Natriuretic peptide receptor 1 antibodies and methods of use

Abstract

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

Description

Background Technology

[0001] 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 incidence (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), leading to a decrease in blood pressure and blood volume (Chen & Burnett, 2006, European Heart Journal Supplements 8 (Supplement E): E18-E25; Ibebuogu et al. 2011, ibid.; Mani et al. 2015, Bioscience Reports 35(5):e00260). ANP binding induces receptor dimerization and torsion, thereby inducing activation of the guanylate cyclase domain and the 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 degraded by neutral endopeptidase (NEP) (Chen & Burnett 2006, ibid.; Schmitt et al., 2003, Clin Sci (Lond). [Clinical Science (London)] 105(2):141-160). For example, certain antibodies against NPR1 (including antibody 5591-IgG) are described in WO 2010 / 065293. However, these antibodies appear to be nonfunctional in vitro in the absence of ANP and also nonfunctional in vivo.

[0002] It has been shown that an increase in ANP may be beneficial for patients with heart failure (heart pumping blood outwards) with a 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 agents with longer-acting effects and alternative modes of action to complement or replace existing therapies. Summary of the Invention

[0003] This article demonstrates that NPR1 can be activated by using agonistic anti-NPR1 antibodies or their antigen-binding fragments. Furthermore, this disclosure demonstrates the existence of 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 to and activate NPR1 without competing with ANP (hereinafter referred to as "ANP-non-competitive" anti-NPR1 antibodies). Such antibodies (e.g., ANP-non-competitive anti-NPR1 antibodies) can be used to enhance the body's natural systems and / or reinforce existing therapeutic mechanisms. In addition, some NPR1 agonist antibodies that can activate NPR1 in the absence of ANP have been found to be functionally equivalent to ANP.

[0004] The antibody described in this application has shown in vivo activity in both mice and rats. Furthermore, crystal structure data have demonstrated the unique epitope binding of the antibody described herein.

[0005] Therefore, this disclosure provides anti-NPR1 antibodies (e.g., human monoclonal antibodies) or antigen-binding fragments thereof that (i) bind to natriuretic peptide receptor 1 (NPR1) and (ii) activate NPR1 in the absence of ANP. Such antibodies are agonistic anti-NPR1 antibodies. In some embodiments of the invention, this disclosure also provides anti-NPR1 antibodies or antigen-binding fragments thereof that (i) bind to natriuretic peptide receptor 1 (NPR1) and (ii) activate NPR1 in the absence of ANP. In some embodiments of the invention, this disclosure also provides antibodies or antigen-binding fragments thereof that (i) bind to natriuretic peptide receptor 1 (NPR1) and (ii) activate NPR1 in both the presence and absence of ANP. A nucleic acid encoding the antibody is also provided, a vector comprising the nucleic acid, a host cell comprising the nucleic acid and / or the vector, and a method for manufacturing the antibody using the nucleic acid, the vector, and / or the host cell. Pharmaceutical compositions and combinations comprising the antibody, nucleic acid, vector, or host cell are also provided, as well as treatment methods using the antibody, nucleic acid, vector, host cell, or pharmaceutical composition. This article also discloses the use of the antibodies, nucleic acids, vectors, host cells, or pharmaceutical compositions or combinations thereof in the treatment of diseases.

[0006] Therefore, in one aspect of the invention, this document provides 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.

[0007] In some embodiments of the present invention, the antibody or antigen-binding fragment binds to (a) human NPR1; and (b) cynomolgus monkey NPR1. In some embodiments of the present invention, the antibody or antigen-binding fragment is ANP-noncompetitive. In some embodiments of the present invention, the antibody or antigen-binding fragment is ANP-competitive. In some embodiments of the present invention, the antibody or antigen-binding fragment is capable of stabilizing the ANP-NPR1 complex.

[0008] 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, for example, within the region of human NPR1 covered 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 containing 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 containing at least 3, 4, 5, 6, 7, or 8 amino acid residues within amino acids 99-133 of SEQ ID NO:1.

[0009] In some embodiments of the present 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 present 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 present 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 present 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 present invention, the antibody or antigen-binding fragment binds to a conformational epitope of human NPR1, wherein the conformational epitope comprises at least one amino acid residue from each of (i) amino acids 99-103 of SEQ ID NO:1, (ii) amino acids 105-111 of SEQ ID NO:1, and (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 present 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 present 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.

[0010] In some embodiments of the present 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 present 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 present 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.

[0011] 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 from 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 present invention, the antibody or antigen-binding fragment is bound to at least amino acids 188, 192, 194, 197, 201, 208, 219 and 295 of SEQ ID NO:1.

[0012] In some embodiments of the present invention, 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), wherein: (a)(I) HCDR1 comprises or is composed of the amino acid sequence shown in SEQ ID NO:28; HCDR2 comprises or is composed of the amino acid sequence shown in 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 is composed of the amino acid sequence shown in SEQ ID NO:30; LCDR1 comprises or is composed of the amino acid sequence shown in SEQ ID NO:41; LCDR2 comprises or is composed of the amino acid sequence shown in SEQ ID NO:42; and LCDR3 comprises or is composed of the amino acid sequence shown in Y1QY2Y3Y4Y5PRT (SEQ ID NO:429). (ii) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:31; HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:429, 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:31; HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:30, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:41, and LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:429. The amino acid sequence shown in NO:42 or composed of it, and LCDR3 contains or is composed of the amino acid sequence shown in 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;(III) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:32, HCDR2 contains or is composed of the amino acid sequence shown in X1SX2GX3Y (SEQ ID NO:431), wherein X1 is S or E, X2 is D or K, or X3 is S or N, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:30, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:44, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:30. The amino acid sequence shown in NO:34 or composed thereof, HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:36, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:47, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:36. The amino acid sequence shown in NO:28 or composed of it; HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:30; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:41; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:42; and LCDR3 contains or is composed 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:31;HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:30, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:41, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:42, and LCDR3 contains or is composed 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; (III) HCDR1 contains the amino acid sequence shown in SEQ ID NO:30. The amino acid sequence shown in NO:32 or composed thereof, HCDR2 contains or is composed of the amino acid sequence X1SX2GX3Y (SEQ ID NO:431), wherein X1 is S or E, X2 is D or K, or X3 is S or N, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:30, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:44, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 contains or is composed of the amino acid sequence 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:34, HCDR2 contains or is composed of the amino acid sequence X1SX2GX3YX4 (SEQ ID NO:431), wherein X1 is S or E, X2 is D or K, or X3 is D or N; or (IV) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:34, HCDR2 contains or is composed of the amino acid sequence X1SX2GX3YX4 (SEQ ID NO:431), wherein X1 is S or E, X2 is D or K, or X3 is D or K ...2 contains or is composed of the amino acid sequence X1SX2GX3YX4 (SEQ ID NO:431), X1 is S or E, X2 is D or K, or X3 is D or K; or (IV) HC (c)(I) HCDR1 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:36; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:47; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:45; and LCDR3 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:28; HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:119; and HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:30.LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:41; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:42; and LCDR3 contains or is composed 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:31; HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:119; HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:30, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:41, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:42, and LCDR3 contains or is composed 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) The amino acid sequence shown in SEQ ID NO:434 or composed thereof; 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:32, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:120, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:30, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:44, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 contains or is composed 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:434. The amino acid sequence shown in NO:34 or composed of it, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:121, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:36, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:47, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 contains or is composed 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;(d)(I) HCDR1 contains or is composed of the amino acid sequence shown in GFTFX1THYIH (SEQ ID NO: 436), wherein X1 is N, S, or Q; HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO: 6; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO: 17; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO: 18; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO: 19; (II) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO: 19. The amino acid sequence shown in NO:7 or composed thereof, HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:6, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:17, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:18, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:19; (III) HCDR1 contains or is composed of the amino acid sequence shown in GFTFX1TH (SEQ ID NO:438), wherein X1 is N, S or Q, HCDR2 contains or is composed of the amino acid sequence shown in Y1Y2Y3GY4Y5 (SEQ ID NO:438). The amino acid sequence shown in SEQ ID NO:439) or composed thereof, 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:6, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:20, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:21, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:22.Or (IV) HCDR1 contains or is composed of the amino acid sequence shown in GFTFX1THY (SEQ ID NO:440), wherein X1 is N, S, or Q; HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:12; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:23; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:21; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:19; (e)(I) HCDR1 contains or is composed of the amino acid sequence shown in GFTFX1THYIH (SEQ ID NO:440). (II) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:436, wherein X1 is N, S, or Q; HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:442, wherein Y1 is S or G, Y2 is S or Q, and Y3 is S or N; HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:6; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:17; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:18; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:19; (II) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:7; HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:442, wherein Y1 is S or G, Y2 is S or Q, and Y3 is S or N; HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:19; The amino acid sequence shown in NO:6 or composed of therein, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:17, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:18, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:19.(III) HCDR1 contains or is composed of the amino acid sequence shown in or consisting of GFTFX1TH (SEQ ID NO:438), wherein X1 is N, S, or Q; HCDR2 contains or is composed of the amino acid sequence shown in or consisting of SY1SGY2Y3 (SEQ ID NO:443), wherein Y1 is S or G, Y2 is S or Q, and Y3 is S or N; HCDR3 contains or is composed of the amino acid sequence shown in or consisting of SEQ ID NO:6; LCDR1 contains or is composed of the amino acid sequence shown in or consisting of SEQ ID NO:20; LCDR2 contains or is composed of the amino acid sequence shown in or consisting of SEQ ID NO:21; and LCDR3 contains or is composed of the amino acid sequence shown in or consisting of SEQ ID NO:22; or (IV) HCDR1 contains or is composed of the amino acid sequence shown in or consisting of GFTFX1THY (SEQ ID NO:440), wherein X1 is N, S, or Q; HCDR2 contains or is composed of the amino acid sequence shown in or consisting of SY1SGY2Y3T (SEQ ID NO:443). (f)(I) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:444, wherein Y1 is S or G, Y2 is S or Q, and Y3 is S or N; HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:12; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:23; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:21; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:19; (f)(I) HCDR1 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:445, wherein Y1 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:445, wherein Y1 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:445, wherein Y1 is S or G ... or Q, and Y3 is S or N; HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:445, wherein Y1 is S or G, X2 is S or Q, and Y3 is S or N; HCDR2 contains or is composed of the amino acid sequence shown The amino acid sequence shown in SEQ ID NO:446) or composed thereof, 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:228, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:237, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:238, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:239.(II) HCDR1 comprises or is composed of the amino acid sequence 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 is composed of the amino acid sequence 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 is composed of the amino acid sequence SEQ ID NO:228; LCDR1 comprises or is composed of the amino acid sequence SEQ ID NO:237; LCDR2 comprises or is composed of the amino acid sequence SEQ ID NO:238; and LCDR3 comprises or is composed of the amino acid sequence SEQ ID NO:238. (III) HCDR1 contains or is composed of the amino acid sequence shown in NO:239 or thereof; wherein X1 is S or T, and X2 is S, K, or R; HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:228; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:240; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:241; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:242; or (IV) HCDR1 contains or is composed of the amino acid sequence shown in GFX1FSX2YX3 (SEQ ID NO:239 or thereof); HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:450, wherein X1 is S or T, X2 is S, K or R, and X3 is W or Y; HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:232; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:243; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:241; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:239.(g)(I) HCDR1 comprises or is composed of the amino acid sequence shown in or consisting of the sequence 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 is composed of the amino acid sequence shown in or consisting of the sequence 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 is composed of the amino acid sequence shown in or consisting of the ... (ii) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:239 or thereof; X1 is S, K, or R, X2 is W or Y, X3 is I or L, and X4 is S or N; HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:447 or thereof, wherein X1 is S, K, or R, X2 is W or Y, X3 is I or L, and X4 is S or N; HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:453 or thereof, 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:228 or thereof; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:237 or thereof; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:238 or thereof; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:239 or thereof. (III) HCDR1 contains or is composed of the amino acid sequence shown in NO:239; HCDR2 contains or is composed of the amino acid sequence shown in GFX1FSX2Y (SEQ ID NO:448), wherein X1 is S or T and X2 is S, K or R; HCDR2 contains or is composed of the amino acid sequence shown in HQY1Y2Y3E (SEQ ID NO:456), wherein Y1 is Q or H, Y2 is G or A and Y3 is H or L; HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:228; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:240; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:241; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:242.Or (IV) HCDR1 contains or is composed of the amino acid sequence as shown 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 contains or is composed of the amino acid sequence as shown 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 contains or is composed of the amino acid sequence as shown in SEQ ID NO:232; LCDR1 contains or is composed of the amino acid sequence as shown in SEQ ID NO:243; LCDR2 contains or is composed of the amino acid sequence as shown in SEQ ID NO:241; and LCDR3 contains or is composed of the amino acid sequence as shown in SEQ ID NO:239; (h)(I) HCDR1 contains or is composed of the amino acid sequence as shown in GFTFSX1YX2IX3 (SEQ ID NO:450). (ii) HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:452, wherein X1 is S or R, X2 is W or Y, and X3 is S or N; HCDR2 contains or is composed of the amino acid sequence 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:228; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:237; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:238; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:239; (ii) HCDR1 contains or is composed of the amino acid sequence shown in X1YX2IX3 (SEQ ID NO:446). HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:454, wherein X1 is S or R, X2 is W or Y, and X3 is S or N; HCDR2 contains or is composed of the amino acid sequence 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:228; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:237; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:238; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:239.(III) HCDR1 contains or is composed of the amino acid sequence shown in GFTFSX1Y (SEQ ID NO:455), wherein X1 is S or R; HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:228; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:240; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:241; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:242; or (IV) HCDR1 contains or is composed of the amino acid sequence shown in GFTFSX1YX2 (SEQ ID NO:455). The amino acid sequence shown in SEQ ID NO:457 or composed thereof, wherein X1 is S or R, and X2 is W or Y, HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:232, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:243, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:241, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:239; or (i)(I) HCDR1 contains the amino acid sequence shown in SEQ ID NO:457, wherein X1 is S or R, and X2 is W or Y, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:241, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:239; or (i)(I) HCDR1 contains the amino acid sequence shown in SEQ ID NO:451, wherein X1 is S or R, and X2 is W or Y, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:457 ...3 contains or is composed of the amino acid sequence shown in SEQ ID NO:457, wherein X HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:452, wherein X1 is S or R, X2 is W or Y, and X3 is S or N; HCDR2 contains or is composed of the amino acid sequence 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:228; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:237; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:238; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:239.(II) HCDR1 contains or is composed of the amino acid sequence X1YX2IX3 (SEQ ID NO:454), wherein X1 is S or R, X2 is W or Y, and X3 is S or N; HCDR2 contains or is composed of the amino acid sequence 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 contains or is composed of the amino acid sequence SEQ ID NO:228; LCDR1 contains or is composed of the amino acid sequence SEQ ID NO:237; LCDR2 contains or is composed of the amino acid sequence SEQ ID NO:238; and LCDR3 contains or is composed of the amino acid sequence SEQ ID NO:239; (III) HCDR1 contains the amino acid sequence GFTFSX1Y (SEQ ID NO:454). (SEQ ID NO:455) contains or is composed of the amino acid sequence shown in SEQ ID NO:455, wherein X1 is S or R, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:456, wherein Y1 is Q or H, Y2 is G or A, and Y3 is H or L, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:228, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:240, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:241, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:242; or (IV) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:457, wherein X1 is S or R, and X2 is W or Y, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:1HQY1Y2Y3EY4 (SEQ ID NO:456). The amino acid sequence shown in SEQ ID NO:458 or composed thereof, wherein Y1 is Q or H, Y2 is G or A, Y3 is H or L, and Y4 is T or K; HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:232; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:243; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:241; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:239.

[0013] In some embodiments of the present invention, 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), 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 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 shown in SEQ ID NO:320, LCDR2 comprises or consists of the amino acid sequence shown in GNSNRPY1 (SEQ ID NO:460), wherein Y1 is S or N, and LCDR3 comprises or consists of the amino acid sequence shown in QSYZ1Z2Z3Z4Z5Z6Z7V (SEQ ID NO:459). (ii) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO: 229, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO: 311, HCDR3 contains or is composed of the amino acid sequence 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 contains or is composed of the amino acid sequence shown in SEQ ID NO: 320, and LCDR2 contains or is composed of the amino acid sequence shown in GNSNRPY1 (SEQ ID NO: 459). The amino acid sequence shown in NO:460) or composed of it, wherein Y1 is S or N, and LCDR3 contains or is composed of the amino acid sequence shown in QSYZ1Z2Z3Z4Z5Z6Z7V (SEQ ID NO:461), 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:80, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:313, HCDR3 contains or is composed of the amino acid sequence 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:323, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:324, and LCDR3 contains the amino acid sequence shown in YZ1Z2Z3Z4Z5Z6Z7 (SEQ ID NO:80). (IV) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO: 462, 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 contains or is composed of the amino acid sequence shown in SEQ ID NO: 82, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO: 314, HCDR3 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO: 326, and LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO: 82. The amino acid sequence shown in NO:324 or composed of it, and LCDR3 contains or is composed of the amino acid sequence shown in QSYZ1Z2Z3Z4Z5Z6Z7V (SEQ ID NO:461), 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 is composed of the amino acid sequence 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 is composed of the amino acid sequence shown 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 is composed of the amino acid sequence shown in SEQ ID NO:331; LCDR1 comprises or is composed of the amino acid sequence shown in SEQ ID NO:337; LCDR2 comprises or is composed of the amino acid sequence shown in SEQ ID NO:338; and LCDR3 comprises or is composed of the amino acid sequence shown in SEQ ID NO:338. (ii) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:339 or thereof; X1 is S or T, X2 is I or M, and X3 is S or T; HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:466 or thereof, wherein X1 is S or T, X2 is I or M, and X3 is S or T; HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:465 or thereof, 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:331 or thereof; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:337 or thereof; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:338 or thereof; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:339 or thereof. (III) HCDR1 contains or is composed of the amino acid sequence shown in NO:339; HCDR2 contains or is composed of the amino acid sequence shown in GFTFX1X2Y (SEQ ID NO:467), wherein X1 is S or G and X2 is S or T; HCDR2 contains or is composed of the amino acid sequence 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:331; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:340; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:341; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:342.Or (IV) HCDR1 contains or is composed of the amino acid sequence as shown in GFTFX1X2YA (SEQ ID NO:469), wherein X1 is S or G and X2 is S or T; HCDR2 contains or is composed of the 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 contains or is composed of the amino acid sequence as shown in SEQ ID NO:332; LCDR1 contains or is composed of the amino acid sequence as shown in SEQ ID NO:343; LCDR2 contains or is composed of the amino acid sequence as shown in SEQ ID NO:341; and LCDR3 contains or is composed of the amino acid sequence as shown in SEQ ID NO:339; or (c)(I) HCDR1 contains or is composed of the amino acid sequence as shown in GFTFX1X2YAX3X4 (SEQ ID NO:469). (ii) HCDR2 contains or consists of the amino acid sequence shown in 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 contains or consists of the amino acid sequence shown in 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 contains or consists of the amino acid sequence shown in SEQ ID NO:331; LCDR1 contains or consists of the amino acid sequence shown in SEQ ID NO:337; LCDR2 contains or consists of the amino acid sequence shown in SEQ ID NO:338; and LCDR3 contains or consists of the amino acid sequence shown in SEQ ID NO:339; (ii) HCDR1 contains the amino acid sequence shown in SEQ ID NO:339. The amino acid sequence shown in SEQ ID NO:466 or composed thereof, wherein X1 is S or T, X2 is I or M, and X3 is S or T, HCDR2 contains or is composed of the amino acid sequence shown in 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 contains or is composed of the amino acid sequence shown in SEQ ID NO:331, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:337, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:338, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:339.(III) HCDR1 contains or is composed of the amino acid sequence shown in or consisting of GFTFX1X2Y (SEQ ID NO:467), wherein X1 is S or G and X2 is S or T; HCDR2 contains or is composed of the amino acid sequence shown in or consisting of SY1Y2GYY (SEQ ID NO:472), wherein Y1 is A or S and Y2 is S or H; HCDR3 contains or is composed of the amino acid sequence shown in or consisting of SEQ ID NO:331; LCDR1 contains or is composed of the amino acid sequence shown in or consisting of SEQ ID NO:340; LCDR2 contains or is composed of the amino acid sequence shown in or consisting of SEQ ID NO:341; and LCDR3 contains or is composed of the amino acid sequence shown in or consisting of SEQ ID NO:342; or (IV) HCDR1 contains or is composed of the amino acid sequence shown in or consisting of GFTFX1X2YA (SEQ ID NO:469), wherein X1 is S or G and X2 is S or T; HCDR2 contains or is composed of the amino acid sequence shown in or consisting of ISY1Y2GYY (SEQ ID NO:472). The amino acid sequence shown in SEQ ID NO:473 or composed thereof, wherein Y1 is A, S, or G, and Y2 is S or H, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:332, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:343, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:341, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:339.

[0014] In some embodiments of the present invention, 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), wherein: (a) (I) HCDR1 comprises or is composed of the amino acid sequence shown in SEQ ID NO:28, HCDR2 comprises or is composed of the amino acid sequence shown in any one of SEQ ID NO:29, 119, and 190, HCDR3 comprises or is composed of the amino acid sequence shown in SEQ ID NO:30, LCDR1 comprises or is composed of the amino acid sequence shown in SEQ ID NO:41, LCDR2 comprises or is composed of the amino acid sequence shown in SEQ ID NO:42, and LCDR3 comprises or is composed of the amino acid sequence shown in any one of SEQ ID NO:43, 126, 134, 145, 172, 178, and 184; (II) HCDR1 comprises or is composed of the amino acid sequence shown in SEQ ID NO:31, HCDR2 comprises or is composed of the amino acid sequence shown in SEQ ID NO:42, and LCDR3 comprises or is composed of the amino acid sequence shown in any one of SEQ ID NO:43, 126, 134, 145, 172, 178, and 184; (III) HCDR1 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:29, 119, and 190, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:30, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:41, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:42, and LCDR3 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:43, 126, 134, 145, 172, 178, and 184; (III) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:32, HCDR2 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:33, 120, and 191, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:30, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:44, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:43, 126, 134, 145, 172, 178, and 184. The amino acid sequence shown in NO:46, 127, 135, 146, 173, 179 and 185 or composed of such sequences;(IV) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:34, HCDR2 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:35, 121, and 192, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:36, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:47, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:45, and LCDR3 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:43, 126, 134, 145, 172, 178, and 184; (b)(I) HCDR1 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:4, 112, and 165, HCDR2 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:5, 100, and 151, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:6, and LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:34. (II) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:17, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:18, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:19; (III) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:8, 113, and 166, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:9, 101, and 152, and HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:19. The amino acid sequence shown in NO:6 or composed of therein, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:20, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:21, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:22.Or (IV) HCDR1 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO: 10, 114, and 167; HCDR2 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO: 11, 102, and 153; HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO: 12; LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO: 23; LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO: 21; and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO: 19; or (c)(I) HCDR1 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO: 226, 367, and 378; HCDR2 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO: 227, 368, and 379; HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO: 228; and LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO: 19. (I) The amino acid sequence shown in NO:237 or composed of therefrom, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:238 or composed of therefrom, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:239; (II) HCDR1 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:229, 369 and 380, HCDR2 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:227, 368 and 379, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:228, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:237, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:238 and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:239; (III) HCDR1 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:32, 370 and 381, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:239, ... The amino acid sequence shown in any one of NO:230, 371 and 382 or composed of therefrom, HCDR3 contains the amino acid sequence shown in SEQ ID NO:228 or composed of therefrom, LCDR1 contains the amino acid sequence shown in SEQ ID NO:240 or composed of therefrom, LCDR2 contains the amino acid sequence shown in SEQ ID NO:241 or composed of therefrom, and LCDR3 contains the amino acid sequence shown in SEQ ID NO:242 or composed of therefrom.Or (IV) HCDR1 contains or is composed of the amino acid sequence shown in or composed of any one of SEQ ID NO:34, 372, and 383; HCDR2 contains or is composed of the amino acid sequence shown in or composed of any one of SEQ ID NO:231, 373, and 384; HCDR3 contains or is composed of the amino acid sequence shown in or composed of SEQ ID NO:232; LCDR1 contains or is composed of the amino acid sequence shown in or composed of SEQ ID NO:243; LCDR2 contains or is composed of the amino acid sequence shown in or composed of SEQ ID NO:241; and LCDR3 contains or is composed of the amino acid sequence shown in or composed of SEQ ID NO:239.

[0015] In some embodiments of the present invention, 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), wherein: (a) (I) HCDR1 comprises or is composed of the amino acid sequence shown in SEQ ID NO:310, HCDR2 comprises or is composed of the amino acid sequence shown in SEQ ID NO:311, HCDR3 comprises or is composed of the amino acid sequence shown in any one of SEQ ID NO:312 and 348, LCDR1 comprises or is composed of the amino acid sequence shown in SEQ ID NO:320, LCDR2 comprises or is composed of the amino acid sequence shown in any one of SEQ ID NO:321 and 354, and LCDR3 comprises or is composed of the amino acid sequence shown in any one of SEQ ID NO:322, 355, and 361; (II) HCDR1 comprises or is composed of the amino acid sequence shown in SEQ ID NO:229, HCDR2 comprises or is composed of the amino acid sequence shown in SEQ ID NO:310, HCDR2 comprises or is composed of the amino acid sequence shown in SEQ ID NO:311, HCDR3 comprises or is composed of the amino acid sequence shown in SEQ ID NO:312 and 348, LCDR1 comprises or is composed of the amino acid sequence shown in SEQ ID NO:320, LCDR2 comprises or is composed of the amino acid sequence shown in SEQ ID NO:321 and 354, and LCDR3 comprises or is composed of the amino acid sequence shown in any one of SEQ ID NO:322, 355, and 361; The amino acid sequence shown in NO:311 or composed thereof, HCDR3 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:312 and 348, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:320, LCDR2 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:321 and 354, and LCDR3 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:322, 355 and 361; (III) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:80, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:313, HCDR3 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:312 and 348, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:323, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:324, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:322, 355 and 361. The amino acid sequence shown in NO:325, 356 and 362 or composed of thereof;Or (IV) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO: 82, HCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO: 314, HCDR3 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO: 315 and 349, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO: 326, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO: 324, and LCDR3 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO: 322, 355, and 361; or (b)(I) HCDR1 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO: 270 and 407, HCDR2 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO: 271, 389, and 408, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO: 331, and LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO: 82. (II) HCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:337, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:338, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:339; (III) HCDR1 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:273 and 409, HCDR2 contains or is composed of the amino acid sequence shown in any one of SEQ ID NO:271, 389 and 408, HCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:331, LCDR1 contains or is composed of the amino acid sequence shown in SEQ ID NO:337, LCDR2 contains or is composed of the amino acid sequence shown in SEQ ID NO:338, and LCDR3 contains or is composed of the amino acid sequence shown in SEQ ID NO:339; The amino acid sequence shown in any one of NO:274, 390 and 411 or composed of therefrom, HCDR3 contains the amino acid sequence shown in SEQ ID NO:331 or composed of therefrom, LCDR1 contains the amino acid sequence shown in SEQ ID NO:340 or composed of therefrom, LCDR2 contains the amino acid sequence shown in SEQ ID NO:341 or composed of therefrom, and LCDR3 contains the amino acid sequence shown in SEQ ID NO:342 or composed of therefrom.Or (IV) HCDR1 contains or is composed of the amino acid sequence shown in or composed of any one of SEQ ID NO: 275 and 412, HCDR2 contains or is composed of the amino acid sequence shown in or composed of any one of SEQ ID NO: 276, 391 and 413, HCDR3 contains or is composed of the amino acid sequence shown in or composed of SEQ ID NO: 332, LCDR1 contains or is composed of the amino acid sequence shown in or composed of SEQ ID NO: 343, LCDR2 contains or is composed of the amino acid sequence shown in or composed of SEQ ID NO: 341, and LCDR3 contains or is composed of the amino acid sequence shown in or composed of SEQ ID NO: 339.

[0016] In some embodiments of the present invention, 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) 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 ...2), SEQ ID NO:120 (HCDR2), SEQ ID NO:30 (HCDR2), SEQ ID NO:120 (HCDR2), SEQ ID NO:120 (HCDR2), SEQ ID NO:120 (HCDR2), SEQ ID NO:120 (HCDR2), SEQ ID NO:120 (HCDR2), SEQ ID NO:120 (HCDR2), SEQ ID NO:12 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 (LCDR(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: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:X (HCDR3), SEQ ID NO:23 (LCDR1), SEQ ID NO:21 (LCDR2), and SEQ ID NO:19 (LCDR3); It should be noted that in the original text, there is an "X" in the "SEQ ID NO:X (HCDR3)" which is likely a typo. I translated it as "X" as it is in the original. If this is incorrect, please provide the correct information.(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 (LCDR)2, 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:23 (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).;

[0017] In some embodiments of the present invention, 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) 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:65 (LCDR1), SEQ ID NO:66 (LCDR2), and SEQ ID NO:67 (LCDR3); 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:(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).;

[0018] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises: (a) 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:136; (b) 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:136; (c) 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:128; (d) 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:128; (e) 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:147; (f) 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:147; (g) 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:147; (h) The heavy chain variable region containing the amino acid sequence of SEQ ID NO:201 and the light chain variable region containing the amino acid sequence of SEQ ID NO:174; (i) The heavy chain variable region containing the amino acid sequence of SEQ ID NO:122 and the light chain variable region containing the amino acid sequence of SEQ ID NO:174; (j) The heavy chain variable region containing the amino acid sequence of SEQ ID NO:122 and the light chain variable region containing the amino acid sequence of SEQ ID NO:180; (k) The heavy chain variable region containing the amino acid sequence of SEQ ID NO:201 and the light chain variable region containing the amino acid sequence of SEQ ID NO:186; (l) The heavy chain variable region containing the amino acid sequence of SEQ ID NO:122 and the light chain variable region containing the amino acid sequence of SEQ ID NO:186; (m) The heavy chain variable region containing the amino acid sequence of SEQ ID NO:103 and the light chain variable region containing the amino acid sequence of SEQ ID NO:186. (n) The light chain variable region of the amino acid sequence of SEQ ID NO:24; and the heavy chain variable region of the amino acid sequence of SEQ ID NO:115 and the light chain variable region of the amino acid sequence of SEQ ID NO:24; (o) The heavy chain variable region of the amino acid sequence of SEQ ID NO:122 and the light chain variable region of the amino acid sequence of SEQ ID NO:48; and (p) The heavy chain variable region of the amino acid sequence of SEQ ID NO:37 and the light chain variable region of the amino acid sequence of SEQ ID NO:128.(q) A heavy chain variable region containing the amino acid sequence of SEQ ID NO:37 and a light chain variable region containing the amino acid sequence of SEQ ID NO:136; (r) A heavy chain variable region containing the amino acid sequence of SEQ ID NO:37 and a light chain variable region containing the amino acid sequence of SEQ ID NO:147; (s) A heavy chain variable region containing the amino acid sequence of SEQ ID NO:154 and a light chain variable region containing the amino acid sequence of SEQ ID NO:24; (t) A heavy chain variable region containing the amino acid sequence of SEQ ID NO:161 and a light chain variable region containing the amino acid sequence of SEQ ID NO:24; (u) A heavy chain variable region containing the amino acid sequence of SEQ ID NO:168 and a light chain variable region containing the amino acid sequence of SEQ ID NO:24; (v) A heavy chain variable region containing the amino acid sequence of SEQ ID NO:37 and a light chain variable region containing the amino acid sequence of SEQ ID NO:174; (w) A heavy chain variable region containing the amino acid sequence of SEQ ID NO:37 and a light chain variable region containing the amino acid sequence of SEQ ID NO:174. (x) The light chain variable region of the amino acid sequence NO:180; (y) The heavy chain variable region of the amino acid sequence SEQ ID NO:37 and the light chain variable region of the amino acid sequence SEQ ID NO:186; (y) The heavy chain variable region of the amino acid sequence SEQ ID NO:193 and the light chain variable region of the amino acid sequence SEQ ID NO:136; (z) The heavy chain variable region of the amino acid sequence SEQ ID NO:193 and the light chain variable region of the amino acid sequence SEQ ID NO:174; (aa) The heavy chain variable region of the amino acid sequence SEQ ID NO:13 and the light chain variable region of the amino acid sequence SEQ ID NO:24; (bb) The heavy chain variable region of the amino acid sequence SEQ ID NO:37 and the light chain variable region of the amino acid sequence SEQ ID NO:48; (cc) The heavy chain variable region of the amino acid sequence SEQ ID NO:374 and the light chain variable region of the amino acid sequence SEQ ID NO:244; (dd) The heavy chain variable region of the amino acid sequence SEQ ID NO:180; (x) The heavy chain variable region of the amino acid sequence SEQ ID NO:374 and the light chain variable region of the amino acid sequence SEQ ID NO:244; (y) The heavy chain variable region of the amino acid sequence SEQ ID NO:193 and the light chain variable region of the amino acid sequence SEQ ID NO:136; (z) The heavy chain variable region of the amino acid sequence SEQ ID NO:193 and the light chain variable region of the amino acid sequence SEQ ID NO:174; (aa) The heavy chain variable region of the amino acid sequence SEQ ID NO:13 and the light chain variable region of the amino acid sequence SEQ ID NO:244; (yb) The heavy chain variable region of the amino acid sequence SEQ ID NO:180 and the light chain variable region of the amino acid sequence SEQ ID NO:244; (yb) The heavy chain variable region of the amino acid sequence SEQ ID NO:180 The heavy chain variable region of the amino acid sequence NO:385 and the light chain variable region of the amino acid sequence containing SEQ ID NO:244; (ee) the heavy chain variable region of the amino acid sequence containing SEQ ID NO:233 and the light chain variable region of the amino acid sequence containing SEQ ID NO:244; (ff) the heavy chain variable region of the amino acid sequence containing SEQ ID NO:278 and the light chain variable region of the amino acid sequence containing SEQ ID NO:287;Or (gg) the heavy chain variable region containing the amino acid sequence of SEQ ID NO:300, and the light chain variable region containing the amino acid sequence of SEQ ID NO:306.

[0019] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 61 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 72; (b) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 85 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 96; (c) 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: 363; (d) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 392 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 344; (e) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 414 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 344; (f) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 316 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 327; (g) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 611 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 327; The heavy chain variable region of the amino acid sequence SEQ ID NO:333 and the light chain variable region of the amino acid sequence SEQ ID NO:344; or (h) the heavy chain variable region of the amino acid sequence SEQ ID NO:350 and the light chain variable region of the amino acid sequence SEQ ID NO:357.

[0020] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises: (a) 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:138; (b) 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:138; (c) 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:130; (d) 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:130; (e) 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:149; (f) 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:149; (g) 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:149. (h) 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:208 and a light chain containing the amino acid sequence of SEQ ID NO:176; (j) 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; (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:176. (o) 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:117 and a light chain containing the amino acid sequence of SEQ ID NO:26; (q) 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; and (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 containing the amino acid sequence of SEQ ID NO:39 and a light chain containing the amino acid sequence of SEQ ID NO:138; (s) A heavy chain containing the amino acid sequence of SEQ ID NO:141 and a light chain containing the amino acid sequence of SEQ ID NO:138; (t) 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:149; (u) A heavy chain containing the amino acid sequence of SEQ ID NO:156 and a light chain containing the amino acid sequence of SEQ ID NO:26; (v) A heavy chain containing the amino acid sequence of SEQ ID NO:159 and a light chain containing the amino acid sequence of SEQ ID NO:26; (w) A heavy chain containing the amino acid sequence of SEQ ID NO:163 and a light chain containing the amino acid sequence of SEQ ID NO:26; (x) A heavy chain containing the amino acid sequence of SEQ ID NO:170 and a light chain containing the amino acid sequence of SEQ ID NO:26; (y) A heavy chain containing the amino acid sequence of SEQ ID NO:170 and a light chain containing the amino acid sequence of SEQ ID NO:26; (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: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:176; (i) a heavy chain containing the amino acid sequence of SEQ ID NO:376 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:387 and a light chain containing the amino acid sequence of SEQ ID NO:246; (iii) 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; and (iv) 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 containing the amino acid sequence of SEQ ID NO:302, and a light chain containing the amino acid sequence of SEQ ID NO:308.

[0021] In some embodiments of the present invention, the antibody or antigen-binding fragment comprises: (a) a heavy chain containing the amino acid sequence of SEQ ID NO: 63 and a light chain containing the amino acid sequence of SEQ ID NO: 74; (b) a heavy chain containing the amino acid sequence of SEQ ID NO: 87 and a light chain containing the amino acid sequence of SEQ ID NO: 98; (c) 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: 365; (d) a heavy chain containing the amino acid sequence of SEQ ID NO: 394 and a light chain containing the amino acid sequence of SEQ ID NO: 346; (e) a heavy chain containing the amino acid sequence of SEQ ID NO: 416 and a light chain containing the amino acid sequence of SEQ ID NO: 346; (f) a heavy chain containing the amino acid sequence of SEQ ID NO: 318 and a light chain containing the amino acid sequence of SEQ ID NO: 329; (g) a heavy chain containing the amino acid sequence of SEQ ID NO: 335 and a light chain containing the amino acid sequence of SEQ ID NO: 74. The light chain containing the amino acid sequence NO:346; or (h) the heavy chain containing the amino acid sequence SEQ ID NO:352, and the light chain containing the amino acid sequence SEQ ID NO:359.

[0022] 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).

[0023] In some embodiments of the present invention, the antibody or antigen-binding fragment is monoclonal. In some embodiments of the present invention, the antibody or antigen-binding fragment is fully human. In some embodiments of the present invention, the antibody or antigen-binding fragment is an IgG antibody. In some embodiments of the present invention, the antibody or antigen-binding fragment is an IgG1 antibody. In some embodiments of the present invention, the antibody or antigen-binding fragment is an IgG1 antibody having a κ light chain. In some embodiments of the present invention, the antibody or antigen-binding fragment is a fully human IgG1 isotype antibody having a κ light chain.

[0024] In some embodiments of the invention, the antibody or antigen-binding fragment additionally has a mutation in the Fc region according to the Kabat EU index, wherein the mutation comprises at least D265A and P329A.

[0025] In some embodiments of the invention, the antibody or antigen-binding fragment additionally has a mutation in the Fc region according to the Cabart EU index, wherein the mutation comprises at least L234A and L235A.

[0026] In some embodiments of the present invention, the antibody or antigen-binding fragment is therapeutic.

[0027] 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 (e.g., XX16) defined herein. In some embodiments of the invention, the antibody or antigen-binding fragment competes with any antibody or antigen-binding fragment or group (e.g., XX16) defined herein for binding to human NPR1.

[0028] In one aspect of the invention, one or more isolated nucleic acids are provided that encode an amino acid sequence of any antibody or antigen-binding fragment or group as defined herein. In another aspect of the invention, a vector comprising said one or more isolated nucleic acids is provided. In yet another aspect of the invention, a host cell comprising said one or more isolated nucleic acids or a vector is provided.

[0029] In one aspect of the invention, methods for generating any of the antibodies or antigen-binding fragments described herein are provided, the methods comprising culturing the host cells described herein under conditions suitable for generating the antibody or antigen-binding fragment. In some embodiments of the invention, the methods further include purifying the antibody or antigen-binding fragment.

[0030] In one aspect of the invention, pharmaceutical compositions comprising a purified antibody or antigen-binding fragment produced by the methods described herein and a pharmaceutically acceptable carrier are provided herein.

[0031] In one aspect of the invention, pharmaceutical compositions comprising any antibody or antigen-binding fragment described herein and a pharmaceutically acceptable carrier are provided herein.

[0032] In one aspect of the invention, a pharmaceutical composition is provided comprising: a) an apparatus for binding to and activating natriuretic peptide receptor 1 (NPR1) in the absence of ANP; and b) a pharmaceutically acceptable excipient. In some embodiments of the invention, the apparatus for binding and activation is ANP-noncompetitive. In some embodiments of the invention, the apparatus for binding and activation is ANP-competitive. In some embodiments of the invention, the apparatus for binding and activation is additionally capable of stabilizing the ANP-NPR1 complex. In some embodiments of the invention, the composition further comprises an additional therapeutic agent.

[0033] In some embodiments of the present invention, additional therapeutic agents are selected from ACE (angiotensin-converting enzyme) inhibitors, angiotensin receptor blockers (ARBs), neprilysin inhibitors, beta-blockers, diuretics, calcium channel blockers, cardiac glycosides, sodium-glucose cotransporter 2 inhibitors (SGLT2i), and combinations thereof. In some embodiments of the present invention, the additional therapeutic agent is selected from enalapril, benazepril, captopril, fosinopril, lisinopril, moxipril, perindopril, quinapril, ramipril, quindopril, valsartan, azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, sacubitril, bisoprolol, carvedilol, propranolol, metoprolol, metoprolol tartrate, metoprolol succinate, thiazide diuretics, cyclic diuretics, potassium-sparing diuretics, amlodipine, clovididipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil, digitoxin, canagliflozin, dapagliflozin, epagliptin, eleggliflozin, and combinations thereof. In some embodiments of the present invention, additional therapeutic agents are selected from chlorothiazide, chlorothiazide, hydrochlorothiazide, indapamide, metoprazone, bumetanide, ethacrynic acid, furosemide, torasemide, amiloride, eplerenone, spironolactone, triamterene, digoxin, and combinations thereof. In some embodiments of the present invention, additional therapeutic agents are angiotensin receptor-neprilysin inhibitors (ARNi).

[0034] In some embodiments of the present invention, additional therapeutic agents are selected from corticosteroids, leukotriene modifiers, bronchodilators, and combinations thereof. In some embodiments of the present invention, additional therapeutic agents are selected from fluticasone, budesonide, mometasone, beclomethasone, cicosonelide, fluticasone furoate, prednisone, methylprednisolone, montelukast, zafirlukast, zilulone, long-acting β-agonists, short-acting β-agonists, theophylline, and ipratropium, and combinations thereof. In some embodiments of the present invention, additional therapeutic agents are selected from salmeterol, formoterol, salbutamol, and levosalbutamol, and combinations thereof.

[0035] In some embodiments of the present invention, additional therapeutic agents are selected from β-adrenergic receptor antagonists, carbonic anhydrase inhibitors, α2-adrenergic receptor agonists, parasympathomimetic drugs, prostaglandin analogs, rho kinase inhibitors, and combinations thereof. In some embodiments of the present invention, additional therapeutic agents are selected from timolol, levobronol, metemolol, cartemolol, betalolol, acetazolamide, dazolamide, brinzolamide, acetazolamide, brimonidine, araclonidine, cholinergic drugs, latanoprost, latanoprostene bunod, travoprost, bimatoprost, tafluprost, netarsudil, and ripasudil, and combinations thereof.

[0036] In one aspect of the invention, this document provides a method for treating a disorder or disease associated with natriuretic peptide receptor activity in a subject in need, 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.

[0037] In one aspect of the invention, a method for treating cardiovascular disorders in a subject in need is provided herein, the method comprising administering to the subject a therapeutically effective amount of any of the antibodies described herein or antigen-binding fragments thereof, or any of the pharmaceutical compositions or combinations described herein.

[0038] In some embodiments of the present invention, the cardiovascular disorder is selected from: 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, arrhythmia, atrial fibrillation (AF), new-onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, harmful vascular remodeling, plaque stabilization, and myocardial infarction (MI).

[0039] In one aspect of the invention, this document provides a method for treating heart failure, hypertrophic cardiomyopathy (HCM), hypertension, preeclampsia, asthma, glaucoma, and / or cytokine release syndrome in a subject in need, the method comprising administering to the subject a therapeutically effective amount of any of the antibodies described herein or antigen-binding fragments thereof, or any of the pharmaceutical compositions or combinations described herein.

[0040] 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 artery hypertension, isolated systolic hypertension, refractory hypertension, and pulmonary artery 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.

[0041] In one aspect of the invention, a method for treating renal impairment in a subject in need is provided, the method comprising administering to the subject a therapeutically effective amount of any of the antibodies or antigen-binding fragments described herein, or any of the pharmaceutical compositions or combinations described herein. In some embodiments of the invention, the renal impairment is selected from: diabetic nephropathy, non-diabetic nephropathy, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast-induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, primary nephrotic proteinuria, renovascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis, and polycystic kidney disease (PKD).

[0042] In one aspect of the invention, this document provides 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 related to natriuretic peptide receptor activity in a subject in need of such treatment.

[0043] In one aspect of the invention, this document provides 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 the treatment of cardiovascular disorders in a subject requiring such treatment.

[0044] In some embodiments of the present invention, the cardiovascular disorder is selected from: 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, arrhythmia, atrial fibrillation (AF), new-onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, harmful vascular remodeling, plaque stabilization, and myocardial infarction (MI).

[0045] In one aspect of the invention, this document provides 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 the treatment of heart failure, hypertrophic cardiomyopathy (HCM), hypertension, preeclampsia, asthma, glaucoma, and / or cytokine release syndrome in subjects requiring such treatment.

[0046] 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 artery hypertension, isolated systolic hypertension, refractory hypertension, and pulmonary artery 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.

[0047] In one aspect of the invention, this document provides 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 renal disorders in subjects requiring 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, renovascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis, and polycystic kidney disease (PKD).

[0048] In one aspect of the invention, this document provides any of the antibodies or antigen-binding fragments thereof described herein, or any of the pharmaceutical compositions or combinations described herein, for treating disorders or diseases related to natriuretic peptide receptor activity in subjects requiring such treatment.

[0049] In one aspect of the invention, this document provides any of the antibodies or antigen-binding fragments thereof described herein, or any of the pharmaceutical compositions or combinations described herein, for treating cardiovascular disorders in subjects requiring such treatment.

[0050] In some embodiments of the present invention, the cardiovascular disorder is selected from: 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, arrhythmia, atrial fibrillation (AF), new-onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, harmful vascular remodeling, plaque stabilization, and myocardial infarction (MI).

[0051] In one aspect of the invention, this document provides any of the antibodies or antigen-binding fragments thereof described herein, or any of the pharmaceutical compositions or combinations described herein, for the treatment of heart failure, hypertrophic cardiomyopathy (HCM), hypertension, preeclampsia, asthma, glaucoma, and / or cytokine release syndrome in subjects requiring such treatment.

[0052] 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 artery hypertension, isolated systolic hypertension, refractory hypertension, and pulmonary artery 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.

[0053] In one aspect of the invention, this document provides any of the antibodies or antigen-binding fragments thereof described herein, or any of the pharmaceutical compositions or combinations described herein, for treating renal disorders in subjects requiring such treatment. In some embodiments of the invention, the renal disorder is selected from: diabetic nephropathy, non-diabetic nephropathy, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast-induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, primary nephrotic proteinuria, renovascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis, and polycystic kidney disease (PKD).

[0054] In one aspect of the invention, this document provides a method for treating a disorder or disease related to natriuretic peptide receptor activity in a subject of need, the method comprising administering a pharmaceutical composition comprising: a device for binding to and activating natriuretic peptide receptor 1 (NPR1) in the absence of ANP; and a pharmaceutically acceptable excipient.

[0055] In one aspect of the invention, this document provides a method for treating cardiovascular disorders in a subject of need, the method comprising administering a pharmaceutical composition comprising: a device for binding to and activating natriuretic peptide receptor 1 (NPR1) in the absence of ANP; and a pharmaceutically acceptable excipient. In some embodiments of the invention, the cardiovascular disorder is selected from: 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, harmful vascular remodeling, plaque stabilization, and myocardial infarction (MI).

[0056] In one aspect of the invention, this document provides a method for treating heart failure, hypertrophic cardiomyopathy (HCM), hypertension, preeclampsia, asthma, glaucoma, and / or cytokine release syndrome in a subject of need, the method comprising administering a pharmaceutical composition comprising: a device for binding to and activating natriuretic peptide receptor 1 (NPR1) in the absence of ANP; and a pharmaceutically acceptable excipient. In some embodiments of the 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 invention, the subject suffers from hypertrophic cardiomyopathy, wherein the hypertrophic cardiomyopathy is ventricular hypertrophy. In some embodiments of the invention, the subject suffers from hypertension, wherein the hypertension is selected from refractory hypertension, hypertensive heart disease, pulmonary hypertension, pulmonary artery hypertension, isolated systolic hypertension, refractory hypertension, and pulmonary artery hypertension. In some embodiments of the invention, the subject suffers from hypertension, wherein the hypertension is selected from refractory hypertension or hypertensive heart disease.

[0057] In one aspect of the invention, a method for treating renal disorders in a subject in need is provided, the method comprising administering a pharmaceutical composition comprising: a device for binding to and activating natriuretic peptide receptor 1 (NPR1) in the absence of ANP; and a pharmaceutically acceptable excipient. In some embodiments of the invention, the renal disorder is selected from: diabetic nephropathy, non-diabetic nephropathy, renal failure, diabetic nephropathy, non-diabetic nephropathy, acute kidney injury, contrast-induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, primary nephrotic proteinuria, renovascular 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 invention, the device for binding and activation is ANP-noncompetitive. In some embodiments of the invention, the device for binding and activation is ANP-competitive. In some embodiments of the invention, the device for binding and activation is additionally capable of stabilizing the ANP-NPR1 complex. Attached Figure Description

[0058] Figure 1 This is a set of graphs (ELISA analysis) showing the results of antibody candidates WW01, WW02, WW03, WW04, and WW06 binding to the following antigens in the absence and presence of 250-fold molar excess of ANP: human NPR1, constitutively active human NPR1 mutant (W74R), rat NPR1, and human NPR3 (reverse target).

[0059] Figure 2 This is a set of figures showing the flow cytometry analysis results of antibody candidates WW01, WW02, WW03, WW04, and WW06 on CHO-K1 cells expressing human NPR1 in the absence and presence of saturated concentrations of ANP, and on parental CHO-K1 cells.

[0060] Figure 3 This is a diagram illustrating a fluorescence resonance energy transfer (FRET)-based assay, in which an NPR1-specific antibody competes with an ANP for binding to NPR1. In this FRET-based assay, either Eu-labeled streptavidin (for measuring IgG) or Eu-labeled anti-hFc antibody (for measuring FabCys) is used as the energy donor, while Cy5-labeled ANP serves as the acceptor.

[0061] Figure 4 It is a set of diagrams showing the use of Figure 3 The results shown are from the ANP competition analysis of candidates WW01, WW02, WW03, WW04 and WW06 based on FRET measurements.

[0062] Figure 5 This is a set of figures depicting the functional activity analysis results of candidates WW01, WW02, WW03, WW04, and WW06 in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. The results represent cellular cGMP[nM] production in the absence of or in the presence of 0.075 nMANP.

[0063] Figure 6 This is a set of figures depicting the results of functional activity analysis of the candidate WW06 in IgG or FabCys form during a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. The results represent cellular cGMP [nM] production in the absence or presence of 0.075 nM ANP.

[0064] Figure 7 The 82 studies showing unique improvements based on parental antibodies HCDR2 or LCDR3 were highlighted. Results of SET screening (hNPR1 affinity) of derivatives.

[0065] Figure 8 The 82 studies showing unique improvements based on parental antibodies HCDR2 or LCDR3 were highlighted. Results of SET screening of derivatives (hNPR1-ANP complex affinity).

[0066] Figure 9 This is a set of graphs (ELISA analysis) showing the results of antibody candidates XX01-XX08, XX10 and XX12 binding to the following antigens in the absence or in the presence of 250-fold molar excess of ANP: human NPR1, constitutively active human NPR1 mutant (W74R), rat NPR1 and human NPR3 (reverse target).

[0067] Figure 10 This is a set of figures showing the flow cytometry analysis results of antibody candidates XX01-XX08, XX10, and XX12 for binding to CHO-K1 cells expressing human NPR1 in the absence or presence of saturated concentrations of ANP and for binding to parental CHO-K1 cells.

[0068] Figure 11 It is a set of diagrams showing the use of Figure 3 The results shown are from an ANP competition analysis of candidates XX01-XX07, XX10, and XX12 based on FRET measurements.

[0069] Figure 12 This is a set of figures depicting the functional activity analysis results of candidates XX01-XX08, XX10, and XX12 in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. The results represent cellular cGMP[nM] production in the absence or presence of 0.075 nM ANP.

[0070] Figure 13This is a set of figures 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. The results represent cellular cGMP[nM] production in the absence or presence of 0.075 nMANP.

[0071] Figure 14 The figure below illustrates the functional activity analysis results of candidate XX16 and the natural ligand ANP in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. The results represent cellular cGMP[nM] production as a function of ANP or XX16.

[0072] Figure 15 This is a diagram illustrating the crystal structure of Fab06 (the Fab form of the WW06 antibody) complexed with the extracellular domain of hNPR1.

[0073] Figure 16 This is a diagram illustrating the conformation of the hNPR1 extracellular domain, as it appears when complexed with Fab06. Fab06 has been removed from this diagram to more clearly reveal the hNPR1 conformation induced by Fab binding. W74R is indicated by space filling.

[0074] Figure 17 The images show the crystal structure of the hNPR1 extracellular domain complexed with ANP (left) and the crystal structure of Fab16 (an XX16 antibody in Fab form) complexed with the hNPR1 extracellular domain (right), where W74 is indicated by space filling.

[0075] Figure 18 This is a set of figures depicting the functional activity analysis results of candidate WW06 in a cellular cGMP production assay when tested on CHO-K1 cells expressing hNPR1 W74R / C232T (constitutive active mutant; Figure A) compared to WT hNPR1 (Figure B).

[0076] Figure 19 This is a set of graphs (ELISA analysis) showing the results of antibody candidates YY01-YY07 binding to the following antigens in the absence or presence of 250-fold molar excess of ANP: human NPR1, constitutively active human NPR1 mutant (W74R), rat NPR1, and human NPR3 (reverse target).

[0077] Figure 20 This is a set of figures showing the flow cytometry analysis results of antibody candidates YY01-YY07 for binding to CHO-K1 cells expressing human NPR1 in the absence or presence of saturated concentrations of ANP and for binding to parental CHO K1 cells.

[0078] Figure 21 It is a set of diagrams showing the use of Figure 3 The results shown are from the FRET-based assays performed on candidates YY01-YY07 using ANP competition analysis.

[0079] Figure 22 This is a set of figures illustrating the functional activity analysis results of candidates YY01-YY07 in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. The results represent cellular cGMP [nM] production in the absence or presence of 0.075 nM ANP.

[0080] Figure 23 This is a set of figures depicting the results of functional activity analysis of candidates YY05 and YY07 in the form of IgG or FabCys in a cellular cGMP production assay using CHO-K1 cells expressing human NPR1. The results represent cellular cGMP[nM] production in the absence or presence of 0.075 nM ANP.

[0081] Figure 24 The study showed unique improvements in 112 cases based on parental antibody HCDR1 / 2 or LCDR3. Results of SET screening (hNPR1 affinity) of derivatives.

[0082] Figure 25 The study showed unique improvements in 112 cases based on parental antibody HCDR1 / 2 or LCDR3. Results of SET screening of derivatives (hNPR1-ANP complex affinity).

[0083] Figure 26 This is a set of graphs showing the change in plasma cGMP (nM) concentration over time in hNPR1 Tg mice that were intravenously injected with 1 mg / kg, 3 mg / kg or 10 mg / kg of WW06 Fab.

[0084] Figure 27 The figure below shows the change in antibody concentration over time in hNPR1 Tg mice, which were injected intravenously with 1 mg / kg, 3 mg / kg or 10 mg / kg of WW06 Fab.

[0085] Figure 28 This is a set of figures showing the results of subcutaneous administration of the mediator, 0.3 mg / kg XX16 or 3 mg / kg XX16, every two weeks in wild-type or ANP knockout (ANP KO) mice, regarding heart weight / body weight ratio (left) and plasma NT-proBNP levels (pg / mL; right). Measurements were taken two weeks after the second administration.

[0086] Figure 29 This is a set of figures showing the results of a single intravenous administration of the mediator, 0.3 mg / kg XX16 or 1 mg / kg XX16, to hypertensive rats (stroke-prone spontaneously hypertensive rats, SHRsp), regarding blood pressure (mean arterial pressure; left) and urine flow rate (right). Measurements were taken three hours after intravenous administration.

[0087] Figure 30 This is a set of figures showing the results of changes in mean arterial pressure (MAP; top) and plasma cGMP (bottom) over time after a single subcutaneous administration of 0.1, 0.3, 1, 3, 10, or 30 mg / kg XX16 in normal rats with telemetry implantation.

[0088] Figure 31 This is a set of figures depicting the functional activity analysis results of candidate WW03 and the contrast 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. The results represent cellular cGMP [nM] production in the absence or presence of 0.075 nM ANP (human or rat).

[0089] General definition

[0090] To facilitate understanding of this disclosure, certain terms are first defined. Further definitions are provided throughout the specific implementation as needed.

[0091] Throughout this specification and claims, the words “comprise” and “containing” and their variations, such as “comprising” and “comprises”, mean “including, but not limited to” and do not exclude other components, integers, or steps. Furthermore, the singular includes the plural unless the context requires otherwise: in particular, where the indefinite article is used, the specification should be understood to cover both the plural and the singular unless the context requires otherwise.

[0092] As used herein, “NPR1” and “NPR1 protein” refer to natriuretic peptide receptor 1. This protein is also known as 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 (house mouse) 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 (brown rat) NPR1. In some embodiments, rat NPR1 has NCBI reference sequence number NP_036745.1 (SEQ ID NO:3). Exemplary NPR1 proteins are shown in Table 1. In the context of this discussion of constitutive activity or the W74R mutant, the mutant refers to the Trp at amino acid position 74 of the mature human NPR1 protein, or the Trp at amino acid position 106 of the hNPR1 protein shown in SEQ ID NO:1.

[0093] Table 1. NPR1 protein sequence

[0094]

[0095]

[0096] In various embodiments, the anti-NPR1 antibody and antigen-binding fragment disclosed herein are capable of binding to and activating NPR1 in the absence of ANP. With this activity, the disclosed anti-NPR1 antibody and antigen-binding fragment 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 pectoris, hypertrophic cardiomyopathy (e.g., ventricular hypertrophy), diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, arrhythmias, atrial fibrillation (AF), new-onset atrial fibrillation, recurrent atrial fibrillation, cardiac fibrosis, atrial flutter, and harmful vascular remodeling). Plaque stability or myocardial infarction (MI), hypertension (refractory hypertension, hypertensive heart disease, pulmonary hypertension, pulmonary artery hypertension, isolated systolic hypertension, refractory hypertension or pulmonary artery hypertension), preeclampsia, asthma, glaucoma, cytokine release syndrome and / or renal disorders (e.g., diabetic nephropathy, nondiabetic nephropathy, renal failure, diabetic nephropathy, nondiabetic nephropathy, acute kidney injury, contrast-induced nephropathy, nephrotic syndrome, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria in primary nephrotic syndrome, renovascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, renal fibrosis and polycystic kidney disease (PKD)).

[0097] As used herein, the term "antibody" refers to a whole antibody or its antigen-binding fragment. A whole antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains linked together by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region consists of three domains: CH1, CH2, and CH3. Each light chain consists of a light chain variable region (VL) and a light chain constant region. The light chain constant region consists of one domain, 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 the antigen. The constant region of an antibody can mediate the binding of immunoglobulins 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, camelized antibodies, and chimeric antibodies. Antibodies can belong to any isotype / class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2).

[0098] 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 complete antibody function. Such fragments include Fab fragments, Fab′ fragments, which are monovalent fragments composed of VL, VH, CL, and CH1 domains; F(ab′)2 fragments, which are bivalent fragments containing two Fab fragments connected by a disulfide bridge in 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 either a VH domain or a VL domain (Ward et al., 1989 Nature 341:544-546).

[0099] The terms "single-chain antibody," "single-chain Fv," or "scFv" refer to a molecule containing a variable domain (or region; VH) of the antibody heavy chain and a variable domain (or region; VL) of the antibody light chain linked by a linker. Such scFv molecules can have a generic structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Any suitable linker can be used. A set of non-restricted linkers that can be used in such single-chain antibodies are described in the following references: Holliger et al. (1993), Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences] 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; the contents of which are hereby incorporated herein by reference. The term “antigen-binding fragment” for antibody is also intended to cover such single-chain antibodies. These antibody fragments were obtained using techniques known to those skilled in the art, and were screened for utility in the same manner as intact antibodies. There are no limitations; antigen-binding fragments can be generated by any suitable method known in the art. For example, the various antigen-binding fragments described herein can be generated by enzymatic or chemical modification of intact antibodies, de novo synthesis using recombinant DNA methods (e.g., single-stranded Fv), or identification using phage display libraries (see, for example, 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). The utility (e.g., binding affinity, activity) of the antigen-binding fragments is screened in the same manner as for intact antibodies.

[0100] Antigen-binding fragments can also be incorporated into single-domain antibodies, macrobodies, minibodies, intracellular antibodies, bisomal antibodies, tripoisome antibodies, tetrasomal antibodies, v-NARs, and bis-scFvs (see, for example, Hollinger and Hudson, 2005, Nature Biotechnology, 23, 9, 1126-1136, the contents of which are hereby incorporated by reference). The antigen-binding portion of an antibody can be grafted into a scaffold based on peptides such as type III fibronectin (Fn3) (see, for example, U.S. Patent No. 6,703,199, which describes a fibronectin peptide monomer, the contents of which are hereby incorporated by reference).

[0101] Antigen-binding fragments can be incorporated into single-chain molecules containing a pair of tandem Fv segments (VH-CH1-VH-CH1), which together with complementary light chain polypeptides form a pair of antigen-binding regions (see Zapata et al., 1995 Protein Eng. 8(10):1057-1062; and U.S. Patent No. 5,641,870; the contents of which are hereby incorporated herein by reference).

[0102] Throughout the specification, the term "isolated" means that the immunoglobulin, antibody, or polynucleotide (as the case may be) exists in a physical environment different from its natural environment. For example, instead of isolating naturally occurring polynucleotides or polypeptides present in a living organism, the same polynucleotides or polypeptides isolated from some or all of the coexisting material in a living organism are isolated.

[0103] As used herein, the term "isolated antibody" refers to an antibody that has been identified and separated (by weight) from one or more (e.g., most) components in its environment of origin, such as components from hybridoma cell cultures or different cell cultures used for their production (e.g., production cells, including but not limited to exemplary host cells expressing recombinant antibodies as described herein). Separation is performed such that it sufficiently removes components that might otherwise interfere with the suitability of the antibody for the desired application (e.g., therapeutic use against 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.

[0104] Throughout this specification, complementarity-determining regions (“CDRs”) are defined according to the Kabat definition unless otherwise specified. The precise amino acid sequence boundaries of a given CDR can be determined using any of many well-known schemes, including those described below: 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 which are hereby incorporated herein by reference. For example, for the classical form, according to the Kabart scheme, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1) and 50-56 (LCDR2). And 89-97 (LCDR3). According to Josiah, the CDR amino acids in VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of both Cabat and Josiah, the CDR consists 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 "Carbat" numbering). Under IMGT, the CDR regions of the antibody can be determined using the IMGT / DomainGap Align procedure.

[0105] By convention, the CDR regions in the heavy chain are usually referred to as HCDR1, HCDR2, and HCDR3, while the CDR regions in the light chain are usually referred to as LCDR1, LCDR2, and LCDR3. They are numbered sequentially from the amino terminus to the carboxyl terminus.

[0106] As used herein, the term "antibody framework" refers to a portion of a variable domain, namely VL or VH, which acts as a scaffold for the antigen-binding loop (CDR) of that variable domain. Essentially, it is a variable domain without a CDR.

[0107] The term "constant region" or "constant domain" refers to the carboxyl-terminal portion of the light and heavy chains, which does not directly participate in antibody-antigen binding but exhibits various effector functions, such as interaction with Fc receptors. The term also refers to a portion of an immunoglobulin molecule, namely the variable domain, which has a more conserved amino acid sequence and contains antigen-binding sites, in contrast to another portion of the immunoglobulin molecule. The constant domain comprises the CH1, CH2, and CH3 domains of the heavy chain and the CHL domain of the light chain.

[0108] The term “epitope” or “antigenic determinant” refers to a site on an antigen where an immunoglobulin or antibody specifically binds (e.g., a specific site on a target molecule). Epitopes typically comprise 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, for example, Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, edited by GEMorris (1996), the contents of which are hereby incorporated by reference. Additionally, as used herein, an epitope may comprise one or more monosaccharide units of a polysaccharide that binds specifically to an antibody. In certain respects, an epitope may be a conformational epitope. See, for example, Thompson et al., 2009, J. of Biol. Chem. 51:35621-35631, the contents of which are hereby incorporated by reference.

[0109] As used herein, the term “monoclonal antibody” or “monoclonal antibody composition” refers to an antibody obtained from a substantially homogeneous population of antibodies produced by a particular cell or cell line, wherein the individual antibodies in the population are substantially identical in sequence, except for possible small amounts of naturally occurring mutations. Monoclonal antibody formulations exhibit single binding specificity and affinity for a specific epitope. In contrast, conventional (polyclonal) antibody formulations typically comprise multiple antibodies targeting or specific to different epitopes. The modifier “monoclonal” indicates the characteristic of an antibody obtained from a substantially homogeneous population of antibodies and should not be construed as requiring the antibody to be produced 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 1975; 256(5517):495-7, the contents of which are hereby incorporated herein by reference). Monoclonal antibodies can also be obtained by other suitable methods, including phage display techniques, such as those described in the following literature: Clackson et al. (Nature 1991; 352(6336):624-8) or Marks et al. (J Mol Biol 1991; 222(3):581-97), the contents of which are hereby incorporated herein by reference. The term “monoclonal antibody” is not limited to antibody sequences from a specific source species or from a single source species. Therefore, the meaning of the term “monoclonal antibody” encompasses chimeric monoclonal antibodies, such as humanized monoclonal antibodies.

[0110] As used herein, the term "chimeric antibody" refers to an antibody in which (a) a constant region is altered, replaced, or exchanged such that the antigen-binding site (variable region) is linked to a constant region of a different or altered class, effector function, and / or species; or (b) a variable region or a portion thereof is altered, replaced, or exchanged with a variable region or a portion thereof that has a different or altered antigen specificity. To generate 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, for example, U.S. Patent No. 4,816,567 (Cabilly et al.), the contents of which are hereby incorporated by reference). For example, a mouse anti-NPR1 antibody can be modified by replacing its constant region with a constant region derived from a human immunoglobulin. Due to the replacement with a human constant region, the chimeric antibody can retain its specificity for recognizing human NPR1 while exhibiting reduced immunogenicity in humans compared to the original mouse antibody.

[0111] 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 conferring specificity for binding to a target antigen and a small subset of non-human sequences. Such antibodies are chimeric antibodies, containing minimal sequences derived from non-human immunoglobulins and retaining the reactivity of non-human antibodies while exhibiting lower immunogenicity in humans. Typically, humanized antibodies are generated 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 frame region sequence of the receptor antibody may also be replaced with a corresponding sequence of the donor antibody (e.g., via affinity maturation). In addition to sequences derived from donor and receptor antibodies, humanized antibodies can also be modified by residue substitution within the frame region and / or substituted non-human residues to improve and optimize antibody specificity, affinity, and / or activity as described herein. Methods for generating humanized antibodies are known in the art. See, for example, Riechmann et al. (Nature 1988; 332(6162):323-7); Jones et al. (Nature 1986; 321(6069):522-5); U.S. Patent No. 5,225,539 (Winter); and U.S. Patent Nos. 5,530,101, 5,585,089, 5,693,762 and 6,180,370 (Queen et al.), the contents of which are hereby incorporated herein by reference.

[0112] As used herein, the term "human antibody" is intended to include antibodies having variable regions, wherein both the frame region and the CDR region are derived from human-derived sequences. Furthermore, if an 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 common frame sequences derived from human frame 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. Human antibodies 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 mutations in vivo).

[0113] The antibody or antigen-binding fragments disclosed herein may include amino acid residues not encoded by human sequences (e.g., mutations introduced in vitro by random or site-specific mutagenesis or in vivo by somatic mutations). However, as used herein, the term "human antibody" is not intended to include antibodies in which a CDR sequence derived from another mammalian species (e.g., mouse) lineage has been transplanted into a human frame sequence.

[0114] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein to refer to polymers of amino acid residues. The terminology encompasses amino acid polymers, where one or more amino acid residues are artificial chemical mimics of the corresponding naturally occurring amino acids, as well as both naturally occurring and non-naturally occurring amino acid polymers. Unless otherwise indicated, a particular polypeptide sequence also implicitly encompasses its conserved variants.

[0115] The term "conserved variant" applies to both amino acid and nucleic acid sequences. For nucleic acid sequences, a conserved variant refers to those nucleic acids that encode the same or substantially the same amino acid sequence, or, if the nucleic acid does not encode an amino acid sequence, 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 designated by the codon for alanine, the codon can be changed to any of the corresponding codons without changing the encoded polypeptide. Such nucleic acid variations are "silent variants," which are a type of conserved variant. Each nucleic acid sequence encoding a polypeptide is also described herein with each possible silent variant of the nucleic acid. Those skilled in the art will recognize that each codon in a nucleic acid (except for 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 variant of the nucleic acid encoding a polypeptide is implicit in each of the sequences described. For polypeptide sequences, "conserved variants" include single substitutions, deletions, or additions to the polypeptide sequence, resulting in the substitution of a particular amino acid for a chemically similar amino acid. Conservative substitutions that provide functionally similar amino acids are well known in the art. The following eight groups contain amino acids that are conservedly substituted for each other:

[0116] 1) Alanine (A), glycine (G);

[0117] 2) Aspartic acid (D), glutamic acid (E);

[0118] 3) Asparagine (N), glutamine (Q);

[0119] 4) Arginine (R), Lysine (K);

[0120] 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);

[0121] 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W);

[0122] 7) Serine (S), threonine (T); and

[0123] 8) Cysteine ​​(C), Methionine (M).

[0124] The term "identity" or "homology" refers to the relationship between the sequences of two or more polypeptides determined by sequence comparison. "Identity" also refers to the degree of sequence relevance between polypeptides, determined by the number of matches between strings of two or more amino acid residues. The percentage of identity between two sequences is a function of the number of shared positions (i.e., percentage of identity equals number of shared 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 for optimal alignment of the two sequences. Sequence comparison and percentage identity determination between two sequences can be accomplished using mathematical algorithms. For sequence comparison, typically one sequence serves as a reference sequence, and the test sequence is compared to said reference sequence. When using a sequence comparison algorithm, the test sequence and reference sequence are input into a computer, specifying subsequence coordinates if necessary, and specifying sequence algorithm program parameters. Default program parameters can be used, or alternative parameters can be specified. The sequence comparison algorithm then calculates the percentage of sequence identity of the test sequence relative to the reference sequence based on the program parameters. Alternatively or additionally, the protein sequences disclosed herein can be further used as "query sequences" for searching in public databases to, for example, identify related sequences. For example, such searches can be performed using the BLAST program by Altschul et al. (J Mol Biol [Journal of Molecular Biology] 1990; 215(3):403-10, the contents of which are hereby incorporated by reference).

[0125] When comparing and aligning within a comparison window or designated region to obtain maximum correspondence using one of the following sequence comparison algorithms or by manual alignment and visual inspection, two sequences are considered "substantially identical" if they have a specified percentage of identical amino acid residues or nucleotides (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identity in a specified region or throughout the entire sequence if not specified). Optionally, the identity is present in a region of at least about 50 nucleotides (or 10 amino acids) or in a region of 100 to 500 or 1000 or more nucleotides (or 20, 50, 200 or more amino acids).

[0126] Binding affinity refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable region of the antibody "arm" interacts with the antigen at numerous sites via weak non-covalent forces. Generally, the more interactions, the stronger the affinity. This type of determination is typically performed using cell-based assays.

[0127] As used herein, the term "Kassoc" or "Ka" is intended to refer to the association rate of a specific binding molecule-antigen interaction, while the term "Kdis" or "Kd" is intended to refer to the dissociation rate of a specific binding molecule-antigen interaction. As used herein, the term "K" is... D "The term refers 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 Value. Determine the K value of the antibody. D The method is to use surface plasmon resonance (such as...) The titration was performed by 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 which are hereby incorporated herein by reference).

[0128] As used herein, the terms “specific,” “specifically binds,” and “binds specifically” refer to the binding reaction between an antibody or antigen-binding fragment (e.g., an 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 mixture of antigens under a given set of conditions. An antibody is considered specific if it binds to an appropriate antigen with an affinity at least 2, 5, 7, preferably 10 or more times higher than that of the unrelated antigen or mixture of antigens. A “specific antibody” or “target-specific antibody” is an antibody that binds only to the target antigen (e.g., NPR1) but not to other antigens (or exhibits minimal binding to them). In some embodiments, the Kx of an antibody or antigen-binding fragment that specifically binds to the target antigen (e.g., NPR1) is... D Less than 1x10 -6 M, less than 1x10 -7 M, less than 1x10 -8 M, less than 1x10 -9 M, less than 1x10 -10 M, less than 1x10 -11 M, less than 1x10 -12 M or less than 1x10 -13 M. In some embodiments, K D The range is from approximately 1 pM to approximately 600 pM. In some embodiments, K DBetween 600 pM and 1 μM, 1 μM and 100 nM, or 100 mM and 10 nM (inclusive).

[0129] In some embodiments, the antibody or its antigen-binding fragment acts as a non-competitive agonist. A “non-competitive agonist” is a molecule that binds to an enzyme or receptor at a site distant 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 activation levels that are substantially independent of the natural ligand. In one 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 at a site distant from the ANP binding site of NPR1 and influences agonistic activity regardless of whether NPR1 binds to an ANP.

[0130] In some embodiments, the antibody or its antigen-binding fragment acts as a competitive agonist. A “competitive agonist” is an agonist that interferes with or competes with a natural ligand for its binding site on an enzyme or receptor. In one 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 an ANP for the ANP binding site on NPR1.

[0131] In some embodiments, activation of NPR1 by an antibody or antigen-binding fragment can be determined by any suitable assay. An exemplary assay for determining NPR1 activation is the generation of cGMP by mammalian cells expressing hNPR1 (e.g., CHO cells or human cell lines).

[0132] 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 the FRET assay described herein (see, for example...). Figure 3 ).

[0133] The term "about" for a numerical value x means, for example, x ± 10%.

[0134] The antibodies disclosed

[0135] The following discloses certain specific anti-NPR1 antibody sequences. As used herein, the terms "anti-NPR1 antibody" or "antibody that binds to NPR1" refer to any form of antibody or antigen-binding fragment that specifically binds to NPR1, for example, in a fraction less than 1 x 102. -8 M of K D Those combined, such as those determined by surface plasmon resonance (SPR) spectroscopy (using Biacore) TMThe determination is made by solution equilibrium titration (SET). The terminology includes monoclonal antibodies (including complete monoclonal antibodies), polyclonal antibodies, and antigen-binding fragments with biological function, provided they specifically bind to NPR1.

[0136] Table 2 lists the amino acid and nucleic acid sequences of exemplary anti-NPR1 antibodies disclosed herein. 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 NPR1 and / or provide complete antibody function (e.g., to activate NPR1 in the absence of ANP). In some embodiments, the anti-NPR1 antibody is an antibody having a CDR having any heavy chain variable region and light chain variable region pair shown in Table 2. In some embodiments, the anti-NPR1 antibody is an antibody having a CDR having any heavy chain and light chain pair shown in Table 2.

[0137] Table 2. Exemplary anti-NPR1 antibody sequences

[0138]

[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] For example, WW01_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:19 (LCDR ... 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). In some embodiments, WW01_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:13, and the light chain variable region contains or has 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.

[0224] For example, WW03_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 ...2), SEQ ID NO:33 (HCDR3), SEQ ID NO:30 (HCDR2), SEQ ID NO:41 (HCDR2), SEQ ID NO:33 (HCDR3), SEQ ID NO:30 (HCDR2), 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). In some embodiments, WW03_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:37, and the light chain variable region contains or has 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.

[0225] For example, WW05_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:67 (LCDR3), SEQ ID NO:68 (LCDR1), SEQ ID NO:69 (LCDR2), SEQ ID NO:60 (LCDR3 ... 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). In some embodiments, WW05_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:61, and the light chain variable region contains or has 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.

[0226] For example, WW06_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:80 (HCDR2), SEQ ID NO:91 (LCDR3), SEQ ID NO:80 (HCDR1), SEQ ID NO:81 (HCDR2), SEQ ID NO:78 (HCDR3), SEQ ID NO:92 (LCDR1), SEQ ID NO:81 (HCDR2), SEQ ID NO:78 (HCDR3), SEQ ID NO:92 (LCDR1), SEQ ID NO:81 (HCDR2), SEQ ID NO:81 (HCDR3), SEQ ID NO:8 ...HCDR3), SEQ ID NO:81 (HCDR2), SEQ ID NO:81 (HCDR3), 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). In some embodiments, WW06_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:85, and the light chain variable region contains or has 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.

[0227] For example, XX01_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:19 (LCDR3), SEQ ID NO:101 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:19 (LCDR3), SEQ ID NO:101 (HCDR2), SEQ ID NO:101 (HCDR3), SEQ ID NO:101 (HCDR1 ... 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). In some embodiments, XX01_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing 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_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:103, and the light chain variable region contains or has 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.

[0228] For example, XX01_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:19 (LCDR3), SEQ ID NO:101 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:20 (LCDR1), SEQ ID NO:19 (LCDR3), SEQ ID NO:101 (HCDR2), SEQ ID NO:101 ... 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). In some embodiments, XX01_DAPA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:103, and the light chain variable region contains or has 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.

[0229] For example, XX01_N30S_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); 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). In some embodiments, XX01_N30S_DAPA may be defined as containing or having the following amino acid sequences: 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 containing 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 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 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:117, and the light chain comprises or has the amino acid sequence of SEQ ID NO:26.

[0230] For example, XX03_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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); 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). In some embodiments, XX03_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:43 (LCDR3).In some embodiments, XX03_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:122, and the light chain variable region contains or has 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.

[0231] For example, XX04_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR2 ... 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). In some embodiments, XX04_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:126 (LCDR3).In some embodiments, XX04_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:37, and the light chain variable region contains or has 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.

[0232] For example, XX06_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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 (LCDR ...1 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (HCDR2), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR2 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). In some embodiments, XX06_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:134 (LCDR3).In some embodiments, XX06_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:37, and the light chain variable region contains or has 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.

[0233] For example, XX06_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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 (LCDR ...1 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (HCDR2), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR2 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). In some embodiments, XX06_DAPA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing 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:134 (LCDR3).In some embodiments, XX06_DAPA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:37, and the light chain variable region contains or has 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.

[0234] For example, XX07_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR2 ... 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). In some embodiments, XX07_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:145 (LCDR3).In some embodiments, XX07_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:37, and the light chain variable region contains or has 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.

[0235] For example, XX08_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:19 (LCDR3), SEQ ID NO:10 (LCDR ... 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). In some embodiments, XX08_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:154, and the light chain variable region contains or has 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.

[0236] For example, XX08_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:19 (LCDR3), SEQ ID NO:10 (LCDR ... 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). In some embodiments, XX08_DAPA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:154, and the light chain variable region contains or has 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.

[0237] For example, XX08_N30S_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:17 (LCDR1), SEQ ID NO:18 (LCDR2), and SEQ ID NO:19 (LCDR3); 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). In some embodiments, XX08_N30S_DAPA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 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:161, and the light chain variable region comprises or has the amino acid sequence of SEQ ID NO:24. In some embodiments, XX08_N30S_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:163, and the light chain comprises or has the amino acid sequence of SEQ ID NO:26.

[0238] For example, XX08_N30Q_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:166 (HCDR1), SEQ ID NO:152 (HCDR2), SEQ ID NO:6 (HCDR3), SEQ ID NO:166 (HCDR1), SEQ ID NO:152 (HCDR2), SEQ ID NO:166 (HCDR3), SEQ ID NO:152 (HCDR2 ...66 (HCDR1), SEQ 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). In some embodiments, XX08_N30Q_DAPA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 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:168, and the light chain variable region comprises or has the amino acid sequence of SEQ ID NO:24. In some embodiments, XX08_N30Q_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:170, and the light chain comprises or has the amino acid sequence of SEQ ID NO:26.

[0239] For example, XX09_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR2 ...2 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). In some embodiments, XX09_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:172 (LCDR3).In some embodiments, XX09_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:37, and the light chain variable region contains or has 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.

[0240] For example, XX11_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:44 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (LCDR2 ... 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). In some embodiments, XX11_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:178 (LCDR3).In some embodiments, XX11_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:37, and the light chain variable region contains or has 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.

[0241] For example, XX12_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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 (LCDR ...1 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (HCDR1), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR3), SEQ ID NO:41 (HCDR2), SEQ ID NO:33 (HCDR2), SEQ ID NO:30 (HCDR2 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). In some embodiments, XX12_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:184 (LCDR3).In some embodiments, XX12_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:37, and the light chain variable region contains or has 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.

[0242] For example, XX13_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:134 (LCDR3); 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). In some embodiments, XX13_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:193, and the light chain variable region contains or has 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.

[0243] For example, XX14_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:41 (LCDR1), SEQ ID NO:42 (LCDR2), and SEQ ID NO:172 (LCDR3); 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). In some embodiments, XX14_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:193, and the light chain variable region contains or has 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.

[0244] For example, XX15_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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); 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). In some embodiments, XX15_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:126 (LCDR3).In some embodiments, XX15_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:201, and the light chain variable region contains or has 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.

[0245] For example, XX15_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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); 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). In some embodiments, XX15_DAPA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing 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:126 (LCDR3).In some embodiments, XX15_DAPA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:122, and the light chain variable region contains or has 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.

[0246] For example, XX16_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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); 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). In some embodiments, XX16_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:134 (LCDR3).In some embodiments, XX16_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:201, and the light chain variable region contains or has 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.

[0247] For example, XX16_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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: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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing 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:134 (LCDR3).In some embodiments, XX16_DAPA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:122, and the light chain variable region contains or has 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.

[0248] For example, XX17_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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); 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). In some embodiments, XX17_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:145 (LCDR3).In some embodiments, XX17_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:201, and the light chain variable region contains or has 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.

[0249] For example, XX17_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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); 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). In some embodiments, XX17_DAPA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing 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:145 (LCDR3).In some embodiments, XX17_DAPA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: (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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:122, and the light chain variable region contains 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.

[0250] For example, XX18_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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); 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). In some embodiments, XX18_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:172 (LCDR3).In some embodiments, XX18_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:201, and the light chain variable region contains or has 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.

[0251] For example, XX18_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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), and SEQ ID NO:172 (LCDR3). 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). In some embodiments, XX18_DAPA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing 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:172 (LCDR3).In some embodiments, XX18_DAPA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:122, and the light chain variable region contains or has 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.

[0252] For example, XX19_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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); 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). In some embodiments, XX19_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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_LALA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:201, and the light chain variable region contains or has 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.

[0253] For example, XX19_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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); 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). In some embodiments, XX19_DAPA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:122, and the light chain variable region contains or has 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.

[0254] For example, XX20_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:184 (LCDR ... 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). In some embodiments, XX20_LALA may be defined as containing or having the following amino acid sequences: 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 containing 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:184 (LCDR3).In some embodiments, XX20_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:201, and the light chain variable region contains or has 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.

[0255] For example, XX20_DAPA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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), and SEQ ID NO:184 (LCDR3). 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). In some embodiments, XX20_DAPA may be defined as containing or having the following amino acid sequences: 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 may be defined as containing 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:184 (LCDR3).In some embodiments, XX20_DAPA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:122, and the light chain variable region contains or has 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.

[0256] For example, YY01_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:239 (LCDR3), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3); 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). In some embodiments, YY01_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:233, and the light chain variable region contains or has 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.

[0257] For example, YY02_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:260 (LCDR1), SEQ ID NO:261 (LCDR2), and SEQ ID NO:262 (LCDR3); SEQ ID NO:250 (HCDR3), SEQ ID NO:263 (LCDR1), SEQ ID NO:241 (LCDR2), and SEQ ID NO:264 (LCDR3); or (IV) 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 may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:256, and the light chain variable region contains or has 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.

[0258] For example, YY03_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:272 (HCDR3), SEQ ID NO:282 (LCDR1), SEQ ID NO:261 (LCDR2), and SEQ ID NO:283 (LCDR3); 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). In some embodiments, YY03_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:278, and the light chain variable region contains or has 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.

[0259] For example, YY04_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:304 (LCDR3); 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). In some embodiments, YY04_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:300, and the light chain variable region contains or has 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.

[0260] For example, YY05_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:320 (LCDR1), SEQ ID NO:321 (LCDR2), and SEQ ID NO:322 (LCDR3); 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). In some embodiments, YY05_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:316, and the light chain variable region contains or has 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.

[0261] For example, YY06_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:339 (LCDR3), SEQ ID NO:331 (HCDR2), SEQ ID NO:337 (LCDR1), SEQ ID NO:338 (LCDR2), and SEQ ID NO:339 (LCDR3); 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). In some embodiments, YY06_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:333, and the light chain variable region contains or has 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.

[0262] For example, YY07_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:348 (HCDR3), SEQ ID NO:320 (LCDR1), SEQ ID NO:354 (LCDR2), and SEQ ID NO:355 (LCDR3); 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). In some embodiments, YY07_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:350, and the light chain variable region contains or has 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.

[0263] For example, ZZ05_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:348 (HCDR3), SEQ ID NO:320 (LCDR1), SEQ ID NO:354 (LCDR2), and SEQ ID NO:361 (LCDR3); 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). In some embodiments, ZZ05_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:350, and the light chain variable region contains or has 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.

[0264] For example, ZZ12_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:368 (HCDR2), SEQ ID NO:369 (HCDR1), SEQ ID NO:368 (HCDR2), SEQ ID NO:237 (LCDR1), SEQ ID NO:238 (LCDR2), and SEQ ID NO:239 (LCDR3); 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). In some embodiments, ZZ12_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:374, and the light chain variable region contains or has 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.

[0265] For example, ZZ13_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:389 (HCDR2), SEQ ID NO:389 (HCDR2), SEQ ID NO:389 (HCDR3), SEQ ID NO:380 (HCDR1), SEQ ID NO:379 (HCDR2), SEQ ID NO:380 (HCDR1), SEQ ID NO:379 (HCDR2), SEQ ID NO:380 (HCDR1), SEQ ID NO:382 (HCDR2), SEQ ID NO:380 (HCDR1), SEQ ID NO:38 ...0 (HCDR2), SEQ ID NO 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). In some embodiments, ZZ13_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: (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, wherein the heavy chain variable region comprises or has the amino acid sequence of SEQ ID NO:385, and the light chain variable region comprises or has the 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, wherein the heavy chain comprises or has the amino acid sequence of SEQ ID NO:387, and the light chain comprises or has the amino acid sequence of SEQ ID NO:246.

[0266] For example, ZZ14_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:399 (LCDR3), SEQ ID NO:399 (LCDR3), SEQ ID NO:399 (LCDR3), SEQ ID NO:399 (LCDR2 ... 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). In some embodiments, ZZ14_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:392, and the light chain variable region contains or has 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.

[0267] For example, ZZ15_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:399 (HCDR1), SEQ ID NO:399 (HCDR2), SEQ ID NO:399 (HCDR1), SEQ ID NO:399 (HCDR2), SEQ ID NO:399 (HCDR1), SEQ ID NO:399 (HCDR2), SEQ ID NO:399 (HCDR2), SEQ ID NO:399 (HCDR1), SEQ ID NO:399 (HCDR2), SEQ ID NO:399 (HCDR3), SEQ ID NO:399 (HCDR1), SEQ ID NO:399 (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: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 may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:403, and the light chain variable region contains or has 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.

[0268] For example, ZZ16_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:411 (HCDR2), SEQ ID NO:412 (HCDR3), SEQ ID NO:412 (HCDR3), SEQ ID NO:412 (HCDR3), SEQ ID NO:413 (HCDR2), SEQ ID NO:413 (HCDR3), SEQ ID NO:413 (HCDR1 ... 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). In some embodiments, ZZ16_LALA may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:414, and the light chain variable region contains or has 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.

[0269] For example, ZZ17_LALA can be defined as having three heavy chain complementarity determination regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determination 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:429 (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: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 may be defined as containing or having the following amino acid sequences: 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 containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having the following amino acid sequences: 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 may be defined as containing or having a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region contains or has the amino acid sequence of SEQ ID NO:425, and the light chain variable region contains or has 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.

[0270] 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 comprises or has the amino acid sequence of SEQ ID NO:13 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:13. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:24 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with 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 comprises or has the amino acid sequence of SEQ ID NO:15 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:15. The light chain comprises or has the amino acid sequence of SEQ ID NO:26 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:26.

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

[0272] 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 comprises or has the amino acid sequence of SEQ ID NO:61 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:61. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:72 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:72. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:63 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:63. The light chain comprises or has the amino acid sequence of SEQ ID NO:74 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:74.

[0273] 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 comprises or has the amino acid sequence of SEQ ID NO:85 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:85. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:96 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:96. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:87 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:87. The light chain comprises or has the amino acid sequence of SEQ ID NO:98 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:98.

[0274] 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 comprises or has the amino acid sequence of SEQ ID NO:103 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:103. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:24 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:105 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:105. The light chain comprises or has the amino acid sequence of SEQ ID NO:26 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:26.

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

[0276] 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 comprises or has the amino acid sequence of SEQ ID NO:115 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:115. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:24 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:117 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:117. The light chain comprises or has the amino acid sequence of SEQ ID NO:26 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:26.

[0277] 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 comprises or has the amino acid sequence of SEQ ID NO:122 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:122. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:48 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:48. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:124 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:124. The light chain comprises or has the amino acid sequence of SEQ ID NO:50 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:50.

[0278] 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 comprises or has the amino acid sequence of SEQ ID NO:37 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:37. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:128 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:128. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:39 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:39. The light chain comprises or has the amino acid sequence of SEQ ID NO:130 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:130.

[0279] 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 comprises or has the amino acid sequence of SEQ ID NO:37 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:37. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:136 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:136. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:39 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:39. The light chain comprises or has the amino acid sequence of SEQ ID NO:138 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:138.

[0280] 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 comprises or has the amino acid sequence of SEQ ID NO:37 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:37. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:136 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:136. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:141 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:141. The light chain comprises or has the amino acid sequence of SEQ ID NO:138 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:138.

[0281] 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 comprises or has the amino acid sequence of SEQ ID NO:37 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:37. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:147 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:147. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:39 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:39. The light chain comprises or has the amino acid sequence of SEQ ID NO:149 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:149.

[0282] 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 comprises or has the amino acid sequence of SEQ ID NO:154 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:154. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:24 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:156 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:156. The light chain comprises or has the amino acid sequence of SEQ ID NO:26 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:26.

[0283] 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 comprises or has the amino acid sequence of SEQ ID NO:154 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:154. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:24 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:159 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:159. The light chain comprises or has the amino acid sequence of SEQ ID NO:26 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:26.

[0284] 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 comprises or has the amino acid sequence of SEQ ID NO:161 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:161. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:24 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:163 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:163. The light chain comprises or has the amino acid sequence of SEQ ID NO:26 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:26.

[0285] 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 comprises or has the amino acid sequence of SEQ ID NO:168 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:168. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:24 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:24. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:170 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:170. The light chain comprises or has the amino acid sequence of SEQ ID NO:26 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:26.

[0286] 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 comprises or has the amino acid sequence of SEQ ID NO:37 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:37. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:174 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:174. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:39 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:39. The light chain comprises or has the amino acid sequence of SEQ ID NO:176 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:176.

[0287] 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 comprises or has the amino acid sequence of SEQ ID NO:37 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:37. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:180 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:180. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:39 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:39. The light chain comprises or has the amino acid sequence of SEQ ID NO:182 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:182.

[0288] 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 comprises or has the amino acid sequence of SEQ ID NO:37 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:37. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:186 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:186. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:39 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:39. The light chain comprises or has the amino acid sequence of SEQ ID NO:188 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:188.

[0289] 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 comprises or has the amino acid sequence of SEQ ID NO:193 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:193. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:136 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:136. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:195 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:195. The light chain comprises or has the amino acid sequence of SEQ ID NO:138 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:138.

[0290] 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 comprises or has the amino acid sequence of SEQ ID NO:193 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:193. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:174 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:174. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:195 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:195. The light chain comprises or has the amino acid sequence of SEQ ID NO:176 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:176.

[0291] 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 comprises or has the amino acid sequence of SEQ ID NO:201 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:201. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:128 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:128. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:203 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:203. The light chain comprises or has the amino acid sequence of SEQ ID NO:130 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:130.

[0292] 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 comprises or has the amino acid sequence of SEQ ID NO:122 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:122. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:128 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:128. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:208 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:208. The light chain comprises or has the amino acid sequence of SEQ ID NO:130 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:130.

[0293] 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 comprises or has the amino acid sequence of SEQ ID NO:201 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:201. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:136 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:136. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:203 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:203. The light chain comprises or has the amino acid sequence of SEQ ID NO:138 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:138.

[0294] 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 comprises or has the amino acid sequence of SEQ ID NO:122 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:122. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:136 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:136. In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain comprises or has the amino acid sequence of SEQ ID NO:208 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:208. The light chain comprises or has the amino acid sequence of SEQ ID NO:138 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:138.

[0295] 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 comprises or has the amino acid sequence of SEQ ID NO:201 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:201. The light chain variable region comprises or has the amino acid sequence of SEQ ID NO:147 or a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:147. In some embodime...

Claims

1. An isolated anti-natriuretic peptide receptor 1 (NPR1) antibody or antigen-binding fragment, 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), wherein the antibody or antigen-binding fragment comprises: (I) HCDR1 consisting of SEQ ID NO:28, HCDR2 consisting of SEQ ID NO:119, HCDR3 consisting of SEQ ID NO:30, LCDR1 consisting of SEQ ID NO:41, LCDR2 consisting of SEQ ID NO:42, and LCDR3 consisting of SEQ ID NO:134; (II) HCDR1 consisting of SEQ ID NO:31, HCDR2 consisting of SEQ ID NO:119, HCDR3 consisting of SEQ ID NO:30, LCDR1 consisting of SEQ ID NO:41, LCDR2 consisting of SEQ ID NO:42, and LCDR3 consisting of SEQ ID NO:134; (III) HCDR1 consisting of SEQ ID NO:32, HCDR2 consisting of SEQ ID NO:120, HCDR3 consisting of SEQ ID NO:30, LCDR1 consisting of SEQ ID NO:44, LCDR2 consisting of SEQ ID NO:45, and LCDR3 consisting of SEQ ID NO:135; or (IV) HCDR1 consisting of SEQ ID NO:34, HCDR2 consisting of SEQ ID NO:121, HCDR3 consisting of SEQ ID NO:36, LCDR1 consisting of SEQ ID NO:47, LCDR2 consisting of SEQ ID NO:45 and LCDR3 consisting of SEQ ID NO:

134.

2. The antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 201, and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 136; or (b) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 122, and a light chain variable region consisting of the amino acid sequence of SEQ ID NO:

136.

3. The antibody or antigen-binding fragment of claim 1 or 2, wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain having an amino acid sequence consisting of SEQ ID NO: 203, and a light chain having an amino acid sequence consisting of SEQ ID NO: 138; or (b) a heavy chain having an amino acid sequence consisting of SEQ ID NO:208, and a light chain having an amino acid sequence consisting of SEQ ID NO:

138.

4. The antibody or antigen-binding fragment of any one of claims 1 to 3, which is an antigen-binding fragment selected from the group consisting of F(ab')2, Fv and single-chain variable fragment (scFv).

5. The antibody or antigen-binding fragment of any one of claims 1-4, wherein the antibody or antigen-binding fragment is therapeutic.

6. One or more isolated nucleic acids encoding the amino acid sequence of the antibody or antigen-binding fragment of any one of claims 1-5.

7. A vector comprising one or more isolated nucleic acids according to claim 6.

8. A host cell comprising one or more isolated nucleic acids according to claim 6 or a vector according to claim 7.

9. A method for producing the antibody or antigen-binding fragment of any one of claims 1 to 5, the method comprising culturing the host cell of claim 8 under conditions suitable for producing the antibody or antigen-binding fragment.

10. The method of claim 9, wherein the method additionally comprises purifying the antibody or antigen-binding fragment.

11. A pharmaceutical composition comprising the antibody or antigen-binding fragment according to any one of claims 1 to 5 or produced by the method according to claim 9 or 10, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, wherein the composition further comprises an additional therapeutic agent.

13. The pharmaceutical composition of claim 11, 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.

14. The pharmaceutical composition of claim 13, wherein the additional therapeutic agent is selected from the group consisting of 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, chlorothiazide, chlorthalidone, hydrochlorothiazide , indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, eplerenone, spironolactone, triamterene, digoxin, fluticasone, budesonide, mometasone, beclomethasone, ciclesonide, fluticasone furoate, prednisone, methylprednisolone, montelukast, zafirlukast, zileuton, long-acting beta-agonists, short-acting beta-agonists, theophylline, ipratropium , salmeterol, formoterol, salbutamol, levalbuterol, timolol, levobunol, metipranolol, carteolol, betaxolol, acetazolamide, dorzolamide, brinzolamide, methazolamide, brimonidine, alaclonidine, cholinergics, latanoprost, latanoprost, travoprost, bimatoprost, tafluprost, netasudil, ripasudil, and combinations thereof.

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