Anti-EGFR / MET Antibody and Its Use

Abstract

The present disclosure relates to antigen-binding protein constructs (e.g., bispecific antibodies, antigen-binding fragments thereof, or ADCs), which specifically bind to two different antigens (e.g., EGFR and MET).

Description

Technical Field

[0001] Claim of Priority This application claims priority to PCT Application No. PCT / CN2022 / 102231 filed on June 29, 2022, PCT Application No. PCT / CN2022 / 108838 filed on July 29, 2022, PCT Application No. PCT / CN2022 / 116678 filed on September 2, 2022, and PCT Application No. PCT / CN2022 / 141416 filed on December 23, 2022. The entire above content is incorporated herein by reference.

[0002] Technical Field The present disclosure relates to antigen-binding protein constructs (e.g., bispecific antibodies, or antigen-binding fragments thereof).

Background Art

[0003] Bispecific antibodies are artificial proteins that can simultaneously bind to two different types of antigens or two different epitopes. This dual specificity opens up a wide range of applications, including redirecting T cells to tumor cells, dual-targeting different disease mediators, and delivering payloads to target sites. The approvals of catumaxomab (anti-EpCAM and anti-CD3) and blinatumomab (anti-CD19 and anti-CD3) have been major milestones in the development of bispecific antibodies.

[0004] Since bispecific antibodies have various applications, it is necessary to continue the development of various therapeutic agents based on bispecific antibodies.

Summary of the Invention

[0005] The present disclosure relates to antigen-binding protein constructs, which specifically bind to two different antigens (e.g., EGFR and MET). In some embodiments, the multispecific antibody (e.g., bispecific antibody) has the same light chain variable region. In some embodiments, the multispecific antibody (e.g., bispecific antibody) has a common light chain. In some embodiments, the multispecific antibody (e.g., bispecific antibody) forms part of an antibody-drug conjugate.

[0006] In one aspect, the present disclosure provides a heavy chain variable region (VH) comprising complementarity-determining regions (CDRs) 1, 2, and 3, wherein in some embodiments, the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH CDR1, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH CDR2, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH CDR3; and a light chain variable region (VL) comprising CDRs 1, 2, and 3, wherein in some embodiments, the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL CDR1, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL CDR2, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL CDR3. The present disclosure also relates to an antibody or antigen-binding fragment thereof that binds to EGFR (epidermal growth factor receptor), wherein in some embodiments, the amino acid sequences of the selected VH CDRs 1, 2, and 3, and the amino acid sequences of the selected VL CDRs 1, 2, and 3 are one of the following. (1) The amino acid sequences of the selected VH CDRs 1, 2, and 3 are shown in SEQ ID NOs: 4-6, respectively, and the amino acid sequences of the selected VL CDRs 1, 2, and 3 are shown in SEQ ID NOs: 1-3, respectively; (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 7-9 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 10-12 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 13-15 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 16-18 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 34-36 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 37-39 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 40-42 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 43-45 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 46-48 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 82 to 84, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; and (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively.

[0007] In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 4-6, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 7-9, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 10-12, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 13-15, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 16-18, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 82-84, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 85-87, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 88-90, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively.In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 91-93, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 34-36, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 37-39, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 40-42, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 43-45, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 46-48, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 94-96, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 97-99, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively.In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 100 to 102, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 103 to 105, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively.

[0008] In one aspect, the present disclosure relates to an antibody that binds to EGFR or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to a selected VH sequence, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to a selected VL sequence. In some embodiments, the selected VH sequence and the selected VL sequence are one of the following. (1) The selected VH sequence is SEQ ID NO: 62 and the selected VL sequence is SEQ ID NO: 61; (2) The selected VH sequence is SEQ ID NO: 63 and the selected VL sequence is SEQ ID NO: 61; (3) The selected VH sequence is SEQ ID NO: 64 and the selected VL sequence is SEQ ID NO: 61; (4) The selected VH sequence is SEQ ID NO: 65 and the selected VL sequence is SEQ ID NO: 61; (5) The selected VH sequence is SEQ ID NO: 66 and the selected VL sequence is SEQ ID NO: 61; (6) The selected VH sequence is SEQ ID NO: 106 and the selected VL sequence is SEQ ID NO: 61; (7) The selected VH sequence is SEQ ID NO: 107 and the selected VL sequence is SEQ ID NO: 61; (8) The selected VH sequence is SEQ ID NO: 108 and the selected VL sequence is SEQ ID NO: 61; and (9) The selected VH sequence is SEQ ID NO: 109, and the selected VL sequence is SEQ ID NO: 61.

[0009] In some embodiments, VH comprises the sequence of SEQ ID NO: 62 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 63 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 64 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 65 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 66 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 106 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 107 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 108 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 109 and VL comprises the sequence of SEQ ID NO: 61.

[0010] In one aspect, the present disclosure relates to an antibody that binds to EGFR or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3 that are identical to the VH CDR1, VH CDR2, and VH CDR3 of the selected VH sequence, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 that are identical to the VL CDR1, VL CDR2, and VL CDR3 of the selected VL sequence. In some embodiments, the selected VH sequence and the selected VL sequence are one of the following. (1) The selected VH sequence is SEQ ID NO: 62 and the selected VL sequence is SEQ ID NO: 61; (2) The selected VH sequence is SEQ ID NO: 63 and the selected VL sequence is SEQ ID NO: 61; (3) The selected VH sequence is SEQ ID NO: 64 and the selected VL sequence is SEQ ID NO: 61; (4) The selected VH sequence is SEQ ID NO: 65, and the selected VL sequence is SEQ ID NO: 61; (5) The selected VH sequence is SEQ ID NO: 66, and the selected VL sequence is SEQ ID NO: 61; (6) The selected VH sequence is SEQ ID NO: 106, and the selected VL sequence is SEQ ID NO: 61; (7) The selected VH sequence is SEQ ID NO: 107, and the selected VL sequence is SEQ ID NO: 61; (8) The selected VH sequence is SEQ ID NO: 108, and the selected VL sequence is SEQ ID NO: 61; and (9) The selected VH sequence is SEQ ID NO: 109, and the selected VL sequence is SEQ ID NO: 61.

[0011] In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to human or monkey EGFR. In some embodiments, the antibody or antigen-binding fragment thereof is a human antibody or a humanized antibody or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment is a single-chain variable fragment (scFv). In some embodiments, the antibody or antigen-binding fragment thereof is a multispecific antibody (e.g., a bispecific antibody) or an antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof further specifically binds to MET. In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that cross-competes with the antibody or antigen-binding fragment thereof described herein.

[0012] In one aspect, the present disclosure relates to a nucleic acid comprising a polynucleotide encoding a polypeptide comprising the following. (1) An immunoglobulin heavy chain or fragment thereof comprising a variable heavy chain region (VH) comprising complementarity-determining regions (CDRs) 1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 4-6, wherein in some embodiments, the VH forms a pair with a variable light chain region (VL) comprising the amino acid sequence shown in SEQ ID NO: 61 and binds to EGFR, an immunoglobulin heavy chain or fragment thereof, (2) An immunoglobulin light chain or a fragment thereof, comprising a variable light chain region (VL) containing complementarity-determining regions (CDR) 1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1-3, wherein in some embodiments, the VL binds to EGFR when pairing with a variable heavy chain region (VH) containing the amino acid sequence shown in SEQ ID NO: 62. (3) An immunoglobulin heavy chain or a fragment thereof, comprising a VH containing CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 7-9, wherein in some embodiments, the VH binds to EGFR when pairing with a VL containing the amino acid sequence shown in SEQ ID NO: 61. (4) An immunoglobulin light chain or a fragment thereof, comprising a VL containing CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1-3, wherein in some embodiments, the VL binds to EGFR when pairing with a VH containing the amino acid sequence shown in SEQ ID NO: 63. (5) An immunoglobulin heavy chain or a fragment thereof, comprising a VH containing CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 10-12, wherein in some embodiments, the VH binds to EGFR when pairing with a VL containing the amino acid sequence shown in SEQ ID NO: 61. (6) An immunoglobulin light chain or a fragment thereof, comprising a VL containing CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1-3, wherein in some embodiments, the VL binds to EGFR when pairing with a VH containing the amino acid sequence shown in SEQ ID NO: 64. (7) An immunoglobulin heavy chain or a fragment thereof, comprising a VH containing CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 13-15, wherein in some embodiments, the VH binds to EGFR when pairing with a VL containing the amino acid sequence shown in SEQ ID NO: 61. (8) An immunoglobulin light chain or a fragment thereof comprising a VL comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 1-3, wherein in some embodiments, the VL binds to EGFR when forming a pair with a VH comprising the amino acid sequence shown in SEQ ID NO: 65, an immunoglobulin light chain or a fragment thereof, (9) An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 16-18, wherein in some embodiments, the VH binds to EGFR when forming a pair with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, (10) An immunoglobulin light chain or a fragment thereof comprising a VL comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 1-3, wherein in some embodiments, the VL binds to EGFR when forming a pair with a VH comprising the amino acid sequence shown in SEQ ID NO: 66, an immunoglobulin light chain or a fragment thereof, (11) An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 34-36, wherein in some embodiments, the VH binds to EGFR when forming a pair with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, (12) An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 37-39, wherein in some embodiments, the VH binds to EGFR when forming a pair with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, (13) An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 40-42, wherein in some embodiments, the VH binds to EGFR when forming a pair with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 43 to 45, wherein in some embodiments, the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 46 to 48, wherein in some embodiments, the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 82 to 84, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, An immunoglobulin light chain or a fragment thereof comprising a VL comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 106, an immunoglobulin light chain or a fragment thereof, An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 85 to 87, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, An immunoglobulin light chain or a fragment thereof comprising a VL comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 107, an immunoglobulin light chain or a fragment thereof, An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 88 to 90, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to EGFR, An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH containing the amino acid sequence shown in SEQ ID NO: 108, the VL binds to EGFR, An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 91 to 93, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to EGFR, An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH containing the amino acid sequence shown in SEQ ID NO: 109, the VL binds to EGFR, An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 94 to 96, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to EGFR, An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 97 to 99, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to EGFR, An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 100 to 102, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, and / or (27) An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 103 to 105, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof.

[0013] In some embodiments, the VH specifically binds to human or monkey EGFR when paired with the VL. In some embodiments, the immunoglobulin heavy chain or a fragment thereof is a heavy chain of a human immunoglobulin or a humanized immunoglobulin or a fragment thereof. In some embodiments, the nucleic acid encodes a single-chain variable fragment (scFv). In some embodiments, the nucleic acid is cDNA.

[0014] In one aspect, the present disclosure relates to an antibody or an antigen-binding fragment thereof that binds to MET (tyrosine protein kinase Met), comprising a heavy-chain variable region (VH) containing complementarity-determining regions (CDR) 1, 2, and 3, wherein in some embodiments, the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to the selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to the selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to the selected VH CDR3 amino acid sequence, and a light-chain variable region (VL) containing CDR1, 2, and 3, wherein in some embodiments, the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to the selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to the selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to the selected VL CDR3 amino acid sequence. In some embodiments, the selected VH CDR1, 2, and 3 amino acid sequences, and the selected VL CDR1, 2, and 3 amino acid sequences are one of the following. (1) The amino acid sequences of the selected VH CDR1, 2, 3 are shown in SEQ ID NOs: 19-21, respectively, and the amino acid sequences of the selected VL CDR1, 2, 3 are shown in SEQ ID NOs: 1-3, respectively; (2) The amino acid sequences of the selected VH CDR1, 2, 3 are shown in SEQ ID NOs: 22-24, respectively, and the amino acid sequences of the selected VL CDR1, 2, 3 are shown in SEQ ID NOs: 1-3, respectively; (3) The amino acid sequences of the selected VH CDR1, 2, 3 are shown in SEQ ID NOs: 25-27, respectively, and the amino acid sequences of the selected VL CDR1, 2, 3 are shown in SEQ ID NOs: 1-3, respectively; (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 112 to 114 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 115 to 117 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 118 to 120 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 121 to 123 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 124 to 126 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 127 to 129 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 130 to 132 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 133 to 135 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 136 to 138 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 139 to 141 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 142 to 144 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; and (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 145 to 147 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively.

[0015] In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 19-21 respectively, and VL comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 22-24 respectively, and VL comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 25-27 respectively, and VL comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 28-30 respectively, and VL comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 112-114 respectively, and VL comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 115-117 respectively, and VL comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 118-120 respectively, and VL comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 121-124 respectively, and VL comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3 respectively.In some embodiments, according to the Kabat numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 127-129 respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 49-51 respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 52-54 respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 55-57 respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 58-60 respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 130-132 respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 133-135 respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 136-138 respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively.In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 139-141, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 142-1144, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering scheme, VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 145-147, respectively, and VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively.

[0016] In one aspect, the present disclosure relates to an antibody or an antigen-binding fragment thereof that binds to MET, comprising a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to a selected VH sequence and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to a selected VL sequence. In some embodiments, the selected VH sequence and the selected VL sequence are one of the following. (1) The selected VH sequence is SEQ ID NO: 67 and the selected VL sequence is SEQ ID NO: 61; (2) The selected VH sequence is SEQ ID NO: 68 and the selected VL sequence is SEQ ID NO: 61; (3) The selected VH sequence is SEQ ID NO: 69 and the selected VL sequence is SEQ ID NO: 61; (4) The selected VH sequence is SEQ ID NO: 70 and the selected VL sequence is SEQ ID NO: 61; (5) The selected VH sequence is SEQ ID NO: 148 and the selected VL sequence is SEQ ID NO: 61; (6) The selected VH sequence is SEQ ID NO: 149 and the selected VL sequence is SEQ ID NO: 61; (7) The selected VH sequence is SEQ ID NO: 150, and the selected VL sequence is SEQ ID NO: 61; (8) The selected VH sequence is SEQ ID NO: 151, and the selected VL sequence is SEQ ID NO: 61; (9) The selected VH sequence is SEQ ID NO: 152, and the selected VL sequence is SEQ ID NO: 61; and (10) The selected VH sequence is SEQ ID NO: 153, and the selected VL sequence is SEQ ID NO: 61.

[0017] In some embodiments, VH comprises the sequence of SEQ ID NO: 67 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 68 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 69 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 70 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 148 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 149 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 150 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 151 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 152 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 153 and VL comprises the sequence of SEQ ID NO: 61. In some embodiments, VH comprises the sequence of SEQ ID NO: 70 and VL comprises the sequence of SEQ ID NO: 61.

[0018] In one aspect, the present disclosure relates to an antibody that binds to MET or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3 that are identical to the VH CDR1, VH CDR2, and VH CDR3 of a selected VH sequence, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 that are identical to the VL CDR1, VL CDR2, and VL CDR3 of a selected VL sequence. In some embodiments, the selected VH sequence and the selected VL sequence are one of the following. (1) The selected VH sequence is SEQ ID NO: 67 and the selected VL sequence is SEQ ID NO: 61; (2) The selected VH sequence is SEQ ID NO: 68 and the selected VL sequence is SEQ ID NO: 61; (3) The selected VH sequence is SEQ ID NO: 69 and the selected VL sequence is SEQ ID NO: 61; (4) The selected VH sequence is SEQ ID NO: 70 and the selected VL sequence is SEQ ID NO: 61; (5) The selected VH sequence is SEQ ID NO: 148 and the selected VL sequence is SEQ ID NO: 61; (6) The selected VH sequence is SEQ ID NO: 149 and the selected VL sequence is SEQ ID NO: 61; (7) The selected VH sequence is SEQ ID NO: 150 and the selected VL sequence is SEQ ID NO: 61; (8) The selected VH sequence is SEQ ID NO: 151 and the selected VL sequence is SEQ ID NO: 61; (9) The selected VH sequence is SEQ ID NO: 152 and the selected VL sequence is SEQ ID NO: 61; and (10) The selected VH sequence is SEQ ID NO: 153 and the selected VL sequence is SEQ ID NO: 61.

[0019] In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to human, monkey, or canine MET. In some embodiments, the antibody or antigen-binding fragment is a human antibody or humanized antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is a single-chain variable fragment (scFv). In some embodiments, the antibody or antigen-binding fragment thereof is a multispecific antibody (e.g., bispecific antibody) or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof further specifically binds to EGFR. In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that cross-competes with the antibody or antigen-binding fragment thereof described herein.

[0020] In one aspect, the present disclosure relates to a nucleic acid comprising a polynucleotide encoding a polypeptide comprising: (1) An immunoglobulin heavy chain or fragment thereof comprising a variable heavy chain region (VH) comprising complementarity-determining regions (CDRs) 1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 19-21, wherein in some embodiments, the VH binds to MET when paired with a variable light chain region (VL) comprising the amino acid sequence shown in SEQ ID NO: 61. (2) An immunoglobulin light chain or fragment thereof comprising a variable light chain region (VL) comprising CDRs 1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 1-3, wherein in some embodiments, the VL binds to MET when paired with a variable heavy chain region (VH) comprising the amino acid sequence shown in SEQ ID NO: 67. (3) An immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 22-24, wherein in some embodiments, the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61. (4) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein in some embodiments, the VL binds to MET when forming a pair with a VH containing the amino acid sequence shown in SEQ ID NO: 68. (5) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 25 to 27, wherein in some embodiments, the VH binds to MET when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61. (6) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein in some embodiments, the VL binds to MET when forming a pair with a VH containing the amino acid sequence shown in SEQ ID NO: 69. (7) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 28 to 30, wherein in some embodiments, the VH binds to MET when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61. (8) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein in some embodiments, the VL binds to MET when forming a pair with a VH containing the amino acid sequence shown in SEQ ID NO: 70. (9) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 49 to 51, wherein in some embodiments, the VH binds to MET when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61. An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 52 to 54, wherein in some embodiments, the VH binds to MET when paired with a VL containing the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 55 to 57, wherein in some embodiments, the VH binds to MET when paired with a VL containing the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 58 to 60, wherein in some embodiments, the VH binds to MET when paired with a VL containing the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 112 to 114, wherein the VH binds to MET when paired with a VL containing the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, An immunoglobulin light chain or a fragment thereof comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein the VL binds to MET when paired with a VH containing the amino acid sequence shown in SEQ ID NO: 148, an immunoglobulin light chain or a fragment thereof, An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 115 to 117, wherein the VH binds to MET when paired with a VL containing the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof, An immunoglobulin light chain or a fragment thereof comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH containing the amino acid sequence shown in SEQ ID NO: 149, the VL binds to MET, the immunoglobulin light chain or a fragment thereof, (17) An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 118 to 120, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET, the immunoglobulin heavy chain or a fragment thereof, (18) An immunoglobulin light chain or a fragment thereof comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH containing the amino acid sequence shown in SEQ ID NO: 150, the VL binds to MET, the immunoglobulin light chain or a fragment thereof, (19) An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 121 to 123, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET, the immunoglobulin heavy chain or a fragment thereof, (20) An immunoglobulin light chain or a fragment thereof comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH containing the amino acid sequence shown in SEQ ID NO: 151, the VL binds to MET, the immunoglobulin light chain or a fragment thereof, (21) An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 124 to 126, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET, the immunoglobulin heavy chain or a fragment thereof, An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH containing the amino acid sequence shown in SEQ ID NO: 152, the VL binds to MET. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 127 to 129, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH containing the amino acid sequence shown in SEQ ID NO: 153, the VL binds to MET. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 130 to 132, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 133 to 135, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 136 to 138, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET. An immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 139-141, wherein the VH binds to MET when pairing with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, (29) An immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 142-144, wherein the VH binds to MET when pairing with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, and (30) An immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 145-147, wherein the VH binds to MET when pairing with a VL comprising the amino acid sequence shown in SEQ ID NO: 61.

[0021] In some embodiments, the VH specifically binds to human, monkey, or canine MET when pairing with the VL. In some embodiments, the immunoglobulin heavy chain or fragment thereof is a heavy chain or fragment thereof of a human immunoglobulin or a humanized immunoglobulin. In some embodiments, the nucleic acid encodes a single-chain variable fragment (scFv). In some embodiments, the nucleic acid is cDNA.

[0022] In one aspect, the present disclosure relates to an antigen-binding protein construct comprising a first antigen-binding domain that specifically binds to EGFR and a second antigen-binding domain that specifically binds to MET. In some embodiments, the first antigen-binding domain comprises a first heavy-chain variable region (VH1) and a first light-chain variable region (VL1), and the second antigen-binding domain comprises a second heavy-chain variable region (VH2) and a second light-chain variable region (VL2).

[0023] In some embodiments, the first heavy chain variable region (VH1) comprises complementarity determining regions (CDR) 1, 2, and 3. In some embodiments, the VH1 CDR1 region comprises an amino acid sequence that is at least 80% identical to the selected VH1 CDR1 amino acid sequence, the VH1 CDR2 region comprises an amino acid sequence that is at least 80% identical to the selected VH1 CDR2 amino acid sequence, and the VH1 CDR3 region comprises an amino acid sequence that is at least 80% identical to the selected VH1 CDR3 amino acid sequence. The first light chain variable region (VL1) comprises CDR1, 2, and 3. In some embodiments, the VL1 CDR1 region comprises an amino acid sequence that is at least 80% identical to the selected VL1 CDR1 amino acid sequence, the VL1 CDR2 region comprises an amino acid sequence that is at least 80% identical to the selected VL1 CDR2 amino acid sequence, and the VL1 CDR3 region comprises an amino acid sequence that is at least 80% identical to the selected VL1 CDR3 amino acid sequence. In some embodiments, the selected VH1 CDR1, 2, and 3 amino acid sequences, and the selected VL1 CDR1, 2, and 3 amino acid sequences are one of the following. (1) The amino acid sequences of the selected VH1 CDR1, 2, 3 are shown in SEQ ID NOs: 4-6 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (2) The amino acid sequences of the selected VH1 CDR1, 2, 3 are shown in SEQ ID NOs: 7-9 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (3) The amino acid sequences of the selected VH1 CDR1, 2, 3 are shown in SEQ ID NOs: 10-12 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (4) The amino acid sequences of the selected VH1 CDR1, 2, 3 are shown in SEQ ID NOs: 13-15 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (5) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 16 to 18, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (6) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 34 to 36, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (7) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 37 to 39, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (8) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 40 to 42, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (9) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 43 to 45, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (10) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 46 to 48, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (11) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 82 to 84, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (12) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (13) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (14) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (15) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (16) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (17) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; and (18) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively.

[0024] In some embodiments, the second heavy chain variable region (VH2) comprises CDR1, 2, and 3. In some embodiments, the VH2 CDR1 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VH2 CDR1. The VH2 CDR2 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VH2 CDR2. The VH2 CDR3 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VH2 CDR3. The second light chain variable region (VL2) comprises CDR1, 2, and 3. In some embodiments, the VL2 CDR1 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VL2 CDR1. The VL2 CDR2 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VL2 CDR2. The VL2 CDR3 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VL2 CDR3. In some embodiments, the amino acid sequences of the selected VH2 CDR1, 2, and 3, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are one of the following. (1) The amino acid sequences of the selected VH2 CDR1, 2, 3 are shown in SEQ ID NOs: 19-21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (2) The amino acid sequences of the selected VH2 CDR1, 2, 3 are shown in SEQ ID NOs: 22-24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (3) The amino acid sequences of the selected VH2 CDR1, 2, 3 are shown in SEQ ID NOs: 25-27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (4) The amino acid sequences of the selected VH2 CDR1, 2, 3 are shown in SEQ ID NOs: 28-30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (5) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49-51 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (6) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52-54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (7) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55-57 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (8) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58-60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (9) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 112-114 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (10) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 115-117 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (11) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 118-120 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (12) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 121-123 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (13) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 124-126 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (14) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 127 to 129 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (15) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 130 to 132 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (16) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 133 to 135 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (17) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 136 to 138 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (18) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 139 to 141 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (19) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 142 to 144 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; and (20) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 145 to 147 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively.

[0025] In some embodiments, the antigen-binding protein construct described herein has one of the following characteristics. (1) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 4-6 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19-21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (2) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 4-6 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22-24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (3) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 4-6 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25-27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (4) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 4-6 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28-30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (5) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 7-9 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19-21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (6) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 7-9 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22-24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (7) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 7-9 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25-27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (8) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 7-9 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28-30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (9) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 10-12 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19-21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (10) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 10-12 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22-24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (11) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 10 to 12 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (12) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 10 to 12 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (13) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 13 to 15 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (14) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 13 to 15 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (15) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 13 to 15 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (16) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 13 to 15 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (17) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 16 to 18 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (18) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 16 to 18 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (19) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 16 to 18 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (20) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 16 to 18 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (21) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 34 to 36, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (22) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 34 to 36, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (23) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 34 to 36, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (24) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 34 to 36, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (25) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 37 to 39, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (26) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 37 to 39 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (27) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 37 to 39 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 31 to 33 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (28) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 37 to 39 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (29) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 40 to 42 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (30) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 40 to 42 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (31) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 40-42 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55-57 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (32) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 40-42 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58-60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (33) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 43-45 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49-51 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (34) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 43-45 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52-54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (35) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 43-45 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55-57 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (36) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 43 to 45 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (37) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 46 to 48 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (38) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 46 to 48 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (39) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 46 to 48 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (40) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 46 to 48 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (41) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 82 to 84 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (42) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 82 to 84 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (43) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 82 to 84 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (44) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 82 to 84 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (45) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (46) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87, respectively. The amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively. The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24, respectively. The amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (47) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87, respectively. The amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively. The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27, respectively. The amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (48) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87, respectively. The amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively. The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30, respectively. The amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (49) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90, respectively. The amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively. The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21, respectively. The amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (50) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90, respectively. The amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively. The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24, respectively. The amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (51) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (52) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (53) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (54) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (55) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (56) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (57) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (58) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (59) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (60) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (61) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (62) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (63) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (64) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (65) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (66) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (67) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (68) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (69) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (70) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (71) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; and (72) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3.

[0026] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 62, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0027] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 62, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0028] In some embodiments, the first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 62, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0029] In some embodiments, the first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 62, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0030] In some embodiments, the first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 63, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0031] In some embodiments, the first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 63, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0032] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 63, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0033] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 63, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0034] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 64, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0035] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 64, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0036] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 64, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0037] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 64, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0038] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 65, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0039] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 65, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0040] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 65, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0041] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 65, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0042] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 66, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0043] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 66, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0044] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 66, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0045] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 66, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0046] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 106, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0047] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 106, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0048] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 106, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0049] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 106, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0050] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 107, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0051] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 107, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0052] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 107, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0053] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 107, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0054] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 108, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0055] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 108, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0056] In some embodiments, the first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 108, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0057] In some embodiments, the first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 108, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0058] In some embodiments, the first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 109, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0059] In some embodiments, the first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 109, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0060] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 109, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0061] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 109, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61.

[0062] In some embodiments, the antigen-binding protein construct is a multispecific antibody (e.g., a bispecific antibody). In some embodiments, the first antigen-binding domain is a single-chain variable fragment (scFv), and / or the second antigen-binding domain is an scFv. In some embodiments, the first light chain variable region and the second light chain variable region are identical.

[0063] In one aspect, the disclosure relates to a vector comprising one or more of the nucleic acids described herein, a nucleic acid encoding an antibody or antigen-binding fragment thereof described herein, or a nucleic acid encoding an antigen-binding protein construct described herein.

[0064] In one aspect, the disclosure relates to a cell comprising a vector described herein. In some embodiments, the cell is a CHO cell.

[0065] In one aspect, the present disclosure relates to a cell comprising one or more of the nucleic acids described herein, a nucleic acid encoding an antibody or an antigen-binding fragment thereof described herein, or a nucleic acid encoding an antigen-binding protein construct described herein.

[0066] In one aspect, the present disclosure relates to a method for producing an antibody or an antigen-binding fragment thereof, or an antigen-binding protein construct, comprising: (a) culturing a cell described herein under conditions sufficient for the cell to produce an antibody or an antigen-binding fragment thereof or an antigen-binding protein construct; and (b) recovering the antibody or an antigen-binding fragment thereof or an antigen-binding protein construct produced by the cell.

[0067] In one aspect, the present disclosure relates to an antibody-drug conjugate (ADC) comprising: (a) an antibody or an antigen-binding fragment thereof described herein, or (b) a therapeutic agent that covalently binds to an antigen-binding protein construct described herein. In some embodiments, the therapeutic agent is a cytotoxic agent or a cytostatic agent. In some embodiments, the therapeutic agent is MMAE or MMAF.

[0068] In some embodiments, the therapeutic agent is selected from the following.

Chemical formula

[0069] In some embodiments, the therapeutic agent is linked to an antibody or an antigen-binding fragment thereof, or an antigen-binding protein construct via a linker. In some embodiments, the linker has the following structure.

Chemical formula

[0070] In some embodiments, the antibody-drug conjugate has the following structure.

Chemical formula

[0071] In some embodiments, n = 1, 2, 3, 4, 5, 6, 7, or 8, and in some embodiments, "Ab" represents an antibody or antigen-binding fragment thereof described herein, or an antigen-binding protein construct.

[0072] In one aspect, the present disclosure relates to a method of treating a subject having cancer, the method comprising administering to the subject a composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment thereof described herein, an antigen-binding protein construct described herein, or an antibody-drug conjugate described herein. In some embodiments, the subject has a cancer that expresses EGFR and / or MET. In some embodiments, the cancer is a solid tumor, lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, or lung carcinoma), gastric cancer (e.g., gastric carcinoma), skin cancer (e.g., cutaneous carcinoma), colorectal cancer, breast cancer, head and neck cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, CNS cancer, liver cancer, nasopharyngeal cancer, or brain tumor. In some embodiments, the subject is human. In some embodiments, the method further comprises administering an anti-PD1 antibody to the subject. In some embodiments, the method further comprises subjecting the subject to chemotherapy.

[0073] In one aspect, the present disclosure relates to a method of reducing tumor growth rate, the method comprising contacting tumor cells with a composition comprising an effective amount of an antibody or antigen-binding fragment thereof described herein, an antigen-binding protein construct described herein, or an antibody-drug conjugate described herein.

[0074] In one aspect, the present disclosure relates to a method of killing tumor cells, the method comprising contacting tumor cells with a composition comprising an effective amount of an antibody or antigen-binding fragment thereof described herein, an antigen-binding protein construct described herein, or an antibody-drug conjugate described herein.

[0075] In one aspect, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) an antibody or an antigen-binding fragment thereof described herein, (b) an antigen-binding protein construct described herein, and / or (c) an antibody-drug conjugate described herein.

[0076] In one aspect, the present disclosure relates to an antibody-drug conjugate (ADC) comprising a therapeutic agent covalently attached to a bispecific antibody or an antigen-binding fragment thereof, the bispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds to EGFR and a second antigen-binding domain that specifically binds to MET. In some embodiments, the drug-to-antibody ratio (DAR) is about 4 or 8.

[0077] In one aspect, the present disclosure provides a nucleic acid comprising a polynucleotide encoding any polypeptide described herein. In some embodiments, the nucleic acid encodes a bispecific antibody. In some embodiments, the nucleic acid is cDNA.

[0078] In one aspect, the present disclosure provides a vector comprising one or more of the nucleic acids described herein.

[0079] In one aspect, the present disclosure provides a cell comprising the vector described herein. In some embodiments, the cell is a CHO cell. In one aspect, the present disclosure provides a cell comprising one or more of the nucleic acids described herein.

[0080] As used herein, the term "antigen-binding protein construct" refers to (i) a single polypeptide comprising at least two different antigen-binding domains, or (ii) a complex of two or more polypeptides (e.g., identical or different polypeptides) that together form at least two different antigen-binding domains. Non-limiting examples and aspects of antigen-binding protein constructs are described herein. Further examples and aspects of antigen-binding protein constructs are well known in the art.

[0081] As used herein, the term "antigen-binding domain" means one or more protein domains (e.g., formed from amino acids derived from a single polypeptide or from two or more polypeptides (e.g., the same or different polypeptides) that can specifically bind to one or more different antigens (e.g., effector antigens or control antigens)). In some examples, the antigen-binding domain can bind to an antigen or epitope with specificity and affinity similar to that of a naturally occurring antibody. In some embodiments, the antigen-binding domain can be an antibody or a fragment thereof. An example of an antigen-binding domain is an antigen-binding domain formed by a VH-VL dimer. In some embodiments, the antigen-binding domain can include an alternative scaffold. In some embodiments, the antigen-binding domain is a VHH. Non-limiting examples of antigen-binding domains are described herein. Further examples of antigen-binding domains are well known in the art. In some examples, the antigen-binding domain can bind to a single antigen (e.g., one of the effector antigen and the control antigen). In other examples, the antigen-binding domain can bind to two different antigens (e.g., the effector antigen and the control antigen).

[0082] The term "antibody" is used herein in its broadest sense and includes certain types of immunoglobulin molecules that include one or more antigen-binding domains that specifically bind to an antigen or epitope. Antibodies specifically include, for example, intact antibodies (e.g., intact immunoglobulins), antibody fragments, bispecific antibodies, and multispecific antibodies. An example of an antibody is a protein complex that includes two heavy chains and two light chains. Further examples of antibodies are described herein.

[0083] As used herein, the term "multispecific antigen-binding protein construct" refers to an antigen-binding protein construct that includes two or more different antigen-binding domains that collectively and specifically bind to two or more different epitopes. The two or more different epitopes may be epitopes on the same antigen (e.g., a single polypeptide present on the surface of a cell), or may be epitopes on different antigens (e.g., different proteins present on the surface of the same cell, or on the surfaces of different cells). In some embodiments, the multispecific antigen-binding protein construct binds to two different epitopes (i.e., a "bispecific antigen-binding protein construct"). In some embodiments, the multispecific antigen-binding protein construct binds to three different epitopes (i.e., a "trispecific antigen-binding protein construct"). In some embodiments, the multispecific antigen-binding protein construct binds to four different epitopes (i.e., a "tetraspecific antigen-binding protein construct"). In some embodiments, the multispecific antigen-binding protein construct binds to five different epitopes (i.e., a "pentaspecific antigen-binding protein construct"). Each binding specificity can be present at any suitable valence. Non-limiting examples of multispecific antigen-binding protein constructs are described herein.

[0084] As used herein, the term "bispecific antibody" means an antibody that binds to two different epitopes. The epitopes can be present on the same antigen or on different antigens.

[0085] As used herein, the term "common light chain" means one light chain that can interact with two or more different heavy chains that form different antigen-binding sites, and these different antigen-binding sites can specifically bind to different antigens or epitopes. Similarly, the term "common light chain variable region" means one light chain variable region that can interact with two or more different heavy chain variable regions that form different antigen-binding sites, and these different antigen-binding sites can specifically bind to different antigens or epitopes. In some embodiments, the antigen-binding construct can have a common light chain. In some embodiments, the antigen-binding construct can have a common light chain variable region.

[0086] Unless defined otherwise, 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 belongs. Methods and materials for use in the present invention are described herein, and other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, this specification, including definitions, will control.

[0087] Other features and advantages of the present invention will become apparent from the following detailed description, drawings, and claims.

Brief Description of the Drawings

[0088]

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Modes for Carrying Out the Invention

[0089] A bispecific antibody or an antigen-binding fragment thereof is an artificial protein that can simultaneously bind to two different epitopes (e.g., on two different antigens). In some embodiments, the bispecific antibody or an antigen-binding fragment thereof can have two arms. Each arm can have one heavy-chain variable region and one light-chain variable region and can form an antigen-binding domain (or antigen-binding region). In some embodiments, the bispecific antibody has a common light chain.

[0090] The present disclosure relates to an anti-EGFR antibody or an antigen-binding fragment thereof, an anti-MET antibody or an antigen-binding fragment thereof, an antigen-binding protein construct (e.g., a bispecific antibody or an antigen-binding fragment thereof) that specifically binds to two different antigens (e.g., EGFR and MET), and an antibody-drug conjugate.

[0091] Anti-EGFR / MET antigen-binding protein construct The epidermal growth factor receptor (EGFR, ErbBI, or HER1) is a 170 kDa type I transmembrane glycoprotein encoded by the c-erbBl proto-oncogene. The epidermal growth factor receptor is a member of the ErbB receptor family, a subfamily of four closely related receptor-type tyrosine kinases: EGFR (ErbB-1), HER2 / neu (ErbB-2), Her3 (ErbB-3), and Her4 (ErbB-4). In many types of cancer, mutations that affect the expression or activity of EGFR can cause cancer. EGFR signaling is initiated by ligand binding, followed by induced structural changes, homodimerization or heterodimerization of the receptor with other ErbB family members, and trans-autophosphorylation of the receptor, which initiates a signaling cascade that ultimately affects different cellular functions such as cell proliferation and survival. Increases in the expression or kinase activity of EGFR are associated with different human cancers, and EGFR has become an attractive target for therapeutic intervention. Increases in both the copy number of the EGFR gene and protein expression are associated with a good response to the EGFR tyrosine kinase inhibitor, IRESSA TM (gefitinib).

[0092] MET, also known as c-Met, tyrosine protein kinase Met, or hepatocyte growth factor receptor (HGFR), is a protein encoded by the MET gene in humans. This protein has tyrosine kinase activity. The major single-chain precursor protein is cleaved after translation to generate an α subunit and a β subunit, which form a mature receptor through disulfide bonding. Activation of MET by its ligand, hepatocyte growth factor (HGF), stimulates numerous cellular processes such as proliferation, motility, invasion, metastasis, epithelial-mesenchymal transition, angiogenesis / wound healing, and tissue regeneration. Although the exact stoichiometry of HGF:MET binding is unknown, it is generally thought that two HGF molecules bind to two MET molecules, causing dimerization and autophosphorylation of the receptor at tyrosines 1230, 1234, and 1235. Ligand-independent MET autophosphorylation can also occur due to gene amplification, mutation, or overexpression of the receptor.

[0093] MET is frequently amplified, mutated, or overexpressed in many types of cancer, including gastric, lung, colorectal, breast, bladder, head and neck, ovarian, prostate, thyroid, pancreatic, and CNS cancers. Missense mutations typically located in the kinase domain are commonly found in hereditary papillary renal cell carcinoma (PRCC) and 13% of sporadic PRCC (Schmidt et al, Oncogene 18:2343-2350, 1999), and MET mutations located in the semaphorin or juxtamembrane domain of MET are frequently found in gastric, head and neck, liver, ovarian, NSCLC, and thyroid cancers. MET amplification is detected in brain tumors, colorectal cancer, gastric cancer, and lung cancer, and is often correlated with disease progression. Up to 4% and 20% of non-small cell lung cancer (NSCLC) and gastric cancer, respectively, show MET amplification. Overexpression of MET is also frequently observed in lung cancer. Furthermore, in clinical samples, nearly half of lung adenocarcinomas showed high levels of both MET and HGF, both of which were correlated with increased tumor growth rate, metastasis, and poor prognosis.

[0094] Approximately 60% of tumors that are resistant to EGF tyrosine kinase inhibitors increase MET expression, amplify MET, or increase HGF, the only known ligand of MET, suggesting the existence of a compensatory pathway for EGFR via MET. MET amplification was first identified in cultured cells that were resistant to gefitinib, an EGFR kinase inhibitor, and showed improved survival through the Her3 pathway. This was further verified in clinical samples, with 9 out of 43 patients who developed resistance to either erlotinib or gefitinib showing MET amplification.

[0095] Aberrant MET signaling is thought to be involved in the development / progression of many human cancers. This is due to overexpression of MET, activating mutations of MET, transactivation, autocrine or paracrine signaling, or amplification of the MET gene. Through research on the outcomes of cancer treatment, a significant relationship between EGFR and MET signaling has been recognized. MET plays an important role in developing resistance to targeted therapies, including those targeting EGFR. Similarly, downstream gene mutations such as EGFR and KRAS, histological transformation, and activation of alternative pathways including the MET signaling pathway have been identified as mechanisms of resistance to EGFR-targeted therapies. Consequently, blocking one receptor tends to upregulate other receptors, leading to resistance to monotherapy. Amplification of MET and / or high-level expression of the HGF ligand have been observed in NSCLC patients with intrinsic or acquired resistance to EGFR tyrosine kinase inhibitors, including erlotinib and gefitinib. Conversely, MET-amplified lung cancer cells that are exposed to MET inhibitors for a long time develop resistance via the EGFR pathway. Signal transduction crosstalk between EGFR and Met may improve the outcomes of patients with MET- and EGFR-driven cancers by inhibiting both receptors in combination. Furthermore, simultaneous inhibition may be able to overcome or delay treatment resistance compared to blocking only one pathway.

[0096] When ligands such as EGF bind to EGFR, it stimulates receptor dimerization, autophosphorylation, activation of the intracellular cytoplasmic tyrosine kinase domain of the receptor, and the initiation of multiple signal transduction and transactivation pathways involved in DNA synthesis (gene activation) and the regulation of cell cycle progression or division. Inhibition of EGFR signaling may lead to inhibition of one or more EGFRs. In some embodiments, EGFR ligands include EGF, TGFα, heparin-binding EGF (HB-EGF), amphiregulin (AR), and epiregulin (EPI).

[0097] When HGF binds to MET, it stimulates receptor dimerization, autophosphorylation, activation of the intracellular cytoplasmic tyrosine kinase domain of the receptor, and the initiation of multiple signal transduction and transactivation pathways involved in DNA synthesis (gene activation) and the regulation of cell cycle progression or division. Inhibition of MET signaling may lead to inhibition of one or more MET downstream signal transduction pathways. Thus, neutralizing MET can have various effects including inhibition of cell growth and differentiation, angiogenesis, cell motility, and metastasis.

[0098] Regarding the roles of EGFR and MET in cancer, for example, they are described in WO2014081954A1, WO2008 / 127710, WO2009 / 111691, WO2009 / 126834, WO2010 / 039248, WO2010 / 115551, and US2009 / 0042906; Engelman et al. “MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.” science 316.5827(2007):1039-1043; Bean et al. “MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib.” Proceedings of the National Academy of Sciences 104.52(2007):20932-20937, and the entirety of each of these is incorporated herein by reference.

[0099] Anti-EGFR antibodies (e.g., E-1C12 ("1C12"), E-1G11 ("1G11"), E-6C4 ("6C4"), E-2B7 ("2B7"), E-3A8 ("3A8"), E-3D8 ("3D8"), E-9A6 ("9A6"), E-9D2 ("9D2"), E-9F3 ("9F3"), and E-9H2 ("9H2")) and anti-MET antibodies (e.g., M-1C5 ("1C5"), M-2F11 ("2F11"), M-2G10 ("2G10"), M-1E9 ("1E9"), M-2F12 ("2F12"), M-6D12 ("6D12"), M-6E6 ("6E6"), M-7D3 ("7D3"), M-8D9 ("8D9"), M-8E2 ("8E2"), M-8H10 ("8H10")) are human antibodies produced in RenLite (registered trademark) mice in the present disclosure. Since these antibodies have the same fully humanized common light chain, anti-EGFR / MET bispecific antibodies having a heavy chain variable region targeting EGFR (e.g., any of the VHs targeting EGFR described herein), a heavy chain variable region targeting MET (e.g., any of the VHs targeting MET described herein), and two identical common light chain variable regions were generated. The exemplary bispecific antibodies obtained are shown in Figure 19. In some embodiments, the anti-EGFR antigen-binding domain includes the CDRs of the anti-EGFR antibody as shown in the first row of Figure 19. In some embodiments, the anti-MET antigen-binding domain includes the CDRs of the anti-MET antibody as shown in the first column of Figure 19. In some embodiments, the anti-EGFR antigen-binding domain includes the VH and VL of the anti-EGFR antibody as shown in the first row of Figure 19. In some embodiments, the anti-MET antigen-binding domain includes the VH and VL of the anti-MET antibody as shown in the first column of Figure 19. For example, E-1G11-M-2F11 refers to a bispecific anti-EGFR / MET antibody comprising an anti-EGFR antigen-binding domain derived from E-1G11 and an anti-MET antigen-binding domain derived from M-2F11. In some embodiments, the anti-EGFR antigen-binding domain includes the CDRs of E-1G11. In some embodiments, the anti-MET antigen-binding domain includes the CDRs of M-2F11.In some embodiments, the anti-EGFR antigen-binding domain comprises the VH and VL of E-1G11. In some embodiments, the anti-MET antigen-binding domain comprises the VH and VL of M-2F11.

[0100] The bispecific antibodies described herein can be designed to have an IgG1 subtype structure with a knob-into-hole (KIH) mutation, which promotes heterodimerization and avoids mispairing between the two heavy chains.

[0101] In some embodiments, the bispecific antibody has a higher endocytosis ratio than the corresponding monoclonal antibody or control bispecific antibody.

[0102] In some embodiments, the bispecific antibodies described herein can be conjugated to a therapeutic agent to form an antibody-drug conjugate (ADC). In some embodiments, the DAR of the ADCs described herein is about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, or about 9.0. In some embodiments, the DAR of the ADCs described herein is from about 3.5 to about 4.5, about 3.6 to about 4.5, about 3.7 to about 4.5, about 3.8 to about 4.5, about 3.9 to about 4.5, about 4.0 to about 4.5, about 4.1 to about 4.5, about 4.2 to about 4.5, about 4.3 to about 4.5, about 4.4 to about 4.5, about 3.5 to about 4.4, about 3.6 to about 4.4, about 3.7 to about 4.4, about 3.8 to about 4.4, about 3.9 to about 4.4, about 4.0 to about 4.4, about 4.1 to about 4.4, about 4.2 to about 4.4, about 4.3 to about 4.4, about 3.5 to about 4.3, about 3.6 to about 4.3, about 3.7 to about 4.3, about 3.8 to about 4.3, about 3.9 to about 4.3, about 4.0 to about 4.3, about 4.1 to about 4.3, about 4.2 to about 4.3, about 3.5 to about 4.2, about 3.6 to about 4.2, about 3.7 to about 4.2, about 3.8 to about 4.2, about 3.9 to about 4.2, about 4.0 to about 4.2, about 4.1 to about 4.2, about 3.5 to about 4.1, about 3.6 to about 4.1, about 3.7 to about 4.1, about 3.8 to about 4.1, about 3.9 to about 4.1, about 4.0 to about 4.1, about 3.5 to about 4.0, about 3.6 to about 4.0, about 3.7 to about 4.0, about 3.8 to about 4.0, about 3.9 to about 4.0, about 3.5 to about 3.9, about 3.6 to about 3.9, about 3.7 to about 3.9, about 3.8 to about 3.9, about 3.5 to about 3.8, about 3.6 to about 3.8, about 3.7 to about 3.8, about 3.5 to about 3.7, about 3.6 to about 3.7, or about 3.5 to about 3.6. In some embodiments, the DAR of the ADCs described herein is from about 7.5 to about 8.5, from about 7.6 to about 8.5, from about 7.7 to about 8.5, from about 7.8 to about 8.5, from about 7.9 to about 8.5, from about 8.0 to about 8.5, from about 8.1 to about 8.5, from about 8.2 to about 8.5, from about 8.3 to about 8.5, from about 8.4 to about 8.5, from about 7.5 to about 8.4, from about 7.6 to about 8.4, from about 7.7 to about 8.4, from about 7.8 to about 8.4, from about 7.9 to about 8.4, from about 8.0 to about 8.4, from about 8.1 to about 8.4, from about 8.2 to about 8.4, from about 8.3 to about 8.4, from about 7.5 to about 8.3, from about 7.6 to about 8.3, from about 7.7 to about 8.3, from about 7.8 to about 8.3, from about 7.9 to about 8.3, from about 8.0 to about 8.3, from about 8.1 to about 8.3, from about 8.2 to about 8.3, from about 7.5 to about 8.2, from about 7.6 to about 8.2, from about 7.7 to about 8.2, from about 7.8 to about 8.2, from about 7.9 to about 8.2, from about 8.0 to about 8.2, from about 8.1 to about 8.2, from about 7.5 to about 8.1, from about 7.6 to about 8.1, from about 7.7 to about 8.1, from about 7.8 to about 8.1, from about 7.9 to about 8.1, from about 8.0 to about 8.1, from about 7.5 to about 8.0, from about 7.6 to about 8.0, from about 7.7 to about 8.0, from about 7.8 to about 8.0, from about 7.9 to about 8.0, from about 7.5 to about 7.9, from about 7.6 to about 7.9, from about 7.7 to about 7.9, from about 7.8 to about 7.9, from about 7.5 to about 7.8, from about 7.6 to about 7.8, from about 7.7 to about 7.8, from about 7.5 to about 7.7, from about 7.6 to about 7.7, or from about 7.5 to about 7.6.

[0103] In some embodiments, the anti-EGFR / MET ADCs described herein can effectively inhibit the proliferation of in vitro cancer cells at a concentration of less than 10 μg / mL, less than 3.33 μg / mL, less than 1.11 μg / mL, less than 0.37 μg / mL, less than 0.12 μg / mL, less than 0.04 μg / mL, or less than 0.01 μg / mL. In some embodiments, the anti-EGFR / MET ADCs described herein can inhibit the proliferation of in vivo cancer cells (e.g., lung cancer, gastric cancer, or skin cancer) in a xenograft mouse model at a dose level of less than 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, or 1 mg / kg.

[0104] In some embodiments, the bispecific antibodies or antigen-binding fragments thereof described herein have a common light chain.

[0105] Anti-MET antibodies and antigen-binding fragments The present disclosure provides antibodies that specifically bind to MET and antigen-binding fragments thereof. Anti-EGFR / MET antigen-binding protein constructs (e.g., bispecific antibodies) can include antigen-binding regions derived from these antibodies.

[0106] The antibodies and antigen-binding fragments described herein are capable of binding to MET. The present disclosure provides anti-MET antibodies M-1C5 ("1C5"), M-2F11 ("2F11"), M-2G10 ("2G10"), M-1E9 ("1E9"), M-2F12 ("2F12"), M-6D12 ("6D12"), M-6E6 ("6E6"), M-7D3 ("7D3"), M-8D9 ("8D9"), M-8E2 ("8E2"), and M-8H10 ("8H10") and antibodies derived therefrom.

[0107] CDR sequences for 2F11 and antibodies derived from 2F11 (e.g., human antibodies) include, as defined by Kabat numbering, CDRs of the heavy chain variable domain, SEQ ID NOs: 19-21, and CDRs of the light chain variable domain, SEQ ID NOs: 1-3. The CDRs can also be defined by the Chothia system. According to Chothia numbering, the CDR sequences of the heavy chain variable domain are shown as SEQ ID NOs: 49-51, respectively, and the CDR sequences of the light chain variable domain are shown as SEQ ID NOs: 1-3. The human light chain variable region and human heavy chain variable region for 2F11 are shown as SEQ ID NOs: 61 and 67, respectively.

[0108] As for the CDR sequences for 2G10 and antibodies derived from 2G10, the CDRs of the heavy chain variable domain defined by Kabat numbering, SEQ ID NOs: 22 to 24, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3, can be mentioned. According to Chothia numbering, the CDR sequences of the heavy chain variable domain are shown in SEQ ID NOs: 52 to 54 respectively, and the CDRs of the light chain variable domain are shown in SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region for 2G10 are shown in SEQ ID NO: 61 and SEQ ID NO: 68 respectively.

[0109] As for the CDR sequences for 1E9 and antibodies derived from 1E9, the CDRs of the heavy chain variable domain defined by Kabat numbering, SEQ ID NOs: 25 to 27, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3, can be mentioned. According to Chothia numbering, the CDR sequences of the heavy chain variable domain are shown in SEQ ID NOs: 55 to 57 respectively, and the CDRs of the light chain variable domain are shown in SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region for 1E9 are shown in SEQ ID NO: 61 and SEQ ID NO: 69 respectively.

[0110] As for the CDR sequences for 2F12 and antibodies derived from 2F12, the CDRs of the heavy chain variable domain defined by Kabat numbering, SEQ ID NOs: 28 to 30, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3, can be mentioned. According to Chothia numbering, the CDR sequences of the heavy chain variable domain are shown in SEQ ID NOs: 58 to 60 respectively, and the CDRs of the light chain variable domain are shown in SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region for 2F12 are shown in SEQ ID NO: 61 and SEQ ID NO: 70 respectively.

[0111] For the CDR sequences against 6D12 and antibodies derived from 6D12 (e.g., human antibodies), there are the CDRs of the heavy chain variable domain defined by the Kabat numbering, SEQ ID NOs: 112 to 114, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3. The CDRs can also be defined by the Chothia system. According to the Chothia numbering, the CDR sequences of the heavy chain variable domain are shown in SEQ ID NOs: 130 to 132 respectively, and the CDR sequences of the light chain variable domain are shown in SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region against 6D12 are shown in SEQ ID NOs: 61 and 148 respectively.

[0112] For the CDR sequences against 6E6 and antibodies derived from 6E6 (e.g., human antibodies), there are the CDRs of the heavy chain variable domain defined by the Kabat numbering, SEQ ID NOs: 115 to 117, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3. The CDRs can also be defined by the Chothia system. According to the Chothia numbering, the CDR sequences of the heavy chain variable domain are shown in SEQ ID NOs: 133 to 135 respectively, and the CDR sequences of the light chain variable domain are shown in SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region against 6E6 are shown in SEQ ID NOs: 61 and 149 respectively.

[0113] For the CDR sequences against 7D3 and antibodies derived from 7D3 (e.g., human antibodies), there are the CDRs of the heavy chain variable domain defined by the Kabat numbering, SEQ ID NOs: 118 to 120, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3. The CDRs can also be defined by the Chothia system. According to the Chothia numbering, the CDR sequences of the heavy chain variable domain are shown in SEQ ID NOs: 136 to 138 respectively, and the CDRs of the light chain variable domain are shown in SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region against 7D3 are shown in SEQ ID NOs: 61 and 150 respectively.

[0114] As the CDR sequences for 8D9 and antibodies derived from 8D9 (e.g., human antibodies), there are the CDRs of the heavy chain variable domain defined by Kabat numbering, SEQ ID NOs: 121 to 123, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3. The CDRs can also be defined by the Chothia system. According to Chothia numbering, the CDR sequences of the heavy chain variable domain are shown as SEQ ID NOs: 139 to 141 respectively, and the CDR sequences of the light chain variable domain are shown as SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region for 8D9 are shown as SEQ ID NOs: 61 and 151 respectively.

[0115] As the CDR sequences for 8E2 and antibodies derived from 8E2 (e.g., human antibodies), there are the CDRs of the heavy chain variable domain defined by Kabat numbering, SEQ ID NOs: 124 to 126, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3. The CDRs can also be defined by the Chothia system. According to Chothia numbering, the CDR sequences of the heavy chain variable domain are shown as SEQ ID NOs: 142 to 144 respectively, and the CDR sequences of the light chain variable domain are shown as SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region for 8E2 are shown as SEQ ID NOs: 61 and 152 respectively.

[0116] As the CDR sequences for 8H10 and antibodies derived from 8H10 (e.g., human antibodies), there are the CDRs of the heavy chain variable domain defined by Kabat numbering, SEQ ID NOs: 127 to 129, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3. The CDRs can also be defined by the Chothia system. According to Chothia numbering, the CDR sequences of the heavy chain variable domain are shown as SEQ ID NOs: 145 to 147 respectively, and the CDRs of the light chain variable domain are shown as SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region for 8H10 are shown as SEQ ID NOs: 61 and 153 respectively.

[0117] Furthermore, in some embodiments, the antibodies or antigen-binding fragments thereof described herein can also contain 1, 2, or 3 heavy chain variable region CDRs selected from the group consisting of SEQ ID NOs: 19-21, SEQ ID NOs: 22-24, SEQ ID NOs: 25-27, SEQ ID NOs: 28-30, SEQ ID NOs: 49-51, SEQ ID NOs: 52-54, SEQ ID NOs: 55-57, SEQ ID NOs: 58-60, SEQ ID NOs: 112-114, SEQ ID NOs: 115-117, SEQ ID NOs: 118-120, SEQ ID NOs: 121-123, SEQ ID NOs: 124-126, SEQ ID NOs: 127-129, SEQ ID NOs: 130-132, SEQ ID NOs: 133-135, SEQ ID NOs: 136-138, SEQ ID NOs: 139-141, SEQ ID NOs: 142-144, and SEQ ID NOs: 145-147, and / or 1, 2, or 3 light chain variable region CDRs selected from the group consisting of SEQ ID NOs: 1-3.

[0118] In some embodiments, the antibody is a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein the CDR1 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VH CDR1, the CDR2 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VH CDR2, and the CDR3 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VH CDR3, and a light chain variable region (VL) comprising CDRs 1, 2, and 3, wherein the CDR1 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VL CDR1, the CDR2 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VL CDR2, and the CDR3 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VL CDR3. The amino acid sequences of the selected VH CDRs 1, 2, and 3, and the selected VL CDRs 1, 2, and 3 are shown in FIGS. 8 and 10 (Kabat CDRs), and FIGS. 9 and 10 (Chothia CDRs).

[0119] In some embodiments, the antibody or antigen-binding fragment described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 19 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 20 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 21 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0120] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy-chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 22 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 23 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 24 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0121] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy-chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 25 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 26 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 27 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0122] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy-chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 28 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 29 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 30 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0123] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy-chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 49 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 50 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 51 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0124] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy-chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 52 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 53 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 54 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0125] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy-chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 55 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 56 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 57 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0126] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy-chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 58 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 59 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 60 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0127] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a light-chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 112 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 113 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 114 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0128] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 115 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 116 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 117 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0129] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 118 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 119 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 120 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0130] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 121 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 122 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 123 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0131] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 124 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 125 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 126 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0132] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 127 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 128 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 129 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0133] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 130 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 131 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 132 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0134] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 133 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 134 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 135 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0135] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 136 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 137 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 138 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0136] In some embodiments, the antibody or antigen-binding fragment described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 139 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 140 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 141 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0137] In some embodiments, the antibody or antigen-binding fragment described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 142 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 143 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 144 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0138] In some embodiments, the antibody or antigen-binding fragment described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 145 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 146 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 147 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0139] In some embodiments, the antibody or antigen-binding fragment described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 1 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 2 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 3 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0140] Insertions, deletions, and substitutions can be present within the CDR sequences or at one or both ends of the CDR sequences.

[0141] The present disclosure also provides an antibody that binds to MET or an antigen-binding fragment thereof. The antibody or antigen-binding fragment thereof contains, or consists of, a heavy chain variable region (VH) having an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VH sequence, and a light chain variable region (VL) having an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VL sequence. In some embodiments, the selected VH sequence is SEQ ID NO: 67, 68, 69, 70, 148, 149, 150, 151, 152, or 153, and the selected VL sequence is SEQ ID NO: 61.

[0142] In some embodiments, the antibody or antigen-binding fragment thereof can have three VH CDRs that are identical to the CDRs of any VH sequence described herein. In some embodiments, the antibody or antigen-binding fragment thereof can have three VL CDRs that are identical to the CDRs of any VL sequence described herein.

[0143] The present disclosure also provides a nucleic acid comprising a polynucleotide encoding an immunoglobulin heavy chain or a polypeptide comprising an immunoglobulin heavy chain. The immunoglobulin heavy chain or immunoglobulin light chain contains the CDRs shown in FIG. 8, FIG. 9, or FIG. 10, or has the sequence shown in FIG. 11. When the polypeptide pairs with a corresponding polypeptide (e.g., a corresponding heavy chain variable region, or a corresponding light chain variable region), the paired polypeptide binds to MET.

[0144] The anti-MET antibodies and antigen-binding fragments can also be antibody variants (including derivatives and conjugates) of the antibody or antibody fragment, as well as multispecific (e.g., bispecific) antibodies or antibody fragments. The additional antibodies provided herein are polyclonal, monoclonal, multispecific (multimeric, e.g., bispecific), human antibodies, chimeric antibodies (e.g., human-mouse chimeric), single-chain antibodies, antibodies produced intracellularly (i.e., intrabodies), and antigen-binding fragments thereof. The antibody or its antigen-binding fragment can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. In some embodiments, the antibody or its antigen-binding fragment is an IgG (e.g., IgG1) antibody or its antigen-binding fragment.

[0145] Antibody fragments are suitable for use in the provided methods as long as they retain the desired affinity and specificity of the full-length antibody. Thus, fragments of antibodies that bind MET retain the ability to bind MET. An Fv fragment is an antibody fragment that contains the complete antigen recognition and binding site. This region is composed of a dimer of one heavy-chain variable domain and one light-chain variable domain closely associated, which can be covalently linked, for example, in an scFv. In this configuration, the three CDRs of each variable domain interact to define the antigen-binding site on the surface of the VH-VL dimer. Overall, the six CDRs or subsets thereof together confer the antigen-binding specificity for the antibody. However, even a single variable domain (or half of an Fv containing only three CDRs specific for a particular antigen) can have the ability to recognize and bind an antigen, but usually with lower affinity than the entire binding site.

[0146] Anti-EGFR antibodies and antigen-binding fragments The present disclosure provides several antibodies and antigen-binding fragments thereof that specifically bind to EGFR. In some embodiments, an anti-EGFR / MET antigen-binding protein construct (e.g., a bispecific antibody) can include an antigen-binding region derived from these antibodies.

[0147] The antibodies and antigen-binding fragments described herein are capable of binding to EGFR. The present disclosure provides, for example, anti-EGFR antibodies E-1C12 (“1C12”), E-1G11 (“1G11”), E-6C4 (“6C4”), E-2B7 (“2B7”), E-3A8 (“3A8”), E-3D8 (“3D8”), E-9A6 (“9A6”), E-9D2 (“9D2”), E-9F3 (“9F3”), and E-9H2 (“9H2”), and antibodies derived therefrom.

[0148] Examples of CDR sequences for 1G11 and antibodies derived from 1G11 (e.g., human antibodies) include the CDRs of the heavy-chain variable domain defined by Kabat numbering, SEQ ID NOs: 4-6, and the CDRs of the light-chain variable domain, SEQ ID NOs: 1-3. The CDRs can also be defined by the Chothia system. According to Chothia numbering, the CDR sequences of the heavy-chain variable domain are shown in SEQ ID NOs: 34-36, respectively, and the CDR sequences of the light-chain variable domain are shown in SEQ ID NOs: 1-3. The human light-chain variable region and human heavy-chain variable region for 1G11 are shown in SEQ ID NOs: 61 and 62, respectively.

[0149] Examples of CDR sequences for 6C4 and antibodies derived from 6C4 (e.g., human antibodies) include the CDRs of the heavy-chain variable domain defined by Kabat numbering, SEQ ID NOs: 7-9, and the CDRs of the light-chain variable domain, SEQ ID NOs: 1-3. According to Chothia numbering, the CDR sequences of the heavy-chain variable domain are shown in SEQ ID NOs: 37-38, respectively, and the CDRs of the light-chain variable domain are shown in SEQ ID NOs: 1-3. The human light-chain variable region and human heavy-chain variable region for 6C4 are shown in SEQ ID NOs: 61 and 63, respectively.

[0150] As for the CDR sequences for 2B7 and antibodies derived from 2B7 (e.g., human antibodies), the CDRs of the heavy chain variable domain defined by Kabat numbering, SEQ ID NOs: 10 to 12, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3, can be mentioned. According to Chothia numbering, the CDR sequences of the heavy chain variable domain are shown in SEQ ID NOs: 40 to 42 respectively, and the CDRs of the light chain variable domain are shown in SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region for 2B8 are shown in SEQ ID NOs: 61 and 64 respectively.

[0151] As for the CDR sequences for 3A8 and antibodies derived from 3A8 (e.g., human antibodies), the CDRs of the heavy chain variable domain defined by Kabat numbering, SEQ ID NOs: 13 to 15, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3, can be mentioned. According to Chothia numbering, the CDR sequences of the heavy chain variable domain are shown in SEQ ID NOs: 43 to 45 respectively, and the CDRs of the light chain variable domain are shown in SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region for 3A8 are shown in SEQ ID NOs: 61 and 65 respectively.

[0152] As for the CDR sequences for 3D8 and antibodies derived from 3D8 (e.g., human antibodies), the CDRs of the heavy chain variable domain defined by Kabat numbering, SEQ ID NOs: 16 to 18, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3, can be mentioned. According to Chothia numbering, the CDR sequences of the heavy chain variable domain are shown in SEQ ID NOs: 46 to 48 respectively, and the CDRs of the light chain variable domain are shown in SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region for 3D8 are shown in SEQ ID NOs: 61 and 66 respectively.

[0153] As for the CDR sequences against 9A6 and antibodies derived from 9A6 (e.g., human antibodies), the CDRs of the heavy chain variable domain defined by the Kabat numbering, SEQ ID NOs: 82 to 84, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3, can be mentioned. The CDRs can also be defined by the Chothia system. According to the Chothia numbering, the CDR sequences of the heavy chain variable domain are shown as SEQ ID NOs: 94 to 96 respectively, and the CDR sequences of the light chain variable domain are shown as SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region against 9A6 are shown as SEQ ID NOs: 61 and 106 respectively.

[0154] As for the CDR sequences against 9D2 and antibodies derived from 9D2 (e.g., human antibodies), the CDRs of the heavy chain variable domain defined by the Kabat numbering, SEQ ID NOs: 85 to 87, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3, can be mentioned. The CDRs can also be defined by the Chothia system. According to the Chothia numbering, the CDR sequences of the heavy chain variable domain are shown as SEQ ID NOs: 97 to 99 respectively, and the CDR sequences of the light chain variable domain are shown as SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region against 9D2 are shown as SEQ ID NOs: 61 and 107 respectively.

[0155] As for the CDR sequences against 9F3 and antibodies derived from 9F3 (e.g., human antibodies), the CDRs of the heavy chain variable domain defined by the Kabat numbering, SEQ ID NOs: 88 to 90, and the CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3, can be mentioned. The CDRs can also be defined by the Chothia system. According to the Chothia numbering, the CDR sequences of the heavy chain variable domain are shown as SEQ ID NOs: 100 to 102 respectively, and the CDRs of the light chain variable domain are shown as SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region against 9F3 are shown as SEQ ID NOs: 61 and 108 respectively.

[0156] As CDR sequences for 9H2 and antibodies derived from 9H2 (e.g., human antibodies), there may be mentioned CDRs of the heavy chain variable domain, SEQ ID NOs: 91 to 93, and CDRs of the light chain variable domain, SEQ ID NOs: 1 to 3, as defined by Kabat numbering. The CDRs can also be defined by the Chothia system. According to Chothia numbering, the CDR sequences of the heavy chain variable domain are shown as SEQ ID NOs: 103 to 105 respectively, and the CDR sequences of the light chain variable domain are shown as SEQ ID NOs: 1 to 3. The human light chain variable region and human heavy chain variable region against 9H2 are shown as SEQ ID NO: 61 and SEQ ID NO: 109 respectively.

[0157] Furthermore, in some embodiments, the antibodies or antigen-binding fragments thereof described herein can also contain 1, 2, or 3 heavy chain variable region CDRs selected from the group consisting of SEQ ID NOs: 4 to 6, SEQ ID NOs: 7 to 9, SEQ ID NOs: 10 to 12, SEQ ID NOs: 13 to 15, SEQ ID NOs: 16 to 18, SEQ ID NOs: 34 to 36, SEQ ID NOs: 37 to 39, SEQ ID NOs: 40 to 42, SEQ ID NOs: 43 to 45, SEQ ID NOs: 46 to 48, SEQ ID NOs: 82 to 84, SEQ ID NOs: 85 to 87, SEQ ID NOs: 88 to 90, SEQ ID NOs: 91 to 93, SEQ ID NOs: 94 to 96, SEQ ID NOs: 97 to 99, SEQ ID NOs: 100 to 102, and SEQ ID NOs: 103 to 105, and / or 1, 2, or 3 light chain variable region CDRs selected from the group consisting of SEQ ID NOs: 1 to 3.

[0158] In some embodiments, the antibody is a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein the CDR1 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VH CDR1, the CDR2 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VH CDR2, and the CDR3 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VH CDR3; and a light chain variable region (VL) comprising CDRs 1, 2, and 3, wherein the CDR1 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VL CDR1, the CDR2 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VL CDR2, and the CDR3 region comprises, or consists of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to the amino acid sequence of a selected VL CDR3. The amino acid sequences of the selected VH CDRs 1, 2, and 3, and the selected VL CDRs 1, 2, and 3 are shown in FIGS. 8 and 10 (Kabat CDRs), and FIGS. 9 and 10 (Chothia CDRs).

[0159] In some embodiments, the antibody or antigen-binding fragment described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 4 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 5 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 6 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0160] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 7 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 8 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 9 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0161] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 10 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 11 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 12 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0162] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 13 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 14 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 15 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0163] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 16 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 17 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 18 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0164] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 34 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 35 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 36 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0165] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 37 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 38 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 39 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0166] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 40 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 41 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 42 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0167] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 43 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 44 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 45 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0168] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 46 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 47 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 48 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0169] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 82 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 83 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 84 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0170] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 85 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 86 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 87 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0171] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 88 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 89 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 90 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0172] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 91 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 92 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 93 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0173] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 94 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 95 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 96 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0174] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 97 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 98 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 99 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0175] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 100 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 101 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, and SEQ ID NO: 102 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0176] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a heavy chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 103 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 104 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 105 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0177] In some embodiments, the antibodies or antigen-binding fragments described herein can contain a light chain variable domain containing one, two, or three of the CDRs of SEQ ID NO: 1 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, SEQ ID NO: 2 having 0, 1, or 2 amino acid insertions, deletions, or substitutions, or SEQ ID NO: 3 having 0, 1, or 2 amino acid insertions, deletions, or substitutions.

[0178] Insertions, deletions, and substitutions can be within the CDR sequences or at one or both ends of the CDR sequences.

[0179] The present disclosure also provides antibodies or antigen-binding fragments thereof that bind to EGFR. The antibody or antigen-binding fragment thereof contains a heavy chain variable region (VH) comprising, or consisting of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VH sequence, and a light chain variable region (VL) comprising, or consisting of, an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VL sequence. In some embodiments, the selected VH sequence is SEQ ID NO: 62, 63, 64, 65, 66, 106, 107, 108, or 109, and the selected VL sequence is SEQ ID NO: 61.

[0180] In some embodiments, the antibody or antigen-binding fragment thereof can have three VH CDRs that are identical to the CDRs of any VH sequence described herein. In some embodiments, the antibody or antigen-binding fragment thereof can have three VL CDRs that are identical to the CDRs of any VL sequence described herein.

[0181] The present disclosure also provides a nucleic acid comprising a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or an immunoglobulin light chain. The immunoglobulin heavy chain or the immunoglobulin light chain comprises a CDR shown in FIG. 8, FIG. 9 or FIG. 10, or has the sequence shown in FIG. 11. When the polypeptide pairs with a corresponding polypeptide (e.g., a corresponding heavy chain variable region, or a corresponding light chain variable region), the paired polypeptide binds to EGFR (e.g., human EGFR).

[0182] The anti-EGFR antibodies and antigen-binding fragments can also be antibody variants (including derivatives and conjugates) of the antibody or antibody fragment, and multispecific (e.g., bispecific) antibodies or antibody fragments. Additional antibodies provided herein are polyclonal, monoclonal, multispecific (multimeric, e.g., bispecific), human antibodies, chimeric antibodies (e.g., human-mouse chimeric), single-chain antibodies, antibodies produced intracellularly (i.e., intrabodies), and antigen-binding fragments thereof. The antibody or its antigen-binding fragment can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. In some embodiments, the antibody or its antigen-binding fragment is an IgG (e.g., IgG1) antibody or its antigen-binding fragment.

[0183] Antibody fragments are suitable for use in the provided methods as long as they retain the desired affinity and specificity of the full-length antibody. Thus, fragments of an antibody that binds to EGFR retain the ability to bind to EGFR. An Fv fragment is an antibody fragment that contains the complete antigen recognition and binding site. This region is composed of a dimer of one heavy-chain variable domain and one light-chain variable domain that are closely associated, which can be covalently linked, for example, in an scFv. In this configuration, the three CDRs of each variable domain interact to define the antigen-binding site on the surface of the VH-VL dimer. Overall, the six CDRs or subsets thereof together confer the antigen-binding specificity for the antibody. However, even a single variable domain (or half of an Fv containing only three CDRs specific for a particular antigen) can have the ability to recognize and bind an antigen, but usually with a lower affinity than the entire binding site.

[0184] Antibodies, antigen-binding fragments, and antigen-binding protein constructs The present disclosure provides antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs (e.g., bispecific antibodies). The antigen-binding protein constructs (e.g., bispecific antibodies) can include an anti-EGFR antibody or an antigen-binding fragment thereof, and an anti-MET antibody or an antigen-binding fragment thereof. These antigen-binding protein constructs (e.g., bispecific antibodies), anti-EGFR antibodies, anti-MET antibodies, and antigen-binding fragments thereof can have various forms.

[0185] Generally, an antibody (also called an immunoglobulin) can be composed of two classes of polypeptide chains, a light chain and a heavy chain. The non-limiting antibodies of the present disclosure can be intact four-immunoglobulin chain antibodies comprising two heavy chains and two light chains. The heavy chain of the antibody can be any isotype including IgM, IgG, IgE, IgA, or IgD, or a sub-isotype including IgG1, IgG2, IgG2a, IgG2b, IgG3, IgG4, IgE1, IgE2, etc. The light chain can be a κ light chain or a λ light chain. The antibody can comprise two identical copies of the light chain and / or two identical copies of the heavy chain. The heavy chains, each containing one variable domain (or variable region, VH) and a plurality of constant domains (or constant regions), are bound to each other via disulfide bonds within those constant domains to form the "stem" of the antibody. The light chains, each containing one variable domain (or variable region, VL) and one constant domain (or constant region), are each bound to one heavy chain via a disulfide bond. The variable region of each light chain is aligned with the variable region of the heavy chain to which it binds. The variable regions of both the light and heavy chains contain three hypervariable regions sandwiched between more conserved framework regions (FRs).

[0186] The hypervariable regions, known as complementarity-determining regions (CDRs), form loops that include the principal antigen-binding surface of the antibody. The four framework regions mostly conform to a β-sheet structure, and the CDRs form connecting loops and in some cases part of the β-sheet structure. The CDRs of each chain are held in proximity to the framework regions and, together with the CDRs of the other chains, contribute to the formation of the antigen-binding region.

[0187] Methods for identifying the CDR regions of an antibody by analyzing the amino acid sequence of the antibody are well known, and several CDR definitions are commonly used. The Kabat definition is based on sequence variability, and the Chothia definition is based on the position of structural loop regions. These methods and definitions are described, for example, in Martin, “Protein sequence and structure analysis of antibody variable domains,” Antibody engineering, Springer Berlin Heidelberg, 2001. 422-439, Abhinandan, et al. “Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains,” Molecular immunology 45.14 (2008): 3832-3839, Wu, T.T. and Kabat, E.A. (1970) J. Exp. Med. 132: 211-250; Martin et al., Methods Enzymol. 203: 121-53 (1991); Morea et al., Biophys Chem. 68(1-3): 9-16 (Oct. 1997); Morea et al., J Mol Biol. 275(2): 269-94 (Jan. 1998); Chothia et al., Nature 342(6252): 877-83 (Dec. 1989); Ponomarenko and Bourne, BMC Structural Biology 7: 64 (2007), each of which is incorporated herein by reference in its entirety.

[0188] CDR is important for recognizing the epitope of an antigen. As used herein, "epitope" refers to the smallest portion of a target molecule that can be specifically bound by the antigen-binding domain of an antibody. The minimum size of an epitope can be about 3, 4, 5, 6, or 7 amino acids, but since the epitope can depend on the three-dimensional structure of the antigen based on its secondary and tertiary structure, these amino acids need not be in a continuous linear sequence of the primary structure of the antigen.

[0189] In some embodiments, the antibody is an intact immunoglobulin molecule (e.g., IgG1, IgG2a, IgG2b, IgG3, IgM, IgD, IgE, IgA). The IgG subclasses (IgG1, IgG2, IgG3, and IgG4) are highly conserved, with differences in their constant regions, particularly in the hinge and upper CH2 domains. The sequences and differences of the IgG subclasses are well known in the art and are described, for example, in Vidarsson, et al, “IgG subclasses and allotypes: from structure to effector functions.” Frontiers in immunology 5(2014); Irani, et al. “Molecular properties of human IgG subclasses and their implications for designing therapeutic monoclonal antibodies against infectious diseases.” Molecular immunology 67.2(2015):171-182; Shakib, Farouk, ed.The human IgG subclasses: molecular analysis of structure, function and regulation. Elsevier, 2016, each of which is incorporated herein by reference in its entirety.

[0190] The antibody can also be an immunoglobulin molecule derived from any species (e.g., human, rodent, mouse, rat, camel). Antibodies disclosed herein include, but are not limited to, polyclonal, monoclonal, monospecific, multispecific antibodies, and chimeric antibodies comprising an immunoglobulin binding domain fused to another polypeptide. An antigen-binding domain or antigen-binding fragment is a part of an antibody that retains the specific binding activity of the intact antibody, i.e., any part of the antibody that can specifically bind to an epitope on the target molecule of the intact antibody. This includes, for example, Fab, Fab’, F(ab’)2, and variants of these fragments. Thus, in some embodiments, the antibody or its antigen-binding fragment can be any polypeptide comprising, for example, scFv, Fv, Fd, dAb, bispecific antibody, bispecific scFv, diabody, linear antibody, single-chain antibody molecule, multispecific antibody formed from antibody fragments, and a binding domain that is an antibody-binding domain or a binding domain homologous thereto. Non-limiting examples of antigen-binding domains include, for example, the heavy and / or light chain CDRs of an intact antibody, the heavy and / or light chain variable regions of an intact antibody, the full-length heavy or light chain of an intact antibody, or an individual CDR derived from either the heavy or light chain of an intact antibody.

[0191] In some embodiments, the scFv has two heavy chain variable domains and two light chain variable domains. In some embodiments, the scFv has two antigen-binding regions (antigen-binding regions: A and B), and the two antigen-binding regions can each bind to a respective target antigen with different affinities.

[0192] In some embodiments, the antigen-binding fragment can form part of a chimeric antigen receptor (CAR). In some embodiments, the chimeric antigen receptor is a fusion of a single-chain variable fragment (scFv) described herein fused to the CD3ζ transmembrane and endodomain. In some embodiments, the chimeric antigen receptor also includes intracellular signaling domains from various co-stimulatory protein receptors (e.g., CD28, 41BB, ICOS). In some embodiments, the chimeric antigen receptor includes multiple signaling domains, e.g., CD3z-CD28-41BB, or CD3z-CD28-OX40, to increase potency. Thus, in one aspect, the disclosure further provides a cell (e.g., a T cell) that expresses a chimeric antigen receptor described herein.

[0193] In some embodiments, an antibody, an antigen-binding fragment thereof, or an antigen-binding protein construct (e.g., a bispecific antibody) can bind two different antigens, or two different epitopes.

[0194] In some embodiments, an antibody, an antigen-binding fragment thereof, or an antigen-binding protein construct (e.g., a bispecific antibody) can include 1, 2, or 3 heavy-chain variable region CDRs selected from FIGS. 8 and 9. In some embodiments, an antibody, an antigen-binding fragment thereof, or an antigen-binding protein construct (e.g., a bispecific antibody) can include 1, 2, or 3 light-chain variable region CDRs selected from FIG. 10.

[0195] Multimerization of an antibody can be achieved by natural aggregation of the antibody or by chemical or recombinant conjugation techniques well known in the art. For example, some percentage of a purified antibody preparation (e.g., purified IgG1 molecules) naturally forms protein aggregates that contain antibody homodimers and other higher-order antibody multimers.

[0196] In some embodiments, the multispecific antibody is a bispecific antibody. Bispecific antibodies can be produced by engineering the interface between a pair of antibody molecules to maximize the proportion of heterodimers recovered from recombinant cell culture. For example, the interface can comprise at least a portion of the CH3 domain of the antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). By replacing a large amino acid side chain with a small one (e.g., alanine or threonine), a compensatory "cavity" of the same or similar size as the large side chain is created at the interface of the second antibody molecule. This provides a mechanism for increasing the yield of heterodimers over other unwanted end products such as homodimers. This method is described, for example, in WO 96 / 27011, which is incorporated herein by reference in its entirety.

[0197] Any of the antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs (e.g., bispecific antibodies) described herein can be conjugated to a stabilizing molecule (e.g., a molecule that increases the half-life of the antibody or its antigen-binding fragment in a subject or in solution). Non-limiting examples of stabilizing molecules include polymers (e.g., polyethylene glycol) or proteins (e.g., serum albumin such as human serum albumin). Conjugation of a stabilizing molecule can increase the half-life of the antibody or antigen-binding fragment in vitro (e.g., in tissue culture or when stored as a pharmaceutical composition) or in vivo (e.g., in a human), or can extend its biological activity.

[0198] Antibodies, their antigen-binding fragments, or antigen-binding protein constructs (e.g., bispecific antibodies) can also take various forms. Many different formats of antigen-binding constructs are well known in the art and are described, for example, in Suurs, et al. “A review of bispecific antibodies and antibody constructs in oncology and clinical challenges,” Pharmacology&therapeutics(2019), the entire content of which is incorporated herein by reference.

[0199] In some embodiments, the antigen-binding protein construct is a BiTe, (scFv)2, nanobody, nanobody-HSA, DART, TandAb, scDiabody, scDiabody-CH3, scFv-CH-CL-scFv, HSAbody, scDiabody-HAS, or tandem-scFv. In some embodiments, the antigen-binding protein construct is a VHH-scAb, VHH-Fab, Dual scFab, F(ab’)2, diabody, crossMab, DAF(2in1), DAF(4in1), DutaMab, DT-IgG, knob-in-hole common light chain, knob-in-hole assembly, charge pair, Fab arm exchange, SEEDbody, LUZ-Y, Fcab, κλ-body, orthogonal Fab, DVD-IgG, IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, diabody-CH3, triple body, miniantibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv, F(ab’)2-scFv2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, diabody-Fc, tandem scFv-Fc, intrabody, dock-and-lock, lmmTAC, IgG-IgG conjugate, Cov-X-Body, or scFv1-PEG-scFv2.

[0200] In some embodiments, the antigen-binding protein construct can be a TrioMab. In a TrioMab, the two heavy chains are derived from different species and the different sequences restrict heavy chain-light chain pairing.

[0201] In some embodiments, the antigen-binding protein construct has two different heavy chains and one common light chain. Heavy chain heterodimerization can be based on knob-into-hole or some other heavy chain pairing technology.

[0202] In some embodiments, bispecific antibodies can be generated using CrossMAb technology. Using CrossMAb technology, correct light chain pairing in bispecific heterodimeric IgG antibodies can be enhanced, and this technology enables the generation of various bispecific antibody formats, including bivalent (1+1), trivalent (2+1), and tetravalent (2+2) bispecific antibodies, as well as non-Fc tandem antigen-binding fragment (Fab)-based antibodies. These formats can be derived from any existing antibody pair without the need to use domain crossover for common light chain identification, post-translational processing / in vitro chemical assembly, or introduction of a series of mutations to enhance correct light chain pairing. This method is described in Klein et al., “The use of CrossMAb technology for the generation of bi-and multispecific antibodies.” MAbs.Vol.8.No.6.Taylor&Francis,2016, which is incorporated herein by reference in its entirety. In some embodiments, the CH1 within the heavy chain and the CL domain within the light chain are exchanged.

[0203] The antigen-binding protein construct can be a Duobody. The Fab exchange mechanism that naturally exists within IgG4 antibodies is mimicked in a controlled manner in IgG1 antibodies, which is a mechanism called controlled Fab exchange. This format can ensure specific pairing between the heavy and light chains.

[0204] In a dual variable domain antibody (DVD-Ig), additional VH and variable light chain (VL) domains are added to each N-terminus for bispecific targeting. This format is similar to IgG-scFv, but the added binding domains bind individually to the corresponding N-termini instead of scFv to each heavy chain N-terminus.

[0205] In scFv-IgG, the two scFvs are linked to the C-terminus of the heavy chain (CH3). The scFv-IgG format has two different bivalent binding sites and is consequently also called tetravalent. There is no problem of heavy and light chain pairing in scFv-IgG.

[0206] In some embodiments, the antigen-binding protein construct can have an IgG-IgG format. Two intact IgG antibodies are conjugated by chemically bonding the C-termini of the heavy chains.

[0207] The antigen-binding protein construct can also have a Fab-scFv-Fc format. In the Fab-scFv-Fc format, a third chain containing the light chain, heavy chain, and an scFv with the Fc region is assembled. This can ensure efficient production and purification.

[0208] In some embodiments, the antigen-binding protein construct can be a TF. Three Fab fragments are linked by disulfide bridges. Two fragments target tumor-associated antigens (TAAs) and one fragment targets a hapten. The TF format does not have an Fc region.

[0209] ADAPTIR has two scFvs bound to both sides of a certain Fc region. It discards the intact IgG that is the basis for the construct, but preserves the Fc region, extending the half-life and facilitating purification.

[0210] Bispecific T cell engagers ("BiTE") are composed of two scFvs, VLA, VHA, and VHB VLB on one peptide chain. It has a binding domain and no Fc region.

[0211] In BiTE-Fc, the Fc region is fused to the BiTE construct. Adding the Fc region extends the half-life, results in a longer effective concentration, and avoids continuous IV.

[0212] Dual Affinity Re-targeting (DART) has two peptide chains that link opposing fragments (i.e., VLA with VHB and VLB with VHA), and a sulfur bond that fuses them together at the C-terminus. In DART, the sulfur bond can improve stability more than in BiTE.

[0213] In DART-Fc, the Fc region is attached to DART. This can be generated by assembling three chains (similar to DART, two via disulfide bonds). One chain contains half of the Fc region, which dimerizes with the third chain to express only the Fc region. Adding the Fc region extends the half-life, provides a longer effective concentration, and avoids continuous IV.

[0214] In tetravalent DART, four peptide chains are assembled. Basically, two DART molecules are made by halves of the Fc region and dimerize. This format has a bivalent bond to both targets, so it is a tetravalent molecule.

[0215] Tandem diabody (TandAb) contains two diabodies. Each diabody is composed of a VHA and a VLB fragment, and a VHA and a VLB fragment, which are associated by a covalent bond. The two diabodies are linked by a peptide chain. This can improve stability more than a diabody composed of two scFvs. It has two bivalent binding sites.

[0216] scFv-scFv-toxin contains a toxin and two scFvs with a stabilizing linker. This can be used for specific delivery of the payload.

[0217] In the molecular scFv-scFv-scFv, the scFv directed against the TAA is tagged with a short recognizable peptide that is assembled against a bsAb composed of two scFvs (one directed against CD3 and one directed against a recognizable peptide).

[0218] In ImmTAC, the stabilized and soluble T cell receptor is fused to an scFv that recognizes CD3. By using the TCR, ImmTAC is suitable for the targets to be treated, such as intracellular proteins.

[0219] The trispecific nanobody has two single variable domains (nanobodies) that include additional molecules for half-life extension. Additional modules are added to extend the half-life.

[0220] In Trispecific Killer Engager (TriKE), two scFvs are linked via a polypeptide linker that incorporates human IL-15. A linker to IL-15 is added to increase NK survival and proliferation.

[0221] In some embodiments, the antigen-binding protein construct is a bispecific antibody. In some embodiments, the bispecific antibodies in the present disclosure are designed to be 1+1 (monovalent for each target) and have an IgG1 subtype structure. Thereby, the binding activity to cells having low expression levels of EGFR and MET can be reduced, the binding activity to cells co-expressing EGFR and MET can be increased, and an improvement in the targeting function can be achieved.

[0222] In some embodiments, the antibody, its antigen-binding fragment, antigen-binding protein construct (e.g., anti-MET antibody, anti-EGFR antibody, or bispecific antibody) has a light chain constant region that is at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 81, and a heavy chain constant region that is at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to either SEQ ID NO: 71 or SEQ ID NO: 72.

[0223] In some embodiments, the anti-EGFR / MET antigen-binding protein construct (e.g., an antibody, bispecific antibody, or antibody fragment thereof) comprises a KIH mutation. In some embodiments, the antigen-binding protein construct comprises a first antigen-binding domain that specifically binds to EGFR and a second antigen-binding domain that specifically binds to MET. In some embodiments, the first antigen-binding domain comprises a heavy chain (knob heavy chain) comprising one or more knob mutations, and the second antigen-binding domain comprises a heavy chain (hole heavy chain) comprising one or more hole mutations. In some embodiments, the first antigen-binding domain comprises a heavy chain (hole heavy chain) comprising one or more hole mutations, and the second antigen-binding domain comprises a heavy chain (knob heavy chain) comprising one or more knob mutations. In some embodiments, the anti-EGFR / MET antigen-binding protein construct comprises a knob heavy chain comprising a constant region that is at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 71. In some embodiments, the anti-EGFR / MET antigen-binding protein construct comprises a hole heavy chain comprising a constant region that is at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 72.

[0224] In some embodiments, the bispecific antibodies or antigen-binding fragments thereof described herein have a common light chain.

[0225] Antibody-drug conjugate (ADC) In some embodiments, the antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs (e.g., bispecific antibodies) described herein can be conjugated to a therapeutic agent, optionally using a linker, to form an antibody-drug conjugate. The antibody-drug conjugate comprising the antibody or antigen-binding fragment thereof can be covalently or non-covalently bound to the therapeutic agent. In some embodiments, the therapeutic agent is a cytotoxic or cytostatic agent (e.g., monomethyl auristatin E, monomethyl auristatin F, camptothecin, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxy anthracene, maytansinoids (such as DM-1 and DM-4), dion, mitoxantrone, mitramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoid, procaine, tetracaine, lidocaine, propranolol, puromycin, epirubicin, and cyclophosphamide, and analogs). In some embodiments, the therapeutic agent is MMAE or MMAF.

[0226] The definitions of specific functional groups and chemical terms are described in detail below. For the purposes of the present invention, chemical elements are identified based on the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside the cover, and specific functional groups are generally defined as described herein. Further, general principles of organic chemistry, and specific functional groups and reactivities are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5 thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 rd is described in Edition, Cambridge University Press, Cambridge, 1987.

[0227] All ranges cited herein are inclusive and, unless expressly stated to the contrary, all values within the ranges are included. When a range of values is recited, each intervening value and subrange within the range are also intended to be included. For example, "C 1-6 " includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 are intended to be included.

[0228] Compounds or any formula depicting and describing the compounds of the present disclosure may have one or more chiral (asymmetric) centers. The present invention encompasses all stereoisomers of the compounds, or any formula depicting and describing the compounds of the present invention. Any asymmetric centers present in the compounds or any formula depicting and describing the compounds of the present invention can each independently have the (R) or (S) configuration. Where a bond to a chiral carbon in a structural formula is drawn as a straight line, or where a compound name is recited without (R) or (S) chiral designation with respect to a chiral carbon, both the (R) and (S) configurations of each chiral carbon, and hence each enantiomer or diastereomer and mixtures thereof, are understood to be included within the formula or name.

[0229] The present disclosure includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers, for example, mixtures of enantiomers and / or diastereomers in any ratio. Thus, enantiomers are the subject of the present disclosure in enantiomerically pure form, as both the levorotatory and dextrorotatory enantiomers, in racemic form, and in the form of mixtures of two enantiomers in any ratio. In the case of cis / trans isomerism, the present disclosure includes both the cis form and the trans form, as well as mixtures of these forms in any ratio. The preparation of individual stereoisomers can be carried out, if necessary, by separation of mixtures by conventional methods such as chromatography or crystallization, by use of stereochemically homogeneous starting materials for synthesis, or by stereoselective synthesis. Optionally, derivatization can also be carried out prior to separation of the stereoisomers. Separation of mixtures of stereoisomers can be carried out at an intermediate step during the synthesis of the compound, or on the final racemic product. The absolute stereochemistry can be determined, if necessary, by X-ray crystal structure analysis of crystalline products or crystalline intermediates derivatized with reagents containing stereocenters of known configuration. Alternatively, the absolute stereochemistry can also be determined by vibrational circular dichroism (VCD) spectroscopy.

[0230] Unless otherwise specified, the structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, i.e., compounds in which one or more atoms are replaced with atoms having the same atomic number but a different atomic mass or mass number than the predominant atomic mass or mass number found in nature. These compounds are referred to as "isotope variants". The present disclosure is intended to encompass pharmaceutically acceptable isotope variants of the compounds, or any formula that depicts and describes the compounds of the invention. Examples of isotopes suitable for inclusion in the compounds of the invention include 2 H (i.e., D) and 3 isotopes of hydrogen such as 11 C, 13 C, and 14 isotopes of carbon such as 36Isotopes of chlorine such as Cl, 18 Isotopes of fluorine such as F, 123 I, and 125 Isotopes of iodine such as I, 13 N and 15 Isotopes of nitrogen such as N, 15 O, 17 O, and 18 Isotopes of oxygen such as O, 32 Isotopes of phosphorus such as P, and 35 Isotopes of sulfur such as S are mentioned, but are not limited thereto. Specific isotope variants of the compounds, or any formula depicting and describing the compounds of the present disclosure, for example those incorporating radioactive isotopes, may be useful in drug and / or substrate tissue distribution studies. In particular, compounds having structures described as differing only in that lighter isotopes are replaced by heavier isotopes, such as replacing hydrogen with deuterium ( 2 H, or D), may offer certain therapeutic advantages such as improved metabolic stability, extended in vivo half-life, or reduced dosing requirements, and thus may be utilized in some situations. Isotope variants of the compounds, or any formula depicting and describing the compounds of the present disclosure, can generally be prepared by using appropriate isotope-labeled reagents in place of the unlabeled reagents previously used, by techniques known to those of ordinary skill in the art or by processes similar to those described in the accompanying examples and syntheses.

[0231] The compounds provided herein are described with reference to both general formulas and specific compounds. Furthermore, the compounds of the present disclosure can exist in numerous different forms or derivatives within the scope of the present disclosure. These include, for example, pharmaceutically acceptable salts, tautomers, stereoisomers, racemic mixtures, positional isomers, prodrugs, solvated forms, different crystal forms or polymorphs, and active metabolites.

[0232] As used herein, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acid / base form of a particular compound and are not biologically or otherwise undesirable, unless otherwise specified. Pharmaceutically acceptable salts include salts formed with inorganic bases or acids and organic bases or acids. When the compounds of the present disclosure contain one or more acidic or basic groups, the present disclosure also includes their corresponding pharmaceutically acceptable salts. Thus, the compounds of the present invention containing acidic groups such as carboxyl groups can exist in the form of salts and can be used in accordance with the present invention, for example, as alkali metal salts, alkaline earth metal salts, aluminum salts, or ammonium salts. More non-limiting examples of these salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, or salts with organic amines such as ammonia or ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine, or amino acids. These salts can be readily obtained, for example, by reacting a compound having an acidic group with a suitable base such as lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide, or barium hydroxide. Other basic salts of the compounds of the present disclosure include, but are not limited to, copper(I), copper(II), iron(II), iron(III), manganese(II), and zinc salts. Compounds of the present disclosure containing one or more basic groups, such as groups that can be protonated, can exist in the form of salts and can be used in accordance with the present invention in the form of addition salts with inorganic or organic acids.Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, embonic acid, mandelic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid, or aspartic acid, and other acids known to those skilled in the art. The salts formed include, inter alia, hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methanesulfonate (mesylate), tosylate, carbonate, bicarbonate, formate, acetate, sulfoacetate, triflate, oxalate, malonate, maleate, succinate, tartrate, malate, embonate, mandelate, fumarate, lactate, citrate, glutarate, stearate, aspartate, and glutamate. The stoichiometry of the salts formed from the compounds of the present disclosure may further be an integer multiple or non-integer multiple of 1.

[0233] Compounds of the present disclosure containing basic nitrogen-containing groups can be quaternized using reagents such as methyl, ethyl, isopropyl, and C 1-4 alkyl halides such as tert-butyl chloride, bromide, and iodide, and di-C 1-4 alkyl sulfates such as dimethyl, diethyl, and diamyl sulfates, and C 10-18 alkyl halides such as decyl, dodecyl, lauryl, myristyl, and stearyl chloride, bromide, and iodide, and aryl-C 1-4 alkyl halides such as benzyl chloride and phenethyl chloride.

[0234] When the compounds of the present disclosure contain both an acidic group and a basic group within the molecule, the present disclosure includes inner salts or betaines (zwitterions) in addition to the aforementioned salt forms. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present disclosure also includes all salts of the compounds of the present disclosure that are not suitable for direct use in pharmaceuticals due to low physiological compatibility, but can be used, for example, as intermediates in chemical reactions or in the preparation of pharmaceutically acceptable salts. For a review of more suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0235] Any formula depicting and describing a compound or a compound of the present disclosure and its pharmaceutically acceptable salts can exist in non-solvated and solvated forms. As used herein, the term "solvate" refers to a molecular complex comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules. For example, when the solvent is water, the term "hydrate" is used.

[0236] Pharmaceutically acceptable solvates according to the present disclosure include those in which the crystallization solvent is isotopically substituted, for example, D2O, d6-acetone, d6-DMSO.

[0237] Linker (binding agent compound) In some embodiments, the therapeutic agent is conjugated via a linker (or linker compound). As used herein, the terms "linker" or "linker compound" refer to a ligand (e.g., an antibody described herein, an antigen-binding fragment thereof, or an antigen-binding protein construct (e.g., a bispecific antibody)), and a therapeutic agent (e.g., any of the therapeutic agents described herein), which can be bound by reacting with the groups of the ligand compound and the therapeutic agent compound, respectively, for example, by a coupling reaction, to form a ligand-drug conjugate.

[0238] In some embodiments, the linker described herein is a compound having the following formula:

Chemical formula

[0239] In some embodiments, the joining moiety (Q of formula (I)) has the following structure.

Chemical formula

[0240] In some embodiments, the linker moiety (L of formula (I)) has the following formula.

Chemical formula

Chemical Formula

[0241] NH -Glu-Val-Ala- COOH . In some embodiments, the hydrophilic group L2 has the following structure.

Chemical Formula

[0242] In some embodiments, the linker described herein is a compound having the following structure.

Chemical Formula

[0243] In some embodiments, the linker is a VC linker. Details of linkers used in ADCs are described, for example, in Su, Z. et al. “Antibody-drug conjugates: Recent advances in linker chemistry.” Acta Pharmaceutica Sinica B (2021), which is incorporated herein by reference in its entirety.

[0244] Therapeutic agent In some embodiments, the therapeutic agents conjugated to the antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs (e.g., bispecific antibodies) described herein are explained as follows.

[0245] In some embodiments, the therapeutic agents described herein are cytotoxic agents. In some embodiments, the cytotoxic agent is a camptothecin compound, an analog or derivative thereof. In some preferred embodiments, the camptothecin compound is a compound having the following structure.

Chemical formula

[0246] In some embodiments, the therapeutic agent is (S)-4-amino-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13H-pyrano[3’,4’:6,7]indolizino[1,2-b]thiopyrano[4,3,2-de]quinoline-10,13(2H)-dione (CPT-1). The structure of CPT-1 is shown below:

Chemical formula

[0247] In some embodiments, the therapeutic agent is (S)-4-amino-9-ethyl-9-hydroxy-1,9,12,15-tetrahydro-13H-pyrano[4,3,2-de]pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-10,13(2H)-dione (CPT-2). The structure of CPT-2 is shown below:

Chemical Structure

[0248] In some embodiments, the therapeutic agent is CPT3. The structure of CPT-3 is shown below:

Chemical Structure

[0249] In some embodiments, the therapeutic agent is (S)-4-amino-9-ethyl-5-fluoro-9-hydroxy-1,9,12,15-tetrahydro-13H-pyrano[4,3,2-de]pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-10,13(2H)-dione (CPT-4). The structure of CPT-4 is shown below:

Chemical Structure

[0250] In some embodiments, the therapeutic agent is an auristatin, such as auristatin E (also well known in the art as a derivative of dolastatin-10), or a derivative thereof. An auristatin can be, for example, an ester formed from auristatin E and a keto acid. For example, auristatin E can react with para-acetylbenzoic acid or benzoylvaleric acid to produce AEB and AEVB, respectively. Other exemplary auristatins include AFP, MMAF, and MMAE. Exemplary syntheses and structures of auristatins are described in U.S. Patent Publication No. 2003-0083263; International Patent Publication Nos. WO 04 / 010957, WO 02 / 088172, and U.S. Patents Nos. 7,498,298; 6,884,869; 6,323,315; 6,239,104; 6,034,065; 5,780,588; 5,665,860; 5,663,149; 5,635,483; 5,599,902; 5,554,725; 5,530,097; 5,521,284; 5,504,191; 5,410,024; 5,138,036; 5,076,973; 4,986,988; 4,978,744; 4,879,278; 4,816,444; and 4,486,414, each of which is hereby incorporated by reference herein for all purposes.

[0251] Auristatins have been shown to interfere with microtubule dynamics and with nuclei and cell division, and have been shown to have anti-cancer activity. Auristatins can bind to tubulin and exert a cytotoxic or cytostatic effect in cancer cells. A number of different assays well known in the art exist and can be used to measure whether an auristatin or an obtained antibody-drug conjugate exerts a cytostatic or cytotoxic effect in a desired cell.

[0252] In some embodiments, the therapeutic agent is a chemotherapeutic agent. Examples of chemotherapeutic agents include thiotepa and cyclophosphamide (CYTOXAN TMalkylating agents such as; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocone, meturedopa, and uredopa; ethyleneimine and methylmelamine such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chloronaphazine, colophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobenbitin, phenesterine, prednimustine, trophosphamide, uracil mustard; nitrosoureas such as carmustine, chloroozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, calminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, keramycin, rhodrubicin, streptozocin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, drostanolone propionate, epitioestanol, mepitiostane, testolactone; adrenocortical suppressants such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;Bestrabucil; Bisantrene; Edatrexate; Defofamine; Demecortin; Diazikuon; Elfomithine; Elliptinium acetate; Etoglucid; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Phenamet; Pirarubicin; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; PSK7; Razoxane; Schizophyllan; Spirogermanium; Tenuaazonic acid; Triazikuon; 2,2’,2’’-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gasitocin; Arabinoside (“Ara-C”); Cyclophosphamide; Taxanes, such as paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, New Jersey), docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France), chlorambucil, gemcitabine, 6-Thioguanine, platinum analogs such as cisplatin or carboplatin, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, navelbine, novantrone, teniposide, daunomycin, aminopterin, Xeloda, ibandronate, CPT-11, topoisomerase inhibitor RFS 2000, difluoromethylornithine (DMFO); Retinoic acid; Esperamicin; Capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. This definition includes, for example, tamoxifen, raloxifene, aromatase inhibitor 4(5)imidazole, 4-hydroxytamoxifen, trioxifen, keoxifen, LY117018, onapristone, and toremifene (Fareston); and antiandrogen agents such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin;Also included are antihormonal agents that have the effect of regulating or inhibiting the hormonal action in tumors, such as antiestrogen agents containing any of the above pharmaceutically acceptable salts, acids, or derivatives. A detailed description of the chemotherapeutic agents can be found, for example, in US20180193477A1, which is incorporated herein by reference in its entirety.;

[0253] Linker-therapeutic agent compound In some embodiments, a linker (e.g., any of the linkers described herein) and a therapeutic agent (e.g., any of the therapeutic agents described herein) can be combined to form a "linker-therapeutic agent" compound.;

[0254] In some embodiments, the linker-therapeutic agent compound has the following structure.; [Chemical formula]

[0255] In some embodiments, the linker-therapeutic agent compound has the following structure.; [Chemical formula]

[0256] In some embodiments, an antibody ("Ab"), such as any of the antibodies described herein, its antigen-binding fragment, or an antigen-binding protein construct (e.g., bispecific antibody), can be conjugated to a linker-therapeutic agent compound (e.g., any of the linker-therapeutic agent compounds described herein) to generate an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate has the following structure.; [Chemical formula] Here, n = 1, 2, 3, 4, 5, 6, 7, or 8.;

[0257] Antibody and ADC properties An anti-EGFR / MET antigen-binding protein construct (e.g., an antibody, a bispecific antibody, or an antibody fragment thereof) can include an antigen-binding region derived from any anti-EGFR antibody described herein, or any antigen-binding fragment thereof.

[0258] The present disclosure provides antibodies and antigen-binding fragments thereof that specifically bind to EGFR. The antibodies and antigen-binding fragments described herein are capable of binding to EGFR. These antibodies can be agonists or antagonists. The anti-EGFR antibodies or antigen-binding fragments thereof described herein can bind to EGFR and block the binding between EGFR and EGF, and / or the binding between EGFR and TGFα. By blocking the binding between EGFR and EGF, and / or the binding between EGFR and TGFα, the anti-EGFR antibodies can inhibit the EGFR-related signaling pathway and thus treat cancer (e.g., NSCLC). In some embodiments, the anti-EGFR antibody or antigen-binding fragment thereof can initiate CDC or ADCC.

[0259] Common techniques that can be used to measure the affinity of an antibody for an antigen include, for example, ELISA, RIA, and surface plasmon resonance (SPR). The affinity can be estimated from the quotient of the kinetic rate constants (KD = koff / kon). In some embodiments, the antibody, its antigen-binding fragment, or antigen-binding protein construct (e.g., bispecific antibody) has a dissociation rate (koff) of less than 0.1 s -1 less than, 0.01 s -1 less than, 0.001 s -1 less than, 0.0001 s -1 less than, or, 0.00001 s -1 less than and can bind to EGFR (e.g., human EGFR, monkey EGFR, mouse EGFR, and / or chimeric EGFR). In some embodiments, the dissociation rate (koff) is greater than 0.01 s -1 greater than, 0.001 s -1 greater than, 0.0001 s -1 greater than, 0.00001 s -1 greater than, or, 0.000001 s-1 is greater than.

[0260] In some embodiments, the association rate (kon) is greater than 1×10 2 / Ms, greater than 1×10 3 / Ms, greater than 1×10 4 / Ms, greater than 1×10 5 / Ms, or greater than 1×10 6 / Ms. In some embodiments, the association rate (kon) is less than 1×10 5 / Ms, less than 1×10 6 / Ms, or less than 1×10 7 / Ms.

[0261] In some embodiments, an antibody, an antigen-binding fragment thereof, or an antigen-binding protein construct (e.g., a bispecific antibody) can bind to EGFR (e.g., human EGFR, monkey EGFR, mouse EGFR, and / or chimeric EGFR) with a KD less than 1×10 -6 M, less than 1×10 -7 M, less than 1×10 -8 M, less than 1×10 -9 M, or less than 1×10 -10 M. In some embodiments, the KD is less than 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM. In some embodiments, the KD is greater than 1×10 -7 M, greater than 1×10 -8 M, greater than 1×10 -9 M, or greater than 1×10 -10 M.

[0262] An anti-EGFR / MET antigen-binding protein construct (e.g., a bispecific antibody) can also include an antigen-binding region derived from any anti-MET antibody or antigen-binding fragment thereof described herein. The anti-MET antibody or antigen-binding fragment thereof described herein can block the binding between MET and HGF. In some embodiments, the antibody can inhibit the MET-related signaling pathway by binding to MET, thereby also inhibiting cell proliferation, differentiation, and / or metastasis. Thus, in some embodiments, the antibody or antigen-binding fragment thereof described herein is a MET agonist. In some embodiments, the antibody or antigen-binding fragment thereof is a MET antagonist.

[0263] In some embodiments, the antibody, its antigen-binding fragment, or antigen-binding protein construct (e.g., bispecific antibody) has a dissociation rate (koff) of less than 0.1 s -1 less than, 0.01 s -1 less than, 0.001 s -1 less than, 0.0001 s -1 less than, or, 0.00001 s -1 less than and can bind to MET (e.g., human MET, monkey MET, mouse MET, and / or chimeric MET). In some embodiments, the dissociation rate (koff) is greater than 0.01 s -1 greater than, 0.001 s -1 greater than, 0.0001 s -1 greater than, 0.00001 s -1 greater than, or, 0.000001 s -1 greater than.

[0264] In some embodiments, the association rate (kon) is greater than 1×10 2 / M s greater than, 1×10 3 / M s greater than, 1×10 4 / M s greater than, 1×10 5 / M s greater than, or, 1×10 6 / M s greater than. In some embodiments, the association rate (kon) is less than 1×10 5 / M s less than, 1×10 6 / M s less than, or, 1×107 Less than / Ms.

[0265] The affinity can be estimated from the quotient of the kinetic rate constants (KD = koff / kon). In some embodiments, KD is 1×10 -6 M or less, 1×10 -7 M or less, 1×10 -8 M or less, 1×10 -9 M or less, or 1×10 -10 M or less. In some embodiments, KD is less than 50 nM, 40 nM, 30 nM, 20 nM, 15 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM. In some embodiments, KD is greater than 1×10 -7 M, greater than 1×10 -8 M, greater than 1×10 -9 M, or greater than 1×10 -10 M.

[0266] Antigen-binding protein constructs (e.g., bispecific antibodies) bind to both MET and EGFR, and thus have a high binding affinity for cells that express both MET and EGFR. The binding activity can be used to measure the binding affinity of the antigen-binding protein construct for these cells. Binding activity is the cumulative strength of the affinities of individual non-covalent interactions.

[0267] Thermal stability can also be measured. The antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs (e.g., bispecific antibodies) described herein can have a Tm above 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95 °C. Since IgG can be described as a multi-domain protein, the melting curve may, in some cases, show two transitions, with the first denaturation temperature being Tm D1 and the second denaturation temperature being Tm D2. The presence of these two peaks often indicates the denaturation of the Fc domain (Tm D1) and the Fab domain (Tm D2), respectively. When two peaks are present, Tm usually refers to Tm D2. Thus, in some embodiments, the antibodies or antigen-binding fragments described herein have a Tm D1 above 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95 °C. In some embodiments, the antibodies or antigen-binding fragments described herein have a Tm D2 above 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95 °C. In some embodiments, Tm, Tm D1, and Tm D2 are less than 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95 °C.

[0268] In some embodiments, an antibody, an antigen-binding fragment thereof, an antigen-binding protein construct (e.g., a bispecific antibody) can bind to human EGFR or cynomolgus EGFR. In some embodiments, an antibody, an antigen-binding fragment thereof, an antigen-binding protein construct (e.g., a bispecific antibody) cannot bind to human EGFR or cynomolgus EGFR. In some embodiments, an antibody, an antigen-binding fragment thereof, an antigen-binding protein construct (e.g., a bispecific antibody) can bind to human MET or cynomolgus MET. In some embodiments, an antibody, an antigen-binding fragment thereof, an antigen-binding protein construct (e.g., a bispecific antibody) cannot bind to human MET or cynomolgus MET.

[0269] In some embodiments, an antibody, an antigen-binding fragment thereof, an antigen-binding protein construct (e.g., an anti-MET antibody, an anti-EGFR antibody, or a bispecific antibody) has a purity of greater than 30%, 40%, 50%, 60%, 70%, 72.5%, 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, as measured by, for example, HPLC. In some embodiments, the purity is less than 30%, 40%, 50%, 60%, 70%, 72.5%, 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, as measured by, for example, HPLC.

[0270] In some embodiments, an antibody, an antigen-binding fragment thereof, or an antigen-binding protein construct (e.g., an anti-MET antibody, an anti-EGFR antibody, or a bispecific antibody) has a tumor growth inhibition rate or ratio (TGI%) of more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. In some embodiments, the antibody has a tumor growth inhibition ratio of less than 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150%. TGI(%) can be measured, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 days after the start of treatment. As used herein, the tumor growth inhibition rate or ratio (TGI%) is calculated using the following formula. TGI(%) = [1 - (Ti - T0) / (Vi - V0)] × 100% Ti is the average tumor volume in the treatment group on day i. T0 is the average tumor volume in the treatment group on day 0. Vi is the average tumor volume in the control group on day i. V0 is the average tumor volume in the control group on day 0.

[0271] In some embodiments, an antibody, an antigen-binding fragment thereof, or an antigen-binding protein construct (e.g., a bispecific antibody) has a functional Fc region. In some embodiments, the effector function of the functional Fc region is antibody-dependent cell cytotoxicity (ADCC). In some embodiments, the effector function of the functional Fc region is phagocytosis. In some embodiments, the effector function of the functional Fc region is ADCC and phagocytosis. In some embodiments, the Fc region is human IgG1, human IgG2, human IgG3, or human IgG4.

[0272] In some embodiments, the antibody, its antigen-binding fragment, or antigen-binding protein construct (e.g., bispecific antibody) does not have a functional Fc region. For example, the antibody or antigen-binding fragment is a Fab, Fab’, F(ab’)2, and Fv fragment. In some embodiments, the protein constructs described herein have an Fc region that lacks effector function. In some embodiments, the Fc is a human IgG4 Fc. In some embodiments, the Fc does not have a functional Fc region. For example, the Fc region has an LALA mutation (L234A and L235A mutations in EU numbering), or an LALA-PG mutation (L234A, L235A, P329G mutations in EU numbering).

[0273] Several other modifications to the Fc region can be made. For example, cysteine residues can be introduced into the Fc region to allow for interchain disulfide bond formation within this region. The homodimeric fusion protein thus generated can have an increased in vitro and / or in vivo half-life, optionally.

[0274] In some embodiments, IgG4 has an S228P mutation (EU numbering). The S228P mutation prevents IgG4 Fab arm exchange in vivo and in vitro.

[0275] In some embodiments, an Fc region having a carbohydrate structure lacking fucose (either directly or indirectly) linked to the Fc region is provided. For example, the amount of fucose in such an Fc region composition may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined, for example, by calculating the average amount of fucose in the sugar chain at Asn297 relative to the total of all sugar structures (e.g., complex, hybrid, and high-mannose structures) linked to Asn297, as measured by MALDI-TOF mass spectrometry as described in WO 2008 / 077546. Asn297 refers to the asparagine residue located at position 297 within the Fc region (the Eu numbering of the Fc region residues, or position 314 in the Kabat numbering), however, Asn297 may also be located upstream or downstream by about ±3 amino acids from position 297, i.e., between positions 294 and 300, due to minor sequence variations in the Fc region sequence. Such fucosylation variants may have improved ADCC function. In some embodiments, to reduce the heterogeneity of the glycan, the Fc region is further recombinantly engineered to substitute the asparagine at position 297 with alanine (N297A).

[0276] In some embodiments, the main peak of the HPLC-SEC accounts for at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% of the protein complex described herein after purification by protein A-based affinity chromatography and / or size exclusion chromatography.

[0277] In some embodiments, the ADCs described herein have an IC50 of less than 2 μg / mL, less than 1.5 μg / mL, less than 1 μg / mL, less than 0.9 μg / mL, less than 0.8 μg / mL, less than 0.7 μg / mL, less than 0.6 μg / mL, less than 0.5 μg / mL, less than 0.4 μg / mL, less than 0.3 μg / mL, less than 0.2 μg / mL, or less than 0.1 μg / mL for the in vitro killing of cancer cells (e.g., the lung cancer cell line NCI-H1975).

[0278] In some embodiments, the bispecific antibodies described herein have a higher endocytosis rate than the corresponding monoclonal antibodies and / or control bispecific antibodies described herein. In some embodiments, the anti-EGFR antibodies described herein have a higher endocytosis rate than cetuximab analogs. In some embodiments, the anti-MET antibodies described herein have a higher endocytosis rate than telisotuzumab analogs. In some embodiments, the bispecific antibodies described herein have a higher endocytosis rate than amivantamab analogs.

[0279] Method for producing an antigen-binding protein construct Isolated fragments of human proteins can be used as immunogens, and antibodies can be generated using standard techniques for the preparation of polyclonal and monoclonal antibodies. Polyclonal antibodies can be raised in animals by injecting the antigenic peptide or protein multiple times (e.g., subcutaneously or intraperitoneally). In some embodiments, the antigenic peptide or protein is injected with at least one adjuvant. In some embodiments, the antigenic peptide or protein can be conjugated to an agent that is immunogenic in the species to be immunized. The animals can be injected with the antigenic peptide or protein two or more times (e.g., 2, 3, or 4 times).

[0280] Full-length polypeptides or proteins can be used, or antigenic peptide fragments thereof can be used as immunogens. The antigenic peptides of the protein comprise at least 8 (e.g., at least 10, 15, 20, or 30) amino acid residues of the amino acid sequence of the protein and encompass the epitope of the protein such that the antibodies generated against the peptide form specific immune complexes with the protein.

[0281] An immunogen is typically used for the preparation of antibodies by immunizing a suitable subject (e.g., a human or transgenic animal expressing at least one human immunoglobulin locus). Suitable immunogenic preparations can contain, for example, recombinantly expressed or chemically synthesized polypeptides. The preparations can further contain an adjuvant such as Freund's complete or incomplete adjuvant, or a similar immunostimulant.

[0282] Polyclonal antibodies can be prepared as described above by immunizing a suitable subject with a polypeptide or its antigenic peptide (e.g., a part of a protein) as an immunogen. Standard techniques such as enzyme-linked immunosorbent assay (ELISA) using immobilized polypeptides or peptides can be used to monitor the antibody titer in the immunized subject over time. If desired, antibody molecules can be isolated from a mammal (e.g., from blood) and further purified by well-known techniques such as protein G or protein A chromatography to obtain the IgG fraction. At an appropriate time after immunization, e.g., when the titer of specific antibodies is at its maximum, antibody-producing cells are obtained from the subject and used to prepare monoclonal antibodies by standard techniques such as the hybridoma technique originally described by Kohler et al. (Nature 256:495-497, 1975), human B cell hybridoma technique (Kozbor et al., Immunol. Today 4:72, 1983), EBV-hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96, 1985), or trioma technique. Techniques for producing hybridomas are well known (generally, see Current Protocols in Immunology, 1994, Coligan et al. (Eds.), John Wiley & Sons, Inc., New York, NY). For example, monoclonal antibodies can be detected by screening hybridoma culture supernatants for antibodies that bind to the polypeptide or epitope of interest using a standard ELISA assay.

[0283] Appropriate nucleotide changes can be introduced into DNA encoding human, humanized, or chimeric antibodies, or the antibodies or antigen-binding fragments thereof described herein, or variants of the antibodies or antigen-binding fragments described herein can be prepared by peptide synthesis. Such variants include, for example, deletions, insertions, or substitutions of residues within the amino acid sequence that generates the antigen-binding site or antigen-binding domain of the antibody. Among such a population of variants, some antibodies or antigen-binding fragments have an increased affinity for the target protein. Any combination of deletions, insertions, and / or combinations can be achieved in an antibody or its antigen-binding fragment with an increased binding affinity for the target. Changes in the number of glycosylation sites (e.g., increase or decrease), changes in the type of glycosylation sites (e.g., changing the amino acid sequence so that different sugars are attached by enzymes present in the cell), or introduction of new glycosylation sites, etc., can change the antibody or antigen-binding fragment, or introduce new post-translational modifications into the antibody or antigen-binding fragment by changes in the amino acids introduced into the antibody or antigen-binding fragment.

[0284] The antibodies disclosed herein can be derived from any species of animal, including mammals. Non-limiting examples of natural antibodies include antibodies derived from humans, primates such as monkeys and apes, cows, pigs, horses, sheep, camelids (e.g., camels and llamas), chickens, goats, and rodents (e.g., rats, mice, hamsters, and rabbits), including transgenic rodents genetically engineered to produce human antibodies.

[0285] Antibody sequences with desired binding affinities can be optimized using phage display (panning). In this technique, a gene encoding a single-chain Fv (including VH or VL) is inserted into the phage coat protein gene, enabling the phage to "display" the scFv on its outer surface while containing the gene for the protein inside, resulting in the linkage of genotype and phenotype. To detect the interaction between the displayed antigen-binding site and the target antigen, the phage displaying the antigen can then be screened against the target antigen. Thus, a large library of proteins can be screened and amplified in a process called in vitro selection, and antibody sequences with desired binding affinities can be obtained.

[0286] Examples of human antibodies and humanized antibodies include antibodies having variable and constant regions derived from human germline immunoglobulin sequences (or having the same amino acid sequences as those derived therefrom). Examples of human antibodies can include amino acid residues encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or somatic mutations in vivo) that are not present within the CDRs.

[0287] Humanized antibodies typically have a human framework (FR) into which non-human CDRs are grafted. Thus, humanized antibodies have one or more amino acid sequences introduced from a non-human source into a human. Therefore, a "humanized" antibody is a chimeric antibody in which a portion considerably smaller than the intact human V domain is replaced by the corresponding sequence derived from a non-human species. In practice, humanized antibodies are typically mouse antibodies in which some CDR residues and some FR residues are replaced by residues derived from similar sites within the human antibody.

[0288] Furthermore, it is important to humanize antibodies while retaining high specificity and affinity for antigens, as well as other favorable biological properties. To achieve this goal, humanized antibodies can be prepared by an analytical process of parental and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are generally available and well known to those skilled in the art. Computer programs are available that can diagrammatically display the possible three-dimensional conformations of selected candidate immunoglobulin sequences. By observing these displays, it is possible to analyze the possible roles of residues in the functionalization of the candidate immunoglobulin sequences, i.e., to analyze the residues of the candidate immunoglobulin that affect its ability to bind to its antigen. In this way, FR residues can be selected and combined from recipient and import sequences to achieve desired antibody properties, such as increased affinity for the target antigen.

[0289] In some embodiments, a mouse having a humanized heavy-chain immunoglobulin locus and a humanized κ-chain immunoglobulin locus (e.g., RenMab TM mouse) is used to generate antibodies. A heavy-chain immunoglobulin locus is a region on a chromosome that contains genes for the heavy chain of an antibody. The locus can include, for example, human IGHV (variable) genes, human IGHD (diversity) genes, human IGHJ (joining) genes, and mouse heavy-chain constant domain genes. A κ-chain immunoglobulin locus is a region on a chromosome that contains genes encoding the light chain (κ-chain) of an antibody. Examples of κ-chain immunoglobulin loci include human IGKV (variable) genes, human IGKJ (joining) genes, and mouse light-chain constant domain genes. RenMab TM Detailed descriptions of the RenMab mouse can be found in PCT / CN2020 / 075698 or US20200390073A1, which are hereby incorporated by reference in their entirety.

[0290] In some embodiments, a mouse having a humanized heavy-chain immunoglobulin locus and a humanized κ-chain immunoglobulin locus (e.g., RenLiteTM Using a mouse, antibodies are generated. A heavy-chain immunoglobulin locus is a region on a chromosome that contains genes for the heavy chains of antibodies. The locus can include, for example, human IGHV (variable) genes, human IGHD (diversity) genes, human IGHJ (joining) genes, and mouse heavy-chain constant domain genes. A κ-chain immunoglobulin locus is a region on a chromosome that contains genes encoding a common light chain. Examples of κ-chain immunoglobulin loci can include human IGKV (variable) genes, human IGKJ (joining) genes, and mouse light-chain constant domain genes. RenLite TM Detailed descriptions regarding the mouse can be found in PCT / CN2021 / 097652, which is hereby incorporated by reference in its entirety.

[0291] Identity or homology to an original sequence is generally the percentage of amino acid residues present in a candidate sequence that is identical to the sequence present in a human, humanized, or chimeric antibody or fragment, without considering conservative substitutions as part of sequence identity, after aligning the sequences and introducing gaps if necessary to achieve maximum percent sequence identity.

[0292] In some embodiments, a covalent modification can be added to an antibody, its antigen-binding fragment, or an antigen-binding protein construct (e.g., a bispecific antibody). These covalent modifications can be added by chemical or enzymatic synthesis or by enzymatic or chemical cleavage. Other types of covalent modifications of an antibody or antibody fragment are introduced into the molecule by reacting the targeted amino acid residues of the antibody or fragment with an organic derivatizing agent capable of reacting with a selected side chain or N- or C-terminal residue.

[0293] In some embodiments, provided is an antibody variant having a carbohydrate structure lacking fucose (directly or indirectly) linked to the Fc region. For example, the amount of fucose in such an antibody may be 1% - 80%, 1% - 65%, 5% - 65%, or 20% - 40%. The amount of fucose is determined, for example, by calculating the average amount of fucose in the sugar chain at Asn297 relative to the total of all sugar structures (e.g., complex, hybrid, and high-mannose structures) linked to Asn297, as measured by MALDI-TOF mass spectrometry as described in WO 2008 / 077546. Asn297 refers to the asparagine residue located at position 297 within the Fc region (Eu numbering of Fc region residues, or position 314 in Kabat numbering), however, Asn297 may also be located upstream or downstream by about ±3 amino acids from position 297, i.e., between positions 294 and 300, due to minor sequence variations in the antibody. Such fucosylation variants may have improved ADCC function. In some embodiments, to reduce glycan heterogeneity, the Fc region of the antibody is further recombinantly engineered to substitute the asparagine at position 297 with alanine (N297A).

[0294] In some embodiments, to promote production efficiency by avoiding Fab-arm exchange, the Fc region of the antibody is further recombinantly engineered to substitute the serine at position 228 (EU numbering) of IgG4 with proline (S228P). A detailed description of the S228 mutation is provided, for example, in Silva et al. “The S228P mutation prevents in vivo and in vitro IgG4 Fab-arm exchange as demonstrated using a combination of novel quantitative immunoassays and physiological matrix preparation.” Journal of Biological Chemistry 290.9 (2015):5462 - 5469, which is incorporated herein by reference in its entirety.

[0295] In some embodiments, the methods described herein are designed to produce bispecific antibodies. By engineering the interface between a pair of antibody molecules to maximize the proportion of heterodimers recovered from recombinant cell culture, bispecific antibodies can be produced. For example, the interface can comprise at least a portion of the CH3 domain of the antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). By replacing large amino acid side chains with smaller ones (e.g., alanine or threonine), a compensatory "cavity" of the same or similar size as the large side chain is created at the interface of the second antibody molecule. This provides a mechanism for increasing the yield of heterodimers over other unwanted end products such as homodimers. The method is described, for example, in WO 96 / 27011, which is incorporated herein by reference in its entirety.

[0296] In some embodiments, Knobs-into-Holes (KIH) technology can be used, which involves engineering the CH3 domain to create either a "knob" or a "hole" on each heavy chain, facilitating heterodimerization. The KIH technology is described, for example, in Xu, Yiren, et al. “Production of bispecific antibodies in ‘knobs-into-holes’ using a cell-free expression system.” MAbs. Vol. 7. No. 1. Taylor & Francis, 2015, which is incorporated herein by reference in its entirety. In some embodiments, one heavy chain has a T366W and / or S354C (knob) substitution (EU numbering), and the other heavy chain has a Y349C, T366S, L368A, and / or Y407V (hole) substitution (EU numbering). In some embodiments, one heavy chain has one or more of the substitutions Y349C and T366W (EU numbering). The other heavy chain can have one or more substitutions E356C, T366S, L368A, and Y407V (EU numbering). Additionally, the substitution (-ppcpScp → -ppcpPcp-) can also be introduced into the hinge region of both substituted IgGs.

[0297] Bispecific antibodies can also include, for example, cross-linked or "heteroconjugate" antibodies. For example, one of the antibodies within the heteroconjugate can be coupled to avidin and the other to biotin. Heteroconjugate antibodies can also be produced using any convenient cross-linking method. Suitable cross-linking agents and cross-linking techniques are well known in the art and are disclosed in U.S. Patent No. 4,676,980, which is incorporated herein by reference in its entirety.

[0298] Methods for generating bispecific antibodies from antibody fragments are also well known in the art. For example, bispecific antibodies can be prepared using chemical linkages. Brennan et al. (Science 229:81, 1985) described procedures in which intact antibodies are cleaved by proteolysis to generate F(ab’)2 fragments. These fragments are reduced in the presence of sodium arsenite, a dithiol crosslinking agent, to stabilize the neighboring dithiols and prevent intermolecular disulfide formation. The resulting Fab’ fragments are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab’ TNB derivatives is then reconverted to the Fab’ thiol by reduction with mercaptoethylamine, mixed with an equimolar amount of another Fab’ TNB derivative, and a bispecific antibody is formed.

[0299] Recombinant vector The present disclosure also provides recombinant vectors (e.g., expression vectors) comprising the isolated polynucleotides disclosed herein (e.g., polynucleotides encoding the polypeptides disclosed herein), host cells into which the recombinant vectors have been introduced (i.e., such that the host cells contain the polynucleotide and / or a vector containing the polynucleotide), and the production of recombinant antibody polypeptides or fragments thereof by recombinant techniques.

[0300] As used herein, a "vector" is any construct that can deliver one or more polynucleotides of interest to a host cell when the vector is introduced into the host cell. An "expression vector" can deliver one or more polynucleotides of interest as a coded polypeptide and express it in a host cell into which the expression vector has been introduced. Thus, in an expression vector, the polynucleotide of interest is placed at or near or adjacent to the integration site of the polynucleotide of interest so that it can be translated in the host cell into which the expression vector has been introduced. It is operably linked to control elements such as promoters, enhancers, and / or polyA tails either within the vector or in the genome of the host cell, so that the polynucleotide of interest is arranged for expression within the vector.

[0301] Vectors can be introduced into host cells by methods well known in the art, such as electroporation, chemical transfection (e.g., DEAE-dextran), transformation, transfection, and infection and / or transduction (e.g., by recombinant virus). Thus, non-limiting examples of vectors include viral vectors (those that can be used to generate recombinant viruses), naked DNA or RNA, plasmids, cosmids, phage vectors, and DNA or RNA expression vectors associated with cationic condensing agents.

[0302] In some embodiments, the polynucleotides disclosed herein (e.g., polynucleotides encoding the polypeptides disclosed herein) are introduced using a viral expression system (e.g., vaccinia or other poxviruses, retroviruses, or adenoviruses), which may involve the use of a non-pathogenic (defective) replicable virus or may involve the use of a replication-incompetent virus. In the latter case, viral propagation generally occurs only in complementing virus packaging cells. For example, suitable systems are disclosed in Fisher-Hoch et al., 1989, Proc. Natl. Acad. Sci. USA 86:317-321; Flexner et al., 1989, Ann. N.Y. Acad Sci. 569:86-103; Flexner et al., 1990, Vaccine, 8:17-21; U.S. Patent Nos. 4,603,112, 4,769,330, and 5,017,487; WO 89 / 01973, U.S. Patent No. 4,777,127; GB 2,200,651; EP 0,345,242; WO 91 / 02805; Berchner-Biotechniques, 6:616-627, 1988; Rosenfeld et al., 1991, Science, 252:431-434; Kolls et al., 1994, Proc. Natl. Acad. Sci. USA, 91:215-219; Kass-Eisler et al., 1993, Proc. Natl. Acad. Sci. USA, 90:11498-11502; Guzman et al., 1993, Circulation, 88:2838-2848; and Guzman et al., 1993, Cir. Res., 73:1202-1207. Techniques for incorporating DNA into such expression systems are well known to those of skill in the art. DNA may also be "naked", as described, for example, in Ulmer et al., 1993, Science, 259:1745-1749 and Cohen, 1993, Science, 259:1691-1692. Incorporation of naked DNA can be increased by coating the DNA onto biodegradable beads that are efficiently transported into cells.

[0303] For expression, the DNA insert containing a polynucleotide encoding an antibody or a polypeptide disclosed herein can be operably linked to a suitable promoter (e.g., a heterologous promoter) such as the phage λPL promoter, the E. coli lac, trp and tac promoters, the SV40 early and late promoters, and the promoter of the retroviral LTR. Other suitable promoters are known to those skilled in the art. The expression construct can further contain sites for transcription initiation and termination, and within the transcription region, a ribosome binding site for translation. The coding portion of the mature transcript expressed by the construct can include a translation initiation at the beginning and a stop codon (UAA, UGA or UAG) approximately located at the end of the translated polypeptide.

[0304] As shown, the expression vector can include at least one selectable marker. Such markers include dihydrofolate reductase for eukaryotic cell culture, or neomycin resistance, and the tetracycline or ampicillin resistance genes for E. coli and other bacterial cultures. Representative examples of suitable hosts include, but are not limited to, bacterial cells such as E. coli, Streptomyces, and Salmonella typhimurium cells, fungal cells such as yeast cells, insect cells such as Drosophila S2 and Spodoptera Sf9 cells, animal cells such as CHO, COS, Bowes melanoma, and HK 293 cells, and plant cells. Suitable culture media and conditions for the host cells described herein are well known in the art.

[0305] Non-limiting vectors for use in bacteria include pQE70, pQE60, and pQE-9 available from Qiagen, pBS vectors, Phagescript vectors, Bluescript vectors, pNH8A, pNH16a, pNH18A, pNH46A available from Stratagene, and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia. Non-limiting eukaryotic cell vectors include pWLNEO, pSV2CAT, pOG44, pXT1, and pSG available from Stratagene, and pSVK3, pBPV, pMSG, and pSVL available from Pharmacia. Other suitable vectors will be readily apparent to those skilled in the art.

[0306] Non-limiting bacterial promoters suitable for use include the E. coli lacI and lacZ promoters, T3 and T7 promoters, gpt promoter, λPR and PL promoters, and trp promoter. Suitable eukaryotic cell promoters include the CMV immediate early promoter, HSV thymidine kinase promoter, early and late SV40 promoters, retroviral LTR promoters such as those of Rous sarcoma virus (RSV), and metallothionein promoters such as the mouse metallothionein-I promoter.

[0307] In the yeast Saccharomyces cerevisiae, several vectors containing constitutive or inducible promoters such as the alpha factor, alcohol oxidase, and PGH may be used. See Ausubel et al. (1989) Current Protocols in Molecular Biology, John Wiley & Sons, New York, N.Y, and Grant et al., Methods Enzymol., 153:516-544 (1997) for a review.

[0308] Introduction of the construct into host cells can be accomplished by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986), the entirety of which is incorporated herein by reference.

[0309] Transcription of the DNA encoding the antibodies of the present disclosure by more eukaryotes can be increased by inserting enhancer sequences into the vector. Enhancers are typically cis-acting elements of DNA, about 10 - 300 bp, that serve to increase the transcriptional activity of a promoter in a given host cell type. Examples of enhancers include the SV40 enhancer, which is located behind the origin of replication at base pairs 100 - 270, the cytomegalovirus immediate early promoter enhancer, the polyoma enhancer behind the origin of replication, and the adenovirus enhancer.

[0310] To secrete the translated protein into the lumen of the endoplasmic reticulum, the periplasmic space, or the extracellular environment, an appropriate secretion signal can be incorporated into the expressed polypeptide. The signal can be endogenous to the polypeptide or the signal can be a heterologous signal.

[0311] A polypeptide (e.g., an antibody) can be expressed in a modified form such as a fusion protein (e.g., a GST fusion), or by a histidine tag, and can also contain not only a secretion signal but also additional heterologous functional regions. For example, regions of additional amino acids, particularly charged amino acids, can be added to the N-terminus of the polypeptide to improve stability and durability in the host cell during purification or subsequent handling and storage. Also, a peptide moiety can be added to the polypeptide to facilitate purification. Such regions can be removed prior to the final preparation of the polypeptide. Adding a peptide moiety to a polypeptide to, inter alia, cause secretion or excretion, improve stability, and facilitate purification is well-known and routine in the art.

[0312] The present disclosure also provides nucleic acid sequences that are at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to any nucleotide sequence described herein, and amino acid sequences that are at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to any amino acid sequence described herein.

[0313] The present disclosure also provides nucleic acid sequences having at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to any nucleotide sequence described herein, and amino acid sequences having at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to any amino acid sequence described herein.

[0314] In some embodiments, the present disclosure relates to a nucleotide sequence encoding any peptide described herein, or any amino acid sequence encoded by any nucleotide sequence described herein. In some embodiments, the nucleic acid sequence is less than 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 150, 200, 250, 300, 350, 400, 500, or 600 nucleotides. In some embodiments, the amino acid sequence is less than 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, or 400 amino acid residues.

[0315] In some embodiments, the amino acid sequence (i) comprises an amino acid sequence; or (ii) consists of an amino acid sequence, wherein the amino acid sequence is any one of the sequences described herein.

[0316] In some embodiments, the nucleic acid sequence (i) comprises a nucleic acid sequence; or (ii) consists of a nucleic acid sequence, wherein the nucleic acid sequence is any one of the sequences described herein.

[0317] To measure the percent identity between two amino acid sequences, or two nucleic acid sequences, the sequences are aligned for optimal comparison (e.g., gaps may be introduced into one or both of the first and second amino acid or nucleic acid sequences to optimize alignment for comparison, and non-homologous sequences may be disregarded). Subsequently, the amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are compared. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are considered identical at that position (as used herein, "identity" of an amino acid or nucleic acid corresponds to "homology" of an amino acid or nucleic acid). The percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps that need to be introduced to optimally align the two sequences and the length of each gap. For example, sequence comparison and measurement of percent identity between two sequences can be performed using the Blossum62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5.

[0318] The percentage of sequence identity (e.g., amino acid sequence identity or nucleic acid identity) can also be measured. Methods for measuring the percentage of sequence identity are well known in the art. In some embodiments, sequence similarity can be measured using amino acid residues conserved with similar physicochemical properties (% identity), such as leucine and isoleucine. Families of amino acid residues having similar physicochemical properties are defined in the art. Such families include, for example, amino acids having basic side chains (e.g., lysine, arginine, histidine), amino acids having acidic side chains (e.g., aspartic acid, glutamic acid), amino acids having uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), amino acids having nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amino acids having β-branched side chains (e.g., threonine, valine, isoleucine), and amino acids having aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Often, the percentage of homology is higher than the percentage of identity.

[0319] The present disclosure provides one or more nucleic acids encoding any of the polypeptides described herein. In some embodiments, the nucleic acid (e.g., cDNA) comprises a polynucleotide encoding a polypeptide of the heavy chain described herein. In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide of the light chain described herein. In some embodiments, the nucleic acid comprises a polynucleotide encoding an scFv polypeptide described herein.

[0320] In some embodiments, the vector can have two of the nucleic acids described herein, and the vector encodes a VL region and a VH region that both bind to EGFR. In some embodiments, a pair of vectors is provided, each vector contains one of the nucleic acids described herein, and the pair of vectors together encodes a VL region and a VH region that both bind to EGFR.

[0321] In some embodiments, the vector contains two of the nucleic acids described herein, and the vector encodes a VL region and a VH region that both bind to MET. In some embodiments, a pair of vectors is provided, each vector contains one of the nucleic acids described herein, and the pair of vectors together encodes a VL region and a VH region that both bind to MET.

[0322] Vectors can also be constructed to express specific antibodies or polypeptides. In some embodiments, a vector can be constructed to co-express the light chain (EGFR-K) and heavy chain (EGFR-H) of an anti-EGFR antibody. In some embodiments, the vector can contain the sequences of the cytomegalovirus promoter (CMV), EGFR-K, polyadenylation (polyA), CMV, EGFR-H, simian vacuolating virus 40 terminator (SV40), and glutamine synthetase marker (GS) from the 5'-end to the 3'-end. In some embodiments, a vector can be constructed to co-express the anti-MET antibody light chain (MET-K) and anti-MET antibody heavy chain (MET-H). In some embodiments, the vector can contain the sequences of CMV, MET-K, polyA, MET-H, SV40, and GS from the 5'-end to the 3'-end. In some embodiments, a vector can be constructed to express the anti-MET antibody scFv polypeptide chain. In some embodiments, cells (e.g., CHO cells) are co-transfected using a first vector expressing an antibody heavy chain (e.g., any of the heavy chains described herein) and a second vector expressing an antibody light chain (e.g., any of the light chains described herein) to generate the monoclonal antibodies or antigen-binding fragments thereof described herein. In some embodiments, cells (e.g., CHO cells) are co-transfected using a first vector expressing an anti-EGFR antibody heavy chain (e.g., any of the anti-EGFR antibody heavy chains described herein), a second vector expressing an anti-MET antibody heavy chain (e.g., any of the anti-MET antibody heavy chains described herein), and a third vector expressing a common light chain (e.g., any of the common light chains described herein) to generate the antigen-binding protein constructs (e.g., any of the anti-EGFR / MET bispecific antibodies described herein) described herein.

[0323] Treatment method The methods described herein include methods of treating disorders associated with cancer. Generally, the methods include administering to a subject in need of or determined to be in need of such treatment a therapeutically effective amount of a recombinant antibody, an antigen-binding fragment thereof, an antigen-binding protein construct (e.g., a bispecific antibody) described herein.

[0324] As used in this context, "treatment" means alleviating at least one symptom of a disorder associated with cancer. In many cases, cancer is life-threatening. Thus, treatment can result in an increase in mean life expectancy (e.g., of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years). Treatment with a therapeutically effective amount of an agent described herein for the treatment of a condition associated with cancer results in a decrease in the number of cancer cells and / or alleviation of symptoms.

[0325] As used herein, the term "cancer" means an abnormal condition or state characterized by cells having the ability of autonomous growth, i.e., rapidly proliferating cell growth. This term means any type of cancerous growth or carcinogenic process, metastatic tissue or malignantly transformed cells, tissues, or organs, regardless of the type of tissue change or stage of invasiveness. As used herein, the term "tumor" means cancerous cells, e.g., a mass of cancerous cells. Cancers treatable or diagnosable using the methods described herein include malignant tumors of various organ systems such as those affecting the lung, chest, thyroid, lymphatic system, gastrointestinal tract, and urogenital tract, in addition to most colorectal cancers, renal cell cancers, prostate cancers and / or testicular tumors, non-small cell lung cancers, small intestine cancers, and adenocarcinomas including malignant tumors such as esophageal cancers. In some embodiments, the agents described herein are designed to treat or diagnose cancer tumors in a subject. The term "cancer tumor" is recognized in the art and means a malignant tumor of epithelial or endocrine gland tissue, including respiratory system cancer, digestive system cancer, urogenital system cancer, testicular cancer, breast cancer, prostate cancer, endocrine system cancer, and melanoma. In some embodiments, the cancer is renal cancer or melanoma. Exemplary cancer tumors include those formed from tissues of the cervix, lung, prostate, chest, head and neck, colon, and ovary. This term also includes carcinosarcomas, for example, malignant tumors composed of cancerous and sarcomatous tissues. "Adenocarcinoma" means a cancer tumor derived from glandular tissue or a cancer tumor in which tumor cells form recognizable glandular structures. The term "sarcoma" is recognized in the art and means a malignant tumor of mesenchymal origin.

[0326] In some embodiments, the cancer is a chemotherapy-resistant cancer.

[0327] In one aspect, the present disclosure also provides a method for treating cancer in a subject, a method for decreasing the rate of increase of tumor volume over time in a subject, a method for reducing the risk of metastasis, or a method for reducing the risk of further metastasis in a subject. In some embodiments, the treatment can interrupt, slow, arrest, or inhibit the progression of cancer. In some embodiments, the treatment can result in a reduction in the number, severity, and / or duration of one or more symptoms of cancer in the subject.

[0328] In one aspect, the present disclosure features a method comprising administering to a subject in need thereof a therapeutically effective amount of an antibody, an antigen-binding fragment thereof, or an antigen-binding protein construct (e.g., a bispecific antibody), or an antibody-drug conjugate disclosed herein, the subject having or identified or diagnosed as having cancer, e.g., a solid tumor, lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, or lung carcinoma), gastric cancer (e.g., gastric carcinoma), skin cancer (e.g., cutaneous carcinoma), colorectal cancer, breast cancer, head and neck cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, CNS cancer, liver cancer, nasopharyngeal cancer, carcinoma of the corpus uteri, or a brain tumor.

[0329] As used herein, the terms "subject" and "patient" are used interchangeably throughout the specification and refer to an animal, human, or non-human to whom treatment according to the methods of the invention is provided. Veterinary and non-veterinary uses are contemplated by the present invention. A human patient can be an adult human or a juvenile human (e.g., a human under 18 years of age). In addition to humans, patients include, but are not limited to, mice, rats, hamsters, guinea pigs, rabbits, ferrets, cats, dogs, and primates. For example, non-human primates (e.g., monkeys, chimpanzees, gorillas, etc.), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, rabbits), lagomorphs, suids (e.g., pigs, mini-pigs), equids, canids, felids, bovids, and other domestic, farm, and zoo animals.

[0330] In some embodiments, the compositions and methods disclosed herein can be used for the treatment of patients at risk of cancer. Patients suffering from cancer can be identified by various methods well known in the art.

[0331] As used herein, "effective amount" means an amount or dose sufficient to produce a beneficial or desired result, including interrupting, delaying, preventing, or inhibiting the progression of a disease, such as cancer. The effective amount will vary depending on, for example, the age and weight of the subject to whom the antibody, antigen-binding fragment, antibody-drug conjugate, polynucleotide encoding the antibody, vector comprising the polynucleotide, and / or composition thereof is administered, the severity of the symptoms, and the route of administration, and thus the administration can be determined individually.

[0332] The effective amount can be administered in one or more administrations. For example, an effective amount of an antibody, antigen-binding fragment, or antibody-drug conjugate is an amount sufficient to alleviate, arrest, stabilize, reverse, inhibit, slow, and / or delay the progression of an autoimmune disease or cancer in a patient, or, in vitro, to alleviate, arrest, stabilize, reverse, slow, and / or delay the growth of a cell (e.g., a biopsy cell, any of the cancer cells described herein, or a cell line (e.g., a cancer cell line)). As will be appreciated in the art, the effective amount of an antibody, antigen-binding fragment, or antibody-drug conjugate may vary depending on, among other factors, the patient's medical history, as well as the type (and / or dose) of antibody used.

[0333] The effective amount and schedule for administering the antibodies, polynucleotides encoding the antibodies, antibody-drug conjugates, and / or compositions disclosed herein can be determined experimentally, and making such determinations is within the skill of the art. Those of skill in the art will understand that the dosage that needs to be administered will vary depending on, for example, the mammal receiving the antibodies, polynucleotides encoding the antibodies, antibody-drug conjugates, and / or compositions disclosed herein, the route of administration, the specific type of antibody, the polynucleotide encoding the antibody, the antigen-binding fragment, the antibody-drug conjugate, and / or the composition disclosed herein that is being used, and other agents being administered to the mammal. Guidance for selecting an appropriate dosage for an antibody or antigen-binding fragment can be found in the literature regarding the therapeutic use of antibodies and antigen-binding fragments, e.g., Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge, N.J., 1985, ch. 22 and pp. 303-357, Smith et al., Antibodies in Human Diagnosis and Therapy, Haber et al., eds., Raven Press, New York, 1977, pp. 365-389.

[0334] The typical daily dosage of an effective amount of an antibody, its antigen-binding fragment, or an antigen-binding protein construct (e.g., a bispecific antibody) is from 0.01 mg / kg to 100 mg / kg. In some embodiments, the dosage can be less than 100 mg / kg, 30 mg / kg, 20 mg / kg, 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, 0.5 mg / kg, or 0.1 mg / kg. In some embodiments, the dosage can be greater than 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, 0.5 mg / kg, 0.1 mg / kg, 0.05 mg / kg, or 0.01 mg / kg. In some embodiments, the dosage is about, or at least 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, 0.9 mg / kg, 0.8 mg / kg, 0.7 mg / kg, 0.6 mg / kg, 0.5 mg / kg, 0.4 mg / kg, 0.3 mg / kg, 0.2 mg / kg, or 0.1 mg / kg.

[0335] In any of the methods described herein, at least one antibody, an antigen-binding fragment thereof, or an antigen-binding protein construct (e.g., a bispecific antibody), an antibody-drug conjugate, or a pharmaceutical composition (e.g., any of the antibodies, antigen-binding fragments, antibody-drug conjugates, or pharmaceutical compositions described herein), and optionally, at least one additional therapeutic agent, can be administered to a subject at least once a week (e.g., once a week, twice a week, three times a week, four times a week, once a day, twice a day, or three times a day). In some embodiments, at least two different antibodies and / or antigen-binding fragments are administered in the same composition (e.g., a liquid composition). In some embodiments, at least one antibody, antigen-binding fragment, antigen-binding protein construct (e.g., a bispecific antibody), or antibody-drug conjugate, and at least one additional therapeutic agent are administered in the same composition (e.g., a liquid composition). In some embodiments, at least one antibody or antigen-binding fragment, and at least one additional therapeutic agent are administered in two different compositions (e.g., a liquid composition containing at least one antibody or antigen-binding fragment, and a solid oral composition containing at least one additional therapeutic agent). In some embodiments, at least one additional therapeutic agent is administered as a pill, tablet, or capsule. In some embodiments, at least one additional therapeutic agent is administered as a sustained-release oral formulation.

[0336] In some embodiments, one or more additional therapeutic agents can be administered to a subject before, or after administering, at least one antibody, antigen-binding antibody fragment, antibody-drug conjugate, or pharmaceutical composition (e.g., any of the antibodies, antigen-binding antibody fragments, or pharmaceutical compositions described herein). In some embodiments, the one or more additional therapeutic agents and the at least one antibody, antigen-binding antibody fragment, antibody-drug conjugate, or pharmaceutical composition (e.g., any of the antibodies, antigen-binding antibody fragments, or pharmaceutical compositions described herein) are administered to the subject such that in the subject, there is an overlap between the bioactive period of the one or more additional therapeutic agents and the bioactive period of the at least one antibody or antigen-binding fragment (e.g., any of the antibodies or antigen-binding fragments described herein).

[0337] In some embodiments, for an extended period of time (e.g., over a period of at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 years, or 5 years), at least one antibody, antigen-binding antibody fragment, antibody-drug conjugate, or pharmaceutical composition (e.g., any of the antibodies, antigen-binding antibody fragments, or pharmaceutical compositions described herein) can be administered to a subject. A skilled medical professional can determine the length of the treatment period using any of the methods described herein to diagnose or monitor the effectiveness of the treatment (e.g., observing at least one symptom of cancer). As described herein, a skilled medical professional can also vary (e.g., increase or decrease) the identity and number of antibodies or antigen-binding antibody fragments, antibody-drug conjugates (and / or one or more additional therapeutic agents) administered to the subject, and can adjust (e.g., increase or decrease) the dosage or frequency of administration of the at least one antibody or antigen-binding antibody fragment (and / or one or more additional therapeutic agents) to the subject based on an assessment of the effectiveness of the treatment (e.g., using any of the methods described herein and well-known in the art).

[0338] In some embodiments, one or more additional therapeutic agents can be administered to a subject. The additional therapeutic agent can include one or more inhibitors selected from the group consisting of an inhibitor of B-Raf, an EGFR inhibitor, an inhibitor of MEK, an inhibitor of ERK, an inhibitor of K-Ras, an inhibitor of c-Met, an inhibitor of anaplastic lymphoma kinase (ALK), an inhibitor of phosphatidylinositol 3-kinase (PI3K), an inhibitor of Akt, an inhibitor of mTOR, a dual PI3K / mTOR inhibitor, an inhibitor of Bruton's tyrosine kinase (BTK), and an inhibitor of isocitrate dehydrogenase 1 (IDH1) and / or isocitrate dehydrogenase 2 (IDH2). In some embodiments, the additional therapeutic agent is an inhibitor of indoleamine 2,3-dioxygenase-1 (IDO1) (e.g., epacadostat).

[0339] In some embodiments, the additional therapeutic agent can include one or more inhibitors selected from the group consisting of an inhibitor of HER3, an inhibitor of LSD1, an inhibitor of MDM2, an inhibitor of BCL2, an inhibitor of CHK1, an inhibitor of the activated hedgehog signaling pathway, and an agent that selectively degrades estrogen receptor.

[0340] In some embodiments, the additional therapeutic agent can include one or more therapeutic agents selected from the group consisting of trabectedin, nab-paclitaxel, trebananib, pazopanib, cediranib, palbociclib, everolimus, fluoropyrimidine, IFL, regorafenib, leurosidine, alimta, dicaida, sutent, temsirolimus, axitinib, everolimus, sorafenib, votrient, pazopanib, IMA-901, AGS-003, cabozantinib, vinflunine, Hsp90 inhibitor, Ad-GM-CSF, temozolomide, IL-2, IFNa, vinblastine, thalidomide, dacarbazine, cyclophosphamide, lenalidomide, azacitidine, lenalidomide, bortezomib, amrubicin, carfilzomib, pralatrexate, and enzastaurin.

[0341] In some embodiments, the additional therapeutic agent can comprise one or more therapeutic agents selected from the group consisting of an adjuvant, a TLR agonist, tumor necrosis factor (TNF)α, IL-1, HMGB1, an IL-10 antagonist, an IL-4 antagonist, an IL-13 antagonist, an IL-17 antagonist, an HVEM antagonist, an ICOS agonist, a treatment targeting CX3CL1, a treatment targeting CXCL9, a treatment targeting CXCL10, a treatment targeting CCL5, an LFA-1 agonist, an ICAM1 agonist, and a selectin agonist.

[0342] In some embodiments, carboplatin, nab-paclitaxel, paclitaxel, cisplatin, pemetrexed, gemcitabine, FOLFOX, or FOLFIRI is administered to the subject.

[0343] In some embodiments, the additional therapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-LAG-3 antibody, an anti-TIGIT antibody, an anti-BTLA antibody, an anti-CTLA-4 antibody, an anti-CD40 antibody, an anti-OX40 antibody, an anti-4-1BB antibody, an anti-TIM3 antibody, or an anti-GITR antibody.

[0344] Pharmaceutical Compositions and Routes of Administration Also provided herein are pharmaceutical compositions containing at least one (e.g., 1, 2, 3, or 4) of the antigen-binding protein constructs, antibodies (e.g., bispecific antibodies), antigen-binding fragments, or antibody-drug conjugates described herein. Any two or more (e.g., 2, 3, or 4) of the antigen-binding protein constructs, antibodies, antigen-binding fragments, or antibody-drug conjugates described herein can be present in the pharmaceutical composition in any combination. The pharmaceutical composition can be formulated in any manner well known in the art.

[0345] The pharmaceutical composition is formulated to be compatible with its intended route of administration (e.g., intravenous, intraarterial, intramuscular, intradermal, subcutaneous, or intraperitoneal). The composition can include a sterile diluent (e.g., sterile water or saline), a nonvolatile oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents, antibacterial or antifungal agents (e.g., benzyl alcohol or methylparaben, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.), antioxidants (such as ascorbic acid or sodium bisulfite), chelating agents (such as ethylenediaminetetraacetic acid), buffering agents (such as acetate, citrate, or phosphate), and isotonic agents (e.g., sugars (e.g., dextrose), polyalcohols (e.g., mannitol or sorbitol), or salts (e.g., sodium chloride)), or any combination thereof. Liposome suspensions can also be used as pharmaceutically acceptable carriers (see, e.g., U.S. Patent No. 4,522,811). The preparation of the composition can be formulated and enclosed in ampoules, disposable syringes, or multi-dose vials. If necessary (e.g., as in injectable formulations), appropriate fluidity can be maintained, for example, by using coatings such as lecithin or surfactants. The absorption of the antibody or its antigen-binding fragment can be prolonged by including agents that delay absorption (e.g., aluminum monostearate and gelatin). Alternatively, sustained release can be achieved by implant and microencapsulation delivery systems, including biodegradable and biocompatible polymers (e.g., ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid; Alza Corporation and Nova Pharmaceutical, Inc.).

[0346] A composition containing one or more of the antigen-binding protein constructs, antibodies, antigen-binding fragments, antibody-drug conjugates described herein can be formulated in unit dosage form (i.e., physically discrete units containing a predetermined amount of the active compound, which are convenient for administration and uniform in dosage) for parenteral (e.g., intravenous, intraarterial, intramuscular, intradermal, subcutaneous, or intraperitoneal) administration.

[0347] The toxicity and therapeutic efficacy of the composition can be determined by standard pharmaceutical procedures in cell cultures or experimental animals (e.g., monkeys). The LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population) can be determined, and the therapeutic index is the ratio of LD50:ED50. Agents with a high therapeutic index are preferred. Care should be taken to minimize the potential for damage (i.e., reduce undesirable side effects) if the agent exhibits undesirable side effects. Toxicity and therapeutic efficacy can be determined by other standard pharmaceutical procedures.

[0348] Data obtained from cell culture assays and animal studies can be used in formulating appropriate dosages of any given agent for use in a subject (e.g., a human). A therapeutically effective amount of one or more (e.g., 1, 2, 3, or 4) antigen-binding protein constructs, antibodies, or antigen-binding fragments thereof (e.g., any of the antibodies or antibody fragments described herein) is an amount that treats (e.g., kills cancer cells) the subject's disease in a subject (e.g., a human subject identified as having cancer), or a subject identified as being at risk of developing a disease (e.g., a subject who previously had cancer but is currently in remission), and reduces the severity, frequency, and / or duration of one or more symptoms of the disease in a subject (e.g., a human). The effectiveness and administration of any of the antigen-binding protein constructs, antibodies, or antigen-binding fragments described herein can be determined by a healthcare professional or a veterinary professional using methods well known in the art, in addition to observing one or more symptoms of the disease in a subject (e.g., a human). Certain factors can affect the dosage and timing required to effectively treat a subject (e.g., the severity of the disease or disorder, previous treatments, the subject's overall health and / or age, and the presence of other diseases).

[0349] Exemplary dosages include the amount (milligrams or micrograms) of any of the antigen-binding protein constructs, antibodies, antigen-binding fragments, or antibody-drug conjugates described herein per kilogram of the subject's body weight (e.g., about 1 μg / kg to about 500 mg / kg; about 100 μg / kg to about 500 mg / kg; about 100 μg / kg to about 50 mg / kg; about 10 μg / kg to about 5 mg / kg; about 10 μg / kg to about 0.5 mg / kg; or about 0.1 mg / kg to about 0.5 mg / kg). Although the...

Claims

1. An antibody or antigen-binding fragment thereof that binds to EGFR (epidermal growth factor receptor), a heavy chain variable region (VH) comprising complementarity-determining regions (CDR) 1, 2, and 3, wherein the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH CDR1, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH CDR2, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH CDR3, said heavy chain variable region, a light chain variable region (VL) comprising CDR1, 2, and 3, wherein the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL CDR1, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL CDR2, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL CDR3, said light chain variable region, and the amino acid sequences of the selected VH CDR1, 2, and 3, and the amino acid sequences of the selected VL CDR1, 2, and 3 are one of the following, an antibody or antigen-binding fragment thereof. (1) The amino acid sequences of the selected VH CDR1, 2, 3 are shown in SEQ ID NOs: 4-6 respectively, and the amino acid sequences of the selected VL CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (2) The amino acid sequences of the selected VH CDR1, 2, 3 are shown in SEQ ID NOs: 7-9 respectively, and the amino acid sequences of the selected VL CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (3) The amino acid sequences of the selected VH CDR1, 2, 3 are shown in SEQ ID NOs: 10-12 respectively, and the amino acid sequences of the selected VL CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (4) The amino acid sequences of the selected VH CDR1, 2, 3 are shown in SEQ ID NOs: 13-15 respectively, and the amino acid sequences of the selected VL CDR1, 2, 3 are shown in SEQ ID NOs: 1-3 respectively; (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 16 to 18 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 34 to 36 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 37 to 39 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 40 to 42 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 43 to 45 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 46 to 48 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 82 to 84 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; and (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3.

2. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 4 to 6, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 1.

3. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 7 to 9, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 1.

4. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 10 to 12, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 1.

5. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 13 to 15, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 1.

6. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 16-18 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively, the antibody or antigen-binding fragment thereof according to claim 1.

7. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 82-84 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively, the antibody or antigen-binding fragment thereof according to claim 1.

8. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 85-87 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively, the antibody or antigen-binding fragment thereof according to claim 1.

9. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 88-90 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively, the antibody or antigen-binding fragment thereof according to claim 1.

10. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 91-93 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively, the antibody or antigen-binding fragment thereof according to claim 1.

11. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 34-36 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively, the antibody or antigen-binding fragment thereof according to claim 1.

12. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 37-39 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1-3 respectively, the antibody or antigen-binding fragment thereof according to claim 1.

13. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 40 to 42, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively, the antibody or antigen-binding fragment thereof according to claim 1.

14. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 43 to 45, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively, the antibody or antigen-binding fragment thereof according to claim 1.

15. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 46 to 48, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively, the antibody or antigen-binding fragment thereof according to claim 1.

16. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 94 to 96, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively, the antibody or antigen-binding fragment thereof according to claim 1.

17. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 97 to 99, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively, the antibody or antigen-binding fragment thereof according to claim 1.

18. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 100 to 102, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively, the antibody or antigen-binding fragment thereof according to claim 1.

19. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 103 to 105, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively, the antibody or antigen-binding fragment thereof according to claim 1.

20. An antibody or antigen-binding fragment thereof that binds to EGFR, A heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to the selected VH sequence, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to the selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following: an antibody or an antigen-binding fragment thereof. (1) The selected VH sequence is SEQ ID NO: 62, and the selected VL sequence is SEQ ID NO: 61; (2) The selected VH sequence is SEQ ID NO: 63, and the selected VL sequence is SEQ ID NO: 61; (3) The selected VH sequence is SEQ ID NO: 64, and the selected VL sequence is SEQ ID NO: 61; (4) The selected VH sequence is SEQ ID NO: 65, and the selected VL sequence is SEQ ID NO: 61; (5) The selected VH sequence is SEQ ID NO: 66, and the selected VL sequence is SEQ ID NO: 61; (6) The selected VH sequence is SEQ ID NO: 106, and the selected VL sequence is SEQ ID NO: 61; (7) The selected VH sequence is SEQ ID NO: 107, and the selected VL sequence is SEQ ID NO: 61; (8) The selected VH sequence is SEQ ID NO: 108, and the selected VL sequence is SEQ ID NO: 61; and (9) The selected VH sequence is SEQ ID NO: 109, and the selected VL sequence is SEQ ID NO:

61.

21. The antibody or antigen-binding fragment thereof according to claim 20, wherein the VH comprises the sequence of SEQ ID NO: 62 and the VL comprises the sequence of SEQ ID NO:

61.

22. The antibody or antigen-binding fragment thereof according to claim 20, wherein the VH comprises the sequence of SEQ ID NO: 63 and the VL comprises the sequence of SEQ ID NO:

61.

23. The antibody or antigen-binding fragment thereof according to claim 20, wherein the VH comprises the sequence of SEQ ID NO: 64 and the VL comprises the sequence of SEQ ID NO:

61.

24. The antibody or antigen-binding fragment thereof according to claim 20, wherein the VH comprises the sequence of SEQ ID NO: 65 and the VL comprises the sequence of SEQ ID NO:

61.

25. The antibody or antigen-binding fragment thereof according to claim 20, wherein the VH comprises the sequence of SEQ ID NO: 66 and the VL comprises the sequence of SEQ ID NO:

61.

26. The antibody or antigen-binding fragment thereof according to claim 20, wherein the VH comprises the sequence of SEQ ID NO: 106 and the VL comprises the sequence of SEQ ID NO:

61.

27. The antibody or antigen-binding fragment thereof according to claim 20, wherein the VH contains the sequence of SEQ ID NO: 107 and the VL contains the sequence of SEQ ID NO:

61.

28. The antibody or antigen-binding fragment thereof according to claim 20, wherein the VH contains the sequence of SEQ ID NO: 108 and the VL contains the sequence of SEQ ID NO:

61.

29. The antibody or antigen-binding fragment thereof according to claim 20, wherein the VH contains the sequence of SEQ ID NO: 109 and the VL contains the sequence of SEQ ID NO:

61.

30. An antibody or antigen-binding fragment thereof that binds to EGFR, comprising a heavy chain variable region (VH) containing VH CDR1, VH CDR2, and VH CDR3 identical to those of a selected VH sequence, and a light chain variable region (VL) containing VL CDR1, VL CDR2, and VL CDR3 identical to those of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following: an antibody or antigen-binding fragment thereof. (1) The selected VH sequence is SEQ ID NO: 62 and the selected VL sequence is SEQ ID NO: 61; (2) The selected VH sequence is SEQ ID NO: 63 and the selected VL sequence is SEQ ID NO: 61; (3) The selected VH sequence is SEQ ID NO: 64 and the selected VL sequence is SEQ ID NO: 61; (4) The selected VH sequence is SEQ ID NO: 65 and the selected VL sequence is SEQ ID NO: 61; (5) The selected VH sequence is SEQ ID NO: 66 and the selected VL sequence is SEQ ID NO: 61; (6) The selected VH sequence is SEQ ID NO: 106 and the selected VL sequence is SEQ ID NO: 61; (7) The selected VH sequence is SEQ ID NO: 107 and the selected VL sequence is SEQ ID NO: 61; (8) The selected VH sequence is SEQ ID NO: 108 and the selected VL sequence is SEQ ID NO: 61; and (9) The selected VH sequence is SEQ ID NO: 109 and the selected VL sequence is SEQ ID NO:

61.

31. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 30, wherein the antibody or antigen-binding fragment thereof specifically binds to human or monkey EGFR.

32. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 31, wherein the antibody or antigen-binding fragment thereof is a human antibody, a humanized antibody, or an antigen-binding fragment thereof.

33. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 32, wherein the antibody or antigen-binding fragment is a single-chain variable fragment (scFv).

34. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 33, wherein the antibody or antigen-binding fragment is a multispecific antibody (e.g., bispecific antibody) or an antigen-binding fragment thereof.

35. The antibody or antigen-binding fragment thereof according to claim 34, wherein the antibody or antigen-binding fragment further specifically binds to MET.

36. An antibody or antigen-binding fragment thereof that cross-competes with the antibody or antigen-binding fragment thereof according to any one of claims 1 to 35.

37. A nucleic acid comprising a polynucleotide encoding a polypeptide comprising the following: (1) An immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) containing complementarity-determining regions (CDRs) 1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 4 to 6, wherein the VH binds to EGFR when paired with a light chain variable region (VL) comprising the amino acid sequence shown in SEQ ID NO: 61; an immunoglobulin heavy chain or a fragment thereof. (2) An immunoglobulin light chain or a fragment thereof comprising a light chain variable region (VL) containing CDRs 1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein the VL binds to EGFR when paired with a heavy chain variable region (VH) comprising the amino acid sequence shown in SEQ ID NO: 62; an immunoglobulin light chain or a fragment thereof. (3) An immunoglobulin heavy chain or a fragment thereof comprising a VH containing CDRs 1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 7 to 9, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; an immunoglobulin heavy chain or a fragment thereof. (4) An immunoglobulin light chain or a fragment thereof comprising a VL containing CDRs 1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 63; an immunoglobulin light chain or a fragment thereof. An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 10 to 12, wherein said VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin light chain or a fragment thereof comprising a VL comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 1 to 3, wherein said VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO:

64. An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 13 to 15, wherein said VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin light chain or a fragment thereof comprising a VL comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 1 to 3, wherein said VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO:

65. An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 16 to 18, wherein said VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin light chain or a fragment thereof comprising a VL comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 1 to 3, wherein said VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO:

66. An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 34 to 36, wherein said VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 37-39, wherein the VH binds to EGFR when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 40-42, wherein the VH binds to EGFR when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 43-45, wherein the VH binds to EGFR when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 46-48, wherein the VH binds to EGFR when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 82-84, wherein the VH binds to EGFR when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1-3, wherein the VL binds to EGFR when forming a pair with a VH containing the amino acid sequence shown in SEQ ID NO:

106. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 85-87, wherein the VH binds to EGFR when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH containing the amino acid sequence shown in SEQ ID NO: 107, it binds to EGFR. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 88 to 90, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, it binds to EGFR. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH containing the amino acid sequence shown in SEQ ID NO: 108, it binds to EGFR. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 91 to 93, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, it binds to EGFR. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH containing the amino acid sequence shown in SEQ ID NO: 109, it binds to EGFR. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 94 to 96, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, it binds to EGFR. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 97 to 99, wherein when the VH pairs with a VL containing the amino acid sequence shown in SEQ ID NO: 61, it binds to EGFR. An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 100 to 102, wherein the VH binds to EGFR when paired with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the immunoglobulin heavy chain or a fragment thereof, and An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 103 to 105, wherein the VH binds to EGFR when paired with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the immunoglobulin heavy chain or a fragment thereof. **Claim 38** The nucleic acid according to claim 37, wherein the VH specifically binds to human or monkey EGFR when paired with a VL. **Claim 39** The nucleic acid according to claim 37 or 38, wherein the immunoglobulin heavy chain or the fragment thereof is a heavy chain of a human immunoglobulin or a humanized immunoglobulin or a fragment thereof. **Claim 40** The nucleic acid according to any one of claims 37 to 39, wherein the nucleic acid encodes a single-chain variable fragment (scFv). **Claim 41** The nucleic acid according to any one of claims 37 to 40, wherein the nucleic acid is cDNA. **Claim 42** An antibody or an antigen-binding fragment thereof that binds to MET (tyrosine protein kinase Met), A heavy chain variable region (VH) comprising complementarity-determining regions (CDR) 1, 2, and 3, wherein the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH CDR1, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH CDR2, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH CDR3, the heavy chain variable region, and A light chain variable region (VL) comprising CDR1, 2, and 3, wherein the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL CDR1, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL CDR2, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL CDR3, the light chain variable region, and The antibody or antigen-binding fragment thereof, wherein the amino acid sequences of the selected VH CDR1, 2, and 3, and the amino acid sequences of the selected VL CDR1, 2, and 3 are one of the following. (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 112 to 114 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 115 to 117 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 118 to 120 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 121 to 123 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 124 to 126 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 127 to 129 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 130 to 132 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 133 to 135 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 136 to 138 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 139 to 141 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 142 to 144 respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; and (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 145 to 147, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively.

43. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 19 to 21, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

44. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 22 to 24, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

45. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 25 to 27, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

46. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 28 to 30, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

47. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 49 to 51, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

48. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 52 to 54, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

49. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 55 to 57, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

50. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 58 to 60, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

51. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 112 to 114, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

52. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 115 to 117, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

53. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 118 to 120, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

54. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 121 to 123, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

55. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 124 to 126, respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3, respectively. The antibody or antigen-binding fragment thereof according to claim 42.

56. According to the Kabat numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 127 to 129 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3 respectively, the antibody or antigen-binding fragment thereof according to claim 42.

57. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 130 to 132 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3 respectively, the antibody or antigen-binding fragment thereof according to claim 42.

58. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 133 to 135 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3 respectively, the antibody or antigen-binding fragment thereof according to claim 42.

59. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 136 to 138 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3 respectively, the antibody or antigen-binding fragment thereof according to claim 42.

60. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 139 to 141 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3 respectively, the antibody or antigen-binding fragment thereof according to claim 42.

61. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 142 to 144 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3 respectively, the antibody or antigen-binding fragment thereof according to claim 42.

62. According to the Chothia numbering scheme, the VH comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 145 to 147 respectively, and the VL comprises CDR1, 2, and 3 having the amino acid sequences shown in SEQ ID NOs: 1 to 3 respectively, the antibody or antigen-binding fragment thereof according to claim 42.

63. An antibody or antigen-binding fragment thereof that binds to MET, A heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to the selected VH sequence, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to the selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following: an antibody or an antigen-binding fragment thereof. (1) The selected VH sequence is SEQ ID NO: 67 and the selected VL sequence is SEQ ID NO: 61; (2) The selected VH sequence is SEQ ID NO: 68 and the selected VL sequence is SEQ ID NO: 61; (3) The selected VH sequence is SEQ ID NO: 69 and the selected VL sequence is SEQ ID NO: 61; (4) The selected VH sequence is SEQ ID NO: 70 and the selected VL sequence is SEQ ID NO: 61; (5) The selected VH sequence is SEQ ID NO: 148 and the selected VL sequence is SEQ ID NO: 61; (6) The selected VH sequence is SEQ ID NO: 149 and the selected VL sequence is SEQ ID NO: 61; (7) The selected VH sequence is SEQ ID NO: 150 and the selected VL sequence is SEQ ID NO: 61; (8) The selected VH sequence is SEQ ID NO: 151 and the selected VL sequence is SEQ ID NO: 61; (9) The selected VH sequence is SEQ ID NO: 152 and the selected VL sequence is SEQ ID NO: 61; and (10) The selected VH sequence is SEQ ID NO: 153 and the selected VL sequence is SEQ ID NO:

61.

64. The antibody or antigen-binding fragment thereof according to claim 63, wherein the VH comprises the sequence of SEQ ID NO: 67 and the VL comprises the sequence of SEQ ID NO:

61.

65. The antibody or antigen-binding fragment thereof according to claim 63, wherein the VH comprises the sequence of SEQ ID NO: 68 and the VL comprises the sequence of SEQ ID NO:

61.

66. The antibody or antigen-binding fragment thereof according to claim 63, wherein the VH comprises the sequence of SEQ ID NO: 69 and the VL comprises the sequence of SEQ ID NO:

61.

67. The antibody or antigen-binding fragment thereof according to claim 63, wherein the VH comprises the sequence of SEQ ID NO: 70 and the VL comprises the sequence of SEQ ID NO:

61.

68. The antibody or antigen-binding fragment thereof according to claim 63, wherein the VH comprises the sequence of SEQ ID NO: 148 and the VL comprises the sequence of SEQ ID NO:

61.

69. The antibody or antigen-binding fragment thereof according to claim 63, wherein the VH comprises the sequence of SEQ ID NO: 149 and the VL comprises the sequence of SEQ ID NO:

61.

70. The antibody or antigen-binding fragment thereof according to claim 63, wherein the VH comprises the sequence of SEQ ID NO: 150 and the VL comprises the sequence of SEQ ID NO:

61.

71. The antibody or antigen-binding fragment thereof according to claim 63, wherein the VH comprises the sequence of SEQ ID NO: 151 and the VL comprises the sequence of SEQ ID NO:

61.

72. The antibody or antigen-binding fragment thereof according to claim 63, wherein the VH comprises the sequence of SEQ ID NO: 152 and the VL comprises the sequence of SEQ ID NO:

61.

73. The antibody or antigen-binding fragment thereof according to claim 63, wherein the VH comprises the sequence of SEQ ID NO: 153 and the VL comprises the sequence of SEQ ID NO:

61.

74. An antibody or antigen-binding fragment thereof that binds to MET, comprising a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3 that are identical to VH CDR1, VH CDR2, and VH CDR3 of a selected VH sequence, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3 that are identical to VL CDR1, VL CDR2, and VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following: the antibody or antigen-binding fragment thereof. (1) The selected VH sequence is SEQ ID NO: 67 and the selected VL sequence is SEQ ID NO: 61; (2) The selected VH sequence is SEQ ID NO: 68 and the selected VL sequence is SEQ ID NO: 61; (3) The selected VH sequence is SEQ ID NO: 69 and the selected VL sequence is SEQ ID NO: 61; (4) The selected VH sequence is SEQ ID NO: 70 and the selected VL sequence is SEQ ID NO: 61; (5) The selected VH sequence is SEQ ID NO: 148 and the selected VL sequence is SEQ ID NO: 61; (6) The selected VH sequence is SEQ ID NO: 149 and the selected VL sequence is SEQ ID NO: 61; (7) The selected VH sequence is SEQ ID NO: 150 and the selected VL sequence is SEQ ID NO: 61; (8) The selected VH sequence is SEQ ID NO: 151 and the selected VL sequence is SEQ ID NO: 61; and (9) The selected VH sequence is SEQ ID NO: 152 and the selected VL sequence is SEQ ID NO: 61; and (10) The selected VH sequence is SEQ ID NO: 153, and the selected VL sequence is SEQ ID NO:

61.

75. The antibody or antigen-binding fragment thereof according to any one of claims 42 to 74, wherein the antibody or antigen-binding fragment thereof specifically binds to human, monkey, or canine MET.

76. The antibody or antigen-binding fragment thereof according to any one of claims 42 to 75, wherein the antibody or antigen-binding fragment is a human antibody or a humanized antibody or an antigen-binding fragment thereof.

77. The antibody or antigen-binding fragment thereof according to any one of claims 42 to 76, wherein the antibody or antigen-binding fragment is a single-chain variable fragment (scFv).

78. The antibody or antigen-binding fragment thereof according to any one of claims 42 to 77, wherein the antibody or antigen-binding fragment is a multispecific antibody (e.g., bispecific antibody) or an antigen-binding fragment thereof.

79. The antibody or antigen-binding fragment thereof according to claim 78, wherein the antibody or antigen-binding fragment further specifically binds to EGFR.

80. An antibody or antigen-binding fragment thereof that cross-competes with the antibody or antigen-binding fragment thereof according to any one of claims 42 to 79.

81. A nucleic acid comprising a polynucleotide encoding a polypeptide comprising the following: (1) An immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity-determining regions (CDRs) 1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 19 to 21, wherein the VH binds to MET when paired with a light chain variable region (VL) comprising the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof; (2) An immunoglobulin light chain or a fragment thereof comprising a light chain variable region (VL) comprising complementarity-determining regions (CDRs) 1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein the VL binds to MET when paired with a heavy chain variable region (VH) comprising the amino acid sequence shown in SEQ ID NO: 67, an immunoglobulin light chain or a fragment thereof; (3) An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 each comprising the amino acid sequences shown in SEQ ID NOs: 22 to 24, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, an immunoglobulin heavy chain or a fragment thereof; An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL forms a pair with a VH containing the amino acid sequence shown in SEQ ID NO: 68, the VL binds to MET, the immunoglobulin light chain or a fragment thereof. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 25 to 27, wherein when the VH forms a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET, the immunoglobulin heavy chain or a fragment thereof. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL forms a pair with a VH containing the amino acid sequence shown in SEQ ID NO: 69, the VL binds to MET, the immunoglobulin light chain or a fragment thereof. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 28 to 30, wherein when the VH forms a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET, the immunoglobulin heavy chain or a fragment thereof. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein when the VL forms a pair with a VH containing the amino acid sequence shown in SEQ ID NO: 70, the VL binds to MET, the immunoglobulin light chain or a fragment thereof. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 49 to 51, wherein when the VH forms a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET, the immunoglobulin heavy chain or a fragment thereof. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequences shown in SEQ ID NOs: 52 to 54, wherein when the VH forms a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET, the immunoglobulin heavy chain or a fragment thereof. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 55 to 57, wherein the VH binds to MET when pairing with a VL comprising the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 58 to 60, wherein the VH binds to MET when pairing with a VL comprising the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 112 to 114, wherein the VH binds to MET when pairing with a VL comprising the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein the VL binds to MET when pairing with a VH comprising the amino acid sequence shown in SEQ ID NO:

148. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 115 to 117, wherein the VH binds to MET when pairing with a VL comprising the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 1 to 3, wherein the VL binds to MET when pairing with a VH comprising the amino acid sequence shown in SEQ ID NO:

149. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 respectively containing the amino acid sequences shown in SEQ ID NOs: 118 to 120, wherein the VH binds to MET when pairing with a VL comprising the amino acid sequence shown in SEQ ID NO:

61. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH comprising the amino acid sequence shown in SEQ ID NO: 150, the VL binds to MET. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 121 to 123, wherein when the VH pairs with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH comprising the amino acid sequence shown in SEQ ID NO: 151, the VL binds to MET. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 124 to 126, wherein when the VH pairs with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH comprising the amino acid sequence shown in SEQ ID NO: 152, the VL binds to MET. An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 127 to 129, wherein when the VH pairs with a VL comprising the amino acid sequence shown in SEQ ID NO: 61, the VH binds to MET. An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2, and 3 each comprising the amino acid sequence shown in SEQ ID NOs: 1 to 3, wherein when the VL pairs with a VH comprising the amino acid sequence shown in SEQ ID NO: 153, the VL binds to MET. An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequence shown in SEQ ID NOs: 130 to 132, wherein the VH binds to MET when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the immunoglobulin heavy chain or a fragment thereof. An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequence shown in SEQ ID NOs: 133 to 135, wherein the VH binds to MET when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the immunoglobulin heavy chain or a fragment thereof. An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequence shown in SEQ ID NOs: 136 to 138, wherein the VH binds to MET when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the immunoglobulin heavy chain or a fragment thereof. An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequence shown in SEQ ID NOs: 139 to 141, wherein the VH binds to MET when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the immunoglobulin heavy chain or a fragment thereof. An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequence shown in SEQ ID NOs: 142 to 144, wherein the VH binds to MET when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the immunoglobulin heavy chain or a fragment thereof, and An immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDR1, 2, and 3 each containing the amino acid sequence shown in SEQ ID NOs: 145 to 147, wherein the VH binds to MET when forming a pair with a VL containing the amino acid sequence shown in SEQ ID NO: 61, the immunoglobulin heavy chain or a fragment thereof.

82. The nucleic acid according to claim 81, wherein the VH specifically binds to human, monkey, or canine MET when forming a pair with a VL.

83. The nucleic acid according to claim 81 or 82, wherein the immunoglobulin heavy chain or the fragment thereof is a heavy chain or a fragment thereof of a human immunoglobulin or a humanized immunoglobulin.

84. The nucleic acid according to any one of claims 81 to 83, which encodes a single-chain variable fragment (scFv).

85. The nucleic acid according to any one of claims 81 to 84, which is cDNA.

86. An antigen-binding protein construct comprising a first antigen-binding domain that specifically binds to EGFR and a second antigen-binding domain that specifically binds to MET.

87. The antigen-binding protein construct according to claim 86, wherein the first antigen-binding domain comprises a first heavy-chain variable region (VH1) and a first light-chain variable region (VL1), and the second antigen-binding domain comprises a second heavy-chain variable region (VH2) and a second light-chain variable region (VL2).

88. The first heavy-chain variable region (VH1) comprises complementarity-determining regions (CDRs) 1, 2, and 3, the VH1 CDR1 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH1 CDR1, the VH1 CDR2 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH1 CDR2, the VH1 CDR3 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VH1 CDR3, and the first light-chain variable region (VL1) comprises CDRs 1, 2, and 3, the VL1 CDR1 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL1 CDR1, the VL1 CDR2 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL1 CDR2, the VL1 CDR3 region comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of a selected VL1 CDR3, the amino acid sequences of the selected VH1 CDRs 1, 2, and 3, and the amino acid sequences of the selected VL1 CDRs 1, 2, and 3 are one of the following: The antigen-binding protein construct according to claim 87. (1) The amino acid sequences of the selected VH1 CDRs 1, 2, and 3 are respectively shown in SEQ ID NOs: 4 to 6, and the amino acid sequences of the selected VL1 CDRs 1, 2, and 3 are respectively shown in SEQ ID NOs: 1 to 3; (2) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 7-9 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (3) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 10-12 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (4) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 13-15 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (5) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 16-18 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (6) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 34-36 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (7) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 37-39 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (8) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 40-42 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (9) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 43-45 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (10) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 46-48 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (11) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 82-84 respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3 respectively; (12) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (13) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (14) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (15) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (16) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (17) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; and (18) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105, respectively, and the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively.

89. The second heavy chain variable region (VH2) includes CDR1, 2, and 3, the VH2 CDR1 region includes an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VH2 CDR1, the VH2 CDR2 region includes an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VH2 CDR2, the VH2 CDR3 region includes an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VH2 CDR3, and The said second light chain variable region (VL2) contains CDR1, 2, and 3. The VL2 CDR1 region contains an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VL2 CDR1. The VL2 CDR2 region contains an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VL2 CDR2. The VL2 CDR3 region contains an amino acid sequence that is at least 80% identical to the amino acid sequence of the selected VL2 CDR3. The antigen-binding protein construct according to claim 87 or 88, wherein the amino acid sequences of the selected VH2 CDR1, 2, and 3, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are one of the following. (1) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 19 to 21, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 1 to 3; (2) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 22 to 24, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 1 to 3; (3) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 25 to 27, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 1 to 3; (4) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 28 to 30, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 1 to 3; (5) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 49 to 51, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 1 to 3; (6) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 52 to 54, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 1 to 3; (7) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 55 to 57, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are respectively shown in SEQ ID NOs: 1 to 3; (8) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (9) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 112 to 114 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (10) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 115 to 117 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (11) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 118 to 120 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (12) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 121 to 123 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (13) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 124 to 126 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (14) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 127 to 129 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (15) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 130 to 132 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (16) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 133 to 135 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (17) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 136 to 138 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (18) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 139 to 141 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (19) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 142 to 144 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; and (20) The amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 145 to 147 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively.

90. The antigen-binding protein construct according to claim 89, which is any one of the following. (1) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 4 to 6 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (2) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 4 to 6 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (3) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 4 to 6 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (4) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 7-9, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25-27, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3, respectively; (5) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 7-9, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28-30, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3, respectively; (6) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 10-12, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19-21, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3, respectively; (7) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 10-12, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22-24, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3, respectively; (8) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 10-12, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25-27, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1-3, respectively; (9) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 10 to 12 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (10) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 13 to 15 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (11) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 13 to 15 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (12) (15) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 13 to 15 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (13) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 13 to 15 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (14) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 16 to 18, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (15) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 16 to 18, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (16) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 16 to 18, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (17) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 16 to 18, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (18) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 34 to 36, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (19) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 34 to 36, respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57, respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (20) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 34 to 36, respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60, respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (21) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 37 to 39, respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 31 to 33, respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57, respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (22) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 37 to 39, respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60, respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (23) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 40 to 42, respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51, respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (24) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 40 to 42 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (25) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 40 to 42 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (26) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 40 to 42 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (27) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 43 to 45 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (28) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 43 to 45 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (29) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 43 to 45, respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57, respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (30) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 43 to 45, respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60, respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (31) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 46 to 48, respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51, respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (32) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 46 to 48, respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54, respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (33) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 46 to 48, respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57, respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (34) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 46 to 48 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (35) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 82 to 84 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (36) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 82 to 84 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (37) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 82 to 84 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (38) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 82 to 84 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (39) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (40) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (41) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (42) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 85 to 87 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (43) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (44) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (45) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (46) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 88 to 90 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (47) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 19 to 21 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (48) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 22 to 24 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (49) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 25 to 27, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (50) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 91 to 93, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 28 to 30, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (51) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (52) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (53) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (54) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 94 to 96, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (55) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (56) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (57) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (58) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 97 to 99, respectively; the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60, respectively; the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3, respectively; (59) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (60) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (61) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (62) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 100 to 102 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (63) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 49 to 51 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (64) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 52 to 54 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; (65) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 55 to 57 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively; and (66) The amino acid sequences of the selected VH1 CDR1, 2, and 3 are shown in SEQ ID NOs: 103 to 105 respectively, the amino acid sequences of the selected VL1 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively, the amino acid sequences of the selected VH2 CDR1, 2, and 3 are shown in SEQ ID NOs: 58 to 60 respectively, and the amino acid sequences of the selected VL2 CDR1, 2, and 3 are shown in SEQ ID NOs: 1 to 3 respectively.

91. The antigen-binding protein construct according to any one of claims 87 to 90, wherein the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 62, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61.

92. The first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 62, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 87 to 90.

93. The first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 62, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 87 to 90.

94. The first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 63, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 87 to 90.

95. The first heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 63, the first light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light-chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 87 to 90. **Claim 96** The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 64, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 87 to 90. **Claim 97** The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 64, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 87 to 90. **Claim 98** The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 64, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 97 to 90. **Claim 99** The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 64, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the antigen-binding protein construct according to any one of claims 87 to 90.

100. The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 65, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the antigen-binding protein construct according to any one of claims 87 to 90.

101. The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 65, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the antigen-binding protein construct according to any one of claims 87 to 90.

102. The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 65, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the antigen-binding protein construct according to any one of claims 87 to 90. **Claim 103** The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 65; the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61; the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70; and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 87 to 90. **Claim 104** The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 66; the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61; the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 67; and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 87 to 90. **Claim 105** The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 66; the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61; the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 68; and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 87 to 90. **Claim 106** The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 66, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 69, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 87 to 90.

107. The first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 66, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 61, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO: 70, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, or 95% identical to SEQ ID NO:

61. The antigen-binding protein construct according to any one of claims 87 to 90.

108. The antigen-binding protein construct according to any one of claims 86 to 107, wherein the antigen-binding protein construct is a multispecific antibody (for example, a bispecific antibody).

109. The antigen-binding protein construct according to any one of claims 86 to 108, wherein the first antigen-binding domain is a single-chain variable fragment (scFv) and / or the second antigen-binding domain is an scFv.

110. The antigen-binding protein construct according to any one of claims 87 to 109, wherein the first light chain variable region and the second light chain variable region are identical.

111. A vector comprising one or more of the nucleic acids according to any one of claims 37 to 41 and 81 to 85, the nucleic acid encoding an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 36 and 42 to 80, or the nucleic acid encoding an antigen-binding protein construct according to any one of claims 86 to 110.

112. A cell comprising the vector according to claim 111.

113. The cell according to claim 112, wherein the cell is a CHO cell.

114. A cell comprising one or more of the nucleic acids according to any one of claims 37 to 41 and 81 to 85, the nucleic acids encoding the antibodies or antigen-binding fragments thereof according to any one of claims 1 to 36 and 42 to 80, or the nucleic acids encoding the antigen-binding protein constructs according to any one of claims 86 to 110.

115. A method for producing an antibody or an antigen-binding fragment thereof, or an antigen-binding protein construct, the method comprising: (a) culturing the cell according to any one of claims 112 to 114 under conditions sufficient for the cell to produce the antibody or the antigen-binding fragment thereof, or the antigen-binding protein construct; and (b) recovering the antibody or the antigen-binding fragment thereof, or the antigen-binding protein construct produced by the cell. A method comprising the above.

116. An antibody-drug conjugate (ADC) comprising: (a) an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 36 and 42 to 80, or (b) an antigen-binding protein construct according to any one of claims 86 to 110, covalently bound to a therapeutic agent.

117. The antibody-drug conjugate according to claim 116, wherein the therapeutic agent is a cytotoxic agent or a cell growth inhibitor.

118. The antibody-drug conjugate according to claim 116 or 117, wherein the therapeutic agent is MMAE or MMAF.

119. The antibody-drug conjugate according to claim 116, wherein the therapeutic agent is selected from the following: 【Chemical 1】

120. The antibody-drug conjugate according to claim 116 or 119, wherein the therapeutic agent is linked to the antibody or an antigen-binding fragment thereof, or the antigen-binding protein construct via a linker.

121. The antibody-drug conjugate according to any one of claims 116, 119, and 120, wherein the linker has the following structure: 【Chemical 2】

122. The antibody-drug conjugate according to any one of claims 116, and 119 to 121, having the following structure: [Chemical Formula 3] Here, n = 1, 2, 3, 4, 5, 6, 7, or 8, and "Ab" represents an antibody or an antigen-binding fragment thereof, or an antigen-binding protein construct.

123. A method for treating a subject having cancer, the method comprising administering to the subject a composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 36 and 42 to 80, an antigen-binding protein construct according to any one of claims 86 to 110, or an antibody-drug conjugate according to any one of claims 116 to 122.

124. The method according to claim 123, wherein the subject has cancer expressing EGFR and / or MET.

125. The cancer is a solid tumor, lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, or lung carcinoma), gastric cancer (e.g., gastric carcinoma), skin cancer (e.g., cutaneous carcinoma), carcinoma of the dilated portion (e.g., carcinoma of the dilated portion), colorectal cancer, breast cancer, head and neck cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, CNS cancer, liver cancer, nasopharyngeal cancer, or brain tumor. The method according to claim 123.

126. The method according to any one of claims 123 to 125, wherein the subject is human.

127. The method according to any one of claims 123 to 126, further comprising administering an anti-PD1 antibody to the subject.

128. The method according to any one of claims 123 to 127, further comprising subjecting the subject to chemotherapy.

129. A method for reducing the tumor growth rate, the method comprising: contacting tumor cells with a composition comprising an effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 36 and 42 to 80, an antigen-binding protein construct according to any one of claims 86 to 110, or an antibody-drug conjugate according to any one of claims 116 to 122.

130. A method for killing tumor cells, the method comprising: contacting tumor cells with a composition comprising an effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 36 and 42 to 80, an antigen-binding protein construct according to any one of claims 86 to 110, or an antibody-drug conjugate according to any one of claims 116 to 122.

131. a pharmaceutically acceptable carrier, and (a) an antibody or antigen-binding fragment thereof according to any one of claims 1 to 36 and 42 to 80, (b) an antigen-binding protein construct according to any one of claims 86 to 110, and / or An antibody-drug conjugate according to any one of claims 116 to 122, and, a pharmaceutical composition comprising the same. **Claim 132** An antibody-drug conjugate (ADC) comprising a therapeutic agent covalently bound to a bispecific antibody or an antigen-binding fragment thereof, the bispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds to EGFR and a second antigen-binding domain that specifically binds to MET. **Claim 133** The antibody-drug conjugate (ADC) according to claim 132, wherein the drug-antibody ratio (DAR) is about 4 or 8.

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