and / or natriuretic peptide receptor 3 (NPR3). In some embodiments of the invention, the isolated antibody or antigen-binding fragment binds to (a) human NPR1; and (b) mouse NPR1 and / or rat NPR1.

[0008] In some embodiments of the invention, the antibody or antigen binding fragment binds to (a) human NPR1; and (b) cynomolgus monkey NPR1. In some embodiments of the invention, the antibody or antigen binding fragment is ANP non-competitive. In some embodiments of the invention, the antibody or antigen binding fragment is ANP competitive. In some embodiments of the invention, the antibody or antigen binding fragment is capable of stabilizing the ANP-NPR1 complex.

[0009] In some embodiments of the invention, the antibody or antigen-binding fragment binds to an epitope within amino acids 99-133 of SEQ ID NO: 1, e.g., within the region of human NPR1 encompassed by amino acids 99-133 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen-binding fragment binds to an epitope comprising at least two amino acid residues within amino acids 99-133 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen-binding fragment binds to an epitope comprising at least 3, 4, 5, 6, 7, or 8 amino acid residues within amino acids 99-133 of SEQ ID NO: 1.

[0010] In some embodiments of the invention, the antibody or antigen binding fragment binds to an epitope within amino acids 99-111 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen binding fragment binds to an epitope within amino acids 99-103 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen binding fragment binds to an epitope within amino acids 105-111 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen binding fragment binds to an epitope comprising at least 2, 3, or 4 amino acid residues within amino acids 105-111 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen-binding fragment binds to a conformational epitope of human NPR1, and wherein the conformational epitope comprises at least one amino acid residue in each of (i) amino acids 99-103 of SEQ ID NO: 1, (ii) amino acids 105-111 of SEQ ID NO: 1, (iii) amino acids 131-134 of SEQ ID NO: 1, and also binds to amino acids 375 and / or 378 of SEQ ID NO: 1. In some embodiments of the invention, the epitope is a conformational epitope, and the conformational epitope additionally comprises at least one amino acid residue selected from the group consisting of amino acids 33, 34, 76, 82, and 104 of SEQ ID NO: 1. In some embodiments of the invention, the conformational epitope additionally comprises at least one amino acid residue selected from the group consisting of amino acids 33, 34, 76, 82, 104, 374, and 375 of SEQ ID NO: 1.

[0011] In some embodiments of the invention, the antibody or antigen binding fragment binds to at least amino acids 82, 102, 103, 105, 106, 109, 132, and 375 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen binding fragment binds to at least amino acids 34, 82, 102, 103, 105, 106, 107, 109, 132, 133, 375, and 378 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen binding fragment binds to at least amino acids 79, 82, 99, 102, 103, 105, 106, 109, 131, 132, and 375 of SEQ ID NO: 1.

[0012] In some embodiments of the invention, the antibody or antigen binding fragment binds to an epitope within amino acids 188-219 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen binding fragment binds to an epitope comprising at least 2, 3, 4, 5, 6, or 7 amino acids within amino acids 188-219 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen binding fragment binds to a conformational epitope within NPR1, and the conformational epitope comprises at least one amino acid residue in each of (i) amino acids 188-198 of SEQ ID NO: 1, (ii) amino acids 201-208 of SEQ ID NO: 1, (iii) amino acids 215-238 of SEQ ID NO: 1, and (iv) amino acids 294-297 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen binding fragment binds to at least amino acids 188, 192, 194, 197, 201, 208, and 219 of SEQ ID NO: 1. In some embodiments of the invention, the antibody or antigen-binding fragment binds to at least amino acids 188, 192, 194, 197, 201, 208, 219 and 295 of SEQ ID NO:1.

[0013] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3), wherein: (a) (I) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 28; HCDR2 comprises or consists of the amino acid sequence shown in X 1 IX 2 SX 3 GX 4 YX 5 X 6YADSVKG (SEQ ID NO: 429) or consisting of the amino acid sequence, wherein X 1 A or V, X 2 It is S or E, X 3 Is D or K, X 4 Is S or N, X 5 is I or T, and X 6 is Y or F; HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 30; LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 41; LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 42; and LCDR3 comprises Y 1 QY 2 Y 3 Y 4 Y 5 PRT (SEQ ID NO: 430) or consisting of the amino acid sequence; wherein Y 1 It is M or Q, Y 2 is S, E, T or I, Y 3 It is Y or W, Y 4 is E, V, R, A, T, or M, and Y 5 is K, V, R or A; (II) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 31; HCDR2 comprises X 1 IX 2 SX 3 GX 4 YX 5 X 6 YADSVKG (SEQ ID NO: 429) or consisting of the amino acid sequence, wherein X 1 A or V, X 2 It is S or E, X 3 Is D or K, X 4 Is S or N, X 5 is I or T, and X 6 is Y or F; HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 30, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 41, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 42, and LCDR3 comprises Y 1 QY 2 Y 3 Y 4 Y 5 PRT (SEQ ID NO: 430) or consisting of the amino acid sequence; wherein Y 1 It is M or Q, Y2 is S, E, T or I, Y 3 It is Y or W, Y 4 is E, V, R, A, T, or M, and Y 5 is K, V, R or A; (III) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 32, and HCDR2 comprises X 1 SX 2 GX 3 Y (SEQ ID NO: 431) or consisting of the amino acid sequence, wherein X 1 It is S or E, X 2 It is D or K, or X 3 is S or N, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 30, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 44, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 45, and LCDR3 comprises Y 1 Y 2 Y 3 Y 4 PR (SEQ ID NO: 432) or consisting of the amino acid sequence thereof; wherein Y 1 is S, E, T or I, Y 2 It is Y or W, Y 3 is E, V, R, A, T, or M, and Y 4 is K, V, R or A; or (IV) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 34, and HCDR2 comprises 1 SX 2 GX 3 YX 4 (SEQ ID NO: 433) or consisting of the amino acid sequence, wherein X 1 It is S or E, X 2 Is D or K, X 3 is S or N, and X 4 is I or T, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 36, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 47, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 45, and LCDR3 comprises Y 1 QY 2 Y 3 Y 4 Y 5 PRT (SEQ ID NO: 430) or consisting of the amino acid sequence thereof; wherein Y 1It is M or Q, Y 2 is S, E, T or I, Y 3 It is Y or W, Y 4 is E, V, R, A, T, or M, and Y 5 is K, V, R or A; (b) (I) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 28; HCDR2 comprises X 1 IX 2 SX 3 GX 4 YX 5 X 6 YADSVKG (SEQ ID NO: 429) or consisting of the amino acid sequence, wherein X 1 A or V, X 2 It is S or E, X 3 Is D or K, X 4 Is S or N, X 5 is I or T, and X 6 is Y or F; HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 30; LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 41; LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 42; and LCDR3 comprises QQY 1 WY 2 Y 3 PRT (SEQ ID NO: 434) or consisting of the amino acid sequence thereof; wherein Y 1 is S, E, T or I, Y 2 is V, R, A, T, or M, and Y 3 is K, V, R or A; (II) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 31; HCDR2 comprises X 1 IX 2 SX 3 GX 4 YX 5 X 6 YADSVKG (SEQ ID NO: 429) or consisting of the amino acid sequence, wherein X 1 A or V, X 2 It is S or E, X 3 Is D or K, X 4 Is S or N, X 5 is I or T, and X 6is Y or F; HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 30, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 41, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 42, and LCDR3 comprises QQY 1 WY 2 Y 3 PRT (SEQ ID NO: 434) or consisting of the amino acid sequence thereof; wherein Y 1 is S, E, T or I, Y 2 is V, R, A, T, or M, and Y 3 is K, V, R or A; (III) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 32, and HCDR2 comprises X 1 SX 2 GX 3 Y (SEQ ID NO: 431) or consisting of the amino acid sequence, wherein X 1 It is S or E, X 2 It is D or K, or X 3 is S or N, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 30, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 44, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 45, and LCDR3 comprises Y 1 WY 2 Y 3 PR (SEQ ID NO: 435) or consisting of the amino acid sequence; wherein Y 1 is S, E, T or I, Y 2 is V, R, A, T, or M, and Y 3 is K, V, R or A; or (IV) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 34, and HCDR2 comprises 1 SX 2 GX 3 YX 4 (SEQ ID NO: 433) or consisting of the amino acid sequence, wherein X 1 It is S or E, X 2 Is D or K, X 3 is S or N, and X 4is I or T, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:36, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:47, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 comprises QQY 1 WY 2 Y 3 PRT (SEQ ID NO: 434) or consisting of the amino acid sequence thereof; wherein Y 1 is S, E, T or I, Y 2 is V, R, A, T, or M, and Y 3 is K, V, R or A; (c)(I) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:28; HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:119; HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:30; LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:41; LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:42; and LCDR3 comprises QQY 1 WY 2 Y 3 PRT (SEQ ID NO: 434) or consisting of the amino acid sequence thereof; wherein Y 1 is S, E, T or I, Y 2 is V, R, A, T, or M, and Y 3 is K, V, R or A; (II) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:31; HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:119; HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:41, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:42, and LCDR3 comprises QQY 1 WY 2 Y 3 PRT (SEQ ID NO: 434) or consisting of the amino acid sequence thereof; wherein Y 1 is S, E, T or I, Y 2 is V, R, A, T, or M, and Y 3is K, V, R or A; (III) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:32, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:120, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:44, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 comprises Y 1 WY 2 Y 3 PR (SEQ ID NO: 435) or consisting of the amino acid sequence; wherein Y 1 is S, E, T or I, Y 2 is V, R, A, T, or M, and Y 3 is K, V, R or A; or (IV) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:34, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:121, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:36, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:47, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 comprises QQY 1 WY 2 Y 3 PRT (SEQ ID NO: 434) or consisting of the amino acid sequence thereof; wherein Y 1 is S, E, T or I, Y 2 is V, R, A, T, or M, and Y 3 is K, V, R or A; (d)(I) HCDR1 comprises GFTFX 1 The amino acid sequence shown in THYIH (SEQ ID NO: 436) or consists of it, wherein X 1 is N, S or Q, HCDR2 contains SIY 1 Y 2 Y 3 GY 4 Y 5 TY 6 YADSVKG (SEQ ID NO: 437) or consisting of the amino acid sequence, wherein Y 1 It is S or G, Y 2 It is S or G, Y 3 It is S or Q, Y 4 is S, Q or G, Y 5 is S, N, or M, and Y 6is Y or L, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:17, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:18, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:19; (II) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:7, HCDR2 comprises SIY 1 Y 2 Y 3 GY 4 Y 5 TY 6 YADSVKG (SEQ ID NO: 437) or consisting of the amino acid sequence, wherein Y 1 It is S or G, Y 2 It is S or G, Y 3 It is S or Q, Y 4 is S, Q or G, Y 5 is S, N, or M, and Y 6 is Y or L, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:17, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:18, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:19; (III) HCDR1 comprises GFTFX 1 TH (SEQ ID NO: 438) or consisting of the amino acid sequence, wherein X 1 is N, S or Q, HCDR2 contains Y 1 Y 2 Y 3 GY 4 Y 5 (SEQ ID NO: 439) or consisting of the amino acid sequence, wherein Y 1 It is S or G, Y 2 It is S or G, Y 3 It is S or Q, Y 4 is S, Q, or G, and Y 5is S, N or M, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:20, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:21, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:22; or (IV) HCDR1 comprises GFTFX 1 The amino acid sequence of THY (SEQ ID NO: 440) or consists of the amino acid sequence thereof, wherein X 1 is N, S or Q, HCDR2 comprises IY 1 Y 2 Y 3 GY 4 Y 5 T (SEQ ID NO: 441) or consisting of the amino acid sequence, wherein Y 1 It is S or G, Y 2 It is S or G, Y 3 It is S or Q, Y 4 is S, Q, or G, and Y 5 is S, N or M, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 12, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 23, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 21, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 19; (e) (I) HCDR1 comprises GFTFX 1 The amino acid sequence shown in THYIH (SEQ ID NO: 436) or consists of it, wherein X 1 is N, S or Q, HCDR2 contains SISY 1 SGY 2 Y 3 TYYADSVKG (SEQ ID NO: 442) or consisting of the amino acid sequence, wherein Y 1 It is S or G, Y 2 is S or Q, and Y 3 is S or N, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:17, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:18, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:19; (II) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:7, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 1SGY 2 Y 3 TYYADSVKG (SEQ ID NO: 442) or consisting of the amino acid sequence, wherein Y 1 It is S or G, Y 2 is S or Q, and Y 3 is S or N, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:17, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:18, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:19; (III) HCDR1 comprises GFTFX 1 TH (SEQ ID NO: 438) or consisting of the amino acid sequence, wherein X 1 is N, S or Q, HCDR2 contains SY 1 SGY 2 Y 3 (SEQ ID NO: 443) or consisting of the amino acid sequence, wherein Y 1 It is S or G, Y 2 is S or Q, and Y 3 is S or N, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:20, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:21, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:22; or (IV) HCDR1 comprises GFTFX 1 The amino acid sequence of THY (SEQ ID NO: 440) or consists of the amino acid sequence thereof, wherein X 1 is N, S or Q, HCDR2 contains ISY 1 SGY 2 Y 3 T (SEQ ID NO: 444) or consisting of the amino acid sequence, wherein Y 1 It is S or G, Y 2 is S or Q, and Y 3 is S or N, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 12, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 23, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 21, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 19; (f)(I) HCDR1 comprises GFX1 FSX 2 YX 3 X 4 X 5 (SEQ ID NO: 445) or consisting of the amino acid sequence, wherein X 1 Is S or T, X 2 is S, K or R, X 3 W or Y, X 4 is I or L, and X 5 is S or N, HCDR2 contains Y 1 IY 2 QY 3 Y 4 Y 5 EY 6 Y 7 The amino acid sequence shown in YVESVKG (SEQ ID NO: 446) or consists of it, wherein Y 1 It is S or N, Y 2 It is K or H, Y 3 is S, Q or H, Y 4 It is G or A, Y 5 S, H or L, Y 6 is T or K, and Y 7 is Y, K or R, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 237, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 238, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 239; (II) HCDR1 comprises X 1 YX 2 X 3 X 4 (SEQ ID NO: 447) or consisting of the amino acid sequence, wherein X 1 is S, K or R, X 2 W or Y, X 3 is I or L, and X 4 is S or N, HCDR2 contains Y 1 IY 2 QY 3 Y 4 Y 5 EY 6 Y 7 The amino acid sequence shown in YVESVKG (SEQ ID NO: 446) or consists of it, wherein Y 1 It is S or N, Y 2 It is K or H, Y 3is S, Q or H, Y 4 It is G or A, Y 5 S, H or L, Y 6 is T or K, and Y 7 is Y, K or R, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 237, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 238, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 239; (III) HCDR1 comprises GFX 1 FSX 2 Y (SEQ ID NO: 448) or consisting of the amino acid sequence, wherein X 1 is S or T, and X 2 is S, K or R, HCDR2 comprises Y 1 QY 2 Y 3 Y 4 E (SEQ ID NO: 449) or consisting thereof, wherein Y 1 It is K or H, Y 2 is S, Q or H, Y 3 is G or A, and Y 4 is S, H or L, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 240, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 241, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 242; or (IV) HCDR1 comprises GFX 1 FSX 2 YX 3 (SEQ ID NO: 450) or consisting of the amino acid sequence, wherein X 1 Is S or T, X 2 is S, K, or R, and X 3 is W or Y, HCDR2 comprises IY 1 QY 2 Y 3 Y 4 EY 5 (SEQ ID NO: 451) or consisting of the amino acid sequence, wherein Y 1 It is K or H, Y 2 is S, Q or H, Y 3 It is G or A, Y 4is S, H or L, and Y 5 is T or K, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 232, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 243, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 241, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 239; (g)(I) HCDR1 comprises GFX 1 FSX 2 YX 3 X 4 X 5 (SEQ ID NO: 445) or consisting of the amino acid sequence, wherein X 1 Is S or T, X 2 is S, K or R, X 3 W or Y, X 4 is I or L, and X 5 is S or N, HCDR2 contains SIHQY 1 Y 2 Y 3 EY 4 Y 5 The amino acid sequence shown in YVESVKG (SEQ ID NO: 453) or consists of it, wherein Y 1 It is Q or H, Y 2 It is G or A, Y 3 It is H or L, Y 4 is T or K, and Y 5 is K or R, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 237, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 238, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 239; (II) HCDR1 comprises X 1 YX 2 X 3 X 4 (SEQ ID NO: 447) or consisting of the amino acid sequence, wherein X 1 is S, K or R, X 2 W or Y, X 3 is I or L, and X 4 is S or N, HCDR2 contains SIHQY 1 Y 2 Y 3 EY 4 Y 5The amino acid sequence shown in YVESVKG (SEQ ID NO: 453) or consists of it, wherein Y 1 It is Q or H, Y 2 It is G or A, Y 3 It is H or L, Y 4 is T or K, and Y 5 is K or R, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 237, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 238, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 239; (III) HCDR1 comprises GFX 1 FSX 2 Y (SEQ ID NO: 448) or consisting of the amino acid sequence, wherein X 1 is S or T, and X 2 is S, K or R, HCDR2 contains HQY 1 Y 2 Y 3 E (SEQ ID NO: 456) or consisting thereof, wherein Y 1 It is Q or H, Y 2 is G or A, and Y 3 is H or L, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 240, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 241, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 242; or (IV) HCDR1 comprises GFX 1 FSX 2 YX 3 (SEQ ID NO: 450) or consisting of the amino acid sequence, wherein X 1 Is S or T, X 2 is S, K, or R, and X 3 is W or Y, HCDR2 comprises IHQY 1 Y 2 Y 3 EY 4 (SEQ ID NO: 458) or consisting of the amino acid sequence, wherein Y 1 It is Q or H, Y 2 It is G or A, Y 3 is H or L, and Y 4is T or K, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 232, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 243, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 241, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 239; (h)(I) HCDR1 comprises GFTFSX 1 YX 2 IX 3 (SEQ ID NO: 452) or consisting of the amino acid sequence, wherein X 1 Is S or R, X 2 is W or Y, and X 3 is S or N, HCDR2 contains Y 1 IY 2 QY 3 Y 4 Y 5 EY 6 Y 7 The amino acid sequence shown in YVESVKG (SEQ ID NO: 446) or consists of it, wherein Y 1 It is S or N, Y 2 It is K or H, Y 3 is S, Q or H, Y 4 It is G or A, Y 5 S, H or L, Y 6 is T or K, and Y 7 is Y, K or R, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 237, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 238, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 239; (II) HCDR1 comprises X 1 YX 2 IX 3 (SEQ ID NO: 454) or consisting of the amino acid sequence, wherein X 1 Is S or R, X 2 is W or Y, and X 3 is S or N, HCDR2 contains Y 1 IY 2 QY 3 Y 4 Y 5 EY 6 Y 7The amino acid sequence shown in YVESVKG (SEQ ID NO: 446) or consists of it, wherein Y 1 It is S or N, Y 2 It is K or H, Y 3 is S, Q or H, Y 4 It is G or A, Y 5 S, H or L, Y 6 is T or K, and Y 7 is Y, K or R, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 237, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 238, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 239; (III) HCDR1 comprises GFTFSX 1 Y (SEQ ID NO: 455) or consisting of the amino acid sequence, wherein X 1 is S or R, HCDR2 contains Y1QY 2 Y 3 Y 4 E (SEQ ID NO: 449) or consisting thereof, wherein Y 1 It is K or H, Y 2 is S, Q or H, Y 3 is G or A, and Y 4 is S, H or L, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 240, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 241, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 242; or (IV) HCDR1 comprises GFTFSX 1 YX 2 (SEQ ID NO: 457) or consists of the amino acid sequence, wherein X 1 is S or R, and X 2 is W or Y, HCDR2 comprises IY 1 QY 2 Y 3 Y 4 EY 5 (SEQ ID NO: 451) or consisting of the amino acid sequence, wherein Y 1 It is K or H, Y 2 is S, Q or H, Y 3 It is G or A, Y 4is S, H or L, and Y 5 is T or K, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 232, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 243, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 241, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 239; or (i) (I) HCDR1 comprises GFTFSX 1 YX 2 IX 3 (SEQ ID NO: 452) or consisting of the amino acid sequence, wherein X 1 Is S or R, X 2 is W or Y, and X 3 is S or N, HCDR2 contains SIHQY 1 Y 2 Y 3 EY 4 Y 5 The amino acid sequence shown in YVESVKG (SEQ ID NO: 453) or consists of it, wherein Y 1 It is Q or H, Y 2 It is G or A, Y 3 It is H or L, Y 4 is T or K, and Y 5 is K or R, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 237, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 238, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 239; (II) HCDR1 comprises X 1 YX 2 IX 3 (SEQ ID NO: 454) or consisting of the amino acid sequence, wherein X 1 Is S or R, X 2 is W or Y, and X 3 is S or N, HCDR2 contains SIHQY 1 Y 2 Y 3 EY 4 Y 5 YVESVKG (SEQ ID NO: 453) or consisting of the amino acid sequence, wherein Y 1 It is Q or H, Y 2 It is G or A, Y 3 It is H or L, Y4 is T or K, and Y 5 is K or R, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 237, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 238, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 239; (III) HCDR1 comprises GFTFSX 1 Y (SEQ ID NO: 455) or consisting of the amino acid sequence, wherein X 1 is S or R, HCDR2 contains HQY1Y 2 Y 3 E (SEQ ID NO: 456) or consisting thereof, wherein Y 1 It is Q or H, Y 2 is G or A, and Y 3 is H or L, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 240, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 241, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 242; or (IV) HCDR1 comprises GFTFSX 1 YX 2 (SEQ ID NO: 457) or consists of the amino acid sequence, wherein X 1 is S or R, and X 2 is W or Y, HCDR2 comprises IHQY 1 Y 2 Y 3 EY 4 (SEQ ID NO: 458) or consisting of the amino acid sequence, wherein Y 1 It is Q or H, Y 2 It is G or A, Y 3 is H or L, and Y 4 is T or K, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 232, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 243, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 241, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 239.

[0014] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3), wherein: (a) (I) HCDR1 comprises or consists of the amino acid sequence as shown in SEQ ID NO: 310, HCDR2 comprises or consists of the amino acid sequence as shown in SEQ ID NO: 311, HCDR3 comprises or consists of the amino acid sequence as shown in SEQ ID NO: 312, 1 X 2 X 3 GX 4 LGFDH (SEQ ID NO: 459) or consisting of the amino acid sequence thereof, wherein X 1 A or S, X 2 It is V or L, X 3 is A or P, and X 4 is Q or L, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 320, and LCDR2 comprises GNSNRPY 1 (SEQ ID NO: 460) or consisting of the amino acid sequence, wherein Y 1 is S or N, and LCDR3 contains QSYZ 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 V (SEQ ID NO: 461) or consisting of the amino acid sequence, wherein Z 1 is Y, D or G, Z 2 It is T, S or A, Z 3 is S, P or F, Z 4 is S, T or P, Z 5 is H, S or R, Z 6 is G, S or F, and Z 7 is P, S or V; (II) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 229, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 311, and HCDR3 comprises GX 1 X 2 X 3 GX 4 LGFDH (SEQ ID NO: 459) or consisting of the amino acid sequence, wherein X 1 A or S, X 2 It is V or L, X 3 is A or P, and X 4is Q or L, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 320, and LCDR2 comprises GNSNRPY 1 (SEQ ID NO: 460) or consisting of the amino acid sequence, wherein Y 1 is S or N, and LCDR3 contains QSYZ 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 V (SEQ ID NO: 461) or consisting of the amino acid sequence, wherein Z 1 is Y, D or G, Z 2 It is T, S or A, Z 3 is S, P or F, Z 4 is S, T or P, Z 5 is H, S or R, Z 6 is G, S or F, and Z 7 is P, S or V; (III) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 80, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 313, and HCDR3 comprises GX 1 X 2 X 3 GX 4 LGFDH (SEQ ID NO: 459) or consisting of the amino acid sequence, wherein X 1 A or S, X 2 It is V or L, X 3 is A or P, and X 4 is Q or L, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 323, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 324, and LCDR3 comprises YZ 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 (SEQ ID NO: 462) or consists of the amino acid sequence, wherein Z 1 is Y, D or G, Z 2 It is T, S or A, Z 3 is S, P or F, Z 4 is S, T or P, Z 5 is H, S or R, Z 6 is G, S or F, and Z7 is P, S or V; or (IV) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 82, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 314, and HCDR3 comprises ARGX 1 X 2 X 3 GX 4 LGFDH (SEQ ID NO: 463) or consisting of the amino acid sequence, wherein X 1 A or S, X 2 It is V or L, X 3 is A or P, and X 4 is Q or L, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 326, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 324, and LCDR3 comprises QSYZ 1 Z 2 Z 3 Z 4 Z 5 Z 6 Z 7 V (SEQ ID NO: 461) or consisting of the amino acid sequence, wherein Z 1 is Y, D or G, Z 2 It is T, S or A, Z 3 is S, P or F, Z 4 is S, T or P, Z 5 is H, S or R, Z 6 is G, S or F, and Z 7 is P, S or V; (b)(I) HCDR1 comprises GFTFX 1 X 2 YAX 3 X 4 (SEQ ID NO: 464) or consisting of the amino acid sequence, wherein X 1 It is S or G, X 2 Is S or T, X 3 is I or M, and X 4 is S or T, HCDR2 contains Y 1 ISY 2 Y 3 GY 4 Y 5 Y 6 Y 7 YAY 8 SVKG (SEQ ID NO: 465) or consisting of the amino acid sequence, wherein Y 1 A or S, Y2 A, S or G, Y 3 It is S or H, Y 4 It is G or Y, Y 5 It is S or Y, Y 6 It is T or A, Y 7 is Y, R, or N, and Y 8 is E or G, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 331, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 337, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 338, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 339; (II) HCDR1 comprises X 1 YAX 2 X 3 (SEQ ID NO: 466) or consisting of the amino acid sequence, wherein X 1 Is S or T, X 2 is I or M, and X 3 is S or T, HCDR2 contains Y 1 ISY 2 Y 3 GY 4 Y 5 Y 6 Y 7 YAY 8 SVKG (SEQ ID NO: 465) or consisting of the amino acid sequence, wherein Y 1 A or S, Y 2 A, S or G, Y 3 It is S or H, Y 4 It is G or Y, Y 5 It is S or Y, Y 6 It is T or A, Y 7 is Y, R, or N, and Y 8 is E or G, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 331, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 337, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 338, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 339; (III) HCDR1 comprises GFTFX 1 X 2 Y (SEQ ID NO: 467) or consisting of the amino acid sequence, wherein X 1 is S or G, and X 2 is S or T, HCDR2 contains SY1 Y 2 GY 3 Y 4 (SEQ ID NO: 468) or consisting of the amino acid sequence, wherein Y 1 A, S or G, Y 2 It is S or H, Y 3 is G or Y, and Y 4 is S or Y, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 331, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 340, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 341, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 342; or (IV) HCDR1 comprises GFTFX 1 X 2 YA (SEQ ID NO: 469) or consisting of the amino acid sequence, wherein X 1 is S or G, and X 2 is S or T, HCDR2 contains ISY 1 Y 2 GY 3 Y 4 T (SEQ ID NO: 470) or consisting of the amino acid sequence, wherein Y 1 It is S or G, Y 2 It is S or H, Y 3 is G or Y, and Y 4 is S or Y, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 332, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 343, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 341, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 339; or (c) (I) HCDR1 comprises GFTFX 1 X 2 YAX 3 X 4 (SEQ ID NO: 464) or consisting of the amino acid sequence, wherein X 1 It is S or G, X 2 Is S or T, X 3 is I or M, and X 4 is S or T, HCDR2 contains SISY 1 Y 2 YYY 3 Y 4 YAY 5SVKG (SEQ ID NO: 471) or consisting of the amino acid sequence, wherein Y 1 A or S, Y 2 It is S or H, Y 3 It is T or A, Y 4 is R or N, and Y 5 is E or G, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 331, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 337, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 338, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 339; (II) HCDR1 comprises X 1 YAX 2 X 3 (SEQ ID NO: 466) or consisting of the amino acid sequence, wherein X 1 Is S or T, X 2 is I or M, and X 3 is S or T, HCDR2 contains SISY 1 Y 2 YYY 3 Y 4 YAY 5 SVKG (SEQ ID NO: 471) or consisting of the amino acid sequence, wherein Y 1 A or S, Y 2 It is S or H, Y 3 It is T or A, Y 4 is R or N, and Y 5 is E or G, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 331, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 337, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 338, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 339; (III) HCDR1 comprises GFTFX 1 X 2 Y (SEQ ID NO: 467) or consisting of the amino acid sequence, wherein X 1 is S or G, and X 2 is S or T, HCDR2 contains SY 1 Y 2 GYY (SEQ ID NO: 472) or consisting of the amino acid sequence, wherein Y 1 is A or S, and Y 2is S or H, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 331, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 340, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 341, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 342; or (IV) HCDR1 comprises GFTFX 1 X 2 YA (SEQ ID NO: 469) or consisting of the amino acid sequence, wherein X 1 is S or G, and X 2 is S or T, HCDR2 contains ISY 1 Y 2 G (SEQ ID NO: 473) or consisting of the amino acid sequence, wherein Y 1 is A, S or G, and Y 2 is S or H, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 332, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 343, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 341, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 339.

[0015] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3), wherein: (a) (I) HCDR1 comprises or consists of the amino acid sequence as shown in SEQ ID NO:28, HCDR2 comprises or consists of the amino acid sequence as shown in any one of SEQ ID NOs:29, 119 and 190, HCDR3 comprises or consists of the amino acid sequence as shown in SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence as shown in SEQ ID NO:41, LCDR2 comprises or consists of the amino acid sequence as shown in SEQ ID NO:42, and LCDR3 comprises or consists of the amino acid sequence as shown in any one of SEQ ID NOs:43, 126, 134, 145, 172, 178 and 184; (II) HCDR1 comprises or consists of the amino acid sequence as shown in SEQ ID NO:31, HCDR2 comprises or consists of the amino acid sequence as shown in SEQ ID NO: NO:29, 119 and 190, or consist of the amino acid sequence shown in any one of SEQ ID NO:29, 119 and 190, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:41, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:42, and LCDR3 comprises or consists of the amino acid sequence shown in any one of SEQ ID NO:43, 126, 134, 145, 172, 178 and 184; (III) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:32, HCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NO:33, 120 and 191, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:44, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 comprises The amino acid sequence shown in any one of NO:46, 127, 135, 146, 173, 179 and 185 or consisting thereof;or (IV) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:34, HCDR2 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:35, 121 and 192, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:36, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:47, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:45, and LCDR3 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:43, 126, 134, 145, 172, 178 and 184; or (b) (I) HCDR1 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:4, 112 and 165, HCDR2 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:5, 100 and 151, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:47, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:45, and LCDR3 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:43, 126, 134, 145, 172, 178 and 184; NO:17 or consists of the amino acid sequence shown in SEQ ID NO:17, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:18, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:19; (II) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:7, HCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs:5, 100 and 151, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:17, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:18, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:19; (III) HCDR1 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs:8, 113 and 166, HCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs:9, 101 and 152, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: NO:6, or consisting of the amino acid sequence shown in SEQ ID NO:20, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:21, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:22;or (IV) HCDR1 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 10, 114 and 167, HCDR2 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 11, 102 and 153, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 12, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 23, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 21, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 19; or (c)(I) HCDR1 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 226, 367 and 378, HCDR2 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 227, 368 and 379, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 228, and LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO: NO: 237 or consists of the amino acid sequence shown in SEQ ID NO: 237, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 238, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 239; (II) HCDR1 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 229, 369 and 380, HCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 227, 368 and 379, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 237, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 238, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 239; (III) HCDR1 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 32, 370 and 381, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 382, ​​and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 383; NO: 230, 371 and 382 or consist thereof, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 240, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 241, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 242;or (IV) HCDR1 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 34, 372 and 383, HCDR2 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 231, 373 and 384, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 232, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 243, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 241, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 239;

[0016] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3), wherein: (a) (I) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 310, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 311, HCDR3 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 312 and 348, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 320, LCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 321 and 354, and LCDR3 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 322, 355 and 361; (II) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 229, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 330. NO: 311 or consists of the amino acid sequence shown in SEQ ID NO: 312, HCDR3 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 312 and 348, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 320, LCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 321 and 354, and LCDR3 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 322, 355 and 361; (III) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 80, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 313, HCDR3 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 312 and 348, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 323, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 324, and LCDR3 comprises NO:325, 356 and 362 or consisting of the amino acid sequence shown in any one of the above;or (IV) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:82, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:314, HCDR3 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:315 and 349, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:326, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:324, and LCDR3 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:322, 355 and 361; or (b)(I) HCDR1 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:270 and 407, HCDR2 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:271, 389 and 408, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:331, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:332. NO: 337 or consists of the amino acid sequence shown in SEQ ID NO: 337, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 338, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 339; (II) HCDR1 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 273 and 409, HCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 271, 389 and 408, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 331, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 337, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 338, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 339; (III) HCDR1 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 32 and 410, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 331. NO: 274, 390 and 411 or consist of the amino acid sequence shown in any one of them, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 331, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 340, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 341, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 342;or (IV) HCDR1 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 275 and 412, HCDR2 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 276, 391 and 413, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 332, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 343, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 341, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 339;

[0017] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (a) (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 134 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 134 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 134 (LCDR3). OR NO: 134 (LCDR3); (b) (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 126 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO:119(HCDR2), SEQ ID NO:30(HCDR3), SEQ ID NO:41(LCDR1), SEQ ID NO:42(LCDR2), and SEQ ID NO: 126 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 127 (LCDR3);or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:126 (LCDR3); (c) (I) SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:145 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:145 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:146 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:145 (LCDR3); (d) (I) SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3);(III) SEQ ID NO:32 (HCDR1), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:173 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:172 (LCDR3); (e) (I) SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:178 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:178 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:179 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:178 (LCDR3); (f) (I) SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:184 (LCDR3);(II) SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:184 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:185 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:184 (LCDR3); (g) (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:101 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:10 (HCDR1), SEQ ID NO:102 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:19 (LCDR3);(h)(I)SEQ ID NO:112 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (II)SEQ ID NO:7 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (III)SEQ ID NO:113 (HCDR1), SEQ ID NO:101 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:22 (LCDR3); or (IV)SEQ ID NO:114 (HCDR1), SEQ ID NO:102 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:19 (LCDR3); (i)(I)SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:43 (LCDR3); (II)SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:43 (LCDR3); (III)SEQ ID NO:32 (HCDR1), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:46 (LCDR3);or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:43 (LCDR3); (j) (I) SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:126 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:126 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:127 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:126 (LCDR3); (k) (I) SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3);(III) SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:135 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:134 (LCDR3); (l) (I) SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:145 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:145 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:146 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:145 (LCDR3); (m) (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3);(II) SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:152 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:10 (HCDR1), SEQ ID NO:153 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:19 (LCDR3); (n) (I) SEQ ID NO:112 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:113 (HCDR1), SEQ ID NO:152 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:114 (HCDR1), SEQ ID NO:153 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:19 (LCDR3);(o)(I) SEQ ID NO:165 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:166 (HCDR1), SEQ ID NO:152 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:167 (HCDR1), SEQ ID NO:153 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:19 (LCDR3); (p)(I) SEQ IDNO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ IDNO:172 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:173 (LCDR3);or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:172 (LCDR3); (q) (I) SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:178 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:178 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:179 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:178 (LCDR3); (r) (I) SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:184 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:184 (LCDR3);(III) SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:185 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:184 (LCDR3); (s) (I) SEQ ID NO:28 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:191 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:135 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:192 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:134 (LCDR3); (t) (I) SEQ ID NO:28 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3);(II) SEQ ID NO:31 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:191 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:173 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:192 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:172 (LCDR3); (u) (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:10 (HCDR1), SEQ ID NO:11 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:19 (LCDR3);(v)(I)SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:43 (LCDR3); (II)SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:43 (LCDR3); (III)SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:46 (LCDR3); or (IV)SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:43 (LCDR3); (w)(I)SEQ ID NO:367 (HCDR1), SEQ ID NO:368 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3); (II)SEQ ID NO:369 (HCDR1), SEQ ID NO:368 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3); (III)SEQ ID NO:370 (HCDR1), SEQ ID NO:371 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:240 (LCDR1), SEQ ID NO:241 (LCDR2), and SEQ ID NO:242 (LCDR3);or (IV) SEQ ID NO:372 (HCDR1), SEQ ID NO:373 (HCDR2), SEQ ID NO:232 (HCDR3), SEQ ID NO:243 (LCDR1), SEQ ID NO:241 (LCDR2), and SEQ ID NO:239 (LCDR3); (x) (I) SEQ ID NO:378 (HCDR1), SEQ ID NO:379 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3); (II) SEQ ID NO:380 (HCDR1), SEQ ID NO:379 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3); (III) SEQ ID NO:381 (HCDR1), SEQ ID NO:382 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:240 (LCDR1), SEQ ID NO:241 (LCDR2), and SEQ ID NO:242 (LCDR3); or (IV) SEQ ID NO:383 (HCDR1), SEQ ID NO:384 (HCDR2), SEQ ID NO:232 (HCDR3), SEQ ID NO:243 (LCDR1), SEQ ID NO:241 (LCDR2), and SEQ ID NO:239 (LCDR3); (y) (I) SEQ ID NO:226 (HCDR1), SEQ ID NO:227 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3); (II) SEQ ID NO:229 (HCDR1), SEQ ID NO:227 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3);(III) SEQ ID NO:32 (HCDR1), SEQ ID NO:230 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:240 (LCDR1), SEQ ID NO:241 (LCDR2), and SEQ ID NO:242 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:231 (HCDR2), SEQ ID NO:232 (HCDR3), SEQ ID NO:243 (LCDR1), SEQ ID NO:241 (LCDR2), and SEQ ID NO:239 (LCDR3); (z) (I) SEQ ID NO:270 (HCDR1), SEQ ID NO:271 (HCDR2), SEQ ID NO:272 (HCDR3), SEQ ID NO:282 (LCDR1), SEQ ID NO:261 (LCDR2), and SEQ ID NO:283 (LCDR3); (II) SEQ ID NO:273 (HCDR1), SEQ ID NO:271 (HCDR2), SEQ ID NO:272 (HCDR3), SEQ ID NO:282 (LCDR1), SEQ ID NO:261 (LCDR2), and SEQ ID NO:283 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:274 (HCDR2), SEQ ID NO:272 (HCDR3), SEQ ID NO:284 (LCDR1), SEQ ID NO:241 (LCDR2), and SEQ ID NO:285 (LCDR3); or (IV) SEQ ID NO:275 (HCDR1), SEQ ID NO:276 (HCDR2), SEQ ID NO:277 (HCDR3), SEQ ID NO:286 (LCDR1), SEQ ID NO:241 (LCDR2), and SEQ ID NO:283 (LCDR3); or (aa) (I) SEQ ID NO:291 (HCDR1), SEQ ID NO:292 (HCDR2), SEQ ID NO:293 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:304 (LCDR3);(II) SEQ ID NO: 294 (HCDR1), SEQ ID NO: 292 (HCDR2), SEQ ID NO: 293 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2), and SEQ ID NO: 304 (LCDR3); (III) SEQ ID NO: 295 (HCDR1), SEQ ID NO: 296 (HCDR2), SEQ ID NO: 293 (HCDR3), SEQ ID NO: 240 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 305 (LCDR3); or (IV) SEQ ID NO: 297 (HCDR1), SEQ ID NO: 298 (HCDR2), SEQ ID NO: 299 (HCDR3), SEQ ID NO: 243 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 304 (LCDR3).;

[0018] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (a) (I) SEQ ID NO: 52 (HCDR1), SEQ ID NO: 53 (HCDR2), SEQ ID NO: 54 (HCDR3), SEQ ID NO: 65 (LCDR1), SEQ ID NO: 66 (LCDR2) and SEQ ID NO: 67 (LCDR3); (II) SEQ ID NO: 55 (HCDR1), SEQ ID NO: 53 (HCDR2), SEQ ID NO: 54 (HCDR3), SEQ ID NO: 65 (LCDR1), SEQ ID NO: 66 (LCDR2) and SEQ ID NO: 67 (LCDR3); (III) SEQ ID NO: 56 (HCDR1), SEQ ID NO: 57 (HCDR2), SEQ ID NO: 54 (HCDR3), SEQ ID NO: OR NO: 67 (LCDR3); (b) (I) SEQ ID NO: 76 (HCDR1), SEQ ID NO: 77 (HCDR2), SEQ ID NO: 78 (HCDR3), SEQ ID NO: 89 (LCDR1), SEQ ID NO: 90 (LCDR2) and SEQ ID NO: 91 (LCDR3); (II) SEQ ID NO: 79 (HCDR1), SEQ ID NO:77(HCDR2), SEQ ID NO:78(HCDR3), SEQ ID NO:89(LCDR1), SEQ ID NO:90(LCDR2) and SEQ ID NO:91(LCDR3); (III) SEQ ID NO:80(HCDR1), SEQ ID NO:81(HCDR2), SEQ ID NO:78(HCDR3), SEQ ID NO:92(LCDR1), SEQ ID NO:93(LCDR2) and SEQ ID NO:94(LCDR3);or (IV) SEQ ID NO:82 (HCDR1), SEQ ID NO:83 (HCDR2), SEQ ID NO:84 (HCDR3), SEQ ID NO:95 (LCDR1), SEQ ID NO:93 (LCDR2), and SEQ ID NO:91 (LCDR3); (c) (I) SEQ ID NO:310 (HCDR1), SEQ ID NO:311 (HCDR2), SEQ ID NO:348 (HCDR3), SEQ ID NO:320 (LCDR1), SEQ ID NO:354 (LCDR2), and SEQ ID NO:361 (LCDR3); (II) SEQ ID NO:229 (HCDR1), SEQ ID NO:311 (HCDR2), SEQ ID NO:348 (HCDR3), SEQ ID NO:320 (LCDR1), SEQ ID NO:354 (LCDR2), and SEQ ID NO:361 (LCDR3); (III) SEQ ID NO:80 (HCDR1), SEQ ID NO:313 (HCDR2), SEQ ID NO:348 (HCDR3), SEQ ID NO:323 (LCDR1), SEQ ID NO:324 (LCDR2), and SEQ ID NO:362 (LCDR3); or (IV) SEQ ID NO:82 (HCDR1), SEQ ID NO:314 (HCDR2), SEQ ID NO:349 (HCDR3), SEQ ID NO:326 (LCDR1), SEQ ID NO:324 (LCDR2), and SEQ ID NO:361 (LCDR3); (d) (I) SEQ ID NO:270 (HCDR1), SEQ ID NO:389 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3); (II) SEQ ID NO:273 (HCDR1), SEQ ID NO:389 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3);(III) SEQ ID NO:32 (HCDR1), SEQ ID NO:390 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:340 (LCDR1), SEQ ID NO:341 (LCDR2) and SEQ ID NO:342 (LCDR3); or (IV) SEQ ID NO:275 (HCDR1), SEQ ID NO:391 (HCDR2), SEQ ID NO:332 (HCDR3), SEQ ID NO:343 (LCDR1), SEQ ID NO:341 (LCDR2) and SEQ ID NO:339 (LCDR3); (e) (I) SEQ ID NO:407 (HCDR1), SEQ ID NO:408 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2) and SEQ ID NO:339 (LCDR3); (II) SEQ ID NO:409 (HCDR1), SEQ ID NO:408 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2) and SEQ ID NO:339 (LCDR3); (III) SEQ ID NO:410 (HCDR1), SEQ ID NO:411 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:340 (LCDR1), SEQ ID NO:341 (LCDR2) and SEQ ID NO:342 (LCDR3); or (IV) SEQ ID NO:412 (HCDR1), SEQ ID NO:413 (HCDR2), SEQ ID NO:332 (HCDR3), SEQ ID NO:343 (LCDR1), SEQ ID NO:341 (LCDR2) and SEQ ID NO:339 (LCDR3); (f) (I) SEQ ID NO:310 (HCDR1), SEQ ID NO:311 (HCDR2), SEQ ID NO:312 (HCDR3), SEQ ID NO:320 (LCDR1), SEQ ID NO:321 (LCDR2) and SEQ ID NO:322 (LCDR3);(II) SEQ ID NO: 229 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 312 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 321 (LCDR2) and SEQ ID NO: 322 (LCDR3); (III) SEQ ID NO: 80 (HCDR1), SEQ ID NO: 313 (HCDR2), SEQ ID NO: 312 (HCDR3), SEQ ID NO: 323 (LCDR1), SEQ ID NO: 324 (LCDR2) and SEQ ID NO: 325 (LCDR3); or (IV) SEQ ID NO: 82 (HCDR1), SEQ ID NO: 314 (HCDR2), SEQ ID NO: 315 (HCDR3), SEQ ID NO: 326 (LCDR1), SEQ ID NO: 324 (LCDR2) and SEQ ID NO: 322 (LCDR3); (g) (I) SEQ ID NO: 270 (HCDR1), SEQ ID NO: 271 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (II) SEQ ID NO: 273 (HCDR1), SEQ ID NO: 271 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 274 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 340 (LCDR1), SEQ ID NO: 341 (LCDR2) and SEQ ID NO: 342 (LCDR3); or (IV) SEQ ID NO: 275 (HCDR1), SEQ ID NO: 276 (HCDR2), SEQ ID NO: 332 (HCDR3), SEQ ID NO: 343 (LCDR1), SEQ ID NO: 341 (LCDR2) and SEQ ID NO: 339 (LCDR3);or (h)(i) SEQ ID NO: 310 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 354 (LCDR2), and SEQ ID NO: 355 (LCDR3); (ii) SEQ ID NO: 229 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 354 (LCDR2), and SEQ ID NO: 355 (LCDR3); (iii) SEQ ID NO: 80 (HCDR1), SEQ ID NO: 313 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 323 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 356 (LCDR3); or (iv) SEQ ID NO: 82 (HCDR1), SEQ ID NO: 314 (HCDR2), SEQ ID NO: 349 (HCDR3), SEQ ID NO: 326 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 355 (LCDR3).;

[0019] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 201, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 136; (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 136; (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 201, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 128; (d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 128; (e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 201, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 147; (f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 147; (g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 147. (h) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 122, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 174; (i) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 201, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 180; (j) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 122, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 180; (k) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 201, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 186; (l) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 122, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 186; (m) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 103, and a light chain variable region containing the amino acid sequence of SEQ ID NO: (n) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; (o) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 48; (p) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 128;(q) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 136; (r) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 147; (s) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 154, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; (t) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 161, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; (u) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 168, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; (v) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 174; (w) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: NO:180; (x) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:186; (y) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:193, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:136; (z) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:193, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:174; (aa) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:24; (bb) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:48; (cc) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:374, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:244; (dd) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:374 NO: 385, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 244; (ee) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 233, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 244; (ff) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 278, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 287;or (gg) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 300, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 306. ;

[0020] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 61, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 72; (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 96; (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 350, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 363; (d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 392, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 344; (e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 414, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 344; (f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 316, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 327; (g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 350, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 353. ID NO: 333, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 344; or (h) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 350, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 357.

[0021] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 203, and a light chain comprising the amino acid sequence of SEQ ID NO: 138; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 208, and a light chain comprising the amino acid sequence of SEQ ID NO: 138; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 203, and a light chain comprising the amino acid sequence of SEQ ID NO: 130; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 208, and a light chain comprising the amino acid sequence of SEQ ID NO: 130; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 203, and a light chain comprising the amino acid sequence of SEQ ID NO: 149; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 208, and a light chain comprising the amino acid sequence of SEQ ID NO: 149; (g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 203, and a light chain comprising the amino acid sequence of SEQ ID NO: NO:176; (h) a heavy chain containing the amino acid sequence of SEQ ID NO:208, and a light chain containing the amino acid sequence of SEQ ID NO:176; (i) a heavy chain containing the amino acid sequence of SEQ ID NO:203, and a light chain containing the amino acid sequence of SEQ ID NO:182; (j) a heavy chain containing the amino acid sequence of SEQ ID NO:208, and a light chain containing the amino acid sequence of SEQ ID NO:182; (k) a heavy chain containing the amino acid sequence of SEQ ID NO:203, and a light chain containing the amino acid sequence of SEQ ID NO:188; (l) a heavy chain containing the amino acid sequence of SEQ ID NO:208, and a light chain containing the amino acid sequence of SEQ ID NO:188; (m) a heavy chain containing the amino acid sequence of SEQ ID NO:105, and a light chain containing the amino acid sequence of SEQ ID NO:26; (n) a heavy chain containing the amino acid sequence of SEQ ID NO:108, and a light chain containing the amino acid sequence of SEQ ID NO: NO:26; (o) a heavy chain containing the amino acid sequence of SEQ ID NO:117, and a light chain containing the amino acid sequence of SEQ ID NO:26; (p) a heavy chain containing the amino acid sequence of SEQ ID NO:124, and a light chain containing the amino acid sequence of SEQ ID NO:50; (q) a heavy chain containing the amino acid sequence of SEQ ID NO:39, and a light chain containing the amino acid sequence of SEQ ID NO:130;(r) a heavy chain comprising the amino acid sequence of SEQ ID NO:39, and a light chain comprising the amino acid sequence of SEQ ID NO:138; (s) a heavy chain comprising the amino acid sequence of SEQ ID NO:141, and a light chain comprising the amino acid sequence of SEQ ID NO:138; (t) a heavy chain comprising the amino acid sequence of SEQ ID NO:39, and a light chain comprising the amino acid sequence of SEQ ID NO:149; (u) a heavy chain comprising the amino acid sequence of SEQ ID NO:156, and a light chain comprising the amino acid sequence of SEQ ID NO:26; (v) a heavy chain comprising the amino acid sequence of SEQ ID NO:159, and a light chain comprising the amino acid sequence of SEQ ID NO:26; (w) a heavy chain comprising the amino acid sequence of SEQ ID NO:163, and a light chain comprising the amino acid sequence of SEQ ID NO:26; (x) a heavy chain comprising the amino acid sequence of SEQ ID NO:170, and a light chain comprising the amino acid sequence of SEQ ID NO:26; (y) a heavy chain comprising the amino acid sequence of SEQ ID NO:171 NO:39, and a light chain containing the amino acid sequence of SEQ ID NO:176; (z) a heavy chain containing the amino acid sequence of SEQ ID NO:39, and a light chain containing the amino acid sequence of SEQ ID NO:182; (aa) a heavy chain containing the amino acid sequence of SEQ ID NO:39, and a light chain containing the amino acid sequence of SEQ ID NO:188; (bb) a heavy chain containing the amino acid sequence of SEQ ID NO:195, and a light chain containing the amino acid sequence of SEQ ID NO:138; (cc) a heavy chain containing the amino acid sequence of SEQ ID NO:195, and a light chain containing the amino acid sequence of SEQ ID NO:176; (dd) a heavy chain containing the amino acid sequence of SEQ ID NO:15, and a light chain containing the amino acid sequence of SEQ ID NO:26; (ee) a heavy chain containing the amino acid sequence of SEQ ID NO:39, and a light chain containing the amino acid sequence of SEQ ID NO:50; (ff) a heavy chain containing the amino acid sequence of SEQ ID NO:195 NO: 376, and a light chain containing the amino acid sequence of SEQ ID NO: 246; (gg) a heavy chain containing the amino acid sequence of SEQ ID NO: 387, and a light chain containing the amino acid sequence of SEQ ID NO: 246; (hh) a heavy chain containing the amino acid sequence of SEQ ID NO: 235, and a light chain containing the amino acid sequence of SEQ ID NO: 246; (ii) a heavy chain containing the amino acid sequence of SEQ ID NO: 280, and a light chain containing the amino acid sequence of SEQ ID NO: 289;or (jj) a heavy chain comprising the amino acid sequence of SEQ ID NO: 302, and a light chain comprising the amino acid sequence of SEQ ID NO: 308. ;

[0022] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 63, and a light chain comprising the amino acid sequence of SEQ ID NO: 74; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 87, and a light chain comprising the amino acid sequence of SEQ ID NO: 98; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 352, and a light chain comprising the amino acid sequence of SEQ ID NO: 365; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 394, and a light chain comprising the amino acid sequence of SEQ ID NO: 346; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 416, and a light chain comprising the amino acid sequence of SEQ ID NO: 346; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 318, and a light chain comprising the amino acid sequence of SEQ ID NO: 329; (g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 335, and a light chain comprising the amino acid sequence of SEQ ID NO: or (h) a heavy chain containing the amino acid sequence of SEQ ID NO:352, and a light chain containing the amino acid sequence of SEQ ID NO:359.

[0023] In some embodiments of the present invention, the antibody or antigen-binding fragment is an antigen-binding fragment selected from the group consisting of: Fab, Fab′, F(ab′) 2 , Fv, single domain antibody (dAb) and single chain variable fragment (scFv). In some embodiments of the present invention, the antibody or antigen binding fragment is an antigen binding fragment selected from the group consisting of: Fab, Fab', Fv, single domain antibody (dAb) and single chain variable fragment (scFv).

[0024] In some embodiments of the invention, the antibody or antigen binding fragment is monoclonal. In some embodiments of the invention, the antibody or antigen binding fragment is fully human. In some embodiments of the invention, the antibody or antigen binding fragment is an IgG antibody. In some embodiments of the invention, the antibody or antigen binding fragment is an IgG1 antibody. In some embodiments of the invention, the antibody or antigen binding fragment is an IgG1 antibody with a kappa light chain. In some embodiments of the invention, the antibody or antigen binding fragment is a fully human antibody of the IgG1 isotype and has a kappa light chain.

[0025] In some embodiments of the invention, the antibody or antigen-binding fragment additionally has mutations in the Fc region according to the EU index of Kabat, wherein the mutations comprise at least D265A and P329A.

[0026] In some embodiments of the invention, the antibody or antigen-binding fragment additionally has mutations in the Fc region according to the EU index of Kabat, wherein the mutations comprise at least L234A and L235A.

[0027] In some embodiments of the invention, the antibody or antigen-binding fragment is therapeutic.

[0028] In some embodiments of the invention, the antibody or antigen binding fragment binds to the same epitope on human NPR1 as any antibody or antigen binding fragment or group defined herein (e.g., XX16). In some embodiments of the invention, the antibody or antigen binding fragment competes with any antibody or antigen binding fragment or group defined herein (e.g., XX16) for binding to human NPR1.

[0029] In one aspect of the invention, one or more isolated nucleic acids are provided herein, encoding the amino acid sequence of any antibody or antigen-binding fragment or group defined herein. In one aspect of the invention, a vector comprising the one or more isolated nucleic acids is provided herein. In one aspect of the invention, a host cell comprising the one or more isolated nucleic acids or vectors is provided herein.

[0030] In one aspect of the invention, provided herein is a method for producing any antibody or antigen-binding fragment described herein, the method comprising culturing a host cell described herein under conditions suitable for producing the antibody or antigen-binding fragment. In some embodiments of the invention, the method additionally comprises purifying the antibody or antigen-binding fragment.

[0031] In one aspect of the present invention, provided herein is a pharmaceutical composition comprising a purified antibody or antigen-binding fragment produced by the method described herein and a pharmaceutically acceptable carrier.

[0032] In one aspect of the present invention, provided herein is a pharmaceutical composition comprising any of the antibodies or antigen-binding fragments described herein and a pharmaceutically acceptable carrier.

[0033] In one aspect of the invention, a pharmaceutical composition is provided herein, comprising: a) a device for binding to natriuretic peptide receptor 1 (NPR1) and activating NPR1 in the absence of ANP; and b) a pharmaceutically acceptable excipient. In some embodiments of the invention, the device for binding and activating is ANP non-competitive. In some embodiments of the invention, the device for binding and activating is ANP competitive. In some embodiments of the invention, the device for binding and activating is additionally capable of stabilizing the ANP-NPR1 complex. In some embodiments of the invention, the composition further comprises an additional therapeutic agent.

[0034] In some embodiments of the invention, the additional therapeutic agent is selected from ACE (angiotensin converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), enkephalinase inhibitors, beta blockers, diuretics, calcium channel blockers, cardiac glycosides, sodium-glucose co-transporter 2 inhibitors (SGLT2i), and combinations thereof. In some embodiments of the invention, the additional therapeutic agent is selected from enalapril, benazepril, captopril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, valsartan, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, sacubitril, bisoprolol, carvedilol, propranolol, metoprolol, metoprolol tartrate, metoprolol succinate, thiazide diuretics, loop diuretics, potassium-sparing diuretics, amlodipine, clevidipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, digitalis glycosides, canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, and combinations thereof. In some embodiments of the invention, the additional therapeutic agent is selected from chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, eplerenone, spironolactone, triamterene, digoxin and combinations thereof. In some embodiments of the invention, the additional therapeutic agent is an angiotensin receptor-neprilysin inhibitor (ARNi).

[0035] In some embodiments of the invention, the additional therapeutic agent is selected from corticosteroids, leukotriene modifiers, bronchodilators, and combinations thereof. In some embodiments of the invention, the additional therapeutic agent is selected from fluticasone, budesonide, mometasone, beclomethasone, ciclesonide, fluticasone furoate, prednisone, methylprednisolone, montelukast, zafirlukast, zileuton, long-acting beta agonists, short-acting beta agonists, theophylline, and ipratropium, and combinations thereof. In some embodiments of the invention, the additional therapeutic agent is selected from salmeterol, formoterol, salbutamol, and levosalbutamol, and combinations thereof.

[0036] In some embodiments of the invention, the additional therapeutic agent is selected from the group consisting of beta-adrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha2-adrenergic receptor agonists, parasympathomimetics, prostaglandin analogs, rho kinase inhibitors, and combinations thereof, and combinations thereof. In some embodiments of the invention, the additional therapeutic agent is selected from the group consisting of timolol, levobunolol, metipranolol, carteolol, betaxolol, acetazolamide, dorzolamide, brinzolamide, methazolamide, brimonidine, alaclonidine, cholinergic agents, latanoprost, latanoprostene bunod, travoprost, bimatoprost, tafluprost, netarsudil, and ripasudil, and combinations thereof.

[0037] In one aspect of the invention, provided herein is a method for treating a disorder or disease associated with natriuretic peptide receptor activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any antibody or antigen-binding fragment described herein, or a pharmaceutical composition or combination as described herein.

[0038] In one aspect of the present invention, provided herein is a method of treating a cardiovascular disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any of the antibodies or antigen-binding fragments thereof described herein or any of the pharmaceutical compositions or combinations described herein.

[0039] In some embodiments of the invention, the cardiovascular disorder is selected from the group consisting of hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset AF, recurrent AF, cardiac fibrosis, atrial flutter, deleterious vascular remodeling, plaque stabilization, and myocardial infarction (MI).

[0040] In one aspect of the invention, provided herein is a method for treating heart failure, hypertrophic cardiomyopathy (HCM), hypertension, preeclampsia, asthma, glaucoma and / or cytokine release syndrome in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any of the antibodies or antigen-binding fragments thereof described herein or any of the pharmaceutical compositions or combinations described herein.

[0041] In some embodiments of the present invention, the subject suffers from heart failure, wherein the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute compensated heart failure. In some embodiments of the present invention, the subject suffers from hypertrophic cardiomyopathy, wherein the hypertrophic cardiomyopathy is ventricular hypertrophy. In some embodiments of the present invention, the subject suffers from hypertension, wherein the hypertension is selected from refractory hypertension, hypertensive heart disease, pulmonary hypertension, pulmonary hypertension, isolated systolic hypertension, refractory hypertension, and pulmonary hypertension. In some embodiments of the present invention, the subject suffers from hypertension, wherein the hypertension is selected from refractory hypertension or hypertensive heart disease.

[0042] In one aspect of the invention, there is provided herein a method for treating a renal disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any of the antibodies or antigen-binding fragments thereof described herein or any of the pharmaceutical compositions or combinations described herein. In some embodiments of the invention, the renal disorder is selected from: diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast-induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, primary nephrotic proteinuria, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD).

[0043] In one aspect of the invention, provided herein is the use of any of the antibodies or antigen-binding fragments thereof described herein, or any of the pharmaceutical compositions or combinations described herein, for the preparation of a medicament for treating a disorder or disease associated with natriuretic peptide receptor activity in a subject in need of such treatment.

[0044] In one aspect of the invention, provided herein is the use of any of the antibodies or antigen-binding fragments thereof described herein or any of the pharmaceutical compositions or combinations described herein for the preparation of a medicament for treating a cardiovascular disorder in a subject in need of such treatment.

[0045] In some embodiments of the invention, the cardiovascular disorder is selected from the group consisting of hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset AF, recurrent AF, cardiac fibrosis, atrial flutter, deleterious vascular remodeling, plaque stabilization, and myocardial infarction (MI).

[0046] In one aspect of the invention, provided herein is the use of any of the antibodies or antigen-binding fragments thereof described herein or any of the pharmaceutical compositions or combinations described herein for the preparation of a medicament for treating heart failure, hypertrophic cardiomyopathy (HCM), hypertension, preeclampsia, asthma, glaucoma and / or cytokine release syndrome in a subject in need of such treatment.

[0047] In some embodiments of the present invention, the subject suffers from heart failure, and the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute compensated heart failure. In some embodiments of the present invention, the subject suffers from hypertrophic cardiomyopathy, wherein the hypertrophic cardiomyopathy is ventricular hypertrophy. In some embodiments of the present invention, the subject suffers from hypertension, wherein the hypertension is selected from refractory hypertension, hypertensive heart disease, pulmonary hypertension, pulmonary hypertension, isolated systolic hypertension, refractory hypertension, and pulmonary hypertension. In some embodiments of the present invention, the subject suffers from hypertension, wherein the hypertension is selected from refractory hypertension or hypertensive heart disease.

[0048] In one aspect of the invention, provided herein is the use of any of the antibodies or antigen-binding fragments thereof described herein or any of the pharmaceutical compositions or combinations described herein for the preparation of a medicament for treating a renal disorder in a subject in need of such treatment. In some embodiments of the invention, the renal disorder is selected from the group consisting of diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast-induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, primary nephrotic proteinuria, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD).

[0049] In one aspect of the invention, provided herein is any of the antibodies or antigen-binding fragments thereof described herein or the pharmaceutical compositions or combinations described herein for use in treating a disorder or disease associated with natriuretic peptide receptor activity in a subject in need of such treatment.

[0050] In one aspect of the invention, provided herein is any of the antibodies or antigen-binding fragments thereof described herein or the pharmaceutical compositions or combinations described herein for use in treating a cardiovascular disorder in a subject in need of such treatment.

[0051] In some embodiments of the invention, the cardiovascular disorder is selected from the group consisting of hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset AF, recurrent AF, cardiac fibrosis, atrial flutter, deleterious vascular remodeling, plaque stabilization, and myocardial infarction (MI).

[0052] In one aspect of the invention, provided herein is any of the antibodies or antigen-binding fragments thereof described herein, or the pharmaceutical compositions or combinations described herein, for use in treating heart failure, hypertrophic cardiomyopathy (HCM), hypertension, preeclampsia, asthma, glaucoma and / or cytokine release syndrome in a subject in need of such treatment.

[0053] In some embodiments of the present invention, the subject suffers from heart failure, and the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute compensated heart failure. In some embodiments of the present invention, the subject suffers from hypertrophic cardiomyopathy, wherein the hypertrophic cardiomyopathy is ventricular hypertrophy. In some embodiments of the present invention, the subject suffers from hypertension, wherein the hypertension is selected from refractory hypertension, hypertensive heart disease, pulmonary hypertension, pulmonary hypertension, isolated systolic hypertension, refractory hypertension, and pulmonary hypertension. In some embodiments of the present invention, the subject suffers from hypertension, wherein the hypertension is selected from refractory hypertension or hypertensive heart disease.

[0054] In one aspect of the invention, provided herein is an antibody or antigen binding fragment thereof as described herein or any one of a pharmaceutical composition or combination as described herein for treating a renal disorder in a subject in need of such treatment. In some embodiments of the invention, the renal disorder is selected from: diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast-induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, primary nephrotic proteinuria, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD).

[0055] In one aspect of the invention, provided herein is a method for treating a disorder or disease associated with natriuretic peptide receptor activity in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising: a device that binds to natriuretic peptide receptor 1 (NPR1) and activates NPR1 in the absence of ANP; and a pharmaceutically acceptable excipient.

[0056] In one aspect of the invention, there is provided herein a method for treating a cardiovascular disorder in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising: a device that binds to natriuretic peptide receptor 1 (NPR1) and activates NPR1 in the absence of ANP; and a pharmaceutically acceptable excipient. In some embodiments of the invention, the cardiovascular disorder is selected from the group consisting of hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new-onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, deleterious vascular remodeling, plaque stability, and myocardial infarction (MI).

[0057] In one aspect of the present invention, there is provided herein a method for treating heart failure, hypertrophic cardiomyopathy (HCM), hypertension, preeclampsia, asthma, glaucoma and / or cytokine release syndrome in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising: a device for binding to natriuretic peptide receptor 1 (NPR1) and activating NPR1 in the absence of ANP; and a pharmaceutically acceptable excipient. In some embodiments of the present invention, the subject suffers from heart failure, wherein the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction, or acute compensated heart failure. In some embodiments of the present invention, the subject suffers from hypertrophic cardiomyopathy, wherein the hypertrophic cardiomyopathy is ventricular hypertrophy. In some embodiments of the present invention, the subject suffers from hypertension, wherein the hypertension is selected from refractory hypertension, hypertensive heart disease, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, refractory hypertension, and pulmonary arterial hypertension. In some embodiments of the present invention, the subject suffers from hypertension, wherein the hypertension is selected from refractory hypertension or hypertensive heart disease.

[0058] In one aspect of the present invention, there is provided herein a method for treating a renal disorder in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising: a device for binding to natriuretic peptide receptor 1 (NPR1) and activating NPR1 in the absence of ANP; and a pharmaceutically acceptable excipient. In some embodiments of the present invention, the renal disorder is selected from: diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute renal injury, contrast-induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, primary renal proteinuria, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD). In some embodiments of the present invention, the device for binding and activation is ANP non-competitive. In some embodiments of the present invention, the device for binding and activation is ANP competitive. In some embodiments of the present invention, the device for binding and activation is additionally capable of stabilizing the ANP-NPR1 complex. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 is a set of graphs showing the results (ELISA analysis) of antibody candidates WW01, WW02, WW03, WW04 and WW06 binding to the following antigens: human NPR1, constitutively active human NPR1 mutant (W74R), rat NPR1 and human NPR3 (reverse target) in the absence and presence of 250-fold molar excess of ANP.

[0060] Figure 2 is a set of graphs showing the results of flow cytometric analysis of antibody candidates WW01, WW02, WW03, WW04 and WW06 for binding to CHO-K1 cells expressing human NPR1 in the absence and presence of saturating concentrations of ANP and on parental CHO-K1 cells.

[0061] Figure 3 is a schematic representation of a fluorescence resonance energy transfer (FRET) based assay in which an NPR1 specific antibody competes with ANPs for binding to NPR1. In this FRET based assay, Eu labeled streptavidin (for measuring IgG) or Eu labeled anti-hFc antibody (for measuring FabCys) was used as the energy donor, while Cy5 labeled ANPs was used as the acceptor.

[0062] Figure 4 is a set of diagrams showing the use of Figure 3 Results of ANP competition analysis of candidates WW01, WW02, WW03, WW04, and WW06 using a FRET-based assay shown in FIG.

[0063] Figure 5 is a set of graphs depicting the results of functional activity analysis of candidates WW01, WW02, WW03, WW04 and WW06 in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. Results represent cellular production of cGMP [nM] in the absence or presence of 0.075 nMANP.

[0064] Figure 6 is a set of graphs depicting the results of functional activity analysis of candidate WW06 in IgG or FabCys form in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. Results represent cellular production of cGMP [nM] in the absence or presence of 0.075 nM ANP.

[0065] Figure 7 82 unique improvements based on parental antibody HCDR2 or LCDR3 were shown Results of SET screening (hNPR1 affinity) of derivatives.

[0066] Figure 8 82 unique improvements based on parental antibody HCDR2 or LCDR3 were shown Results of SET screening (hNPR1-ANP complex affinity) of derivatives.

[0067] Fig. 9 is a set of graphs showing the results (ELISA analysis) of antibody candidates XX01-XX08, XX10 and XX12 binding to the following antigens: human NPR1, constitutively active human NPR1 mutant (W74R), rat NPR1 and human NPR3 (reverse target) in the absence or presence of 250-fold molar excess of ANP.

[0068] Fig.10 is a set of graphs showing the results of flow cytometric analysis of antibody candidates XX01-XX08, XX10 and XX12 for binding to CHO-K1 cells expressing human NPR1 in the absence or presence of saturating concentrations of ANP and on parental CHO-K1 cells.

[0069] Fig.11 is a set of diagrams showing the use of Figure 3 Results of ANP competition analysis of candidates XX01-XX07, XX10 and XX12 using a FRET-based assay shown in FIG.

[0070] Fig.12is a set of graphs depicting the results of functional activity analysis of candidates XX01-XX08, XX10 and XX12 in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. Results represent cellular production of cGMP [nM] in the absence or presence of 0.075 nM ANP.

[0071] Fig.13 is a set of graphs depicting the results of functional activity analysis of candidates XX06 and XX16 and the natural ligand ANP in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. Results represent cellular production of cGMP [nM] in the absence or presence of 0.075 nMANP.

[0072] Fig.14 The following figure depicts the results of functional activity analysis of candidate XX16 and natural ligand ANP in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. The results represent cellular production of cGMP [nM] as a function of ANP or XX16.

[0073] Fig.15 is a representation of the crystal structure of Fab06 (WW06 antibody in Fab form) in complex with the hNPR1 extracellular domain.

[0074] Fig.16 is a representation of the conformation of the hNPR1 extracellular domain as in complex with Fab06. Fab06 was removed from the representation to more clearly reveal the conformation of hNPR1 induced by Fab binding. W74R is represented as space filling.

[0075] Fig.17 Schematic representation of the crystal structure of the hNPR1 extracellular domain in complex with ANP (left) and the crystal structure of Fab16 (XX16 antibody in Fab form) in complex with the hNPR1 extracellular domain (right), with W74 represented as space filling.

[0076] Fig.18 is a set of graphs depicting the results of functional activity analysis of candidate WW06 in a cellular cGMP production assay when tested on CHO-K1 cells expressing hNPR1 W74R / C232T (constitutively active mutant; panel A) compared to WT hNPR1 (panel B).

[0077] Fig.19is a set of graphs showing the results (ELISA analysis) of antibody candidates YY01-YY07 binding to the following antigens: human NPR1, constitutively active human NPR1 mutant (W74R), rat NPR1, and human NPR3 (reverse target) in the absence or presence of 250-fold molar excess of ANP.

[0078] Fig. 20 is a set of graphs showing the results of flow cytometric analysis of antibody candidates YY01-YY07 for binding to CHO-K1 cells expressing human NPR1 in the absence or presence of saturating concentrations of ANP and on parental CHO K1 cells.

[0079] Fig.21 is a set of diagrams showing the use of Figure 3 Results of ANP competition analysis of candidates YY01-YY07 using the FRET-based assay shown in FIG.

[0080] Fig. 22 is a set of graphs depicting the results of functional activity analysis of candidates YY01-YY07 in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. Results represent cellular production of cGMP [nM] in the absence or presence of 0.075 nM ANP.

[0081] Fig.23 is a set of graphs depicting the results of functional activity analysis of candidates YY05 and YY07 in IgG or FabCys format in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. Results represent cellular production of cGMP [nM] in the absence or presence of 0.075 nM ANP.

[0082] Fig.24 112 unique improvements based on parental antibody HCDR1 / 2 or LCDR3 were shown Results of SET screening (hNPR1 affinity) of derivatives.

[0083] Fig.25 112 unique improvements based on parental antibody HCDR1 / 2 or LCDR3 were shown Results of SET screening (hNPR1-ANP complex affinity) of derivatives.

[0084] Fig.26 is a set of graphs showing the changes in plasma cGMP (nM) concentration over time in hNPR1 Tg mice injected intravenously with 1 mg / kg, 3 mg / kg or 10 mg / kg of WW06 Fab.

[0085] Fig. 27 The following graph shows the change in antibody concentration over time in hNPR1 Tg mice injected intravenously with 1 mg / kg, 3 mg / kg or 10 mg / kg of WW06 Fab.

[0086] Fig.28 is a set of graphs showing the results of biweekly subcutaneous administration of vehicle, 0.3 mg / kg XX16 or 3 mg / kg XX16 in wild-type or ANP knockout (ANP KO) mice on heart weight / body weight ratio (left) and plasma NT-proBNP levels (pg / mL; right). Measurements were taken two weeks after the second administration.

[0087] Fig.29 is a set of graphs showing the results of a single intravenous administration of vehicle, 0.3 mg / kg XX16 or 1 mg / kg XX16 in hypertensive rats (stroke-prone spontaneously hypertensive rats, SHRsp) on blood pressure (mean arterial pressure; left) and urine flow rate (right). Measurements were performed three hours after intravenous administration.

[0088] Fig.30 is a set of graphs showing the results of a single subcutaneous administration of 0.1, 0.3, 1, 3, 10 or 30 mg / kg XX16 in normal telemetry-implanted rats regarding the changes in mean arterial pressure (MAP; upper graph) and plasma cGMP (lower graph) over time.

[0089] Fig.31 is a set of graphs depicting the results of functional activity analysis of candidate WW03 and comparator antibody (antibody 5591-IgG from PCT application number WO 2010 / 065293 A1) in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1 or rat cells expressing rat NPR1. Results represent cellular production of cGMP [nM] in the absence or presence of 0.075 nM ANP (human or rat).

[0090] General Definition

[0091] In order that the present disclosure may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description as necessary.

[0092] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations thereof, such as "comprising and comprises", mean "including but not limited to", and do not exclude other components, integers or steps. In addition, the singular encompasses the plural, unless the context requires otherwise: in particular, where the indefinite article is used, the specification is to be understood as covering the plural as well as the singular, unless the context requires otherwise.

[0093] As used herein, "NPR1" and "NPR1 protein" refer to natriuretic peptide receptor 1. The protein is also called atrial natriuretic peptide receptor type A (ANP-A, ANPR-A or NPR-A) and guanylate cyclase A (GC-A). In some embodiments, the NPR1 mentioned is human NPR1. In some embodiments, human NPR1 has UniProt accession number P16066 or GenBank accession number EAW53284.1 (SEQ ID NO: 1). In some embodiments, the NPR1 mentioned is mouse (Mus musculus) NPR1. In some embodiments, mouse NPR1 has NCBI reference sequence number NP_032753.5 (SEQ ID NO: 2). In some embodiments, the NPR1 mentioned is rat (Rattus norvegicus) NPR1. In some embodiments, rat NPR1 has NCBI reference sequence number NP_036745.1 (SEQID NO: 3). Exemplary NPR1 proteins are shown in Table 1. Where a constitutively active or W74R mutant is discussed herein, the mutant refers to the Trp at amino acid position 74 of the mature human NPR1 protein, and may also be referred to as the Trp at amino acid position 106 of the hNPR1 protein as shown in SEQ ID NO:1.

[0094] Table 1. NPR1 protein sequences

[0095]

[0096]

[0097] In various embodiments, the anti-NPR1 antibodies and antigen-binding fragments disclosed herein are capable of binding to NPR1 and activating NPR1 in the absence of ANP. With this activity, the disclosed anti-NPR1 antibodies and antigen-binding fragments can be used to treat undesirable conditions, diseases and disorders, including cardiovascular disorders (e.g., hypertension, peripheral vascular disease, heart failure (including but not limited to heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction or acute compensated heart failure), coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina, hypertrophic cardiomyopathy (e.g., ventricular hypertrophy), diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset AF, recurrent AF, cardiac fibrosis, atrial flutter, deleterious vascular remodeling , plaque stability or myocardial infarction (MI)), hypertension (resistant hypertension, hypertensive heart disease, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, resistant hypertension or pulmonary arterial hypertension), preeclampsia, asthma, glaucoma, cytokine release syndrome and / or renal disorder (e.g., diabetic renal insufficiency, non-diabetic renal insufficiency, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast-induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, primary renal proteinuria, renovascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD)).

[0098] As used herein, the term "antibody" refers to a whole antibody or an antigen-binding fragment thereof. A whole antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains, namely CH1, CH2 and CH3. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain, namely CL. The VH and VL regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of an antibody can mediate the binding of an immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. The term "antibody" includes, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, camelid antibodies, and chimeric antibodies. Antibodies can be of any isotype / class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) or subclass (e.g., IgG 1 IgG 2 IgG 3 IgG 4 , IgA 1 and IgA 2 ).

[0099] The term "antigen-binding fragment" refers to a fragment of an intact antibody that retains the ability to specifically bind to a given antigen (e.g., NPR1) and / or provide the function of an intact antibody. Such fragments include Fab fragments, Fab' fragments, which are monovalent fragments consisting of VL, VH, CL, and CH1 domains; F(ab')2 fragments, which are bivalent fragments comprising two Fab fragments connected by a disulfide bridge at the hinge region; Fd fragments, which consist of VH and CH1 domains; Fv fragments, which consist of VL and VH domains, single-chain Fv fragments (scFv), which consist of VL and VH domains connected by a linker sequence; and single-domain antibody (dAb) fragments, which consist of VH domains or VL domains (Ward et al., 1989 Nature 341: 544-546).

[0100] The term "single-chain antibody", "single-chain Fv" or "scFv" means a molecule comprising an antibody heavy chain variable domain (or region; VH) and an antibody light chain variable domain (or region; VL) connected by a linker. Such scFv molecules can have a general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Any suitable linker can be used. A non-limiting set of linkers that can be used in such single chain antibodies is described in Holliger et al. (1993), Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States of America] 90:6444-6448, Alfthan et al. (1995), Protein Eng. [Protein Engineering] 8:725-731, Choi et al. (2001), Eur. J. Immunol. [European Journal of Immunology] 31:94-106, Hu et al. (1996), Cancer Res. [Cancer Research] 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. [Journal of Molecular Biology] 293:41-56 and Roovers et al. (2001), Cancer Immunol [Cancer Immunology]; the contents of each of which are hereby incorporated by reference herein. The term "antigen-binding fragment" of an antibody is also intended to cover such single chain antibodies. These antibody fragments are obtained using techniques known to those skilled in the art, and are screened for utility in the same manner as intact antibodies. Without limitation, antigen-binding fragments can be produced by any suitable method known in the art. For example, the various antigen-binding fragments described herein can be produced by enzymatic or chemical modification of intact antibodies, synthesized de novo using recombinant DNA methods (e.g., single-chain Fv), or identified using phage display libraries (see, e.g., Pini and Bracci, Curr Protein Pept Sci [Current Protein and Peptide Science] 2000; 1 (2): 155-69, the contents of which are hereby incorporated by reference herein). The utility (e.g., binding affinity, activity) of antigen-binding fragments can be screened in the same manner as intact antibodies.

[0101] Antigen binding fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs and bis-scFvs (see, e.g., Hollinger and Hudson, 2005, Nature Biotechnology, 23, 9, 1126-1136, the contents of which are hereby incorporated by reference herein). Antigen binding portions of antibodies can be grafted into scaffolds based on polypeptides such as type III fibronectin (Fn3) (see, e.g., U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monomers, the contents of which are hereby incorporated by reference herein).

[0102] The antigen binding fragment can be incorporated into a single chain molecule comprising a pair of tandem Fv segments (VH-CH1-VH-CH1), which together with a complementary light chain polypeptide form a pair of antigen binding regions (see Zapata et al., 1995 Protein Eng. 8(10):1057-1062; and U.S. Pat. No. 5,641,870; the contents of each of which are hereby incorporated by reference herein).

[0103] Throughout this specification, the term "isolated" means that the immunoglobulin, antibody or polynucleotide (as the case may be) is present in a physical environment different from that in which it naturally occurs. For example, a naturally occurring polynucleotide or polypeptide present in a living organism is not isolated, but rather the same polynucleotide or polypeptide is separated from some or all of the coexisting materials in the living organism.

[0104] As used herein, the term "isolated antibody" refers to an antibody that has been identified and separated from one or more (e.g., a majority) of the components (by weight) of its source environment, such as from a hybridoma cell culture or a different cell culture used for its production (e.g., a production cell, including but not limited to the exemplary host cells for recombinantly expressing antibodies described herein). The separation is performed so that it is sufficiently free of components that may otherwise interfere with the suitability of the antibody for a desired application (e.g., for therapeutic use of anti-NPR1 antibodies). Methods for preparing isolated antibodies are known in the art and include protein A chromatography, anion exchange chromatography, cation exchange chromatography, virus retention filtration, and ultrafiltration.

[0105] Throughout the specification, complementarity determining regions ("CDRs") are defined according to the Kabat definition unless it is indicated that a CDR is defined according to another definition. The precise amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme) and ImMunoGenTics (IMGT) numbering (Lefranc, M.-P., The Immunologist, 7, 132-136 (1999); Lefranc, M.-P. et al., Dev. Comp. Immunol., 27, 55-77 (2003) ("IMGT" numbering scheme); the contents of each of which are hereby incorporated by reference herein. For example, for the classical form, according to Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2) and 95-102 (HCDR3); the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2) and 89-97 (LCDR3). According to Josiah, the CDR amino acids in VH are numbered as 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered as 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of Kabat and Josiah, the CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL.According to IMGT, the CDR amino acid residues in VH are numbered approximately 26-35 (CDR1), 51-57 (CDR2), and 93-102 (CDR3), and the CDR amino acid residues in VL are numbered approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3) (according to "Kabat" numbering). Under IMGT, the CDR regions of an antibody can be determined using the program IMGT / DomainGap Align.

[0106] By convention, the CDR regions in the heavy chain are usually referred to as HCDR1, HCDR2 and HCDR3, and the CDR regions in the light chain are usually referred to as LCDR1, LCDR2 and LCDR3. They are numbered sequentially in the direction from the amino terminus to the carboxyl terminus.

[0107] As used herein, the term "antibody framework" refers to a portion of a variable domain, i.e., VL or VH, that serves as a scaffold for the antigen binding loops (CDRs) of the variable domain. Essentially, it is a variable domain without CDRs.

[0108] The term "constant region" or "constant domain" refers to the carboxyl terminal portion of the light and heavy chains that is not directly involved in the binding of the antibody to the antigen, but exhibits various effector functions, such as interaction with Fc receptors. The term refers to a portion of the immunoglobulin molecule that has a more conserved amino acid sequence relative to another portion of the immunoglobulin, the variable domain, and contains the antigen binding site. The constant domain contains the CH1, CH2, and CH3 domains of the heavy chain, and the CHL domain of the light chain.

[0109] The term "epitope" or "antigenic determinant" refers to a site on an antigen to which an immunoglobulin or antibody specifically binds (e.g., a specific site on a target molecule). An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 conserved or non-conserved amino acids in a unique spatial conformation. See, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, ed. G. E. Morris (1996), the contents of which are hereby incorporated herein by reference. In addition, as used herein, an epitope may comprise one or more monosaccharide units of a polysaccharide to which an antibody specifically binds. In particular aspects, an epitope may be a conformational epitope. See, e.g., Thompson et al., 2009, J. of Biol. Chem. 51: 35621-35631, the contents of which are hereby incorporated herein by reference.

[0110] As used herein, the term "monoclonal antibody" or "monoclonal antibody composition" refers to an antibody obtained from a substantially homogeneous antibody population produced by a particular cell or cell line, wherein the individual antibodies comprising the population are substantially identical in sequence, except for possible naturally occurring mutations that may be present in small amounts. Monoclonal antibody preparations exhibit a single binding specificity and affinity for a particular epitope. In contrast, conventional (polyclonal) antibody preparations typically include multiple antibodies specific for or to different epitopes. The modifier "monoclonal" indicates the characteristic of an antibody obtained from a substantially homogeneous antibody population and should not be interpreted as requiring the production of antibodies by any particular method. Monoclonal antibodies (mAbs) can be produced by a variety of techniques, including conventional methods, such as the standard somatic cell hybridization technique of Kohler and Milstein (Nature [Nature] 1975; 256 (5517): 495-7, the contents of which are hereby incorporated by reference herein). Monoclonal antibodies may also be obtained from other suitable methods, including phage display techniques, such as those described in the following literature: Clackson et al. (Nature [Nature] 1991; 352 (6336): 624-8) or Marks et al. (J Mol Biol [Molecular Biology Journal] 1991; 222 (3): 581-97), the contents of each of which are hereby incorporated by reference herein. The term "monoclonal antibody" is also not limited to antibody sequences from a specific source species or from a single source species. Thus, the term "monoclonal antibody" is intended to encompass chimeric monoclonal antibodies, such as humanized monoclonal antibodies.

[0111] As used herein, the term "chimeric antibody" refers to an antibody in which (a) the constant region is altered, replaced or exchanged so that the antigen binding site (variable region) is connected to a constant region of a different or altered class, effector function and / or species; or (b) the variable region or portion thereof is altered, replaced or exchanged with a variable region or portion thereof having a different or altered antigenic specificity. To produce a chimeric antibody, a variable region sequence from a non-human donor antibody (e.g., a mouse, rabbit or rat donor antibody) can be linked to a human constant region using methods known in the art (see, e.g., U.S. Pat. No. 4,816,567 (Cabilly et al.), the contents of which are hereby incorporated by reference herein). For example, a mouse anti-NPR1 antibody can be modified by replacing its constant region with a constant region from a human immunoglobulin. Due to replacement by a human constant region, the chimeric antibody can retain its specificity for recognizing human NPR1 while having reduced immunogenicity in humans compared to the original mouse antibody.

[0112] As used herein, the term "humanized antibody" refers to an antibody form comprising at least some human sequences and at least some non-human sequences. Typically, an antibody comprises a human sequence that imparts target antigen binding specificity and a small portion of a non-human sequence. Such antibodies are chimeric antibodies that comprise a minimal sequence derived from a non-human immunoglobulin and retain the reactivity of a non-human antibody while having low immunogenicity in humans. Typically, humanized antibodies are produced by replacing the hypervariable region sequence of a human receptor antibody with a non-human donor antibody (e.g., a mouse, rabbit, or rat donor antibody) that binds to a target antigen (e.g., NPR1). In some cases, the framework region sequence of the receptor antibody may also be replaced with the corresponding sequence of a donor antibody (e.g., via affinity maturation). In addition to sequences derived from donor and receptor antibodies, humanized antibodies may also be modified by residue substitutions in the framework region and / or the replaced non-human residues to improve and optimize antibody specificity, affinity, and / or activity as described herein. Methods for producing humanized antibodies are known in the art. See, e.g., Riechmann et al. (Nature 1988; 332(6162):323-7); Jones et al. (Nature 1986; 321(6069):522-5); U.S. Pat. No. 5,225,539 (Winter); and U.S. Pat. Nos. 5,530,101, 5,585,089, 5,693,762 and 6,180,370 (Queen et al.), the contents of each of which are hereby incorporated by reference herein.

[0113] As used herein, the term "human antibody" is intended to include antibodies having variable regions, wherein both the framework region and the CDR region are derived from sequences of human origin. In addition, if the antibody contains a constant region, the constant region is also derived from such human sequences, such as human germline sequences, or mutant forms of human germline sequences or antibodies containing a consensus framework sequence derived from human framework sequence analysis, for example, as described in Knappik et al., (2000), J Mol Biol [Journal of Molecular Biology]; 296:57-86, the contents of which are hereby incorporated by reference herein. Human antibodies may include amino acid residues that are not encoded by human sequences (e.g., mutations introduced by random mutagenesis or site-specific mutagenesis in vitro or by somatic mutations in vivo).

[0114] The antibodies or antigen-binding fragments of the present disclosure may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species (e.g., a mouse) have been grafted into human framework sequences.

[0115] The terms "peptide," "polypeptide," and "protein" are used interchangeably herein to refer to polymers of amino acid residues. The terms encompass amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of the corresponding naturally occurring amino acids, as well as applicable to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. Unless otherwise indicated, a particular polypeptide sequence also implicitly encompasses conservatively modified variants thereof.

[0116] The term "conservatively modified variant" is applicable to both amino acids and nucleic acid sequences. For nucleic acid sequences, conservatively modified variants refer to those nucleic acids encoding the same or substantially the same amino acid sequence, or, in the case where the nucleic acid does not encode an amino acid sequence, to substantially the same sequence. Due to the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For example, the codons GCA, GCC, GCG, and GCU all encode the amino acid alanine. Therefore, at each position where alanine is specified by a codon, the codon can be changed to any of the corresponding codons described without changing the encoded polypeptide. Such nucleic acid variations are "silent variations", which are one of conservatively modified variations. Each nucleic acid sequence encoding a polypeptide herein also describes each possible silent variation of the nucleic acid. The technician will recognize that each codon in the nucleic acid (except AUG, which is usually the only codon for methionine, and TGG, which is usually the only codon for tryptophan) can be modified to produce functionally identical molecules. Therefore, each silent variation of the nucleic acid encoding the polypeptide is implied in each of the described sequences. For polypeptide sequences, "conservatively modified variants" include single substitutions, deletions or additions to the polypeptide sequence, thereby replacing an amino acid with a chemically similar amino acid. Conservative substitution tables that provide functionally similar amino acids are well known in the art. The following 8 groups contain amino acids that are conservatively substituted for each other:

[0117] 1) Alanine (A), glycine (G);

[0118] 2) Aspartic acid (D), glutamic acid (E);

[0119] 3) Asparagine (N), glutamine (Q);

[0120] 4) Arginine (R), Lysine (K);

[0121] 5) Isoleucine (I), leucine (L), methionine (M), valine (V);

[0122] 6) Phenylalanine (F), tyrosine (Y), tryptophan (W);

[0123] 7) serine (S), threonine (T); and

[0124] 8) Cysteine ​​(C), methionine (M).

[0125] The term "identity" or "homology" refers to the relationship between the sequences of two or more polypeptides determined by comparing sequences. "Identity" also refers to the degree of sequence relatedness between polypeptides, which is determined by the number of matches between strings of two or more amino acid residues. The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., the percent identity is equal to the number of identical positions / total number of positions x 100), taking into account the number of gaps and the length of each gap, which need to be introduced in order to optimally align the two sequences. Sequence comparison and percent identity determination between two sequences can be completed using a mathematical algorithm. For sequence comparison, typically one sequence serves as a reference sequence, and a test sequence is compared with the reference sequence. When using a sequence comparison algorithm, the test sequence and the reference sequence are input into a computer, subsequence coordinates are specified if necessary, and sequence algorithm program parameters are specified. Default program parameters can be used, or alternative parameters can be specified. Then, the sequence comparison algorithm will calculate the percent sequence identity of the test sequence relative to the reference sequence based on the program parameters. Additionally or alternatively, the protein sequence of the present disclosure can be further used as a "query sequence" to search in a public database, such as to identify related sequences. For example, such searches can be performed using the BLAST programs of Altschul et al. (J Mol Biol 1990; 215(3):403-10, the contents of which are hereby incorporated by reference).

[0126] When compared and aligned over a comparison window or specified region to obtain maximum correspondence using one of the following sequence comparison algorithms or by manual alignment and visual inspection, if the two sequences have a specified percentage of identical amino acid residues or nucleotides (e.g., 60% identity, 65% identity, 70% identity, 75% identity, 80% identity, 85% identity, 90% identity, 95% identity or 99% identity over a specified region or over the entire sequence when not specified), the two sequences are "substantially identical". Optionally, the identity exists over a region of at least about 50 nucleotides (or 10 amino acids) in length, or over a region of 100 to 500 or 1000 or more nucleotides (or 20, 50, 200 or more amino acids) in length.

[0127] Binding "affinity" refers to the strength of interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable regions of the antibody "arms" interact with the antigen at many sites through weak non-covalent forces. In general, the more interactions, the stronger the affinity. Typically, such determinations can be made using cell-based assays.

[0128] As used herein, the term "Kassoc" or "Ka" is intended to refer to the association rate of a particular binding molecule-antigen interaction, while the term "Kdis" or "Kd" as used herein is intended to refer to the dissociation rate of a particular binding molecule-antigen interaction. D " is intended to refer to the equilibrium dissociation constant, which is obtained from the ratio of Kd to Ka (i.e., Kd / Ka) and expressed as a molar concentration (M). The K of an antibody can be determined using methods well established in the art. D Determine the K value of the antibody D The method is to use surface plasmon resonance (such as System or solution equilibrium titration (SET)) (see Friguet et al. (1985) J. Immunol. Methods; 77(2):305-319; and Hanel et al. (2005) Anal. Biochem.; 339(1):182-184, the contents of each of which are hereby incorporated by reference).

[0129] As used herein, the terms "specificity," "specifically binds," and "binds specifically" refer to the binding reaction between an antibody or antigen-binding fragment (e.g., anti-NPR1 antibody) and a target antigen (e.g., NPR1) in a homogeneous population of proteins and other biological products. The binding specificity of an antibody can be tested by comparing binding to an appropriate antigen with binding to an unrelated antigen or antigen mixture under a given set of conditions. An antibody is considered specific if it binds to the appropriate antigen with an affinity that is at least 2, 5, 7, and preferably 10 or more times higher than that of an unrelated antigen or antigen mixture. A "specific antibody" or "target-specific antibody" is an antibody that binds only to a target antigen (e.g., NPR1) but not to other antigens (or exhibits minimal binding thereto). In certain embodiments, the K of an antibody or antigen-binding fragment that specifically binds to a target antigen (e.g., NPR1) is greater than or equal to 1. D Less than 1x 10 -6 M, less than 1x 10 -7 M, less than 1x 10 -8 M, less than 1x10 -9 M, less than 1x 10 -10 M, less than 1x 10 -11 M, less than 1x 10 -12 M or less than 1x 10 -13 M. In certain embodiments, K D In certain embodiments, K DBetween 600 pM and 1 μM, 1 μM and 100 nM or 100 mM and 10 nM (inclusive).

[0130] In some embodiments, the antibody or antigen binding fragment thereof acts as a non-competitive agonist. "Non-competitive agonist" refers to a molecule that binds to an enzyme or receptor at a site away from the binding site of its natural ligand. Non-competitive or allosteric agonists are generally independent of the association or concentration of the natural ligand of the enzyme or receptor. Such non-competitive agonists can, for example, provide an activation level that can be substantially independent of the natural ligand. In a specific embodiment, the anti-NPR1 antibody or antigen binding fragment described herein is ANP non-competitive, meaning that the antibody or antigen binding fragment acts as an agonist that binds and affects agonistic activity at a site away from the ANP binding site of NPR1, regardless of whether NPR1 is combined with ANP.

[0131] In some embodiments, the antibody or antigen binding fragment thereof acts as a competitive agonist. A "competitive agonist" refers to an agonist that interferes with a natural ligand or competes with it for its binding site on an enzyme or receptor. In a specific embodiment, the anti-NPR1 antibody or antigen binding fragment described herein is ANP competitive, meaning that the antibody or antigen binding fragment acts as an agonist that competes with ANP at the ANP binding site of NPR1.

[0132] In some embodiments, activation of NPR1 by the antibody or antigen binding fragment can be determined by any suitable assay. An exemplary assay for determining NPR1 activation is the production of cGMP by mammalian cells (eg, CHO cells or human cell lines) expressing hNPR1.

[0133] In some embodiments, the stabilization of the ANP-NPR1 complex can be determined by any suitable assay. An exemplary assay for determining the stability of the ANP-NPR1 complex is a FRET assay described herein (see, e.g., Figure 3 ).

[0134] The term "about" with respect to a value x means, for example, x ± 10%.

[0135] Antibodies of the Disclosure

[0136] The following discloses certain specific anti-NPR1 antibody sequences of the present disclosure. As used herein, the term "anti-NPR1 antibody" or "antibody that binds to NPR1" refers to any form of antibody or antigen-binding fragment that specifically binds to NPR1, for example, with a specificity of less than 1 x 10 -8 M of K D Those bound, as determined by, for example, surface plasmon resonance (SPR) spectroscopy (using Biacore TM) or solution equilibrium titration (SET). The term includes monoclonal antibodies (including intact monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, as long as they specifically bind to NPR1.

[0137] Table 2 lists the amino acid and nucleic acid sequences of exemplary anti-NPR1 antibodies of the present disclosure. In some embodiments, the antibody has the heavy and light chain CDRs, VH and VL sequences and / or heavy and light chain sequences of any antibody described in Table 2. In some embodiments, the anti-NPR1 antibody is a four-chain antibody (also referred to as a complete antibody) comprising two heavy chains and two light chains. In some embodiments, the anti-NPR1 antibody is an antigen-binding fragment of a complete antibody, such as a functional fragment of a complete antibody selected from those listed in Table 2, which retains the ability to bind to NPR1 and / or provide complete antibody functions (e.g., activating NPR1 in the absence of ANP). In some embodiments, the anti-NPR1 antibody is an antibody having any heavy chain variable region and light chain variable region pairs shown in Table 2. In some embodiments, the anti-NPR1 antibody is an antibody having any heavy chain and light chain pairs shown in Table 2.

[0138] Table 2. Exemplary anti-NPR1 antibody sequences

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224] For example, WW01_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), SEQ ID NO:22 (LCDR3); NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:10 (HCDR1), SEQ ID NO:11 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3). In some embodiments, WW01_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3). In some embodiments, WW01_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3).In some embodiments, WW01_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 8 (HCDR1), SEQ ID NO: 9 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 22 (LCDR3). In some embodiments, WW01_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 10 (HCDR1), SEQ ID NO: 11 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 19 (LCDR3). In some embodiments, WW01_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 13, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 24. In some embodiments, WW01_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 15, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 26.

[0225] For example, WW03_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 43 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 43 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 33 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), SEQ ID NO: 46 (LCDR3). NO:45 (LCDR2) and SEQ ID NO:46 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:43 (LCDR3). In some embodiments, WW03_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:43 (LCDR3). In some embodiments, WW03_LALA can be defined as comprising or having the following amino acid sequences: SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:43 (LCDR3).In some embodiments, WW03_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 33 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 46 (LCDR3). In some embodiments, WW03_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 35 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 43 (LCDR3). In some embodiments, WW03_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 37, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 48. In some embodiments, WW03_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:39, and the light chain comprises or has the amino acid sequence of SEQ ID NO:50.

[0226] For example, WW05_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 52 (HCDR1), SEQ ID NO: 53 (HCDR2), SEQ ID NO: 54 (HCDR3), SEQ ID NO: 65 (LCDR1), SEQ ID NO: 66 (LCDR2) and SEQ ID NO: 67 (LCDR3); (II) SEQ ID NO: 55 (HCDR1), SEQ ID NO: 53 (HCDR2), SEQ ID NO: 54 (HCDR3), SEQ ID NO: 65 (LCDR1), SEQ ID NO: 66 (LCDR2) and SEQ ID NO: 67 (LCDR3); (III) SEQ ID NO: 56 (HCDR1), SEQ ID NO: 57 (HCDR2), SEQ ID NO: 54 (HCDR3), SEQ ID NO: 68 (LCDR1), SEQ ID NO: 69 (LCDR2), and SEQ ID NO: 70 (LCDR3). NO:69 (LCDR2) and SEQ ID NO:70 (LCDR3); or (IV) SEQ ID NO:58 (HCDR1), SEQ ID NO:59 (HCDR2), SEQ ID NO:60 (HCDR3), SEQ ID NO:71 (LCDR1), SEQ ID NO:69 (LCDR2) and SEQ ID NO:67 (LCDR3). In some embodiments, WW05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:52 (HCDR1), SEQ ID NO:53 (HCDR2), SEQ ID NO:54 (HCDR3), SEQ ID NO:65 (LCDR1), SEQ ID NO:66 (LCDR2), and SEQ ID NO:67 (LCDR3). In some embodiments, WW05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:55 (HCDR1), SEQ ID NO:53 (HCDR2), SEQ ID NO:54 (HCDR3), SEQ ID NO:65 (LCDR1), SEQ ID NO:66 (LCDR2), and SEQ ID NO:67 (LCDR3).In some embodiments, WW05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 56 (HCDR1), SEQ ID NO: 57 (HCDR2), SEQ ID NO: 54 (HCDR3), SEQ ID NO: 68 (LCDR1), SEQ ID NO: 69 (LCDR2), and SEQ ID NO: 70 (LCDR3). In some embodiments, WW05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 58 (HCDR1), SEQ ID NO: 59 (HCDR2), SEQ ID NO: 60 (HCDR3), SEQ ID NO: 71 (LCDR1), SEQ ID NO: 69 (LCDR2), and SEQ ID NO: 67 (LCDR3). In some embodiments, WW05_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 61, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 72. In some embodiments, WW05_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:63, and the light chain comprises or has the amino acid sequence of SEQ ID NO:74.

[0227] For example, WW06_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO:76 (HCDR1), SEQ ID NO:77 (HCDR2), SEQ ID NO:78 (HCDR3), SEQ ID NO:89 (LCDR1), SEQ ID NO:90 (LCDR2) and SEQ ID NO:91 (LCDR3); (II) SEQ ID NO:79 (HCDR1), SEQ ID NO:77 (HCDR2), SEQ ID NO:78 (HCDR3), SEQ ID NO:89 (LCDR1), SEQ ID NO:90 (LCDR2) and SEQ ID NO:91 (LCDR3); (III) SEQ ID NO:80 (HCDR1), SEQ ID NO:81 (HCDR2), SEQ ID NO:78 (HCDR3), SEQ ID NO:92 (LCDR1), SEQ ID NO:93 (LCDR2), and SEQ ID NO:94 (LCDR3). NO:93 (LCDR2) and SEQ ID NO:94 (LCDR3); or (IV) SEQ ID NO:82 (HCDR1), SEQ ID NO:83 (HCDR2), SEQ ID NO:84 (HCDR3), SEQ ID NO:95 (LCDR1), SEQ ID NO:93 (LCDR2) and SEQ ID NO:91 (LCDR3). In some embodiments, WW06_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:76 (HCDR1), SEQ ID NO:77 (HCDR2), SEQ ID NO:78 (HCDR3), SEQ ID NO:89 (LCDR1), SEQ ID NO:90 (LCDR2), and SEQ ID NO:91 (LCDR3). In some embodiments, WW06_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:79 (HCDR1), SEQ ID NO:77 (HCDR2), SEQ ID NO:78 (HCDR3), SEQ ID NO:89 (LCDR1), SEQ ID NO:90 (LCDR2), and SEQ ID NO:91 (LCDR3).In some embodiments, WW06_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 80 (HCDR1), SEQ ID NO: 81 (HCDR2), SEQ ID NO: 78 (HCDR3), SEQ ID NO: 92 (LCDR1), SEQ ID NO: 93 (LCDR2), and SEQ ID NO: 94 (LCDR3). In some embodiments, WW06_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 82 (HCDR1), SEQ ID NO: 83 (HCDR2), SEQ ID NO: 84 (HCDR3), SEQ ID NO: 95 (LCDR1), SEQ ID NO: 93 (LCDR2), and SEQ ID NO: 91 (LCDR3). In some embodiments, WW06_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 85, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 96. In some embodiments, WW06_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:87, and the light chain comprises or has the amino acid sequence of SEQ ID NO:98.

[0228] For example, XX01_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 4 (HCDR1), SEQ ID NO: 100 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 17 (LCDR1), SEQ ID NO: 18 (LCDR2) and SEQ ID NO: 19 (LCDR3); (II) SEQ ID NO: 7 (HCDR1), SEQ ID NO: 100 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 17 (LCDR1), SEQ ID NO: 18 (LCDR2) and SEQ ID NO: 19 (LCDR3); (III) SEQ ID NO: 8 (HCDR1), SEQ ID NO: 101 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2), SEQ ID NO: 22 (LCDR3); NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:10 (HCDR1), SEQ ID NO:102 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3). In some embodiments, XX01_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:4 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3). In some embodiments, XX01_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:7 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3).In some embodiments, XX01_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 8 (HCDR1), SEQ ID NO: 101 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 22 (LCDR3). In some embodiments, XX01_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 10 (HCDR1), SEQ ID NO: 102 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 19 (LCDR3). In some embodiments, XX01_LALA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 103, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 24. In some embodiments, XX01_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 105, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 26.

[0229] For example, XX01_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:101 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), SEQ ID NO:22 (LCDR3); NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:10 (HCDR1), SEQ ID NO:102 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3). In some embodiments, XX01_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:4 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3). In some embodiments, XX01_DAPA can be defined as comprising or having the following amino acid sequences: SEQ ID NO:7 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3).In some embodiments, XX01_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 8 (HCDR1), SEQ ID NO: 101 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 22 (LCDR3). In some embodiments, XX01_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 10 (HCDR1), SEQ ID NO: 102 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 19 (LCDR3). In some embodiments, XX01_DAPA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 103, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 24. In some embodiments, XX01_DAPA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 108, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 26.

[0230] For example, XX01_N30S_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 112 (HCDR1), SEQ ID NO: 100 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 17 (LCDR1), SEQ ID NO: 18 (LCDR2) and SEQ ID NO: 19 (LCDR3); (II) SEQ ID NO: 7 (HCDR1), SEQ ID NO: 100 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 17 (LCDR1), SEQ ID NO: 18 (LCDR2) and SEQ ID NO: 19 (LCDR3); (III) SEQ ID NO: 113 (HCDR1), SEQ ID NO: 101 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 1 NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:114 (HCDR1), SEQ ID NO:102 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3). In some embodiments, XX01_N30S_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:112 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3). In some embodiments, XX01_N30S_DAPA can be defined as comprising or having the following amino acid sequences: SEQ ID NO:7 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3).In some embodiments, XX01_N30S_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 113 (HCDR1), SEQ ID NO: 101 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 22 (LCDR3). In some embodiments, XX01_N30S_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 114 (HCDR1), SEQ ID NO: 102 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 19 (LCDR3). In some embodiments, XX01_N30S_DAPA may be defined as comprising or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises or has the amino acid sequence of SEQ ID NO: 115, and the light chain variable region comprises or has the amino acid sequence of SEQ ID NO: 24. In some embodiments, XX01_N30S_DAPA may be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 117, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 26.

[0231] For example, XX03_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 43 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 43 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 43 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:46 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:43 (LCDR3). In some embodiments, XX03_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:43 (LCDR3). In some embodiments, XX03_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:43 (LCDR3).In some embodiments, XX03_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 46 (LCDR3). In some embodiments, XX03_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 43 (LCDR3). In some embodiments, XX03_LALA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 122, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 48. In some embodiments, XX03_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 124, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 50.

[0232] For example, XX04_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 126 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 126 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 33 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), SEQ ID NO: 46 (LCDR3). In some embodiments, XX04_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 126 (LCDR3). In some embodiments, XX04_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:126 (LCDR3).In some embodiments, XX04_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:127 (LCDR3). In some embodiments, XX04_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:126 (LCDR3). In some embodiments, XX04_LALA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO:37, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO:128. In some embodiments, XX04_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:39, and the light chain comprises or has the amino acid sequence of SEQ ID NO:130.

[0233] For example, XX06_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 33 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 135 (LCDR2); In some embodiments, XX06_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 134 (LCDR3). In some embodiments, XX06_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3).In some embodiments, XX06_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:135 (LCDR3). In some embodiments, XX06_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:134 (LCDR3). In some embodiments, XX06_LALA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO:37, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO:136. In some embodiments, XX06_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:39, and the light chain comprises or has the amino acid sequence of SEQ ID NO:138.

[0234] For example, XX06_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2, and LCDR3) selected from the group consisting of: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 134 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 134 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 33 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 135 (LCDR2); In some embodiments, XX06_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 134 (LCDR3). In some embodiments, XX06_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3).In some embodiments, XX06_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:135 (LCDR3). In some embodiments, XX06_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:134 (LCDR3). In some embodiments, XX06_DAPA may be defined as comprising or having a heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO:37 and a light chain variable region comprising or having the amino acid sequence of SEQ ID NO:136. In some embodiments, XX06_DAPA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 141, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 138.

[0235] For example, XX07_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 145 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 145 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 33 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2); In some embodiments, XX07_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 145 (LCDR3). In some embodiments, XX07_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:145 (LCDR3).In some embodiments, XX07_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:146 (LCDR3). In some embodiments, XX07_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:145 (LCDR3). In some embodiments, XX07_LALA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO:37, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO:147. In some embodiments, XX07_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:39, and the light chain comprises or has the amino acid sequence of SEQ ID NO:149.

[0236] For example, XX08_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:152 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), SEQ ID NO:22 (LCDR3); NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:10 (HCDR1), SEQ ID NO:153 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3). In some embodiments, XX08_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:4 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3). In some embodiments, XX08_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3).In some embodiments, XX08_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 8 (HCDR1), SEQ ID NO: 152 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 22 (LCDR3). In some embodiments, XX08_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 10 (HCDR1), SEQ ID NO: 153 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 19 (LCDR3). In some embodiments, XX08_LALA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 154, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 24. In some embodiments, XX08_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 156, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 26.

[0237] For example, XX08_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO:4 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:152 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), SEQ ID NO:22 (LCDR3); NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:10 (HCDR1), SEQ ID NO:153 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3). In some embodiments, XX08_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:4 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3). In some embodiments, XX08_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3).In some embodiments, XX08_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 8 (HCDR1), SEQ ID NO: 152 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 22 (LCDR3). In some embodiments, XX08_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 10 (HCDR1), SEQ ID NO: 153 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 19 (LCDR3). In some embodiments, XX08_DAPA may be defined as comprising or having a heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 154 and a light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 24. In some embodiments, XX08_DAPA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 159, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 26.

[0238] For example, XX08_N30S_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 112 (HCDR1), SEQ ID NO: 151 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 17 (LCDR1), SEQ ID NO: 18 (LCDR2) and SEQ ID NO: 19 (LCDR3); (II) SEQ ID NO: 7 (HCDR1), SEQ ID NO: 151 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 17 (LCDR1), SEQ ID NO: 18 (LCDR2) and SEQ ID NO: 19 (LCDR3); (III) SEQ ID NO: 113 (HCDR1), SEQ ID NO: 152 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 1 NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:114 (HCDR1), SEQ ID NO:153 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3). In some embodiments, XX08_N30S_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:112 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3). In some embodiments, XX08_N30S_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3).In some embodiments, XX08_N30S_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 113 (HCDR1), SEQ ID NO: 152 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 22 (LCDR3). In some embodiments, XX08_N30S_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 114 (HCDR1), SEQ ID NO: 153 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 19 (LCDR3). In some embodiments, XX08_N30S_DAPA may be defined as comprising or having a heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 161 and a light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 24. In some embodiments, XX08_N30S_DAPA may be defined as comprising or having a heavy chain and a light chain, the heavy chain comprising or having the amino acid sequence of SEQ ID NO: 163 and the light chain comprising or having the amino acid sequence of SEQ ID NO: 26.

[0239] For example, XX08_N30Q_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 165 (HCDR1), SEQ ID NO: 151 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 17 (LCDR1), SEQ ID NO: 18 (LCDR2) and SEQ ID NO: 19 (LCDR3); (II) SEQ ID NO: 7 (HCDR1), SEQ ID NO: 151 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 17 (LCDR1), SEQ ID NO: 18 (LCDR2) and SEQ ID NO: 19 (LCDR3); (III) SEQ ID NO: 166 (HCDR1), SEQ ID NO: 152 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 1 NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:167 (HCDR1), SEQ ID NO:153 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3). In some embodiments, XX08_N30Q_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:165 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3). In some embodiments, XX08_N30Q_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3).In some embodiments, XX08_N30Q_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 166 (HCDR1), SEQ ID NO: 152 (HCDR2), SEQ ID NO: 6 (HCDR3), SEQ ID NO: 20 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 22 (LCDR3). In some embodiments, XX08_N30Q_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 167 (HCDR1), SEQ ID NO: 153 (HCDR2), SEQ ID NO: 12 (HCDR3), SEQ ID NO: 23 (LCDR1), SEQ ID NO: 21 (LCDR2), and SEQ ID NO: 19 (LCDR3). In some embodiments, XX08_N30Q_DAPA may be defined as comprising or having a heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 168 and a light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 24. In some embodiments, XX08_N30Q_DAPA may be defined as comprising or having a heavy chain comprising or having the amino acid sequence of SEQ ID NO: 170 and a light chain comprising or having the amino acid sequence of SEQ ID NO: 26.

[0240] For example, XX09_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 172 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 172 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 33 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), SEQ ID NO: 46 (LCDR3). In some embodiments, XX09_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 172 (LCDR3). In some embodiments, XX09_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3).In some embodiments, XX09_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 33 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 173 (LCDR3). In some embodiments, XX09_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 35 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 172 (LCDR3). In some embodiments, XX09_LALA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 37, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 174. In some embodiments, XX09_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:39, and the light chain comprises or has the amino acid sequence of SEQ ID NO:176.

[0241] For example, XX11_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 178 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 178 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 33 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), SEQ ID NO: 46 (LCDR3). In some embodiments, XX11_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 178 (LCDR3). In some embodiments, XX11_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:178 (LCDR3).In some embodiments, XX11_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:179 (LCDR3). In some embodiments, XX11_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:178 (LCDR3). In some embodiments, XX11_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO:37, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO:180. In some embodiments, XX11_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:39, and the light chain comprises or has the amino acid sequence of SEQ ID NO:182.

[0242] For example, XX12_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 184 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 184 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 33 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 184 (LCDR3). In some embodiments, XX12_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 28 (HCDR1), SEQ ID NO: 29 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2), and SEQ ID NO: 184 (LCDR3). In some embodiments, XX12_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:184 (LCDR3).In some embodiments, XX12_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 33 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 185 (LCDR3). In some embodiments, XX12_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 35 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 184 (LCDR3). In some embodiments, XX12_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 37, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 186. In some embodiments, XX12_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:39, and the light chain comprises or has the amino acid sequence of SEQ ID NO:188.

[0243] For example, XX13_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 190 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 190 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 191 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:135 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:192 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:134 (LCDR3). In some embodiments, XX13_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3). In some embodiments, XX13_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3).In some embodiments, XX13_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 191 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 135 (LCDR3). In some embodiments, XX13_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 192 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 134 (LCDR3). In some embodiments, XX13_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 193, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 136. In some embodiments, XX13_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 195, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 138.

[0244] For example, XX14_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 190 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 172 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 190 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 172 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 191 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:173 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:192 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:172 (LCDR3). In some embodiments, XX14_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3). In some embodiments, XX14_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3).In some embodiments, XX14_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 191 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 173 (LCDR3). In some embodiments, XX14_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 192 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 172 (LCDR3). In some embodiments, XX14_LALA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 193, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 174. In some embodiments, XX14_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 195, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 176.

[0245] For example, XX15_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 126 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 126 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 126 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:127 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:126 (LCDR3). In some embodiments, XX15_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:126 (LCDR3). In some embodiments, XX15_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:126 (LCDR3).In some embodiments, XX15_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 127 (LCDR3). In some embodiments, XX15_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 126 (LCDR3). In some embodiments, XX15_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 201, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 128. In some embodiments, XX15_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:203, and the light chain comprises or has the amino acid sequence of SEQ ID NO:130.

[0246] For example, XX15_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 126 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 126 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 126 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:127 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:126 (LCDR3). In some embodiments, XX15_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:126 (LCDR3). In some embodiments, XX15_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:126 (LCDR3).In some embodiments, XX15_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 127 (LCDR3). In some embodiments, XX15_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 126 (LCDR3). In some embodiments, XX15_DAPA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 122, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 128. In some embodiments, XX15_DAPA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:208, and the light chain comprises or has the amino acid sequence of SEQ ID NO:130.

[0247] For example, XX16_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:135 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:134 (LCDR3). In some embodiments, XX16_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3). In some embodiments, XX16_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3).In some embodiments, XX16_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 135 (LCDR3). In some embodiments, XX16_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 134 (LCDR3). In some embodiments, XX16_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 201, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 136. In some embodiments, XX16_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:203, and the light chain comprises or has the amino acid sequence of SEQ ID NO:138.

[0248] For example, XX16_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:135 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:134 (LCDR3). In some embodiments, XX16_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3). In some embodiments, XX16_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3).In some embodiments, XX16_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 135 (LCDR3). In some embodiments, XX16_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 134 (LCDR3). In some embodiments, XX16_DAPA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 122, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 136. In some embodiments, XX16_DAPA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:208, and the light chain comprises or has the amino acid sequence of SEQ ID NO:138.

[0249] For example, XX17_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 145 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 145 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 145 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:146 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:145 (LCDR3). In some embodiments, XX17_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:145 (LCDR3). In some embodiments, XX17_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:145 (LCDR3).In some embodiments, XX17_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 146 (LCDR3). In some embodiments, XX17_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 145 (LCDR3). In some embodiments, XX17_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 201, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 147. In some embodiments, XX17_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:203, and the light chain comprises or has the amino acid sequence of SEQ ID NO:149.

[0250] For example, XX17_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 145 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 145 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 145 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:146 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:145 (LCDR3). In some embodiments, XX17_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:145 (LCDR3). In some embodiments, XX17_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:145 (LCDR3).In some embodiments, XX17_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 146 (LCDR3). In some embodiments, XX17_DAPA may be defined as comprising or having the following amino acid sequence: (IV) SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 145 (LCDR3). In some embodiments, XX17_DAPA may be defined as comprising or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises or has the amino acid sequence of SEQ ID NO: 122, and the light chain variable region comprises or has the amino acid sequence of SEQ ID NO: 147. In some embodiments, XX17_DAPA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:208, and the light chain comprises or has the amino acid sequence of SEQ ID NO:149.

[0251] For example, XX18_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 172 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 172 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:173 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:172 (LCDR3). In some embodiments, XX18_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3). In some embodiments, XX18_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3).In some embodiments, XX18_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 173 (LCDR3). In some embodiments, XX18_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 172 (LCDR3). In some embodiments, XX18_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 201, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 174. In some embodiments, XX18_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:203, and the light chain comprises or has the amino acid sequence of SEQ ID NO:176.

[0252] For example, XX18_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 172 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 172 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 172 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:173 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:172 (LCDR3). In some embodiments, XX18_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3). In some embodiments, XX18_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3).In some embodiments, XX18_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 173 (LCDR3). In some embodiments, XX18_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 172 (LCDR3). In some embodiments, XX18_DAPA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 122, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 174. In some embodiments, XX18_DAPA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:208, and the light chain comprises or has the amino acid sequence of SEQ ID NO:176.

[0253] For example, XX19_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 178 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 178 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 178 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:179 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:178 (LCDR3). In some embodiments, XX19_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:178 (LCDR3). In some embodiments, XX19_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:178 (LCDR3).In some embodiments, XX19_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 179 (LCDR3). In some embodiments, XX19_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 178 (LCDR3). In some embodiments, XX19_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 201, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 180. In some embodiments, XX19_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:203, and the light chain comprises or has the amino acid sequence of SEQ ID NO:182.

[0254] For example, XX19_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 178 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 178 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 178 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:179 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:178 (LCDR3). In some embodiments, XX19_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:178 (LCDR3). In some embodiments, XX19_DAPA can be defined as comprising or having the following amino acid sequences: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:178 (LCDR3).In some embodiments, XX19_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 179 (LCDR3). In some embodiments, XX19_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 178 (LCDR3). In some embodiments, XX19_DAPA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 122, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 180. In some embodiments, XX19_DAPA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:208, and the light chain comprises or has the amino acid sequence of SEQ ID NO:182.

[0255] For example, XX20_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 184 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 184 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 184 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:185 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:184 (LCDR3). In some embodiments, XX20_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:184 (LCDR3). In some embodiments, XX20_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:184 (LCDR3).In some embodiments, XX20_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 185 (LCDR3). In some embodiments, XX20_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 184 (LCDR3). In some embodiments, XX20_LALA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 201, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 186. In some embodiments, XX20_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:203, and the light chain comprises or has the amino acid sequence of SEQ ID NO:188.

[0256] For example, XX20_DAPA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 184 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 184 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 184 (LCDR3). NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:185 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:184 (LCDR3). In some embodiments, XX20_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:184 (LCDR3). In some embodiments, XX20_DAPA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:184 (LCDR3).In some embodiments, XX20_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 185 (LCDR3). In some embodiments, XX20_DAPA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2), and SEQ ID NO: 184 (LCDR3). In some embodiments, XX20_DAPA may be defined as comprising or having a heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 122 and a light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 186. In some embodiments, XX20_DAPA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:208, and the light chain comprises or has the amino acid sequence of SEQ ID NO:188.

[0257] For example, YY01_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 226 (HCDR1), SEQ ID NO: 227 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 239 (LCDR3); (II) SEQ ID NO: 229 (HCDR1), SEQ ID NO: 227 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 239 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 230 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 332 (LCDR2), SEQ ID NO: 333 (LCDR3), SEQ ID NO: 334 (LCDR2), SEQ ID NO: 335 (LCDR3), SEQ ID NO: 336 (LCDR2), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); NO: 226 (HCDR1), SEQ ID NO: 227 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2), and SEQ ID NO: 239 (LCDR3). In some embodiments, YY01_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 226 (HCDR1), SEQ ID NO: 227 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2), and SEQ ID NO: 239 (LCDR3). In some embodiments, YY01_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 229 (HCDR1), SEQ ID NO: 227 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2), and SEQ ID NO: 239 (LCDR3).In some embodiments, YY01_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 230 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 240 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 242 (LCDR3). In some embodiments, YY01_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO: 34 (HCDR1), SEQ ID NO: 231 (HCDR2), SEQ ID NO: 232 (HCDR3), SEQ ID NO: 243 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 239 (LCDR3). In some embodiments, YY01_LALA may be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 233, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 244. In some embodiments, YY01_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:235, and the light chain comprises or has the amino acid sequence of SEQ ID NO:246.

[0258] For example, YY02_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 248 (HCDR1), SEQ ID NO: 249 (HCDR2), SEQ ID NO: 250 (HCDR3), SEQ ID NO: 260 (LCDR1), SEQ ID NO: 261 (LCDR2) and SEQ ID NO: 262 (LCDR3); (II) SEQ ID NO: 251 (HCDR1), SEQ ID NO: 249 (HCDR2), SEQ ID NO: 250 (HCDR3), SEQ ID NO: 260 (LCDR1), SEQ ID NO: 261 (LCDR2) and SEQ ID NO: 262 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 252 (HCDR2), SEQ ID NO: 3 NO:250 (HCDR3), SEQ ID NO:260 (LCDR1), SEQ ID NO:261 (LCDR2), and SEQ ID NO:262 (LCDR3). In some embodiments, YY02_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO:248 (HCDR1), SEQ ID NO:249 (HCDR2), SEQ ID NO:250 (HCDR3), SEQ ID NO:260 (LCDR1), SEQ ID NO:261 (LCDR2), and SEQ ID NO:262 (LCDR3). In some embodiments, YY02_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:251 (HCDR1), SEQ ID NO:249 (HCDR2), SEQ ID NO:250 (HCDR3), SEQ ID NO:260 (LCDR1), SEQ ID NO:261 (LCDR2), and SEQ ID NO:262 (LCDR3).In some embodiments, YY02_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 252 (HCDR2), SEQ ID NO: 250 (HCDR3), SEQ ID NO: 263 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 264 (LCDR3). In some embodiments, YY02_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 253 (HCDR1), SEQ ID NO: 254 (HCDR2), SEQ ID NO: 255 (HCDR3), SEQ ID NO: 265 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 262 (LCDR3). In some embodiments, YY02_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 256, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 266. In some embodiments, YY02_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 258, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 268.

[0259] For example, YY03_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 270 (HCDR1), SEQ ID NO: 271 (HCDR2), SEQ ID NO: 272 (HCDR3), SEQ ID NO: 282 (LCDR1), SEQ ID NO: 261 (LCDR2) and SEQ ID NO: 283 (LCDR3); (II) SEQ ID NO: 273 (HCDR1), SEQ ID NO: 271 (HCDR2), SEQ ID NO: 272 (HCDR3), SEQ ID NO: 282 (LCDR1), SEQ ID NO: 261 (LCDR2) and SEQ ID NO: 283 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 274 (HCDR2), SEQ ID NO: 275 (HCDR3), SEQ ID NO: 276 (LCDR1), SEQ ID NO: 277 (LCDR2), and SEQ ID NO: 278 (LCDR3). NO: 272 (HCDR3), SEQ ID NO: 274 (LCDR1), SEQ ID NO: 276 (HCDR2), SEQ ID NO: 277 (HCDR3), SEQ ID NO: 286 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 283 (LCDR3). In some embodiments, YY03_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 270 (HCDR1), SEQ ID NO: 271 (HCDR2), SEQ ID NO: 272 (HCDR3), SEQ ID NO: 282 (LCDR1), SEQ ID NO: 261 (LCDR2), and SEQ ID NO: 283 (LCDR3). In some embodiments, YY03_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 273 (HCDR1), SEQ ID NO: 271 (HCDR2), SEQ ID NO: 272 (HCDR3), SEQ ID NO: 282 (LCDR1), SEQ ID NO: 261 (LCDR2), and SEQ ID NO: 283 (LCDR3).In some embodiments, YY03_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 274 (HCDR2), SEQ ID NO: 272 (HCDR3), SEQ ID NO: 284 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 285 (LCDR3). In some embodiments, YY03_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 275 (HCDR1), SEQ ID NO: 276 (HCDR2), SEQ ID NO: 277 (HCDR3), SEQ ID NO: 286 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 283 (LCDR3). In some embodiments, YY03_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 278, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 287. In some embodiments, YY03_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 280, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 289.

[0260] For example, YY04_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 291 (HCDR1), SEQ ID NO: 292 (HCDR2), SEQ ID NO: 293 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 304 (LCDR3); (II) SEQ ID NO: 294 (HCDR1), SEQ ID NO: 292 (HCDR2), SEQ ID NO: 293 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 304 (LCDR3); (III) SEQ ID NO: 295 (HCDR1), SEQ ID NO: 296 (HCDR2), SEQ ID NO: 297 (HCDR3), SEQ ID NO: 298 (HCDR3), SEQ ID NO: 299 (HCDR4), SEQ ID NO: 300 (LCDR5), SEQ ID NO: 301 (LCDR6), SEQ ID NO: 302 (LCDR7), SEQ ID NO: 303 (LCDR8), SEQ ID NO: 304 (LCDR9), SEQ ID NO: 305 (LCDR1), SEQ ID NO: 306 (HCDR1), SEQ ID NO: 307 (LCDR2), SEQ ID NO: 308 (LCDR3), SEQ ID NO: 309 (LCDR3), SEQ ID NO: 310 (LCDR1), SEQ ID NO: 311 (LCDR2), SEQ ID NO: 312 (LCDR3), SEQ ID NO: 313 (LCDR1), SEQ ID NO: NO:293 (HCDR3), SEQ ID NO:240 (LCDR1), SEQ ID NO:241 (LCDR2) and SEQ ID NO:305 (LCDR3); or (IV) SEQ ID NO:297 (HCDR1), SEQ ID NO:298 (HCDR2), SEQ ID NO:299 (HCDR3), SEQ ID NO:243 (LCDR1), SEQ ID NO:241 (LCDR2) and SEQ ID NO:304 (LCDR3). In some embodiments, YY04_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:291 (HCDR1), SEQ ID NO:292 (HCDR2), SEQ ID NO:293 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:304 (LCDR3). In some embodiments, YY04_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:294 (HCDR1), SEQ ID NO:292 (HCDR2), SEQ ID NO:293 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:304 (LCDR3).In some embodiments, YY04_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 295 (HCDR1), SEQ ID NO: 296 (HCDR2), SEQ ID NO: 293 (HCDR3), SEQ ID NO: 240 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 305 (LCDR3). In some embodiments, YY04_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 297 (HCDR1), SEQ ID NO: 298 (HCDR2), SEQ ID NO: 299 (HCDR3), SEQ ID NO: 243 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 304 (LCDR3). In some embodiments, YY04_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 300, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 306. In some embodiments, YY04_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:302, and the light chain comprises or has the amino acid sequence of SEQ ID NO:308.

[0261] For example, YY05_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 310 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 312 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 321 (LCDR2) and SEQ ID NO: 322 (LCDR3); (II) SEQ ID NO: 229 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 312 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 321 (LCDR2) and SEQ ID NO: 322 (LCDR3); (III) SEQ ID NO: 80 (HCDR1), SEQ ID NO: 313 (HCDR2), SEQ ID NO: 314 (HCDR3), SEQ ID NO: 315 (LCDR2), SEQ ID NO: 316 (LCDR3), SEQ ID NO: 317 (LCDR2), SEQ ID NO: 318 (LCDR3), SEQ ID NO: 319 (LCDR1), SEQ ID NO: 321 (LCDR2) and SEQ ID NO: 322 (LCDR3). NO:312 (HCDR3), SEQ ID NO:323 (LCDR1), SEQ ID NO:324 (LCDR2) and SEQ ID NO:325 (LCDR3); or (IV) SEQ ID NO:82 (HCDR1), SEQ ID NO:314 (HCDR2), SEQ ID NO:315 (HCDR3), SEQ ID NO:326 (LCDR1), SEQ ID NO:324 (LCDR2) and SEQ ID NO:322 (LCDR3). In some embodiments, YY05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:310 (HCDR1), SEQ ID NO:311 (HCDR2), SEQ ID NO:312 (HCDR3), SEQ ID NO:320 (LCDR1), SEQ ID NO:321 (LCDR2), and SEQ ID NO:322 (LCDR3). In some embodiments, YY05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:229 (HCDR1), SEQ ID NO:311 (HCDR2), SEQ ID NO:312 (HCDR3), SEQ ID NO:320 (LCDR1), SEQ ID NO:321 (LCDR2), and SEQ ID NO:322 (LCDR3).In some embodiments, YY05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 80 (HCDR1), SEQ ID NO: 313 (HCDR2), SEQ ID NO: 312 (HCDR3), SEQ ID NO: 323 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 325 (LCDR3). In some embodiments, YY05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 82 (HCDR1), SEQ ID NO: 314 (HCDR2), SEQ ID NO: 315 (HCDR3), SEQ ID NO: 326 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 322 (LCDR3). In some embodiments, YY05_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 316, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 327. In some embodiments, YY05_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:318, and the light chain comprises or has the amino acid sequence of SEQ ID NO:329.

[0262] For example, YY06_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 270 (HCDR1), SEQ ID NO: 271 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (II) SEQ ID NO: 273 (HCDR1), SEQ ID NO: 271 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 274 (HCDR2), SEQ ID NO: 335 (HCDR3), SEQ ID NO: 336 (LCDR1), SEQ ID NO: 337 (LCDR2), and SEQ ID NO: 338 (LCDR2). NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3). In some embodiments, YY06_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO:270 (HCDR1), SEQ ID NO:271 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3). In some embodiments, YY06_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:273 (HCDR1), SEQ ID NO:271 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3).In some embodiments, YY06_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 274 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 340 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 342 (LCDR3). In some embodiments, YY06_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 275 (HCDR1), SEQ ID NO: 276 (HCDR2), SEQ ID NO: 332 (HCDR3), SEQ ID NO: 343 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 339 (LCDR3). In some embodiments, YY06_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 333, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 344. In some embodiments, YY06_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 335, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 346.

[0263] For example, YY07_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 310 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 354 (LCDR2) and SEQ ID NO: 355 (LCDR3); (II) SEQ ID NO: 229 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 354 (LCDR2) and SEQ ID NO: 355 (LCDR3); (III) SEQ ID NO: 80 (HCDR1), SEQ ID NO: 313 (HCDR2), SEQ ID NO: 314 (HCDR3), SEQ ID NO: 315 (LCDR2), SEQ ID NO: 316 (LCDR3), SEQ ID NO: 317 (LCDR2), SEQ ID NO: 318 (LCDR3), SEQ ID NO: 319 (LCDR3), SEQ ID NO: 321 (LCDR1), SEQ ID NO: 323 (LCDR2), SEQ ID NO: 324 (LCDR3), SEQ ID NO: 325 (LCDR3), SEQ ID NO: 326 (LCDR1), SEQ ID NO: 327 (LCDR2), SEQ ID NO: 328 (LCDR3), SEQ ID NO: 329 (LCDR1), SEQ ID NO: NO:348 (HCDR3), SEQ ID NO:323 (LCDR1), SEQ ID NO:324 (LCDR2) and SEQ ID NO:356 (LCDR3); or (IV) SEQ ID NO:82 (HCDR1), SEQ ID NO:314 (HCDR2), SEQ ID NO:349 (HCDR3), SEQ ID NO:326 (LCDR1), SEQ ID NO:324 (LCDR2) and SEQ ID NO:355 (LCDR3). In some embodiments, YY07_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:310 (HCDR1), SEQ ID NO:311 (HCDR2), SEQ ID NO:348 (HCDR3), SEQ ID NO:320 (LCDR1), SEQ ID NO:354 (LCDR2), and SEQ ID NO:355 (LCDR3). In some embodiments, YY07_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:229 (HCDR1), SEQ ID NO:311 (HCDR2), SEQ ID NO:348 (HCDR3), SEQ ID NO:320 (LCDR1), SEQ ID NO:354 (LCDR2), and SEQ ID NO:355 (LCDR3).In some embodiments, YY07_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 80 (HCDR1), SEQ ID NO: 313 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 323 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 356 (LCDR3). In some embodiments, YY07_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 82 (HCDR1), SEQ ID NO: 314 (HCDR2), SEQ ID NO: 349 (HCDR3), SEQ ID NO: 326 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 355 (LCDR3). In some embodiments, YY07_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 350, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 357. In some embodiments, YY07_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:352, and the light chain comprises or has the amino acid sequence of SEQ ID NO:359.

[0264] For example, ZZ05_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 310 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 354 (LCDR2) and SEQ ID NO: 361 (LCDR3); (II) SEQ ID NO: 229 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 354 (LCDR2) and SEQ ID NO: 361 (LCDR3); (III) SEQ ID NO: 80 (HCDR1), SEQ ID NO: 313 (HCDR2), SEQ ID NO: 3 NO:348 (HCDR3), SEQ ID NO:323 (LCDR1), SEQ ID NO:324 (LCDR2) and SEQ ID NO:362 (LCDR3); or (IV) SEQ ID NO:82 (HCDR1), SEQ ID NO:314 (HCDR2), SEQ ID NO:349 (HCDR3), SEQ ID NO:326 (LCDR1), SEQ ID NO:324 (LCDR2) and SEQ ID NO:361 (LCDR3). In some embodiments, ZZ05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:310 (HCDR1), SEQ ID NO:311 (HCDR2), SEQ ID NO:348 (HCDR3), SEQ ID NO:320 (LCDR1), SEQ ID NO:354 (LCDR2), and SEQ ID NO:361 (LCDR3). In some embodiments, ZZ05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:229 (HCDR1), SEQ ID NO:311 (HCDR2), SEQ ID NO:348 (HCDR3), SEQ ID NO:320 (LCDR1), SEQ ID NO:354 (LCDR2), and SEQ ID NO:361 (LCDR3).In some embodiments, ZZ05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 80 (HCDR1), SEQ ID NO: 313 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 323 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 362 (LCDR3). In some embodiments, ZZ05_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 82 (HCDR1), SEQ ID NO: 314 (HCDR2), SEQ ID NO: 349 (HCDR3), SEQ ID NO: 326 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 361 (LCDR3). In some embodiments, ZZ05_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 350, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 363. In some embodiments, ZZ05_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:352, and the light chain comprises or has the amino acid sequence of SEQ ID NO:365.

[0265] For example, ZZ12_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 367 (HCDR1), SEQ ID NO: 368 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 239 (LCDR3); (II) SEQ ID NO: 369 (HCDR1), SEQ ID NO: 368 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 239 (LCDR3); (III) SEQ ID NO: 370 (HCDR1), SEQ ID NO: 371 (HCDR2), SEQ ID NO: 372 (HCDR3), SEQ ID NO: 373 (LCDR1), SEQ ID NO: 374 (LCDR2), SEQ ID NO: 375 (LCDR3). NO:228 (HCDR3), SEQ ID NO:240 (LCDR1), SEQ ID NO:241 (LCDR2) and SEQ ID NO:242 (LCDR3); or (IV) SEQ ID NO:372 (HCDR1), SEQ ID NO:373 (HCDR2), SEQ ID NO:232 (HCDR3), SEQ ID NO:243 (LCDR1), SEQ ID NO:241 (LCDR2) and SEQ ID NO:239 (LCDR3). In some embodiments, ZZ12_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:367 (HCDR1), SEQ ID NO:368 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3). In some embodiments, ZZ12_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:369 (HCDR1), SEQ ID NO:368 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3).In some embodiments, ZZ12_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 370 (HCDR1), SEQ ID NO: 371 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 240 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 242 (LCDR3). In some embodiments, ZZ12_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 372 (HCDR1), SEQ ID NO: 373 (HCDR2), SEQ ID NO: 232 (HCDR3), SEQ ID NO: 243 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 239 (LCDR3). In some embodiments, ZZ12_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 374, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 244. In some embodiments, ZZ12_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO: 376, and the light chain comprises or has the amino acid sequence of SEQ ID NO: 246.

[0266] For example, ZZ13_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 378 (HCDR1), SEQ ID NO: 379 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 239 (LCDR3); (II) SEQ ID NO: 380 (HCDR1), SEQ ID NO: 379 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 239 (LCDR3); (III) SEQ ID NO: 381 (HCDR1), SEQ ID NO: 382 (HCDR2), SEQ ID NO: 383 (LCDR3), SEQ ID NO: 384 (LCDR1), SEQ ID NO: 385 (LCDR2), SEQ ID NO: 386 (LCDR3), SEQ ID NO: 387 (LCDR1), SEQ ID NO: 388 (LCDR2) and SEQ ID NO: 389 (LCDR3); NO:228 (HCDR3), SEQ ID NO:240 (LCDR1), SEQ ID NO:241 (LCDR2) and SEQ ID NO:242 (LCDR3); or (IV) SEQ ID NO:383 (HCDR1), SEQ ID NO:384 (HCDR2), SEQ ID NO:232 (HCDR3), SEQ ID NO:243 (LCDR1), SEQ ID NO:241 (LCDR2) and SEQ ID NO:239 (LCDR3). In some embodiments, ZZ13_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:378 (HCDR1), SEQ ID NO:379 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3). In some embodiments, ZZ13_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:380 (HCDR1), SEQ ID NO:379 (HCDR2), SEQ ID NO:228 (HCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3).In some embodiments, ZZ13_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 381 (HCDR1), SEQ ID NO: 382 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 240 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 242 (LCDR3). In some embodiments, ZZ13_LALA can be defined as comprising or having the following amino acid sequence: (IV) SEQ ID NO: 383 (HCDR1), SEQ ID NO: 384 (HCDR2), SEQ ID NO: 232 (HCDR3), SEQ ID NO: 243 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 239 (LCDR3). In some embodiments, ZZ13_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 385, and the light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 244. In some embodiments, ZZ13_LALA can be defined as comprising or having a heavy chain and a light chain, the heavy chain comprising or having an amino acid sequence of SEQ ID NO: 387, and the light chain comprising or having an amino acid sequence of SEQ ID NO: 246.

[0267] For example, ZZ14_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 270 (HCDR1), SEQ ID NO: 389 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (II) SEQ ID NO: 273 (HCDR1), SEQ ID NO: 389 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 390 (HCDR2), SEQ ID NO: 391 (HCDR3), SEQ ID NO: 393 (LCDR1), SEQ ID NO: 394 (LCDR2); NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3). In some embodiments, ZZ14_LALA may be defined as comprising or having the following amino acid sequence: SEQ ID NO:270 (HCDR1), SEQ ID NO:389 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3). In some embodiments, ZZ14_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:273 (HCDR1), SEQ ID NO:389 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3).In some embodiments, ZZ14_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 32 (HCDR1), SEQ ID NO: 390 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 340 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 342 (LCDR3). In some embodiments, ZZ14_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 275 (HCDR1), SEQ ID NO: 391 (HCDR2), SEQ ID NO: 332 (HCDR3), SEQ ID NO: 343 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 339 (LCDR3). In some embodiments, ZZ14_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 392, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 344. In some embodiments, ZZ14_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:394, and the light chain comprises or has the amino acid sequence of SEQ ID NO:346.

[0268] For example, ZZ15_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 396 (HCDR1), SEQ ID NO: 397 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (II) SEQ ID NO: 398 (HCDR1), SEQ ID NO: 397 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (III) SEQ ID NO: 399 (HCDR1), SEQ ID NO: 400 (HCDR2), SEQ ID NO: 411 (HCDR3), SEQ ID NO: 412 (LCDR1), SEQ ID NO: 413 (LCDR2), SEQ ID NO: 414 (LCDR3). NO:331 (HCDR3), SEQ ID NO:340 (LCDR1), SEQ ID NO:341 (LCDR2) and SEQ ID NO:342 (LCDR3); or (IV) SEQ ID NO:401 (HCDR1), SEQ ID NO:402 (HCDR2), SEQ ID NO:332 (HCDR3), SEQ ID NO:343 (LCDR1), SEQ ID NO:341 (LCDR2) and SEQ ID NO:339 (LCDR3). In some embodiments, ZZ15_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:396 (HCDR1), SEQ ID NO:397 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3). In some embodiments, ZZ15_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:398 (HCDR1), SEQ ID NO:397 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3).In some embodiments, ZZ15_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 399 (HCDR1), SEQ ID NO: 400 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 340 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 342 (LCDR3). In some embodiments, ZZ15_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 401 (HCDR1), SEQ ID NO: 402 (HCDR2), SEQ ID NO: 332 (HCDR3), SEQ ID NO: 343 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 339 (LCDR3). In some embodiments, ZZ15_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 403, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 344. In some embodiments, ZZ15_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:405, and the light chain comprises or has the amino acid sequence of SEQ ID NO:346.

[0269] For example, ZZ16_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 407 (HCDR1), SEQ ID NO: 408 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (II) SEQ ID NO: 409 (HCDR1), SEQ ID NO: 408 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (III) SEQ ID NO: 410 (HCDR1), SEQ ID NO: 411 (HCDR2), SEQ ID NO: NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3). In some embodiments, ZZ16_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:407 (HCDR1), SEQ ID NO:408 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3). In some embodiments, ZZ16_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:409 (HCDR1), SEQ ID NO:408 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3).In some embodiments, ZZ16_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 410 (HCDR1), SEQ ID NO: 411 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 340 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 342 (LCDR3). In some embodiments, ZZ16_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 412 (HCDR1), SEQ ID NO: 413 (HCDR2), SEQ ID NO: 332 (HCDR3), SEQ ID NO: 343 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 339 (LCDR3). In some embodiments, ZZ16_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 414, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 344. In some embodiments, ZZ16_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:416, and the light chain comprises or has the amino acid sequence of SEQ ID NO:346.

[0270] For example, ZZ17_LALA can be defined as having three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (I) SEQ ID NO: 418 (HCDR1), SEQ ID NO: 419 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (II) SEQ ID NO: 420 (HCDR1), SEQ ID NO: 419 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (III) SEQ ID NO: 421 (HCDR1), SEQ ID NO: 422 (HCDR2), SEQ ID NO: 333 (LCDR2) and SEQ ID NO: 339 (LCDR3). NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3). In some embodiments, ZZ17_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:418 (HCDR1), SEQ ID NO:419 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3). In some embodiments, ZZ17_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO:420 (HCDR1), SEQ ID NO:419 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3).In some embodiments, ZZ17_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 421 (HCDR1), SEQ ID NO: 422 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 340 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 342 (LCDR3). In some embodiments, ZZ17_LALA can be defined as comprising or having the following amino acid sequence: SEQ ID NO: 423 (HCDR1), SEQ ID NO: 424 (HCDR2), SEQ ID NO: 332 (HCDR3), SEQ ID NO: 343 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 339 (LCDR3). In some embodiments, ZZ17_LALA can be defined as comprising or having a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having the amino acid sequence of SEQ ID NO: 425, and the light chain variable region comprising or having the amino acid sequence of SEQ ID NO: 344. In some embodiments, ZZ17_LALA can be defined as comprising or having a heavy chain and a light chain, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:427, and the light chain comprises or has the amino acid sequence of SEQ ID NO:346.

[0271] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 13 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, and the light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 24 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24. In some other embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain, the heavy chain comprising or having an amino acid sequence of SEQ ID NO: 15 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15, and the light chain comprising or having an amino acid sequence of SEQ ID NO: 26 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26.

[0272] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 37 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 37, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 48 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain, the heavy chain comprising or having an amino acid sequence of SEQ ID NO: 39 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39, and the light chain comprising or having an amino acid sequence of SEQ ID NO: 50 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 50.

[0273] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 61 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 72 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain, the heavy chain comprising or having an amino acid sequence of SEQ ID NO: 63 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprising or having an amino acid sequence of SEQ ID NO: 74 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0274] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 85, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 96, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 87, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 98, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0275] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 103, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 103, and the light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 24, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain, the heavy chain comprising or having an amino acid sequence of SEQ ID NO: 105, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 105, and the light chain comprising or having an amino acid sequence of SEQ ID NO: 26, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26.

[0276] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 103 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 103, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 24 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain, the heavy chain comprising or having an amino acid sequence of SEQ ID NO: 108 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 108, and the light chain comprising or having an amino acid sequence of SEQ ID NO: 26 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26.

[0277] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 115 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 115, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 24 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain, the heavy chain comprising or having an amino acid sequence of SEQ ID NO: 117 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 117, and the light chain comprising or having an amino acid sequence of SEQ ID NO: 26 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26.

[0278] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 122, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 48, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 124, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 50, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0279] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 37, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 128, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 39, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 130, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0280] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 37, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 136, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 39, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 138, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0281] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 37, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 136, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 141, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 138, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0282] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 37, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 147, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 39, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 149, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0283] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 154, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 24, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 156, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 26, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0284] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 154, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 154, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 24, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain, the heavy chain comprising or having an amino acid sequence of SEQ ID NO: 159, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 159, and the light chain comprising or having an amino acid sequence of SEQ ID NO: 26, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26.

[0285] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 161 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 161, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 24 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain, the heavy chain comprising or having an amino acid sequence of SEQ ID NO: 163 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 163, and the light chain comprising or having an amino acid sequence of SEQ ID NO: 26 or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26.

[0286] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 168, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 168, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 24, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain, the heavy chain comprising or having an amino acid sequence of SEQ ID NO: 170, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 170, and the light chain comprising or having an amino acid sequence of SEQ ID NO: 26, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26.

[0287] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 37, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 174, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 39, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 176, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0288] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 37, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 180, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 39, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 182, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0289] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 37, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 186, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 39, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 188, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0290] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 193, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 136, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 195, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 138, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0291] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 193, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 174, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 195, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 176, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0292] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 201, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 201, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 128, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 128. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 203, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 203, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 130, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 130.

[0293] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 122, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 122, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 128, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 128. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 208, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 208, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 130, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 130.

[0294] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 201, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 136, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 203, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 138, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0295] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 122, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 122, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 136, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 136. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 208, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 208, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 138, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 138.

[0296] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 201, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 201, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 147, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 147. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 203, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 203, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 149, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 149.

[0297] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 122, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 122, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 147, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 147. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 208, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 208, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 149, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 149.

[0298] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 201, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 174, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 203, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 176, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0299] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 122, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 174, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 208, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 176, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0300] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 201, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 180, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 203, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 182, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0301] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 122, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 122, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 180, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 180. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 208, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 208, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 182, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 182.

[0302] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 201, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 186, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 203, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 188, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0303] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 122, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 122, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 186, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 186. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 208, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 208, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 188, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 188.

[0304] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 233, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 244, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 235, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 246, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0305] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 256, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 266, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 258, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 268, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0306] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 278, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 278, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 287, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 287. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 280, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 280, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 289, or a sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 289.

[0307] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 300, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 306, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 302, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 308, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0308] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 316, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 327, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 318, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 329, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0309] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 333, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 344, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising or having an amino acid sequence of SEQ ID NO: 335, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain comprising or having an amino acid sequence of SEQ ID NO: 346, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.

[0310] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising or having an amino acid sequence of SEQ ID NO: 350, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto, and a light chain variable region comprising or having an amino acid sequence of SEQ ID NO: 357, or a sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments,...

Claims

1. An isolated antibody or antigen-binding fragment that (i) binds to natriuretic peptide receptor 1 (NPR1); and (ii) is capable of activating NPR1 in the absence of atrial natriuretic peptide (ANP).

2. An isolated anti-NPR1 antibody or antigen-binding fragment; or the isolated antibody or antigen-binding fragment of claim 1, which is ANP non-competitive.

3. An isolated anti-NPR1 antibody or antigen-binding fragment; or the isolated antibody or antigen-binding fragment of claim 1, which is ANP competitive.

4. An isolated anti-NPR1 antibody or antigen-binding fragment; or the isolated antibody or antigen-binding fragment of claim 1 or 2, wherein the antibody or antigen-binding fragment thereof binds to an epitope within amino acids 99-133 of SEQ ID NO:

1.

5. An isolated anti-NPR1 antibody or antigen-binding fragment; or an isolated antibody or antigen-binding fragment as described in any one of claims 1, 2 or 4, wherein the antibody or antigen-binding fragment thereof binds to a conformational epitope of human NPR1, and wherein the conformational epitope comprises at least one amino acid residue in each of (i) amino acids 99-103 of SEQ ID NO:1, (ii) amino acids 105-111 of SEQ ID NO:1, (iii) amino acids 131-134 of SEQ ID NO:1, and also binds to amino acids 375 and / or 378 of SEQ ID NO:

1.

6. An isolated anti-NPR1 antibody or antigen-binding fragment; or the isolated antibody or antigen-binding fragment of claim 1 or 3, wherein the antibody or antigen-binding fragment thereof binds to an epitope within amino acids 188-219 of SEQ ID NO:

1.

7. An isolated anti-NPR1 antibody or antigen-binding fragment; or an isolated antibody or antigen-binding fragment as described in any of claims 1, 3 or 6, wherein the antibody or antigen-binding fragment thereof binds to a conformational epitope within NPR1, and wherein the conformational epitope comprises at least one amino acid residue in each of (i) amino acids 188-198 of SEQ ID NO:1, (ii) amino acids 201-208 of SEQ ID NO:1, (iii) amino acids 215-238 of SEQ ID NO:1, and (iv) amino acids 294-297 of SEQ ID NO:1, optionally wherein the antibody or antigen-binding fragment thereof binds to at least amino acids 188, 192, 194, 197, 201, 208 and 219 of SEQ ID NO:

1.

8. An isolated anti-NPR1 antibody or antigen-binding fragment; or the antibody or antigen-binding fragment of any one of claims 1, 2, 4 or 5, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), and wherein: (a)(I) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:28; HCDR2 comprises or consists of the amino acid sequence of XIIX2SX3GX4YX5X6YADSVKG (SEQ ID NO:429), wherein X1 is A or V, X2 is S or E, X3 is D or K, X4 is S or N, X5 is I or T, and X6 is Y or F; HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:30; LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:41; LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:42; and LCDR3 comprises Y1QY2Y3Y4Y5PRT (SEQ ID NO:430) or consisting of the amino acid sequence shown therein; wherein Y1 is M or Q, Y2 is S, E, T or I, Y3 is Y or W, Y4 is E, V, R, A, T or M, and Y5 is K, V, R or A; (II) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:31; HCDR2 comprises or consists of the amino acid sequence of X1IX2SX3GX4YX5X6YADSVKG (SEQ ID NO:429), wherein X1 is A or V, X2 is S or E, X3 is D or K, X4 is S or N, X5 is I or T, and X6 is Y or F; HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:41, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:42, and LCDR3 comprises Y1QY2Y3Y4Y5PRT (SEQ ID NO:430) or consisting of the amino acid sequence shown therein; wherein Y1 is M or Q, Y2 is S, E, T or I, Y3 is Y or W, Y4 is E, V, R, A, T or M, and Y5 is K, V, R or A; (III) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:32, HCDR2 comprises or consists of the amino acid sequence of X1SX2GX3Y (SEQ ID NO:431), wherein X1 is S or E, X2 is D or K, or X3 is S or N, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:44, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:45, and LCDR3 comprises or consists of the amino acid sequence of Y1Y2Y3Y4PR (SEQ ID NO:432); wherein Y1 is S, E, T or I, Y2 is Y or W, Y3 is E, V, R, A, T or M, and Y4 is K, V, R or A; or (IV) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:34, HCDR2 comprises or consists of the amino acid sequence of IX1SX2GX3YX4 (SEQ ID NO:433), wherein X1 is S or E, X2 is D or K, X3 is S or N, and X4 is I or T, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:36, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:47, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:45, and LCDR3 comprises or consists of the amino acid sequence of Y1QY2Y3Y4Y5PRT (SEQ ID NO:430); wherein Y1 is M or Q, Y2 is S, E, T or I, Y3 is Y or W, Y4 is E, V, R, A, T or M, and Y5 is K, V, R or A; (b)(I) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:28; HCDR2 comprises or consists of the amino acid sequence of XIIX2SX3GX4YX5X6YADSVKG (SEQ ID NO:429), wherein X1 is A or V, X2 is S or E, X3 is D or K, X4 is S or N, X5 is I or T, and X6 is Y or F; HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:30; LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:41; LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:42; and LCDR3 comprises or consists of the amino acid sequence of QQY1WY2Y3PRT (SEQ ID NO:434); wherein Y1 is S, E, T or I, Y2 is V, R, A, T or M, and Y3 is K, V, R or A; (II) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:31; HCDR2 comprises or consists of the amino acid sequence of X1IX2SX3GX4YX5X6YADSVKG (SEQ ID NO:429), wherein X1 is A or V, X2 is S or E, X3 is D or K, X4 is S or N, X5 is I or T, and X6 is Y or F; HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:41, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:42, and LCDR3 comprises or consists of the amino acid sequence of QQY1WY2Y3PRT (SEQ ID NO:434); wherein Y1 is S, E, T or I, Y2 is V, R, A, T or M, and Y3 is K, V, R or A; (III) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:32, HCDR2 comprises or consists of the amino acid sequence of X1SX2GX3Y (SEQ ID NO:431), wherein X1 is S or E, X2 is D or K, or X3 is S or N, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:44, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:45, and LCDR3 comprises or consists of the amino acid sequence of Y1WY2Y3PR (SEQ ID NO:435); wherein Y1 is S, E, T or I, Y2 is V, R, A, T or M, and Y3 is K, V, R or A; or (IV) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:34, HCDR2 comprises or consists of the amino acid sequence of IX1SX2GX3YX4 (SEQ ID NO:433), wherein X1 is S or E, X2 is D or K, X3 is S or N, and X4 is I or T, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:36, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:47, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:45, and LCDR3 comprises or consists of the amino acid sequence of QQY1WY2Y3PRT (SEQ ID NO:434); wherein Y1 is S, E, T or I, Y2 is V, R, A, T or M, and Y3 is K, V, R or A; (c)(I) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:28; HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:119; HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:30; LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:41; LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:42; and LCDR3 comprises or consists of the amino acid sequence shown in QQY1WY2Y3PRT (SEQ ID NO:434); wherein Y1 is S, E, T or I, Y2 is V, R, A, T or M, and Y3 is K, V, R or A; (II) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:31; HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:119; HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:41, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:42, and LCDR3 comprises or consists of the amino acid sequence of QQY1WY2Y3PRT (SEQ ID NO:434); wherein Y1 is S, E, T or I, Y2 is V, R, A, T or M, and Y3 is K, V, R or A; (III) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:32, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:120, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:44, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 comprises or consists of the amino acid sequence shown in Y1WY2Y3PR (SEQ ID NO:435); wherein Y1 is S, E, T or I, Y2 is V, R, A, T or M, and Y3 is K, V, R or A; or (IV) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:34, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:121, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:36, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:47, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:45, and LCDR3 comprises or consists of the amino acid sequence of QQY1WY2Y3PRT (SEQ ID NO:434); wherein Y1 is S, E, T or I, Y2 is V, R, A, T or M, and Y3 is K, V, R or A; (d)(I) HCDR1 comprises or consists of the amino acid sequence of GFTFX1THYIH (SEQ ID NO:436), wherein X1 is N, S or Q, HCDR2 comprises or consists of the amino acid sequence of SIY1Y2Y3GY4Y5TY6YADSVKG (SEQ ID NO:437), wherein Y1 is S or G, Y2 is S or G, Y3 is S or Q, Y4 is S, Q or G, Y5 is S, N or M, and Y6 is Y or L, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:17, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:18, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:19; (II) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:7, HCDR2 comprises or consists of the amino acid sequence of SIY1Y2Y3GY4Y5TY6YADSVKG (SEQ ID NO:437), wherein Y1 is S or G, Y2 is S or G, Y3 is S or Q, Y4 is S, Q or G, Y5 is S, N or M, and Y6 is Y or L, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:17, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:18, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:19; (III) HCDR1 comprises or consists of the amino acid sequence shown as GFTFX1TH (SEQ ID NO:438), wherein X1 is N, S or Q, HCDR2 comprises or consists of the amino acid sequence shown as Y1Y2Y3GY4Y5 (SEQ ID NO:439), wherein Y1 is S or G, Y2 is S or G, Y3 is S or Q, Y4 is S, Q or G, and Y5 is S, N or M, HCDR3 comprises or consists of the amino acid sequence shown as SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence shown as SEQ ID NO:20, LCDR2 comprises or consists of the amino acid sequence shown as SEQ ID NO:21, and LCDR3 comprises or consists of the amino acid sequence shown as SEQ ID NO:22; or (IV) HCDR1 comprises or consists of the amino acid sequence of GFTFX1THY (SEQ ID NO:440), wherein X1 is N, S or Q, HCDR2 comprises or consists of the amino acid sequence of IY1Y2Y3GY4Y5T (SEQ ID NO:441), wherein Y1 is S or G, Y2 is S or G, Y3 is S or Q, Y4 is S, Q or G, and Y5 is S, N or M, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:12, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:23, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:21, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:19; (e)(I) HCDR1 comprises or consists of the amino acid sequence of GFTFX1THYIH (SEQ ID NO:436), wherein X1 is N, S or Q, HCDR2 comprises or consists of the amino acid sequence of SISY1SGY2Y3TYYADSVKG (SEQ ID NO:442), wherein Y1 is S or G, Y2 is S or Q, and Y3 is S or N, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:17, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:18, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:19; (II) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:7, HCDR2 comprises or consists of the amino acid sequence of SISY1SGY2Y3TYYADSVKG (SEQ ID NO:442), wherein Y1 is S or G, Y2 is S or Q, and Y3 is S or N, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:17, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:18, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:19; (III) HCDR1 comprises or consists of the amino acid sequence shown as GFTFX1TH (SEQ ID NO:438), wherein X1 is N, S or Q, HCDR2 comprises or consists of the amino acid sequence shown as SY1SGY2Y3 (SEQ ID NO:443), wherein Y1 is S or G, Y2 is S or Q, and Y3 is S or N, HCDR3 comprises or consists of the amino acid sequence shown as SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence shown as SEQ ID NO:20, LCDR2 comprises or consists of the amino acid sequence shown as SEQ ID NO:21, and LCDR3 comprises or consists of the amino acid sequence shown as SEQ ID NO:22; or (IV) HCDR1 comprises or consists of the amino acid sequence of GFTFX1THY (SEQ ID NO:440), wherein X1 is N, S or Q, HCDR2 comprises or consists of the amino acid sequence of ISY1SGY2Y3T (SEQ ID NO:444), wherein Y1 is S or G, Y2 is S or Q, and Y3 is S or N, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:12, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:23, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:21, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:19; (f)(I) HCDR1 comprises or consists of the amino acid sequence of GFX1FSX2YX3X4X5 (SEQ ID NO:445), wherein X1 is S or T, X2 is S, K or R, X3 is W or Y, X4 is I or L, and X5 is S or N, HCDR2 comprises or consists of the amino acid sequence of Y1IY2QY3Y4Y5EY6Y7YVESVKG (SEQ ID NO:446), wherein Y1 is S or N, Y2 is K or H, Y3 is S, Q or H, Y4 is G or A, Y5 is S, H or L, Y6 is T or K, and Y7 is Y, K or R, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:228, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:237, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: NO:238 or consists of the amino acid sequence thereof, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:239; (II) HCDR1 comprises or consists of an amino acid sequence as shown in X1YX2X3X4 (SEQ ID NO:447), wherein X1 is S, K or R, X2 is W or Y, X3 is I or L, and X4 is S or N, HCDR2 comprises or consists of an amino acid sequence as shown in Y1IY2QY3Y4Y5EY6Y7YVESVKG (SEQ ID NO:446), wherein Y1 is S or N, Y2 is K or H, Y3 is S, Q or H, Y4 is G or A, Y5 is S, H or L, Y6 is T or K, and Y7 is Y, K or R, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:228, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO:237, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO:238, and LCDR3 comprises an amino acid sequence as shown in SEQ ID NO: The amino acid sequence shown in NO:239 or consisting thereof; (III) HCDR1 comprises or consists of the amino acid sequence of GFX1FSX2Y (SEQ ID NO:448), wherein X1 is S or T, and X2 is S, K or R, HCDR2 comprises or consists of the amino acid sequence of Y1QY2Y3Y4E (SEQ ID NO:449), wherein Y1 is K or H, Y2 is S, Q or H, Y3 is G or A, and Y4 is S, H or L, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:228, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:240, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:241, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:242; or (IV) HCDR1 comprises or consists of an amino acid sequence as set forth in GFX1FSX2YX3 (SEQ ID NO:450), wherein X1 is S or T, X2 is S, K or R, and X3 is W or Y, HCDR2 comprises or consists of an amino acid sequence as set forth in IY1QY2Y3Y4EY5 (SEQ ID NO:451), wherein Y1 is K or H, Y2 is S, Q or H, Y3 is G or A, Y4 is S, H or L, and Y5 is T or K, HCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:232, LCDR1 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:243, LCDR2 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:241, and LCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:239; (g)(I) HCDR1 comprises or consists of an amino acid sequence as set forth in GFX1FSX2YX3X4X5 (SEQ ID NO:445), wherein X1 is S or T, X2 is S, K or R, X3 is W or Y, X4 is I or L, and X5 is S or N, HCDR2 comprises or consists of an amino acid sequence as set forth in SIHQY1Y2Y3EY4Y5YVESVKG (SEQ ID NO:453), wherein Y1 is Q or H, Y2 is G or A, Y3 is H or L, Y4 is T or K, and Y5 is K or R, HCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:228, LCDR1 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:237, LCDR2 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:238, and LCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:239; (II) HCDR1 comprises or consists of an amino acid sequence as shown in X1YX2X3X4 (SEQ ID NO:447), wherein X1 is S, K or R, X2 is W or Y, X3 is I or L, and X4 is S or N, HCDR2 comprises or consists of an amino acid sequence as shown in SIHQY1Y2Y3EY4Y5YVESVKG (SEQ ID NO:453), wherein Y1 is Q or H, Y2 is G or A, Y3 is H or L, Y4 is T or K, and Y5 is K or R, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:228, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO:237, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO:238, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:239; (III) HCDR1 comprises or consists of the amino acid sequence of GFX1FSX2Y (SEQ ID NO:448), wherein X1 is S or T, and X2 is S, K or R, HCDR2 comprises or consists of the amino acid sequence of HQY1Y2Y3E (SEQ ID NO:456), wherein Y1 is Q or H, Y2 is G or A, and Y3 is H or L, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:228, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:240, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:241, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:242; or (IV) HCDR1 comprises or consists of an amino acid sequence as set forth in GFX1FSX2YX3 (SEQ ID NO:450), wherein X1 is S or T, X2 is S, K or R, and X3 is W or Y, HCDR2 comprises or consists of an amino acid sequence as set forth in IHQY1Y2Y3EY4 (SEQ ID NO:458), wherein Y1 is Q or H, Y2 is G or A, Y3 is H or L, and Y4 is T or K, HCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:232, LCDR1 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:243, LCDR2 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:241, and LCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:239; (h)(I) HCDR1 comprises or consists of the amino acid sequence of GFTFSX1YX2IX3 (SEQ ID NO:452), wherein X1 is S or R, X2 is W or Y, and X3 is S or N, HCDR2 comprises or consists of the amino acid sequence of Y1IY2QY3Y4Y5EY6Y7YVESVKG (SEQ ID NO:446), wherein Y1 is S or N, Y2 is K or H, Y3 is S, Q or H, Y4 is G or A, Y5 is S, H or L, Y6 is T or K, and Y7 is Y, K or R, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:228, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:237, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:238, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:239; (II) HCDR1 comprises or consists of an amino acid sequence as shown in X1YX2IX3 (SEQ ID NO:454), wherein X1 is S or R, X2 is W or Y, and X3 is S or N, HCDR2 comprises or consists of an amino acid sequence as shown in Y1IY2QY3Y4Y5EY6Y7YVESVKG (SEQ ID NO:446), wherein Y1 is S or N, Y2 is K or H, Y3 is S, Q or H, Y4 is G or A, Y5 is S, H or L, Y6 is T or K, and Y7 is Y, K or R, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:228, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO:237, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO:238, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:239; (III) HCDR1 comprises or consists of the amino acid sequence of GFTFSX1Y (SEQ ID NO:455), wherein X1 is S or R, HCDR2 comprises or consists of the amino acid sequence of Y1QY2Y3Y4E (SEQ ID NO:449), wherein Y1 is K or H, Y2 is S, Q or H, Y3 is G or A, and Y4 is S, H or L, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:228, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:240, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:241, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:242; or (IV) HCDR1 comprises or consists of the amino acid sequence of GFTFSX1YX2 (SEQ ID NO:457), wherein X1 is S or R, and X2 is W or Y, HCDR2 comprises or consists of the amino acid sequence of IY1QY2Y3Y4EY5 (SEQ ID NO:451), wherein Y1 is K or H, Y2 is S, Q or H, Y3 is G or A, Y4 is S, H or L, and Y5 is T or K, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:232, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:243, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:241, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:239; or (i) (I) HCDR1 comprises or consists of the amino acid sequence of GFTFSX1YX2IX3 (SEQ ID NO:452), wherein X1 is S or R, X2 is W or Y, and X3 is S or N, HCDR2 comprises or consists of the amino acid sequence of SIHQY1Y2Y3EY4Y5YVESVKG (SEQ ID NO:453), wherein Y1 is Q or H, Y2 is G or A, Y3 is H or L, Y4 is T or K, and Y5 is K or R, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:228, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:237, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:238, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:239; (II) HCDR1 comprises or consists of an amino acid sequence as shown in X1YX2IX3 (SEQ ID NO:454), wherein X1 is S or R, X2 is W or Y, and X3 is S or N, HCDR2 comprises or consists of an amino acid sequence as shown in SIHQY1Y2Y3EY4Y5YVESVKG (SEQ ID NO:453), wherein Y1 is Q or H, Y2 is G or A, Y3 is H or L, Y4 is T or K, and Y5 is K or R, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:228, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO:237, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO:238, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:239; (III) HCDR1 comprises or consists of the amino acid sequence of GFTFSX1Y (SEQ ID NO:455), wherein X1 is S or R, HCDR2 comprises or consists of the amino acid sequence of HQY1Y2Y3E (SEQ ID NO:456), wherein Y1 is Q or H, Y2 is G or A, and Y3 is H or L, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:228, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:240, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:241, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:242; or (IV) HCDR1 comprises or consists of the amino acid sequence of GFTFSX1YX2 (SEQ ID NO:457), wherein X1 is S or R, and X2 is W or Y, HCDR2 comprises or consists of the amino acid sequence of IHQY1Y2Y3EY4 (SEQ ID NO:458), wherein Y1 is Q or H, Y2 is G or A, Y3 is H or L, and Y4 is T or K, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:232, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:243, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:241, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:

239.

9. An isolated anti-NPR1 antibody or antigen-binding fragment; or the antibody or antigen-binding fragment of any one of claims 1, 3, 6 or 7, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), and wherein: (a)(I) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:310, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:311, HCDR3 comprises or consists of the amino acid sequence of GX1X2X3GX4LGFDH (SEQ ID NO:459), wherein X1 is A or S, X2 is V or L, X3 is A or P, and X4 is Q or L, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:320, LCDR2 comprises or consists of the amino acid sequence of GNSNRPY1 (SEQ ID NO:460), wherein Y1 is S or N, and LCDR3 comprises or consists of the amino acid sequence of QSYZ1Z2Z3Z4Z5Z6Z7V (SEQ ID NO:470). NO:461) or consisting of the amino acid sequence shown in, wherein Z1 is Y, D or G, Z2 is T, S or A, Z3 is S, P or F, Z4 is S, T or P, Z5 is H, S or R, Z6 is G, S or F, and Z7 is P, S or V; (II) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 229, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 311, HCDR3 comprises or consists of the amino acid sequence of GX1X2X3GX4LGFDH (SEQ ID NO: 459), wherein X1 is A or S, X2 is V or L, X3 is A or P, and X4 is Q or L, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 320, LCDR2 comprises or consists of the amino acid sequence of GNSNRPY1 (SEQ ID NO: 460), wherein Y1 is S or N, and LCDR3 comprises or consists of the amino acid sequence of QSYZ1Z2Z3Z4Z5Z6Z7V (SEQ ID NO: 470). NO:461) or consisting of the amino acid sequence shown in, wherein Z1 is Y, D or G, Z2 is T, S or A, Z3 is S, P or F, Z4 is S, T or P, Z5 is H, S or R, Z6 is G, S or F, and Z7 is P, S or V; (III) HCDR1 comprises or consists of the amino acid sequence as shown in SEQ ID NO: 80, HCDR2 comprises or consists of the amino acid sequence as shown in SEQ ID NO: 313, HCDR3 comprises or consists of the amino acid sequence as shown in GX1X2X3GX4LGFDH (SEQ ID NO: 459), wherein X1 is A or S, X2 is V or L, X3 is A or P, and X4 is Q or L, LCDR1 comprises or consists of the amino acid sequence as shown in SEQ ID NO: 323, LCDR2 comprises or consists of the amino acid sequence as shown in SEQ ID NO: 324, and LCDR3 comprises or consists of YZ1Z2Z3Z4Z5Z6Z7 (SEQ ID NO:462) or consisting of the amino acid sequence shown in, wherein Z1 is Y, D or G, Z2 is T, S or A, Z3 is S, P or F, Z4 is S, T or P, Z5 is H, S or R, Z6 is G, S or F, and Z7 is P, S or V; or (IV) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 82, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 314, HCDR3 comprises or consists of the amino acid sequence of ARGX1X2X3GX4LGFDH (SEQ ID NO: 463), wherein X1 is A or S, X2 is V or L, X3 is A or P, and X4 is Q or L, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 326, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 324, and LCDR3 comprises QSYZ1Z2Z3Z4Z5Z6Z7V (SEQ ID NO: 464). NO:461) or consisting of the amino acid sequence shown in, wherein Z1 is Y, D or G, Z2 is T, S or A, Z3 is S, P or F, Z4 is S, T or P, Z5 is H, S or R, Z6 is G, S or F, and Z7 is P, S or V; (b)(I) HCDR1 comprises or consists of the amino acid sequence of GFTFX1X2YAX3X4 (SEQ ID NO:464), wherein X1 is S or G, X2 is S or T, X3 is I or M, and X4 is S or T, HCDR2 comprises or consists of the amino acid sequence of Y1ISY2Y3GY4Y5Y6Y7YAY8SVKG (SEQ ID NO:465), wherein Y1 is A or S, Y2 is A, S or G, Y3 is S or H, Y4 is G or Y, Y5 is S or Y, Y6 is T or A, Y7 is Y, R or N, and Y8 is E or G, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:331, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:337, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:338, and LCDR3 comprises the amino acid sequence of SEQ ID NO:

339. The amino acid sequence shown in NO:339 or consisting thereof; (II) HCDR1 comprises or consists of an amino acid sequence as set forth in X1YAX2X3 (SEQ ID NO:466), wherein X1 is S or T, X2 is I or M, and X3 is S or T, HCDR2 comprises or consists of an amino acid sequence as set forth in Y1ISY2Y3GY4Y5Y6Y7YAY8SVKG (SEQ ID NO:465), wherein Y1 is A or S, Y2 is A, S or G, Y3 is S or H, Y4 is G or Y, Y5 is S or Y, Y6 is T or A, Y7 is Y, R or N, and Y8 is E or G, HCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:331, LCDR1 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:337, LCDR2 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:338, and LCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:339; (III) HCDR1 comprises or consists of an amino acid sequence as shown in GFTFX1X2Y (SEQ ID NO:467), wherein X1 is S or G, and X2 is S or T, HCDR2 comprises or consists of an amino acid sequence as shown in SY1Y2GY3Y4 (SEQ ID NO:468), wherein Y1 is A, S or G, Y2 is S or H, Y3 is G or Y, and Y4 is S or Y, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:331, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO:340, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO:341, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:342; or (IV) HCDR1 comprises or consists of an amino acid sequence as shown in GFTFX1X2YA (SEQ ID NO:469), wherein X1 is S or G, and X2 is S or T, HCDR2 comprises or consists of an amino acid sequence as shown in ISY1Y2GY3Y4T (SEQ ID NO:470), wherein Y1 is S or G, Y2 is S or H, Y3 is G or Y, and Y4 is S or Y, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:332, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO:343, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO:341, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:339; or (c)(I) HCDR1 comprises or consists of an amino acid sequence as shown in GFTFX1X2YAX3X4 (SEQ ID NO:464), wherein X1 is S or G, X2 is S or T, X3 is I or M, and X4 is S or T, HCDR2 comprises or consists of an amino acid sequence as shown in SISY1Y2GYYY3Y4YAY5SVKG (SEQ ID NO:471), wherein Y1 is A or S, Y2 is S or H, Y3 is T or A, Y4 is R or N, and Y5 is E or G, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:331, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO:337, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO:338, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:339; (II) HCDR1 comprises or consists of an amino acid sequence as shown in X1YAX2X3 (SEQ ID NO:466), wherein X1 is S or T, X2 is I or M, and X3 is S or T, HCDR2 comprises or consists of an amino acid sequence as shown in SISY1Y2GYYY3Y4YAY5SVKG (SEQ ID NO:471), wherein Y1 is A or S, Y2 is S or H, Y3 is T or A, Y4 is R or N, and Y5 is E or G, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:331, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO:337, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO:338, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:339; (III) HCDR1 comprises or consists of an amino acid sequence as shown in GFTFX1X2Y (SEQ ID NO: 467), wherein X1 is S or G, and X2 is S or T, HCDR2 comprises or consists of an amino acid sequence as shown in SY1Y2GYY (SEQ ID NO: 472), wherein Y1 is A or S, and Y2 is S or H, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 331, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 340, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 341, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 342; or (IV) HCDR1 comprises or consists of an amino acid sequence as shown in GFTFX1X2YA (SEQ ID NO:469), wherein X1 is S or G, and X2 is S or T, HCDR2 comprises or consists of an amino acid sequence as shown in ISY1Y2G (SEQ ID NO:473), wherein Y1 is A, S or G, and Y2 is S or H, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:332, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO:343, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO:341, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:

339.

10. An isolated anti-NPR1 antibody or antigen-binding fragment; or the antibody or antigen-binding fragment of any one of claims 1, 2, 4, 5 or 8, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), and wherein: (a) (I) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:28, HCDR2 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:29, 119 and 190, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:41, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO:42, and LCDR3 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:43, 126, 134, 145, 172, 178 and 184; (II) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:31, HCDR2 comprises or consists of the amino acid sequence of any one of SEQ ID NOs:29, 119 and 190, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO:41, NO:41, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:42, and LCDR3 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs:43, 126, 134, 145, 172, 178 and 184; (III) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:32, HCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs:33, 120 and 191, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:30, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:44, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs:46, 127, 135, 146, 173, 179 and 185; or (IV) HCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: NO:34, HCDR2 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs:35, 121 and 192, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO:36, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO:47, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO:45, and LCDR3 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs:43, 126, 134, 145, 172, 178 and 184; (b) (I) HCDR1 comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs:4, 112 and 165, HCDR2 comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs:5, 100 and 151, HCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:6, LCDR1 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:17, LCDR2 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:18, and LCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:19; (II) HCDR1 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:7, HCDR2 comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs:5, 100 and 151, HCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:6, LCDR1 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:17, and LCDR2 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:

18. NO:18 or consists of the amino acid sequence, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:19; (III) HCDR1 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs:8, 113 and 166, HCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs:9, 101 and 152, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:6, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:20, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:21, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:22; or (IV) HCDR1 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs:10, 114 and 167, HCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs:11, 102 and 153, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: NO:12, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:23, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:21, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:19; or (c) (I) HCDR1 comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 226, 367 and 378, HCDR2 comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 227, 368 and 379, HCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 228, LCDR1 comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 237, LCDR2 comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 238, and LCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 239; (II) HCDR1 comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 229, 369 and 380, HCDR2 comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 227, 368 and 379, HCDR3 comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 228, and LCDR1 comprises or consists of an amino acid sequence as set forth in SEQ ID NO:

237. NO: 237 or consists of the amino acid sequence shown in SEQ ID NO: 238, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 238, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 239; (III) HCDR1 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 32, 370 and 381, HCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 230, 371 and 382, ​​HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 228, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 240, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 241, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 242; or (IV) HCDR1 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 34, 372 and 383, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 35 NO:231, 373 and 384 or consist of the amino acid sequence shown in any one of them, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:232, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:243, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:241, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:

239.

11. An isolated anti-NPR1 antibody or antigen-binding fragment; or the antibody or antigen-binding fragment of any one of claims 1, 3, 6, 7 or 9, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), and wherein: (a)(I) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 310, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 311, HCDR3 comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 312 and 348, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 320, LCDR2 comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 321 and 354, and LCDR3 comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 322, 355 and 361; (II) HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 229, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 311, HCDR3 comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 312 and 348, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 320, LCDR2 comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 321 and 354, and LCDR3 comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 322, 355 and 361. NO: 320, LCDR2 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 321 and 354, and LCDR3 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 322, 355 and 361; (III) HCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 80, HCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 313, HCDR3 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 312 and 348, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 323, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 324, and LCDR3 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 325, 356 and 362; or (IV) HCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 82, HCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO: NO: 314, or consisting thereof, HCDR3 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 315 and 349, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 326, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 324, and LCDR3 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 322, 355 and 361; or (b) (I) HCDR1 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 270 and 407, HCDR2 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 271, 389 and 408, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 331, LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 337, LCDR2 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 338, and LCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 339; (II) HCDR1 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 273 and 409, HCDR2 comprises or consists of an amino acid sequence as shown in any one of SEQ ID NOs: 271, 389 and 408, HCDR3 comprises or consists of an amino acid sequence as shown in SEQ ID NO: 331, and LCDR1 comprises or consists of an amino acid sequence as shown in SEQ ID NO:

337. ID NO: 337 or consists of the amino acid sequence shown in SEQ ID NO: 338, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 338, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 339; (III) HCDR1 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 32 and 410, HCDR2 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 274, 390 and 411, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 331, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO: 340, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 341, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO: 342; or (IV) HCDR1 comprises or consists of the amino acid sequence shown in any one of SEQ ID NOs: 275 and 412, HCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO: 276, NO:276, 391 and 413 or consist of the amino acid sequence shown in any one of them, HCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:332, LCDR1 comprises or consists of the amino acid sequence shown in SEQ ID NO:343, LCDR2 comprises or consists of the amino acid sequence shown in SEQ ID NO:341, and LCDR3 comprises or consists of the amino acid sequence shown in SEQ ID NO:

339.

12. The antibody or antigen-binding fragment of any one of claims 1, 2, 4, 5, 8 or 10, wherein the antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (a) (I) SEQ ID NO: 28 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3); (II) SEQ ID NO: 31 (HCDR1), SEQ ID NO: 119 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 41 (LCDR1), SEQ ID NO: 42 (LCDR2) and SEQ ID NO: 134 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 120 (HCDR2), SEQ ID NO: 30 (HCDR3), SEQ ID NO: 44 (LCDR1), SEQ ID NO: 45 (LCDR2) and SEQ ID NO: 135 (LCDR3); or (IV) SEQ ID NO: 34 (HCDR1), SEQ ID NO: 121 (HCDR2), SEQ ID NO: 36 (HCDR3), SEQ ID NO: 47 (LCDR1), SEQ ID NO: 45 (LCDR2) and SEQ ID NO: 134 (LCDR3); (b)(I) SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:126 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:126 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:127 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:126 (LCDR3); (c)(I) SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:145 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:145 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:146 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:145 (LCDR3); (d)(I)SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:172 (LCDR3); (II)SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:172 (LCDR3); (III)SEQ ID NO:32 (HCDR1), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:173 (LCDR3); or (IV)SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:172 (LCDR3); (e)(I) SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:178 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:178 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:179 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:178 (LCDR3); (f)(I) SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:184 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:184 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:185 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:184 (LCDR3); (g)(I) SEQ ID NO:4 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:101 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:10 (HCDR1), SEQ ID NO:102 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:19 (LCDR3); (h)(I) SEQ ID NO:112 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:100 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:113 (HCDR1), SEQ ID NO:101 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:114 (HCDR1), SEQ ID NO:102 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:19 (LCDR3); (i)(I) SEQ ID NO:28 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:43 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:119 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:43 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:46 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:121 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:43 (LCDR3); (j)(I)SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:126 (LCDR3); (II)SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:126 (LCDR3); (III)SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:127 (LCDR3); or (IV)SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:126 (LCDR3); (k)(I)SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:134 (LCDR3); (II)SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:134 (LCDR3); (III)SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:135 (LCDR3); or (IV)SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:134 (LCDR3); (l)(I) SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:145 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:145 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:146 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:145 (LCDR3); (m)(I) SEQ ID NO:4 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:152 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:10 (HCDR1), SEQ ID NO:153 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:19 (LCDR3); (n)(I) SEQ ID NO:112 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:113 (HCDR1), SEQ ID NO:152 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:114 (HCDR1), SEQ ID NO:153 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3); (o)(I) SEQ ID NO:165 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:151 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:166 (HCDR1), SEQ ID NO:152 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:167 (HCDR1), SEQ ID NO:153 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3); (p)(I) SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:172 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:172 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:173 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:172 (LCDR3); (q)(I)SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:178 (LCDR3); (II)SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:178 (LCDR3); (III)SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:179 (LCDR3); or (IV)SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:178 (LCDR3); (r)(I)SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:184 (LCDR3); (II)SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:184 (LCDR3); (III)SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:185 (LCDR3); or (IV)SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2), and SEQ ID NO:184 (LCDR3); (s)(I) SEQ ID NO:28 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:134 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:134 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:191 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:135 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:192 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:134 (LCDR3); (t)(I) SEQ ID NO:28 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:172 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:190 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:172 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:191 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:173 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:192 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:172 (LCDR3); (u)(I) SEQ ID NO:4 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (II) SEQ ID NO:7 (HCDR1), SEQ ID NO:5 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:17 (LCDR1), SEQ ID NO:18 (LCDR2) and SEQ ID NO:19 (LCDR3); (III) SEQ ID NO:8 (HCDR1), SEQ ID NO:9 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:22 (LCDR3); or (IV) SEQ ID NO:10 (HCDR1), SEQ ID NO:11 (HCDR2), SEQ ID NO:12 (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2) and SEQ ID NO:19 (LCDR3); (v)(I) SEQ ID NO:28 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:43 (LCDR3); (II) SEQ ID NO:31 (HCDR1), SEQ ID NO:29 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:42 (LCDR2) and SEQ ID NO:43 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:46 (LCDR3); or (IV) SEQ ID NO:34 (HCDR1), SEQ ID NO:35 (HCDR2), SEQ ID NO:36 (HCDR3), SEQ ID NO:47 (LCDR1), SEQ ID NO:45 (LCDR2) and SEQ ID NO:43 (LCDR3); (w)(I) SEQ ID NO: 367 (HCDR1), SEQ ID NO: 368 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 239 (LCDR3); (II) SEQ ID NO: 369 (HCDR1), SEQ ID NO: 368 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 239 (LCDR3); (III) SEQ ID NO: 370 (HCDR1), SEQ ID NO: 371 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 240 (LCDR1), SEQ ID NO: 241 (LCDR2) and SEQ ID NO: 242 (LCDR3); or (IV) SEQ ID NO: 372 (HCDR1), SEQ ID NO: 373 (HCDR2), SEQ ID NO: 232 (HCDR3), SEQ ID NO: 243 (LCDR1), SEQ ID NO: 241 (LCDR2) and SEQ ID NO: 239 (LCDR3); (x)(I) SEQ ID NO: 378 (HCDR1), SEQ ID NO: 379 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2), and SEQ ID NO: 239 (LCDR3); (II) SEQ ID NO: 380 (HCDR1), SEQ ID NO: 379 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2), and SEQ ID NO: 239 (LCDR3); (III) SEQ ID NO: 381 (HCDR1), SEQ ID NO: 382 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 240 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 242 (LCDR3); or (IV) SEQ ID NO: 383 (HCDR1), SEQ ID NO: 384 (HCDR2), SEQ ID NO: 232 (HCDR3), SEQ ID NO: 243 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 239 (LCDR3); (y)(I) SEQ ID NO: 226 (HCDR1), SEQ ID NO: 227 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2), and SEQ ID NO: 239 (LCDR3); (II) SEQ ID NO: 229 (HCDR1), SEQ ID NO: 227 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2), and SEQ ID NO: 239 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 230 (HCDR2), SEQ ID NO: 228 (HCDR3), SEQ ID NO: 240 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 242 (LCDR3); or (IV) SEQ ID NO: 34 (HCDR1), SEQ ID NO: 231 (HCDR2), SEQ ID NO: 232 (HCDR3), SEQ ID NO: 243 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 239 (LCDR3); (z)(I) SEQ ID NO: 270 (HCDR1), SEQ ID NO: 271 (HCDR2), SEQ ID NO: 272 (HCDR3), SEQ ID NO: 282 (LCDR1), SEQ ID NO: 261 (LCDR2), and SEQ ID NO: 283 (LCDR3); (II) SEQ ID NO: 273 (HCDR1), SEQ ID NO: 271 (HCDR2), SEQ ID NO: 272 (HCDR3), SEQ ID NO: 282 (LCDR1), SEQ ID NO: 261 (LCDR2), and SEQ ID NO: 283 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 274 (HCDR2), SEQ ID NO: 272 (HCDR3), SEQ ID NO: 284 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 285 (LCDR3); or (IV) SEQ ID NO: 275 (HCDR1), SEQ ID NO: 276 (HCDR2), SEQ ID NO: 277 (HCDR3), SEQ ID NO: 286 (LCDR1), SEQ ID NO: 241 (LCDR2), and SEQ ID NO: 283 (LCDR3); or (aa) (I) SEQ ID NO: 291 (HCDR1), SEQ ID NO: 292 (HCDR2), SEQ ID NO: 293 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 304 (LCDR3); (II) SEQ ID NO: 294 (HCDR1), SEQ ID NO: 292 (HCDR2), SEQ ID NO: 293 (HCDR3), SEQ ID NO: 237 (LCDR1), SEQ ID NO: 238 (LCDR2) and SEQ ID NO: 304 (LCDR3); (III) SEQ ID NO: 295 (HCDR1), SEQ ID NO: 296 (HCDR2), SEQ ID NO: 293 (HCDR3), SEQ ID NO:240 (LCDR1), SEQ ID NO:241 (LCDR2) and SEQ ID NO:305 (LCDR3); or (IV) SEQ ID NO:297 (HCDR1), SEQ ID NO:298 (HCDR2), SEQ ID NO:299 (HCDR3), SEQ ID NO:243 (LCDR1), SEQ ID NO:241 (LCDR2) and SEQ ID NO:304 (LCDR3).

13. The antibody or antigen-binding fragment of any one of claims 1, 3, 6, 7, 9 or 11, wherein the antibody or antigen-binding fragment comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3) selected from the following: (a)(I)SEQ ID NO:52 (HCDR1), SEQ ID NO:53 (HCDR2), SEQ ID NO:54 (HCDR3), SEQ ID NO:65 (LCDR1), SEQ ID NO:66 (LCDR2), and SEQ ID NO:67 (LCDR3); (II)SEQ ID NO:55 (HCDR1), SEQ ID NO:53 (HCDR2), SEQ ID NO:54 (HCDR3), SEQ ID NO:65 (LCDR1), SEQ ID NO:66 (LCDR2), and SEQ ID NO:67 (LCDR3); (III)SEQ ID NO:56 (HCDR1), SEQ ID NO:57 (HCDR2), SEQ ID NO:54 (HCDR3), SEQ ID NO:68 (LCDR1), SEQ ID NO:69 (LCDR2), and SEQ ID NO:70 (LCDR3); or (IV)SEQ ID NO:58 (HCDR1), SEQ ID NO:59 (HCDR2), SEQ ID NO:60 (HCDR3), SEQ ID NO:71 (LCDR1), SEQ ID NO:69 (LCDR2), and SEQ ID NO:67 (LCDR3); (b)(I)SEQ ID NO:76 (HCDR1), SEQ ID NO:77 (HCDR2), SEQ ID NO:78 (HCDR3), SEQ ID NO:89 (LCDR1), SEQ ID NO:90 (LCDR2), and SEQ ID NO:91 (LCDR3); (II)SEQ ID NO:79 (HCDR1), SEQ ID NO:77 (HCDR2), SEQ ID NO:78 (HCDR3), SEQ ID NO:89 (LCDR1), SEQ ID NO:90 (LCDR2), and SEQ ID NO:91 (LCDR3); (III)SEQ ID NO:80 (HCDR1), SEQ ID NO:81 (HCDR2), SEQ ID NO:78 (HCDR3), SEQ ID NO:92 (LCDR1), SEQ ID NO:93 (LCDR2), and SEQ ID NO:94 (LCDR3); or (IV)SEQ ID NO:82 (HCDR1), SEQ ID NO:83 (HCDR2), SEQ ID NO:84 (HCDR3), SEQ ID NO:95 (LCDR1), SEQ ID NO:93 (LCDR2), and SEQ ID NO:91 (LCDR3); (c)(I) SEQ ID NO: 310 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 354 (LCDR2), and SEQ ID NO: 361 (LCDR3); (II) SEQ ID NO: 229 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 354 (LCDR2), and SEQ ID NO: 361 (LCDR3); (III) SEQ ID NO: 80 (HCDR1), SEQ ID NO: 313 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 323 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 362 (LCDR3); or (IV) SEQ ID NO: 82 (HCDR1), SEQ ID NO: 314 (HCDR2), SEQ ID NO: 349 (HCDR3), SEQ ID NO: 326 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 361 (LCDR3); (d)(I) SEQ ID NO: 270 (HCDR1), SEQ ID NO: 389 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2), and SEQ ID NO: 339 (LCDR3); (II) SEQ ID NO: 273 (HCDR1), SEQ ID NO: 389 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2), and SEQ ID NO: 339 (LCDR3); (III) SEQ ID NO: 32 (HCDR1), SEQ ID NO: 390 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 340 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 342 (LCDR3); or (IV) SEQ ID NO: 275 (HCDR1), SEQ ID NO: 391 (HCDR2), SEQ ID NO: 332 (HCDR3), SEQ ID NO: 343 (LCDR1), SEQ ID NO: 341 (LCDR2), and SEQ ID NO: 339 (LCDR3); (e)(I) SEQ ID NO: 407 (HCDR1), SEQ ID NO: 408 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (II) SEQ ID NO: 409 (HCDR1), SEQ ID NO: 408 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 337 (LCDR1), SEQ ID NO: 338 (LCDR2) and SEQ ID NO: 339 (LCDR3); (III) SEQ ID NO: 410 (HCDR1), SEQ ID NO: 411 (HCDR2), SEQ ID NO: 331 (HCDR3), SEQ ID NO: 340 (LCDR1), SEQ ID NO: 341 (LCDR2) and SEQ ID NO: 342 (LCDR3); or (IV) SEQ ID NO: 412 (HCDR1), SEQ ID NO: 413 (HCDR2), SEQ ID NO: 332 (HCDR3), SEQ ID NO: 343 (LCDR1), SEQ ID NO: 341 (LCDR2) and SEQ ID NO: 339 (LCDR3); (f)(I) SEQ ID NO: 310 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 312 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 321 (LCDR2), and SEQ ID NO: 322 (LCDR3); (II) SEQ ID NO: 229 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 312 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 321 (LCDR2), and SEQ ID NO: 322 (LCDR3); (III) SEQ ID NO: 80 (HCDR1), SEQ ID NO: 313 (HCDR2), SEQ ID NO: 312 (HCDR3), SEQ ID NO: 323 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 325 (LCDR3); or (IV) SEQ ID NO: 82 (HCDR1), SEQ ID NO: 314 (HCDR2), SEQ ID NO: 315 (HCDR3), SEQ ID NO: 326 (LCDR1), SEQ ID NO: 324 (LCDR2), and SEQ ID NO: 322 (LCDR3); (g)(I) SEQ ID NO:270 (HCDR1), SEQ ID NO:271 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3); (II) SEQ ID NO:273 (HCDR1), SEQ ID NO:271 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3); (III) SEQ ID NO:32 (HCDR1), SEQ ID NO:274 (HCDR2), SEQ ID NO:331 (HCDR3), SEQ ID NO:340 (LCDR1), SEQ ID NO:341 (LCDR2), and SEQ ID NO:342 (LCDR3); or (IV) SEQ ID NO:275 (HCDR1), SEQ ID NO:276 (HCDR2), SEQ ID NO:332 (HCDR3), SEQ ID NO:343 (LCDR1), SEQ ID NO:341 (LCDR2), and SEQ ID NO:339 (LCDR3); or (h) (I) SEQ ID NO: 310 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 354 (LCDR2) and SEQ ID NO: 355 (LCDR3); (II) SEQ ID NO: 229 (HCDR1), SEQ ID NO: 311 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO: 320 (LCDR1), SEQ ID NO: 354 (LCDR2) and SEQ ID NO: 355 (LCDR3); (III) SEQ ID NO: 80 (HCDR1), SEQ ID NO: 313 (HCDR2), SEQ ID NO: 348 (HCDR3), SEQ ID NO:323 (LCDR1), SEQ ID NO:324 (LCDR2) and SEQ ID NO:356 (LCDR3); or (IV) SEQ ID NO:82 (HCDR1), SEQ ID NO:314 (HCDR2), SEQ ID NO:349 (HCDR3), SEQ ID NO:326 (LCDR1), SEQ ID NO:324 (LCDR2) and SEQ ID NO:355 (LCDR3).

14. An isolated anti-NPR1 antibody or antigen-binding fragment; or the antibody or antigen-binding fragment of any one of claims 1, 2, 4, 5, 8, 10 or 12, wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 201, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 136; (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 136; (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 201, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 128; (d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 128; (e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 201, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 147; (f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 147; (g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 201, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 174; (h) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 174; (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 201, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 180; (j) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 180; (k) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 201, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 186; (l) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 186; (m) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 103, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; (n) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 115, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; (o) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 48; (p) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 128; (q) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 136; (r) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:147; (s) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 154, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; (t) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 161, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; (u) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 168, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; (v) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 174; (w) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 180; (x) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 186; (y) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 193, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 136; (z) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 193, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 174; (aa) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24; (bb) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:37, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:48; (cc) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 374, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 244; (dd) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 385, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 244; (ee) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 233, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 244; (ff) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 278, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 287; or (gg) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 300, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

306.

15. An isolated anti-NPR1 antibody or antigen-binding fragment; or the antibody or antigen-binding fragment of any one of claims 1, 3, 6, 7, 9, 11 or 13, wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 61, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 72; (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 85, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 96; (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 350, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 363; (d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 392, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 344; (e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 414, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 344; (f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 316, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 327; (g) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 333, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 344; or (h) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 350, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

357.

16. An isolated anti-NPR1 antibody or antigen-binding fragment; or the antibody or antigen-binding fragment of any one of claims 1, 2, 4, 5, 8, 10, 12 or 14, wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 203, and a light chain comprising the amino acid sequence of SEQ ID NO: 138; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 208, and a light chain comprising the amino acid sequence of SEQ ID NO: 138; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 203, and a light chain comprising the amino acid sequence of SEQ ID NO: 130; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 208, and a light chain comprising the amino acid sequence of SEQ ID NO: 130; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 203, and a light chain comprising the amino acid sequence of SEQ ID NO: 149; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 208, and a light chain comprising the amino acid sequence of SEQ ID NO: 149; (g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 203, and a light chain comprising the amino acid sequence of SEQ ID NO: 176; (h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 208, and a light chain comprising the amino acid sequence of SEQ ID NO: 176; (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 203, and a light chain comprising the amino acid sequence of SEQ ID NO: 182; (j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 208, and a light chain comprising the amino acid sequence of SEQ ID NO: 182; (k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 203, and a light chain comprising the amino acid sequence of SEQ ID NO: 188; (l) a heavy chain comprising the amino acid sequence of SEQ ID NO: 208, and a light chain comprising the amino acid sequence of SEQ ID NO: 188; (m) a heavy chain comprising the amino acid sequence of SEQ ID NO: 105, and a light chain comprising the amino acid sequence of SEQ ID NO: 26; (n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 108, and a light chain comprising the amino acid sequence of SEQ ID NO: 26; (o) a heavy chain comprising the amino acid sequence of SEQ ID NO: 117, and a light chain comprising the amino acid sequence of SEQ ID NO: 26; (p) a heavy chain comprising the amino acid sequence of SEQ ID NO: 124, and a light chain comprising the amino acid sequence of SEQ ID NO: 50; (q) a heavy chain comprising the amino acid sequence of SEQ ID NO: 39, and a light chain comprising the amino acid sequence of SEQ ID NO: 130; (r) a heavy chain comprising the amino acid sequence of SEQ ID NO:39, and a light chain comprising the amino acid sequence of SEQ ID NO:138; (s) a heavy chain comprising the amino acid sequence of SEQ ID NO: 141, and a light chain comprising the amino acid sequence of SEQ ID NO: 138; (t) a heavy chain comprising the amino acid sequence of SEQ ID NO:39, and a light chain comprising the amino acid sequence of SEQ ID NO:149; (u) a heavy chain comprising the amino acid sequence of SEQ ID NO: 156, and a light chain comprising the amino acid sequence of SEQ ID NO: 26; (v) a heavy chain comprising the amino acid sequence of SEQ ID NO: 159, and a light chain comprising the amino acid sequence of SEQ ID NO: 26; (w) a heavy chain comprising the amino acid sequence of SEQ ID NO: 163, and a light chain comprising the amino acid sequence of SEQ ID NO: 26; (x) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, and a light chain comprising the amino acid sequence of SEQ ID NO: 26; (y) a heavy chain comprising the amino acid sequence of SEQ ID NO: 39, and a light chain comprising the amino acid sequence of SEQ ID NO: 176; (z) a heavy chain comprising the amino acid sequence of SEQ ID NO: 39, and a light chain comprising the amino acid sequence of SEQ ID NO: 182; (aa) a heavy chain comprising the amino acid sequence of SEQ ID NO:39, and a light chain comprising the amino acid sequence of SEQ ID NO:188; (bb) a heavy chain comprising the amino acid sequence of SEQ ID NO: 195, and a light chain comprising the amino acid sequence of SEQ ID NO: 138; (cc) a heavy chain comprising the amino acid sequence of SEQ ID NO: 195, and a light chain comprising the amino acid sequence of SEQ ID NO: 176; (dd) a heavy chain comprising the amino acid sequence of SEQ ID NO: 15, and a light chain comprising the amino acid sequence of SEQ ID NO: 26; (ee) a heavy chain comprising the amino acid sequence of SEQ ID NO: 39, and a light chain comprising the amino acid sequence of SEQ ID NO: 50; (ff) a heavy chain comprising the amino acid sequence of SEQ ID NO: 376, and a light chain comprising the amino acid sequence of SEQ ID NO: 246; (gg) a heavy chain comprising the amino acid sequence of SEQ ID NO: 387, and a light chain comprising the amino acid sequence of SEQ ID NO: 246; (hh) a heavy chain comprising the amino acid sequence of SEQ ID NO: 235, and a light chain comprising the amino acid sequence of SEQ ID NO: 246; (ii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 280, and a light chain comprising the amino acid sequence of SEQ ID NO: 289; or (jj) a heavy chain comprising the amino acid sequence of SEQ ID NO:302, and a light chain comprising the amino acid sequence of SEQ ID NO:

308.

17. An isolated anti-NPR1 antibody or antigen-binding fragment; or the antibody or antigen-binding fragment of any one of claims 1, 3, 6, 7, 9, 11, 13 or 15, wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 63, and a light chain comprising the amino acid sequence of SEQ ID NO: 74; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 87, and a light chain comprising the amino acid sequence of SEQ ID NO: 98; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 352, and a light chain comprising the amino acid sequence of SEQ ID NO: 365; (d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 394, and a light chain comprising the amino acid sequence of SEQ ID NO: 346; (e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 416, and a light chain comprising the amino acid sequence of SEQ ID NO: 346; (f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 318, and a light chain comprising the amino acid sequence of SEQ ID NO: 329; (g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 335, and a light chain comprising the amino acid sequence of SEQ ID NO: 346; or (h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 352, and a light chain comprising the amino acid sequence of SEQ ID NO:

359.

18. The antibody or antigen-binding fragment of any one of claims 1-17, which is an antigen-binding fragment selected from the group consisting of: Fab, Fab', F(ab')2, Fv, single domain antibody (dAb) and single chain variable fragment (scFv).

19. The antibody or antigen-binding fragment of any one of claims 1-19, wherein the antibody or antigen-binding fragment is therapeutic.

20. One or more isolated nucleic acids encoding the amino acid sequence of the antibody or antigen-binding fragment of any one of claims 1-19.

21. A vector comprising one or more isolated nucleic acids of claim 20.

22. A host cell comprising one or more isolated nucleic acids of claim 20 or a vector of claim 21.

23. A method for producing an antibody or antigen-binding fragment as described in any one of claims 1 to 19, the method comprising culturing the host cell as described in claim 22 under conditions suitable for producing the antibody or antigen-binding fragment, optionally wherein the method additionally comprises purifying the antibody or antigen-binding fragment.

24. A pharmaceutical composition comprising the antibody or antigen-binding fragment of any one of claims 1-19 or produced by the method of claim 23, and a pharmaceutically acceptable carrier; optionally, wherein the composition further comprises an additional therapeutic agent.

25. A pharmaceutical composition as claimed in claim 24, or a combination comprising the antibody or antigen-binding fragment as described in any one of claims 1 to 19, wherein the additional therapeutic agent is selected from ACE (angiotensin converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), enkephalinase inhibitors, beta blockers, diuretics, calcium channel blockers, cardiac glycosides, sodium-glucose co-transporter 2 inhibitors (SGLT2i), angiotensin receptor-enkephalinase inhibitors (ARNi), corticosteroids, leukotriene modifiers, bronchodilators, beta-adrenergic receptor antagonists, carbonic anhydrase inhibitors, alpha2-adrenergic receptor agonists, parasympathomimetics, prostaglandin analogs, rho kinase inhibitors and combinations thereof.

26. The antibody or antigen-binding fragment of any one of claims 1 to 19, or the pharmaceutical composition of claim 24 or 25, for use in treating a disorder or disease associated with natriuretic peptide receptor activity in a subject in need of such treatment.

27. The antibody or antigen-binding fragment of any one of claims 1 to 19, or the pharmaceutical composition or combination of claims 24 or 25, for use in treating a cardiovascular disorder in a subject in need of such treatment, optionally wherein the cardiovascular disorder is selected from the group consisting of: hypertension, peripheral vascular disease, heart failure, coronary artery disease (CAD), ischemic heart disease (IHD), mitral stenosis and regurgitation, angina pectoris, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new onset AF, recurrent AF, cardiac fibrosis, atrial flutter, deleterious vascular remodeling, plaque stabilization, and myocardial infarction (MI).

28. An antibody or antigen-binding fragment as described in any one of claims 1 to 19, or a pharmaceutical composition or combination as described in claim 24 or 25, for use in treating heart failure, hypertrophic cardiomyopathy (HCM), hypertension, pre-eclampsia, asthma, glaucoma, renal disorders and / or cytokine release syndrome in a subject in need of such treatment, optionally wherein the heart failure is selected from heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure after acute myocardial infarction or acute compensated heart failure.

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