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

Abstract

Antigen-binding polypeptides and 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 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.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 357,331 filed on June 30, 2022, 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 / 381,842 filed on November 1, 2022, U.S. Provisional Application No. 63 / 381,850 filed on November 1, 2022, U.S. Provisional Application No. 63 / 433,719 filed on December 9, 2022, and U.S. Provisional Application No. 63 / 481,368 filed on January 24, 2023, all of which are incorporated herein by reference in their entirety.

[0003] Reference to a sequence listing submitted electronically

[0004] The contents of the electronically submitted Sequence Listing (Name: 4850_0110003_SEQLISTING_ST26.xml; Size: 1,589,914 bytes; Creation Date: June 29, 2023) are incorporated herein by reference in their entirety. 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 under a cooperative research and development agreement with the National Institutes of Health, a component of the U.S. Department of Health and Human Services. The U.S. Government has certain rights in this invention. Background Art

[0008] The outbreak of severe acute respiratory syndrome coronavirus (SARS-CoV-2) has resulted in over 450 million infections and over 6 million deaths worldwide. SARS-CoV-2 is the coronavirus strain 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 in humans during the pandemic has led to genetic variants that resist containment and eradication. While optimal protection against viral infection requires both cellular and humoral immune responses, neutralizing antibodies play an important role in the prevention and eradication of pathogens.

[0009] SARS-CoV-2 spike protein mutants and SARS-CoV-2 variants α (B.1.1.7), β (B.1.351), γ (P.1), δ (B.1.617.2), ε variant (B.1.427), and ο (B.1.1.529) have emerged that 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 (VOCs).

[0010] Therapeutic antibodies have emerged as an important class of agents for treating human diseases and disorders. Therapeutic antibodies have been engineered to have specificity for two or more different antigens or epitopes (i.e., "multispecific" antibodies, which are, for example, bispecific, trispecific, or tetraspecific). Multispecific antibodies have been used to form multi-targeting strategies to treat human diseases and disorders 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. There is a need for therapeutic antibodies with broad VOC reactivity and SARS-CoV-2 escape resistance. There is also a need for therapeutic antibodies that are easier to manufacture and administer than current therapeutic antibody cocktails. There is also a need for treating or preventing 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 a multispecific antibody selected from the group consisting of:

[0013] (a) an antigen-binding polypeptide having a structure represented by the following formula:

[0014] VL1-L1-VH1 or VH1-L2-VL1;

[0015] in:

[0016] VL1 is the first immunoglobulin light chain variable region that specifically binds to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein;

[0017] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and

[0018] L1 and L2 are amino acid linkers; or

[0019] An antigen-binding polypeptide having a structure represented by the following formula:

[0020] VL1-L1-VL2-L2-VH2-L3-VH1;

[0021] VL1-L1-VH2-L2-VL2-L3-VH1;

[0022] VH1-L4-VH2-L5-VL2-L6-VL1; or

[0023] VH1-L4-VL2-L5-VH2-L6-VL1;

[0024] in:

[0025] VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0026] VL2 is the second immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0027] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0028] VH2 is a second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and

[0029] L1-L6 are amino acid linkers; and

[0030] wherein (a) is selected from any of the more specific embodiments provided herein for an antigen-binding polypeptide in an antigen-binding polypeptide complex having no more than three polypeptide chains;

[0031] (b) an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide;

[0032] The first polypeptide has a structure represented by the following formula:

[0033] VL1-L1-CL;

[0034] The second polypeptide has a structure represented by the following formula:

[0035] VH1-L2-CH1;

[0036] The third polypeptide has a structure represented by the following formula:

[0037] VH2-L3-VH3-L4-CH1;

[0038] The fourth polypeptide has a structure represented by the following formula:

[0039] VL3-L5-VL2-L6-CL; and

[0040] in:

[0041] VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0042] VL2 is the second immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0043] VL3 is the third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0044] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0045] VH2 is the second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0046] VH3 is the third immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0047] CH1 is the immunoglobulin heavy chain constant region 1;

[0048] CL is the immunoglobulin light chain constant region; and

[0049] L1-L6 are amino acid linkers; and

[0050] (c) an antigen-binding polypeptide having a structure represented by the following formula:

[0051] VL1-L1-VH1 or VH1-L2-VL1;

[0052] in:

[0053] VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0054] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and

[0055] L1 and L2 are amino acid linkers; or

[0056] An antigen-binding polypeptide having a structure represented by the following formula:

[0057] VL1-L1-VL2-L2-VH2-L3-VH1;

[0058] VL1-L1-VH2-L2-VL2-L3-VH1;

[0059] VH1-L4-VH2-L5-VL2-L6-VL1; or

[0060] VH1-L4-VL2-L5-VH2-L6-VL1;

[0061] in:

[0062] VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0063] VL2 is the second immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0064] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0065] VH2 is a second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and

[0066] L1-L6 are amino acid linkers;

[0067] wherein (c) is selected from any of the more specific embodiments provided herein for an antigen-binding polypeptide in an antigen-binding polypeptide complex having no more than three polypeptide chains; and

[0068] wherein the antigen-binding polypeptide further comprises an amino acid linker between any variable region and / or amino acid linker (e.g., between VL1 and L1, between L1 and VH1, between VH1 and L2, between L2 and VL1, between L1 and VL2, between VL2 and L2, between L2 and VH2, between VH2 and L3, between L3 and VH1, between VL1 and L1, between L1 and VH2, between VH2 and L2, between L2 and VL2, between VL2 and L3, between L3 and VH1 H1, between VH1 and L4, between L4 and VH2, between VH2 and L5, between L5 and VL2, between VL2 and L6, between L6 and VL1, between VH1 and L4, between L4 and VL2, between L4 and VL2, between VL2 and L5, between L5 and VH2, between VH2 and L6, or between L6 and VL1).

[0069] Also provided herein is a multispecific antibody comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide;

[0070] wherein the first polypeptide has a structure represented by VL1-L1-CL;

[0071] wherein the second polypeptide has a structure represented by VH1-L2-CH1-L3-Fc;

[0072] wherein the third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc;

[0073] wherein the fourth polypeptide has a structure represented by VL3-L7-VL2-L8-CL; and

[0074] Among them, VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0075] VL2 is the second immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0076] VL3 is the third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0077] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0078] VH2 is the second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0079] VH3 is the third immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0080] Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge;

[0081] CH1 is the immunoglobulin heavy chain constant region 1;

[0082] CL is the immunoglobulin light chain constant region; and

[0083] L1-L8 are amino acid linkers.

[0084] Provided herein is an antigen-binding polypeptide having a structure represented by VL1-L1-VH1 or VH1-L2-VL1; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1 and L2 are amino acid linkers.

[0085] Provided herein is an antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1; VL1-L1-VH2-L2-VL2-L3-VH1; VH1-L4-VH2-L5-VL2-L6-VL1; or VH1-L4-VL2-L5-VH2-L6-VL1; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1-L6 are amino acid linkers.

[0086] Also provided herein is an antigen-binding polypeptide having a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1 or VH1-L4-VH2-L5-VL2-L6-VL1; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; VL2 is a second immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1-L6 are amino acid linkers.

[0087] Also provided herein is an antigen-binding polypeptide having a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1 or VH1-L4-VL2-L5-VH2-L6-VL1; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; VL2 is a second immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1-L6 are amino acid linkers.

[0088] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1; VL1-L1-VH2-L2-VL2-L3-VH1; VH1-L4-VH2-L5-VL2-L6-VL1; or VH1-L4-VL2-L5-VH2- L6-VL1; wherein the second polypeptide has a structure represented by the following formula: VL3-L7-VL4-L8-VH4-L9-VH3; VL3-L7-VH4-L8-VL4-L9-VH3; VH3-L10-VH4-L11-VL4-L12-VL3; or VH3-L10-VL4-L11-VH4-L12-VL3; wherein VL1 is a polypeptide that specifically binds to S The first immunoglobulin light chain variable region of the ARS-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; VL4 is the fourth 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; VH4 is the fourth immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and L1-L12 are amino acid linkers.

[0089] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH1 or VH1-L2-VL1; wherein the second polypeptide has a structure represented by VL2-L3-VH2 or VH2-L4-VL2; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy 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; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1-L4 are amino acid linkers.

[0090] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH1-L2-Fc or VH1-L3-VL1-L4-Fc; wherein the second polypeptide has a structure represented by VL2-L5-VH2-L6-Fc or VH2-L7-VL2-L8-Fc; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy 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; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L8 are amino acid linkers.

[0091] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1 or VH1-L4-VH2-L5-VL2-L6-VL1; wherein the second polypeptide has a structure represented by VL3-L7-VL4-L8-VH4-L9-VH3 or VH3-L10-VH4-L11-VL4-L12-VL3; 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 chain variable region; VL3 is a third immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1-L12 are amino acid linkers.

[0092] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1 or VH1-L4-VL2-L5-VH2-L6-VL1; wherein the second polypeptide has a structure represented by VL3-L7-VH4-L8-VL4-L9-VH3 or VH3-L10-VL4-L11-VH4-L12-VL3; 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 chain variable region; VL3 is a third immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1-L12 are amino acid linkers.

[0093] Also provided herein is an antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; wherein VL1 is the first immune polypeptide that specifically binds to the SARS-CoV-2 protein. globulin light chain variable region; VL2 is a second 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; Fc is a region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L8 are amino acid linkers.

[0094] Also provided herein is an antigen-binding polypeptide having a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L8 are amino acid linkers.

[0095] Also provided herein is an antigen-binding polypeptide having a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L8 are amino acid linkers.

[0096] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8- Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc; wherein VL1 is specific a first immunoglobulin light chain variable region that 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 a third immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L16 are amino acid linkers.

[0097] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; 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 a third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VL4 is a fourth 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; VH4 is a fourth 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 an optional immunoglobulin hinge; and L1-L16 are amino acid linkers.

[0098] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc; 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 a first immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; a third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VL4 is a fourth 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; VH4 is a fourth 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 an optional immunoglobulin hinge; and L1-L16 are amino acid linkers.

[0099] Also provided herein is an antigen-binding polypeptide having a structure represented by the following formulae: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; VH1-L11-VL2-L12-VL2-L13-VH1-L14-CL-L15-CH1; -L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-CH1; or VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-CH1; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L20 are amino acid linkers.

[0100] Also provided herein is an antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; or VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-CH1 1; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L20 are amino acid linkers.

[0101] Also provided herein is an antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-CH1; or VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-CH1 1; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L20 are amino acid linkers.

[0102] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; V L1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-CH1; VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-CH1; or VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-CH1; wherein the second polypeptide has a structure represented by the following formula: VL3-L21-VL4-L22-VH4-L23-VH3-L24-CH1-L25-CL; VL3-L21-VH4-L22-VL4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VH4-L2 7-VL4-L28-VL3-L29-CH1-L30-CL; VH3-L26-VL4-L27-VH4-L28-VL3-L29- CH1-L30-CL; VL3-L31-VL4-L32-VH4-L33-VH3-L34-CL-L35-CH1; VL3-L31- VH4-L32-VL4-L33-VH3-L34-CL-L35-CH1; VH3-L36-VH4-L37-VL4-L38-VL 3-L39-CL-L40-CH1; or VH3-L36-VL4-L37-VH4-L38-VL3-L39-CL-L40-CH1; its 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; VL4 is the fourth 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;VH4 is the fourth 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-L40 is an amino acid linker.

[0103] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; or VH1-L16-VH2-L 17-VL2-L18-VL1-L19-CL-L20-CH1; wherein the second polypeptide has a structure represented by the following formula: VL3-L21-VL4-L22-VH4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VH4-L27-VL4-L28-VL3-L29-CH1-L30-CL; VL3-L31-VL4-L32-VH4-L33-VH3-L34-CL-L35-CH1; or VH3-L 36-VH4-L37-VL4-L38-VL3-L39-CL-L40-CH1; 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 a third immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L40 are amino acid linkers.

[0104] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-CH1; or VH1-L16-VL2-L 17-VH2-L18-VL1-L19-CL-L20-CH1; wherein the second polypeptide has a structure represented by the following formula: VL3-L21-VH4-L22-VL4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VL4-L27-VH4-L28-VL3-L29-CH1-L30-CL; VL3-L31-VH4-L32-VL4-L33-VH3-L34-CL-L35-CH1; or VH3-L 36-VL4-L37-VH4-L38-VL3-L39-CL-L40-CH1; 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 a third immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L40 are amino acid linkers.

[0105] Also provided herein is an antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VH1-L7-VL2-L8-VH2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-VH2-L15-VH1-L16-CL -L17-CH1-L18-Fc;VL1-L13-VH2-L14-VL2-L15-VH1-L16-CL-L17-CH1-L18-Fc;VH1-L19-VH2-L20- VL2-L21-VL1-L22-CL-L23-CH1-L24-Fc; or VH1-L19-VL2-L20-VH2-L21-VL1-L22-CL-L23-CH1-L24-Fc; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L24 is an amino acid linker.

[0106] Also provided herein is an antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-VH2-L15-VH1-L16-CL-L17-CH1-L18-Fc; or VH1-L19-VH2-L20-VL2-L21-VL1-L22-CL-L23-CH1-L24-Fc; wherein VL1 is a specific binding polypeptide. The invention further comprises 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L24 are amino acid linkers.

[0107] Also provided herein is an antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VL2-L8-VH2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VH2-L14-VL2-L15-VH1-L16-CL-L17-CH1-L18-Fc; or VH1-L19-VH2-L20-VL2-L21-VL1-L22-CL-L23-CH1-L24-Fc; wherein VL1 is a specific binding polypeptide. The invention further comprises 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L24 are amino acid linkers.

[0108] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VH1-L7-VL2-L8-VH2 -L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-VH2-L15-VH1-L16-CL-L17-CH1-L18-Fc; VL1-L13-VH2-L14-VL2- L15-VH1-L16-CL-L17-CH1-L18-Fc; VH1-L19-VH2-L20-VL2-L21-VL1-L22-CL-L23-CH1-L24-Fc; or VH1-L19-VL2-L20-VH2

[0109] -L21-VL1-L22-CL-L23-CH1-L24-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L25-VL4-L26-VH4-L27-VH3-L28-CH1-L29-CL-L30-Fc; VL3-L25-VH4-L26-VL4-L27-VH3-L28-CH1-L29-CL-L30-Fc; VH3-L31-VH4-L32-VL4-L33-VL3-L34-CH1-L35-CL-L36-Fc; VH3-L31 -VL4-L32-VH4-L33-VL3-L34-CH1-L35-CL-L36-Fc; VL3-L37-VL4-L38-VH4-L39-VH3-L40-CL-L41-CH1-L42-Fc; VL3-L37-VH4 -L38-VL4-L39-VH3-L40-CL-L41-CH1-L42-Fc; VH3-L43-VH4-L44-VL4-L45-VL3-L46-CL-L47-CH1-L48-Fc; or VH3-L43-VL4-L4 4-VH4-L45-VL3-L46-CL-L47-CH1-L48-Fc; wherein 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; VL4 is the fourth immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VH1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein chain variable region; 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; VH4 is a fourth 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; Fc is a region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L48 is an amino acid linker.

[0110] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-VH2-L15-VH1-L16-CL-L17-CH1-L18-Fc; or VH1-L19-VH2-L20-VL2- L21-VL1-L22-CL-L23-CH1-L24-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L25-VL4-L26-VH4-L27-VH3-L28-CH1-L29-CL-L30-Fc; VH3-L31-VH4-L32-VL4-L33-VL3-L34-CH1-L35-CL-L36-Fc; VL3-L37-VL4-L38-VH4-L39-VH3-L40-CL-L41-CH1-L42-Fc; or VH3-L43-V H4-L44-VL4-L45-VL3-L46-CL-L47-CH1-L48-Fc; wherein 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; VL4 is the fourth immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VH1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein protein heavy chain variable region; 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; VH4 is a fourth 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; Fc is a region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3) and an optional immunoglobulin hinge; and L1-L48 is an amino acid linker.

[0111] Also provided herein is an antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VL2-L8-VH2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VH2-L14-VL2-L15-VH1-L16-CL-L17-CH1-L18-Fc; or VH1-L19-VL2-L20-VH2- L21-VL1-L22-CL-L23-CH1-L24-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L25-VH4-L26-VL4-L27-VH3-L28-CH1-L29-CL-L30-Fc; VH3-L31-VL4-L32-VH4-L33-VL3-L34-CH1-L35-CL-L36-Fc; VL3-L37-VH4-L38-VL4-L39-VH3-L40-CL-L41-CH1-L42-Fc; or VH3-L43-V L4-L44-VH4-L45-VL3-L46-CL-L47-CH1-L48-Fc; wherein 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; VL4 is the fourth immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VH1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein protein heavy chain variable region; 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; VH4 is a fourth 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; Fc is a region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3) and an optional immunoglobulin hinge; and L1-L48 is an amino acid linker.

[0112] Also provided herein is an antigen-binding polypeptide or antigen-binding polypeptide complex comprising a polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-Fc-L10-Fc; or VH1-L6-VL2-L7-VH2-L8-VL1-L9-Fc-L10-Fc; wherein VL1 is specific for VL2 is a second immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L10 are amino acid linkers.

[0113] Also provided herein is an antigen-binding polypeptide or antigen-binding polypeptide complex comprising a polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc-L5-Fc or VH1-L6-VH2-L7-VL2-L8-VL1-L9-Fc-L10-Fc; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L10 are amino acid linkers.

[0114] Also provided herein is an antigen-binding polypeptide or antigen-binding polypeptide complex comprising a polypeptide having a structure represented by the following formula: VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc-L5-Fc; or VH1-L6-VL2-L7-VH2-L8-VL1-L9-Fc-L10-Fc; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L10 are amino acid linkers.

[0115] In some aspects, VH1, VH2, VH3, and VH4 each comprise the same heavy chain variable region, and VL1, VL2, VL3, and VL4 each comprise the same light chain variable region.

[0116] In some aspects, VH1 comprises the same heavy chain variable region as VH3, and VL1 comprises the same light chain variable region as VL3.

[0117] In some aspects, VH2 comprises the same heavy chain variable region as VH4, and VL2 comprises the same light chain variable region as VL4.

[0118] In some aspects, two of VH1, VH2, VH3, and VH4 comprise the same heavy chain variable region, and two of VL1, VL2, VL3, and VL4 comprise the same light chain variable region.

[0119] In some aspects, VH2 comprises the same heavy chain variable region as VH4, and VL2 comprises the same light chain variable region as VL4.

[0120] In some aspects, VH2 comprises the same heavy chain variable region as VH3, and VL2 comprises the same light chain variable region as VL3.

[0121] In some aspects, VH1 comprises the same heavy chain variable region as VH4, and VL1 comprises the same light chain variable region as VL4.

[0122] In some aspects, VH1 comprises the same heavy chain variable region as VH3, and VL1 comprises the same light chain variable region as VL3.

[0123] In some aspects, the immunoglobulin hinge comprises an upper hinge region, a middle hinge region, a lower hinge region, or a combination thereof.

[0124] In some aspects, linkers L1-L48 each independently have a length of 0 amino acids to about 50 amino acids.

[0125] In some aspects, linkers L1-L48 that do not have a length of 0 amino acids each independently comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 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: 1-34, wherein SEQ ID NO: 1 has the amino acid sequence of G, SEQ ID NO: 2 has the amino acid sequence of A, SEQ ID NO: 3 has the amino acid sequence of GSS, and SEQ ID NO: 4 has the amino acid sequence of ASG.

[0126] In some aspects, one or more of linkers L1-L48 are non-immunogenic.

[0127] In some aspects, one or more of the linkers L1-L48 do not contain a consensus T cell epitope.

[0128] In some aspects, the Fc region comprises at least one knob-into-hole modification or an Fc effector function knockout mutation.

[0129] In some aspects, the antigen-binding polypeptide complex is an IgG1 or IgG4 antibody and the knob-into-hole modification comprises (i) knob substitutions S354C and T366W and hole substitutions Y349C, T366S, L368A, and Y407V; (ii) hole substitutions M428L and N434S or N434A; (iii) hole substitutions M252Y, S254T, and T256E; or (iv) a combination thereof, based on the EU numbering scheme. In some aspects, based on the EU numbering scheme, the hole substitutions are M428L and N424S. In some aspects, based on the EU numbering scheme, the hole substitution is N434A.

[0130] 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.

[0131] In some aspects, the antigen-binding polypeptide or antigen-binding polypeptide complex comprises a detectable label. In some aspects, the detectable label is a radiolabel, 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 4 to about 10 histidine residues. In some aspects, the polyhistidine tag is composed of about eight histidine residues.

[0132] In some aspects, the antigen-binding polypeptide or 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.

[0133] In some aspects, the variable region of the antibody may require site-specific deglycosylation. In some aspects, and for the E8VH 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.

[0134] In some aspects, the antigen-binding polypeptide complex is bispecific, trispecific, or tetraspecific and has greater neutralizing potency against the SARS-CoV-2 virus than a monospecific antigen-binding polypeptide complex that specifically binds to one of the same antigens as the bispecific, trispecific, or tetraspecific antigen-binding polypeptide complex.

[0135] In some aspects, the antigen-binding polypeptide complex is bispecific, trispecific, or tetraspecific and has greater neutralizing potency against the SARS-CoV-2 virus than a mixture of monospecific antigen-binding polypeptide complexes that specifically bind to the same antigen as the bispecific, trispecific, or tetraspecific antigen-binding polypeptide complex.

[0136] In some aspects, the SARS-CoV-2 virus is the original strain (WA1), the D614G spike protein mutant (D614G), an alpha variant (B.1.1.7), a beta variant (B.1.351), a gamma variant (P.1), a delta variant, an epsilon variant (B.1.427), or an o variant (B.1.1.529), or a combination thereof. In some aspects, the o 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.

[0137] 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.

[0138] Also provided herein is an antibody or antigen-binding fragment thereof comprising an antigen-binding polypeptide or antigen-binding polypeptide complex provided herein.

[0139] In some aspects, the antibody is IgG, IgM, IgE, IgA or IgD. In some aspects, the IgG is IgG1, IgG2, IgG3 or IgG4.

[0140] In some aspects, the antigen binding fragment is a Fab, scFab, Fab', F(ab')2, Fv, or scFv.

[0141] In some aspects, the antibody is a human or humanized antibody.

[0142] In some aspects, the antibody is a monoclonal antibody, a transplanted antibody, or a chimeric antibody.

[0143] Also provided herein is a pharmaceutical composition comprising an antigen-binding polypeptide, an antigen-binding polypeptide complex, an antibody or its antigen-binding fragment as provided herein. In some aspects, the pharmaceutical composition comprises (1) one or more polynucleotides encoding an antigen-binding polypeptide or an antigen-binding polypeptide complex, and (2) a carrier. In some aspects, the pharmaceutical composition comprises (1) one or more polynucleotides encoding an antigen-binding polypeptide or an antigen-binding polypeptide complex (e.g., an antibody or its antigen-binding fragment) as provided herein, and (2) a carrier selected from the group consisting of lipids or lipid nanoparticles. In some aspects, the one or more polynucleotides encoding the antigen-binding polypeptide or the antigen-binding polypeptide complex are stabilized polynucleotides that resist degradation or decomposition in vivo. In some aspects, the stabilized polynucleotide is capped at one end (5' cap) and has a long polyadenylation (polyA) tail at the other end to form a stabilized mRNA with 5' and 3' UTRs. 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.

[0144] Also provided herein is a pharmaceutical composition comprising an antigen-binding polypeptide, antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof provided herein, and an additional pharmaceutical agent.

[0145] Also provided herein is a kit comprising the antigen-binding polypeptide, antigen-binding polypeptide complex, antibody or antigen-binding fragment thereof, or pharmaceutical composition provided herein.

[0146] 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 a therapeutically 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 the therapeutic antigen-binding polypeptide or antigen-binding polypeptide complex can be performed by direct administration of a therapeutic agent or by an indirect method including a modified mRNA composition, wherein the modified mRNA composition is administered to a patient in need of treatment by translating a therapeutic antigen-binding polypeptide or antigen-binding polypeptide complex from a modified mRNA encoding the therapeutic polypeptide or polypeptide complex.

[0147] 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 a therapeutically 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.

[0148] Also provided herein is a method for diagnosing a subject as being 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 comprising the polypeptide, polypeptide complex, antibody or fragment and the SARS-CoV-2 virus, virion or fragment thereof; and (iii) when the presence of the viral complex is detected, diagnosing the subject as being infected with or suspected of being infected with the SARS-CoV-2 virus.

[0149] Also provided herein is a method for diagnosing a subject as not infected with SARS-CoV-2 virus or not suspected of being infected with 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 comprising the polypeptide, 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 the subject as not infected with SARS-CoV-2 virus or not suspected of being infected with SARS-CoV-2 virus.

[0150] 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 comprising the polypeptide, 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.

[0151] Also provided herein is a method for diagnosing a subject as not having COVID-19 or 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 comprising the polypeptide, 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 the subject as not having COVID-19 or not suspected of having COVID-19.

[0152] In some aspects, the sample is a nasal swab, tissue sample, saliva, plasma, or blood.

[0153] In some aspects, detecting the presence or absence of viral complexes comprises enzyme-linked immunosorbent assay (ELISA), immunodot assay, lateral flow assay, flow cytometry, immunohistochemistry, or Western blot.

[0154] In some aspects, the polypeptide, polypeptide complex, antibody, or fragment is bispecific, trispecific, or tetraspecific and has greater neutralizing potency against the SARS-CoV-2 virus than a monospecific polypeptide, polypeptide complex, antibody, or fragment that specifically binds to one of the same antigens as the bispecific, trispecific, or tetraspecific polypeptide, polypeptide complex, antibody, or fragment.

[0155] In some aspects, the polypeptide, polypeptide complex, antibody, or fragment is bispecific, trispecific, or tetraspecific and has greater neutralizing potency against the SARS-CoV-2 virus than a mixture of monospecific polypeptides, polypeptide complexes, antibodies, or fragments that specifically bind to the same antigen as the bispecific, trispecific, or tetraspecific polypeptide, polypeptide complex, antibody, or fragment.

[0156] In some aspects, the SARS-CoV-2 virus is the original strain (WA1), the D614G spike protein mutant (D614G), an alpha variant (B.1.1.7), a beta variant (B.1.351), a gamma variant (P.1), a delta variant, an epsilon variant (B.1.427), an o variant (B.1.1.529), or a combination thereof. In some aspects, the o 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.

[0157] 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.

[0158] 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 a combination of (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 monovalent anti-SARS-CoV2 antibody that binds to the same antigen as the anti-SARS-CoV2 multivalent antibody.

[0159] Also provided herein is a method of 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 an antigen-binding polypeptide or polypeptide complex provided herein, an antibody or antigen-binding fragment thereof provided herein, or a combination thereof.

[0160] 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.

[0161] Also provided herein is a method of increasing the neutralization potency against SARS-CoV-2 virus in a subject infected with 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 a combination of (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 monovalent anti-SARS-CoV2 antibody that binds to the same antigen as the anti-SARS-CoV2 multivalent antibody.

[0162] Also provided herein is an anti-SARS-CoV2 multivalent antibody that exhibits improved prevention of immune escape compared to a combination of (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 monovalent anti-SARS-CoV2 antibody that binds to the same antigen as the anti-SARS-CoV2 multivalent antibody. BRIEF DESCRIPTION OF THE DRAWINGS

[0163] 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 by way of example and for purposes of illustrative discussion of aspects of the invention.

[0164] Figures 1A-1D Configurations of exemplary monospecific tetravalent molecules described in the Examples are shown. Figure 1A : A monospecific tetravalent molecule (MX241) containing the VH, VL and Fc regions of the anti-SARS-CoV-2 antibody B1-182. Figure 1B : A monospecific tetravalent molecule (MX365) containing the VH and VL of B1-182 with Fc, CL, and CH1. Figure 1C : A monospecific tetravalent molecule (MX409) containing the VH, VL and Fc of the anti-SARS-CoV-2 hybrid antibody A23-58H / B1-182L. Figure 1D : A monospecific tetravalent molecule (MX466) containing the VH and VL of A23-58H / B1-182L with Fc, CL and CH1.

[0165] Figures 2A-2P Configurations of exemplary bispecific tetravalent molecules described in the Examples are shown. Figure 2A : A bispecific tetravalent molecule (MX179) containing the VH and VL of B1-182 and the VH, VL and Fc of the anti-SARS-CoV-2 antibody A19-46. Figure 2B : A bispecific tetravalent molecule (MX180) containing the VH and VL of B1-182 and the VH and VL of A19-46 with Fc. Figure 2C : A bispecific tetravalent molecule (MX183) containing the VH and VL of B1-182 and the VH, VL and Fc of the anti-SARS-CoV-2 antibody A19-61. Figure 2D : A bispecific tetravalent molecule (MX184) containing the VH and VL of B1-182 and the VH and VL of A19-61 with Fc. Figure 2E : A bispecific tetravalent molecule (MX366) containing the VH and VL of B1-182 and the VH and VL of A19-61 with Fc, CL and CH1. Figure 2F : A bispecific tetravalent molecule (MX367) containing the VH and VL of B1-182 and the VH and VL of A19-61 with Fc, CL and CH1. Figure 2G : A bispecific tetravalent molecule (MX412) containing the VH and VL of A23-58H / B1-182L and the VH and VL of A19-61 with Fc. Figure 2H: A bispecific tetravalent molecule (MX413) containing the VH and VL of A23-58H / B1-182L and the VH and VL of A19-61 with Fc. Figure 2I : A bispecific tetravalent molecule (MX490) containing the VH and VL of A23-58H / B1-182L and the VH and VL of A19-46 with Fc. Figure 2J : A bispecific tetravalent molecule (MX492) containing the VH and VL of A23-58H / B1-182L and the VH and VL of A19-46 with Fc. Figure 2K : A bispecific tetravalent molecule (MX467) containing the VH and VL of A23-58H / B1-182L and the VH and VL of A19-61 with Fc, CL and CH1. Figure 2L : A bispecific tetravalent molecule (MX468) containing the VH and VL of A23-58H / B1-182L and the VH and VL of A19-61 with Fc, CL and CH1. Figure 2M : A bispecific tetravalent molecule (MX491) containing the VH and VL of A23-58H / B1-182L and the VH and VL of A19-46 with Fc, CL and CH1. Figure 2N : A bispecific tetravalent molecule (MX493) containing the VH and VL of A23-58H / B1-182L and the VH and VL of A19-46 with Fc, CL and CH1. Figure 2O : A bispecific tetravalent molecule (MX326) containing the VH and VL of the anti-SARS-CoV-2 antibody A23-58 and the VH and VL of A19-61. Figure 2P : A bispecific tetravalent molecule (MX327) containing the VH and VL of A23-58 and the VH and VL of A19-61.

[0166] Figures 3A-3H Exemplary configurations of trispecific tetravalent molecules described in the Examples are shown. Figure 3A : A trispecific tetravalent molecule (MX494) containing the VH and VL of A19-46, the VH and VL of A19-61, and the VH and VL of B1-182 with Fc and knob-in-hole modifications. Figure 3B : A trispecific tetravalent molecule (MX495) containing the VH and VL of A19-46, the VH and VL of A19-61, and the VH and VL of B1-182 with Fc and knob-in-hole modifications. Figure 3C : A trispecific tetravalent molecule (MX496) containing the VH and VL of A19-46, the VH and VL of A19-61, and the VH and VL of B1-182 with Fc and knob-in-hole modifications. Figure 3D: A trispecific tetravalent molecule (MX497) containing the VH and VL of A19-46, the VH and VL of A19-61, and the VH and VL of B1-182 with Fc and knob-in-hole modifications. Figure 3E : A trispecific tetravalent molecule (MX498) containing the VH and VL of A19-46, the VH and VL of A19-61, and the VH and VL of A23-58H / B1-182L with Fc and knob-in-hole modifications. Figure 3F : A trispecific tetravalent molecule (MX499) containing the VH and VL of A19-46, the VH and VL of A19-61, and the VH and VL of A23-58H / B1-182L with Fc and knob-in-hole modifications. Figure 3G : A trispecific tetravalent molecule (MX500) containing the VH and VL of A19-46, the VH and VL of A19-61, and the VH and VL of A23-58H / B1-182L with Fc and knob-in-hole modifications. Figure 3H : A trispecific tetravalent molecule (MX501) containing the VH and VL of A19-46, the VH and VL of A19-61, and the VH and VL of A23-58H / B1-182L with Fc and knob-in-hole modifications.

[0167] Figure 4 Shown are the percent neutralization of the o variant (B.1.1.529) in the presence of increasing concentrations of the MX179 and MX180 antibodies described in Example 1 and the B1-182 and A19-46 parent antibodies.

[0168] Figure 5 Shown are the percent neutralization of the o variant (B.1.1.529) in the presence of increasing concentrations of either MX179 or MX180 antibodies as described in Example 1, compared to a combination of the B1-182 and A19-46 parent antibodies. The concentration of each antibody in the combination of the two antibody mixtures is plotted.

[0169] Figure 6 Shown are the percent neutralization of the o variant (B.1.1.529) in the presence of increasing concentrations of MX494, MX495, MX496, or MX497 antibodies described in Example 1, compared to a combination of the B1-182, A19-46, and A19-61 parent antibodies. The concentration of each antibody in the combination of the three antibody cocktails is plotted.

[0170] Figure 7Serum antibody levels are shown in Tg32-humanized FcRn mice (n=5) treated with parental or tetravalent bispecific MX413 (A19-61 x A23-58H / B1-182L) antibodies. Concentrations of VRC01 LS (dashed line, circle symbols), B1-182.1 (dotted line, square symbols), and MX413 (solid line, triangle symbols), antibodies containing Fc mutations to extend half-life, were measured in serum over a 35-day period following intravenous administration of a single 5 mg / kg dose of each antibody. Each data point represents the mean ± standard error of the mean (SEM) of triplicate determinations.

[0171] Figure 8A Graph showing the in vivo passive transfer challenge study described in Example 4.

[0172] Figures 8B-8D The results of the BA.1 attack are shown. Figure 8B The weight loss of the animals is shown. Symbols and error bars represent the mean and SEM, respectively. Figure 8C Lung viral loads of the animals are shown. Figure 8D The nasal viral load of the animals is shown. Each symbol represents a single animal and can overlap for equal values. The significance between treated and untreated animals at each time point was determined using an unpaired two-tailed Student's t-test. Significant p-values ​​are indicated as: *(≤0.05), and ¥(≤0.0001). Boxes and horizontal bars represent the median (IQR) and median of infected subjects, respectively. Box and whisker endpoints are equal to the maximum and minimum values. The dotted line indicates the lower limit of detection of the assay. An unpaired two-tailed Student's t-test was used to determine the significance between treated and untreated animals at each time point. Significant p-values ​​are indicated on the graph.

[0173] Figures 8E-8G The results of the BA.2 attack are shown. Figure 8E The weight loss of the animals is shown. Symbols and error bars represent the mean and SEM, respectively. Figure 8F Lung viral loads of the animals are shown. Figure 8G The nasal viral load of the animals is shown. Each symbol represents a single animal and can overlap for equal values. The significance between treated and untreated animals at each time point was determined using an unpaired two-tailed Student's t-test. Significant p-values ​​are indicated as: *(≤0.05), and ¥(≤0.0001). Boxes and horizontal bars represent the IQR and median, respectively. Box and whisker endpoints are equal to the maximum and minimum values. The dotted line indicates the lower limit of detection of the assay. Significance between treated and untreated animals at each time point was determined using an unpaired two-tailed Student's t-test. Significant p-values ​​are indicated on the graph.

[0174] Figures 8H-8J The results of the BA.5 attack are shown. Figure 8H The weight loss of the animals is shown. Symbols and error bars represent the mean and SEM, respectively. Figure 8I Lung viral loads of the animals are shown. Figure 8J The nasal viral load of the animals is shown. Each symbol represents a single animal and can overlap for equal values. The significance between treated and untreated animals at each time point was determined using an unpaired two-tailed Student's t-test. Significant p-values ​​are indicated as: *(≤0.05), and ¥(≤0.0001). Boxes and horizontal bars represent the IQR and median, respectively. Box and whisker endpoints are equal to the maximum and minimum values. The dotted line indicates the lower limit of detection of the assay. Significance between treated and untreated animals at each time point was determined using an unpaired two-tailed Student's t-test. Significant p-values ​​are indicated on the graph.

[0175] Figure 9 Two configurations of trispecific trivalent crossover bivariable (CODV) antibodies prepared using variable fragments (Fv) from B1-182.1 ("182.1," dotted; light chain = light shade; heavy chain = dark shade), anti-SARS-CoV-2 antibody A19-46.1 ("46.1," striped; light chain = light shade; heavy chain = dark shade), and A19-61.1 ("61.1," checkered; light chain = light shade; heavy chain = dark shade). Also indicated are the CH1, CL, and Fc regions, as well as the knob-in-hole modification in the Fc region.

[0176] Figure 10 The SARS-CoV-2 escape potential of a monospecific antibody (B1-182.1), a combination of monospecific antibodies (B1-182.1 + A19-61.1 + A19-46.1), and a multispecific antibody (46.1 / 61.1-182.1 and 61.1 / 46.1-182.1) is shown. The maximum concentration with >20% cytopathic effect (CPE) that was forwarded in each round of selection is shown for each antibody.

[0177] Figure 11Exemplary configurations of tetravalent bispecific and tetravalent trispecific molecules are shown. MX828 contains two VH / VL pairs of A19-46 and two VH / VL pairs of A23-58H / A23-58L93VGLTG. MX829 contains two VH / VL pairs of A19-61 and two VH / VL pairs of A23-58H / A23-58L93VGLTG. MX830 contains two VH / VL pairs of A19-46 and two VH / VL pairs of A23-58H / A23-58L94GLTG. MX831 contains two VH / VL pairs of A19-61 and two VH / VL pairs of A23-58H / A23-58L94GLTG. MX834 and MX837 contain one VH / VL pair from A19-46, one VH / VL pair from A19-61, and two VH / VL pairs from A23-58H / A23-58L93VGLTG. MX835 and MX838 contain one VH / VL pair from A19-46, one VH / VL pair from A19-61, and two VH / VL pairs from A23-58H / A23-58L94GLTG.

[0178] Figures 12A-12F Additional exemplary configurations of divalent and tetravalent molecules are shown.

[0179] Figures 13A-13F Additional exemplary configurations of tetravalent molecules with VH / VL binding pairs selected from B8, E8, and A19-46 are shown.

[0180] Figures 14A-14L Additional exemplary configurations of tetravalent molecules with VH / VL binding pairs selected from B8, A19-46, and E8 are shown.

[0181] Figures 15A-15F Additional exemplary configurations of tetravalent molecules with VH / VL binding pairs selected from E12, A19-46, and E8 are shown.

[0182] Figures 16A-16L Additional exemplary configurations of tetravalent molecules with VH / VL binding pairs selected from E12, A19-46, and E8 are shown.

[0183] Figures 17A-17E Additional exemplary configurations of tetravalent molecules with VH / VL binding pairs selected from B8, E12, A23-58H / L93VGLTG, A19-46, and E8 are shown.

[0184] Figures 18A-18L Additional exemplary configurations of tetravalent molecules with VH / VL binding pairs selected from A23-58H / L93VGLTG, A19-46, and E8 are shown.

[0185] Figure 19 IC50 values ​​(in nM) are shown for the indicated molecules neutralizing sublineages BA.1, BA.4 / 5, BA.2.12.1, BA.2.75, BA.4.6, BA.2.75.2, BQ.1.1, BJ.1, and XBB.

[0186] Figure 20 IC50 values ​​(in nM) are shown for the indicated molecules neutralizing sublineages BA.4 / 5, BQ.1, BQ.1.1, BA.2.75.2, and XBB.

[0187] Figure 21 IC50 values ​​(in nM) are shown for the indicated molecules neutralizing sublineages BA.4 / 5, BQ.1, BQ.1.1, BA.2.75.2, and XBB.

[0188] Figure 22 IC50 and IC80 values ​​(in nM) are shown for the indicated molecules neutralizing sublineages BA.4 / 5, BQ.1, BQ.1.1, BA.2.75.2, XBB, XBB1.5, BF.7, and CH.1.1. Class names are shown in column 2 of the table.

[0189] Figure 23 An epitope map of o is shown, indicating various mutations and variants.

[0190] Figure 24 Blood levels of MX1069, MX1043, MX1206, MX1089, and MX1042 are shown for Syrian hamsters up to 21 days post-infusion.

[0191] Figure 25 Graph showing passive transfer experiments in Syrian hamsters using MX1069 and MX1089 and XBB viruses.

[0192] Figure 26A Shown are the percent body weight changes of XBB-infected animals treated with MX1069 and MX1089.

[0193] Figure 26B Shown are lung viral loads (left panel) and nares viral loads (right panel) of XXB-infected animals treated with MX1069 and MX1089.

[0194] Figure 27 Graph showing passive transfer experiments in Syrian hamsters using MX1042 and MX1043 and XBB viruses.

[0195] Figure 28AShown are the percent body weight changes of XBB-infected animals treated with MX1042, MX1043, and the combination of MX1042 and MX1043.

[0196] Figure 28B Shown are lung viral loads (left panel) and nasal viral loads (right panel) of XXB-infected animals treated with MX1042, MX1043, and the combination of MX1042 and MX1043.

[0197] Figure 29A Preparative and analytical size exclusion chromatography (SEC) elution profiles of 46.1-182.1v / 61.1-182.1v are shown.

[0198] Figure 29B Shown are IC50 and IC80 values ​​(in pM) for the indicated molecules neutralizing sublineages B.1.1.7, BA.1, BA.2, and BA.4 / 5.

[0199] Figure 30A Representative images of lung histopathology of BA.5-infected Syrian hamsters treated with PBS or 46.1-182.1v / 61.1-182.1v on days 2 and 4 are shown.

[0200] Figure 30B Representative images of lung histopathology of BA.5-infected Syrian hamsters treated with PBS or 46.1-182.1v / 61.1-182.1v on days 6 and 10 are shown.

[0201] Figure 31 The SARS-CoV-2 escape potential of multispecific antibodies MX1043, MX1042, MX1069, and MX1089 is shown compared to antibody combinations (E12+A19-46.1+E8; E12+E8; and MX1042+MX1043) and LY1404. The maximum concentration with >20% CPE that was forwarded in each round of selection is shown for each antibody. The structures of the relevant antibodies and the resulting IC50 and IC80 values ​​are also shown.

[0202] Figure 32Shown are the results of a pharmacokinetic study evaluating the properties of parental monoclonal antibodies F769-E12, F769-B1, E76-B8, and F770-E8 compared to the bispecific antibodies MX1042 (E8 x E12) and MX 1043 (E12 x A19-46), the trispecific antibody MX1069 (A19-46 x E12 / E12 x E8), and the tetraspecific antibodies MX1089 (A19-46 x B8 / E8 x A23-58H / L93VGLTG) and MX1206 (A19-46 x E12 / E8 x A23-58H / L93VGLTL).

[0203] Figure 33 Characterization of the mRNA-LNPs described in the Examples is shown, including the average diameter (nm) and polydispersity index (PDI).

[0204] Figure 34 A diagram shows a mouse model used to evaluate the in vivo expression of mRNA-LNPs.

[0205] Figure 35 Blood antibody concentrations in μg / mL of mice treated with the indicated mRNA-LNPs are shown.

[0206] Figure 36 An exemplary configuration of a monospecific trivalent crossover bivariable (CODV) immunoglobulin antibody prepared using the variable fragment (Fv) from the anti-SARS-CoV-2 antibody B1-182.1 (Fv182.1, dotted) is shown. The Fc region contains a knob-into-hole modification to increase yield and correct association of the heavy chain.

[0207] Figures 37A-37C An exemplary configuration of a bispecific trivalent CoV immunoglobulin antibody prepared using variable fragments (Fv) from B1-182.1 (Fv182.1, dotted) and anti-SARS-CoV-2 antibody A19-61.1 (Fv61.1, squared) is shown. The Fc region contains a knob-into-hole modification to increase yield and correct association of the heavy chain.

[0208] Figures 38A-38D Shown are exemplary configurations of trispecific, trivalent CoV immunoglobulin antibodies prepared using variable fragments (Fv) from B1-182.1 ("182.1" or "Fv182 class I," dotted), anti-SARS-CoV-2 antibodies A19-46.1 ("46.1" or "Fv46 class II," striped), and A19-61.1 ("61.1" or "Fv61 class III," squared). The Fc region contains knob-in-hole modifications to increase yield and correct association of the heavy chain.

[0209] Figure 39A The purity of CODV immunoglobulin antibodies evaluated on Coomassie SDS-PAGE gels (representative gels shown) under non-reducing (nr) and reducing (r) conditions is shown. Molecular weight marker standards (MW) are also shown.

[0210] Figure 39B The CODV immunoglobulin bispecific and trispecific antibody traces shown before (top row) and after (bottom row) size exclusion chromatography (SEC) are shown. The dotted line frame indicates the fractions that were combined to prepare the final formulation of the indicated multispecific antibodies. The bottom row shows the analytical SEC trace of the purified multispecific antibodies.

[0211] Figure 40A Show Figures 40B-40E Design of crossover bivariable immunoglobulin antibodies used in.

[0212] Figure 40B Shown are the predicted binding of Fv182.1 ("Fv182"), Fv46.1 ("Fv46"), and Fv61.1 ("Fv61") to viral spike receptor binding domain (RBD) proteins containing the indicated Fv split mutations, which were selected to knock out binding to a single component Fv while leaving binding to the remaining Fv components unchanged.

[0213] Figures 40C-40E Validation of multispecific Fv binding activity using Fv separation mutations in the RBD and enzyme-linked immunosorbent assay (ELISA) is shown. Parent component antibody control ( Figure 40C , B1-182.1, A19-46.1 and A19-61.1), bispecific antibodies ( Figure 40D , 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 40E , 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 are indicated and selected to interrogate binding to one Fv component at a time in each multispecific antibody.

[0214] Figure 41ASchematic 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 the constant domain are dotted, striped, grid and grey, respectively.

[0215] Figure 41B Shown are combinations of RBD mutations on the SARS-CoV-2 spike designed to distinguish between different binding modes of CODV.

[0216] Figure 41C It is a schematic diagram of the combination of CODV61.1-182.1 (left) and CODV61.1-182.1 with spike protein mutants (center left and center right). For the sake of clarity, the Fv domain that can not be combined with mutants is black. The combination of CODV and K444E / L452R mutants was observed, indicating that CODV 61.1-182.1 can be combined with spike protein by Fv182 domains (center left). However, CODV was not observed to combine with L452R / F486S mutants (center right), indicating that CODV 61.1-182.1 can not be combined by Fv61 domains in a trimeric environment. The model that CODV61.1-182.1 is bound to SARS-CoV-2 spike protein is shown in the Fv182-binding mode allowed (right). For the sake of clarity, only one CODV is shown to be combined with spike protein with RBD in the conformation on. The white scale bar represents 10 nm.

[0217] Figure 41D Schematic diagram 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 domain that cannot bind to the mutant is black. CODV was observed to bind to both 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). The model of CODV 182.1-61.1 binding to the SARS-CoV-2 spike protein is shown in Fv182.1-binding and Fv61.1-binding modes (right). Ratio and Figure 41C Same as in.

[0218] Figure 41ESchematic diagram 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 domain that cannot bind to the mutant is black. CODV was observed to bind to both 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). The model of CODV 46.1-182.1 binding to the SARS-CoV-2 spike protein is shown as binding through the Fv182 and Fv46 binding modes (right). Ratio and Figure 41C Same as in.

[0219] Figure 41F Schematic diagram of CODV 182.1-46.1 (left) and CODV 182.1-46.1 binding to spike protein mutants (center left and center right). For clarity, the Fv domain that cannot bind to the mutant is 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 (center left). However, CODV binding to the K444E / F486S mutant was not observed (center right), indicating that CODV 182.1-46.1 cannot bind through the Fv46 domain in a trimeric environment. The model of CODV 182.1-46.1 binding to the SARS-CoV-2 spike protein is shown as binding through the allowed Fv182 domain (right). Ratio and Figure 41C Same as in.

[0220] Figure 41G CODV 46.1-182.1 and 182.1-46.1-induced o spike protein aggregation obtained using negative stain electron microscopy (NSEM) is shown.

[0221] Figure 41H The spike aggregation potential of 61.1 / 46.1-182.1 using NSEM is shown.

[0222] Figure 42 Shown are the results of three independent experiments 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 182.1 binding region (182.1), bebtelovimab (LY1404), and an AZD7442 cocktail (2196+2130).

[0223] Figure 43 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

[0224] Provided herein are antigen-binding polypeptides and polypeptide complexes with improved characteristics. In some aspects, the antigen-binding polypeptides and polypeptide complexes have a wide range of reactivity for the SARS-CoV-2 variants (VOCs) of interest and / or resistance to SARS-CoV-2 escape. In some aspects, provided herein are antigen-binding polypeptides and polypeptide complexes that are easier to manufacture and administer than current therapeutic antibody cocktails. In some aspects, the antigen-binding polypeptides and polypeptide complexes treat and / or prevent SARS-CoV-2 infections and / or COVID-19 in immunocompromised individuals who cannot produce an effective immune response through vaccination.

[0225] Throughout the specification and claims, various terms related to aspects of the present disclosure are used. Unless otherwise indicated, such terms will be given their ordinary meanings in the art. Other specifically defined terms will be interpreted in a manner consistent with the definitions provided herein.

[0226] definition

[0227] As used herein, the term "SARS-CoV-2" refers to "Severe Acute Respiratory Syndrome Coronavirus 2." SARS-CoV-2 is the coronavirus strain that causes coronavirus disease 2019 (COVID-19).

[0228] As used herein, the term "SARS-CoV-2 virus" includes SARS-CoV-2 virus, virions, or fragments thereof.

[0229] 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, difficulty breathing, loss of smell, and loss of taste. Symptoms can begin one to 14 days after exposure to the virus; however, at least one-third of infected people do not develop obvious symptoms. Of those who develop symptoms obvious enough to be classified as patients, most have mild to moderate symptoms (up to mild pneumonia), with approximately 15% developing severe symptoms (difficulty breathing, hypoxia, or more than 50% lung involvement on imaging), and approximately 5% developing severe symptoms (respiratory failure, shock, or multiple organ dysfunction). Some people continue to experience a range of effects that last for months after recovery (“long COVID”).

[0230] 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 is composed of 16 non-structural proteins and 4 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. This 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 to 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 a combination thereof. In some aspects, the SARS-CoV-2 protein is a spike protein.

[0231] In some aspects, an antigen-binding polypeptide or antigen-binding polypeptide complex provided herein (eg, an antibody or antigen-binding fragment thereof) is a Class I antibody, a Class II antibody, or a Class III antibody, or is a portion thereof.

[0232] 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 only recognize the "up" 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 RBD, and are capable of binding to RBD in "up" and "down" configurations. As used herein, "Class III" refers to antibodies that can bind to RBD in "up" and "down" configurations and are typically bound to antibodies outside the ACE2 binding region. As used herein, "Class IV" refers to antibodies that bind to highly conserved hidden epitopes on RBD outside the receptor binding motif (RBM) of the spike protein.

[0233] In some aspects, provided herein are antigen-binding polypeptides or antigen-binding polypeptide complexes (e.g., antibodies or their antigen-binding fragments) belonging to two, three or four classes. Therefore, in some aspects, provided herein are antigen-binding polypeptides or antigen-binding polypeptide complexes (e.g., antibodies or their antigen-binding fragments) belonging to two, three or four classes.

[0234] In some aspects, the antigen-binding polypeptides or antigen-binding polypeptide complexes provided herein comprise 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, and 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.

[0235] As used herein, the term "spike protein" refers to the largest of the four structural proteins found in the SARS-CoV-2 virus. The spike protein assembles into trimers, forming a large structure called a spike or envelope protrusion (peplomer), which protrudes from the surface of the SARS-CoV-2 virion and mediates the entry of the virion into the host cell. The SARS-CoV-2 spike protein is also called "spike (S) glycoprotein" and E2. The structural and functional properties of this protein have been characterized. See, for example, Huang et al., ActaPharmacol.Sin.41:1141-1149, 2020; Wu et al., Nature 579(7798):265-269, 2020; and GeneID:43740568.

[0236] Antigen binding sequences of anti-SARS-CoV-2 proteins (e.g., CDRs, VH, VL, heavy and light chain sequences from antibodies) are known. Such sequences include, but are not limited to, SEQ ID NOs: 38-788.

[0237] 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 (ie, one or more antigens or epitopes).

[0238] As used herein, the term "antigen-binding polypeptide complex" refers to a group of two, three, four or more associated polypeptides, at least one of which has the ability to specifically bind to one or more antigens. Antigen-binding polypeptide complexes include, but are not limited to, antibodies or antigen-binding fragments thereof.

[0239] 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, namely 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, known as complementarity determining regions (CDRs), interspersed with more conserved regions, known as framework regions (FRs). Each VH and VL comprises three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant region of an antibody can mediate the binding of 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 herein, amino acids in the variable region are numbered using the Kabat numbering system and those in the constant region are numbered using the EU system.

[0240] As used herein, the term "monoclonal antibody" refers to an antibody produced by a single clone of B cells and that binds to the same epitope. In contrast, the term "polyclonal antibody" refers to a population of antibodies produced by different B cells and that bind to different epitopes of the same antigen. The term "antibody" includes, for example, monoclonal and polyclonal antibodies; chimeric 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.

[0241] 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 antibody properties (e.g., functional properties) 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 of the antibody in a patient. The term antibody also includes artificial polypeptide constructs that comprise at least one antibody-derived antigen-binding site.

[0242] The "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 intact 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 can contain the antigenic determining regions (e.g., complementary determining regions (CDRs)) of an intact antibody. Examples of antigen-binding fragments of an antibody include, but are not limited to, Fab, Fab', F(ab')2 and Fv fragments, linear antibodies and single-chain antibodies. Antigen-binding fragments of an antibody can be derived from any animal species, such as rodents (e.g., mice, rats or hamsters) and humans, or can be artificially produced.

[0243] In addition, although the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be linked by synthetic linkers using recombinant methods, which enables them to be prepared as a single protein chain in which the VL and VH regions pair 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 intended to be encompassed within the term "antigen-binding fragment" of an antibody.

[0244] Antigen-binding fragments are obtained using conventional techniques known to those skilled in the art, and the 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.

[0245] As used herein, the term "variable region" generally refers to a part of an antibody, generally a part of a light chain or a heavy chain, typically about 90 to 115 amino acids in about 110 to 120 amino acids of amino terminal or 110 to 125 amino acids and a mature light chain in a mature heavy chain, whose sequence is very different between antibodies and is used for the combination 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). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of light and heavy chains are primarily responsible for the interaction and specificity of the antibody with the antigen. In some aspects, the variable region is a mammalian variable region, for example, people, mice or rabbit variable regions. In some aspects, the variable region comprises rodent or mouse CDRs and human framework regions (FRs). In some aspects, the variable region is a primate (for example, 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).

[0246] As used herein, the term "complementarity determining region" or "CDR" refers to each of the regions 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.

[0247] 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 an antigen-binding fragment thereof. 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. An enumerated VL region (e.g., VL1) can have the same or different antigen-binding properties and / or the same or different sequence as another enumerated VL region (e.g., VL2).

[0248] 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, antigen-binding polypeptide complex, antibody, or 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, VH3 to indicate the third heavy chain variable region, and VH4 to indicate the fourth heavy chain variable region. A listed VH region (e.g., VH1) can have the same or different antigen-binding properties and / or the same or different sequence as another listed VH region (e.g., VH2).

[0249] As used herein, " Kabat numbering " and similar terms are art-recognized, and refer to the system that the amino acid residues in the heavy chain and light chain variable region of antibody or its Fab are numbered.In some respects, CDR can be determined according to Kabat numbering system (see, for example, Kabat EA and Wu TT (1971) Ann NY Acad Sci 190:382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, the 5th edition, U.S. Department of Health and Human Services (USDepartment of Health and Human Services), NIH publication number 91-3242). Using Kabat numbering system, the CDR in antibody heavy chain molecule is generally present in amino acid position 31 to 35 (it optionally can be included in one or two other amino acid (referred to as 35A and 35B in Kabat numbering scheme) after 35) (CDR1), amino acid position 50 to 65 (CDR2) and amino acid position 95 to 102 (CDR3). Using the Kabat numbering system, CDRs within an antibody light chain molecule typically occur at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3).

[0250] As used herein, the terms "constant region" or "constant domain" are used interchangeably and refer to a portion of an antigen-binding polypeptide, an antigen-binding polypeptide complex, an antibody, or its antigen-binding fragment, for example, a light chain and / or a heavy chain carboxyl terminal portion that is not directly involved in the binding of the antibody to the antigen, but can exhibit various effector functions, such as interactions with the Fc region. Relative to the variable region, the constant region generally has a more conserved amino acid sequence. In some aspects, the antigen-binding polypeptide, the antigen-binding polypeptide complex, an antibody, or its antigen-binding fragment comprises a constant region or portion thereof that is sufficient to achieve antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). Constant regions include, but are not limited to, light chain constant regions (CL) or heavy chain constant regions (CH1, CH2, CH3).

[0251] 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 certain proteins of the complement system. The Fc region typically comprises CH2 and CH3 regions, and optionally an immunoglobulin hinge.

[0252] As used herein, the terms "immunoglobulin hinge," "hinge," "hinge domain," or "hinge region" are used interchangeably and refer to the heavy chain segment 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 that contribute 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 composition. 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 ​​to the glycine of CH2. The cysteines present in the hinge form interchain disulfide bonds that connect the immunoglobulin monomers.

[0253] 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.

[0254] 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 with respect to an antibody, a heavy chain can refer to any unique type based on the amino acid sequence of the constant region, for example, alpha (α), delta (δ), epsilon (ε), gamma (γ) and mu (μ), which produce IgA, IgD, IgE, IgG and IgM class antibodies, including IgG subclasses, for example, IgG1, IgG2, IgG3 and IgG4. Heavy chain amino acid sequences are known in the art. In some aspects, a heavy chain is a human heavy chain.

[0255] As used herein, the term "light chain" refers to a portion of an antigen-binding polypeptide, an antigen-binding polypeptide complex, an antibody, or its antigen-binding fragment, typically consisting 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 with respect to an antibody, a light chain can refer to any unique type based on the amino acid sequence of the constant region, such as 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.

[0256] The term "chimeric" antibody or antigen-binding fragment thereof refers to an antibody or antigen-binding fragment thereof in which the amino acid sequences are 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 from one mammalian species (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capacity, while the constant regions are homologous to sequences in an antibody or antigen-binding fragment thereof from another species (usually human) to avoid eliciting an immune response in that species.

[0257] The term "humanized" antibody or its antigen-binding fragment refers to the form of non-human (e.g., mouse) antibody or antigen-binding fragment, which is a specific immunoglobulin chain, chimeric immunoglobulin or its fragment containing a minimum non-human (e.g., mouse) sequence. Generally, humanized antibodies or their antigen-binding fragments are human immunoglobulins, wherein the residues from the complementary determining region (CDR) are replaced by residues from the CDR of non-human species (e.g., mouse, rat, rabbit, hamster) 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 immunoglobulin 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 replacing additional residues in the Fv framework region and / or in the substituted 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 comprise substantially all of at least one and typically two or three variable domains, wherein the variable domains contain all or substantially all of the CDR regions corresponding to non-human immunoglobulins, and all or substantially all of the FR regions are those of the human immunoglobulin consensus sequence. A humanized antibody or its antigen-binding fragment may also comprise 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 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).

[0258] 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 human immunoglobulin loci, wherein such antibody or antigen-binding fragment is prepared using recombinant techniques known in the art. This definition of human antibody or antigen-binding fragment thereof includes intact or full-length antibodies and fragments thereof.

[0259] 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 non-naturally occurring form. An isolated polypeptide, polypeptide complex, antibody, antigen-binding fragment thereof, polynucleotide, vector, or host cell includes those that have been purified to the extent that they are no longer in a naturally occurring form. In some aspects, an isolated polypeptide, polypeptide complex, antibody, antigen-binding fragment thereof, polynucleotide, vector, or host cell is substantially pure. As used herein, "substantially pure" refers to 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.

[0260] 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, may contain modified amino acids, and 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 within the definition are, for example, polypeptides containing one or more analogs of amino acids (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 based on antibodies, in some aspects, the polypeptides may exist as single chains or associated chains.

[0261] 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.

[0262] As used herein, "pH" refers to a quantitative measure of acidity or alkalinity. The term describes the concentration of hydrogen ions (usually between about 1 and 10). -14 gram equivalents per liter) is converted to a number between 0 and 14.

[0263] 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.

[0264] As used herein, "SARS-CoV-2 evolution" refers to the heritable genetic changes that accumulate in the SARS-CoV-2 virus during its lifespan, which may result from adaptation in response to environmental changes or the host's immune response.

[0265] The use of alternatives (e.g., "or") should be understood to refer to one, both, or a combination of the alternatives. As used herein, the indefinite articles "a" or "an" should be understood to refer to "one or more" of any recited or listed components.

[0266] As used herein, the term "and / or" should be taken as a specific disclosure of each of two specified features or components with or without the other. Thus, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include: "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: 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).

[0267] It should be understood that whenever aspects are described herein using the terms "comprising," "having," etc., other similar aspects described with "consisting of" and / or "consisting essentially of" are also provided.

[0268] 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 one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limits of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation according to the practice of this art. Alternatively, "about" can mean a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). In addition, especially with respect to biological systems or processes, the term can represent up to an order of magnitude of a value or up to 5 times the value. When a specific value or composition is provided in the application and claims, unless otherwise indicated, the meaning of "about" should be assumed to be within an acceptable error range of the specific value or composition.

[0269] 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, fractions thereof (such as tenths and hundredths of integers).

[0270] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention relates. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 5th ed., 2013, Academic Press, and Oxford Dictionary of Biochemistry And Molecular Biology, 2006, Oxford University Press provide a general dictionary for those of skill in the art of many of the terms used in this disclosure.

[0271] Units, prefixes, and symbols are expressed in a form acceptable to the International System of Units (SI). Numerical ranges are inclusive of the quantities defining the ranges. The headings provided herein do not limit 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 specification as a whole.

[0272] Various aspects are described in more detail in the following sections.

[0273] Antigen-binding polypeptides and polypeptide complexes

[0274] Provided herein are antigen-binding polypeptides and polypeptide complexes having certain structural and / or functional characteristics.

[0275] For example, provided herein is a multispecific antibody selected from the group consisting of:

[0276] (a) an antigen-binding polypeptide having a structure represented by the following formula:

[0277] VL1-L1-VH1 or VH1-L2-VL1;

[0278] in:

[0279] VL1 is the first immunoglobulin light chain variable region that specifically binds to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein;

[0280] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and

[0281] L1 and L2 are amino acid linkers; or

[0282] An antigen-binding polypeptide having a structure represented by the following formula:

[0283] VL1-L1-VL2-L2-VH2-L3-VH1;

[0284] VL1-L1-VH2-L2-VL2-L3-VH1;

[0285] VH1-L4-VH2-L5-VL2-L6-VL1; or

[0286] VH1-L4-VL2-L5-VH2-L6-VL1;

[0287] in:

[0288] VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0289] VL2 is the second immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0290] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0291] VH2 is a second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and

[0292] L1-L6 are amino acid linkers; and

[0293] wherein (a) is selected from any of the more specific embodiments provided herein for an antigen-binding polypeptide in an antigen-binding polypeptide complex having no more than three polypeptide chains;

[0294] (b) an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide;

[0295] The first polypeptide has a structure represented by the following formula:

[0296] VL1-L1-CL;

[0297] The second polypeptide has a structure represented by the following formula:

[0298] VH1-L2-CH1;

[0299] The third polypeptide has a structure represented by the following formula:

[0300] VH2-L3-VH3-L4-CH1;

[0301] The fourth polypeptide has a structure represented by the following formula:

[0302] VL3-L5-VL2-L6-CL; and

[0303] in:

[0304] VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0305] VL2 is the second immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0306] VL3 is the third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0307] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0308] VH2 is the second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0309] VH3 is the third immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0310] CH1 is the immunoglobulin heavy chain constant region 1;

[0311] CL is the immunoglobulin light chain constant region; and

[0312] L1-L6 are amino acid linkers; and

[0313] (c) an antigen-binding polypeptide having a structure represented by the following formula:

[0314] VL1-L1-VH1 or VH1-L2-VL1;

[0315] in:

[0316] VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0317] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and

[0318] L1 and L2 are amino acid linkers; or

[0319] An antigen-binding polypeptide having a structure represented by the following formula:

[0320] VL1-L1-VL2-L2-VH2-L3-VH1;

[0321] VL1-L1-VH2-L2-VL2-L3-VH1;

[0322] VH1-L4-VH2-L5-VL2-L6-VL1; or

[0323] VH1-L4-VL2-L5-VH2-L6-VL1;

[0324] in:

[0325] VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0326] VL2 is the second immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0327] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0328] VH2 is a second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and

[0329] L1-L6 are amino acid linkers;

[0330] wherein (c) is selected from any of the more specific embodiments provided herein for an antigen-binding polypeptide in an antigen-binding polypeptide complex having no more than three polypeptide chains; and

[0331] wherein the antigen-binding polypeptide further comprises an amino acid linker between any variable region and / or amino acid linker (e.g., between VL1 and L1, between L1 and VH1, between VH1 and L2, between L2 and VL1, between L1 and VL2, between VL2 and L2, between L2 and VH2, between VH2 and L3, between L3 and VH1, between VL1 and L1, between L1 and VH2, between VH2 and L2, between L2 and VL2, between VL2 and L3, between L3 and VH1 H1, between VH1 and L4, between L4 and VH2, between VH2 and L5, between L5 and VL2, between VL2 and L6, between L6 and VL1, between VH1 and L4, between L4 and VL2, between L4 and VL2, between VL2 and L5, between L5 and VH2, between VH2 and L6, or between L6 and VL1).

[0332] Also provided herein is a multispecific antibody comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide;

[0333] wherein the first polypeptide has a structure represented by VL1-L1-CL;

[0334] wherein the second polypeptide has a structure represented by VH1-L2-CH1-L3-Fc;

[0335] wherein the third polypeptide has a structure represented by VH2-L4-VH3-L5-CH1-L6-Fc;

[0336] wherein the fourth polypeptide has a structure represented by VL3-L7-VL2-L8-CL; and

[0337] Among them, VL1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0338] VL2 is the second immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0339] VL3 is the third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein;

[0340] VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0341] VH2 is the second immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0342] VH3 is the third immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein;

[0343] Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge;

[0344] CH1 is the immunoglobulin heavy chain constant region 1;

[0345] CL is the immunoglobulin light chain constant region; and

[0346] L1-L8 are amino acid linkers.

[0347] In some aspects, the VH1, VH2 and / or VH3 (VH1; VH2; VH3; VH1 and VH2; VH1 and VH3; VH2 and VH3; VH1, VH2 and VH3) of the multispecific antibody comprises: any one of NO:43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656 and 664 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; comprising a CDR1 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 to SEQ ID NO: NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665 having a CDR2 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprises a CDR2 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 to any one of SEQ ID NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, Any one of NO:45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658 and 666 has at least 80%, at least 85%, at least at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to a CDR3 of an amino acid sequence; and / or a VL1, VL2 and / or VL3 of a multispecific antibody (VL1; VL2; VL3; VL1 and VL2; VL1 and VL3; VL2 and VL3;VL1, VL2 and VL3) 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 any one of SEQ ID NOs: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656 and 664; NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665 having a CDR2 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprises a CDR2 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 to any one of SEQ ID NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, any one of NOs:45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658 and 666 having a CDR3 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 are at least 90% identical to the corresponding amino acid sequences specified above. 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 cited. 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.

[0348] In some aspects, VH1 and VH3 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., 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 any one of SEQ ID NOs: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; 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 any one of SEQ ID NOs: any of NOs: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657, and 665 having a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprising SEQ ID , at least 98%, at least 99% or 100% identical to any of SEQ ID NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658 and 666, or any other CDR sequence within a larger VH or full-length polypeptide chain sequence disclosed herein), and / or VL1 and VL3 each comprise the same CDR1, CDR2 and / or CDR3 sequence (e.g., comprising an amino acid sequence identical to SEQ ID NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515 any one of SEQ ID NO: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664 having a CDR1 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; NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665 having a CDR2 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprises a CDR2 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 to any one of SEQ ID NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, any one of NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666 having a CDR3 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical;or any other CDR sequence within a larger VH or full-length polypeptide chain sequence disclosed herein). In some preferred aspects, the CDR1, CDR2, and CDR3 of each of VH1, VH3, VL1, and VL3 are at least 90% identical to the corresponding amino acid sequences specified above. 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 cited. In some particularly preferred aspects, the CDR1, CDR2, and CDR3 of each of VH1, VH3, VL1, and VL3 comprise or consist of the corresponding amino acid sequences specified above. ;

[0349] In some aspects, VH1 and VH2 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., 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 any one of SEQ ID NOs: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; 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 any one of SEQ ID NOs: any of NOs: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657, and 665 having a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprising SEQ ID , at least 98%, at least 99% or 100% identical to any of SEQ ID NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658 and 666, or any other CDR sequence within a larger VH or full-length polypeptide chain sequence disclosed herein), and / or VL1 and VL2 each comprise the same CDR1, CDR2 and / or CDR3 sequence (e.g., comprising an amino acid sequence identical to SEQ ID NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515 any one of SEQ ID NO: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664 having a CDR1 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; NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665 having a CDR2 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprises a CDR2 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 to any one of SEQ ID NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, any one of NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666 having a CDR3 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical;or any other CDR sequence within a larger VH or full-length polypeptide chain sequence disclosed herein). In some preferred aspects, the CDR1, CDR2, and CDR3 of each of VH1, VH2, VL1, and VL2 are at least 90% identical to the corresponding amino acid sequences specified above. 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 cited. In some particularly preferred aspects, the CDR1, CDR2, and CDR3 of each of VH1, VH2, VL1, and VL2 comprise or consist of the corresponding amino acid sequences specified above. ;

[0350] In some aspects, VH2 and VH3 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., 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 any one of SEQ ID NOs: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; 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 any one of SEQ ID NOs: any of NOs: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657, and 665 having a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprising SEQ ID , at least 98%, at least 99% or 100% identical to any of SEQ ID NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658 and 666, or any other CDR sequence within a larger VH or full-length polypeptide chain sequence disclosed herein), and / or VL2 and VL3 each comprise the same CDR1, CDR2 and / or CDR3 sequence (e.g., comprising an amino acid sequence identical to SEQ ID NOs: any one of SEQ ID NO: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664 having a CDR1 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; NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665 having a CDR2 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprises a CDR2 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 to any one of SEQ ID NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, any one of NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666 having a CDR3 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical;or any other CDR sequence within a larger VH or full-length polypeptide chain sequence disclosed herein). In some preferred aspects, the CDR1, CDR2, and CDR3 of each of VH2, VH3, VL2, and VL3 are at least 90% identical to the corresponding amino acid sequences specified above. 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 cited. In some particularly preferred aspects, the CDR1, CDR2, and CDR3 of each of VH2, VH3, VL2, and VL3 comprise or consist of the corresponding amino acid sequences specified above. ;

[0351] In some aspects, VH1, VH2, and VH3 each comprise the same CDR1, CDR2, and / or CDR3 sequence (e.g., 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 any one of SEQ ID NOs: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; 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 any one of SEQ ID NOs: any of NOs: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657, and 665 having a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprising a sequence having at least 80%, at least 85%, at least 90%, at least 91% affinity to any one of SEQ ID NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666. , at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to, or any other CDR sequence within a larger VH or full-length polypeptide chain sequence disclosed herein), and / or VL1, VL2 and VL3 each comprise the same CDR1, CDR2 and / or CDR3 sequence (e.g., comprising an amino acid sequence identical to SEQ any one of SEQ ID NO: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664 having a CDR1 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; NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665 having a CDR2 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprises a CDR2 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 to any one of SEQ ID NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, any one of NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666 having a CDR3 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical;or any other CDR sequence within a larger VH or full-length polypeptide chain sequence disclosed herein). In some preferred aspects, the CDR1, CDR2, and CDR3 of each of VH1, VH2, VH3, VL1, VL2, and VL3 are at least 90% identical to the corresponding amino acid sequences specified above. 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 cited. 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. ;

[0352] In some aspects, each of VH1, VH2, and VH3 comprises a different CDR1, CDR2, and / or CDR3 sequence (e.g., 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 NOs: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; 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 NOs: any of NOs: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657, and 665 having a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprising a sequence having at least 80%, at least 85%, at least 90%, at least 91% affinity to any one of SEQ ID NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666. , at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to, or any other CDR sequence within a larger VH or full-length polypeptide chain sequence disclosed herein), and / or VL1, VL2 and VL3 each comprise a different CDR1, CDR2 and / or CDR3 sequence (e.g., comprising an amino acid sequence identical to SEQ any one of SEQ ID NO: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664 having a CDR1 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; NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665 having a CDR2 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprises a CDR2 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 to any one of SEQ ID NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, any one of NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666 having a CDR3 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical;or any other CDR sequence within a larger VH or full-length polypeptide chain sequence disclosed herein). In some preferred aspects, the CDR1, CDR2, and CDR3 of each of VH1, VH2, VH3, VL1, VL2, and VL3 are at least 90% identical to the corresponding amino acid sequences specified above. 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 cited. 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. ;

[0353] 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] In some aspects, VH1, VH2 and VH3 each comprise different heavy chain variable regions. In some aspects, VL1, VL2 and VL3 each comprise different light chain variable regions. In some aspects, VH1, VH2 and VH3 each comprise different heavy chain variable regions, and VL1, VL2 and VL3 each comprise different light chain variable regions.

[0358] In some aspects, VH1, VH2 and / or VH3 comprise a polypeptide corresponding to SEQ ID NO: 42, 50, 58, 66, 74, 170, 178, 186, 263, 271, 279, 287, 510, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 626, 628, 630, 632, 634, 636, 638, 64 6, 654, 663, 779, 781, 785 and 787 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, VL2 and / or VL3 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 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 of SEQ any of ID NOs: 38, 46, 54, 62, 70, 166, 174, 182, 259, 267, 275, 283, 508, 509, 511, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 625, 627, 629, 631, 633, 635, 637, 642, 650, 659, and 667 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, VH3, VL1, VL2 and VL3 have at least 90% identity with the corresponding amino acid sequences specified above. In some particularly preferred aspects, VH1, VH2, VH3, VL1, VL2 and VL3 comprise or consist of 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 cited.

[0359] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by VL1-L1-VH1 or VH1-L2-VL1; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1 and L2 are amino acid linkers.

[0360] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1; VL1-L1-VH2-L2-VL2-L3-VH1; VH1-L4-VH2-L5-VL2-L6-VL1; or VH1-L4-VL2-L5-VH2-L6-VL1; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1-L6 are amino acid linkers. In some aspects, the antigen-binding polypeptide further comprises an Fc region, a CH1 region, a CL region, or a combination thereof. In some aspects, the antigen-binding polypeptide is part of an antigen-binding polypeptide complex provided herein (eg, an antibody or antigen-binding fragment thereof).

[0361] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1 or VH1-L4-VH2-L5-VL2-L6-VL1; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; VL2 is a second immunoglobulin light chain variable region that specifically binds to SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to SARS-CoV-2 protein; and L1-L6 is an amino acid linker. In some aspects, the antigen-binding polypeptides further comprise an Fc region, a CH1 region, a CL region, or a combination thereof. In some aspects, the antigen-binding polypeptides are part of an antigen-binding polypeptide complex (e.g., an antibody or its antigen-binding fragment) provided herein.

[0362] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1 or VH1-L4-VL2-L5-VH2-L6-VL1; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; VL2 is a second immunoglobulin light chain variable region that specifically binds to SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to SARS-CoV-2 protein; and L1-L6 is an amino acid linker. In some aspects, the antigen-binding polypeptides further comprise an Fc region, a CH1 region, a CL region, or a combination thereof. In some aspects, the antigen-binding polypeptides are part of an antigen-binding polypeptide complex (e.g., an antibody or its antigen-binding fragment) provided herein.

[0363] In some aspects, the antigen-binding polypeptide complexes provided herein comprise a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH1 or VH1-L2-VL1; wherein the second polypeptide has a structure represented by VL2-L3-VH2 or VH2-L4-VL2; wherein VL1 is a first immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; wherein VL2 is a second immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; wherein VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1-L4 are amino acid linkers. For example, the antigen-binding polypeptide complexes provided herein comprise a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH1; and wherein the second polypeptide has a structure represented by VL2-L3-VH2 or VH2-L4-VL2. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VH1-L2-VL1; wherein the second polypeptide has a structure represented by VL2-L3-VH2 or VH2-L4-V.

[0364] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1; VL1-L1-VH2-L2-VL2-L3-VH1; VH1-L4-VH2-L5-VL2-L6-VL1; or VH1-L4-VL2-L5-VH2 -L6-VL1; wherein the second polypeptide has a structure represented by the following formula: VL3-L7-VL4-L8-VH4-L9-VH3; VL3-L7-VH4-L8-VL4-L9-VH3; VH3-L10-VH4-L11-VL4-L12-VL3; or VH3-L10-VL4-L11-VH4-L12-VL3; wherein VL1 is a specific binding polypeptide The first immunoglobulin light chain variable region of 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; VL4 is the fourth 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; VH4 is the fourth immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and L1-L12 are amino acid linkers. In some aspects, the antigen-binding polypeptide complex further comprises an Fc region, a CH1 region, a CL region, or a combination thereof in the first and / or second polypeptide. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1; and wherein the second polypeptide has a structure represented by the following formula: VL3-L7-VL4-L8-VH4-L9-VH3; VL3-L7-VH4-L8-VL4-L9-VH3; VH3-L10-VH4-L11-VL4-L12-VL3; or VH3-L10-VL4-L11-VH4-L12-VL3.For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1; and wherein the second polypeptide has a structure represented by the following formula: VL3-L7-VL4-L8-VH4-L9-VH3; VL3-L7-VH4-L8-VL4-L9-VH3; VH3-L10-VH4-L11-VL4-L12-VL3; or VH3-L10-VL4-L11-VH4-L12-VL3. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VH1-L4-VH2-L5-VL2-L6-VL1; and wherein the second polypeptide has a structure represented by the following formula: VL3-L7-VL4-L8-VH4-L9-VH3; VL3-L7-VH4-L8-VL4-L9-VH3; VH3-L10-VH4-L11-VL4-L12-VL3; or VH3-L10-VL4-L11-VH4-L12-VL3. For example, the antigen-binding polypeptide complexes provided herein comprise a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VH1-L4-VL2-L5-VH2-L6-VL1; and wherein the second polypeptide has a structure represented by the following formulas: VL3-L7-VL4-L8-VH4-L9-VH3; VL3-L7-VH4-L8-VL4-L9-VH3; VH3-L10-VH4-L11-VL4-L12-VL3; or VH3-L10-VL4-L11-VH4-L12-VL3. In each example, the first polypeptide may further comprise an Fc region. In each example, the second polypeptide may further comprise an Fc region. In each example, the first polypeptide and the second polypeptide may further comprise an Fc region. Alternatively or additionally, in each example, the first polypeptide may further comprise a CH1 region. In each example, the second polypeptide may further comprise a CH1 region. In each example, the first polypeptide and the second polypeptide may further comprise a CH1 region. Alternatively or additionally, in each example, the first polypeptide may further comprise a CL region. In each example, the second polypeptide may further comprise a CL region. In each example, the first polypeptide and the second polypeptide may further comprise a CL region.

[0365] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1 or VH1-L4-VH2-L5-VL2-L6-VL1; wherein the second polypeptide has a structure represented by VL3-L7-VL4-L8-VH4-L9-VH3 or VH3-L10-VH4-L11-VL4-L12-VL3; 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. Chain variable region; VL3 is a third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VL4 is a fourth 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; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and L1-L12 are amino acid linkers. In some aspects, the antigen-binding polypeptide complex further comprises an Fc region, a CH1 region, a CL region, or a combination thereof in the first and / or second polypeptide. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1; and wherein the second polypeptide has a structure represented by VL3-L7-VL4-L8-VH4-L9-VH3 or VH3-L10-VH4-L11-VL4-L12-VL3. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VH1-L4-VH2-L5-VL2-L6-VL1; and wherein the second polypeptide has a structure represented by VL3-L7-VL4-L8-VH4-L9-VH3 or VH3-L10-VH4-L11-VL4-L12-VL3. In each example, the first polypeptide may further comprise an Fc region. In each example, the second polypeptide may further comprise an Fc region. In each example, the first polypeptide and the second polypeptide may further comprise an Fc region. Alternatively or additionally, in each example, the first polypeptide may further comprise a CH1 region. In each example, the second polypeptide may further comprise a CH1 region. In each example, the first polypeptide and the second polypeptide may further comprise a CH1 region. Alternatively or additionally, in each example, the first polypeptide may further comprise a CL region.In each example, the second polypeptide may further comprise a CL region. In each example, the first polypeptide and the second polypeptide may further comprise a CL region.

[0366] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1 or VH1-L4-VL2-L5-VH2-L6-VL1; wherein the second polypeptide has a structure represented by VL3-L7-VH4-L8-VL4-L9-VH3 or VH3-L10-VL4-L11-VH4-L12-VL3; 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. Chain variable region; VL3 is a third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VL4 is a fourth 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; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and L1-L12 are amino acid linkers. In some aspects, the antigen-binding polypeptide complex further comprises an Fc region, a CH1 region, a CL region, or a combination thereof in the first and / or second polypeptide. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1; and wherein the second polypeptide has a structure represented by VL3-L7-VH4-L8-VL4-L9-VH3 or VH3-L10-VL4-L11-VH4-L12-VL3. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VH1-L4-VL2-L5-VH2-L6-VL1; and wherein the second polypeptide has a structure represented by VL3-L7-VH4-L8-VL4-L9-VH3 or VH3-L10-VL4-L11-VH4-L12-VL3. In each example, the first polypeptide may further comprise an Fc region. In each example, the second polypeptide may further comprise an Fc region. In each example, the first polypeptide and the second polypeptide may further comprise an Fc region. Alternatively or additionally, in each example, the first polypeptide may further comprise a CH1 region. In each example, the second polypeptide may further comprise a CH1 region. In each example, the first polypeptide and the second polypeptide may further comprise a CH1 region. Alternatively or additionally, in each example, the first polypeptide may further comprise a CL region.In each example, the second polypeptide may further comprise a CL region. In each example, the first polypeptide and the second polypeptide may further comprise a CL region.

[0367] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; wherein VL1 is the first immune cell that specifically binds to the SARS-CoV-2 protein. Globulin light chain variable region; VL2 is a second immunoglobulin light chain variable region that specifically binds to SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to SARS-CoV-2 protein; Fc is a region comprising immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3) and an optional immunoglobulin hinge; and L1-L8 is an amino acid linker. In some aspects, the antigen-binding polypeptide further comprises a CH1 region, a CL region, or a combination thereof. In some aspects, the antigen-binding polypeptide is part of an antigen-binding polypeptide complex (e.g., an antibody or an antigen-binding fragment thereof) provided herein.

[0368] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L8 is an amino acid linker. In some aspects, the antigen-binding polypeptide further comprises a CH1 region, a CL region, or a combination thereof. In some aspects, the antigen-binding polypeptide is part of an antigen-binding polypeptide complex provided herein (eg, an antibody or antigen-binding fragment thereof).

[0369] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L8 is an amino acid linker. In some aspects, the antigen-binding polypeptide further comprises a CH1 region, a CL region, or a combination thereof. In some aspects, the antigen-binding polypeptide is part of an antigen-binding polypeptide complex provided herein (eg, an antibody or antigen-binding fragment thereof).

[0370] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8 -Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc; wherein VL1 is specific The first immunoglobulin light chain variable region 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; VL4 is the fourth 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; VH4 is the fourth 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; and L1-L16 are amino acid linkers. In some aspects, the antigen-binding polypeptide complex further comprises a CH1 region, a CL region, or a combination thereof in the first and / or second polypeptide. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof.For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; and wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; and wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; and wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; and wherein the second polypeptide has a structure represented by the following formulas: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc. In each example, the first polypeptide may further comprise a CH1 region. In each example, the second polypeptide may further comprise a CH1 region.In each example, the first polypeptide and the second polypeptide may further comprise a CH1 region. Alternatively or additionally, in each example, the first polypeptide may further comprise a CL region. In each example, the second polypeptide may further comprise a CL region. In each example, the first polypeptide and the second polypeptide may further comprise a CL region.

[0371] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; 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 A third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VL4 is a fourth 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; VH4 is a fourth 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 an optional immunoglobulin hinge; and L1-L16 is an amino acid linker. In some aspects, the antigen-binding polypeptide complex further comprises a CH1 region, a CL region, or a combination thereof in the first and / or second polypeptide. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; and wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; and wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc. In each example, the first polypeptide may further comprise a CH1 region.In each example, the second polypeptide may further comprise a CH1 region. In each example, the first polypeptide and the second polypeptide may further comprise a CH1 region. Alternatively or additionally, in each example, the first polypeptide may further comprise a CL region. In each example, the second polypeptide may further comprise a CL region. In each example, the first polypeptide and the second polypeptide may further comprise a CL region.

[0372] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc; 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 A third immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VL4 is a fourth 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; VH4 is a fourth 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 an optional immunoglobulin hinge; and L1-L16 is an amino acid linker. In some aspects, the antigen-binding polypeptide complex further comprises a CH1 region, a CL region, or a combination thereof in the first and / or second polypeptide. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc. In each example, the first polypeptide may further comprise a CH1 region.In each example, the second polypeptide may further comprise a CH1 region. In each example, the first polypeptide and the second polypeptide may further comprise a CH1 region. Alternatively or additionally, in each example, the first polypeptide may further comprise a CL region. In each example, the second polypeptide may further comprise a CL region. In each example, the first polypeptide and the second polypeptide may further comprise a CL region.

[0373] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1 -L10-CL;VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-CL;VL1-L11-VL2-L12-VH2-L 13-VH1-L14-CL-L15-CH1; VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-CH1; VH1 -L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-CH1; or VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-CH1; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L20 is an amino acid linker. In some aspects, the antigen-binding polypeptide further comprises an Fc region. In some aspects, the antigen-binding polypeptide is part of an antigen-binding polypeptide complex (e.g., an antibody or an antigen-binding fragment thereof) provided herein.

[0374] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; or VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-CL H1; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L20 is an amino acid linker. In some aspects, the antigen-binding polypeptide further comprises an Fc region. In some aspects, the antigen-binding polypeptide is part of an antigen-binding polypeptide complex (e.g., an antibody or an antigen-binding fragment thereof) provided herein.

[0375] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by the following formula: VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-CH1; or VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-CL H1; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L20 is an amino acid linker. In some aspects, the antigen-binding polypeptide further comprises an Fc region. In some aspects, the antigen-binding polypeptide is part of an antigen-binding polypeptide complex (e.g., an antibody or an antigen-binding fragment thereof) provided herein.

[0376] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-CH1; VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-CH1; or VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-CH1; wherein the second polypeptide has a structure represented by the following formula: VL3-L21-VL4-L22-VH4-L23-VH3-L24-CH1-L25-CL; VL3-L21-VH4-L22-VL4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VH4-L 27-VL4-L28-VL3-L29-CH1-L30-CL; VH3-L26-VL4-L27-VH4-L28-VL3-L29 -CH1-L30-CL;VL3-L31-VL4-L32-VH4-L33-VH3-L34-CL-L35-CH1;VL3-L31 -VH4-L32-VL4-L33-VH3-L34-CL-L35-CH1; VH3-L36-VH4-L37-VL4-L38-V L3-L39-CL-L40-CH1; or VH3-L36-VL4-L37-VH4-L38-VL3-L39-CL-L40-CH1; Wherein 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; VL4 is the fourth 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;VH4 is the fourth 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-L40 is an amino acid linker. In some aspects, the antigen-binding polypeptide complex further comprises an Fc region in the first and / or second polypeptide. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof. Any combination of the above-mentioned VH1, VH2, VH3 and / or VH4 can be used in combination with any combination of the above-mentioned VL1, VL2, VL3 and / or VL4. Specifically, any of the above-mentioned first polypeptides can be combined with any of the above-mentioned second polypeptides to form an antigen-binding polypeptide complex. ;

[0377] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; or VH1-L16-VH2- L17-VL2-L18-VL1-L19-CL-L20-CH1; wherein the second polypeptide has a structure represented by the following formula: VL3-L21-VL4-L22-VH4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VH4-L27-VL4-L28-VL3-L29-CH1-L30-CL; VL3-L31-VL4-L32-VH4-L33-VH3-L34-CL-L35-CH1; or VH3-L 36-VH4-L37-VL4-L38-VL3-L39-CL-L40-CH1; 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 a third immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L40 are amino acid linkers. In some aspects, the antigen-binding polypeptide complex further comprises an Fc region in the first and / or second polypeptide. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof. Any combination of the above-mentioned VH1, VH2, VH3 and / or VH4 can be used in combination with any combination of the above-mentioned VL1, VL2, VL3 and / or VL4.For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; wherein the second polypeptide has a structure represented by the following formula: VL3-L21-VL4-L22-VH4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VH4-L27-VL4-L28-VL3-L29-CH1-L30-CL; VL3-L31-VL4-L32-VH4-L33-VH3-L34-CL-L35-CH1; or VH3-L36-VH4-L37-VL4-L38-VL3-L39-CL-L40-CH1. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; wherein the second polypeptide has a structure represented by the following formula: VL3-L21-VL4-L22-VH4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VH4-L27-VL4-L28-VL3-L29- CH1-L30-CL; VL3-L31-VL4-L32-VH4-L33-VH3-L34-CL-L35-CH1; or VH3-L36-VH4-L37-VL4-L38-VL3-L39- CL-L40-CH1.VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CLVH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL. For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; wherein the second polypeptide has a structure represented by the following formula: VL3-L21-VL4-L22-VH4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VH4-L27-VL4-L28-VL3-L2 9-CH1-L30-CL; VL3-L31-VL4-L32-VH4-L33-VH3-L34-CL-L35-CH1; or VH3-L36-VH4-L37-VL4-L38-VL3-L39 -CL-L40-CH1.VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CLVH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL.For example, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-CH1; wherein the second polypeptide has a structure represented by the following formula: VL3-L21-VL4-L22-VH4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VH4-L27-VL4-L28-VL3-L2 9-CH1-L30-CL; VL3-L31-VL4-L32-VH4-L33-VH3-L34-CL-L35-CH1; or VH3-L36-VH4-L37-VL4-L38-VL3-L39 -CL-L40-CH1.VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CLVH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL.

[0378] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-CH1; or VH1-L16-VL2- L17-VH2-L18-VL1-L19-CL-L20-CH1; wherein the second polypeptide has a structure represented by the following formula: VL3-L21-VH4-L22-VL4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VL4-L27-VH4-L28-VL3-L29-CH1-L30-CL; VL3-L31-VH4-L32-VL4-L33-VH3-L34-CL-L35-CH1; or VH3-L 36-VL4-L37-VH4-L38-VL3-L39-CL-L40-CH1; 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 a third immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VL4 is a fourth immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH3 is a third immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; and L1-L40 are amino acid linkers. In some aspects, the antigen-binding polypeptide complex further comprises an Fc region in the first and / or second polypeptide. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof. Any combination of the above-mentioned VH1, VH2, VH3 and / or VH4 can be used in combination with any combination of the above-mentioned VL1, VL2, VL3 and / or VL4. Specifically, any of the above-mentioned first polypeptides can be combined with any of the above-mentioned second polypeptides to form an antigen-binding polypeptide complex.

[0379] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc ;VH1-L7-VL2-L8-VH2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-VH2-L15-VH1-L16-C L-L17-CH1-L18-Fc; VL1-L13-VH2-L14-VL2-L15-VH1-L16-CL-L17-CH1-L18-Fc; VH1-L19-VH2-L20 -VL2-L21-VL1-L22-CL-L23-CH1-L24-Fc; or VH1-L19-VL2-L20-VH2-L21-VL1-L22-CL-L23-CH1-L24-Fc; 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; VH1 is a first immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; VH2 is a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; CH1 is an immunoglobulin heavy chain constant region 1; CL is an immunoglobulin light chain constant region; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L24 are amino acid linkers. In some aspects, the antigen-binding polypeptide is part of an antigen-binding polypeptide complex provided herein (eg, an antibody or antigen-binding fragment thereof).

[0380] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-VH2-L15-VH1-L16-CL-L17-CH1-L18-Fc; or VH1-L19-VH2-L20-VL2-L21-VL1-L22-CL-L23-CH1-L24-Fc; wherein VL1 is a specific binding polypeptide. 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; 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; CH1 is the immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; Fc is the region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L24 are amino acid linkers. In some aspects, the antigen-binding polypeptide is part of an antigen-binding polypeptide complex (e.g., an antibody or antigen-binding fragment thereof) provided herein.

[0381] In some aspects, the antigen-binding polypeptides provided herein have a structure represented by the following formula: VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VL2-L8-VH2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VH2-L14-VL2-L15-VH1-L16-CL-L17-CH1-L18-Fc; or VH1-L19-VL2-L20-VH2-L21-VL1-L22-CL-L23-CH1-L24-Fc; wherein VL1 is a specific binding polypeptide. 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; 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; CH1 is the immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; Fc is the region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L24 are amino acid linkers. In some aspects, the antigen-binding polypeptide is part of an antigen-binding polypeptide complex (e.g., an antibody or antigen-binding fragment thereof) provided herein.

[0382] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VH1-L7-VL2-L8-VH2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-V VH1-L19-VH2-L20-VL2-L21-VL1-L22-CL-L23-CH1-L24-Fc; or VH1-L19-VL2-L20-VH2-L21-VL1-L22-CL-L23-CH1-L24-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L25-VL4-L26-VH4-L27-VH3-L28-CH1-L29-CL-L3 0-Fc;VL3-L25-VH4-L26-VL4-L27-VH3-L28-CH1-L29-CL-L30-Fc;VH3-L31 -VH4-L32-VL4-L33-VL3-L34-CH1-L35-CL-L36-Fc; VH3-L31-VL4-L32-VH4 -L33-VL3-L34-CH1-L35-CL-L36-Fc; VL3-L37-VL4-L38-VH4-L39-VH3-L40 -CL-L41-CH1-L42-Fc; VL3-L37-VH4-L38-VL4-L39-VH3-L40-CL-L41-CH1-L 42-Fc; VH3-L43-VH4-L44-VL4-L45-VL3-L46-CL-L47-CH1-L48-Fc; or VH3-L43-VL4-L44-VH4-L45-VL3-L46-CL-L47-CH1-L48-Fc; 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 a third immunoglobulin light chain variable region that specifically binds to a SARS-CoV-2 protein; and VL4 is a fourth immunoglobulin light chain variable region that specifically binds to a 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; VH4 is the fourth 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; Fc is a region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L48 is an amino acid linker. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof. Any combination of the above-mentioned VH1, VH2, VH3, and / or VH4 can be used in combination with any combination of the above-mentioned VL1, VL2, VL3, and / or VL4. Specifically, any of the above-mentioned first polypeptides can be combined with any of the above-mentioned second polypeptides to form an antigen-binding polypeptide complex.

[0383] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-VH2-L15-VH1-L16-CL-L17-CH1-L18-Fc; or VH1-L19-VH2-L20-VL2 -L21-VL1-L22-CL-L23-CH1-L24-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L25-VL4-L26-VH4-L27-VH3-L28-CH1-L29-CL-L30-Fc; VH3-L31-VH4-L32-VL4-L33-VL3-L34-CH1-L35-CL-L36-Fc; VL3-L37-VL4-L38-VH4-L39-VH3-L40-CL-L41-CH1-L42-Fc; or VH3-L43-V H4-L44-VL4-L45-VL3-L46-CL-L47-CH1-L48-Fc; wherein 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; VL4 is the fourth immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VH1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein Protein heavy chain variable region; 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; VH4 is a fourth 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; Fc is a region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L48 is an amino acid linker. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof. Any combination of the above-mentioned VH1, VH2, VH3, and / or VH4 can be used in combination with any combination of the above-mentioned VL1, VL2, VL3, and / or VL4. Specifically, any of the above-mentioned first polypeptides can be combined with any of the above-mentioned second polypeptides to form an antigen-binding polypeptide complex.

[0384] In some aspects, the antigen-binding polypeptide complex provided herein comprises a first polypeptide and a second polypeptide; wherein the first polypeptide has a structure represented by the following formula: VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VL2-L8-VH2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VH2-L14-VL2-L15-VH1-L16-CL-L17-CH1-L18-Fc; or VH1-L19-VL2-L20-VH2 -L21-VL1-L22-CL-L23-CH1-L24-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L25-VH4-L26-VL4-L27-VH3-L28-CH1-L29-CL-L30-Fc; VH3-L31-VL4-L32-VH4-L33-VL3-L34-CH1-L35-CL-L36-Fc; VL3-L37-VH4-L38-VL4-L39-VH3-L40-CL-L41-CH1-L42-Fc; or VH3-L43-V L4-L44-VH4-L45-VL3-L46-CL-L47-CH1-L48-Fc; wherein 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; VL4 is the fourth immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein; VH1 is the first immunoglobulin light chain variable region that specifically binds to the SARS-CoV-2 protein Protein heavy chain variable region; 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; VH4 is a fourth 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; Fc is a region comprising the immunoglobulin heavy chain constant region 2 (CH2), the immunoglobulin heavy chain constant region 3 (CH3), and an optional immunoglobulin hinge; and L1-L48 is an amino acid linker. In some aspects, the antigen-binding polypeptide complex comprises an antigen-binding polypeptide provided herein. In some aspects, the antigen-binding polypeptide complex is an antibody or an antigen-binding fragment thereof. Any combination of the above-mentioned VH1, VH2, VH3, and / or VH4 can be used in combination with any combination of the above-mentioned VL1, VL2, VL3, and / or VL4. Specifically, any of the above-mentioned first polypeptides can be combined with any of the above-mentioned second polypeptides to form an antigen-binding polypeptide complex.

[0385] In some aspects, one or more of VH1, VH2, VH3, and VH4 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 NOs: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665 having a CDR2 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprises a CDR2 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 to any one of SEQ ID NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 97, at least 98%, at least 99% or 100% identical to any of NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658 and 666, or any other CDR sequence within a larger VH or full-length polypeptide chain sequence disclosed herein. In some preferred aspects, the CDR1, CDR2, and CDR3 of one or more of VH1, VH2, VH3, and VH4 are at least 90% identical to the corresponding amino acid sequences specified above. 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 cited. In some particularly preferred aspects, the CDR1, CDR2, and CDR3 of one or more of VH1, VH2, VH3, and VH4 comprise or consist of the corresponding amino acid sequences specified above.In some preferred aspects, the CDR1, CDR2, and CDR3 of VH1, VH2, VH3, and VH4 are at least 90% identical to the corresponding amino acid sequences specified above. 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 cited. In some particularly preferred aspects, the CDR1, CDR2, and CDR3 of VH1, VH2, VH3, and VH4 comprise or consist of the corresponding amino acid sequences specified above.

[0386] In some aspects, one or more of VL1, VL2, VL3, and VL4 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 any one of SEQ ID NOs: 39, 47, 55, 63, 71, 167, 175, 183, 260, 268, 276, 284, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 613, 621, 643, 651, 660, and 668; NO:40, 48, 56, 64, 72, 168, 176, 184, 261, 269, 277 (sequence with LGS), 285, 518 (sequence with DAS), 526 (sequence with DVS), 534 (sequence with EDS), 542 (sequence with KDS), 550 (sequence with DAS), 558 (sequence with AAS), 566 (sequence with GAS), 574 (sequence with DDS), 582 (sequence with KDS), 590 (sequence with SAS), 598 (sequence with SAS), ), 606 (having a sequence of GAS), 614 (having a sequence of GAS), 622 (having a sequence of GAS), 644 (having a sequence of GAS), 652 (having a sequence of SAS), 661 (having a sequence of GAS), and 669 (having a sequence of DAS) having a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprises a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to SEQ 98, at least 99% or 100% identical to any of ID NOs: 41, 49, 57, 65, 73, 169, 177, 185, 262, 270, 278, 286, 519, 527, 535, 543, 551, 559, 567, 575, 583, 591, 599, 607, 615, 623, 645, 653, 662 and 670, or any other CDR sequence within a larger VL or full-length polypeptide chain sequence disclosed herein. In some preferred aspects, the CDR1, CDR2, and CDR3 of one or more of VL1, VL2, VL3, and VL4 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 cited. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of one or more of VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, the CDR1, CDR2 and CDR3 of VL1, VL2, VL3 and VL4 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 cited. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0387] In some aspects, one or more of VH1, VH2, VH3, and VH4 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 99%, or 100% identical to any one of SEQ ID NOs: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; NO:44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665 having a CDR2 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprises a CDR2 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 to any one of SEQ ID NO: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658 and 666 having a CDR3 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 one or more of VL1, VL2, VL3 and VL4 comprises: comprising an amino acid sequence that is identical to SEQ ID NO: any of NOs: 39, 47, 55, 63, 71, 167, 175, 183, 260, 268, 276, 284, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 613, 621, 643, 651, 660, and 668 having a CDR1 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;comprising sequences corresponding to SEQ ID NOs: 40, 48, 56, 64, 72, 168, 176, 184, 261, 269, 277 (sequences with LGS), 285, 518 (sequences with DAS), 526 (sequences with DVS), 534 (sequences with EDS), 542 (sequences with KDS), 550 (sequences with DAS), 558 (sequences with AAS), 566 (sequences with GAS), 574 (sequences with DDS), 582 (sequences with KDS), 590 (sequences with SAS), 598 (sequences with a CDR2 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 to any of 601 (having a sequence of SAS), 606 (having a sequence of GAS), 614 (having a sequence of GAS), 622 (having a sequence of GAS), 644 (having a sequence of GAS), 652 (having a sequence of SAS), 661 (having a sequence of GAS), and 669 (having a sequence of DAS);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 of SEQ ID NOs: 41, 49, 57, 65, 73, 169, 177, 185, 262, 270, 278, 286, 591, 599, 607, 615, 623, 645, 653, 662 and 670, or any other CDR sequence within a larger VH, VL or full-length polypeptide chain sequence disclosed herein. In some preferred aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. Any combination of the above-mentioned VH1, VH2, VH3 and / or VH4 can be used in combination with any combination of the above-mentioned VL1, VL2, VL3 and / or VL4. In some preferred aspects, the CDR1, CDR2, and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3, and VL4 are at least 90% identical to the corresponding amino acid sequences specified above. 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 cited. In some particularly preferred aspects, the CDR1, CDR2, and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3, and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0388] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise a polypeptide corresponding to SEQ ID NO: 42, 50, 58, 66, 74, 170, 178, 186, 263, 271, 279, 287, 510, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 626, 628, 630, 632, 634, 636, 638, 646 , 654, 663, 779, 781, 785 and 787 have 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, or any other VH sequence within the full-length polypeptide chain sequence disclosed herein. In some aspects, the sequence has a mutation at N62, such as N62Q or N62Q at SEQ ID NO: 279. In some preferred aspects, one or more of VH1, VH2, VH3 and VH4 have at least 90% identity to the corresponding amino acid sequence specified above, optionally with a mutation at N62 as 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 cited. In some particularly preferred aspects, one or more of VH1, VH2, VH3 and VH4 comprises or consists of the corresponding amino acid sequences specified above, optionally with a mutation at N62 as specified above. In some preferred aspects, VH1, VH2, VH3 and VH4 have at least 90% identity to the corresponding amino acid sequences specified above, optionally with a mutation at N62 as 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 cited. In some particularly preferred aspects, VH1, VH2, VH3 and VH4 comprise or consist of the corresponding amino acid sequences specified above, optionally with a mutation at N62 as specified above.

[0389] In some aspects, one or more of VL1, VL2, VL3, and VL4 comprise the amino acid sequence of SEQ ID NO: 98, at least 99%, or 100% identical to any of VL sequences 38, 46, 54, 62, 70, 166, 174, 182, 259, 267, 275, 283, 508, 509, 511, 519, 527, 535, 543, 551, 559, 567, 575, 583, 588, 596, 604, 612, 620, 625, 627, 629, 631, 633, 635, 637, 642, 650, 659, and 667, or any other VL sequence within the full-length polypeptide chain sequences disclosed herein. In some preferred aspects, one or more of VL1, VL2, VL3, and VL4 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 cited. In some particularly preferred aspects, one or more of VL1, VL2, VL3, and VL4 comprise or consist of the corresponding amino acid sequence specified above. In some preferred aspects, VL1, VL2, VL3, and VL4 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 cited. In some particularly preferred aspects, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0390] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise a polypeptide corresponding to SEQ ID NO: 42, 50, 58, 66, 74, 170, 178, 186, 263, 271, 279, 287, 510, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 626, 628, 630, 632, 634, 636, 638, 646, 65 4, 663, 779, 781, 785 and 787 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 one or more of VL1, VL2, VL3 and VL4 comprises an amino acid sequence that is identical to SEQ ID NO: NO:38, 46, 54, 62, 70, 166, 174, 182, 259, 267, 275, 283, 508, 509, 511, 516, 524, 532 ,540,548,556,564,572,580,588,596,604,612,620,625,627,629,631,633,635, Any of 637, 642, 650, 659 and 667 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, or any other VH or VL sequence within the full-length polypeptide chain sequences disclosed herein. In some aspects, the sequence has a mutation at N62, such as N62Q or N62Q at SEQ ID NO: 279. In some preferred aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some particularly preferred aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprises or consists of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0391] In some aspects, one or more of VH1, VH2, VH3, and VH4 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: 513; 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: 514; and / or 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: 515. NO:515 has a CDR3 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an amino acid sequence; and one or more of VL1, VL2, VL3 and VL4 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:517; NO: 518 (sequence with DAS) has a CDR2 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 SEQ ID NO: 519. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0392] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 512; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 516. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0393] In some aspects, one or more of VH1, VH2, VH3, and VH4 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: 521; 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: 522; and / or 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: 523. NO:523 has a CDR3 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an amino acid sequence; and one or more of VL1, VL2, VL3 and VL4 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:525; NO: 526 (sequence with DVS) has a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 SEQ ID NO: 527. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0394] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 520; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 524. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0395] In some aspects, one or more of VH1, VH2, VH3, and VH4 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: 529; 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: 530; and / or 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: 531; NO:531 has a CDR3 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an amino acid sequence; and one or more of VL1, VL2, VL3 and VL4 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:533; NO: 534 (sequence with EDS) has a CDR2 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 SEQ ID NO: 535. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0396] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 528; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 532. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0397] In some aspects, one or more of VH1, VH2, VH3, and VH4 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: 537; 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: 538; and / or 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: 539. NO:539 has a CDR3 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an amino acid sequence; and one or more of VL1, VL2, VL3 and VL4 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:541; NO: 542 (sequence with KDS) has a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 SEQ ID NO: 543. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0398] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise 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: 536; and one or more of VL1, VL2, VL3, and VL4 comprise 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: 540. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0399] In some aspects, one or more of VH1, VH2, VH3, and VH4 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: 545; 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: 546; and / or 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: 547. NO:547 has a CDR3 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an amino acid sequence; and one or more of VL1, VL2, VL3 and VL4 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:549; NO: 550 (sequence with DAS) has a CDR2 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 SEQ ID NO: 551. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0400] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 544; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 548. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0401] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 624; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 625. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0402] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 626; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 627. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0403] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 628; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 629. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0404] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 630; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 631. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0405] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 632; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 633. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0406] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 634; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 635. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0407] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 636; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 637. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0408] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 638; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 642. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0409] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 646; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 650. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0410] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 654; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 659. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0411] In some aspects, one or more of VH1, VH2, VH3, and VH4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 663; and one or more of VL1, VL2, VL3, and VL4 comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 667. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some aspects, one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0412] In some aspects, one or more of VH1, VH2, VH3, and VH4 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: 639; 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: 640; and / or 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: 641; NO: 641 has a CDR3 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an amino acid sequence; and one or more of VL1, VL2, VL3 and VL4 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: 643; NO: 644 (with the sequence of GAS) has a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 SEQ ID NO: 645. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0413] In some aspects, one or more of VH1, VH2, VH3, and VH4 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: 647; 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: 648; and / or 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: 649. NO: 649 has a CDR3 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an amino acid sequence; and one or more of VL1, VL2, VL3 and VL4 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: 651; NO: 652 (sequence with SAS) has a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 SEQ ID NO: 653. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0414] In some aspects, one or more of VH1, VH2, VH3, and VH4 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: 656; 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: 657; and / or 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: 658. NO:658 has a CDR3 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an amino acid sequence; and one or more of VL1, VL2, VL3 and VL4 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:660; NO: 661 (having a sequence of GAS) has a CDR2 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 SEQ ID NO: 662. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited reference sequence. In some aspects, the CDR1, CDR2 and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 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 cited. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0415] In some aspects, one or more of VH1, VH2, VH3, and VH4 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: 664; 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: 665; and / or 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: 666. NO:666 has a CDR3 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an amino acid sequence; and one or more of VL1, VL2, VL3 and VL4 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:668; NO: 669 (sequence with DAS) has a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 SEQ ID NO: 670. In some aspects, the CDR1, CDR2, and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3, and VL4 have at least 90% identity to the corresponding amino acid sequences specified above. In some aspects, the CDR1, CDR2, and CDR3 of one or more of VH1, VH2, VH3, VH4, VL1, VL2, VL3, and VL4 comprise or consist of 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 cited reference sequence.In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 have at least 90% identity with the corresponding amino acid sequences specified above. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 comprise or consist of the corresponding amino acid sequences specified above.

[0416] In some aspects, VH1, VH2, VH3 and VH4 each comprise the same CDR1, CDR2 and CDR3 district. In some aspects, VL1, VL2, VL3 and VL4 each comprise the same CDR1, CDR2 and CDR3 district. In some aspects, VH1, VH2, VH3 and VH4 each comprise the same CDR1, CDR2 and CDR3 district, and VL1, VL2, VL3 and VL4 each comprise the same CDR1, CDR2 and CDR3 district.

[0417] In some aspects, each of VH1, VH2, VH3, and VH4 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 NOs: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665 having a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprising a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 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: In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3 and VH4 are each 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 cited reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3 and VH4 each comprise or consist of the corresponding amino acid sequences specified above.

[0418] In some aspects, each of VL1, VL2, VL3, and VL4 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 NOs: 39, 47, 55, 63, 71, 167, 175, 183, 260, 268, 276, 284, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 613, 621, 643, 651, 660, and 668; NO:40, 48, 56, 64, 72, 168, 176, 184, 261, 269, 277 (sequence with LGS), 285, 518 (sequence with DAS), 526 (sequence with DVS), 534 (sequence with EDS), 542 (sequence with KDS), 550 (sequence with DAS), 558 (sequence with AAS), 566 (sequence with GAS), 574 (sequence with DDS), 582 (sequence with KDS), 590 (sequence with SAS), 598 (sequence with SAS), ), 606 (having a sequence of GAS), 614 (having a sequence of GAS), 622 (having a sequence of GAS), 644 (having a sequence of GAS), 652 (having a sequence of SAS), 661 (having a sequence of GAS), and 669 (having a sequence of DAS) having a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 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 In some preferred aspects, the CDR1, CDR2 and CDR3 of VL1, VL2, VL3 and VL4 are each 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 cited reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VL1, VL2, VL3 and VL4 each comprise or consist of the corresponding amino acid sequences specified above.

[0419] In some aspects, each of VH1, VH2, VH3, and VH4 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 NOs: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665 having a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 comprising a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 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: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658 and 666 having a CDR3 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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, VL3 and VL4 each comprise: 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; any of NOs: 39, 47, 55, 63, 71, 167, 175, 183, 260, 268, 276, 284, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 613, 621, 643, 651, 660, and 668 having a CDR1 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;comprising sequences corresponding to SEQ ID NOs: 40, 48, 56, 64, 72, 168, 176, 184, 261, 269, 277 (sequence with LGS), 285, 518 (sequence with DAS), 526 (sequence with DVS), 534 (sequence with EDS), 542 (sequence with KDS), 550 (sequence with DAS), 558 (sequence with AAS), 566 (sequence with GAS), 574 (sequence with DDS), 582 (sequence with KDS), 590 (sequence with SAS), 598 (sequence with SAS), ), 606 (sequence of GAS), 614 (sequence of GAS), 622 (sequence of GAS), 644 (sequence of GAS), 652 (sequence of SAS), 661 (sequence of GAS), and 669 (sequence of DAS) having a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 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 any of ID NOs: 41, 49, 57, 65, 73, 169, 177, 185, 262, 270, 278, 286, 519, 527, 535, 543, 551, 559, 567, 575, 583, 591, 599, 607, 615, 623, 645, 653, 662, and 670 having a CDR3 of an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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 VH1, VH2, VH3, VH4, VL1, VL2, VL3, and VL4 are each at least 90% identical to the corresponding amino acid sequences specified above. 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 cited. In some particularly preferred aspects, the CDR1, CDR2, and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3, and VL4 are each comprised of or consist of the corresponding amino acid sequences specified above.

[0420] In some aspects, each of VH1, VH2, VH3, and VH4 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: 43; 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: 44; 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: 45. NO:45 has a CDR3 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an amino acid sequence; and VL1, VL2, VL3 and VL4 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:39; NO:40 (sequence with GAS) has a CDR2 with an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, 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:41. In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 each 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 cited reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 each comprise or consist of the corresponding amino acid sequence specified above.

[0421] In some aspects, each of VH1, VH2, VH3, and VH4 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: 51; 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: 52; 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: 53. NO:53 has a CDR3 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to an amino acid sequence; and VL1, VL2, VL3 and VL4 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:47; NO: 48 (having a sequence of GAS) has a CDR2 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: 49. In some preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 each 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 cited reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 each comprise or consist of the corresponding amino acid sequence specified above.

[0422] In some aspects, VH1, VH2, VH3 and VH4 each comprise the same variable region of heavy chain. In some aspects, VL1, VL2, VL3 and VL4 each comprise the same variable region of light chain. In some aspects, VH1, VH2, VH3 and VH4 each comprise the same variable region of heavy chain, and VL1, VL2, VL3 and VL4 each comprise the same variable region of light chain.

[0423] In some aspects, VH1, VH2, VH3, and VH4 each comprise a polypeptide corresponding to SEQ ID any of NOs:42, 50, 58, 66, 74, 170, 178, 186, 263, 271, 279, 287, 510, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 626, 628, 630, 632, 634, 636, 638, 646, 654, 663, 779, 781, 785, and 787 have the same 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 aspects, VL1, VL2, VL3, and VL4 each comprise a polypeptide corresponding to SEQ ID any of NOs: 38, 46, 54, 62, 70, 166, 174, 182, 259, 267, 275, 283, 508, 509, 511, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 625, 627, 629, 631, 633, 635, 637, 642, 650, 659, and 667 having the same 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 aspects, each of VH1, VH2, VH3, and VH4 comprises a polypeptide corresponding to SEQ ID NO: 42, 50, 58, 66, 74, 170, 178, 186, 263, 271, 279, 287, 510, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 626, 628, 630, 632, 634, 636, 638, 646, any of 654, 663, 779, 781, 785 and 787 having an identical 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; and VL1, VL2, VL3 and VL4 each comprise an amino acid sequence identical to SEQ any of ID NOs: 38, 46, 54, 62, 70, 166, 174, 182, 259, 267, 275, 283, 508, 509, 511, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 625, 627, 629, 631, 633, 635, 637, 642, 650, 659, and 667 having the same 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 aspects, the sequence has a mutation at N62, such as N62Q or N62Q at SEQ ID NO: 279. In some preferred aspects, each of VH1, VH2, VH3, VH4, VL1, VL2, VL3, and VL4 has at least 90% identity to the corresponding amino acid sequence specified above, optionally with a mutation at N62 as described 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 cited. In some particularly preferred aspects, each of VH1, VH2, VH3, VH4, VL1, VL2, VL3, and VL4 comprises or consists of the corresponding amino acid sequence specified above, optionally with a mutation at N62 as described above.

[0424] In some aspects, each of VH1, VH2, VH3, and VH4 comprises an identical amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 42. In some aspects, each of VL1, VL2, VL3, and VL4 comprises an identical amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 38. In some aspects, VH1, VH2, VH3, and VH4 each comprise an identical amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:42; and VL1, VL2, VL3, and VL4 each comprise an identical amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:38. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 each 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 cited. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 each comprise or consist of the corresponding amino acid sequences specified above.

[0425] In some aspects, each of VH1, VH2, VH3, and VH4 comprises an identical amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 50. In some aspects, each of VL1, VL2, VL3, and VL4 comprises an identical amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 46. In some aspects, VH1, VH2, VH3, and VH4 each comprise an identical amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:50; and VL1, VL2, VL3, and VL4 each comprise an identical amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:46. In some preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 each 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 cited. In some particularly preferred aspects, VH1, VH2, VH3, VH4, VL1, VL2, VL3 and VL4 each comprise or consist of the corresponding amino acid sequences specified above.

[0426] In some aspects, VH1 comprises the same CDR1, CDR2 and CDR3 regions as VH3. In some aspects, VL1 comprises the same CDR1, CDR2 and CDR3 regions as VL3. In some aspects, VH1 comprises the same CDR1, CDR2 and CDR3 regions as VH3, and VL1 comprises the same CDR1, CDR2 and CDR3 regions as VL3.

[0427] In some aspects, VH2 comprises the same CDR1, CDR2 and CDR3 district as VH4. In some aspects, VL2 comprises the same CDR1, CDR2 and CDR3 district as VL4. In some aspects, VH2 comprises the same CDR1, CDR2 and CDR3 district as VH4, and VL2 comprises the same CDR1, CDR2 and CDR3 district as VL4.

[0428] In some aspects, VH1 comprises the same CDR1, CDR2, and CDR3 regions as VH3, VL1 comprises the same CDR1, CDR2, and CDR3 regions as VL3, VH2 comprises the same CDR1, CDR2, and CDR3 regions as VH4, and VL2 comprises the same CDR1, CDR2, and CDR3 regions as VL4.

[0429] In some aspects, the VH1 CDR1 and VH3 CDR1 each comprise an identical 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 any one of SEQ ID NO: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664. In some aspects, the VH1 CDR2 and VH3 CDR2 each comprise an identical 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 any one of SEQ ID NO: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657, and 665. In some aspects, the VH1 CDR3 and VH3 CDR3 each comprise an identical 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 any one of SEQ ID NO: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666. In some preferred aspects, the CDR1, CDR2, and CDR3 of VH1 and VH3 each 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 cited. In some particularly preferred aspects, the CDR1, CDR2, and CDR3 of VH1 and VH3 each comprise or consist of the corresponding amino acid sequences specified above.

[0430] In some aspects, the VH1 CDR1 and VH3 CDR1 each comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 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: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; and the VH1 CDR2 and VH3 CDR2 each comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 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: any of NO:44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657, and 665 having an identical 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; and the VH1 CDR3 and VH3 CDR3 each comprise the same amino acid sequence as SEQ ID NO:44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, Any of NOs:45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666 has an identical 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, each of the CDR1, CDR2, and CDR3 of VH1 and VH3 has 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 cited reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VH1 and VH3 each comprise or consist of the corresponding amino acid sequences specified above.

[0431] In some aspects, the VL1 CDR1 and VL3 CDR1 each comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 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: 39, 47, 55, 63, 71, 167, 175, 183, 260, 268, 276, 284, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 613, 621, 643, 651, 660, and 668. In some aspects, the VL1 CDR2 and VL3 CDR2 each comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 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: 39, 47, 55, 63, 71, 167, 175, 183, 260, 268, NO: 40, 48, 56, 64, 72, 168, 176, 184, 261, 269, 277 (sequence with LGS), 285, 518 (sequence with DAS), 526 (sequence with DVS), 534 (sequence with EDS), 542 (sequence with KDS), 550 (sequence with DAS), 558 (sequence with AAS), 566 (sequence with GAS), 574 (sequence with DDS), 582 (sequence with KDS), 590 (sequence with SAS), 598 (sequence with any of 60 (having a sequence of SAS), 606 (having a sequence of GAS), 614 (having a sequence of GAS), 622 (having a sequence of GAS), 644 (having a sequence of GAS), 652 (having a sequence of SAS), 661 (having a sequence of GAS), and 669 (having a sequence of DAS) have the same 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 aspects, the VL1 CDR3 and VL3 CDR3 each comprise an identical 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 any one of SEQ ID NO: 41, 49, 57, 65, 73, 169, 177, 185, 262, 270, 278, 286, 519, 527, 535, 543, 551, 559, 567, 575, 583, 591, 599, 607, 615, 623, 645, 653, 662, and 670. In some preferred aspects, the CDR1, CDR2, and CDR3 of VL1 and VL3 are each 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 cited reference sequence. In some particularly preferred aspects, the CDR1, CDR2 and CDR3 of VL1 and VL3 each comprise or consist of the corresponding amino acid sequences specified above.

[0432] In some aspects, the VL1 CDR1 and VL3 CDR1 each comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 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: 39, 47, 55, 63, 71, 167, 175, 183, 260, 268, 276, 284, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 613, 621, 643, 651, 660, and 668; and the VL1 CDR2 and VL3 CDR2 each comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at 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: NO: 40, 48, 56, 64, 72, 168, 176, 184, 261, 269, 277 (sequence with LGS), 285, 518 (sequence with DAS), 526 (sequence with DVS), 534 (sequence with EDS), 542 (sequence with KDS), 550 (sequence with DAS), 558 (sequence with AAS), 566 (sequence with GAS), 574 (sequence with DDS), 582 (sequence with KDS), 590 (sequence with SAS), 59...

Claims

1. An antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1; VL1-L1-VH2-L2-VL2-L3-VH1; VH1-L4-VH2-L5-VL2-L6-VL1; or VH1-L4-VL2-L5-VH2-L6-VL1; in: VL1 is the first immunoglobulin light chain variable region that specifically binds to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; VL2 is the second 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 a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1-L6 are amino acid linkers.

2. The antigen-binding polypeptide according to claim 1, which has the following formula: VL1-L1-VL2-L2-VH2-L3-VH1; or VH1-L4-VH2-L5-VL2-L6-VL1; in: VL1 is the first immunoglobulin light chain variable region that specifically binds to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; VL2 is the second 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 a second immunoglobulin heavy chain variable region that specifically binds to a SARS-CoV-2 protein; and L1-L6 are amino acid linkers.

3. An antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; The first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1; VL1-L1-VH2-L2-VL2-L3-VH1; VH1-L4-VH2-L5-VL2-L6-VL1; or VH1-L4-VL2-L5-VH2-L6-VL1; The second polypeptide has a structure represented by the following formula: VL3-L7-VL4-L8-VH4-L9-VH3; VL3-L7-VH4-L8-VL4-L9-VH3; VH3-L10-VH4-L11-VL4-L12-VL3; or VH3-L10-VL4-L11-VH4-L12-VL3; 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; VL4 is the fourth 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; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and L1-L12 are amino acid linkers.

4. The antigen-binding polypeptide complex according to claim 3, comprising a first polypeptide and a second polypeptide; The first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1; or VH1-L4-VH2-L5-VL2-L6-VL1; The second polypeptide has a structure represented by the following formula: VL3-L7-VL4-L8-VH4-L9-VH3; or VH3-L10-VH4-L11-VL4-L12-VL3; 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; VL4 is the fourth 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; VH4 is a fourth immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and L1-L12 are amino acid linkers.

5. An antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; 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; 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; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L8 are amino acid linkers.

6. The antigen-binding polypeptide according to claim 5, which has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; 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; 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; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L8 are amino acid linkers.

7. An antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; The first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc; VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; or VH1-L5-VL2-L6-VH2-L7-VL1-L8-Fc; The second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; VL3-L9-VH4-L10-VL4-L11-VH3-L12-Fc; VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; or VH3-L13-VL4-L14-VH4-L15-VL3-L16-Fc; 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; VL4 is the fourth 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; VH4 is the fourth immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L16 are amino acid linkers.

8. The antigen-binding polypeptide complex according to claim 7, comprising a first polypeptide and a second polypeptide; The first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or VH1-L5-VH2-L6-VL2-L7-VL1-L8-Fc; The second polypeptide has a structure represented by the following formula: Fc; VL3-L9-VL4-L10-VH4-L11-VH3-L12-Fc; or VH3-L13-VH4-L14-VL4-L15-VL3-L16-Fc; 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; VL4 is the fourth 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; VH4 is the fourth immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L16 are amino acid linkers.

9. An antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-CH1; VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-CH1; or VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-CH1; 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; 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; CH1 is the immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; and L1-L20 are amino acid linkers.

10. The antigen-binding polypeptide according to claim 9, which has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; or VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-CH1; 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; 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; CH1 is the immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; and L1-L20 are amino acid linkers.

11. An antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; The first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; VH1-L6-VL2-L7-VH2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; VL1-L11-VH2-L12-VL2-L13-VH1-L14-CL-L15-CH1; VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-CH1; or VH1-L16-VL2-L17-VH2-L18-VL1-L19-CL-L20-CH1; The second polypeptide has a structure represented by the following formula: VL3-L21-VL4-L22-VH4-L23-VH3-L24-CH1-L25-CL; VL3-L21-VH4-L22-VL4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VH4-L27-VL4-L28-VL3-L29-CH1-L30-CL; VH3-L26-VL4-L27-VH4-L28-VL3-L29-CH1-L30-CL; VL3-L31-VL4-L32-VH4-L33-VH3-L34-CL-L35-CH1; VL3-L31-VH4-L32-VL4-L33-VH3-L34-CL-L35-CH1; VH3-L36-VH4-L37-VL4-L38-VL3-L39-CL-L40-CH1; or VH3-L36-VL4-L37-VH4-L38-VL3-L39-CL-L40-CH1; 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; VL4 is the fourth 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; VH4 is the fourth 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-L40 is an amino acid linker.

12. The antigen-binding polypeptide complex according to claim 11, comprising a first polypeptide and a second polypeptide; The first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL; VH1-L6-VH2-L7-VL2-L8-VL1-L9-CH1-L10-CL; VL1-L11-VL2-L12-VH2-L13-VH1-L14-CL-L15-CH1; or VH1-L16-VH2-L17-VL2-L18-VL1-L19-CL-L20-CH1; The second polypeptide has a structure represented by the following formula: VL3-L21-VL4-L22-VH4-L23-VH3-L24-CH1-L25-CL; VH3-L26-VH4-L27-VL4-L28-VL3-L29-CH1-L30-CL; VL3-L31-VL4-L32-VH4-L33-VH3-L34-CL-L35-CH1; or VH3-L36-VH4-L37-VL4-L38-VL3-L39-CL-L40-CH1; 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; VL4 is the fourth 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; VH4 is the fourth 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-L40 is an amino acid linker.

13. An antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VH1-L7-VL2-L8-VH2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-VH2-L15-VH1-L16-CL-L17-CH1-L18-Fc; VL1-L13-VH2-L14-VL2-L15-VH1-L16-CL-L17-CH1-L18-Fc; VH1-L19-VH2-L20-VL2-L21-VL1-L22-CL-L23-CH1-L24-Fc; or VH1-L19-VL2-L20-VH2-L21-VL1-L22-CL-L23-CH1-L24-Fc; 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; 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; CH1 is the immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L24 are amino acid linkers.

14. The antigen-binding polypeptide according to claim 13, which has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-VH2-L15-VH1-L16-CL-L17-CH1-L18-Fc; or VH1-L19-VH2-L20-VL2-L21-VL1-L22-CL-L23-CH1-L24-Fc; 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; 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; CH1 is the immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L24 are amino acid linkers.

15. An antigen-binding polypeptide complex comprising a first polypeptide and a second polypeptide; The first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VH1-L7-VL2-L8-VH2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-VH2-L15-VH1-L16-CL-L17-CH1-L18-Fc; VL1-L13-VH2-L14-VL2-L15-VH1-L16-CL-L17-CH1-L18-Fc; VH1-L19-VH2-L20-VL2-L21-VL1-L22-CL-L23-CH1-L24-Fc; or VH1-L19-VL2-L20-VH2-L21-VL1-L22-CL-L23-CH1-L24-Fc; wherein the second polypeptide has a structure represented by the following formula: Fc; VL3-L25-VL4-L26-VH4-L27-VH3-L28-CH1-L29-CL-L30-Fc; VL3-L25-VH4-L26-VL4-L27-VH3-L28-CH1-L29-CL-L30-Fc; VH3-L31-VH4-L32-VL4-L33-VL3-L34-CH1-L35-CL-L36-Fc; VH3-L31-VL4-L32-VH4-L33-VL3-L34-CH1-L35-CL-L36-Fc; VL3-L37-VL4-L38-VH4-L39-VH3-L40-CL-L41-CH1-L42-Fc; VL3-L37-VH4-L38-VL4-L39-VH3-L40-CL-L41-CH1-L42-Fc; VH3-L43-VH4-L44-VL4-L45-VL3-L46-CL-L47-CH1-L48-Fc; or VH3-L43-VL4-L44-VH4-L45-VL3-L46-CL-L47-CH1-L48-Fc; wherein: 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; VL4 is the fourth 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; VH4 is the fourth 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; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L48 is an amino acid linker.

16. The antigen-binding polypeptide complex according to claim 15, comprising a first polypeptide and a second polypeptide; The first polypeptide has a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-L5-CL-L6-Fc; VH1-L7-VH2-L8-VL2-L9-VL1-L10-CH1-L11-CL-L12-Fc; VL1-L13-VL2-L14-VH2-L15-VH1-L16-CL-L17-CH1-L18-Fc; or VH1-L19-VH2-L20-VL2-L21-VL1-L22-CL-L23-CH1-L24-Fc; The second polypeptide has a structure represented by the following formula: Fc; VL3-L25-VL4-L26-VH4-L27-VH3-L28-CH1-L29-CL-L30-Fc; VH3-L31-VH4-L32-VL4-L33-VL3-L34-CH1-L35-CL-L36-Fc; VL3-L37-VL4-L38-VH4-L39-VH3-L40-CL-L41-CH1-L42-Fc; or VH3-L43-VH4-L44-VL4-L45-VL3-L46-CL-L47-CH1-L48-Fc; 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; VL4 is the fourth 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; VH4 is the fourth 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; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L48 is an amino acid linker.

17. An antigen-binding polypeptide or antigen-binding polypeptide complex comprising a polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc-L5-Fc; VL1-L1-VH2-L2-VL2-L3-VH1-L4-Fc-L5-Fc; VH1-L6-VH2-L7-VL2-L8-VL1-L9-Fc-L10-Fc; or VH1-L6-VL2-L7-VH2-L8-VL1-L9-Fc-L10-Fc; 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; 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; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L10 are amino acid linkers.

18. The antigen-binding polypeptide or antigen-binding polypeptide complex according to claim 17, comprising a polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc-L5-Fc; or VH1-L6-VH2-L7-VL2-L8-VL1-L9-Fc-L10-Fc; 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; 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; Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; and L1-L10 are amino acid linkers.

19. The antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-18, wherein VH1, VH2, VH3 and VH4 each comprise the same heavy chain variable region, and VL1, VL2, VL3 and VL4 each comprise the same light chain variable region.

20. The antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-18, wherein VH1 comprises the same heavy chain variable region as VH3, and VL1 comprises the same light chain variable region as VL3.

21. The antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-18, wherein VH2 comprises the same heavy chain variable region as VH4, and VL2 comprises the same light chain variable region as VL4.

22. The antigen-binding polypeptide complex of any one of claims 1-18, wherein two of VH1, VH2, VH3 and VH4 comprise the same heavy chain variable region, and two of VL1, VL2, VL3 and VL4 comprise the same light chain variable region.

23. The antigen-binding polypeptide complex of any one of claims 1-18, wherein VH2 comprises the same heavy chain variable region as VH4, and VL2 comprises the same light chain variable region as VL4.

24. The antigen-binding polypeptide complex of any one of claims 1-18, wherein VH2 comprises the same heavy chain variable region as VH3, and VL2 comprises the same light chain variable region as VL3.

25. The antigen-binding polypeptide complex of any one of claims 1-18, wherein VH1 comprises the same heavy chain variable region as VH4, and VL1 comprises the same light chain variable region as VL4.

26. The antigen-binding polypeptide complex of any one of claims 1-18, wherein VH1 comprises the same heavy chain variable region as VH3, and VL1 comprises the same light chain variable region as VL3.

27. The antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-18, 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 or antigen-binding polypeptide complex of any one of claims 1-27, wherein linkers L1-L48 each independently have a length of 0 amino acids to about 50 amino acids.

29. An antigen-binding polypeptide or antigen-binding polypeptide complex as described in any one of claims 1-28, wherein the linkers L1-L48 that do not have a length of 0 amino acids each independently comprise an amino acid sequence that is at least 80%, at least 85%, at least 90% or at least 95% identical to any one of SEQ ID NOs: 1-34, wherein SEQ ID NO: 1 has an amino acid sequence of G, SEQ ID NO: 2 has an amino acid sequence of A, SEQ ID NO: 3 has an amino acid sequence of GSS and SEQ ID NO: 4 has an amino acid sequence of ASG.

30. The antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-29, wherein one or more of linkers L1-L48 is non-immunogenic.

31. The antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-30, wherein one or more of the linkers L1-L48 do not contain a shared T cell epitope.

32. The antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-31, 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) knobs replaced by S354C and T366W and holes replaced by Y349C, T366S, L368A, and Y407V; (ii) pore substitutions M428L and N434S or N434A; (iii) the pore substitutions M252Y, S254T and T256E; or (iv) combinations thereof; 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 or antigen-binding polypeptide complex of any one of claims 1-34, comprising a detectable label.

36. The antigen-binding polypeptide or 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 or 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 or antigen-binding polypeptide complex of claim 37, wherein the poly-histidine tag consists of about eight histidine residues.

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

40. An antigen-binding polypeptide complex as described in any one of claims 1-39, wherein the antigen-binding polypeptide complex is bispecific, trispecific or tetraspecific and has a greater neutralizing potency against the SARS-CoV-2 virus than a monospecific antigen-binding polypeptide complex that specifically binds to one of the same antigens as the bispecific, trispecific or tetraspecific antigen-binding polypeptide complex.

41. An antigen-binding polypeptide complex as described in any one of claims 1-40, wherein the antigen-binding polypeptide complex is bispecific, trispecific or tetraspecific and has a neutralizing potency against the SARS-CoV-2 virus greater than a mixture of monospecific antigen-binding polypeptide complexes that specifically bind to the same antigen as the bispecific, trispecific or tetraspecific antigen-binding polypeptide complex.

42. An antigen-binding polypeptide complex as described in claim 40 or 41, wherein the SARS-CoV-2 virus is the original strain (WA1), the D614G spike protein mutant (D614G), the α variant (B.1.1.7), the β variant (B.1.351), the γ variant (P.1), the δ variant, the ε variant (B.1.427) or the ο variant (B.1.1.529) or a combination thereof.

43. An antibody or antigen-binding fragment thereof comprising the antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-42.

44. The antibody or antigen-binding fragment thereof of claim 43, wherein the antibody is IgG, IgM, IgE, IgA or IgD.

45. The antibody or antigen-binding fragment thereof of claim 44, wherein the IgG is IgG1, IgG2, IgG3 or IgG4.

46. ​​The antibody or antigen-binding fragment thereof of claim 43, wherein the antigen-binding fragment is Fab, scFab, Fab', F(ab')2, Fv or scFv.

47. The antibody or antigen-binding fragment thereof of claim 43, wherein the antibody is a human or humanized antibody.

48. The antibody or antigen-binding fragment thereof of claim 43, wherein the antibody is a monoclonal antibody, a grafted antibody or a chimeric antibody.

49. An anti-SARS-CoV2 multivalent antibody that exhibits improved prevention of immune escape compared to a combination of (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 monovalent anti-SARS-CoV2 antibody that binds to the same antigen as the anti-SARS-CoV2 multivalent antibody.

50. A pharmaceutical composition comprising the antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-42.

51. A pharmaceutical composition comprising the antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-42 and an additional agent.

52. A pharmaceutical composition comprising the antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-42 and a pharmaceutically acceptable carrier.

53. A pharmaceutical composition comprising the antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-42, an additional agent, and a pharmaceutically acceptable carrier.

54. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to any one of claims 43-49.

55. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of claims 43-49 and an additional agent.

56. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof as described in any one of claims 43-49 and a pharmaceutically acceptable carrier.

57. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of claims 43-49, an additional agent, and a pharmaceutically acceptable carrier.

58. A pharmaceutical composition as described in any of claims 51, 53, 55 and 57, 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.

59. The pharmaceutical composition of claim 58, wherein the additional agent is 25-hydroxyvitamin D.

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

61. The pharmaceutical composition of claim 58, 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.

62. The pharmaceutical composition of claim 58, wherein the antiviral agent is maraviroc, enfuvirtide, amantadine, lamivudine, nevirapine, efavirenz, dolutegravir, elvitegravir, raltegravir, acyclovir and any nucleoside analog of acyclovir, ganciclovir, cidofovir, trisodium phosphate formate, ribavirin, interferon alpha, pegylated interferon alpha, boceprevir, atazanavir, darunavir, indinavir, oseltamivir, zanavir, Aminavir, rimantadine, peramivir, valacyclovir, penciclovir, valganciclovir, foscarnet, tenofovir, adefovir, entecavir, lamivudine, telbivudine, ribavirin, glecaprevir, grazoprevir, paritaprevir, semideprevir, voxilaprevir, daclatasvir, elbavir, ledipasvir, ombitasvir, pibrentasvir, velpatasvir, dasabuvir, famciclovir, remdesivir, trifluridine, sofosbuvir, bectelovisimab, or a combination thereof.

63. The pharmaceutical composition of claim 62, wherein the antiviral agent is bectovizumab.

64. The pharmaceutical composition of claim 58, 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]diazepine-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), polymannoacetate, (Enfuweidi, T-20), (abacavir and lamivudine), (abacavir, lamivudine and zidovudine), (Emtricitabine and Tenofovir DF), (lamivudine and zidovudine), (lopinavir and ritonavir), bectovimab, or a combination thereof.

65. The pharmaceutical composition of claim 64, wherein the antiviral agent is bectovizumab.

66. A kit comprising the antigen-binding polypeptide or antigen-binding polypeptide complex of any one of claims 1-42 or the antibody or antigen-binding fragment thereof of any one of claims 43-49.

67. A kit comprising (i) an antigen-binding polypeptide or antigen-binding polypeptide complex as described in any one of claims 1-42 or an antibody or antigen-binding fragment thereof as described in any one of claims 43-49, and (ii) an additional agent.

68. A kit comprising the pharmaceutical composition of any one of claims 50-65.

69. A kit comprising (i) the pharmaceutical composition of any one of claims 50-65, and (ii) an additional pharmaceutical agent.

70. A kit comprising (i) the pharmaceutical composition of any one of claims 50-65, and (ii) a pharmaceutical composition comprising an additional pharmaceutical agent.

71. A kit comprising (i) the pharmaceutical composition of any one of claims 50-65, and (ii) a pharmaceutical composition comprising an additional agent and a pharmaceutically acceptable carrier.

72. The kit of any one of claims 66-71, further comprising instructions for use.

73. A method for preventing or treating SARS-CoV-2 viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antigen-binding polypeptide or polypeptide complex as described in any one of claims 1-42, an antibody or antigen-binding fragment thereof as described in any one of claims 43-49, a pharmaceutical composition as described in any one of claims 50-65, or a combination thereof.

74. A method for preventing or treating coronavirus disease 2019 (COVID-19) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antigen-binding polypeptide or polypeptide complex as described in any one of claims 1-42, an antibody or antigen-binding fragment thereof as described in any one of claims 43-49, a pharmaceutical composition as described in any one of claims 50-65, or a combination thereof.

75. A method for diagnosing a subject as being 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 or polypeptide complex as described in any one of claims 1 to 42 or an antibody or antigen-binding fragment thereof as described in any one of claims 43 to 49; (ii) detecting the presence or absence of a viral complex containing the polypeptide, 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 the subject as being infected with or suspected of being infected with SARS-CoV-2 virus.

76. A method for diagnosing a subject as not infected with SARS-CoV-2 virus or not suspected of being infected with SARS-CoV-2 virus, comprising (i) contacting a sample obtained from the subject with an antigen-binding polypeptide or polypeptide complex as described in any one of claims 1 to 42 or an antibody or antigen-binding fragment thereof as described in any one of claims 43 to 49; (ii) detecting the presence or absence of a viral complex containing the polypeptide, 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 the subject as not infected with SARS-CoV-2 virus or not suspected of being infected with SARS-CoV-2 virus.

77. 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 as described in any one of claims 1-42 or an antibody or antigen-binding fragment thereof as described in any one of claims 43-49; (ii) detecting the presence or absence of a viral complex containing the polypeptide, 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.

78. A method for diagnosing a subject as not having COVID-19 or not suspected of having COVID-19, comprising (i) contacting a sample obtained from the subject with an antigen-binding polypeptide or polypeptide complex as described in any one of claims 1-42 or an antibody or antigen-binding fragment thereof as described in any one of claims 43-49; (ii) detecting the presence or absence of a viral complex containing the polypeptide, 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 the subject as not having COVID-19 or not suspected of having COVID-19.

79. The method of any one of claims 75-78, wherein the sample is a nasal swab, a tissue sample, saliva, plasma, or blood.

80. The method of any one of claims 75-79, 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.

81. The method of any one of claims 73-80, wherein the polypeptide, polypeptide complex, antibody or fragment is bispecific, trispecific or tetraspecific and has a greater neutralizing potency against the SARS-CoV-2 virus than a monospecific polypeptide, polypeptide complex, antibody or fragment that specifically binds to one of the same antigens as the bispecific, trispecific or tetraspecific polypeptide, polypeptide complex, antibody or fragment.

82. The method of any one of claims 73-81, wherein the polypeptide, polypeptide complex, antibody or fragment is bispecific, trispecific or tetraspecific and has a neutralizing potency against the SARS-CoV-2 virus greater than a mixture of monospecific polypeptides, polypeptide complexes, antibodies or fragments that specifically bind to the same antigen as the bispecific, trispecific or tetraspecific polypeptide, polypeptide complex, antibody or fragment.

83. A method as described in any one of claims 73-82, 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 (B.1.351), the gamma variant (P.1), the delta variant, the epsilon variant (B.1.427), the o variant (B.1.1.529), or a combination thereof.

84. 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 a combination of (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 monovalent anti-SARS-CoV2 antibody that binds to the same antigen as the anti-SARS-CoV2 multivalent antibody.

85. A method of increasing neutralization potency against 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 increased neutralization potency compared to a combination of (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 monovalent anti-SARS-CoV2 antibody that binds to the same antigen as the anti-SARS-CoV2 multivalent antibody.

86. The method of claim 84 or 85, 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.

87. The method of any one of claims 84-86, 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.

88. The method of any one of claims 84-87, wherein the anti-SARS-CoV2 multispecific antibody continues for at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 rounds of selection to prevent immune escape of the anti-SARS-CoV2 multivalent antibody as measured by an antibody escape assay.

89. The method of any one of claims 84-88, wherein the anti-SARS-CoV2 multispecific antibody prevents immune escape of the anti-SARS-CoV2 multivalent antibody after at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 exposures of the subject to the SARS-CoV2 virus.

90. The method of any one of claims 84-89, 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 in 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.

91. The method of any one of claims 84-90, 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.

92. The method of claim 91, wherein the first antigen binding site is different from the second antigen binding site.

93. The method of claim 91 or 92, 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.

94. The method of claim 93, wherein the first and second heavy chain variable regions each comprise a CDR1, CDR2, and CDR3 region, and the first and second light chain variable regions each comprise a CDR1, CDR2, and CDR3 region.

95. The method of any one of claims 84-94, 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:43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; 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:44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657, and 665; 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:45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666; 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 NOs: 39, 47, 55, 63, 71, 167, 175183, 260, 268, 276, 284, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 613, 621, 643, 651, 660, and 668; The CDR2 of the first light chain variable region comprises the same sequence as SEQ ID NO: 40, 48, 56, 64, 72, 168, 176, 184, 261, 269, 277 (sequence with LGS), 285, 518 (sequence with DAS), 526 (sequence with DVS), 534 (sequence with EDS), 542 (sequence with KDS), 550 (sequence with DAS), 558 (sequence with AAS), 566 (sequence with GAS), 574 (sequence with DDS), 582 (sequence with KDS), ), 590 (sequence with SAS), 598 (sequence with SAS), 606 (sequence with GAS), 614 (sequence with GAS), 622 (sequence with GAS), 644 (sequence with GAS), 652 (sequence with SAS), 661 (sequence with GAS), and 669 (sequence with DAS) 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:41, 49, 57, 65, 73, 169, 177, 185, 262, 270, 278, 286, 519, 527, 535, 543, 551, 559, 567, 575, 583, 591, 599, 607, 615, 623, 645, 653, 662, and 670; 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:43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; 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:44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657, and 665; 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:45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666; 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 NOs: 39, 47, 55, 63, 71, 167, 175, 183, 260, 268, 276, 284, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 613, 621, 643, 651, 660, and 668; The CDR2 of the second light chain variable region comprises a sequence corresponding to SEQ ID NO: 40, 48, 56, 64, 72, 168, 176, 184, 261, 269, 277 (sequence with LGS), 518 (sequence with DAS), 526 (sequence with DVS), 534 (sequence with EDS), 542 (sequence with KDS), 550 (sequence with DAS), 558 (sequence with AAS), 566 (sequence with GAS), 574 (sequence with DDS), 582 (sequence with KDS), any of 590 (sequence having SAS), 598 (sequence having SAS), 606 (sequence having GAS), 614 (sequence having GAS), 622 (sequence having GAS), 644 (sequence having GAS), 652 (sequence having SAS), 661 (sequence having GAS), and 669 (sequence having DAS) 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:41, 49, 57, 65, 73, 169, 177, 185, 262, 270, 278, 286, 519, 527, 535, 543, 551, 559, 567, 575, 583, 591, 599, 607, 615, 623, 645, 653, 662 and 670.

96. The method of any one of claims 84-95, 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 NOs: 42, 50, 58, 66, 74, 170, 178, 186, 263, 271, 279, 287, 510, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 626, 628, 630, 632, 634, 636, 638, 646, 654, 663, 779, 781, 785, and 787; 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 NOs: 38, 46, 54, 62, 70, 166, 174, 182, 259, 267, 275, 283, 508, 509, 511, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 625, 627, 629, 631, 633, 635, 637, 642, 650, 659, and 667; 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 NOs: 42, 50, 58, 66, 74, 170, 178, 186, 263, 271, 279, 287, 510, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 626, 628, 630, 632, 634, 636, 638, 646, 654, 663, 779, 781, 785, and 787; 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 NOs: 38, 46, 54, 62, 70, 166, 174, 182, 259, 267, 275, 283, 508, 509, 511, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 625, 627, 629, 631, 633, 635, 637, 642, 650, 659 and 667.

97. The method of any one of claims 84-96, wherein the anti-SARS-CoV2 multivalent antibody further comprises a third antigen binding domain.

98. The method of claim 97, wherein the third antigen binding site is different from the first antigen binding site, the second antigen binding site, or both the first and second antigen binding sites.

99. The method of claim 97 or 98, wherein the third antigen binding site comprises a third heavy chain variable domain and a third light chain variable domain.

100. The method of any one of claims 84-99, 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 NOs: 42, 50, 58, 66, 74, 170, 178, 186, 263, 271, 279, 287, 510, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 626, 628, 630, 632, 634, 636, 638, 646, 654, 663, 779, 781, 785, and 787; 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 NOs: Any of NO:38, 46, 54, 62, 70, 166, 174, 182, 259, 267, 275, 283, 508, 509, 511, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 625, 627, 629, 631, 633, 635, 637, 642, 650, 659 and 667 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% or 100% identical.

101. The method of any one of claims 84-100, wherein the third heavy chain variable region comprises CDR1, CDR2, and CDR3 regions.

102. The method of any one of claims 84 to 101, 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:43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; 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:44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657, and 665; 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:45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666; 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 NOs: 39, 47, 55, 63, 71, 167, 175, 183, 260, 268, 276, 284, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 613, 621, 643, 651, 660, and 668; The CDR2 of the third light chain variable region comprises the same sequence as SEQ ID NO: 40, 48, 56, 64, 72, 168, 176, 184, 261, 269, 277 (sequence with LGS), 285, 518 (sequence with DAS), 526 (sequence with DVS), 534 (sequence with EDS), 542 (sequence with KDS), 550 (sequence with DAS), 558 (sequence with AAS), 566 (sequence with GAS), 574 (sequence with DDS), 582 (sequence with KDS). ), 590 (sequence with SAS), 598 (sequence with SAS), 606 (sequence with GAS), 614 (sequence with GAS), 622 (sequence with GAS), 644 (sequence with GAS), 652 (sequence with SAS), 661 (sequence with GAS), and 669 (sequence with DAS) 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 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 NOs: 41, 49, 57, 65 and 73, 169, 177, 185, 262, 270, 278, 286, 519, 527, 535, 543, 551, 559, 567, 575, 583, 591, 599, 607, 615, 623, 645, 653, 662 and 670.

103. The method of any one of claims 84-102, wherein the anti-SARS-CoV2 multivalent antibody further comprises a fourth antigen binding domain.

104. The method of claim 103, wherein the fourth antigen binding site is different from one or more of the first, second, and third antigen binding sites.

105. The method of claim 103 or 104, wherein the first, second, third and fourth antigen binding sites are different.

106. The method of any one of claims 84-105, wherein the fourth antigen binding site comprises a third heavy chain variable domain and a fourth light chain variable domain.

107. The method of any one of claims 84-106, 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 NOs: 42, 50, 58, 66, 74, 170, 178, 186, 263, 271, 279, 287, 510, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 626, 628, 630, 632, 634, 636, 638, 646, 654, 663, 779, 781, 785, and 787; 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 NOs: Any of NO:38, 46, 54, 62, 70, 166, 174, 182, 259, 267, 275, 283, 508, 509, 511, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 625, 627, 629, 631, 633, 635, 637, 642, 650, 659 and 667 has an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% or 100% identical.

108. The method of any one of claims 84-107, wherein the fourth heavy chain variable region comprises CDR1, CDR2, and CDR3 regions.

109. The method of claim 108, 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:43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; 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 NOs: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657, and 665; 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:45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658, and 666; 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 NOs: 39, 47, 55, 63, 71, 167, 175, 183, 260, 268, 276, 284, 517, 525, 533, 541, 549, 557, 565, 573, 581, 589, 597, 605, 613, 621, 643, 651, 660, and 668; The CDR2 of the fourth light chain variable region comprises the same sequence as SEQ ID NO: 40, 48, 56, 64, 72, 168, 176, 184, 261, 269, 277 (sequence with LGS), 285, 518 (sequence with DAS), 526 (sequence with DVS), 534 (sequence with EDS), 542 (sequence with KDS), 550 (sequence with DAS), 558 (sequence with AAS), 566 (sequence with GAS), 574 (sequence with DDS), 582 (sequence with KDS). ), 590 (sequence with SAS), 598 (sequence with SAS), 606 (sequence with GAS), 614 (sequence with GAS), 622 (sequence with GAS), 644 (sequence with GAS), 652 (sequence with SAS), 661 (sequence with GAS), and 669 (sequence with DAS) 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 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:41, 49, 57, 65, 73, 169, 177, 185, 262, 270, 278, 286, 519, 527, 535, 543, 551, 559, 567, 575, 583, 591, 599, 607, 615, 623, 645, 653, 662 and 670.

110. The method of any one of claims 84-109, wherein the anti-SARS-CoV2 multivalent antibody is an antibody or antigen-binding fragment thereof as described in any one of claims 43-48.

111. The method of any one of claims 84-110, wherein the antigen is a SARS-CoV-2 protein.

112. The method of any one of claims 84-111, wherein the SARS-CoV2 virus is a SARS-CoV2 variant.

113. The method of claim 112, 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 epsilon variant (B.1.427), or an o variant (B.1.1.529), or a combination thereof.

114. A method as described in claim 113, wherein the o 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.

115. The method of any one of claims 73-114, further comprising administering to the subject an effective amount of an additional agent.

116. The method of any one of claims 73-114, further comprising administering to the subject an effective amount of a pharmaceutical composition comprising (i) an additional agent and (ii) a pharmaceutically acceptable carrier.

117. The method of claim 115 or 116, wherein the additional agent is 25-hydroxyvitamin D, an agent that enhances the action of vitamin D, an antiviral agent, an antimalarial agent, an antibiotic, or a combination thereof.

118. The method of claim 115, wherein the additional agent is 25-hydroxyvitamin D.

119. The method of claim 117, wherein the agent that enhances the effect of vitamin D is a CYP24 inhibitor, a 1,25-dihydroxyvitamin D compound, or a combination thereof.

120. The method of claim 117, 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.

121. The method of claim 117, wherein the antiviral agent is maraviroc, enfuvirtide, amantadine, lamivudine, nevirapine, efavirenz, dolutegravir, elvitegravir, raltegravir, acyclovir and any nucleoside analog of acyclovir, ganciclovir, cidofovir, trisodium phosphate formate, ribavirin, interferon alpha, pegylated interferon alpha, boceprevir, atazanavir, darunavir, indinavir, oseltamivir, zanavir, Aminavir, rimantadine, peramivir, valacyclovir, penciclovir, valganciclovir, foscarnet, tenofovir, adefovir, entecavir, lamivudine, telbivudine, ribavirin, glecaprevir, grazoprevir, paritaprevir, semideprevir, voxilaprevir, daclatasvir, elbavir, ledipasvir, ombitasvir, pibrentasvir, velpatasvir, dasabuvir, famciclovir, remdesivir, trifluridine, sofosbuvir, bectelovisimab, or a combination thereof.

122. The method of claim 117, wherein the antiviral agent is bectovizumab.

123. The method of claim 117, 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]diazepine-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), polymannoacetate, (Enfuweidi, T-20), (abacavir and lamivudine), (abacavir, lamivudine and zidovudine), (Emtricitabine and Tenofovir DF), (lamivudine and zidovudine), (lopinavir and ritonavir), bectovimab, or a combination thereof.

124. The method of any one of claims 115-123, wherein the additional agent is administered prior to the antigen-binding polypeptide, antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof.

125. The method of any one of claims 115-123, wherein the additional agent is administered after the antigen-binding polypeptide, antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof.

126. The method of any one of claims 115-123, wherein the additional agent is administered concurrently with the antigen-binding polypeptide, antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof.

127. The method of any one of claims 115-126, wherein the additional agent and the antigen-binding polypeptide, antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof are administered in the same pharmaceutical composition.

128. The method of any one of claims 115-126, wherein the additional agent and the antigen-binding polypeptide, antigen-binding polypeptide complex, antibody, or antigen-binding fragment thereof are administered in different pharmaceutical compositions.

129. A multispecific antibody selected from the group consisting of: (a) an antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VH1 or VH1-L2-VL1; in: VL1 is the first immunoglobulin light chain variable region that specifically binds to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; VH1 is the first immunoglobulin heavy chain variable region that specifically binds to the SARS-CoV-2 protein; and L1 and L2 are amino acid linkers; or An antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1; VL1-L1-VH2-L2-VL2-L3-VH1; VH1-L4-VH2-L5-VL2-L6-VL1; or VH1-L4-VL2-L5-VH2-L6-VL1; 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; VH1 is the 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 a SARS-CoV-2 protein; and L1-L6 are amino acid linkers; and wherein (a) is selected from any of the more specific embodiments provided herein for an antigen-binding polypeptide in an antigen-binding polypeptide complex having no more than three polypeptide chains; (b) an antigen-binding polypeptide complex comprising a first polypeptide, a second polypeptide, a third polypeptide and a fourth polypeptide; The first polypeptide has a structure represented by the following formula: VL1-L1-CL; The second polypeptide has a structure represented by the following formula: VH1-L2-CH1; The third polypeptide has a structure represented by the following formula: VH2-L3-VH3-L4-CH1; The fourth polypeptide has a structure represented by the following formula: VL3-L5-VL2-L6-CL; and 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; and (c) an antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VH1 or VH1-L2-VL1; in: VL1 is the first 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; and L1 and L2 are amino acid linkers; or An antigen-binding polypeptide having a structure represented by the following formula: VL1-L1-VL2-L2-VH2-L3-VH1; VL1-L1-VH2-L2-VL2-L3-VH1; VH1-L4-VH2-L5-VL2-L6-VL1; or VH1-L4-VL2-L5-VH2-L6-VL1; 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; VH1 is the 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 a SARS-CoV-2 protein; and L1-L6 are amino acid linkers; wherein (c) is selected from any of the more specific embodiments provided herein for an antigen-binding polypeptide in an antigen-binding polypeptide complex having no more than three polypeptide chains; and wherein the antigen-binding polypeptide further comprises an amino acid linker between any of the variable regions and / or amino acid linkers (e.g., between VL1 and L1, between L1 and VH1, between VH1 and L2, between L2 and VL1, between L1 and VL2, between VL2 and L2, between L2 and VH2, between VH2 and L3, between L3 and VH1, between VL1 and L1, between L1 and VH2, between VH2 and L2, between L2 and VL2, between VL2 and L3, between L3 and VH1 between VH1 and L4, between L4 and VL2, between VH2 and L5, between L5 and VL2, between VL2 and L6, between L6 and VL1, between VH1 and L4, between L4 and VL2, between L4 and VL2, between VL2 and L5, between L5 and VH2, between VH2 and L6, or between L6 and VL1).

130. A multispecific antibody 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; and 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 immunoglobulin heavy chain constant region 2 (CH2), immunoglobulin heavy chain constant region 3 (CH3), and optionally an immunoglobulin hinge; CH1 is immunoglobulin heavy chain constant region 1; CL is the immunoglobulin light chain constant region; and L1-L8 are amino acid linkers.

131. The multispecific antibody of claim 129 or 130, wherein: VH1, VH2 and / or VH3 contain: 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: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; 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: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665; and / or 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 NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658 and 666; and / or VL1, VL2 and / or VL3 contain: 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: 43, 51, 59, 67, 75, 171, 179, 187, 264, 272, 280, 288, 513, 521, 529, 537, 545, 553, 561, 569, 577, 585, 593, 601, 609, 617, 639, 647, 656, and 664; 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: 44, 52, 60, 68, 76, 172, 180, 188, 265, 273, 281, 289, 514, 522, 530, 538, 546, 554, 562, 570, 578, 586, 594, 602, 610, 618, 640, 648, 657 and 665; and / or 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 NOs: 45, 53, 61, 69, 77, 173, 181, 189, 266, 274, 282, 290, 515, 523, 531, 539, 547, 555, 563, 571, 579, 587, 595, 603, 611, 619, 641, 649, 658 and 666.

132. The multispecific antibody of any one of claims 129-131, wherein: VH1, VH2 and / or VH3 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: 42, 50, 58, 66, 74, 170, 178, 186, 263, 271, 279, 287, 510, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 626, 628, 630, 632, 634, 636, 638, 646, 654, 663, 779, 781, 785, and 787; and / or VL1, VL2 and / or VL3 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: 38, 46, 54, 62, 70, 166, 174, 182, 259, 267, 275, 283, 508, 509, 511, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 625, 627, 629, 631, 633, 635, 637, 642, 650, 659 and 667.

Images