Anti-SARS-CoV-2 antigen binding polypeptides, polypeptide complexes, and methods of use thereof

Abstract

Antigen-binding antigen-binding polypeptide complexes (e.g., antibodies and antigen-binding fragments thereof) having certain structural and / or functional characteristics are disclosed. Also disclosed are polynucleotides and vectors encoding such polypeptide complexes; host cells, pharmaceutical compositions and kits containing such polypeptide complexes; and methods of using such polypeptide complexes.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 357,336 filed on June 30, 2022, U.S. Provisional Application No. 63 / 357,873 filed on July 1, 2022, U.S. Provisional Application No. 63 / 404,473 filed on September 7, 2022, U.S. Provisional Application No. 63 / 381,850 filed on November 1, 2022, and U.S. Provisional Application No. 63 / 433,719 filed on December 9, 2022; all of which are incorporated herein by reference in their entirety.

[0003] Reference to electronically submitted sequence listings

[0004] The entire contents of the electronically submitted sequence listing (name: 4850_0100003_SEQLISTING_ST26.xml; size: 486,871 bytes; creation date: June 28, 2023) are incorporated herein by reference. Technical Field

[0005] The present disclosure relates to anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antigen-binding polypeptides and polypeptide complexes (e.g., antibodies and antigen-binding fragments thereof) having certain structural and / or functional characteristics. The present disclosure also relates to polynucleotides and vectors encoding such polypeptides and polypeptide complexes; host cells, pharmaceutical compositions and kits containing such polypeptides and polypeptide complexes; and methods of using such polypeptides and polypeptide complexes.

[0006] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0007] This invention was made during the performance of a cooperative research and development agreement with the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. The Government has certain rights in this invention. Background Art

[0008] The outbreak of severe acute respiratory syndrome coronavirus (SARS-CoV-2) has resulted in more than 450 million infections and more than 6 million deaths worldwide. SARS-CoV-2 is the strain of coronavirus that causes COVID-19 (coronavirus disease 2019). The sequencing and publication of the original Hu-1 (WA-1) genome enabled rapid vaccine design and production of the spike protein for therapeutic antibody development. However, the continued circulation of the virus during the human pandemic has led to genetic variants that resist containment and eradication. Although both cellular and humoral immune responses are required for optimal protection from viral infection, neutralizing antibodies play a major role in the prevention and eradication of pathogens.

[0009] SARS-CoV-2 spike protein mutants and SARS-CoV-2 variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Ypsilon (B.1.427), and Omicron (B.1.1.529) have emerged to contain mutations that are resistant to current therapies, have increased pathogenicity, and evade current vaccines. This has led to their classification as variants of concern (VOC).

[0010] Therapeutic antibodies have emerged as an important class of agents for treating human diseases and conditions. Therapeutic antibodies have been engineered to have specificity for two or more different antigens or epitopes (i.e., "multispecific" antibodies, such as bispecific, trispecific, or tetraspecific). Multispecific antibodies have been used to form multi-targeted strategies for treating human diseases and conditions, and are an important technology platform for developing neutralizing antibody-based therapeutics for the prevention and treatment of SARS-CoV-2 infection and COVID-19.

[0011] Improved therapies are needed to prevent and treat SARS-CoV-2 infection and COVID-19. Therapeutic antibodies with broad VOC reactivity and resistance to SARS-CoV-2 escape are needed. Therapeutic antibodies that are easier to make and administer than current therapeutic antibody cocktails are also needed. There is also a need to treat or prevent SARS-CoV-2 infection and COVID-19 in immunocompromised individuals who cannot mount an effective immune response through vaccination. Summary of the invention

[0012] Provided herein is an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-CL; wherein the second polypeptide has a structure represented by VH1-L2-CH1; wherein the third polypeptide has a structure represented by VH2-L3-VH3-L4-CH1; wherein the fourth polypeptide has a structure represented by VL3-L5-VL2-L6-CL; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL2 is a first immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; and V-2 protein is a second immunoglobulin light chain variable region; VL3 is a third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L6 are amino acid linkers.

[0013] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide and a fourth polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-CL; wherein the second polypeptide has a structure represented by VH1-L2-CH1-L3-Fc; wherein the third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc; wherein the fourth polypeptide has a structure represented by VL3-L7-VL2-L8-CL; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL2 is a second immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; V L3 is the third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH2 is the second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH3 is the third immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; Fc is a region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is the immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; and L1-L8 are amino acid linkers.

[0014] In some aspects, VH1 comprises the same heavy chain variable region as VH3, and VL1 comprises the same light chain variable region as VL3.

[0015] In some aspects, VH1 comprises the same heavy chain variable region as VH2, and VL1 comprises the same light chain variable region as VL2.

[0016] In some aspects, VH2 comprises the same heavy chain variable region as VH3, and VL2 comprises the same light chain variable region as VL3.

[0017] In some aspects, VH1, VH2, and VH3 each comprise the same heavy chain variable region, and VL1, VL2, and VL3 each comprise the same light chain variable region.

[0018] In some aspects, VH1, VH2, and VH3 each comprise a different heavy chain variable region, and VL1, VL2, and VL3 each comprise a different light chain variable region.

[0019] In some aspects, VH1, VH2, and VH3 each independently comprise a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NOs: 2, 10, 18, 26, 34, 148, 160, 168, 176, 184, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 319, 327, 335, and 343; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NOs: NO:3, 11, 19, 27, 35, 149, 161, 169, 177, 185, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 320, 328, 336 and 344 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of SEQ ID NO:4, 12, 20, 28, 36, 150, 162, 170, 178, 186, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 321, 329, 337 and 345 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and VL1, VL2 and VL3 each independently comprise a CDR1, which comprises an amino acid sequence identical to SEQ ID any one of NO:6, 14, 22, 30, 38, 152, 156, 164, 172, 180, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 323, 331, 339 and 347 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical;CDR2, which comprises a sequence with SEQ ID NO: 7 (sequence with SAS), 15 (sequence with GTN), 23 (sequence with GAS), 31 (sequence with DAS), 39 (sequence with GAS), 153, 157, 165 (sequence with GAS), 173 (sequence with LGS), 181, 198 (sequence with DAS), 206 (sequence with DVS), 214 (sequence with EDS), 222 (sequence with KDS), 230 (sequence with DAS), 238 (sequence with AAS), 246 (sequence with GAS), 254 (sequence with DDS), 262 (sequence with KDS), 270 (sequence with SAS), 278 (sequence with SAS), 286 (sequence with GAS), 294 (sequence with GAS), 302 (sequence with GAS), 324 (sequence with GAS), 332 (sequence with DAS), 340 (sequence with SAS), and 348 (sequence with GAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 1; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 1 any one of ID NO: 8, 16, 24, 32, 40, 154, 158, 166, 174, 182, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 325, 333, 341 and 349 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical. ;

[0020] In some aspects, VH1, VH2, and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; and VL1, VL2, and VL3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 23. NO:23 (having a sequence of GAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:24.

[0021] In some aspects, VH1 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; VH2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; NO:27 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; and CDR3, which comprises an amino acid sequence with SEQ ID NO:28 having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; VL1 and VL3 each comprise a CDR1, which comprises an amino acid sequence with SEQ ID NO:22 having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; CDR2, which comprises an amino acid sequence with SEQ ID NO:23 (sequence with GAS) having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; and CDR3, which comprises an amino acid sequence with SEQ ID NO: NO:24 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and VL2 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:30; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:31 (sequence with DAS); and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:32.

[0022] In some aspects, VH1 and VH2 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; VH3 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; NO:27 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; and CDR3, it comprises and SEQ ID NO:28 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; VL1 and VL2 each comprise CDR1, it comprises and SEQ ID NO:22 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; CDR2, it comprises and SEQ ID NO:23 (sequence with GAS) has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; and CDR3, it comprises and SEQ ID NO:24 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; NO:24 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and VL3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:30; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:31 (sequence with DAS); and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:32.

[0023] In some aspects, VH2 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; NO:27 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; and CDR3, which comprises an amino acid sequence with SEQ ID NO:28 having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; VL2 and VL3 each comprise a CDR1, which comprises an amino acid sequence with SEQ ID NO:22 having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; CDR2, which comprises an amino acid sequence with SEQ ID NO:23 (sequence with GAS) having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; and CDR3, which comprises an amino acid sequence with SEQ ID NO:24 having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity. NO:24 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and VL1 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:30; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:31 (sequence with DAS); and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:32.

[0024] In some aspects, VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 12; VH2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; NO:19 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; and CDR3, it comprises and SEQ ID NO:20 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; VH3 comprises CDR1, it comprises and SEQ ID NO:26 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; CDR2, it comprises and SEQ ID NO:27 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; and CDR3, it comprises and SEQ ID NO:28 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; NO:28 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; VL1 comprises CDR1, which comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:14; CDR2, which comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:15 (sequence with GTN); and CDR3, which comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:16; VL2 comprises CDR1, which comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:17. NO:22 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:23 (having a sequence of GAS);and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 24; and VL3 comprises CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 30; CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 31 (sequence with DAS); and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 32. ;

[0025] In some aspects, VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 12; VH2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; NO:27 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity to the amino acid sequence; and CDR3, which comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:28; VH3 comprises CDR1, which comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:18; CDR2, which comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:19; and CDR3, which comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:29; NO:20 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; VL1 comprises CDR1, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO:14; CDR2, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO:15 (sequence with GTN); and CDR3, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO:16; VL2 comprises CDR1, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO:17. NO:30 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:31 (sequence with DAS);and CDR3 comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 32; and VL3 comprising CDR1 comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 22; CDR2 comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 23 (sequence having GAS); and CDR3 comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity to SEQ ID NO: 24. ;

[0026] In some aspects, the VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 28; the VH2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 11; NO:11 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; and CDR3, which comprises an amino acid sequence with SEQ ID NO:12 having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; VH3 comprises CDR1, which comprises an amino acid sequence with SEQ ID NO:18 having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; CDR2, which comprises an amino acid sequence with SEQ ID NO:19 having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; and CDR3, which comprises an amino acid sequence with SEQ ID NO:11 having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity NO:20 having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity; VL1 comprises CDR1, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO:30; CDR2, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO:31 (sequence with DAS); and CDR3, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO:32; VL2 comprises CDR1, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO: NO:14 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:15 (sequence with GTN);and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 16; and VL3 comprises CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 22; CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 23 (sequence with GAS); and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 24. ;

[0027] In some aspects, the VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 28; the VH2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 29; and a CDR4 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 21. NO:19 has at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity of the amino acid sequence; and CDR3, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO:20; VH3 comprises CDR1, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO:10; CDR2, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO:11; and CDR3, which comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identity with SEQ ID NO:21. NO:12 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; VL1 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:30; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:31 (sequence with DAS); and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:32; VL2 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:30; NO:22 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:23 (having a sequence of GAS);and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 24; and VL3 comprises CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 14; CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 15 (sequence with GTN); and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 16. ;

[0028] In some aspects, VH1, VH2, and VH3 each independently comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 1, 9, 17, 25, 33, 147, 159, 167, 175, 183, 190, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 306, 308, 310, 312, 314, 316, 318, 326, 334, 342, 351, 353, 357, and 359. In some aspects, the sequence has a mutation at N62 (eg, N62Q or N62Q), for example, of SEQ ID NO: 175.

[0029] In some aspects, VL1, VL2, and VL3 each independently comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to any one of SEQ ID NO: 5, 13, 21, 29, 37, 151, 155, 163, 171, 179, 188, 189, 191, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 305, 307, 309, 311, 313, 315, 317, 322, 330, 338, and 346.

[0030] In some aspects, VH1, VH2, and VH3 each comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 17; and VL1, VL2, and VL3 each comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 21.

[0031] In some aspects, VH1 and VH3 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 17; VH2 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 25; VL1 and VL3 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 21; and VL2 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 29.

[0032] In some aspects, VH1 and VH2 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 17; VH3 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 25; VL1 and VL2 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 21; and VL3 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 29.

[0033] In some aspects, VH2 and VH3 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 17; VH1 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 25; VL2 and VL3 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 21; and VL1 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 29.

[0034] In some aspects, VH1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:9; VH2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:17; VH3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:25; VL1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:13; VL2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:21; and VL3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: NO:29 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical.

[0035] In some aspects, VH1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:9; VH2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:25; VH3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:17; VL1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:13; VL2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:29; and VL3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: NO:21 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical.

[0036] In some aspects, VH1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 25; VH2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 9; VH3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 17; VL1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 29; VL2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 13; and VL3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: NO:21 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical.

[0037] In some aspects, VH1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 25; VH2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 17; VH3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 9; VL1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 29; VL2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 21; and VL3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: NO:13 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical.

[0038] In some aspects, the immunoglobulin hinge comprises an upper hinge region, a middle hinge region, a lower hinge region, or a combination thereof.

[0039] In some aspects, linkers L1-L8 each independently have a length of about 0 amino acids to about 50 amino acids.

[0040] In some aspects, linkers L1-L8 each independently comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NOs:46-80 (wherein SEQ ID NO:47 has a sequence of G, SEQ ID NO:48 has a sequence of A, SEQ ID NO:49 has a sequence of GSS, and SEQ ID NO:50 has a sequence of ASG).

[0041] In some aspects, one or more of linkers L1-L8 are non-immunogenic.

[0042] In some aspects, one or more of the linkers L1-L8 do not contain a shared T cell epitope.

[0043] In some aspects, the Fc region comprises at least one knob-into-hole modification or an Fc effector function knockout mutation.

[0044] In some aspects, the antigen-binding polypeptide complex is an IgG1 or IgG4 antibody, and the knob-into-hole modification includes (i) a knob substitution of S354C and T366W and a hole substitution of Y349C, T366S, L368A, and Y407V; (ii) a hole substitution of M428L and N434S or N434A; (iii) a hole substitution of M252Y, S254T, and T256E; or (iv) a combination thereof; this is based on the EU numbering scheme. In some aspects, the hole substitution is M428L and N434S, which is based on the EU numbering scheme. In some aspects, the hole substitution is N434A, which is based on the EU numbering scheme.

[0045] In some aspects, the antigen binding polypeptide complex is an IgG1 or IgG4 antibody and the Fc effector function knockout mutation is L234A, L235A, P239A, or a combination thereof, based on the EU numbering scheme.

[0046] In some aspects, the antigen-binding polypeptide complex comprises a detectable label. In some aspects, the detectable label is a radioactive label, a chemiluminescent label, a fluorescent label, an enzyme, a peptide tag, or a combination thereof. In some aspects, the peptide tag is a polyhistidine tag consisting of about four to about 10 histidine residues. In some aspects, the polyhistidine tag consists of about eight histidine residues.

[0047] In some aspects, the antigen-binding polypeptide complex has an equilibrium dissociation constant (K) of about 10 μM to about 1 pM. D ) specifically binds to SARS-CoV-2 protein.

[0048] In some aspects, the variable region of the antibody may require site-specific deglycosylation. In some aspects, and for the E8 VH mAb, an N62 mutation is performed to remove a high mannose glycosylated residue or moiety. Preferred mutations include, but are not limited to, N62Q or N62S.

[0049] In some aspects, the SARS-CoV-2 virus is the original strain (WA1), the D614G spike protein mutant (D614G), the alpha variant (B.1.1.7), the beta variant (B.1.351), the gamma variant (P.1), the kappa variant (B.1.617.1), the delta variant (B.1.617.2 or AY.1), the ypsilon variant (B.1.427), the yota variant (B.1.526), ​​the lambda variant (C.37), Mu variant (B.1.621), C.1.2 variant, Omicron variant (BA1.1.529, BA.1, BA.2, BA.2.12.1, BA.4, BA.4 / 5, BA.5, BQ.1, BQ.1.1, BA.2.75, BA.2.75.2, BA.4.6, BQ.1.1, BJ.1, XBB, XBB1.5, BF.7 or CH.1.1), or a combination thereof.

[0050] In some aspects, the SARS-CoV-2 protein is a membrane protein, a nucleocapsid protein, an envelope protein, or a spike protein. In some aspects, the SARS-CoV-2 protein is a spike protein.

[0051] Also provided herein is an antibody or antigen-binding fragment thereof, which comprises an antigen-binding polypeptide complex provided herein. In some aspects, the antibody is IgG, IgM, IgE, IgA or IgD. In some aspects, the IgG is IgG1, IgG2, IgG3 or IgG4. In some aspects, the antigen-binding fragment is Fab, scFab, Fab', F(ab') or Fab'. 2 In some aspects, the antibody is a human antibody or a humanized antibody. In some aspects, the antibody is a monoclonal antibody, a transplanted antibody or a chimeric antibody.

[0052] Also provided herein is an anti-SARS-CoV2 multivalent antibody that exhibits improved prevention of immune escape compared to: (i) a monovalent anti-SARS-CoV2 antibody that binds to one of the same antigens as the anti-SARS-CoV2 multivalent antibody, and / or (ii) a combination of monovalent anti-SARS-CoV2 antibodies that bind to the same antigen as the anti-SARS-CoV2 multivalent antibody.

[0053] Also provided herein is a pharmaceutical composition comprising an antigen-binding polypeptide, an antigen-binding polypeptide complex, an antibody or its antigen-binding fragment provided herein. In some aspects, the pharmaceutical composition comprises (1) one or more polynucleotides encoding antigen-binding polypeptides or antigen-binding polypeptide complexes and (2) a carrier. In some aspects, the pharmaceutical composition comprises (1) one or more polynucleotides encoding antigen-binding polypeptides or antigen-binding polypeptide complexes (e.g., antibodies or their antigen-binding fragments) provided herein, and (2) a carrier selected from the group consisting of lipids or lipid nanoparticles. In some aspects, one or more polynucleotides encoding antigen-binding polypeptides or antigen-binding polypeptide complexes are stable polynucleotides that are resistant to degradation or decomposition in vivo. In some aspects, a stable polynucleotide is capped at one end (5' cap) and has a long polyadenylation (polyA) tail at the other end to form a stable mRNA with 5' and 3' UTR. In some aspects, the polyA tail is about 50bp, about 100bp, about 120bp, or about 150bp. In some aspects, modified nucleosides can be incorporated into mRNA to increase translation and / or reduce potential immunogenicity.

[0054] Also provided herein is a pharmaceutical composition comprising the antigen-binding polypeptide complex, antibody or antigen-binding fragment thereof provided herein, and another pharmaceutical agent.

[0055] Also provided herein is a kit comprising an antigen-binding polypeptide complex, an antibody or antigen-binding fragment thereof, or a pharmaceutical composition provided herein.

[0056] Also provided herein is a method for preventing or treating SARS-CoV-2 virus infection in a subject in need thereof, comprising administering to the subject an effective amount of an antigen-binding polypeptide or polypeptide complex provided herein, an antibody or antigen-binding fragment thereof provided herein, a pharmaceutical composition provided herein, or a combination thereof. Delivery of a therapeutic antigen-binding polypeptide or antigen-binding polypeptide complex can be performed by direct administration of a therapeutic agent or by an indirect method, the indirect method comprising administering a modified mRNA composition to a patient in need of treatment by translating a therapeutic antigen-binding polypeptide or antigen-binding polypeptide complex from a modified mRNA encoding a therapeutic polypeptide or polypeptide complex.

[0057] Also provided herein is a method for preventing or treating coronavirus disease 2019 (COVID-19) in a subject in need thereof, comprising administering to the subject an effective amount of an antigen-binding polypeptide or polypeptide complex provided herein, an antibody or antigen-binding fragment thereof provided herein, a pharmaceutical composition provided herein, or a combination thereof.

[0058] Also provided herein is a method for diagnosing that a subject is infected with or suspected of being infected with the SARS-CoV-2 virus, comprising (i) contacting a sample obtained from the subject with an antigen-binding polypeptide or polypeptide complex provided herein or an antibody or antigen-binding fragment thereof provided herein; (ii) detecting the presence or absence of a viral complex containing a polypeptide complex, antibody or fragment and a SARS-CoV-2 virus, virion or fragment thereof; and (iii) when the presence of the viral complex is detected, diagnosing that the subject is infected with or suspected of being infected with the SARS-CoV-2 virus.

[0059] Also provided herein is a method for diagnosing that a subject is not infected with the SARS-CoV-2 virus or is not suspected of being infected with the SARS-CoV-2 virus, comprising (i) contacting a sample obtained from the subject with an antigen-binding polypeptide or polypeptide complex provided herein or an antibody or antigen-binding fragment thereof provided herein; (ii) detecting the presence or absence of a viral complex containing a polypeptide complex, an antibody or fragment and a SARS-CoV-2 virus, a virion or a fragment thereof; and (iii) when the presence of the viral complex is not detected, diagnosing that the subject is not infected with the SARS-CoV-2 virus or is not suspected of being infected with the SARS-CoV-2 virus.

[0060] Also provided herein is a method for diagnosing a subject as having COVID-19 or suspected of having COVID-19, comprising (i) contacting a sample obtained from the subject with an antigen-binding polypeptide or polypeptide complex provided herein or an antibody or antigen-binding fragment thereof provided herein; (ii) detecting the presence or absence of a viral complex containing a polypeptide complex, antibody or fragment and a SARS-CoV-2 virus, virion or fragment thereof; and (iii) when the presence of the viral complex is detected, diagnosing the subject as having COVID-19 or suspected of having COVID-19.

[0061] Also provided herein is a method for diagnosing that a subject does not have COVID-19 or is not suspected of having COVID-19, comprising (i) contacting a sample obtained from the subject with an antigen-binding polypeptide or polypeptide complex provided herein or an antibody or antigen-binding fragment thereof provided herein; (ii) detecting the presence or absence of a viral complex containing a polypeptide complex, antibody or fragment and a SARS-CoV-2 virus, virion or fragment thereof; and (iii) when the presence of the viral complex is not detected, diagnosing that the subject does not have COVID-19 or is not suspected of having COVID-19.

[0062] In some aspects, the sample is a nasal swab, tissue sample, saliva, plasma, or blood.

[0063] In some aspects, detecting the presence or absence of viral complexes comprises enzyme-linked immunosorbent assay (ELISA), immunospot assay, lateral flow assay, flow cytometry, immunohistochemistry, or western blot.

[0064] In some aspects, the SARS-CoV-2 virus is the original strain (WA1), the D614G spike protein mutant (D614G), the alpha variant (B.1.1.7), the beta variant (B.1.351), the gamma variant (P.1), the kappa variant (B.1.617.1), the delta variant (B.1.617.2 or AY.1), the ypsilon variant (B.1.427), the yota variant (B.1.526), ​​the lambda variant (C.37), Mu variant (B.1.621), C.1.2 variant, Omicron variant (BA1.1.529, BA.1, BA.2, BA.2.12.1, BA.4, BA.4 / 5, BA.5, BQ.1, BQ.1.1, BA.2.75, BA.2.75.2, BA.4.6, BQ.1.1, BJ.1, XBB, XBB1.5, BF.7 or CH.1.1), or a combination thereof.

[0065] In some aspects, the SARS-CoV-2 virus is the original strain (WA1), the D614G spike protein mutant (D614G), the alpha variant (B.1.1.7), the beta variant (B.1.351), the gamma variant (P.1), the kappa variant (B.1.617.1), the delta variant (B.1.617.2 or AY.1), the ypsilon variant (B.1.427), the yota variant (B.1.526), ​​the lambda variant (C.37), Mu variant (B.1.621), C.1.2 variant, Omicron variant (BA1.1.529, BA.1, BA.2, BA.2.12.1, BA.4, BA.4 / 5, BA.5, BQ.1, BQ.1.1, BA.2.75, BA.2.75.2, BA.4.6, BQ.1.1, BJ.1, XBB, XBB1.5, BF.7 or CH.1.1), or a combination thereof.

[0066] Also provided herein is a method for preventing immune escape of SARS-CoV2 virus in a subject infected with SARS-CoV2 virus, comprising administering to the subject an effective amount of the antigen-binding polypeptide or polypeptide complex provided herein, the antibody or antigen-binding fragment thereof provided herein, the pharmaceutical composition provided herein, or a combination thereof.

[0067] Also provided herein is a method for preventing immune escape of a SARS-CoV2 virus in a subject infected with the SARS-CoV2 virus, comprising administering to the subject an effective amount of an anti-SARS-CoV2 multivalent antibody that exhibits improved prevention of immune escape compared to: (i) a monovalent anti-SARS-CoV2 antibody that binds to one of the same antigens as the anti-SARS-CoV2 multivalent antibody, and / or (ii) a combination of monovalent anti-SARS-CoV2 antibodies that bind to the same antigen as the anti-SARS-CoV2 multivalent antibody.

[0068] Also provided herein is a method for neutralizing the SARS-CoV-2 virus in a subject infected with the SARS-CoV-2 virus, comprising administering to the subject an effective amount of the antigen-binding polypeptide or polypeptide complex provided herein, the antibody or antigen-binding fragment thereof provided herein, or a combination thereof.

[0069] Also provided herein is a method for increasing the neutralization efficacy against SARS-CoV-2 virus in a subject infected with SARS-CoV-2 virus, comprising administering to the subject an effective amount of an antigen-binding polypeptide or polypeptide complex provided herein, an antibody or antigen-binding fragment thereof provided herein, or a combination thereof.

[0070] Also provided herein is a method of increasing the neutralization potency against a SARS-CoV-2 virus in a subject infected with the SARS-CoV2 virus, comprising administering to the subject an effective amount of an anti-SARS-CoV2 multivalent antibody that exhibits increased neutralization potency compared to: (i) a monovalent anti-SARS-CoV2 antibody that binds to one of the same antigens as the anti-SARS-CoV2 multivalent antibody, and / or (ii) a combination of monovalent anti-SARS-CoV2 antibodies that bind to the same antigen as the anti-SARS-CoV2 multivalent antibody. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Some aspects of the present invention are herein described, by way of example only, with reference to the accompanying drawings.With specific reference now to the drawings in detail, it is stressed that the particulars shown are exemplary and are for purposes of illustrative discussion of aspects of the invention.

[0072] Figure 1 An exemplary configuration of a monospecific, trivalent crossover dual variable (CODV) immunoglobulin antibody prepared using the variable fragment (Fv) from the anti-SARS-CoV-2 antibody B1-182.1 (Fv182.1, dotted line) is shown. The Fc region contains a knob-in-hole modification to increase production and correct association of the heavy chain.

[0073] FIG. 2A to FIG. 2CAn exemplary configuration of a bispecific, trivalent CODV immunoglobulin antibody prepared using variable fragments (Fv) from B1-182.1 (Fv182.1, dotted line) and anti-SARS-CoV-2 antibody A19-61.1 (Fv61.1, grid) is shown. The Fc region contains a knob-in-hole modification to increase production and correct association of the heavy chain.

[0074] FIG. 3A to FIG. 3D Shown are exemplary configurations of trispecific, trivalent CODV immunoglobulin antibodies prepared using variable fragments (Fv) from B1-182.1 ("182.1" or "Class I Fv182", dashed lines), anti-SARS-CoV-2 antibodies A19-46.1 ("46.1" or "Class II Fv46", stripes), and A19-61.1 ("61.1" or "Class III Fv61", grids). The Fc region contains knob-in-hole modifications to increase yield and proper association of the heavy chain.

[0075] Figure 4A The purity of CODV immunoglobulin antibodies assessed on Coomassie SDS-PAGE gels under non-reducing (nr) and reducing (r) conditions is shown (representative gels are shown). Molecular weight marker standards (MW) are also shown.

[0076] Figure 4B CODV immunoglobulin bispecific and trispecific antibody blotting shown before (top row) and after (bottom row) size exclusion chromatography (SEC) is shown. The dotted line box indicates the fractions merged for the final preparation of the multispecific antibody shown. The bottom row shows the analytical SEC trace of the purified multispecific antibody.

[0077] Figure 5A Shown in FIG. 5B to FIG. 5E and the crossover dual variable immunoglobulin antibody designs used in Table 4.

[0078] Figure 5B The expected binding of Fv182.1 ("Fv182"), Fv46.1 ("Fv46"), and Fv61.1 ("Fv61") to viral spike receptor binding domain (RBD) proteins containing the indicated Fv separation mutations, which were selected to knock out Fv binding to a single component while leaving binding of the remaining Fv components unchanged.

[0079] FIG. 5C to FIG. 5E Validation of multispecific Fv binding activity using Fv separation mutations in RBD and ELISA is shown. Parental component antibody controls ( Figure 5C , B1-182.1, A19-46.1 and A19-61.1), bispecific antibodies ( Figure 5D , 182.1 / 182.1-61.1, 182.1 / 61.1-182.1, 61.1 / 182.1-182.1, 61.1 / 61.1-182.1 and 61.1 / 182.1-61.1) and trispecific antibodies ( Figure 5E , 46.1 / 61.1-182.1, 46.1 / 182.1-61.1, 61.1 / 46.1-182.1 and 61.1 / 182.1-46.1) ELISA binding to WA-1 RBD (wt) or RBD proteins containing one or more Fv-specific mutations, which were displayed and selected to probe the binding of one Fv component at a time in each multispecific antibody.

[0080] Fig. 6A Schematic diagram showing the arrangement of antibody variable domains in different CODVs. The domains of Fv182.1 (182.1), Fv46.1 (46.1), Fv61.1 (61.1) and constant domains are dashed, striped, grid and grey, respectively.

[0081] Figure 6B Combinations of RBD mutations on the SARS-CoV-2 spike designed to distinguish different binding modes of CODV are shown.

[0082] Figure 6C Schematic diagram of CODV 61.1-182.1 (left) and CODV 61.1-182.1 binding to spike protein mutants (center left and center right). For clarity, the Fv domain that cannot bind to the mutant is stained black. CODV binding to the K444E / L452R mutant was observed, indicating that CODV 61.1-182.1 can bind to the spike protein through the Fv182 domain (center left). However, CODV binding to the L452R / F486S mutant was not observed (center right), indicating that CODV 61.1-182.1 cannot bind through the Fv61 domain in a trimer environment. The model of CODV61.1-182.1 bound to the SARS-CoV-2 spike protein is shown in an allowed Fv182-binding mode (right). For clarity, only one CODV is shown bound to the spike protein in the RBD-up conformation. The white scale bar represents 10 nm.

[0083] Fig.6DSchematic representation of CODV 182.1-61.1 (left) and CODV 182.1-61.1 binding to spike protein mutants (center left and center right). For clarity, the Fv domains that cannot bind to the mutants are stained black. CODV was observed to bind to the K444E / L452R and L452R / F486S mutants, indicating that CODV 182.1-61.1 can bind to the spike protein through the Fv182 domain (center left) or the Fv61 domain (center right). Models of CODV 182.1-61.1 bound to the SARS-CoV-2 spike protein are shown in Fv182.1-bound and Fv61.1-bound modes (right). Scale and Figure 6C The scale in is the same.

[0084] Fig. 6E Schematic representation of CODV 46.1-182.1 (left) and CODV 46.1-182.1 binding to spike protein mutants (center left and center right). For clarity, the Fv domains that cannot bind to the mutants are stained black. CODV was observed to bind to the K444E / L452R and K444E / F486S mutants, indicating that CODV 46.1-182.1 can bind to the spike protein through the Fv182 and Fv46 domains (center left and center right). Model of CODV 46.1-182.1 bound to the SARS-CoV-2 spike protein showing binding through the Fv182 and Fv46-binding modes (right). Scale and Figure 6C The scale in is the same.

[0085] Fig. 6F Schematic representation of CODV 182.1-46.1 (left) and CODV 182.1-46.1 binding to spike protein mutants (middle left and middle right). For clarity, the Fv domain that cannot bind to the mutants is stained black. CODV binding to K444E / L452R was observed, indicating that CODV 182.1-46.1 can bind to the spike protein through the Fv182.1 domain (middle left). However, CODV binding to the K444E / F486S mutant was not observed (middle right), indicating that CODV 182.1-46.1 cannot bind through the Fv46 domain in a trimeric environment. Model of CODV 182.1-46.1 binding to the SARS-CoV-2 spike protein shows binding through the permissive Fv182 domain (right). Scale and Figure 6C The scale in is the same.

[0086] Figure 6G Aggregation of CODV 46.1-182.1 and 182.1-46.1-induced Omicron spike protein using negative stain-electron microscopy (NSEM) is shown.

[0087] Figure 6H The spike aggregation potential of 61.1 / 46.1-182.1 using NSEM is shown.

[0088] Figure 7 The SARS-CoV-2 escape potential of single antibodies, combinations of single antibodies, and candidate multispecific antibodies is shown.

[0089] Figure 8 Results from three independent experiments are shown, showing the SARS-CoV-2 escape potential of T3_V3 (with 61.1, 46.1, and 182.1 binding regions) compared to an antibody with 182.1, 61.1, and 46.1 binding regions (182.1+61.1+46.1); an antibody with a binding region of 182.1 (182.1); bebtelovimab (LY1404); and an AZD7442 mixture (2196+2130).

[0090] Fig. 9 Shown are the resulting serum concentrations of E8 glycosylation mutant antibodies in μg / mL on days 1, 2, 5, 7, 9, 14, 21, 28 and 35 after infusion of mice at 5 mg antibody / kg body weight. DETAILED DESCRIPTION

[0091] Provided herein are antigen-binding polypeptides and polypeptide complexes with improved features. In some aspects, antigen-binding polypeptides and polypeptide complexes have extensive reactivity, high neutralization efficacy and / or resistance to SARS-CoV-2 escape for SARS-CoV-2 variants (VOC) of interest. In some aspects, provided herein are antigen-binding polypeptides and polypeptide complexes that are easier to manufacture and apply than current therapeutic antibody mixtures. In some aspects, antigen-binding polypeptides and polypeptide complexes treat and / or prevent SARS-CoV-2 infection and / or COVID-19 in immunocompromised individuals, who cannot produce an effective immune response by vaccination.

[0092] Various terms related to aspects of the present disclosure are used throughout the specification and claims. Unless otherwise indicated, such terms will be given their ordinary meanings in the art. Other specifically defined terms should be interpreted in a manner consistent with the definitions provided herein.

[0093] definition

[0094] As used herein, the term "SARS-CoV-2" refers to "Severe Acute Respiratory Syndrome Coronavirus 2." SARS-CoV-2 is the strain of coronavirus that causes coronavirus disease 2019 (COVID-19).

[0095] As used herein, the term "SARS-CoV-2 virus" includes SARS-CoV-2 virus, virions, or fragments thereof.

[0096] As used herein, the term "COVID-19" refers to "coronavirus disease 2019." COVID-19 is caused by the SARS-CoV-2 virus. Symptoms of COVID-19 are variable but generally include fever, cough, headache, fatigue, dyspnea, loss of smell, and loss of taste. Symptoms may begin one to fourteen days after exposure to the virus; however, at least one-third of people who are infected do not develop obvious symptoms. Of those who develop significant symptoms sufficient to be classified as patients, most develop mild to moderate symptoms (up to mild pneumonia), with approximately 15% developing severe symptoms (dyspnea, hypoxia, or greater than 50% lung involvement on imaging), and approximately 5% suffering severe symptoms (respiratory failure, shock, or multi-organ dysfunction). Some people continue to experience a range of effects for months after recovery ("long COVID").

[0097] As used herein. The term "SARS-CoV-2 protein" refers to any protein associated with the SARS-CoV-2 virus. The SARS-CoV-2 virus consists of 16 non-structural proteins and four structural proteins. Non-structural proteins are mainly involved in viral replication. Structural proteins include membrane proteins, nucleocapsid proteins, envelope proteins, and spike proteins, which are involved in the assembly and infection of the virus. The spike protein has two subunits, S1 and S2, which are responsible for the specific recognition of human angiotensin-converting enzyme 2 (hACE2) on the surface of host cells and viral entry. S1 specifically binds hACE2 through its receptor binding domain (RBD), while S2 promotes the fusion of the virus with the cell membrane. Therefore, as used herein, SARS-CoV-2 proteins include, but are not limited to, membrane proteins, nucleocapsid proteins, envelope proteins, or spike proteins, or combinations thereof. In some aspects, the SARS-CoV-2 protein is a spike protein.

[0098] In some aspects, an antigen-binding polypeptide or antigen-binding polypeptide complex (eg, an antibody or antigen-binding fragment thereof) provided herein is a Class I antibody, a Class II antibody, or a Class III antibody, or a portion thereof.

[0099] As used herein, "Class I" refers to antibodies that typically contain a short heavy chain CDR3 region and compete with angiotensin-converting enzyme 2 (ACE2) for binding to the receptor binding domain (RBD) of the spike protein and recognize only the "upward" configuration of the RBD. See, for example, Shrestha et al., Front.Immunol.12:7520003,2021. As used herein, "Class II" refers to antibodies that typically have a long heavy chain CDR3 loop, compete with ACE2 for binding to the RBD, and can bind to the RBD in an "upward" and "downward" configuration. As used herein, "Class III" refers to antibodies that can bind to the RBD in an "upward" and "downward" configuration and are typically bound to the ACE2 binding region. As used herein, "Class IV" refers to antibodies that bind to highly conserved hidden epitopes on the RBD outside the receptor binding motif (RBM) of the spike protein.

[0100] In some aspects, the antigen-binding polypeptides or antigen-binding polypeptide complexes (e.g., antibodies or their antigen-binding fragments) provided herein belong to two, three or four classes. Therefore, in some aspects, the antigen-binding polypeptides or antigen-binding polypeptide complexes (e.g., antibodies or their antigen-binding fragments) provided herein are Class I and Class II antibodies, Class I and Class III antibodies, Class I and Class IV antibodies, Class II and Class III antibodies, Class II and Class IV antibodies, Class I, Class II and Class III antibodies, Class I, Class II and Class IV antibodies, Class I, Class III and Class IV antibodies, Class II, Class III and Class IV antibodies, or Class I, Class II, Class III and Class IV antibodies.

[0101] In some aspects, the antigen-binding polypeptide or antigen-binding polypeptide complex provided herein comprises one or more class I antigen binding sites, one or more class II antigen binding sites and / or one or more class III antigen binding sites. In some aspects, VH1 and VL1 and / or VH3 and VL3 are class III antigen binding sites. In some aspects, VH2 and VL2 and / or VH4 and VL4 are class I antigen binding sites. In some aspects, VH1, VL1, VH3 and VL3 are class III antigen binding sites, while VH2, VL2, VH4 and VL4 are class I antigen binding sites. In some aspects, VH1 and VL1 are class II antigen binding sites. In some aspects, VH2 and VL2 are class I antigen binding sites. In some aspects, VH3 and VL3 are class I antigen binding sites. In some aspects, VH4 and VL4 are class III antigen binding sites. In some aspects, VH1 and VL1 are class II antigen binding sites, VH2 and VL2 are class I antigen binding sites, VH3 and VL3 are class I antigen binding sites, and VH4 and VL4 are class III antigen binding sites.

[0102] As used herein, the term "spike protein" refers to the largest of the four major structural proteins found in the SARS-CoV-2 virus. The spike protein assembles into trimers that form large structures, called spikes or envelopes, that protrude from the surface of the SARS-CoV-2 virion and mediate the entry of the virion into the host cell. The SARS-CoV-2 spike protein is also referred to as "spike (S) glycoprotein" and "E2". The structural and functional properties of this protein have been characterized. See, for example, Huang et al., Acta Pharmacol. Sin. 41: 1141-1149, 2020; Wu et al., Nature 579 (7798): 265-269, 2020; and Gene ID: 43740568.

[0103] Antigen binding sequences of anti-SARS-CoV-2 proteins (e.g., CDR, VH, VL, heavy chain and light chain sequences from antibodies) are known and described, for example, in U.S. Patent Application No. 63 / 147,419. Such sequences include, but are not limited to, SEQ ID NOs: 1-40, 81-186 and 188-360.

[0104] As used herein, the term "antigen-binding polypeptide" refers to a polypeptide that has the ability to specifically bind to one or more substances that induce an immune response (i.e., one or more antigens or epitopes of SARS-CoV-2 proteins).

[0105] As used herein, the term "antigen-binding polypeptide complex" refers to a group of four related polypeptides that have the ability to specifically bind to one or more substances that induce an immune response (e.g., one or more antigens or epitopes of SARS-CoV-2 proteins). Antigen-binding polypeptide complexes include, but are not limited to, antibodies or antigen-binding fragments thereof.

[0106] The term "antibody" includes, but is not limited to, glycoprotein immunoglobulins that specifically bind to an antigen and comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three constant domains CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one constant domain CL. The VH and VL regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), interspersed with more conservative regions, called framework regions (FRs). Each VH and VL comprises three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: 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 the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The heavy chain may or may not have a C-terminal lysine. Unless otherwise indicated, the amino acids in the variable region are numbered using the Kabat numbering system, and the amino acids in the constant region are numbered using the EU system.

[0107] As used herein, the term "monoclonal antibody" refers to an antibody produced by a single clone of a B cell and binding to the same epitope. In contrast, the term "polyclonal antibody" refers to a population of antibodies produced by different B cells and binding to different epitopes of the same antigen. The term "antibody" includes, for example, monoclonal and polyclonal antibodies; chimeric antibodies and humanized antibodies; human or non-human antibodies; fully synthetic antibodies; and single-chain antibodies. Non-human antibodies can be humanized by recombinant methods to reduce their immunogenicity in humans.

[0108] An antibody can be an antibody that has been altered (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). For example, an antibody can include one or more variant amino acids that alter a property (e.g., a functional property) of the antibody (compared to a naturally occurring antibody). For example, several such alterations are known in the art that affect, for example, the half-life, effector function, and / or immune response to the antibody in a patient. The term antibody also includes artificial polypeptide constructs that include at least one antibody-derived antigen binding site.

[0109] An "antigen-binding fragment" of an antibody refers to one or more fragments or portions of an antibody that retain the ability to specifically bind to the antigen bound by the full antibody. It has been shown that the antigen-binding function of an antibody can be performed by a fragment or portion of a full-length antibody. An antigen-binding fragment may contain the antigenic determining regions (e.g., the complementary determining regions (CDRs)) of the full antibody. Examples of antigen-binding fragments of antibodies include, but are not limited to, Fab, Fab', F(ab') and2 And Fv fragments, linear antibodies and single-chain antibodies. Antigen-binding fragments of antibodies can be derived from any animal species, such as rodents (eg, mice, rats or hamsters) and humans, or can be artificially produced.

[0110] In addition, although the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be connected by a synthetic linker using recombinant methods, which enables them to be made into a single protein chain in which the VL and VH regions are paired to form a monovalent molecule (called single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain antibodies are also included in the term "antigen-binding fragment" of an antibody.

[0111] Antigen binding fragments are obtained using conventional techniques known to those skilled in the art, and these fragments are screened for utility in the same manner as intact antibodies. Antigen binding fragments can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.

[0112] As used herein, the term "variable region" generally refers to a part of an antibody, typically a part of a light chain or a heavy chain, typically about 110 to 120 amino acids in a mature heavy chain, or 110 to 125 amino acids of the amino terminal and about 90 to 115 amino acids of the amino terminal in a mature light chain, which are very different in sequence between antibodies, and are used for the binding and specificity of a particular antibody to its specific antigen. The variability of the sequence is concentrated in those regions referred to as complementary determining regions (CDRs), while the more highly conserved regions in the variable domains are referred to as framework regions (FRs). It is not desirable to be bound by any particular mechanism or theory, and it is believed that the CDRs of light and heavy chains are primarily responsible for the interaction and specificity of antibodies with antigens. In some respects, the variable region is a mammalian variable region, such as a human, mouse or rabbit variable region. In some respects, the variable region comprises rodent or mouse CDRs and human framework regions (FRs). In some respects, the variable region is a primate (e.g., non-human primate) variable region. In some aspects, the variable regions comprise rodent or murine CDRs and primate (eg, non-human primate) framework regions (FRs).

[0113] As used herein, the term "complementarity determining region" or "CDR" refers to each region of an antibody variable domain whose sequence is hypervariable and / or forms structurally defined loops (hypervariable loops) and / or contains antigen contact residues. An antibody may comprise six CDRs, e.g., three in VH and three in VL.

[0114] The terms "VL", "VL region" and "VL domain" are used interchangeably herein and refer to the light chain variable region of an antigen-binding polypeptide, an antigen-binding polypeptide complex, an antibody or its antigen-binding fragment. In some aspects, the VL region is referred to herein as VL1 to represent the first light chain variable region, VL2 to represent the second light chain variable region, VL3 to represent the third light chain variable region, and VL4 to represent the fourth light chain variable region. The listed VL region (e.g., VL1) may have the same or different antigen binding properties and / or the same or different sequence as another listed VL region (e.g., VL2).

[0115] The terms "VH", "VH region" and "VH domain" are used interchangeably herein and refer to the heavy chain variable region of an antigen-binding polypeptide, an antigen-binding polypeptide complex, an antibody or an antigen-binding fragment thereof. In some aspects, the VH region is referred to herein as VH1 to indicate the first heavy chain variable region, VH2 to indicate the second heavy chain variable region, and VH3 to indicate the third heavy chain variable region. A listed VH region (e.g., VH1) may have the same or different antigen binding properties and / or the same or different sequence as another listed VH region (e.g., VH2).

[0116] As used herein, "Kabat numbering" and similar terms are recognized in the art, and refer to a system for numbering the amino acid residues in the heavy chain and light chain variable region of an antibody or its antigen-binding fragment. In some aspects, CDR can be determined according to the Kabat numbering system (see, for example, Kabat EA & Wu TT (1971) Ann NY Acad Sci 190: 382-391 and Kabat EA et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242). Using the Kabat numbering system, the CDR in the antibody heavy chain molecule is usually present at amino acid positions 31 to 35, which optionally can include one or two other amino acids, followed by 35 (referred to as 35A and 35B in the Kabat numbering scheme) (CDR1), amino acid positions 50 to 65 (CDR2) and amino acid positions 95 to 102 (CDR3). Using the Kabat numbering system, CDRs within an antibody light chain molecule generally occur at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3).

[0117] As used herein, the term "constant region" or "constant domain" is used interchangeably and refers to a portion of an antigen-binding polypeptide, an antigen-binding polypeptide complex, an antibody or its antigen-binding fragment, such as a carboxyl terminal portion of a light chain and / or a heavy chain, which is not directly involved in the binding of the antibody to the antigen, but which can exhibit various effector functions, such as interactions with the Fc region. Relative to the variable region, the constant region generally has a more conservative amino acid sequence. In some aspects, the antigen-binding polypeptide, the antigen-binding polypeptide complex, the antibody or its antigen-binding fragment comprises a constant region or a portion thereof sufficient to achieve antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). The constant region includes, but is not limited to, a light chain constant region (CL) or a heavy chain constant region (CH1, CH2, CH3).

[0118] As used herein, the terms "fragment crystallizable region", "Fc region" or "Fc domain" are used interchangeably herein and refer to the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. The Fc region typically comprises CH2 and CH3 regions, and optionally comprises an immunoglobulin hinge.

[0119] As used herein, the terms "immunoglobulin hinge", "hinge", "hinge domain" or "hinge region" are used interchangeably and refer to the heavy chain fragment between the Fab and Fc portions of an antigen-binding polypeptide, an antigen-binding polypeptide complex, an antibody or an antigen-binding fragment thereof. The hinge provides structure, position and flexibility, which contributes to the normal function of the antibody (e.g., for cross-linking two antigens or binding to two antigenic determinants on the same antigen molecule). The immunoglobulin hinge is divided into an upper hinge region, a middle hinge region and a lower hinge region, which can be separated based on structure and / or genetic components. The immunoglobulin hinge of the present invention may contain one, two or all three of these regions. Structurally, the upper hinge region extends from the C-terminus of CH1 to the first hinge disulfide bond. The middle hinge region extends from the first cysteine ​​in the hinge to the last cysteine. The lower hinge region extends from the last cysteine ​​of CH2 to glycine. The cysteines present in the hinge form interchain disulfide bonds that connect immunoglobulin monomers.

[0120] As used herein, the term "Fab" refers to the region of an antibody that binds to an antigen. It is typically composed of one constant domain and one variable domain of each of the heavy and light chains.

[0121] As used herein, the term "heavy chain" refers to a part of an antigen-binding polypeptide, an antigen-binding polypeptide complex, an antibody or its antigen-binding fragment, generally consisting of a heavy chain variable region (VH), a heavy chain constant region 1 (CH1), a heavy chain constant region 2 (CH2) and a heavy chain constant region 3 (CH3). A typical antibody consists of two heavy chains and two light chains. When used to refer to an antibody, a heavy chain can refer to any different types based on the amino acid sequence of the constant region, such as alpha (α), delta (δ), epsilon (ε), gamma (γ) and mu (μ), which produce IgA, IgD, IgE, IgG and IgM class antibodies, including IgG subclasses, such as IgG1, IgG2, IgG3 and IgG4, respectively. The heavy chain amino acid sequence is known in the art. In some aspects, the heavy chain is a human heavy chain.

[0122] As used herein, the term "light chain" refers to a part of an antigen-binding polypeptide, an antigen-binding polypeptide complex, an antibody or its antigen-binding fragment, which is generally composed of a light chain variable region (VL) and a light chain constant region (CL). A typical antibody consists of two light chains and two heavy chains. When used to refer to an antibody, a light chain can refer to any different types of amino acid sequences based on the constant region, for example, kappa (κ) or lambda (λ). Light chain amino acid sequences are known in the art. In some aspects, a light chain is a human light chain.

[0123] The term "chimeric" antibody or antigen-binding fragment thereof refers to an antibody or antigen-binding fragment thereof in which the amino acid sequence is derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of an antibody or antigen-binding fragment thereof derived from one mammalian species (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capacity, while the constant region is homologous to sequences in an antibody or antigen-binding fragment thereof derived from another mammalian species (usually human) to avoid causing an immune response in that species.

[0124] The term "humanized" antibody or its antigen-binding fragment refers to the form of non-human (e.g., mouse) antibodies or antigen-binding fragments, which are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof containing minimal non-human (e.g., mouse) sequences. Typically, humanized antibodies or their antigen-binding fragments are human immunoglobulins, wherein residues from complementary determining regions (CDRs) are replaced by residues from CDRs of non-human species (e.g., mice, rats, rabbits, hamsters) with desired specificity, affinity, and ability (Jones et al., Nature 321: 522-525 (1986); Riechmann et al., Nature 332: 323-327 (1988); Verhoeyen et al., Science 239: 1534-1536 (1988)). In some aspects, the Fv framework region (FR) residues of human immunoglobulins are replaced by corresponding residues in antibodies or fragments from non-human species with desired specificity, affinity, and ability. Humanized antibodies or their antigen binding fragments can be further modified by substitution of additional residues in the Fv framework region and / or in the replaced non-human residues to improve and optimize the specificity, affinity and / or ability of the antibody or its antigen binding fragment. In general, a humanized antibody or its antigen binding fragment will contain substantially all at least one, and usually two or three variable domains, which contain all or substantially all CDR regions corresponding to non-human immunoglobulins, and all or substantially all FR regions are those of human immunoglobulin consensus sequences. A humanized antibody or its antigen binding fragment may also contain at least a portion of a constant region, typically at least a portion of a constant region of a human immunoglobulin. Examples of methods for producing humanized antibodies are known and are described in, for example, U.S. Patent No. 5,225,539; Roguska et al., Proc. Natl. Acad. Sci., USA, 91 (3): 969-973 (1994), and Roguska et al., Protein Eng. 9 (10): 895-904 (1996).

[0125] As used herein, the term "human" antibody or antigen-binding fragment thereof refers to an antibody or antigen-binding fragment thereof having an amino acid sequence derived from a human immunoglobulin locus, wherein such antibody or antigen-binding fragment is prepared using recombinant techniques known in the art. This definition of human antibodies or antigen-binding fragments thereof includes complete or full-length antibodies and fragments thereof.

[0126] An "isolated" polypeptide, polypeptide complex, antibody, antigen-binding fragment thereof, polynucleotide, vector or host cell is a polypeptide, polypeptide complex, antibody, antigen-binding fragment thereof, polynucleotide, vector or host cell that is in a form not found in nature. Isolated polypeptides, polypeptide complexes, antibodies, antigen-binding fragments thereof, polynucleotides, vectors or host cells include those that have been purified to the extent that they no longer exist in the form in which they are found in nature. In some aspects, the isolated polypeptide, polypeptide complex, antibody, antigen-binding fragment thereof, polynucleotide, vector or host cell is substantially pure. As used herein, "substantially pure" refers to a material that is at least 50% pure (i.e., free of contaminants), at least 90% pure, at least 95% pure, at least 98% pure or at least 99% pure.

[0127] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may contain modified amino acids, and it may be interrupted by non-amino acids. These terms also encompass amino acid polymers that have been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification (such as conjugation with a labeling component). Also included in the definition are, for example, polypeptides containing one or more amino acid analogs (including, for example, non-natural amino acids, etc.), as well as other modifications known in the art. It should be understood that because the polypeptides of the present invention are antibody-based, in some aspects, the polypeptides may exist as single chains or related chains.

[0128] As used herein, "isoelectric point" or "pi" refers to the pH at which the net charge of a polypeptide (eg, an antigen-binding polypeptide or antigen-binding polypeptide complex provided herein) is zero.

[0129] As used herein, "pH" refers to a quantitative measure of acidity or alkalinity. This term describes the concentration of hydrogen ions (usually between about 1 and 10). -14 gram equivalent / liter) is converted to a number between 0 and 14.

[0130] As used herein, "SARS-CoV-2 escape" refers to the process by which the SARS-CoV-2 virus acquires one or more mutations that allow the virus to evade antibodies produced by a particular vaccine.

[0131] As used herein, "SARS-CoV-2 evolution" refers to the heritable genetic changes that the SARS-CoV-2 virus accumulates during its lifespan, which can be caused by responses to environmental changes or adaptations of the host's immune response.

[0132] The use of alternatives (e.g., "or") should be understood to refer to any one, both, or combinations of the alternatives. As used herein, the indefinite articles "a / an" should be understood to refer to "one or more" of any listed or listed components.

[0133] As used herein, the term "and / or" is considered to be a specific disclosure of each of the two specified features or components together with or without the other. Therefore, the term "and / or" used herein in phrases such as "A and / or B" is meant to include: "both A and B"; "A or B"; "A" (alone); and "B" (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to cover each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0134] It should be understood that wherever aspects are described using the language "comprising," "having," etc., similar aspects described using "consisting of" and / or "consisting essentially of" are also provided.

[0135] As used herein, the term "about" refers to a value or composition within an acceptable error range of a particular value or composition determined by a person of ordinary skill in the art, which will depend in part on how to measure or determine the value or composition, i.e., the limitations of the measurement system. For example, according to the practice of the art, "about" may mean within or exceeding 1 standard deviation. Alternatively, "about" may mean a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg may include any numerical value between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). In addition, particularly for biological systems or processes, these terms may refer to up to an order of magnitude or up to 5 times of a value. When a specific value or composition is provided in the present application and claims, unless otherwise stated, the meaning of "about" should be assumed to be within an acceptable error range of the specific value or composition.

[0136] As described herein, unless otherwise indicated, any numerical range, concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer within the range, and where appropriate, include fractions thereof (such as tenths and hundredths of integers).

[0137] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure relates. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd edition, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 5th edition, 2013, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, 2006, Oxford University Press provide a general dictionary of many of the terms used in the present disclosure for those skilled in the art.

[0138] Units, prefixes and symbols are expressed in a form acceptable to the Système International de Unites (SI). Numerical ranges include the number of defined ranges. The headings provided herein are not limitations of the various aspects of the disclosure, which can be obtained by reference to the specification as a whole. Therefore, the terms defined herein are more fully defined by reference to the entirety of the specification.

[0139] Various aspects are described in more detail in the following sections.

[0140] Antigen-binding peptides and peptide complexes

[0141] Provided herein are antigen-binding polypeptides and polypeptide complexes with certain structural features. These features include a cross-dual variable (CODV) structure, which has been described in, for example, International Publication No. WO2017180913A2.

[0142] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-CL; wherein the second polypeptide has a structure represented by VH1-L2-CH1; wherein the third polypeptide has a structure represented by VH2-L3-VH3-L4-CH1; wherein the fourth polypeptide has a structure represented by VL3-L5-VL2-L6-CL; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL2 is a first immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; oV-2 protein; VL3 is the third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH2 is the second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH3 is the third immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; CH1 is the immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; and L1-L6 are amino acid linkers.

[0143] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-CL; wherein the second polypeptide has a structure represented by VH1-L2-CH1-L3-Fc; wherein the third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc; wherein the fourth polypeptide has a structure represented by VL3-L7-VL2-L8-CL; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL2 is a second immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL3 is the third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH2 is the second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH3 is the third immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; Fc is a region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is the immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; and L1-L8 are amino acid linkers.

[0144] In some aspects, VH1 and VH3 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., identical to SEQ ID NO: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 27 In some aspects, VL1 and VL3 each comprise the same CDR1, CDR2 and / or CDR3 sequence (e.g., the same as SEQ ID NO: 1). NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 -279, 285-287, 293-295, 301-303, 323-325, 331-333, 339-341, and 347-349 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical.In some aspects, VH1 and VH3 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., the same as SEQ ID NO: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 273-275, 281-283, 289-291, 297-299, 319-321, 327-329, 335-337 and 343-345 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical), and VL1 and VL3 each comprise the same CDR1, CDR2 and / or CDR3 sequence (e.g., the same as SEQ ID NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 -279, 285-287, 293-295, 301-303, 323-325, 331-333, 339-341, and 347-349 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical.In some aspects, VH2 comprises a CDR1, CDR2, and / or CDR3 sequence that is different from VH1 and VH3 (e.g., different from SEQ ID NOs: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 273-275, 281-283, 289-291, 2 97-299, 319-321, 327-329, 335-337 and 343-345 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to any one of SEQ ID NOs: 1 to 5, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequences specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0145] In some aspects, VH1 and VH2 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., identical to SEQ ID NO: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 27 In some aspects, VL1 and VL2 each comprise the same CDR1, CDR2 and / or CDR3 sequence (e.g., the same as SEQ ID NO: 1). NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 -279, 285-287, 293-295, 301-303, 323-325, 331-333, 339-341, and 347-349 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical.In some aspects, VH1 and VH2 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., the same as SEQ ID NO: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 273-275, 281-283, 289-291, 297-299, 319-321, 327-329, 335-337 and 343-345 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical), and VL1 and VL2 each comprise the same CDR1, CDR2 and / or CDR3 sequence (e.g., the same as SEQ ID NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 -279, 285-287, 293-295, 301-303, 323-325, 331-333, 339-341, and 347-349 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical.In some aspects, VH3 comprises a CDR1, CDR2, and / or CDR3 sequence that is different from VH1 and VH2 (e.g., different from SEQ ID NOs: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 273-275, 281-283, 289-291, 2 97-299, 319-321, 327-329, 335-337 and 343-345 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical), and / or VL3 comprises a CDR1, CDR2 and / or CDR3 sequence that is different from VL1 and VL2 (e.g., the same as SEQ ID NO: 1). NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequences specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0146] In some aspects, VH2 and VH3 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., identical to SEQ ID NO: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 27 In some aspects, VL2 and VL3 each comprise the same CDR1, CDR2 and / or CDR3 sequence (e.g., the same as SEQ ID NO: 1). NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 -279, 285-287, 293-295, 301-303, 323-325, 331-333, 339-341, and 347-349 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical.In some aspects, VH2 and VH3 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., identical to SEQ ID NO: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 273-275, 281-283, 289-291, 319-321, 327-329, 335-337 and 343-345 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical), and VL2 and VL3 each comprise the same CDR1, CDR2 and / or CDR3 sequence (e.g., the same as SEQ ID NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 -279, 285-287, 293-295, 301-303, 323-325, 331-333, 339-341, and 347-349 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical.In some aspects, VH1 comprises a CDR1, CDR2, and / or CDR3 sequence that is different from VH2 and VH3 (e.g., different from SEQ ID NOs: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 273-275, 281-283, 289-291, 2 97-299, 319-321, 327-329, 335-337 and 343-345 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical), and / or VL1 comprises a CDR1, CDR2 and / or CDR3 sequence that is different from VL2 and VL3 (e.g., the same as SEQ ID NO: 1). NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequences specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0147] In some aspects, VH1, VH2, and VH3 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., identical to SEQ ID NO: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 273 -275, 281-283, 289-291, 297-299, 319-321, 327-329, 335-337, and 343-345 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical. In some aspects, VL1, VL2, and VL3 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., identical to SEQ ID NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 -279, 285-287, 293-295, 301-303, 323-325, 331-333, 339-341, and 347-349 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical.In some aspects, VH1, VH2, and VH3 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., identical to SEQ ID NO: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 273-275, 281-283, 289-291, 29 7-299, 319-321, 327-329, 335-337 and 343-345 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical), and VL1, VL2 and VL3 each comprise the same CDR1, CDR2 and / or CDR3 sequence (e.g., the same as SEQ ID NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequences specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0148] In some aspects, VH1, VH2, and VH3 each comprise a different CDR1, CDR2, and / or CDR3 sequence (e.g., identical to SEQ ID NO: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 273 -275, 281-283, 289-291, 297-299, 319-321, 327-329, 335-337, and 343-345 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical. In some aspects, VL1, VL2, and VL3 each comprise a different CDR1, CDR2, and / or CDR3 sequence (e.g., identical to SEQ ID NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 -279, 285-287, 293-295, 301-303, 323-325, 331-333, 339-341, and 347-349 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical.In some aspects, VH1, VH2, and VH3 each comprise a different CDR1, CDR2, and / or CDR3 sequence (e.g., identical to SEQ ID NO: 2-4, 10-12, 18-20, 26-28, 34-36, 148-150, 160-162, 168-170, 176-178, 184-186, 193-195, 201-203, 209-211, 217-219, 225-227, 233-235, 241-243, 249-251, 257-259, 265-267, 273-275, 281-283, 289-291, 29 7-299, 319-321, 327-329, 335-337 and 343-345 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical), and VL1, VL2 and VL3 each comprise a different CDR1, CDR2 and / or CDR3 sequence (e.g., identical to SEQ ID NO:6-8, 14-16, 22-24, 30-32, 38-40, 152-154, 156-158, 164-166, 172-174, 180-182, 197-19 9. 205-207, 213-215, 221-223, 229-231, 237-239, 245-247, 253-255, 261-263, 269-271, 277 In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequences specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0149] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2 and VH3) each independently comprises a CDR1 comprising the sequence of SEQ ID NO: 2, 10, 18, 26, 34, 148, 160, 168, 176, 184, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 319, 327, 335 and 343 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to any one of SEQ ID NO: NO:3, 11, 19, 27, 35, 149, 161, 169, 177, 185, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 320, 328, 336 and 344 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and / or CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to any one of SEQ ID NO:4, 12, 20, 28, 36, 150, 162, 170, 178, 186, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 321, 329, 337 and 345 have an amino acid sequence of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity with the corresponding amino acid sequences specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0150] In some aspects, VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) each independently comprises a CDR1 comprising a sequence identical to SEQ ID NO:6, 14, 22, 30, 38, 152, 156, 164, 172, 180, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 323, 331, 339 and 347 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to any one of SEQ ID NO:7 (sequence with SAS), 15 (sequence with GTN), 23 (sequence with GAS), 31 (sequence with DAS) and 39 (sequence with GAS), 153, 157, 165 (sequence with GAS), 173 (sequence with LGS), 181, 198 (sequence with DAS), 206 (sequence with DVS), 214 (sequence with EDS), 222 (sequence with KDS), 230 (sequence with DAS), 238 (sequence with AAS), 246 (sequence with GAS), 254 (sequence with DDS), 262 (sequence with KDS), , at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NO: 270 (sequence with SAS), 278 (sequence with SAS), 286 (sequence with GAS), 294 (sequence with GAS), 302 (sequence with GAS), 324 (sequence with GAS), 332 (sequence with DAS), 340 (sequence with SAS), and 348 (sequence with GAS); and / or a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NO: 271 (sequence with SAS), 278 (sequence with SAS), 286 (sequence with GAS), 294 (sequence with GAS), 302 (sequence with GAS), 324 (sequence with GAS), 332 (sequence with DAS), 340 (sequence with SAS), and 348 (sequence with GAS); and / or a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NO: 272 any of ID NOs: 8, 16, 24, 32, 40, 154, 158, 166, 174, 182, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 325, 333, 341, and 349 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical.In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity with the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity with the reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequence specified above.

[0151] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2 and VH3) each independently comprises a CDR1 comprising the sequence of SEQ ID NO: 2, 10, 18, 26, 34, 148, 160, 168, 176, 184, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 319, 327, 335 and 343 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to any one of SEQ ID NO: NO:3, 11, 19, 27, 35, 149, 161, 169, 177, 185, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 320, 328, 336 and 344 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and / or CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to any one of SEQ ID NO:4, 12, 20, 28, 36, 150, 162, 170, 178, 186, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 321, 329, 337 and 345 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3;VL1, VL2 and VL3) each independently comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to any one of SEQ ID NO:6, 14, 22, 30, 38, 152, 156, 164, 172, 180, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 323, 331, 339 and 347; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to any one of SEQ ID NO:6, 14, 22, 30, 38, 152, 156, 164, 172, NO: 7 (sequence with SAS), 15 (sequence with GTN), 23 (sequence with GAS), 31 (sequence with DAS) and 39 (sequence with GAS), 153, 157, 165 (sequence with GAS), 173 (sequence with LGS), 181, 198 (sequence with DAS), 206 (sequence with DVS), 214 (sequence with EDS), 222 (sequence with KDS), 230 (sequence with DAS), 238 (sequence with AAS), 246 (sequence with GAS), 254 (sequence with DDS), 262 (sequence with ), 270 (sequence with KDS), 278 (sequence with SAS), 286 (sequence with GAS), 294 (sequence with GAS), 302 (sequence with GAS), 324 (sequence with GAS), 332 (sequence with DAS), 340 (sequence with SAS), and 348 (sequence with GAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical;and / or a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NO: 8, 16, 24, 32, 40, 154, 158, 166, 174, 182, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 325, 333, 341, and 349. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity with the corresponding amino acid sequences specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity with the reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above. ;

[0152] In some aspects, VH1, VH2, and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19. NO:20 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some preferred aspects, VH1, VH2 and VH3 each comprise a CDR1 comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:18; a CDR2 comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:19; and a CDR3 comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:20. As used herein, "at least 90% identical" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identical to the reference sequence. In some particularly preferred aspects, VH1, VH2 and VH3 each comprise a CDR1 comprising the amino acid sequence of SEQ ID NO: 18; a CDR2 comprising the amino acid sequence of SEQ ID NO: 19; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 20.

[0153] In some aspects, VL1, VL2, and VL3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 (sequence with GAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 (sequence with GAS); NO:24 has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity. In some preferred aspects, VL1, VL2 and VL3 each comprise a CDR1 comprising an amino acid sequence with at least 90% identity to SEQ ID NO:22; a CDR2 comprising an amino acid sequence with at least 90% identity to SEQ ID NO:23 (sequence with GAS); and a CDR3 comprising an amino acid sequence with at least 90% identity to SEQ ID NO:24. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VL1, VL2 and VL3 each comprise a CDR1 comprising the amino acid sequence of SEQ ID NO: 22; a CDR2 comprising the amino acid sequence of SEQ ID NO: 23 (having a sequence of GAS); and a CDR3 comprising the amino acid sequence of SEQ ID NO: 24.

[0154] In some aspects, VH1, VH2, and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19. NO:20 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and VL3 each comprise a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:22; and a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:22. NO:23 (sequence with GAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:24. In some preferred aspects, VH1, VH2 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; and VL1, VL2 and VL3 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24.As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VH1, VH2 and VH3 each comprise a CDR1 comprising the amino acid sequence of SEQ ID NO: 18; a CDR2 comprising the amino acid sequence of SEQ ID NO: 19; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and VL1, VL2 and VL3 each comprise a CDR1 comprising the amino acid sequence of SEQ ID NO: 22; a CDR2 comprising the amino acid sequence of SEQ ID NO: 23 (with a sequence of GAS); and a CDR3 comprising the amino acid sequence of SEQ ID NO: 24.

[0155] In some aspects, VH1 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19. NO:20 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; and VH2 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26; and a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26. NO:27 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28. In some preferred aspects, VH1 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; and VH2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28.As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VH1 and VH3 each comprise a CDR1 comprising the amino acid sequence of SEQ ID NO: 18; a CDR2 comprising the amino acid sequence of SEQ ID NO: 19; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and VH2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 26; a CDR2 comprising the amino acid sequence of SEQ ID NO: 27; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0156] In some aspects, VL1 and VL3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 (sequence with GAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 (sequence with GAS); NO:24 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; and VL2 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:30; and a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:31. NO:31 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32. In some preferred aspects, VL1 and VL3 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24; and VL2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 30; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31 (a sequence having DAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32.As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VL1 and VL3 each comprise a CDR1 comprising the amino acid sequence of SEQ ID NO: 22; a CDR2 comprising the amino acid sequence of SEQ ID NO: 23 (having a sequence of GAS); and a CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and VL2 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 30; a CDR2 comprising the amino acid sequence of SEQ ID NO: 31 (having a sequence of DAS); and a CDR3 comprising the amino acid sequence of SEQ ID NO: 32.

[0157] In some aspects, VH1 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19. NO:20 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VH2 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26; CDR2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26; NO:27 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28; VL1 and VL3 each comprise a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28; NO:22 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:23 (sequence having GAS);and CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:24; and VL2 comprises CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:30; and CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:31. NO:31 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32. In some preferred aspects, VH1 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; and VH2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28; VL1 and VL3 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: NO:24 has at least 90% identity to the amino acid sequence; and VL2 comprises CDR1, which comprises an amino acid sequence at least 90% identical to SEQ ID NO:30; CDR2, which comprises an amino acid sequence at least 90% identical to SEQ ID NO:31 (sequence with DAS);and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32. As used herein, "at least 90% identical" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identical to the reference sequence. In some particularly preferred aspects, VH1 and VH3 each comprise a CDR1 comprising an amino acid sequence of SEQ ID NO: 18; a CDR2 comprising an amino acid sequence of SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence of SEQ ID NO: 20; VH2 comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 26; a CDR2 comprising an amino acid sequence of SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence of SEQ ID NO: 28; VL1 and VL3 each comprise a CDR1 comprising an amino acid sequence of SEQ ID NO: 22; a CDR2 comprising an amino acid sequence of SEQ ID NO: 23 (having a sequence of GAS); and a CDR3 comprising an amino acid sequence of SEQ ID NO: 24; and VL2 comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 30; a CDR2 comprising an amino acid sequence of SEQ ID NO: 31 (having a sequence of DAS); and a CDR3 comprising an amino acid sequence of SEQ ID NO: 32. ;

[0158] In some aspects, VH1 and VH2 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19. NO:20 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; and VH3 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26; and a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26. NO:27 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28. In some preferred aspects, VH1 and VH2 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; and VH3 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28.As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VH1 and VH2 each comprise a CDR1 comprising the amino acid sequence of SEQ ID NO: 18; a CDR2 comprising the amino acid sequence of SEQ ID NO: 19; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and VH3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 26; a CDR2 comprising the amino acid sequence of SEQ ID NO: 27; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0159] In some aspects, VL1 and VL2 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 (sequence with GAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 (sequence with GAS); NO:24 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; and VL3 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:30; and a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:31; NO:31 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32. In some preferred aspects, VL1 and VL2 each comprise CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO:22; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO:23 (a sequence with GAS); and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO:24; and VL3 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO:30; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO:31 (a sequence with DAS); and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO:32.As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VL1 and VL2 each comprise a CDR1 comprising the amino acid sequence of SEQ ID NO: 22; a CDR2 comprising the amino acid sequence of SEQ ID NO: 23 (having a sequence of GAS); and a CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and VL3 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 30; a CDR2 comprising the amino acid sequence of SEQ ID NO: 31 (having a sequence of DAS); and a CDR3 comprising the amino acid sequence of SEQ ID NO: 32.

[0160] In some aspects, VH1 and VH2 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19. NO:20 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VH3 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26; CDR2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26; NO:27 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28; VL1 and VL2 each comprise a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28; NO:22 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:23 (sequence having GAS);and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24; and VL3 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 30; and a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31. NO:31 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32. In some preferred aspects, VH1 and VH2 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; VH3 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28; VL1 and VL2 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24. NO:24 has an amino acid sequence at least 90% identical to; and VL3 comprises CDR1, which comprises an amino acid sequence at least 90% identical to SEQ ID NO:30; CDR2, which comprises an amino acid sequence at least 90% identical to SEQ ID NO:31 (sequence with DAS);and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32. As used herein, "at least 90% identical" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identical to the reference sequence. In some particularly preferred aspects, VH1 and VH2 each comprise a CDR1 comprising an amino acid sequence of SEQ ID NO: 18; a CDR2 comprising an amino acid sequence of SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence of SEQ ID NO: 20; VH3 comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 26; a CDR2 comprising an amino acid sequence of SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence of SEQ ID NO: 28; VL1 and VL2 each comprise a CDR1 comprising an amino acid sequence of SEQ ID NO: 22; a CDR2 comprising an amino acid sequence of SEQ ID NO: 23 (having a sequence of GAS); and a CDR3 comprising an amino acid sequence of SEQ ID NO: 24; and VL3 comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 30; a CDR2 comprising an amino acid sequence of SEQ ID NO: 31 (having a sequence of DAS); and a CDR3 comprising an amino acid sequence of SEQ ID NO: 32. ;

[0161] In some aspects, VH2 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19. NO:20 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; and VH1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26; and a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26. NO:27 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28. In some preferred aspects, VH2 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; and VH1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28.As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VH2 and VH3 each comprise a CDR1 comprising the amino acid sequence of SEQ ID NO: 18; a CDR2 comprising the amino acid sequence of SEQ ID NO: 19; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and VH1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 26; a CDR2 comprising the amino acid sequence of SEQ ID NO: 27; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 28.

[0162] In some aspects, VL2 and VL3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 (sequence with GAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 (sequence with GAS); NO:24 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; and VL1 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:30; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:31; NO:31 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32. In some preferred aspects, VL2 and VL3 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24; and VL1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 30; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31 (a sequence having DAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32.As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VL2 and VL3 each comprise a CDR1 comprising the amino acid sequence of SEQ ID NO: 22; a CDR2 comprising the amino acid sequence of SEQ ID NO: 23 (having a sequence of GAS); and a CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and VL1 comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 30; a CDR2 comprising the amino acid sequence of SEQ ID NO: 31 (having a sequence of DAS); and a CDR3 comprising the amino acid sequence of SEQ ID NO: 32.

[0163] In some aspects, VH2 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19. NO:20 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VH1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26; CDR2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26; NO:27 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28; VL2 and VL3 each comprise a CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28; NO:22 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:23 (sequence having GAS);and CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:24; and VL1 comprises CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:30; and CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:31. NO:31 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32. In some preferred aspects, VH2 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; and VH1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28; VL2 and VL3 each comprise a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24. NO:24 has at least 90% identity to the amino acid sequence; and VL1 comprises CDR1, which comprises an amino acid sequence at least 90% identical to SEQ ID NO:30; CDR2, which comprises an amino acid sequence at least 90% identical to SEQ ID NO:31 (sequence with DAS);and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32. As used herein, "at least 90% identical" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identical to the reference sequence. In some particularly preferred aspects, VH2 and VH3 each comprise a CDR1 comprising an amino acid sequence of SEQ ID NO: 18; a CDR2 comprising an amino acid sequence of SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence of SEQ ID NO: 20; VH1 comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 26; a CDR2 comprising an amino acid sequence of SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence of SEQ ID NO: 28; VL2 and VL3 each comprise a CDR1 comprising an amino acid sequence of SEQ ID NO: 22; a CDR2 comprising an amino acid sequence of SEQ ID NO: 23 (having a sequence of GAS); and a CDR3 comprising an amino acid sequence of SEQ ID NO: 24; and VL1 comprises a CDR1 comprising an amino acid sequence of SEQ ID NO: 30; a CDR2 comprising an amino acid sequence of SEQ ID NO: 31 (having a sequence of DAS); and a CDR3 comprising an amino acid sequence of SEQ ID NO: 32. ;

[0164] In some aspects, VH1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11. NO:12 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VH2 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:18; CDR2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:18; NO:19 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:20; and VH3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:20 NO:26 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:27;and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28. In some preferred aspects, VH1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 12; VH2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; and VH3 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VH1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 10; CDR2 comprising the amino acid of SEQ ID NO: 11; and CDR3 comprising the amino acid sequence of SEQ ID NO: 12; VH2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 18; CDR2 comprising the amino acid sequence of SEQ ID NO: 19; and CDR3 comprising the amino acid sequence of SEQ ID NO: 20; and VH3 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 26; CDR2 comprising the amino acid sequence of SEQ ID NO: 27; and CDR3 comprising the amino acid sequence of SEQ ID NO: 28. ;

[0165] In some aspects, VL1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 15 (sequence with GTN); and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 15 (sequence with GTN); NO:16 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VL2 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:22; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:22 NO:23 (sequence with GAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:24; and VL3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:24; NO:30 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:31 (sequence with DAS);and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32. In some preferred aspects, VL1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 14; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 15 (a sequence having GTN); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 16; VL2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24; and VL3 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 30; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31 (a sequence having DAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: NO:32 has an amino acid sequence with at least 90% identity. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VL1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 14; CDR2 comprising the amino acid sequence of SEQ ID NO: 15 (having a sequence of GTN); and CDR3 comprising the amino acid sequence of SEQ ID NO: 16; VL2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 22; CDR2 comprising the amino acid sequence of SEQ ID NO: 23 (having a sequence of GAS); and CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and VL3 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 30; CDR2 comprising the amino acid sequence of SEQ ID NO: 31 (having a sequence of DAS); and CDR3 comprising the amino acid sequence of SEQ ID NO: 32. ;

[0166] In some aspects, VH1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11. NO:12 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VH2 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:18; CDR2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:18; NO:19 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:20; VH3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:20 NO:26 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:27;and CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 28; VL1 comprises CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14; and CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14. NO:15 (sequence with GTN) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:16; VL2 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:16 , at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 23 (sequence having GAS); and a CDR3 comprising an amino acid sequence identical to SEQ ID NO: 24 (sequence having GAS). NO:24 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; and VL3 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:30;CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:31 (sequence with DAS); and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32. In some preferred aspects, VH1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 12; VH2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; VH3 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28; VL1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: NO:14 having at least 90% identity; CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:15 (sequence having GTN); and CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:16; VL2 comprises CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:22; CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:23 (sequence having GAS); and CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:24; and VL3 comprises CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:30; CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:31 (sequence having DAS);and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32. As used herein, "at least 90% identical" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identical to the reference sequence. In some particularly preferred aspects, VH1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 10; CDR2 comprising the amino acid of SEQ ID NO: 11; and CDR3 comprising the amino acid sequence of SEQ ID NO: 12; VH2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 18; CDR2 comprising the amino acid sequence of SEQ ID NO: 19; and CDR3 comprising the amino acid sequence of SEQ ID NO: 20; VH3 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 26; CDR2 comprising the amino acid sequence of SEQ ID NO: 27; and CDR3 comprising the amino acid sequence of SEQ ID NO: 28; VL1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 14; CDR2 comprising the amino acid sequence of SEQ ID NO: 15 (sequence with GTN); and CDR3 comprising the amino acid sequence of SEQ ID NO: 16; VL2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: NO:22 amino acid sequence; CDR2, which comprises the amino acid sequence of SEQ ID NO:23 (sequence with GAS); and CDR3, which comprises the amino acid sequence of SEQ ID NO:24; and VL3 comprises CDR1, which comprises the amino acid sequence of SEQ ID NO:30; CDR2, which comprises the amino acid sequence of SEQ ID NO:31 (sequence with DAS); and CDR3, which comprises the amino acid sequence of SEQ ID NO:32. ;

[0167] In some aspects, VH1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11. NO:12 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VH2 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26; CDR2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:26 NO:27 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28; and VH3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28; NO:18 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:19;and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:20. In some preferred aspects, VH1 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 10; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 11; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 12; VH2 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28; and VH3 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VH1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 10; CDR2 comprising the amino acid sequence of SEQ ID NO: 11; and CDR3 comprising the amino acid sequence of SEQ ID NO: 12; VH2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 26; CDR2 comprising the amino acid sequence of SEQ ID NO: 27; and CDR3 comprising the amino acid sequence of SEQ ID NO: 28; and VH3 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 18; CDR2 comprising the amino acid sequence of SEQ ID NO: 19; and CDR3 comprising the amino acid sequence of SEQ ID NO: 20. ;

[0168] In some aspects, VL1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 15 (sequence with GTN); and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 15 (sequence with GTN); NO:16 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VL2 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:30; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:31; NO:31 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32; and VL3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32; NO:22 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:23 (sequence having GAS);and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:24. In some preferred aspects, VL1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 14; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 15 (a sequence with GTN); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 16; VL2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 30; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31 (a sequence with DAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32; and VL3 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 (a sequence with GAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: NO:24 has an amino acid sequence with at least 90% identity. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VL1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 14; CDR2 comprising the amino acid sequence of SEQ ID NO: 15 (having a sequence of GTN); and CDR3 comprising the amino acid sequence of SEQ ID NO: 16; VL2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 30; CDR2 comprising the amino acid sequence of SEQ ID NO: 31 (having a sequence of DAS); and CDR3 comprising the amino acid sequence of SEQ ID NO: 32; and VL3 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 22; CDR2 comprising the amino acid sequence of SEQ ID NO: 23 (having a sequence of GAS); and CDR3 comprising the amino acid sequence of SEQ ID NO: 24. ;

[0169] In some aspects, VH1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11. NO:12 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; VH2 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 99% or 100% identical to SEQ ID NO:26; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:27; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:28. NO:28 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; and VH3 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:18; and a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:18; NO:19 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:20;VL1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 91%, at least 92%, at least 93%, at least 94%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 15 (sequence with GTN); and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: NO:16 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VL2 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:30; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:31; NO:31 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32; and VL3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32. NO:22 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:23 (sequence having GAS);and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:24. In some preferred aspects, VH1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 12; VH2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28; VH3 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; VL1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: NO:14 having at least 90% identity; CDR2 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:15 (sequence having GTN); and CDR3 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:16; VL2 comprises CDR1 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:30; CDR2 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:31 (sequence having DAS); and CDR3 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:32; and VL3 comprises CDR1 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:22; CDR2 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:23 (sequence having GAS); and CDR3 comprising an amino acid sequence having at least 90% identity with SEQ ID NO:24. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VH1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 10;CDR2, which comprises the amino acid sequence of SEQ ID NO: 11; and CDR3, which comprises the amino acid sequence of SEQ ID NO: 12; VH2 comprises CDR1, which comprises the amino acid sequence of SEQ ID NO: 26; CDR2, which comprises the amino acid sequence of SEQ ID NO: 27; and CDR3, which comprises the amino acid sequence of SEQ ID NO: 28; VH3 comprises CDR1, which comprises the amino acid sequence of SEQ ID NO: 18; CDR2, which comprises the amino acid sequence of SEQ ID NO: 19; and CDR3, which comprises the amino acid sequence of SEQ ID NO: 20; VL1 comprises CDR1, which comprises the amino acid sequence of SEQ ID NO: 14; CDR2, which comprises the amino acid sequence of SEQ ID NO: 15 (sequence with GTN); and CDR3, which comprises the amino acid sequence of SEQ ID NO: 16; VL2 comprises CDR1, which comprises the amino acid sequence of SEQ ID NO: 30; CDR2, which comprises the amino acid sequence of SEQ ID NO: NO:31 (having a sequence of DAS); and CDR3 comprising an amino acid sequence of SEQ ID NO:32; and VL3 comprising CDR1 comprising an amino acid sequence of SEQ ID NO:22; CDR2 comprising an amino acid sequence of SEQ ID NO:23 (having a sequence of GAS); and CDR3 comprising an amino acid sequence of SEQ ID NO:24. ;

[0170] In some aspects, VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27. NO:28 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VH2 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:10; CDR2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:11; NO:11 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:12; and VH3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:12 NO:18 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:19;and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:20. In some preferred aspects, VH1 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO:26; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO:27; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO:28; VH2 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO:10; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO:11; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO:12; and VH3 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO:18; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO:19; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO:20. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VH1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO:26; CDR2 comprising the amino acid sequence of SEQ ID NO:27; and CDR3 comprising the amino acid sequence of SEQ ID NO:28; VH2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO:10; CDR2 comprising the amino acid sequence of SEQ ID NO:11; and CDR3 comprising the amino acid sequence of SEQ ID NO:12; and VH3 comprises CDR1 comprising the amino acid sequence of SEQ ID NO:18; CDR2 comprising the amino acid sequence of SEQ ID NO:19; and CDR3 comprising the amino acid sequence of SEQ ID NO:20. ;

[0171] In some aspects, VL1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 30; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31 (sequence with DAS); and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: NO:32 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VL2 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:14; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:14 NO:15 (sequence with GTN) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:16; and VL3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:16 NO:22 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:23 (sequence having GAS);and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:24. In some preferred aspects, VL1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 30; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31 (a sequence having DAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32; VL2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 14; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 15 (a sequence having GTN); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 16; and VL3 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: NO:24 has an amino acid sequence with at least 90% identity. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VL1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 30; CDR2 comprising the amino acid sequence of SEQ ID NO: 31 (having the sequence of DAS); and CDR3 comprising the amino acid sequence of SEQ ID NO: 32; VL2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 14; CDR2 comprising the amino acid sequence of SEQ ID NO: 15 (having the sequence of GTN); and CDR3 comprising the amino acid sequence of SEQ ID NO: 16; and VL3 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 22; CDR2 comprising the amino acid sequence of SEQ ID NO: 23 (having the sequence of GAS); and CDR3 comprising the amino acid sequence of SEQ ID NO: 24. ;

[0172] In some aspects, VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27. NO:28 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VH2 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:10; CDR2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:11; NO:11 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:12; VH3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:12; NO:18 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:19;and CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:20; VL1 comprises CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:30; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:30; NO:31 (sequence with DAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32; VL2 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32; , at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 14; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 15 (sequence with GTN); and a CDR3 comprising an amino acid sequence identical to SEQ ID NO: 16 (sequence with GTN). NO:16 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; and VL3 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:22;CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:23 (sequence with GAS); and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:24. In some preferred aspects, VH1 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28; VH2 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 10; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 11; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 12; VH3 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; VL1 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 1 NO:30 having at least 90% identity; CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:31 (sequence having DAS); and CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:32; VL2 comprises CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:14; CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:15 (sequence having GTN); and CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:16; and VL3 comprises CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:22; CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:23 (sequence having GAS);and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24. As used herein, "at least 90% identical" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identical to the reference sequence. In some particularly preferred aspects, VH1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 26; CDR2 comprising the amino acid sequence of SEQ ID NO: 27; and CDR3 comprising the amino acid sequence of SEQ ID NO: 28; VH2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 10; CDR2 comprising the amino acid sequence of SEQ ID NO: 11; and CDR3 comprising the amino acid sequence of SEQ ID NO: 12; VH3 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 18; CDR2 comprising the amino acid sequence of SEQ ID NO: 19; and CDR3 comprising the amino acid sequence of SEQ ID NO: 20; VL1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 30; CDR2 comprising the amino acid sequence of SEQ ID NO: 31 (sequence with DAS); and CDR3 comprising the amino acid sequence of SEQ ID NO: 32; VL2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: NO:14 amino acid sequence; CDR2, which comprises the amino acid sequence of SEQ ID NO:15 (having the sequence of GTN); and CDR3, which comprises the amino acid sequence of SEQ ID NO:16; and VL3 comprises CDR1, which comprises the amino acid sequence of SEQ ID NO:22; CDR2, which comprises the amino acid sequence of SEQ ID NO:23 (having the sequence of GAS); and CDR3, which comprises the amino acid sequence of SEQ ID NO:24. ;

[0173] In some aspects, VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27. NO:28 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VH2 comprises a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:18; CDR2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:18 NO:19 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:20; and VH3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:20 NO:10 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:11;and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:12. In some preferred aspects, VH1 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO:26; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO:27; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO:28; VH2 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO:18; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO:19; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO:20; and VH3 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO:10; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO:11; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO:12. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VH1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO:26; CDR2 comprising the amino acid sequence of SEQ ID NO:27; and CDR3 comprising the amino acid sequence of SEQ ID NO:28; VH2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO:18; CDR2 comprising the amino acid sequence of SEQ ID NO:19; and CDR3 comprising the amino acid sequence of SEQ ID NO:20; and VH3 comprises CDR1 comprising the amino acid sequence of SEQ ID NO:10; CDR2 comprising the amino acid sequence of SEQ ID NO:11; and CDR3 comprising the amino acid sequence of SEQ ID NO:12. ;

[0174] In some aspects, VL1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 30; a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31 (sequence with DAS); and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: NO:32 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VL2 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:22; CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:22 NO:23 (sequence with GAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:24; and VL3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:24; NO:14 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:15 (sequence with GTN);and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:16. In some preferred aspects, VL1 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 30; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31 (a sequence having DAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32; VL2 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24; and VL3 comprises a CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 14; a CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 15 (a sequence having GTN); and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: NO: 16 has an amino acid sequence with at least 90% identity. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VL1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 30; CDR2 comprising the amino acid sequence of SEQ ID NO: 31 (having a sequence of DAS); and CDR3 comprising the amino acid sequence of SEQ ID NO: 32; VL2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 22; CDR2 comprising the amino acid sequence of SEQ ID NO: 23 (having a sequence of GAS); and CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and VL3 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 14; CDR2 comprising the amino acid sequence of SEQ ID NO: 15 (having a sequence of GTN); and CDR3 comprising the amino acid sequence of SEQ ID NO: 16. ;

[0175] In some aspects, VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27. NO:28 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; VH2 comprises a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:18; CDR2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:18 NO:19 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:20; VH3 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:20 NO:10 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:11;and CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12; VL1 comprises CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 30; CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; NO:31 (sequence with DAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32; VL2 comprises CDR1, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:32; , at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 23 (sequence having GAS); and a CDR3 comprising an amino acid sequence identical to SEQ ID NO: 24 (sequence having GAS). NO:24 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical; and VL3 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:14;CDR2, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:15 (sequence with GTN); and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:16. In some preferred aspects, VH1 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 26; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 27; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 28; VH2 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20; VH3 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 10; CDR2 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 11; and CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 12; VL1 comprises CDR1 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 13; NO:30 having at least 90% identity; CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:31 (sequence having DAS); and CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:32; VL2 comprises CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:22; CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:23 (sequence having GAS); and CDR3 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:24; and VL3 comprises CDR1 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:14; CDR2 comprising an amino acid sequence having at least 90% identity to SEQ ID NO:15 (sequence having GTN);and a CDR3 comprising an amino acid sequence at least 90% identical to SEQ ID NO: 16. As used herein, "at least 90% identical" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identical to the reference sequence. In some particularly preferred aspects, VH1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 26; CDR2 comprising the amino acid sequence of SEQ ID NO: 27; and CDR3 comprising the amino acid sequence of SEQ ID NO: 28; VH2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 18; CDR2 comprising the amino acid sequence of SEQ ID NO: 19; and CDR3 comprising the amino acid sequence of SEQ ID NO: 20; VH3 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 10; CDR2 comprising the amino acid sequence of SEQ ID NO: 11; and CDR3 comprising the amino acid sequence of SEQ ID NO: 12; VL1 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: 30; CDR2 comprising the amino acid sequence of SEQ ID NO: 31 (sequence with DAS); and CDR3 comprising the amino acid sequence of SEQ ID NO: 32; VL2 comprises CDR1 comprising the amino acid sequence of SEQ ID NO: NO:22 amino acid sequence; CDR2, which comprises the amino acid sequence of SEQ ID NO:23 (having the sequence of GAS); and CDR3, which comprises the amino acid sequence of SEQ ID NO:24; and VL3 comprises CDR1, which comprises the amino acid sequence of SEQ ID NO:14; CDR2, which comprises the amino acid sequence of SEQ ID NO:15 (having the sequence of GTN); and CDR3, which comprises the amino acid sequence of SEQ ID NO:16. ;

[0176] In some aspects, VH1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 148. In some aspects, VH1 comprises a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 149. In some aspects, VH1 comprises a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 150. In some aspects, VH2 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 148. In some aspects, VH2 comprises a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 149. In some aspects, VH2 comprises a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 150. In some aspects, the VH3 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 148. In some aspects, the VH3 comprises a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 149.In some aspects, VH3 comprises a CDR3 comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 150. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2 and VH3 are at least 90% identical to the corresponding amino acid sequences specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2 and VH3 comprise or consist of the corresponding amino acid sequences specified above.

[0177] In some aspects, VL1 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 152. In some aspects, VL1 comprises a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 153. In some aspects, VL1 comprises a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 154. In some aspects, VL2 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 152. In some aspects, VL2 comprises a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 153. In some aspects, VL2 comprises a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 154. In some aspects, VL3 comprises a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 152. In some aspects, VL3 comprises a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 153.In some aspects, VL3 comprises a CDR3 comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 154. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of each of VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequence specified above.

[0178] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 193; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 194; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 194. NO:195 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:197; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:197; NO: 198 (sequence with DAS) having an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 199. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0179] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 201; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 202; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 202. NO:203 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:205; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:205; NO: 206 (sequence with DVS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 207. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0180] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 209; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 210; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 211; NO:211 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:213; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:214; NO: 214 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 215. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0181] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 217; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 218; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 219. NO:219 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:221; and a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:221. NO: 222 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 223. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0182] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 225; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 226; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 226. NO:227 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:229; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:229; NO: 230 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 231. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0183] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 233; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 234; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 234. NO:235 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:237; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:237; NO:238 (sequence with AAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:239. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0184] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 241; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 242; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 242. NO:243 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:245; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:245; NO: 246 (sequence with GAS) has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity; and CDR3, which comprises an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 247. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0185] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 249; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 250; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 251. NO:251 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:253; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:253; NO:254 (sequence with DDS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:255. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0186] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 257; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 258; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 259. NO:259 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:261; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:261; NO: 262 (sequence with KDS) has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity; and CDR3, which comprises an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 263. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0187] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 265; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 266; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 267. NO:267 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:269; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:269; NO: 270 (sequence with SAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 271. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0188] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 273; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 274; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 274. NO:275 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:277; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:277; NO: 278 (sequence with SAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO: 279. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0189] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 281; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 282; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 282. NO:283 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:285; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:285; NO:286 (sequence with GAS) has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity; and CDR3, which comprises an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO:287. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0190] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 289; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 290; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 291. NO:291 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:293; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:293; NO: 294 (sequence with GAS) has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity; and CDR3, which comprises an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO: 295. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0191] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 297; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 298; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 298. NO:299 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:301; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:301; NO:302 (sequence with GAS) has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity; and CDR3, which comprises an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO:303. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0192] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 319; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 320; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 321. NO:321 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:323; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:323; NO:324 (sequence with GAS) has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity; and CDR3, which comprises an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO:325. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0193] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 327; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 328; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 329; NO:329 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:331; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:331; NO:332 (sequence with DAS) has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:333. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0194] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 335; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 336; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 337. NO:337 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:339; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:339; NO:340 (sequence with SAS) has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity; and CDR3, which comprises an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO:341. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0195] In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 343; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 344; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 345. NO:345 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise a CDR1 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:347; a CDR2 that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ ID NO:348; NO:348 (sequence with GAS) has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity; and CDR3, which comprises an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to SEQ ID NO:349. In some preferred aspects, the CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 have at least 90% identity to the corresponding amino acid sequence specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence.In some particularly preferred aspects, CDR1, CDR2 and CDR3 of each of VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above.

[0196] In some aspects, VH1 comprises the same heavy chain variable region as VH3. In some aspects, VL1 comprises the same light chain variable region as VL3. In some aspects, VH1 comprises the same heavy chain variable region as VH3, and VL1 comprises the same light chain variable region as VL3.

[0197] In some aspects, VH1 comprises the same heavy chain variable region as VH2. In some aspects, VL1 comprises the same light chain variable region as VL2. In some aspects, VH1 comprises the same heavy chain variable region as VH2, and VL1 comprises the same light chain variable region as VL2.

[0198] In some aspects, VH2 comprises the same heavy chain variable region as VH3. In some aspects, VL2 comprises the same light chain variable region as VL3. In some aspects, VH2 comprises the same heavy chain variable region as VH3, and VL2 comprises the same light chain variable region as VL3.

[0199] In some aspects, VH1, VH2 and VH3 each comprise the same variable region of heavy chain. In some aspects, VL1, VL2 and VL3 each comprise the same variable region of light chain. In some aspects, VH1, VH2 and VH3 each comprise the same variable region of heavy chain, and VL1, VL2 and VL3 each comprise the same variable region of light chain.

[0200] In some aspects, VH1, VH2, and VH3 each comprise a different heavy chain variable region. In some aspects, VL1, VL2, and VL3 each comprise a different light chain variable region. In some aspects, VH1, VH2, and VH3 each comprise a different heavy chain variable region, and VL1, VL2, and VL3 each comprise a different light chain variable region. In some aspects, VH1, VH2, and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2, and VH3) comprise the same as SEQ ID any of NOS: 1, 9, 17, 25, 33, 147, 159, 167, 175, 183, 190, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 306, 308, 310, 312, 314, 316, 318, 326, 334, 342, 351, 353, 357, and 359 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical. In some preferred aspects, VH1, VH2 and VH3 have at least 90% identity with the corresponding amino acid sequences specified above. As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity with the reference sequence. In some particularly preferred aspects, VH1, VH2 and VH3 comprise or consist of the corresponding amino acid sequences specified above. In some aspects, VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise the same amino acid sequence as SEQ ID any of NO:5, 13, 21, 29, 37, 151, 155, 163, 171, 179, 188, 189, 191, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 305, 307, 309, 311, 313, 315, 317, 322, 330, 338, and 346 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical. In some preferred aspects, VL1, VL2, and VL3 are at least 90% identical to the corresponding amino acid sequences specified above.As used herein, "at least 90% identity" includes at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% identity to the reference sequence. In some particularly preferred aspects, VL1, VL2 and VL3 comprise or consist of the corresponding amino acid sequences specified above. In some aspects, VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2 and VH3) comprise the same amino acid sequence as SEQ ID Any one of NO: 1, 9, 17, 25, 33, 147, 159, 167, 175, 183, 190, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 306, 308, 310, 312, 314, 316, 318, 326, 334, 342, 351, 353, 357 and 359 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical; and VL1, VL2 and / or VL3 (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3; VL1, VL2 and VL3) comprise an amino acid sequence that is identical to SEQ ID any of NO:5, 13, 21, 29, 37, 151, 155, 163, 171, 179, 188, 189, 191, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 305, 307, 309, 311, 313, 315, 317, 322, 330, 338, and 346 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical. In some aspects, the sequence has a mutation at N62 (e.g., N62Q or N62Q) of, for example, SEQ ID NO: 175. In some preferred aspects, VH1, VH2, VH3, VL1, VL2, and VL3 have at least 90% identity with the corresponding amino acid sequences specified above. As u...

Claims

1. An antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide and a fourth polypeptide; Wherein the first polypeptide has a structure represented by: VL1-L1-CL; Wherein the second polypeptide has a structure represented by: VH1-L2-CH1; Wherein the third polypeptide has a structure represented by: VH2-L3-VH3-L4-CH1; Wherein the fourth polypeptide has a structure represented by: VL3-L5-VL2-L6-CL; in: VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VL2 is the second immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VL3 is the third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH2 is the second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH3 is the third immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; CH1 is the immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; and L1-L6 are amino acid linkers.

2. An antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide and a fourth polypeptide; Wherein the first polypeptide has a structure represented by: VL1-L1-CL; Wherein the second polypeptide has a structure represented by: VH1-L2-CH1-L3-Fc; Wherein the third polypeptide has a structure represented by: VH2-L4-VH3-L5-CH1-L6-Fc; Wherein the fourth polypeptide has a structure represented by: VL3-L7-VL2-L8-CL; in: VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VL2 is the second immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VL3 is the third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH2 is the second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; VH3 is the third immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; Fc is a region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is the immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; and L1-L8 are amino acid linkers.

3. The antigen-binding polypeptide complex of claim 1 or 2, wherein VH1 comprises the same heavy chain variable region as VH3, and VL1 comprises the same light chain variable region as VL3. 4 . The antigen-binding polypeptide complex of claim 1 , wherein VH1 comprises the same heavy chain variable region as VH2, and VL1 comprises the same light chain variable region as VL2.

5. The antigen-binding polypeptide complex of claim 1 or 2, wherein VH2 comprises the same heavy chain variable region as VH3, and VL2 comprises the same light chain variable region as VL3.

6. The antigen-binding polypeptide complex of claim 1 or 2, wherein VH1, VH2 and VH3 each comprise the same heavy chain variable region, and VL1, VL2 and VL3 each comprise the same light chain variable region.

7. The antigen-binding polypeptide complex of claim 1 or 2, wherein VH1, VH2 and VH3 each comprise a different heavy chain variable region, and VL1, VL2 and VL3 each comprise a different light chain variable region.

8. The antigen-binding polypeptide complex according to claim 1 or 2, wherein VH1, VH2 and VH3 each independently comprise a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of SEQ ID NO: 2, 10, 18, 26, 34, 148, 160, 168, 176, 184, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 319, 327, 335 and 343; and a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of SEQ ID NO: 2, 10, 18, 26, 34, 148, 160, 168, 176, 184, 193, 201, 209, 217, NO:3, 11, 19, 27, 35, 149, 161, 169, 177, 185, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 320, 328, 336 and 344 have an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and CDR3, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of SEQ ID any one of NO:4, 12, 20, 28, 36, 150, 162, 170, 178, 186, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 321, 329, 337 and 345 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and wherein VL1, VL2 and VL3 each independently comprise a CDR1 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of SEQ ID NO: 6, 14, 22, 30, 38, 152, 156, 164, 172, 180, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 323, 331, 339 and 347; and a CDR2 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of SEQ ID NO: 6, 14, 22, 30, 38, 152, 156, 164, 172, 180, 197, 205, 213, NO: 7 (sequence with SAS), 15 (sequence with GTN), 23 (sequence with GAS), 31 (sequence with DAS) and 39 (sequence with GAS), 153, 157, 165 (sequence with GAS), 173 (sequence with LGS), 181, 198 (sequence with DAS), 206 (sequence with DVS), 214 (sequence with EDS), 222 (sequence with KDS), 230 (sequence with DAS), 238 (sequence with AAS), 246 (sequence with GAS), 254 (sequence with DDS), 262 (sequence with KDS), 270 (sequence with SAS), 278 (sequence with SAS), 286 (sequence with GAS), 294 (sequence with GAS), 302 (sequence with GAS), 324 (sequence with GAS), 332 (sequence with DAS), 340 (sequence with SAS), and 348 (sequence with GAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical; and a CDR3 comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO:

1. any one of ID NOs: 8, 16, 24, 32, 40, 154, 158, 166, 174, 182, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 325, 333, 341 and 349 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical.

9. The antigen-binding polypeptide complex according to claim 1 or 2, wherein VH1, VH2, and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; and wherein VL1, VL2 and VL3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

24.

10. The antigen-binding polypeptide complex according to claim 1 or 2, wherein VH1 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; wherein VH2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 28; wherein VL1 and VL3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 24; and wherein VL2 comprises CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:30; CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:31 (sequence with DAS); and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

32.

11. The antigen-binding polypeptide complex according to claim 1 or 2, wherein VH1 and VH2 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; wherein VH3 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 28; wherein VL1 and VL2 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 24; and wherein VL3 comprises CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:30; CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:31 (sequence with DAS); and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

32.

12. The antigen-binding polypeptide complex according to claim 1 or 2, wherein VH2 and VH3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; wherein VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 28; wherein VL2 and VL3 each comprise a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 24; and wherein VL1 comprises CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:30; CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:31 (sequence with DAS); and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

32.

13. The antigen-binding polypeptide complex according to claim 1 or 2, wherein VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 12; wherein VH2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; wherein VH3 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 28; wherein VL1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 14; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 15 (sequence with GTN); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 16; wherein VL2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 24; and wherein VL3 comprises CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:30; CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:31 (sequence with DAS); and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

32.

14. The antigen-binding polypeptide complex according to claim 1 or 2, wherein VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 12; wherein VH2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 28; wherein VH3 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; wherein VL1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 14; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 15 (sequence with GTN); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 16; wherein VL2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 30; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 31 (sequence with DAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 32; and wherein VL3 comprises CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:22; CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:23 (a sequence having GAS); and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

24.

15. The antigen-binding polypeptide complex according to claim 1 or 2, wherein VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 28; wherein VH2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 12; wherein VH3 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; wherein VL1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 30; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 31 (sequence with DAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 32; wherein VL2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 14; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 15 (sequence with GTN); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 16; and wherein VL3 comprises CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:22; CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:23 (a sequence having GAS); and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

24.

16. The antigen-binding polypeptide complex according to claim 1 or 2, wherein VH1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 26; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 27; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 28; wherein VH2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 18; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 19; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 20; wherein VH3 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 10; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 11; and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 12; wherein VL1 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 30; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 31 (sequence with DAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 32; wherein VL2 comprises a CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 22; a CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 23 (a sequence having GAS); and a CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 24; and wherein VL3 comprises CDR1 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 14; CDR2 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 15 (sequence with GTN); and CDR3 comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

16.

17. The antigen-binding polypeptide complex of claim 1 or 2, wherein VH1, VH2 and VH3 each independently comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of SEQ ID NO: 1, 9, 17, 25, 33, 147, 159, 167, 175, 183, 190, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 306, 308, 310, 312, 314, 316, 318, 326, 334, 342, 351, 353, 357 and 359.

18. The antigen-binding polypeptide complex of claim 17, wherein VL1, VL2 and VL3 each independently comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of SEQ ID NO: 5, 13, 21, 29, 37, 151, 155, 163, 171, 179, 188, 189, 191, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 305, 307, 309, 311, 313, 315, 317, 322, 330, 338 and 346.

19. The antigen-binding polypeptide complex of claim 17, wherein VH1, VH2 and VH3 each comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 17; and VL1, VL2 and VL3 each comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

21.

20. The antigen-binding polypeptide complex of claim 17, wherein VH1 and VH3 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 17; VH2 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 25; VL1 and VL3 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 21; and VL2 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

29.

21. The antigen-binding polypeptide complex of claim 17, wherein VH1 and VH2 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 17; VH3 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 25; VL1 and VL2 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 21; and VL3 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

29.

22. The antigen-binding polypeptide complex of claim 17, wherein VH2 and VH3 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 17; VH1 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 25; VL2 and VL3 each comprise an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO: 21; and VL1 comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

29.

23. The antigen-binding polypeptide complex of claim 17, wherein VH1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 9; VH2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 17; VH3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 25; VL1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 13; VL2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: NO:21 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and VL3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

29.

24. The antigen-binding polypeptide complex of claim 17, wherein VH1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:9; VH2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:25; VH3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:17; VL1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO:13; VL2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: NO:29 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and VL3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

21.

25. The antigen-binding polypeptide complex of claim 17, wherein VH1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 25; VH2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 9; VH3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 17; VL1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 29; VL2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: NO:13 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and VL3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

21.

26. The antigen-binding polypeptide complex of claim 17, wherein VH1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 25; VH2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 17; VH3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 9; VL1 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: 29; VL2 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to SEQ ID NO: NO:21 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical; and VL3 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to SEQ ID NO:

13.

27. The antigen-binding polypeptide complex of any one of claims 1 to 26, wherein the immunoglobulin hinge comprises an upper hinge region, a middle hinge region, a lower hinge region, or a combination thereof.

28. The antigen-binding polypeptide complex of any one of claims 1 to 27, wherein linkers L1-L8 each independently have a length of about 0 amino acids to about 50 amino acids.

29. The antigen-binding polypeptide complex of any one of claims 1 to 28, wherein linkers L1-L8 each independently comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of SEQ ID NOs: 46-80 (wherein SEQ ID NO: 47 has a sequence of G, SEQ ID NO: 48 has a sequence of A, SEQ ID NO: 49 has a sequence of GSS, and SEQ ID NO: 50 has a sequence of ASG).

30. The antigen-binding polypeptide complex of any one of claims 1 to 29, wherein one or more of the linkers L1-L8 are non-immunogenic.

31. The antigen-binding polypeptide complex of any one of claims 1 to 30, wherein one or more of the linkers L1-L8 do not comprise a shared T-cell epitope.

32. The antigen-binding polypeptide complex of any one of claims 1 to 31, wherein the Fc region comprises at least one knob-into-hole modification or Fc effector function knockout mutation.

33. The antigen-binding polypeptide complex of claim 32, wherein the antigen-binding polypeptide complex is an IgG1 or IgG4 antibody, and the knob-into-hole modification comprises: (i) Knob substitutions of S354C and T366W and hole substitutions of Y349C, T366S, L368A, and Y407V; (ii) a substitution of M428L and N434S or N434A; (iii) substitutions of M252Y, S254T and T256E; or (iv) combinations thereof; This is based on the EU numbering scheme.

34. The antigen-binding polypeptide complex of claim 32, wherein the antigen-binding polypeptide complex is an IgG1 or IgG4 antibody, and the Fc effector function knockout mutation is L234A, L235A, P239A, or a combination thereof, based on the EU numbering scheme.

35. The antigen-binding polypeptide complex of any one of claims 1 to 34, comprising a detectable label.

36. The antigen-binding polypeptide complex of claim 35, wherein the detectable label is a radioactive label, a chemiluminescent label, a fluorescent label, an enzyme, a peptide tag, or a combination thereof.

37. The antigen-binding polypeptide complex of claim 36, wherein the peptide tag is a polyhistidine tag consisting of about four to about 10 histidine residues.

38. The antigen-binding polypeptide complex of claim 37, wherein the polyhistidine tag consists of about eight histidine residues.

39. The antigen-binding polypeptide complex of any one of claims 1 to 38, which has an equilibrium dissociation constant (K) of about 10 μM to about 1 pM. D ) specifically binds to SARS-CoV-2 protein.

40. The antigen-binding polypeptide complex of any one of claims 1 to 39, wherein the SARS-CoV-2 virus is the original strain (WA1), the D614G spike protein mutant (D614G), the alpha variant (B.1.1.7), the beta variant 1 (B.1.351.v1), the gamma variant (P.1), the delta variant (B.1.617.2 or AY.1), the kappa variant (B.1.617.1), the Yota variant (B.1.526), ​​the lambda variant ( C.37), Mu variant (B.1.621), C.1.2 variant, Ipsilon variant (B.1.427) or Omicron variant (BA1.1.529, BA.1, BA.2, BA.2.12.1, BA.4, BA.4 / 5, BA.5, BQ.1, BQ.1.1, BA.2.75, BA.2.75.2, BA.4.6, BQ.1.1, BJ.1, XBB, XBB1.5, BF.7 or CH.1.1), or a combination thereof.

41. An antibody or antigen-binding fragment thereof comprising the antigen-binding polypeptide complex of any one of claims 1 to 40.

42. The antibody or antigen-binding fragment thereof of claim 41, wherein the antibody is IgG, IgM, IgE, IgA or IgD.

43. The antibody or antigen-binding fragment thereof of claim 42, wherein the IgG is IgG1, IgG2, IgG3 or IgG4.

44. The antibody or antigen-binding fragment thereof of claim 41, wherein the antigen-binding fragment is Fab, scFab, Fab', F(ab')2, Fv or scFv.

45. The antibody or antigen-binding fragment thereof of any one of claims 41 to 44, wherein the antibody is a human antibody or a humanized antibody.

46. ​​The antibody or antigen-binding fragment thereof of any one of claims 41 to 45, wherein the antibody is a monoclonal antibody, a grafted antibody or a chimeric antibody.

47. An anti-SARS-CoV2 multivalent antibody that exhibits improved prevention of immune escape compared to: (i) a monovalent anti-SARS-CoV2 antibody that binds to one of the same antigens as the anti-SARS-CoV2 multivalent antibody, and / or (ii) a combination of monovalent anti-SARS-CoV2 antibodies that bind to the same antigen as the anti-SARS-CoV2 multivalent antibody.

48. A pharmaceutical composition comprising the antigen-binding polypeptide complex of any one of claims 1 to 40.

49. A pharmaceutical composition comprising the antigen-binding polypeptide complex of any one of claims 1 to 40 and an additional agent.

50. A pharmaceutical composition comprising the antigen-binding polypeptide complex of any one of claims 1 to 40 and a pharmaceutically acceptable carrier.

51. A pharmaceutical composition comprising the antigen-binding polypeptide complex of any one of claims 1 to 40, an additional agent and a pharmaceutically acceptable carrier.

52. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof as claimed in any one of claims 41 to 47.

53. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof as claimed in any one of claims 41 to 47 and an additional agent.

54. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof as described in any one of claims 41 to 47 and a pharmaceutically acceptable carrier.

55. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof as claimed in any one of claims 41 to 47, an additional agent and a pharmaceutically acceptable carrier.

56. A pharmaceutical composition as described in any of claims 49, 51, 53 and 55, wherein the additional agent is 25-hydroxyvitamin D, an agent that enhances the effect of vitamin D, an antiviral agent, an antimalarial agent, an antibiotic, or a combination thereof.

57. The pharmaceutical composition of claim 56, wherein the additional agent is 25-hydroxyvitamin D.

58. The pharmaceutical composition of claim 56, wherein the agent that enhances the effect of vitamin D is a CYP24 inhibitor, a 1,25-dihydroxyvitamin D compound, or a combination thereof.

59. The pharmaceutical composition of claim 56, wherein the antiviral agent is an antiretroviral agent, an antibody against the SARS-CoV-2 virus, an inhibitor of reverse transcriptase, or a combination thereof.

60. The pharmaceutical composition of claim 56, wherein the antiviral agent is maraviroc, enfuvirtide, amantadine, lamivudine, nevirapine, efavirenz, dolutegravir, elvitegravir, raltegravir, acyclovir and any nucleoside analog of acyclovir, ganciclovir, cidofovir, foscarnet, ribavirin, interferon alpha, pegylated interferon alpha, boceprevir, atazanavir, darunavir, indinavir, oseltamivir, zanamivir , rimantadine, peramivir, valacyclovir, penciclovir, valganciclovir, foscarnet, tenofovir, adefovir, entecavir, lamivudine, telbivudine, ribavirin, glecaprevir, gezoprevir, paritaprevir, simeprevir, voxiprevir, daclatasvir, elbavir, ledipasvir, ombitasvir, pibrentasvir, velpatasvir, dasabuvir, famciclovir, remdesivir, drofluridine, sofosbuvir, becterovir, or a combination thereof.

61. The pharmaceutical composition of claim 60, wherein the antiviral agent is beclovir monoclonal antibody.

62. The pharmaceutical composition of claim 56, wherein the antiviral agent is (3′-azido-3′-deoxypyrimidine, zidovudine), 3′-azido-3′-deoxythymidine (AZT), (2′,3′-dideoxycytidine, zalcitabine), (2′,3′ dideoxyinosine, didanosine), (Lamivudine), (Stavudine), (tenofovir DF), (abacavir), (Emtricitabine, FTC), (Delavirdine), (Efavirenz), (nevirapine, 11-cyclopropyl-4-methyl-5,11-dihydro-6H-bipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one), trisodium phosphonoformate, ammonium-21-tungstate-9-antimonate, 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, (Amprenavir), (Azanavir), (fosamprenavir), C (Indinavir), (nelfinavir), (ritonavir), or (saquinavir), lasinavir (5 (S) - (tert-butyloxycarbonylamino) -4 (S) -hydroxy-6-phenyl-2 (R) (2,3,4-trimethoxyphenylmethyl) -hexanoyl - (L) -valyl -N- (2-methoxy-ethyl) -amide), doxorubicin, KVX-478, VX-478, 141W94, AG-1343, KNI-272, U-96988, BILA-2011BS (parinavir), polymanganese acetate, (Enfuweidi, T-20), (abacavir and lamivudine), (abacavir, lamivudine and zidovudine), (Emtricitabine and Tylenol DF), (lamivudine and zidovudine), (lopinavir and ritonavir) or a combination thereof.

63. A kit comprising the antigen-binding polypeptide complex of any one of claims 1 to 40.

64. A kit comprising the antibody or antigen-binding fragment thereof as described in any one of claims 41 to 47.

65. A kit comprising (i) the antigen-binding polypeptide complex of any one of claims 1 to 40 or the antibody or antigen-binding fragment thereof of any one of claims 41 to 47, and (ii) an additional pharmaceutical agent.

66. A kit comprising the pharmaceutical composition of any one of claims 48 to 62.

67. A kit comprising (i) a pharmaceutical composition as claimed in any one of claims 48 to 62, and (ii) an additional pharmaceutical agent.

68. A kit comprising (i) a pharmaceutical composition as claimed in any one of claims 48 to 62, and (ii) a pharmaceutical composition comprising an additional pharmaceutical agent.

69. A kit comprising (i) a pharmaceutical composition as claimed in any one of claims 48 to 62, and (ii) a pharmaceutical composition comprising an additional agent and a pharmaceutically acceptable carrier.

70. The kit of any one of claims 63 to 69, further comprising instructions for use.

71. A method for preventing or treating SARS-CoV-2 viral infection in a subject in need thereof, comprising administering to the subject an effective amount of an antigen-binding polypeptide complex as described in any one of claims 1 to 40, an antibody or antigen-binding fragment thereof as described in any one of claims 41 to 47, a pharmaceutical composition as described in any one of claims 48 to 62, or a combination thereof.

72. A method for preventing or treating coronavirus disease 2019 (COVID-19) in a subject in need thereof, comprising administering to the subject an effective amount of an antigen-binding polypeptide complex as described in any one of claims 1 to 40, an antibody or antigen-binding fragment thereof as described in any one of claims 41 to 47, a pharmaceutical composition as described in any one of claims 48 to 62, or a combination thereof.

73. A method for diagnosing that a subject is infected with or suspected of being infected with SARS-CoV-2 virus, comprising (i) contacting a sample obtained from the subject with an antigen-binding polypeptide complex as described in any one of claims 1 to 40 or an antibody or antigen-binding fragment thereof as described in any one of claims 41 to 47; (ii) detecting the presence or absence of a viral complex containing the polypeptide complex, antibody or fragment and SARS-CoV-2 virus, virion or fragment thereof; and (iii) when the presence of the viral complex is detected, diagnosing that the subject is infected with or suspected of being infected with SARS-CoV-2 virus.

74. A method for diagnosing that a subject is not infected with or suspected of being infected with SARS-CoV-2 virus, comprising (i) contacting a sample obtained from the subject with the antigen-binding polypeptide complex of any one of claims 1 to 40 or the antibody or antigen-binding fragment thereof of any one of claims 41 to 47; (ii) detecting the presence or absence of a viral complex containing the polypeptide complex, antibody or fragment and SARS-CoV-2 virus, virion or fragment thereof; and (iii) when the presence of the viral complex is not detected, diagnosing that the subject is not infected with or suspected of being infected with SARS-CoV-2 virus.

75. A method for diagnosing a subject as having COVID-19 or suspected of having COVID-19, comprising (i) contacting a sample obtained from the subject with an antigen-binding polypeptide complex as described in any one of claims 1 to 40 or an antibody or antigen-binding fragment thereof as described in any one of claims 41 to 47; (ii) detecting the presence or absence of a viral complex containing the polypeptide complex, antibody or fragment and a SARS-CoV-2 virus, virion or fragment thereof; and (iii) when the presence of the viral complex is detected, diagnosing the subject as having COVID-19 or suspected of having COVID-19.

76. A method for diagnosing that a subject does not have COVID-19 or is not suspected of having COVID-19, comprising (i) contacting a sample obtained from the subject with an antigen-binding polypeptide complex as described in any one of claims 1 to 40 or an antibody or antigen-binding fragment thereof as described in any one of claims 41 to 47; (ii) detecting the presence or absence of a viral complex containing the polypeptide complex, antibody or fragment and a SARS-CoV-2 virus, virion or fragment thereof; and (iii) when the presence of the viral complex is not detected, diagnosing that the subject does not have COVID-19 or is not suspected of having COVID-19.

77. The method of any one of claims 73 to 76, wherein the sample is a nasal swab, a tissue sample, saliva, plasma, or blood.

78. The method of any one of claims 73 to 77, wherein detecting the presence or absence of the viral complex comprises enzyme-linked immunosorbent assay (ELISA), immunospot assay, lateral flow assay, flow cytometry, immunohistochemistry, or Western blot.

79. The method of any one of claims 71 to 78, wherein the SARS-CoV-2 virus is the original strain (WA1), the D614G spike protein mutant (D614G), the alpha variant (B.1.1.7), the beta variant 1 (B.1.351.v1), the gamma variant (P.1), the kappa variant (B.1.617.1), the delta variant (B.1.617.2 or AY.1), the ypsilon variant (B.1.427), the yota ... 1.526), ​​Lambda variant (C.37), Mu variant (B.1.621), C.1.2 variant, Omicron variant (BA1.1.529, BA.1, BA.2, BA.2.12.1, BA.4, BA.4 / 5, BA.5, BQ.1, BQ.1.1, BA.2.75, BA.2.75.2, BA.4.6, BQ.1.1, BJ.1, XBB, XBB1.5, BF.7 or CH.1.1), or a combination thereof.

80. A method of preventing immune escape of a SARS-CoV2 virus in a subject infected with the SARS-CoV2 virus, comprising administering to the subject an effective amount of an anti-SARS-CoV2 multivalent antibody that exhibits improved prevention of immune escape compared to: (i) a monovalent anti-SARS-CoV2 antibody that binds to one of the same antigens as the anti-SARS-CoV2 multivalent antibody, and / or (ii) a combination of monovalent anti-SARS-CoV2 antibodies that bind to the same antigen as the anti-SARS-CoV2 multivalent antibody.

81. A method of increasing neutralization potency against a SARS-CoV-2 virus in a subject infected with the SARS-CoV2 virus, comprising administering to the subject an effective amount of an anti-SARS-CoV2 multivalent antibody that exhibits increased neutralization potency compared to: (i) a monovalent anti-SARS-CoV2 antibody that binds to one of the same antigens as the anti-SARS-CoV2 multivalent antibody, and / or (ii) a combination of monovalent anti-SARS-CoV2 antibodies that bind to the same antigen as the anti-SARS-CoV2 multivalent antibody.

82. The method of claim 80 or 81, wherein the anti-SARS-CoV2 multivalent antibody exhibits improved prevention of immune escape compared to a monovalent anti-SARS-CoV2 antibody that binds to one of the same antigens as the anti-SARS-CoV2 multivalent antibody.

83. The method of any one of claims 80 to 82, wherein the anti-SARS-CoV2 multivalent antibody exhibits increased neutralizing potency compared to a combination of monovalent anti-SARS-CoV2 antibodies that bind to the same antigen as the anti-SARS-CoV2 multivalent antibody.

84. The method of any one of claims 80 to 83, wherein the anti-SARS-CoV2 multispecific antibody prevents immune escape of the anti-SARS-CoV2 multivalent antibody for at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 selection rounds as measured by an antibody escape assay.

85. The method of any one of claims 80 to 84, wherein the anti-SARS-CoV2 multispecific antibody prevents immune escape of the anti-SARS-CoV2 multivalent antibody after the subject is exposed to the SARS-CoV2 virus at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, or at least 7 times.

86. The method of any one of claims 80 to 85, wherein the anti-SARS-CoV2 multispecific antibody is at least 100-fold, at least 500-fold, at least 1,000-fold, or at least 2,000-fold more effective at inhibiting the growth of the SARS-CoV2 virus than (i) a monovalent anti-SARS-CoV2 antibody that binds to one of the same antigens as the anti-SARS-CoV2 multivalent antibody and / or (ii) a combination of monovalent anti-SARS-CoV2 antibodies that bind to the same antigen as the anti-SARS-CoV2 multivalent antibody.

87. The method of any one of claims 80 to 86, wherein the anti-SARS-CoV2 multivalent antibody comprises a first antigen binding site that specifically binds to a SARS-CoV-2 protein and a second antigen binding site that specifically binds to a SARS-CoV-2 protein.

88. The method of claim 87, wherein the first antigen binding site is different from the second antigen binding site.

89. The method of claim 87 or 88, wherein the first antigen binding site comprises a first heavy chain variable domain and a first light chain variable domain, and the second antigen binding site comprises a second heavy chain variable domain and a second light chain variable domain.

90. The method of claim 89, wherein the first heavy chain variable region and the second heavy chain variable region each comprise a CDR1 region, a CDR2 region, and a CDR3 region, and the first light chain variable region and the second light chain variable region each comprise a CDR1 region, a CDR2 region, and a CDR3 region.

91. The method of any one of claims 80 to 90, wherein: the CDR1 of the first heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 2, 10, 18, 26, 34, 148, 160, 168, 176, 184, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 319, 327, 335, and 343; the CDR2 of the first heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 3, 11, 19, 27, 35, 149, 161, 169, 177, 185, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 320, 328, 336, and 344; the CDR3 of the first heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO:4, 12, 20, 28, 36, 150, 162, 170, 178, 186, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 321, 329, 337, and 345; the CDR1 of the first light chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 6, 14, 22, 30, 38, 152, 156, 164, 172, 180, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 323, 331, 339, and 347; The CDR2 of the first light chain variable region comprises SEQ ID NO: 7 (sequence with SAS), 15 (sequence with GTN), 23 (sequence with GAS), 31 (sequence with DAS) and 39 (sequence with GAS), 153, 157, 165 (sequence with GAS), 173 (sequence with LGS), 181, 198 (sequence with DAS), 206 (sequence with DVS), 214 (sequence with EDS), 222 (sequence with KDS), 230 (sequence with DAS), 238 (sequence with AAS), 246 (sequence with GAS) , 254 (sequence with DDS), 262 (sequence with KDS), 270 (sequence with SAS), 278 (sequence with SAS), 286 (sequence with GAS), 294 (sequence with GAS), 302 (sequence with GAS), 324 (sequence with GAS), 332 (sequence with DAS), 340 (sequence with SAS), and 348 (sequence with GAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical; the CDR3 of the first light chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 8, 16, 24, 32, 40, 154, 158, 166, 174, 182, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 325, 333, 341, and 349; the CDR1 of the second heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 2, 10, 18, 26, 34, 148, 160, 168, 176, 184, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 319, 327, 335, and 343; the CDR2 of the second heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 3, 11, 19, 27, 35, 149, 161, 169, 177, 185, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 320, 328, 336, and 344; the CDR3 of the second heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO:4, 12, 20, 28, 36, 150, 162, 170, 178, 186, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 321, 329, 337, and 345; the CDR1 of the second light chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 6, 14, 22, 30, 38, 152, 156, 164, 172, 180, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 323, 331, 339, and 347; The CDR2 of the second light chain variable region comprises a sequence identical to SEQ ID NO: 7 (having a sequence of SAS), 15 (having a sequence of GTN), 23 (having a sequence of GAS), 31 (having a sequence of DAS) and 39 (having a sequence of GAS), 153, 157, 165 (having a sequence of GAS), 173 (having a sequence of LGS), 181, 198 (having a sequence of DAS), 206 (having a sequence of DVS), 214 (having a sequence of EDS), 222 (having a sequence of KDS), 230 (having a sequence of DAS), 238 (having a sequence of AAS), 246 (having a sequence of GAS), any one of 254 (sequence with DDS), 262 (sequence with KDS), 270 (sequence with SAS), 278 (sequence with SAS), 286 (sequence with GAS), 294 (sequence with GAS), 302 (sequence with GAS), 324 (sequence with GAS), 332 (sequence with DAS), 340 (sequence with SAS), and 348 (sequence with GAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical; and The CDR3 of the second light chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of SEQ ID NO: 8, 16, 24, 32, 40, 154, 158, 166, 174, 182, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 325, 333, 341 and 349.

92. The method of any one of claims 80 to 91, wherein: the first heavy chain variable domain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to any one of SEQ ID NO: 1, 9, 17, 25, 33, 147, 159, 167, 175, 183, 190, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 306, 308, 310, 312, 314, 316, 318, 326, 334, 342, 351, 353, 357, and 359; the first light chain variable domain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to any one of SEQ ID NO: 5, 13, 21, 29, 37, 151, 155, 163, 171, 179, 188, 189, 191, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 305, 307, 309, 311, 313, 315, 317, 322, 330, 338, and 346; the second heavy chain variable domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to any one of SEQ ID NO: 1, 9, 17, 25, 33, 147, 159, 167, 175, 183, 190, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 306, 308, 310, 312, 314, 316, 318, 326, 334, 342, 351, 353, 357, and 359; and The second light chain variable domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% or 100% identical to any one of SEQ ID NO: 5, 13, 21, 29, 37, 151, 155, 163, 171, 179, 188, 189, 191, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 305, 307, 309, 311, 313, 315, 317, 322, 330, 338 and 346.

93. The method of any one of claims 80 to 92, wherein the anti-SARS-CoV2 multivalent antibody further comprises a third antigen binding domain.

94. The method of claim 93, wherein the third antigen binding site is different from the first antigen binding site, the second antigen binding site, or both the first antigen binding site and the second antigen binding site.

95. The method of claim 93 or 94, wherein the third antigen binding site comprises a third heavy chain variable domain and a third light chain variable domain.

96. The method of any one of claims 80 to 95, wherein the third heavy chain variable domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to any one of SEQ ID NO: 1, 9, 17, 25, 33, 147, 159, 167, 175, 183, 190, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 306, 308, 310, 312, 314, 316, 318, 326, 334, 342, 351, 353, 357, and 359; and the third light chain variable domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to any one of SEQ ID NO: 1, 9, 17, 25, 33, 147, 159, 167, 175, 183, 190, 192, 200, 208, 216, 224, 232, 240, 248, 256, any one of NO:5, 13, 21, 29, 37, 151, 155, 163, 171, 179, 188, 189, 191, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 305, 307, 309, 311, 313, 315, 317, 322, 330, 338 and 346 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% or 100% identical.

97. The method of any one of claims 80 to 96, wherein the third heavy chain variable region comprises a CDR1 region, a CDR2 region, and a CDR3 region.

98. The method of any one of claims 80 to 97, wherein: the CDR1 of the third heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 2, 10, 18, 26, 34, 148, 160, 168, 176, 184, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 319, 327, 335, and 343; the CDR2 of the third heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 3, 11, 19, 27, 35, 149, 161, 169, 177, 185, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 320, 328, 336, and 344; the CDR3 of the third heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO:4, 12, 20, 28, 36, 150, 162, 170, 178, 186, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 321, 329, 337, and 345; the CDR1 of the third light chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 6, 14, 22, 30, 38, 152, 156, 164, 172, 180, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 323, 331, 339, and 347; The CDR2 of the third light chain variable region comprises a sequence identical to SEQ ID NO: 7 (having a sequence of SAS), 15 (having a sequence of GTN), 23 (having a sequence of GAS), 31 (having a sequence of DAS) and 39 (having a sequence of GAS), 153, 157, 165 (having a sequence of GAS), 173 (having a sequence of LGS), 181, 198 (having a sequence of DAS), 206 (having a sequence of DVS), 214 (having a sequence of EDS), 222 (having a sequence of KDS), 230 (having a sequence of DAS), 238 (having a sequence of AAS), 246 (having a sequence of GAS), any one of 254 (sequence with DDS), 262 (sequence with KDS), 270 (sequence with SAS), 278 (sequence with SAS), 286 (sequence with GAS), 294 (sequence with GAS), 302 (sequence with GAS), 324 (sequence with GAS), 332 (sequence with DAS), 340 (sequence with SAS), and 348 (sequence with GAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical; and The CDR3 of the third light chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of SEQ ID NO: 8, 16, 24, 32, 40, 154, 158, 166, 174, 182, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 325, 333, 341 and 349.

99. The method of any one of claims 80 to 98, wherein the anti-SARS-CoV2 multivalent antibody further comprises a fourth antigen binding domain.

100. The method of claim 99, wherein the fourth antigen binding site is different from one or more of the first antigen binding site, the second antigen binding site, and the third antigen binding site.

101. The method of claim 99 or 100, wherein the first antigen binding site, the second antigen binding site, the third antigen binding site, and the fourth antigen binding site are different.

102. The method of any one of claims 80 to 101, wherein the fourth antigen binding site comprises a third heavy chain variable domain and a fourth light chain variable domain.

103. The method of any one of claims 80 to 102, wherein the fourth heavy chain variable domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to any one of SEQ ID NO: 1, 9, 17, 25, 33, 147, 159, 167, 175, 183, 190, 192, 200, 208, 216, 224, 232, 240, 248, 256, 264, 272, 280, 288, 296, 304, 306, 308, 310, 312, 314, 316, 318, 326, 334, 342, 351, 353, 357, and 359; and the fourth light chain variable domain comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to any one of SEQ ID NO: any one of NO:5, 13, 21, 29, 37, 151, 155, 163, 171, 179, 188, 189, 191, 196, 204, 212, 220, 228, 236, 244, 252, 260, 268, 276, 284, 292, 300, 305, 307, 309, 311, 313, 315, 317, 322, 330, 338 and 346 having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% or 100% identical.

104. The method of any one of claims 80 to 103, wherein the fourth heavy chain variable region comprises a CDR1 region, a CDR2 region, and a CDR3 region.

105. The method of claim 104, wherein: the CDR1 of the fourth heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 2, 10, 18, 26, 34, 148, 160, 168, 176, 184, 193, 201, 209, 217, 225, 233, 241, 249, 257, 265, 273, 281, 289, 297, 319, 327, 335, and 343; the CDR2 of the fourth heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 3, 11, 19, 27, 35, 149, 161, 169, 177, 185, 194, 202, 210, 218, 226, 234, 242, 250, 258, 266, 274, 282, 290, 298, 320, 328, 336, and 344; the CDR3 of the fourth heavy chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 4, 12, 20, 28, 36, 150, 162, 170, 178, 186, 195, 203, 211, 219, 227, 235, 243, 251, 259, 267, 275, 283, 291, 299, 321, 329, 337, and 345; the CDR1 of the fourth light chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to any one of SEQ ID NO: 6, 14, 22, 30, 38, 152, 156, 164, 172, 180, 197, 205, 213, 221, 229, 237, 245, 253, 261, 269, 277, 285, 293, 301, 323, 331, 339, and 347; The CDR2 of the fourth light chain variable region comprises a sequence identical to SEQ ID NO: 7 (having a sequence of SAS), 15 (having a sequence of GTN), 23 (having a sequence of GAS), 31 (having a sequence of DAS) and 39 (having a sequence of GAS), 153, 157, 165 (having a sequence of GAS), 173 (having a sequence of LGS), 181, 198 (having a sequence of DAS), 206 (having a sequence of DVS), 214 (having a sequence of EDS), 222 (having a sequence of KDS), 230 (having a sequence of DAS), 238 (having a sequence of AAS), 246 (having a sequence of GAS), any one of 254 (sequence with DDS), 262 (sequence with KDS), 270 (sequence with SAS), 278 (sequence with SAS), 286 (sequence with GAS), 294 (sequence with GAS), 302 (sequence with GAS), 324 (sequence with GAS), 332 (sequence with DAS), 340 (sequence with SAS), and 348 (sequence with GAS) having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical; and The CDR3 of the fourth light chain variable region comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% identical to any one of SEQ ID NO: 8, 16, 24, 32, 40, 158, 166, 174, 182, 199, 207, 215, 223, 231, 239, 247, 255, 263, 271, 279, 287, 295, 303, 325, 333, 341 and 349.

106. The method of any one of claims 80 to 105, wherein the anti-SARS-CoV2 multivalent antibody is an antibody or antigen-binding fragment thereof as described in any one of claims 43 to 48.

107. The method of any one of claims 80 to 106, wherein the antigen is a SARS-CoV-2 protein.

108. The method of any one of claims 80 to 107, wherein the SARS-CoV2 virus is a SARS-CoV2 variant.

109. The method of claim 108, wherein the SARS-CoV2 variant is an alpha variant (B.1.1.7), a beta variant (B.1.351), a gamma variant (P.1), a delta variant, an ipsilon variant (B.1.427), or an omicron variant (B.1.1.529), or a combination thereof.

110. The method of claim 109, wherein the omikron variant is BA.1, BA.2, BA.2.12.1, BA.4, BA.4 / 5, BA.5, BQ.1, BQ.1.1, BA.2.75, BA.2.75.2, BA.4.6, BQ.1.1, BJ.1, XBB, XBB1.5, BF.7, CH.1.1, or a combination thereof.

111. The method of any one of claims 71 to 110, further comprising administering to the subject an effective amount of an additional agent.

112. The method of any one of claims 71 to 110, further comprising administering to the subject an effective amount of a pharmaceutical composition comprising (i) an additional agent and (ii) a pharmaceutically acceptable carrier.

113. The method of claim 111 or 112, wherein the additional agent is 25-hydroxyvitamin D, an agent that enhances the effects of vitamin D, an antiviral agent, an antimalarial agent, an antibiotic, or a combination thereof.

114. The method of claim 113, wherein the additional agent is 25-hydroxyvitamin D.

115. The method of claim 113, wherein the agent that enhances the action of vitamin D is a CYP24 inhibitor, a 1,25-dihydroxyvitamin D compound, or a combination thereof.

116. The method of claim 113, wherein the antiviral agent is an antiretroviral agent, an antibody against the SARS-CoV-2 virus, an inhibitor of reverse transcriptase, or a combination thereof.

117. The method of claim 113, wherein the antiviral agent is maraviroc, enfuvirtide, amantadine, lamivudine, nevirapine, efavirenz, dolutegravir, elvitegravir, raltegravir, acyclovir and any nucleoside analog of acyclovir, ganciclovir, cidofovir, foscarnet, ribavirin, interferon alpha, pegylated interferon alpha, boceprevir, atazanavir, darunavir, indinavir, oseltamivir, zanamivir, Rimantadine, peramivir, valacyclovir, penciclovir, valganciclovir, foscarnet, tenofovir, adefovir, entecavir, lamivudine, telbivudine, ribavirin, glecaprevir, gezoprevir, paritaprevir, simeprevir, voxiprevir, daclatasvir, elbavir, ledipasvir, ombitasvir, pibrentasvir, velpatasvir, dasabuvir, famciclovir, remdesivir, drofluridine, sofosbuvir, becterovir, or a combination thereof.

118. The method of claim 117, wherein the antiviral agent is bectclovir.

119. The method of claim 113, wherein the antiviral agent is (3′-azido-3′-deoxypyrimidine, zidovudine), 3′-azido-3′-deoxythymidine (AZT), (2′,3′-dideoxycytidine, zalcitabine), (2′,3′ dideoxyinosine, didanosine), (Lamivudine), (Stavudine), (tenofovir DF), (abacavir), (Emtricitabine, FTC), (Delavirdine), (Efavirenz), (nevirapine, 11-cyclopropyl-4-methyl-5,11-dihydro-6H-bipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one), trisodium phosphonoformate, ammonium-21-tungstate-9-antimonate, 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide, (Amprenavir), (Azanavir), (fosamprenavir), (Indinavir), (nelfinavir), (ritonavir), or (saquinavir), lasinavir (5 (S) - (tert-butyloxycarbonylamino) -4 (S) -hydroxy-6-phenyl-2 (R) (2,3,4-trimethoxyphenylmethyl) -hexanoyl - (L) -valyl -N- (2-methoxy-ethyl) -amide), doxorubicin, KVX-478, VX-478, 141W94, AG-1343, KNI-272, U-96988, BILA-2011BS (parinavir), polymanganese acetate, (Enfuweidi, T-20), (abacavir and lamivudine), (abacavir, lamivudine and zidovudine), (Emtricitabine and Tylenol DF), (lamivudine and zidovudine), (lopinavir and ritonavir) or a combination thereof.

120. The method of any one of claims 111 to 119, wherein the additional agent is administered prior to the antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof.

121. The method of any one of claims 111 to 119, wherein the additional agent is administered after the antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof.

122. The method of any one of claims 111 to 119, wherein the additional agent is administered concurrently with the antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof.

123. The method of any one of claims 111 to 119 and 122, wherein the additional agent and the antigen-binding polypeptide complex, antibody or antigen-binding fragment thereof are administered in the same pharmaceutical composition.

124. The method of any one of claims 111 to 123, wherein the additional agent and the antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof are administered in different pharmaceutical compositions.

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