Anti-EGFR / MET antibodies and uses thereof

Abstract

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

Description

[0001] Priority declaration

[0002] This application claims the benefit of 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 entireties of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to antigen binding protein constructs (eg, bispecific antibodies or antigen binding fragments thereof). Background Art

[0004] Bispecific antibodies are artificial proteins that can bind to two different types of antigens or two different epitopes at the same time. This dual specificity opens up a wide range of applications, including redirecting T cells to tumor cells, dual targeting of different disease mediators, and delivering payloads to targeted sites. The approval of catumaxomab (anti-EpCAM and anti-CD3) and blinatumomab (anti-CD19 and anti-CD3) has become an important milestone in the development of bispecific antibodies.

[0005] Since bispecific antibodies have various applications, there is a need to continue to develop various bispecific antibody-based therapeutic agents. Summary of the invention

[0006] The present disclosure relates to antigen binding protein constructs, wherein the antigen binding protein constructs bind two different antigens (e.g., EGFR and MET). In some embodiments, multispecific antibodies (e.g., bispecific antibodies) have identical light chain variable regions. In some embodiments, multispecific antibodies (e.g., bispecific antibodies) have common light chains. In some embodiments, multispecific antibodies (e.g., bispecific antibodies) form part of an antibody drug conjugate.

[0007] In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds to EGFR (human epidermal growth factor receptor), the antibody or antigen-binding fragment thereof comprising: a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, in some embodiments, the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; and a light chain variable region (VL) comprising CDRs 1, 2, and 3, in some embodiments, the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL The CDR3 amino acid sequence has an amino acid sequence with at least 80% identity, in some embodiments, the selected VH CDR 1, 2, and 3 amino acid sequence and the selected VL CDR 1, 2, and 3 amino acid sequence are one of the following:

[0008] (1) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 4-6, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0009] (2) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 7-9, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0010] (3) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 10-12, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0011] (4) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 13-15, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0012] (5) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 16-18, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0013] (6) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 34-36, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0014] (7) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 37-39, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0015] (8) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 40-42, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0016] (9) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 43-45, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0017] (10) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 46-48, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0018] (11) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 82-84, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0019] (12) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 85-87, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0020] (13) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 88-90, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0021] (14) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 91-93, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0022] (15) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 94-96, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0023] (16) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 97-99, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0024] (17) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 100-102, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; and

[0025] (18) The selected VH CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 103-105, respectively, and the selected VL CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively.

[0026] In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 4-6, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 7-9, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 10-12, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 13-15, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 16-18, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 82-84, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 85-87, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 88-90, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 91-93, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively.In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 34-36, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 37-39, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 40-42, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 43-45, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 46-48, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 94-96, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 97-99, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 100-102, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 103-105, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively.

[0027] In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds to EGFR, the antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH), the VH comprising an amino acid sequence that is at least 90% identical to a selected VH sequence, and a light chain variable region (VL), the VL comprising an amino acid sequence that is at least 90% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0028] (1) the selected VH sequence is SEQ ID NO: 62, and the selected VL sequence is SEQ ID NO: 61;

[0029] (2) the selected VH sequence is SEQ ID NO:63, and the selected VL sequence is SEQ ID NO:61;

[0030] (3) the selected VH sequence is SEQ ID NO: 64, and the selected VL sequence is SEQ ID NO: 61;

[0031] (4) the selected VH sequence is SEQ ID NO: 65, and the selected VL sequence is SEQ ID NO: 61;

[0032] (5) the selected VH sequence is SEQ ID NO:66, and the selected VL sequence is SEQ ID NO:61;

[0033] (6) the selected VH sequence is SEQ ID NO: 106, and the selected VL sequence is SEQ ID NO: 61;

[0034] (7) the selected VH sequence is SEQ ID NO: 107, and the selected VL sequence is SEQ ID NO: 61;

[0035] (8) the selected VH sequence is SEQ ID NO: 108, and the selected VL sequence is SEQ ID NO: 61; and

[0036] (9) The selected VH sequence is SEQ ID NO:109, and the selected VL sequence is SEQ ID NO:61.

[0037] In some embodiments, the VH comprises the sequence of SEQ ID NO:62, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:63, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:64, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:65, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:66, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:106, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:107, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO: 108, and the VL comprises the sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the sequence of SEQ ID NO: 109, and the VL comprises the sequence of SEQ ID NO: 61.

[0038] In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds to EGFR, the antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH), the VH comprising VH CDR1, VH CDR2, and VH CDR3 identical to those of a selected VH sequence; and a light chain variable region (VL), the VL comprising VL CDR1, VL CDR2, and VL CDR3 identical to those of a selected VL sequence, in some embodiments, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0039] (1) the selected VH sequence is SEQ ID NO: 62, and the selected VL sequence is SEQ ID NO: 61;

[0040] (2) the selected VH sequence is SEQ ID NO:63, and the selected VL sequence is SEQ ID NO:61;

[0041] (3) the selected VH sequence is SEQ ID NO: 64, and the selected VL sequence is SEQ ID NO: 61;

[0042] (4) the selected VH sequence is SEQ ID NO: 65, and the selected VL sequence is SEQ ID NO: 61;

[0043] (5) the selected VH sequence is SEQ ID NO:66, and the selected VL sequence is SEQ ID NO:61;

[0044] (6) the selected VH sequence is SEQ ID NO: 106, and the selected VL sequence is SEQ ID NO: 61;

[0045] (7) the selected VH sequence is SEQ ID NO: 107, and the selected VL sequence is SEQ ID NO: 61;

[0046] (8) the selected VH sequence is SEQ ID NO: 108, and the selected VL sequence is SEQ ID NO: 61; and

[0047] (9) The selected VH sequence is SEQ ID NO:109, and the selected VL sequence is SEQ ID NO:61.

[0048] In some embodiments, the antibody or its antigen binding fragment specifically binds to human or monkey EGFR. In some embodiments, the antibody or antigen binding fragment is a human or humanized antibody or its antigen binding fragment. In some embodiments, the antibody or antigen binding fragment is a single chain variable fragment (scFV). In some embodiments, the antibody or its antigen binding fragment is a multispecific antibody (e.g., a bispecific antibody) or its antigen binding fragment. In some embodiments, the antibody or its antigen binding fragment also specifically binds to MET. On the one hand, the present disclosure relates to an antibody or its antigen binding fragment that cross-competes with an antibody or its antigen binding fragment described herein.

[0049] In one aspect, the present disclosure relates to a nucleic acid comprising a polynucleotide encoding a polypeptide comprising:

[0050] (1) an immunoglobulin heavy chain or a fragment thereof, comprising a heavy chain variable region (VH), wherein the VH comprises complementarity determining regions (CDRs) 1, 2 and 3, wherein the CDRs 1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 4-6, respectively, and in some embodiments, 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;

[0051] (2) an immunoglobulin light chain or a fragment thereof, comprising a light chain variable region (VL), wherein the VL comprises complementarity determining regions (CDRs) 1, 2, and 3, wherein CDRs 1, 2, and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and in some embodiments, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 62;

[0052] (3) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 7-9, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0053] (4) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and in some embodiments, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 63;

[0054] (5) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 10-12, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0055] (6) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and in some embodiments, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 64;

[0056] (7) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 13-15, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0057] (8) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 65;

[0058] (9) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 16-18, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0059] (10) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 66;

[0060] (11) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 34-36, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0061] (12) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 37-39, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0062] (13) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 40-42, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0063] (14) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 43-45, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0064] (15) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 46-48, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0065] (16) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 82-84, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0066] (17) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 106;

[0067] (18) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 85-87, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0068] (19) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 107;

[0069] (20) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 88-90, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0070] (21) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 108;

[0071] (22) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 91-93, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0072] (23) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 109;

[0073] (24) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 94-96, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0074] (25) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 97-99, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0075] (26) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 100-102, respectively, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; and / or

[0076] (27) An immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 respectively comprise the amino acid sequences shown in SEQ ID NO:103-105, and in some embodiments, wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO:61.

[0077] In some embodiments, when the VH is paired with the VL, it specifically binds to human or monkey EGFR. In some embodiments, the immunoglobulin heavy chain or its fragment is a human or humanized immunoglobulin heavy chain or its fragment. In some embodiments, the nucleic acid encodes a single-chain variable fragment (scFv). In some embodiments, the nucleic acid is a cDNA.

[0078] In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds MET (tyrosine protein kinase Met), the antibody or antigen-binding fragment thereof comprising: a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, in some embodiments, the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; and a light chain variable region (VL) comprising CDRs 1, 2, and 3, in some embodiments, the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL The CDR3 amino acid sequence has an amino acid sequence with at least 80% identity, in some embodiments, wherein the selected VH CDR 1, 2, and 3 amino acid sequence and the selected VL CDR 1, 2, and 3 amino acid sequence are one of the following:

[0079] (1) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 19-21, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0080] (2) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 22-24, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0081] (3) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 25-27, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0082] (4) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 28-30, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0083] (5) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 49-51, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0084] (6) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 52-54, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0085] (7) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 55-57, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0086] (8) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 58-60, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0087] (9) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 112-114, respectively, and the selected VL CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0088] (10) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 115-117, respectively, and the selected VL CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0089] (11) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 118-120, respectively, and the selected VL CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0090] (12) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 121-123, respectively, and the selected VL CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0091] (13) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 124-126, respectively, and the selected VL CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0092] (14) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 127-129, respectively, and the selected VL CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0093] (15) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 130-132, respectively, and the selected VL CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0094] (16) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 133-135, respectively, and the selected VL CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0095] (17) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 136-138, respectively, and the selected VL CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0096] (18) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 139-141, respectively, and the selected VL CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0097] (19) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 142-144, respectively, and the selected VL CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; and

[0098] (20) The selected VH CDR 1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 145-147, respectively, and the selected VL CDR 1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively.

[0099] In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 19-21, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 22-24, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 25-27, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 28-30, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 112-114, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 115-117, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 118-120, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 121-124, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Kabat numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 127-129, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively.In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 49-51, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 52-54, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 55-57, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 58-60, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 130-132, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 133-135, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having amino acid sequences as shown in SEQ ID NOs: 136-138, respectively, and the VL comprises CDR1, 2, 3 having amino acid sequences as shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having amino acid sequences as shown in SEQ ID NOs: 139-141, respectively, and the VL comprises CDR1, 2, 3 having amino acid sequences as shown in SEQ ID NOs: 1-3, respectively.In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having amino acid sequences as shown in SEQ ID NOs: 142-1144, respectively, and the VL comprises CDR1, 2, 3 having amino acid sequences as shown in SEQ ID NOs: 1-3, respectively. In some embodiments, according to the Chothia numbering convention, the VH comprises CDR1, 2, 3 having amino acid sequences as shown in SEQ ID NOs: 145-147, respectively, and the VL comprises CDR1, 2, 3 having amino acid sequences as shown in SEQ ID NOs: 1-3, respectively.

[0100] In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds to MET, the antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH), the VH comprising an amino acid sequence that is at least 90% identical to a selected VH sequence, and a light chain variable region (VL), the VL comprising an amino acid sequence that is at least 90% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0101] (1) the selected VH sequence is SEQ ID NO: 67, and the selected VL sequence is SEQ ID NO: 61;

[0102] (2) the selected VH sequence is SEQ ID NO:68, and the selected VL sequence is SEQ ID NO:61;

[0103] (3) the selected VH sequence is SEQ ID NO:69, and the selected VL sequence is SEQ ID NO:61;

[0104] (4) the selected VH sequence is SEQ ID NO:70, and the selected VL sequence is SEQ ID NO:61;

[0105] (5) the selected VH sequence is SEQ ID NO: 148, and the selected VL sequence is SEQ ID NO: 61;

[0106] (6) the selected VH sequence is SEQ ID NO: 149, and the selected VL sequence is SEQ ID NO: 61;

[0107] (7) the selected VH sequence is SEQ ID NO: 150, and the selected VL sequence is SEQ ID NO: 61;

[0108] (8) the selected VH sequence is SEQ ID NO: 151, and the selected VL sequence is SEQ ID NO: 61;

[0109] (9) the selected VH sequence is SEQ ID NO: 152, and the selected VL sequence is SEQ ID NO: 61; and

[0110] (10) The selected VH sequence is SEQ ID NO:153, and the selected VL sequence is SEQ ID NO:61.

[0111] In some embodiments, the VH comprises the sequence of SEQ ID NO:67, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:68, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:69, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:70, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:148, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:149, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO:150, and the VL comprises the sequence of SEQ ID NO:61. In some embodiments, the VH comprises the sequence of SEQ ID NO: 151, and the VL comprises the sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the sequence of SEQ ID NO: 152, and the VL comprises the sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the sequence of SEQ ID NO: 153, and the VL comprises the sequence of SEQ ID NO: 61. In some embodiments, the VH comprises the sequence of SEQ ID NO: 70, and the VL comprises the sequence of SEQ ID NO: 61.

[0112] In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds MET, comprising a heavy chain variable region (VH), the VH comprising VH CDR1, VH CDR2, and VH CDR3 identical to those of a selected VH sequence; and a light chain variable region (VL), the VL comprising VL CDR1, VL CDR2, and VL CDR3 identical to those of a selected VL sequence, wherein in some embodiments, the selected VH sequence and the selected VL sequence are one of the following:

[0113] (1) the selected VH sequence is SEQ ID NO: 67, and the selected VL sequence is SEQ ID NO: 61;

[0114] (2) the selected VH sequence is SEQ ID NO:68, and the selected VL sequence is SEQ ID NO:61;

[0115] (3) the selected VH sequence is SEQ ID NO:69, and the selected VL sequence is SEQ ID NO:61;

[0116] (4) the selected VH sequence is SEQ ID NO:70, and the selected VL sequence is SEQ ID NO:61;

[0117] (5) the selected VH sequence is SEQ ID NO: 148, and the selected VL sequence is SEQ ID NO: 61;

[0118] (6) the selected VH sequence is SEQ ID NO: 149, and the selected VL sequence is SEQ ID NO: 61;

[0119] (7) the selected VH sequence is SEQ ID NO: 150, and the selected VL sequence is SEQ ID NO: 61;

[0120] (8) the selected VH sequence is SEQ ID NO: 151, and the selected VL sequence is SEQ ID NO: 61;

[0121] (9) the selected VH sequence is SEQ ID NO: 152, and the selected VL sequence is SEQ ID NO: 61; and

[0122] (10) The selected VH sequence is SEQ ID NO:153, and the selected VL sequence is SEQ ID NO:61.

[0123] 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 or humanized antibody or 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 also specifically binds to EGFR. On the one hand, the present disclosure relates to an antibody or antigen binding fragment thereof that cross-competes with an antibody or antigen binding fragment thereof described herein.

[0124] In one aspect, the present disclosure relates to a nucleic acid comprising a polynucleotide encoding a polypeptide comprising:

[0125] (1) an immunoglobulin heavy chain or a fragment thereof, comprising a heavy chain variable region (VH), wherein the VH comprises complementarity determining regions (CDRs) 1, 2, and 3, wherein the CDRs 1, 2, and 3 comprise the amino acid sequences shown in SEQ ID NOs: 19-21, respectively, and in some embodiments, 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;

[0126] (2) an immunoglobulin light chain or fragment thereof, comprising a light chain variable region (VL), wherein the VL comprises complementarity determining regions (CDRs) 1, 2, and 3, wherein CDRs 1, 2, and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and in some embodiments, wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 67;

[0127] (3) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 22-24, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0128] (4) an immunoglobulin light chain or fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and in some embodiments, wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 68;

[0129] (5) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 25-27, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0130] (6) an immunoglobulin light chain or fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and in some embodiments, wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 69;

[0131] (7) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 28-30, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0132] (8) an immunoglobulin light chain or fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 70;

[0133] (9) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 49-51, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0134] (10) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 52-54, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0135] (11) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 55-57, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0136] (12) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 58-60, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0137] (13) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 112-114, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0138] (14) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 148;

[0139] (15) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 115-117, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0140] (16) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 149;

[0141] (17) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 118-120, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0142] (18) an immunoglobulin light chain or fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 150;

[0143] (19) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 121-123, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0144] (20) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 151;

[0145] (21) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 124-126, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0146] (22) an immunoglobulin light chain or fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 152;

[0147] (23) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 127-129, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0148] (24) an immunoglobulin light chain or fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and in some embodiments, wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 153;

[0149] (25) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 130-132, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0150] (26) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 133-135, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0151] (27) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 136-138, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0152] (28) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 139-141, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61;

[0153] (29) an immunoglobulin heavy chain or fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 142-144, respectively, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; and

[0154] (30) An immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 respectively comprise the amino acid sequences shown in SEQ ID NO:145-147, and in some embodiments, wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO:61.

[0155] In some embodiments, when the VH is paired with the VL, it specifically binds to human, monkey or canine MET. In some embodiments, the immunoglobulin heavy chain or fragment thereof is a human or humanized immunoglobulin heavy chain or fragment thereof. In some embodiments, the nucleic acid encodes a single-chain variable fragment (scFv). In some embodiments, the nucleic acid is a cDNA.

[0156] 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).

[0157] In some embodiments, the first heavy chain variable region (VH1) includes complementarity determining regions (CDRs) 1, 2, and 3, and in some embodiments, the VH1 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR1 amino acid sequence, the VH1 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR2 amino acid sequence, and the VH1 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR3 amino acid sequence; and the first light chain variable region (VL1) includes CDRs 1, 2, and 3, and in some embodiments, the VL1 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 CDR1 amino acid sequence, the VL1 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 CDR2 amino acid sequence, and the VL1 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 The CDR3 amino acid sequence has an amino acid sequence with at least 80% identity, in some embodiments, wherein the selected VH1 CDR 1, 2, and 3 amino acid sequence and the selected VL1 CDR 1, 2, and 3 amino acid sequence are one of the following:

[0158] (1) the selected VH1 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 4-6, respectively, and the selected VL1 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0159] (2) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 7-9, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0160] (3) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 10-12, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0161] (4) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 13-15, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0162] (5) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 16-18, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0163] (6) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 34-36, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0164] (7) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 37-39, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0165] (8) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 40-42, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0166] (9) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 43-45, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0167] (10) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 46-48, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0168] (11) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 82-84, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0169] (12) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 85-87, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0170] (13) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 88-90, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0171] (14) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 91-93, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0172] (15) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 94-96, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0173] (16) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 97-99, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0174] (17) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 100-102, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; and

[0175] (18) The selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 103-105, respectively, and the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively.

[0176] 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 a selected VH2 CDR1 amino acid sequence, the VH2 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH2 CDR2 amino acid sequence, and the VH2 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH2 CDR3 amino acid sequence; and the second light chain variable region (VL2) comprises CDR 1, 2, and 3, in some embodiments, the VL2 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR1 amino acid sequence, the VL2 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR2 amino acid sequence, and the VL2 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR3 amino acid sequence, in some embodiments, wherein the selected VH2 CDR 1, 2 and 3 amino acid sequences and the selected VL2 CDR 1, 2 and 3 amino acid sequences are one of the following:

[0177] (1) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 19-21, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0178] (2) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 22-24, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0179] (3) the selected VH2 CDR 1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 25-27, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0180] (4) the selected VH2 CDR 1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 28-30, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0181] (5) the selected VH2 CDR 1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 49-51, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0182] (6) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 52-54, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0183] (7) the selected VH2 CDR 1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 55-57, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0184] (8) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 58-60, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0185] (9) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 112-114, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0186] (10) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 115-117, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0187] (11) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 118-120, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0188] (12) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 121-123, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0189] (13) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 124-126, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0190] (14) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 127-129, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0191] (15) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 130-132, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0192] (16) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 133-135, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0193] (17) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 136-138, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0194] (18) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 139-141, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0195] (19) the selected VH2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 142-144, respectively, and the selected VL2 CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; and

[0196] (20) The selected VH CDR 1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 145-147, respectively, and the selected VL CDR 1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively.

[0197] In some embodiments, the antigen binding protein constructs described herein have one of the following features:

[0198] (1) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 4-6, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 19-21, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0199] (2) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 4-6, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 22-24, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0200] (3) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 4-6, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 25-27, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0201] (4) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 4-6, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 28-30, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0202] (5) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 7-9, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 19-21, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0203] (6) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 7-9, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 22-24, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0204] (7) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 7-9, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 25-27, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0205] (8) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 7-9, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 28-30, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0206] (9) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 10-12, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 19-21, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0207] (10) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 10-12, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 22-24, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0208] (11) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 10-12, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 25-27, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0209] (12) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 10-12, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 28-30, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0210] (13) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 13-15, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 19-21, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0211] (14) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 13-15, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 22-24, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0212] (15) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 13-15, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 25-27, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0213] (16) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 13-15, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 28-30, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0214] (17) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 16-18, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 19-21, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0215] (18) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 16-18, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 22-24, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0216] (19) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 16-18, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 25-27, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0217] (20) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 16-18, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 28-30, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0218] (21) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 34-36, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 49-51, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0219] (22) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 34-36, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 52-54, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0220] (23) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 34-36, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 55-57, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0221] (24) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 34-36, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 58-60, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0222] (25) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 37-39, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 49-51, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0223] (26) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 37-39, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 52-54, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0224] (27) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 37-39, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 31-33, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 55-57, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0225] (28) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 37-39, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 58-60, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0226] (29) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 40-42, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 49-51, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0227] (30) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 40-42, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 52-54, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0228] (31) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 40-42, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 55-57, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0229] (32) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 40-42, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 58-60, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0230] (33) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 43-45, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 49-51, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0231] (34) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 43-45, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 52-54, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0232] (35) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 43-45, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 55-57, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0233] (36) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 43-45, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 58-60, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0234] (37) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 46-48, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 49-51, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0235] (38) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 46-48, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 52-54, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0236] (39) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 46-48, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 55-57, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0237] (40) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 46-48, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 58-60, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0238] (41) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 82-84, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 19-21, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0239] (42) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 82-84, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 22-24, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0240] (43) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 82-84, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 25-27, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0241] (44) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 82-84, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 28-30, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0242] (45) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 85-87, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 19-21, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0243] (46) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 85-87, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 22-24, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0244] (47) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 85-87, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 25-27, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0245] (48) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 85-87, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 28-30, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0246] (49) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 88-90, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 19-21, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0247] (50) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 88-90, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 22-24, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0248] (51) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 88-90, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 25-27, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0249] (52) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 88-90, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 28-30, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0250] (53) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 91-93, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 19-21, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0251] (54) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 91-93, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 22-24, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0252] (55) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 91-93, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 25-27, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0253] (56) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 91-93, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 28-30, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0254] (57) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 94-96, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 49-51, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0255] (58) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 94-96, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 52-54, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0256] (59) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 94-96, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 55-57, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0257] (60) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 94-96, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 58-60, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0258] (61) the selected VH1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 97-99, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 49-51, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0259] (62) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 97-99, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 52-54, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0260] (63) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 97-99, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 55-57, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively;

[0261] (64) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 97-99, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 58-60, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0262] (65) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 100-102, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 49-51, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0263] (66) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 100-102, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 52-54, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0264] (67) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 100-102, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 55-57, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0265] (68) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 100-102, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 58-60, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0266] (69) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 103-105, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 49-51, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0267] (70) the selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 103-105, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 52-54, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively;

[0268] (71) the selected VH1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 103-105, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 55-57, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as shown in SEQ ID NOs: 1-3, respectively; and

[0269] (72) The selected VH1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 103-105, respectively, the selected VL1 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 58-60, respectively, and the selected VL2 CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] 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.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] 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 a scFv. In some embodiments, the first light chain variable region and the second light chain variable region are the same.

[0307] In one aspect, the disclosure relates to a vector comprising one or more of a nucleic acid 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.

[0308] In one aspect, the disclosure relates to a cell comprising a vector described herein. In some embodiments, the cell is a CHO cell.

[0309] In one aspect, the disclosure relates to a cell comprising one or more of a nucleic acid described herein, or 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.

[0310] In one aspect, the present disclosure relates to a method of producing an antibody or antigen-binding fragment thereof, or an antigen-binding protein construct, the method comprising

[0311] (a) culturing the cell described herein under conditions sufficient for the cell to produce the antibody or antigen-binding fragment thereof, or the antigen-binding protein construct; and

[0312] (b) collecting the antibody or antigen-binding fragment thereof, or antigen-binding protein construct produced by the cell.

[0313] In one aspect, the present disclosure relates to an antibody drug conjugate (ADC) comprising a therapeutic agent covalently bound to each of the following: (a) an antibody or antigen-binding fragment thereof as described herein; or (b) an antigen-binding protein construct as 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.

[0314] In some embodiments, the therapeutic agent is selected from

[0315]

[0316] In some embodiments, the therapeutic agent is connected to the antibody or antigen-binding fragment thereof, or the antigen-binding protein construct via a linker. In some embodiments, the linker has the following structure:

[0317]

[0318] In some embodiments, the antibody drug conjugate has the following structure:

[0319]

[0320] In some embodiments, n=1, 2, 3, 4, 5, 6, 7 or 8; in some embodiments, "Ab" represents an antibody or antigen-binding fragment thereof, or an antigen-binding protein construct described herein.

[0321] On the one hand, the present disclosure relates to a method for treating a subject with cancer, the method comprising: administering to the subject a therapeutically effective amount of a composition comprising an antibody or antigen-binding fragment thereof as described herein, an antigen-binding protein construct as described herein, or an antibody-drug conjugate as described herein. In some embodiments, the subject suffers from cancer expressing EGFR and / or MET. In some embodiments, the cancer is a solid tumor, lung cancer (such as non-small cell lung cancer, lung adenocarcinoma or lung cancer), gastric cancer (such as gastric cancer), skin cancer (such as skin cancer), colorectal cancer, breast cancer, head and neck cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, central nervous system (CNS) cancer, liver cancer, nasopharyngeal carcinoma or brain cancer. In some embodiments, the subject is a human. In some embodiments, the method further comprises administering an anti-PD1 antibody to the subject. In some embodiments, the method further comprises administering chemotherapy to the subject.

[0322] In one aspect, the present disclosure relates to a method of reducing tumor growth rate, the method comprising: contacting tumor cells with an effective amount of a composition comprising an antibody or antigen-binding fragment thereof described herein, an antigen-binding protein construct described herein, or an antibody drug conjugate described herein.

[0323] In one aspect, the disclosure relates to a method of killing tumor cells, the method comprising contacting the tumor cells with an effective amount of a composition comprising an antibody or antigen-binding fragment thereof described herein, an antigen-binding protein construct described herein, or an antibody drug conjugate described herein.

[0324] In one aspect, the present disclosure relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) an antibody or antigen-binding fragment thereof described herein, (b) an antigen-binding protein construct described herein, and / or (c) an antibody drug conjugate described herein.

[0325] In one aspect, the present disclosure relates to an antibody drug conjugate (ADC), the antibody drug conjugate comprising a therapeutic agent covalently bound to a bispecific antibody or an antigen-binding fragment thereof, the bispecific antibody or its antigen-binding fragment 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-antibody ratio (DAR) is about 4 or 8.

[0326] 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 a cDNA.

[0327] In one aspect, the disclosure provides a vector comprising one or more of the nucleic acids described herein.

[0328] In one aspect, the disclosure provides a cell comprising a vector described herein. In some embodiments, the cell is a CHO cell. In one aspect, the disclosure provides a cell comprising one or more of the nucleic acids described herein.

[0329] 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., the same 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. Other examples and aspects of antigen-binding protein constructs are known in the art.

[0330] As used herein, the term "antigen binding domain" refers to one or more protein domains (e.g., formed by amino acids from a single polypeptide or formed by amino acids from two or more polypeptides (e.g., the same or different polypeptides)) that are capable of specifically binding to one or more different antigens (e.g., effector antigens or control antigens). In some embodiments, the antigen binding domain can bind to an antigen or epitope with a 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 may include an alternative scaffold. In some embodiments, the antigen binding domain is a VHH. Non-limiting examples of antigen binding domains are described herein. Other examples of antigen binding domains are known in the art. In some embodiments, the antigen binding domain can bind to a single antigen (e.g., one of an effector antigen and a control antigen). In other embodiments, the antigen binding domain can bind to two different antigens (e.g., an effector antigen and a control antigen).

[0331] 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, complete antibodies (e.g., complete immunoglobulins), antibody fragments, bispecific antibodies, and multispecific antibodies. An example of an antibody is a protein complex comprising two heavy chains and two light chains. Other examples of antibodies are described herein.

[0332] As used herein, the term "multi-specific antigen-binding protein construct" is an antigen-binding protein construct comprising two or more different antigen-binding domains that are co-specifically bound to two or more different epitopes. Two or more different epitopes can be epitopes of the same antigen (e.g., a single polypeptide present on a cell surface) or different antigens (e.g., different proteins present on the same cell or different cell surfaces). In some aspects, a multi-specific antigen-binding protein construct binds two different epitopes (i.e., "bispecific antigen-binding protein construct"). In some aspects, a multi-specific antigen-binding protein construct binds three different epitopes (i.e., "tri-specific antigen-binding protein construct"). In some aspects, a multi-specific antigen-binding protein construct binds four different epitopes (i.e., "tetra-specific antigen-binding protein construct"). In some aspects, a multi-specific antigen-binding protein construct binds five different epitopes (i.e., "five-specific antigen-binding protein construct"). Each binding specificity can exist in any suitable valence state. Non-limiting examples of multi-specific antigen-binding protein constructs are described herein.

[0333] As used herein, the term "bispecific antibody" refers to an antibody that binds to two different epitopes. The epitopes can be on the same antigen or on different antigens.

[0334] As used herein, the term "common light chain" refers to a light chain that can interact with two or more different heavy chains to form different antigen binding sites, wherein these different antigen binding sites can specifically bind to different antigens or epitopes. Similarly, the term "common light chain variable region" refers to a light chain variable region that can interact with two or more different heavy chain variable regions to form different antigen binding sites, wherein these different antigen binding sites can specifically bind to different antigens or epitopes. In some embodiments, an antigen binding construct may have a common light chain. In some embodiments, an antigen binding construct may have a common light chain variable region.

[0335] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. The entire text of all publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference. In the event of a conflict, the present specification (including definitions) shall prevail.

[0336] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0337] Figure 1 Schematic diagram of a bispecific antibody with a knob-in-hole structure and a common light chain.

[0338] Figure 2 Shown are the cancer cell killing activities of E-6C4-M-2F11 and E-6C4-M-2F11-ADC at 10 μg / mL for 72 hours. ISO-ADC is a human IgG1 isotype control conjugated to MMAE. Evantumab analog is a bispecific antibody used as a control for E-6C4-M-2F11. Culture medium was used as a blank control.

[0339] Figure 3 Shown are the mean tumor volumes of different groups of B-NDG mice injected with NCI-H1975 cells and treated with 10 mg / kg E-6C4-M-2F11-ADC (G2), 3 mg / kg E-6C4-M-2F11-ADC (G3), 10 mg / kg E-6C4-M-2F11 (G4) or 3 mg / kg E-6C4-M-2F11 (G5). PBS was injected as a control (G1).

[0340] Figure 4 Shown are the mean tumor volumes of different groups of B-NDG mice injected with NCI-H292 cells and treated with 10 mg / kg E-6C4-M-2F11-ADC (G2), 3 mg / kg E-6C4-M-2F11-ADC (G3), 1 mg / kg E-6C4-M-2F11-ADC (G4), 10 mg / kg ervantumab analog (G5), 3 mg / kg ervantumab analog (G6), or 1 mg / kg ervantumab analog (G7). PBS was injected as a control (G1).

[0341] Figure 5 Shown are the mean tumor volumes of different groups of B-NDG mice injected with NCI-H292 cells and treated with 3 mg / kg of ISO-ADC (G2), E-6C4-M-2F11-ADC (G3), E-6C4-M-2G10-ADC (G4), E-6C4-ADC (G5), M-2G10-ADC (G6), M-2F11-ADC (G7), CD28-E-6C4-ADC (G8), CD28-M-2F11-ADC (G9) or M-2G10-CD28-ADC (G10). PBS was injected as a control (G1).

[0342] Figure 6Shown are the mean tumor volumes of different groups of B-NDG mice injected with SNU-5 cells and treated with 10 mg / kg ervantumab analog (G2), 3 mg / kg ervantumab analog (G3), 10 mg / kg E-6C4-M-2F11-ADC (G4), 3 mg / kg E-6C4-M-2F11-ADC (G5), 10 mg / kg E-6C4-M-2G10-ADC (G6), 3 mg / kg E-6C4-M-2G10-ADC (G7), 10 mg / kg E-6C4-M-2F11 (G8), 3 mg / kg E-6C4-M-2F11 (G9), 10 mg / kg E-6C4-M-2G10 (G10), or 3 mg / kg E-6C4-M-2G10 (G11). PBS was injected as a control (G1).

[0343] Figure 7 Shown are the mean tumor volumes of different groups of B-NDG mice injected with A431 cells and treated with 3 mg / kg of ISO-ADC (G2), E-6C4-M-2F11-ADC (G3), E-6C4-M-2F11 (G4), or ervantumab analogs (G5). PBS was injected as a control (G1).

[0344] Figure 8 The CDR sequences of anti-EGFR antibodies E-1G11, E-6C4, E-2B7, E-3A8, E-3D8, E-9A6, E-9D2, E-9F3, E-9H2 and anti-MET antibodies M-2F11, M-2G10, M-1E9, M-2F12 defined by Kabat numbering are listed.

[0345] Fig. 9 The CDR sequences of anti-EGFR antibodies E-1G11, E-6C4, E-2B7, E-3A8, E-3D8, E-9A6, E-9D2, E-9F3, E-9H2 and anti-MET antibodies M-2F11, M-2G10, M-1E9, M-2F12 defined by Chothia numbering are listed.

[0346] Fig.10 The CDR sequences of the common light chain defined by Kabat and Chothia numbering are listed.

[0347] Fig.11 The antibody heavy and light chain variable region sequences described in this disclosure are listed.

[0348] Fig.12 Other amino acid sequences described in this disclosure are listed.

[0349] Fig.13Shown are the mean tumor volumes of different groups of B-NDG mice injected with NCI-H1975 cells and treated with M-2F11-ADC (G2 and G4), E-6C4-ADC (G3 and G5), E-6C4-M-2F11 (G9 and G10), E-6C4-M-2F11-ADC (G11 and G12), or a combination of E-6C4-ADC and M-2F11-ADC (G6, G7, and G8). PBS was injected as a control (G1).

[0350] Fig.14 Shown are the mean tumor volumes of different groups of B-NDG mice injected with NCI-H1975 cells and treated with 3 mg / kg cetuximab analog-ADC (G2), 3 mg / kg E-9A6-ADC (G3), 3 mg / kg E-9F3-ADC (G4), or 3 mg / kg E-9D2-ADC (G5). PBS was injected as a control (G1).

[0351] Fig.15 Shown are the mean tumor volumes of different groups of Balb / c nude mice injected with NCI-H292 cells and treated with E-6C4-M-2F11-ADC (G2-G4), terituzumab analog-ADC (G5), MRG003 analog-ADC (G6), or ervantuzumab (G7). PBS was injected as a control (G1).

[0352] Fig.16 Shown are the mean tumor volumes of different groups of B-NDG mice inoculated with patient-derived ampullary carcinoma fragments and treated with E-6C4-M-2F11-ADC (G2-G4), E-6C4-ADC (G5), cetuximab analog-ADC (G6-G7), or evitumomab (G8). PBS was injected as a control (G1).

[0353] Fig.17 Shown are the mean tumor volumes of different groups of B-NDG mice inoculated with patient-derived gastric cancer fragments and treated with E-6C4-M-2F11-ADC (G2-G4), or evitumomab (G5). PBS was injected as a control (G1).

[0354] Fig.18A Shown are the mean tumor volumes of different groups of B-NDG mice injected with NUGC-4 cells and treated with anti-MET antibody ADCs (G3-G9). PBS was injected as a control (G1).

[0355] Fig.18B yes Fig.18AA local magnified image showing the average tumor volume of different groups of B-NDG mice injected with NUGC-4 cells and treated with anti-MET antibody ADCs (G3-G9).

[0356] Fig.19 Shown are exemplary anti-EGFR / MET bispecific antibodies with antigen-binding arms from different antibodies. DETAILED DESCRIPTION

[0357] Bispecific antibodies or their antigen-binding fragments are artificial proteins that can simultaneously bind to two different epitopes (e.g., on two different antigens). In some embodiments, a bispecific antibody or its antigen-binding fragment may have two arms. Each arm has a heavy chain variable region and a light chain variable region, forming an antigen-binding domain (or antigen-binding region). In some embodiments, the bispecific antibody has a common light chain.

[0358] The present disclosure relates to anti-EGFR antibodies or antigen-binding fragments thereof, anti-MET antibodies or antigen-binding fragments thereof, antigen-binding protein constructs (e.g., bispecific antibodies or antigen-binding fragments thereof) that specifically bind to two different antigens (e.g., EGFR and MET), and antibody drug conjugates.

[0359] Anti-EGFR / MET antigen binding protein constructs

[0360] The epidermal growth factor receptor (EGFR, ErbBI or HER1) is a 170 kDa type 1 transmembrane glycoprotein encoded by the c-erbB1 proto-oncogene. The EGFR is a member of the ErbB receptor family, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2 / neu (ErbB-2), Her3 (ErbB-3), and Her4 (ErbB-4). Mutations affecting EGFR expression or activity may lead to cancer in many cancer types. EGFR signaling is initiated by ligand binding, which subsequently induces conformational changes, homodimerization or heterodimerization of the receptor with other ErbB family members, and trans autophosphorylation of the receptor, thereby initiating a signal transduction cascade that ultimately affects a variety of cellular functions, including cell proliferation and survival. Increased EGFR expression or kinase activity has been implicated in a range of human cancers, making EGFR an attractive target for therapeutic intervention. Increased EGFR gene copy number and protein expression in non-small cell lung cancer are associated with the EGFR tyrosine kinase inhibitor IRESSA TM (gefitinib) was associated with a good response.

[0361] MET, also known as c-Met, tyrosine protein kinase Met, or hepatocyte growth factor receptor (HGFR), is a protein that in humans is encoded by the MET gene. The protein has tyrosine kinase activity. The primary single-chain precursor protein is post-translationally cleaved to produce α and β subunits, which are disulfide-linked to form the mature receptor. MET is activated by its ligand, hepatocyte growth factor (HGF), and promotes a number of cellular processes, including growth, motility, invasion, metastasis, epithelial-mesenchymal transition, angiogenesis / wound healing, and tissue regeneration. The exact stoichiometry of HGF:MET binding is unknown, but it is generally believed that two HGF molecules bind to two MET molecules, resulting in receptor dimerization and autophosphorylation of tyrosines at positions 1230, 1234, and 1235. Ligand-independent MET autophosphorylation may also occur due to gene amplification, mutation, or receptor overexpression.

[0362] MET is often amplified, mutated or overexpressed in many types of cancer, including gastric cancer, lung cancer, colon cancer, breast cancer, bladder cancer, head and neck cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer and central nervous system cancer. Missense mutations, usually located in the kinase domain, are common 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 MET signaling protein or near the membrane domain are common in gastric cancer, head and neck cancer, liver cancer, ovarian cancer, non-small cell lung cancer and thyroid cancer. MET amplification has been detected in brain cancer, colorectal cancer, gastric cancer and lung cancer, and is usually associated with disease progression. Up to 4% and 20% of non-small cell lung cancer (NSCLC) and gastric cancer show MET amplification, respectively. MET overexpression is also often observed in lung cancer. In addition, high levels of MET and HGF were found in nearly half of clinical lung adenocarcinoma samples, both of which are associated with accelerated tumor growth, metastasis and poor prognosis.

[0363] Nearly 60% of all tumors that are resistant to EGF tyrosine kinase inhibitors increase MET expression, amplify MET, or increase HGF, the only known ligand of MET, indicating the existence of a pathway to compensate for EGFR through MET. MET amplification was first discovered in cultured cells that were resistant to the EGFR kinase inhibitor gefitinib and exhibited higher survival rates through the Her3 pathway. This was further validated clinically, with samples from 9 of 43 patients who were resistant to erlotinib or gefitinib exhibiting MET amplification.

[0364] Aberrant MET signaling has been implicated in the development / progression of many human cancers. This is due to MET overexpression, MET activating mutations, transactivation, autocrine or paracrine signaling, or MET gene amplification. A significant relationship between EGFR and MET signaling has been recognized through studies of cancer treatment outcomes. MET plays a key role in the development of resistance to targeted therapies, including those directed against EGFR. Similarly, EGFR and downstream gene mutations (e.g., KRAS), histological transformation, and activation of alternative pathways, including the MET signaling pathway, have been identified as mechanisms of resistance to EGFR-targeted therapies. Thus, blocking one receptor tends to upregulate the other, leading to resistance to monotherapy. MET amplification and / or high levels of HGF ligand expression 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 exposed to MET inhibitors for a long period of time develop resistance through the EGFR pathway. Due to the signaling crosstalk between EGFR and Met, combined inhibition of both receptors may improve outcomes for patients with MET- and EGFR-driven cancers. Furthermore, simultaneous inhibition may overcome or delay treatment resistance compared to blocking only one pathway.

[0365] The binding of ligands such as EGF to EGFR promotes receptor dimerization, autophosphorylation, activation of the cytoplasmic tyrosine kinase domain inside the receptor, and initiates a variety of signal transduction and transactivation pathways, participating in the regulation of DNA synthesis (gene activation) and cell cycle progression or division. Inhibition of EGFR signaling may lead to the inhibition of one or more EGFRs. In some embodiments, EGFR ligands include EGF, TGFα, heparin-binding EGF (HB-EGF), amphiregulin (AR) and epiregulin (EPI).

[0366] HGF binding to MET promotes receptor dimerization, autophosphorylation, activation of the cytoplasmic tyrosine kinase domain within the receptor and initiates multiple signal transduction and transactivation pathways, which are involved in the regulation of DNA synthesis (gene activation) and cell cycle progression or division. Inhibition of MET signaling may lead to inhibition of one or more MET downstream signaling pathways, so neutralizing MET may have multiple effects, including inhibition of cell proliferation and differentiation, angiogenesis, cell motility and metastasis.

[0367] The role of EGFR and MET in cancer is described in, for example, 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, the entire text of which is incorporated herein by reference.

[0368] The 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 ( For example, 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 in Since these antibodies have the same fully humanized common light chain, an anti-EGFR / MET bispecific antibody having a heavy chain variable region targeting EGFR (e.g., any one of the VHs targeting EGFR described herein), a heavy chain variable region targeting MET (e.g., any one of the VHs targeting MET described herein), and two identical common light chain variable regions is generated. Exemplary bispecific antibodies obtained are as follows Fig.19 As shown. The anti-EGFR antigen binding domain comprises Fig.19 The CDRs of the anti-EGFR antibody shown in the first row. In some embodiments, the anti-MET antigen binding domain comprises Fig.19 The CDRs of the anti-MET antibodies shown in the first column. In some embodiments, the anti-EGFR antigen binding domain comprises Fig.19 The VH and VL of the anti-EGFR antibody shown in the first row. In some embodiments, the anti-MET antigen binding domain comprises Fig.19 The VH and VL of the anti-MET antibody shown in the first column. For example, E-1G11-M-2F11 refers to an anti-EGFR / MET bispecific antibody that comprises 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 comprises the CDRs of E-1G11. In some embodiments, the anti-MET antigen binding domain comprises 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.

[0369] The bispecific antibodies described herein can be designed as IgG1 subtype structures with knob-in-hole (KIH) mutations, which can promote heterodimerization and avoid mispairing between the two heavy chains.

[0370] In some embodiments, the bispecific antibody has a higher internalization rate than a corresponding monoclonal antibody or a control bispecific antibody.

[0371] In some embodiments, the bispecific antibodies described herein can be conjugated with a therapeutic agent to form an antibody drug conjugate (ADC). In some embodiments, the DAR of the ADC 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 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 ... .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 ... 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.

[0372] In some embodiments, the DAR of the ADCs described herein is about 7.5 to about 8.5, about 7.6 to about 8.5, about 7.7 to about 8.5, about 7.8 to about 8.5, about 7.9 to about 8.5, about 8.0 to about 8.5, about 8.1 to about 8.5, about 8.2 to about 8.5, about 8.3 to about 8.5, about 8.4 to about 8.5, about 7.5 to about 8.4, about 7.6 to about 8.4, about 7.9 to about 8.5, about 8.0 to about 8.5, about 8.1 to about 8.5, about 8.2 to about 8.5, about 8.3 to about 8.5, about 8.4 to about 8.5, about 8.5 to about 8.4, about 8.6 to about 8.4, about 8.6 to about 8.4, about 8.6 to about 8.4, about 8.6 to about 8.4, about 8.6 to about 8.4, about 8.6 to about 8.4, about 8.6 to about 8.4, about 8.6 to about 8.4, about 8.6 to about 8.5 ... .7 to about 8.4, about 7.8 to about 8.4, about 7.9 to about 8.4, about 8.0 to about 8.4, about 8.1 to about 8.4, about 8.2 to about 8.4, about 8.3 to about 8.4, about 7.5 to about 8.3, about 7.6 to about 8.3, about 7.7 to about 8.3, about 7.8 to about 8.3, about 7.9 to about 8.3, about 8.0 to about 8.3, about 8.1 to about 8.3, about 8.2 to about 8.3, about 7.5 to about 8.2, about 7.6 to about 8.2, about 7.7 to about 8.2, about 7.8 to about 8.2, about 7.9 to about 8.2, about 8.0 to about 8.2, about 8.1 to about 8.2, about 7.5 to about 8.1, about 7.6 to about 8.1, about 7.7 to about 8.1, about 7.8 to about 8.1, about 7.9 to about 8.1, about 8.0 to about 8.1, about 7.5 to about 8 .0, about 7.6 to about 8.0, about 7.7 to about 8.0, about 7.8 to about 8.0, about 7.9 to about 8.0, about 7.5 to about 7.9, about 7.6 to about 7.9, about 7.7 to about 7.9, about 7.8 to about 7.9, about 7.5 to about 7.8, about 7.6 to about 7.8, about 7.7 to about 7.8, about 7.5 to about 7.7, about 7.6 to about 7.7 or about 7.5 to about 7.6.

[0373] In some embodiments, the anti-EGFR / MET ADC described herein can effectively inhibit the growth of cancer cells in vitro 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 ADC described herein can inhibit the growth of cancer cells (such as 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.

[0374] In some embodiments, the bispecific antibodies or antigen-binding fragments thereof described herein have a common light chain.

[0375] Anti-MET Antibodies and Antigen-Binding Fragments

[0376] The present disclosure provides antibodies and antigen-binding fragments thereof that specifically bind to MET.Anti-EGFR / MET antigen-binding protein constructs (eg, bispecific antibodies) may include antigen-binding regions derived from these antibodies.

[0377] 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"), as well as antibodies derived therefrom.

[0378] The CDR sequences of 2F11 and 2F11-derived antibodies (e.g., human antibodies) include 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) as defined by Kabat numbering. CDRs may 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: 49-51, 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 the human heavy chain variable region of 2F11 are shown in SEQ ID NOs: 61 and 67, respectively.

[0379] The CDR sequences of 2G10 and 2G10-derived antibodies include CDRs of the heavy chain variable domain (SEQ ID NOs: 22-24) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 52-54, 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 the human heavy chain variable region of 2G10 are shown in SEQ ID NOs: 61 and 68, respectively.

[0380] The CDR sequences of 1E9 and 1E9-derived antibodies include CDRs of the heavy chain variable domain (SEQ ID NOs: 25-27) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 55-57, 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 of 1E9 are shown in SEQ ID NOs: 61 and 69, respectively.

[0381] The CDR sequences of 2F12 and 2F12-derived antibodies include CDRs of the heavy chain variable domain (SEQ ID NOs: 28-30) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 58-60, 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 the human heavy chain variable region of 2F12 are shown in SEQ ID NOs: 61 and 70, respectively.

[0382] The CDR sequences of 6D12 and 6D12-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 112-114) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 130-132, 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 the human heavy chain variable region of 6D12 are shown in SEQ ID NOs: 61 and 148, respectively.

[0383] The CDR sequences of 6E6 and 6E6-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 115-117) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 133-135, 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 the human heavy chain variable region of 6E6 are shown in SEQ ID NOs: 61 and 149, respectively.

[0384] The CDR sequences of 7D3 and 7D3-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 118-120) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 136-138, 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 the human heavy chain variable region of 7D3 are shown in SEQ ID NOs: 61 and 150, respectively.

[0385] The CDR sequences of 8D9 and 8D9-derived antibodies (e.g., human antibodies) include CDRs of heavy chain variable domains (SEQ ID NOs: 121-123) and CDRs of light chain variable domains (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may also be defined by the Chothia system. According to Chothia numbering, the CDR sequences of heavy chain variable domains are shown in SEQ ID NOs: 139-141, and the CDR sequences of light chain variable domains are shown in SEQ ID NOs: 1-3. The human light chain variable region and human heavy chain variable region of 8D9 are shown in SEQ ID NOs: 61 and 151, respectively.

[0386] The CDR sequences of 8E2 and 8E2-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 124-126) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 142-144, 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 the human heavy chain variable region of 8E2 are shown in SEQ ID NOs: 61 and 152, respectively.

[0387] The CDR sequences of 8H10 and 8H10-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 127-129) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 145-147, 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 the human heavy chain variable region of 8H10 are shown in SEQ ID NOs: 61 and 153, respectively.

[0388] In addition, in some embodiments, the antibodies or antigen-binding fragments thereof described herein may further contain one, two or three 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: NO:145-147; and / or one, two or three light chain variable region CDRs selected from SEQ ID NO:1-3.

[0389] In some embodiments, the antibody may have a heavy chain variable region (VH) comprising complementarity determining regions (CDR) 1, 2, 3, wherein the CDR1 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected VH CDR1 amino acid sequence, the CDR2 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected VH CDR2 amino acid sequence, and the CDR3 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected VH CDR3 amino acid sequence; and a light chain variable region (VL) comprising CDR1, 2, 3, wherein the CDR1 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected VL CDR1 amino acid sequence, the CDR2 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected VL The CDR2 amino acid sequence has at least 80%, 85%, 90% or 95% identity or consists of an amino acid sequence, and the CDR3 region comprises or consists of an amino acid sequence having at least 80%, 85%, 90% or 95% identity to the selected VLCDR3 amino acid sequence. The selected VH CDR1, 2, 3 amino acid sequence and the selected VL CDR1, 2, 3 amino acid sequence are as follows: Figure 8 and Fig.10 (Kabat CDR) and Fig. 9 and Fig.10 (Chothia CDR) shown.

[0390] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 19 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 20 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 21 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0391] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:22 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:23 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:24 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0392] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:25 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:26 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:27 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0393] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:28 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:29 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:30 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0394] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:49 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:50 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:51 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0395] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:52 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:53 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:54 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0396] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:55 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:56 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:57 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0397] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:58 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:59 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:60 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0398] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 112 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 113 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 114 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0399] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 115 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 116 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 117 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0400] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 118 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 119 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 120 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0401] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 121 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 122 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 123 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0402] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 124 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 125 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 126 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0403] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 127 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 128 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 129 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0404] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 130 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 131 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 132 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0405] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 133 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 134 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 135 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0406] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 136 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 137 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 138 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0407] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 139 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 140 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 141 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0408] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 142 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 143 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 144 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0409] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 145 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 146 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 147 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0410] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a light chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 1 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 2 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 3 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0411] Insertions, deletions and substitutions may be within the CDR sequence or at one or both ends of the CDR sequence.

[0412] The present disclosure also provides an antibody or antigen-binding fragment thereof that binds to MET. The antibody or antigen-binding fragment thereof contains: a heavy chain variable region (VH), the VH comprising or consisting of an amino acid sequence having at least 80%, 85%, 90% or 95% identity with a selected VH sequence, and a light chain variable region (VL), the VL comprising or consisting of an amino acid sequence having at least 80%, 85%, 90% or 95% identity with 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.

[0413] In some embodiments, the antibody or antigen-binding fragment thereof may have 3 VH CDRs that are identical to the CDRs of any VH sequence as described herein. In some embodiments, the antibody or antigen-binding fragment thereof may have 3 VL CDRs that are identical to the CDRs of any VL sequence as described herein.

[0414] The present disclosure also provides nucleic acids comprising polynucleotides encoding polypeptides comprising an immunoglobulin heavy chain or an immunoglobulin light chain. An immunoglobulin heavy chain or an immunoglobulin light chain comprises Figure 8 , Fig. 9 or Fig.10 The CDRs shown, or having Fig.11 When the polypeptide is paired with a corresponding polypeptide (eg, a corresponding heavy chain variable region or a corresponding light chain variable region), the paired polypeptide binds to MET.

[0415] Anti-MET antibodies and antigen-binding fragments can also be antibody variants (including derivatives and conjugates) of antibodies or antibody fragments and multispecific (e.g., bispecific) antibodies or antibody fragments. Other antibodies provided herein are polyclonal antibodies, monoclonal antibodies, multispecific (multimers, e.g., bispecific) antibodies, human antibodies, chimeric antibodies (e.g., human-mouse chimeras), single-chain antibodies, antibodies prepared in cells (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), category (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. In some embodiments, the antibody or its antigen-binding fragment is an IgG antibody or its antigen-binding fragment.

[0416] As long as the antibody fragment retains the affinity and specificity required of the full-length antibody, it is suitable for the provided method. Therefore, an antibody fragment that binds to MET will retain the ability to bind to MET. The Fv fragment is an antibody fragment that contains a complete antigen recognition and binding site. This region consists of a dimer of a heavy chain variable domain and a light chain variable domain in tight association, and the tight association can be covalent in nature, such as scFv. In this configuration, it is the three CDRs of each variable domain that interact to define the antigen binding site on the surface of the VH-VL dimer. The six CDRs or a subset thereof together give the antibody antigen binding specificity. However, even a single variable domain (or half an Fv that includes only three CDRs specific for a certain antigen) has the ability to recognize and bind to an antigen, but its affinity is usually lower than that of the complete binding site.

[0417] Anti-EGFR antibodies and antigen-binding fragments

[0418] The present disclosure provides several antibodies and antigen-binding fragments thereof that specifically bind to EGFR. In some embodiments, anti-EGFR / MET antigen-binding protein constructs (eg, bispecific antibodies) may include antigen-binding regions derived from these antibodies.

[0419] The antibodies and antigen-binding fragments described herein can bind to EGFR. The present disclosure provides 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"), as well as antibodies derived therefrom.

[0420] The CDR sequences of 1G11 and 1G11-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 4-6) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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, 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 the human heavy chain variable region of 1G11 are shown in SEQ ID NOs: 61 and 62, respectively.

[0421] The CDR sequences of 6C4 and 6C4-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 7-9) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 37-38, 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 the human heavy chain variable region of 6C4 are shown in SEQ ID NOs: 61 and 63, respectively.

[0422] The CDR sequences of 2B7 and 2B7-derived antibodies (e.g., human antibodies) include CDRs of heavy chain variable domains (SEQ ID NOs: 10-12) and CDRs of light chain variable domains (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may also be defined by the Chothia system. According to Chothia numbering, the CDR sequences of heavy chain variable domains are shown in SEQ ID NOs: 40-42, and the CDR sequences of light chain variable domains are shown in SEQ ID NOs: 1-3. The human light chain variable region and human heavy chain variable region of 2B7 are shown in SEQ ID NOs: 61 and 64, respectively.

[0423] The CDR sequences of 3A8 and 3A8-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 13-15) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 43-45, 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 the human heavy chain variable region of 3A8 are shown in SEQ ID NOs: 61 and 65, respectively.

[0424] The CDR sequences of 3D8 and 3D8-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 16-18) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 46-48, 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 the human heavy chain variable region of 3D8 are shown in SEQ ID NOs: 61 and 66, respectively.

[0425] The CDR sequences of 9A6 and 9A6-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 82-84) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 94-96, 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 the human heavy chain variable region of 9A6 are shown in SEQ ID NOs: 61 and 106, respectively.

[0426] The CDR sequences of 9D2 and 9D2-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 85-87) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 97-99, 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 the human heavy chain variable region of 9D2 are shown in SEQ ID NOs: 61 and 107, respectively.

[0427] The CDR sequences of 9F3 and 9F3-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 88-90) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 100-102, 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 the human heavy chain variable region of 9F3 are shown in SEQ ID NOs: 61 and 108, respectively.

[0428] The CDR sequences of 9H2 and 9H2-derived antibodies (e.g., human antibodies) include CDRs of the heavy chain variable domain (SEQ ID NOs: 91-93) and CDRs of the light chain variable domain (SEQ ID NOs: 1-3) as defined by Kabat numbering. CDRs may 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: 103-105, 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 the human heavy chain variable region of 9H2 are shown in SEQ ID NOs: 61 and 109, respectively.

[0429] In addition, in some embodiments, the antibodies or antigen-binding fragments thereof described herein may also contain one, two or three heavy chain variable region CDRs selected from the following items: SEQ ID NO:4-6, SEQ ID NO:7-9, SEQ ID NO:10-12, SEQ ID NO:13-15, SEQ ID NO:16-18, SEQ ID NO:34-36, SEQ ID NO:37-39, SEQ ID NO:40-42, SEQ ID NO:43-45, SEQ ID NO:46-48, SEQ ID NO:82-84, SEQ ID NO:85-87, SEQ ID NO:88-90, SEQ ID NO:91-93, SEQ ID NO:94-96, SEQ ID NO:97-99, SEQ ID NO:100-102 and SEQ ID NO:103-105; and / or one, two or three light chain variable region CDRs selected from SEQ ID NO:1-3.

[0430] In some embodiments, the antibody may have a heavy chain variable region (VH) comprising complementarity determining regions (CDR) 1, 2, 3, wherein the CDR1 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected VH CDR1 amino acid sequence, the CDR2 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected VH CDR2 amino acid sequence, and the CDR3 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected VH CDR3 amino acid sequence; and a light chain variable region (VL) comprising CDR1, 2, 3, wherein the CDR1 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected VL CDR1 amino acid sequence, the CDR2 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected VL CDR2 amino acid sequence. The CDR2 amino acid sequence has at least 80%, 85%, 90% or 95% identity or consists of an amino acid sequence, and the CDR3 region comprises or consists of an amino acid sequence that has at least 80%, 85%, 90% or 95% identity to the selected VL CDR3 amino acid sequence. The selected VH CDR1, 2, 3 amino acid sequence and the selected VL CDR1, 2, 3 amino acid sequence are as follows: Figure 8 and Fig.10 (Kabat CDR) and Fig. 9 and Fig.10 (Chothia CDR) shown.

[0431] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 4 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 5 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 6 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0432] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 7 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 8 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 9 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0433] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 10 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 11 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 12 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0434] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 13 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 14 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 15 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0435] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 16 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 17 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 18 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0436] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:34 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:35 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:36 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0437] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:37 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:38 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:39 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0438] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:40 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:41 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:42 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0439] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:43 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:44 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:45 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0440] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:46 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:47 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:48 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0441] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:82 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:83 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:84 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0442] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:85 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:86 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:87 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0443] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 88 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 89 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 90 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0444] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two or three of the following CDRs: SEQ ID NO:91 having zero, one or two amino acid insertions, deletions or substitutions; SEQ ID NO:92 having zero, one or two amino acid insertions, deletions or substitutions; SEQ ID NO:93 having zero, one or two amino acid insertions, deletions or substitutions.

[0445] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:94 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:95 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:96 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0446] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO:97 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:98 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO:99 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0447] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 100 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 101 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 102 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0448] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 103 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 104 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 105 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0449] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a light chain variable domain comprising one, two, or three of the following CDRs: SEQ ID NO: 1 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 2 having zero, one, or two amino acid insertions, deletions, or substitutions; SEQ ID NO: 3 having zero, one, or two amino acid insertions, deletions, or substitutions.

[0450] Insertions, deletions and substitutions may be within the CDR sequence or at one or both ends of the CDR sequence.

[0451] The present disclosure also provides an antibody or antigen-binding fragment thereof that binds to EGFR. The antibody or antigen-binding fragment thereof contains: a heavy chain variable region (VH), the VH comprising or consisting of an amino acid sequence having at least 80%, 85%, 90% or 95% identity with a selected VH sequence, and a light chain variable region (VL), the VL comprising or consisting of an amino acid sequence having at least 80%, 85%, 90% or 95% identity with 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.

[0452] In some embodiments, the antibody or antigen-binding fragment thereof may have 3 VH CDRs that are identical to the CDRs of any VH sequence as described herein. In some embodiments, the antibody or antigen-binding fragment thereof may have 3 VL CDRs that are identical to the CDRs of any VL sequence as described herein.

[0453] The present disclosure also provides nucleic acids comprising polynucleotides encoding polypeptides comprising an immunoglobulin heavy chain or an immunoglobulin light chain. An immunoglobulin heavy chain or an immunoglobulin light chain comprises Figure 8 , Fig. 9 or Fig.10 The CDRs shown, or having Fig.11When the polypeptide is paired with a corresponding polypeptide (eg, a corresponding heavy chain variable region or a corresponding light chain variable region), the paired polypeptide binds to EGFR (eg, human EGFR).

[0454] Anti-EGFR antibodies and antigen-binding fragments can also be antibody variants (including derivatives and conjugates) of antibodies or antibody fragments and multispecific (e.g., bispecific) antibodies or antibody fragments. Other antibodies provided herein are polyclonal antibodies, monoclonal antibodies, multispecific (polymers, e.g., bispecific) antibodies, human antibodies, chimeric antibodies (e.g., human-mouse chimeras), single-chain antibodies, antibodies prepared in cells (i.e., intrabodies) and their antigen-binding fragments. The antibody or its antigen-binding fragment can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), category (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. In some embodiments, the antibody or its antigen-binding fragment is an IgG antibody or its antigen-binding fragment.

[0455] As long as the antibody fragment retains the affinity and specificity required for the full-length antibody, it is suitable for the provided method. Therefore, the antibody fragment that binds to EGFR will retain the ability to bind to EGFR. The Fv fragment is an antibody fragment containing a complete antigen recognition and binding site. This region consists of a dimer of a heavy chain variable domain and a light chain variable domain that are tightly bound, and the tight binding can be covalent in nature, such as scFv. In this configuration, it is the three CDRs of each variable domain that interact to define the antigen binding site on the surface of the VH-VL dimer. The six CDRs or their subsets together give the antibody antigen binding specificity. However, even a single variable domain (or half an Fv that only includes three CDRs specific to a certain antigen) has the ability to recognize and bind to an antigen, but its affinity is usually lower than that of a complete binding site.

[0456] Antibodies, antigen-binding fragments and antigen-binding protein constructs

[0457] The present disclosure provides antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs (e.g., bispecific antibodies). Antigen-binding protein constructs (e.g., bispecific antibodies) may include anti-EGFR antibodies or antigen-binding fragments thereof, and anti-MET antibodies or antigen-binding fragments thereof. These antigen-binding protein constructs (e.g., bispecific antibodies), anti-EGFR antibodies, anti-MET antibodies, and antigen-binding fragments thereof may have various forms.

[0458] Typically, antibodies (also known as immunoglobulins) can be composed of two types of polypeptide chains, namely light chains and heavy chains. The non-limiting antibodies of the present disclosure can be complete tetra-immunoglobulin chain antibodies including two heavy chains and two light chains. The heavy chain of the antibody can be of any isotype (including IgM, IgG, IgE, IgA or IgD) or subisotype (including IgG1, IgG2, IgG2a, IgG2b, IgG3, IgG4, IgE1, IgE2, etc.). The light chain can be a kappa light chain or a lambda light chain. The antibody may include two identical copies of the light chain and / or two identical copies of the heavy chain. The heavy chains, each containing a variable domain (or variable region, VH) and multiple constant domains (or constant regions), are bound to each other through disulfide bonds within their constant domains to form the "backbone" of the antibody. The light chains, each containing a variable domain (or variable region VL) and a constant domain (or constant region), are each bound to a heavy chain through a disulfide bond. The variable region of each light chain is aligned with the variable region of the heavy chain to which it is bound. The variable regions of both the light and heavy chains contain three hypervariable regions sandwiched between more conserved framework regions (FR).

[0459] These hypervariable regions, called complementarity determining regions (CDRs), form loops that comprise the major antigen-binding surface of the antibody. The four framework regions largely adopt a β-sheet conformation, while the CDRs form loops that connect and in some cases form part of the β-sheet structure. The CDRs in each chain are held tightly together by the framework regions and, together with the CDRs from the other chain, contribute to the formation of the antigen-binding region.

[0460] Methods for identifying the CDR regions of an antibody by analyzing its amino acid sequence are well known, and various definitions of CDRs are commonly used. The Kabat definition is based on sequence variability, and the Chothia definition is based on the location 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, TT and Kabat, EA (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), the entire contents of which are incorporated herein by reference.

[0461] CDR is very important for recognizing the epitope of an antigen. As used herein, an "epitope" is the smallest part 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 three, four, five, six or seven amino acids, but these amino acids do not have to be in a continuous linear sequence of the primary structure of the antigen, because the epitope can depend on the three-dimensional configuration of the antigen based on the secondary and tertiary structures of the antigen.

[0462] In some embodiments, the antibody is a complete immunoglobulin molecule (e.g., IgG1, IgG2a, IgG2b, IgG3, IgM, IgD, IgE, IgA). The IgG subclasses (IgG1, IgG2, IgG3, and IgG4) are highly conserved, but differ in their constant regions, particularly the hinge and upper CH2 domains. The sequences and differences of IgG subclasses are known in the art and are described in, for example, 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, all of which are incorporated herein by reference in their entirety.

[0463] Antibodies can also be immunoglobulin molecules derived from any species (e.g., humans, rodents, mice, rats, camelids). Antibodies disclosed herein also include, but are not limited to, polyclonal antibodies, monoclonal antibodies, monospecific antibodies, multispecific antibodies, and chimeric antibodies comprising immunoglobulin binding domains fused to another polypeptide. Antigen binding domains or antigen binding fragments are parts of antibodies that retain the specific binding activity of intact antibodies, i.e., any antibody part that can specifically bind to the epitope on the target molecule of intact antibodies. It includes, for example, Fab, Fab', F(ab')2, and variants of these fragments. Therefore, in some embodiments, antibodies or their antigen binding fragments can be, for example, scFv, Fv, Fd, dAb, bispecific antibodies, bispecific scFv, double-chain antibodies, linear antibodies, single-chain antibody molecules, multispecific antibodies formed by antibody fragments, and any polypeptides comprising antibody binding domains or binding domains homologous thereto. Non-limiting examples of antigen binding domains include, e.g., heavy and / or light chain CDRs of an intact antibody, heavy and / or light chain variable regions of an intact antibody, the full length heavy or light chain of an intact antibody, or a single CDR from a heavy or light chain of an intact antibody.

[0464] In some embodiments, scFV has two heavy chain variable domains and two light chain variable domains.In some embodiments, scFV has two antigen binding regions (antigen binding region A and B), and the two antigen binding regions can bind to respective target antigens with different affinities.

[0465] In some embodiments, the antigen binding fragment may constitute a part of a chimeric antigen receptor (CAR). In some embodiments, the chimeric antigen receptor is a fusion of a single-chain variable fragment (scFv) fused to a CD3-ζ transmembrane domain and an intracellular domain as described herein. In some embodiments, the chimeric antigen receptor also includes intracellular signaling domains from various costimulatory protein receptors (e.g., CD28, 41BB, ICOS). In some embodiments, the chimeric antigen receptor includes multiple signaling domains, such as CD3z-CD28-41BB or CD3z-CD28-OX40, to increase effectiveness. Therefore, on the one hand, the present disclosure also provides cells (e.g., T cells) expressing chimeric antigen receptors as described herein.

[0466] In some embodiments, an antibody, antigen-binding fragment thereof, or antigen-binding protein construct (eg, a bispecific antibody) can bind to two different antigens or two different epitopes.

[0467] In some embodiments, an antibody, antigen-binding fragment thereof, or antigen-binding protein construct (eg, a bispecific antibody) may include one, two, or three selected from Figure 8 and Fig. 9In some embodiments, an antibody, an antigen-binding fragment thereof, or an antigen-binding protein construct (eg, a bispecific antibody) may include one, two, or three selected from Fig.10 The light chain variable region CDRs.

[0468] The multimerization of antibodies can be achieved by natural aggregation of antibodies or by chemical or recombinant connection techniques known in the art. For example, a certain percentage of purified antibody preparations (e.g., purified IgG1 molecules) spontaneously form protein aggregates containing antibody homodimers and other higher-order antibody multimers.

[0469] In some embodiments, multispecific antibodies are bispecific antibodies. Bispecific antibodies can be prepared by engineering the interface between a pair of antibody molecules to maximize the ratio of heterodimers recovered from recombinant cell culture. For example, the interface can include at least a portion of the CH3 domain of an antibody constant domain. In this method, one or more small amino acid side chains at the interface of the first antibody molecule are replaced with larger side chains (for example, tyrosine or tryptophan). By replacing the large amino acid side chains with smaller amino acid side chains (for example, alanine or threonine), a compensation "cavity" identical or similar to the large side chain size is produced on the interface of the second antibody molecule. This provides a mechanism that can make the yield of heterodimers higher than other unwanted end products (such as homodimers). The method is described in, for example, WO 96 / 27011, which is incorporated herein by reference in its entirety.

[0470] Any antibody, antigen-binding fragment thereof, or antigen-binding protein construct described herein (e.g., bispecific antibody) 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 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 stabilizing molecules 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 the human body) or extend its biological activity.

[0471] Antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs (e.g., bispecific antibodies) may also have various forms. Many different forms of antigen-binding constructs are known in the art and are described in, for example, Suurs, et al. "A review of bispecific antibodies and antibody constructs in oncology and clinical challenges," Pharmacology & therapeutics (2019), which is incorporated herein by reference in its entirety.

[0472] 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-HSA, or a tandem scFv. In some embodiments, the antigen binding protein construct is VHH-scAb, VHH-Fab, dual scFab, F(ab')2, diabody, crossMab, DAF (two-in-one), DAF (four-in-one), DutaMab, DT-IgG, a common light chain of a knob-in-hole structure, a knob-in-hole structure assembly, a charge pair, a 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, a diabody-CH3, a triple antibody (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.

[0473] In some embodiments, the antigen binding protein construct can be a TrioMab. In a TrioMab, the two heavy chains are from different species, with different sequences restricting the heavy chain-light chain pairing.

[0474] In some embodiments, the antigen binding protein construct has two different heavy chains and one common light chain. Heterodimerization of the heavy chains can be based on a knob-in-hole structure or some other heavy chain pairing technology.

[0475] In some embodiments, bispecific antibodies can be produced using CrossMAb technology. CrossMAb technology can be used to achieve correct light chain binding in bispecific heterodimer IgG antibodies, which allows the production of various bispecific antibody formats, including bi-(1+1), tri-(2+1) and tetra-(2+2) valence bispecific antibodies, and antibodies based on non-Fc tandem antigen binding fragments (Fab). These forms can be derived from any existing antibody pairs using domain crossovers, without the need to identify a common light chain, post-translational processing / in vitro chemical assembly, or introduce a group of mutations that can achieve correct light chain binding. The method is described in Klein et al., "The use of CrossMAb technology for the generation of bi-andmultispecific antibodies." MAbs. Vol. 8. No. 6. Taylor & Francis, 2016, which is incorporated herein by reference in its entirety. In some embodiments, the CH1 in the heavy chain and the CL domain in the light chain are exchanged.

[0476] The antigen binding protein construct can be a Duobody. The naturally occurring Fab exchange mechanism in IgG4 antibodies is similar to the controlled substance in IgG1 antibodies, which is called controlled Fab exchange. This format ensures specific pairing between heavy and light chains.

[0477] In dual variable domain antibodies (DVD-Ig), additional VH and variable light (VL) domains are added to each N-terminus for bispecific targeting. This format is similar to IgG-scFv, but the added binding domains bind to their respective N-termini alone, rather than scFv binding to each heavy chain N-terminus.

[0478] In scFv-IgG, 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 therefore also called tetravalent. scFv-IgG does not have the problem of pairing the heavy and light chains.

[0479] In some embodiments, the antigen binding protein construct may have an IgG-IgG format. Two intact IgG antibodies are conjugated by chemically linking the C-termini of the heavy chains.

[0480] The antigen binding protein construct may also have a Fab-scFv-Fc format. In the Fab-scFv-Fc format, a light chain, a heavy chain, and a third chain containing an Fc region and scFv are assembled. This format ensures efficient preparation and purification.

[0481] In some embodiments, the antigen binding protein construct can be TF. Three Fab fragments are linked by disulfide bridges. Two fragments target tumor associated antigens (TAA) and one fragment targets a hapten. The TF form does not have an Fc region.

[0482] ADAPTIR has two scFvs bound to either side of the Fc region. This format abandons the full IgG as the basis of its construction, but retains the Fc region to extend half-life and facilitate purification.

[0483] Bispecific T cell engagers ("BiTEs") consist of two scFvs, VLA VHA and VHB VLB, on one peptide chain. They only have binding domains and no Fc region.

[0484] In BiTE-Fc, the Fc region is fused to the BiTE construct. The addition of the Fc region increases the half-life, thereby extending the effective concentration and avoiding continuous intravenous (IV) administration.

[0485] Dual-affinity retargeting (DART) antibodies have two peptide chains connecting opposite fragments, namely VLA and VHB and VLB and VHA, and have a sulfide bond at their C-termini fusing them together. In DART, the sulfide bond can improve its stability compared to BiTE.

[0486] In DART-Fc, the Fc region is attached to the DART structure. It can be produced by assembling three chains, two of which are linked by disulfide bonds, like DART. One chain contains half of the Fc region, which will dimerize with the third chain that only expresses the Fc region. The addition of the Fc region increases the half-life, thereby extending the effective concentration and avoiding continuous intravenous administration (IV).

[0487] A tetravalent DART consists of four peptide chains. Basically, two DART molecules have half of the Fc region and dimerize. This form binds both targets bivalently, making it a tetravalent molecule.

[0488] Tandem diabodies (TandAb) include two diabodies. Each diabody consists of a VHA and a VLB fragment, and the VHA and VLB fragments are covalently bound. The two diabodies are connected to a peptide chain. Compared with a diabody consisting of two scFvs, its stability is improved. It has two bivalent binding sites.

[0489] ScFv-scFv-toxins include a toxin and two scFvs with a stabilizing linker. They can be used to specifically deliver payloads.

[0490] In the module scFv-scFv-scFv, one scFv targeting a TAA is tagged with a short recognizable peptide and assembled onto a bsAb consisting of two scFvs, one targeting CD3 and one targeting the recognizable peptide.

[0491] In ImmTAC, a stable and soluble T cell receptor is fused to a scFv that recognizes CD3. By using the TCR, ImmTAC is suitable for targeting processed proteins, such as intracellular proteins.

[0492] Trispecific nanobodies have two single variable domains (nanobodies), and another module for extending half-life. Additional modules are added to increase half-life.

[0493] In the trispecific killer adapter (TriKE), two scFvs are connected by a peptide linker incorporating human IL- 15. The linker to IL-15 is added to increase the survival and proliferation of NK cells.

[0494] In some embodiments, the antigen binding protein construct is a bispecific antibody. In some embodiments, the bispecific antibody of the present disclosure is designed as 1+1 (unit price per target) and has an IgG1 subtype structure. This can reduce the affinity for cells with low expression levels of EGFR and MET, and increase the affinity for cells co-expressing EGFR and MET to achieve enhanced targeting function.

[0495] In some embodiments, the antibody, antigen-binding fragment thereof, antigen-binding protein construct (e.g., an anti-MET antibody, an anti-EGFR antibody, or a bispecific antibody), or related antibody drug conjugate (ADC) 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 any one of SEQ ID NOs: 71 and 72.

[0496] In some embodiments, an anti-EGFR / MET antigen binding protein construct (e.g., an antibody, a bispecific antibody, or an antibody fragment thereof) comprises a KIH mutation. In some embodiments, an 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 comprising one or more knob mutations (knob heavy chain), and the second antigen binding domain comprises a heavy chain comprising one or more hole mutations (hole heavy chain). In some embodiments, the first antigen binding domain comprises a heavy chain comprising one or more hole mutations (hole heavy chain), and the second antigen binding domain comprises a heavy chain comprising one or more knob mutations (knob heavy chain). 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.

[0497] In some embodiments, the bispecific antibodies or antigen-binding fragments thereof described herein have a common light chain.

[0498] Antibody Drug Conjugate (ADC)

[0499] The antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs described herein (e.g., bispecific antibodies) can be conjugated to therapeutic agents (drugs) via any linker to form antibody drug conjugates. Antibody drug conjugates comprising antibodies or antigen-binding fragments thereof can be covalently or non-covalently bound to therapeutic agents. In some embodiments, the therapeutic agent is a cytotoxic agent or a 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 anthracin, maytansinoid alkaloids (such as DM-1 and DM-4), diketones, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, epirubicin, and cyclophosphamide and the like). In certain embodiments, the therapeutic agent is MMAE or MMAF.

[0500] Definitions of specific functional groups and chemical terms are detailed below. For the purposes of the present invention, identification of chemical elements is based on Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and definitions of specific functional groups are generally as described therein. In addition, general principles of organic chemistry as well as specific functional groups and reactivity are described in the following literature: Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modem Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0501] Unless otherwise expressly stated, all ranges cited herein are inclusive. When a numerical range is listed, the range should include each value and subrange within the range. For example, "C1-6" includes C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6.

[0502] The compounds of the present disclosure or any formula depicting and describing the compounds may have one or more chiral (asymmetric) centers. The present invention includes all stereoisomeric forms of the compounds described herein or any formula depicting and describing the compounds. Asymmetric centers present in the compounds of the present invention or any formula depicting and describing the compounds may have the (R) or (S) configuration independently of each other. When the bonds to chiral carbons in a structural formula are depicted as straight lines in the structural formula, or when there is no (R) or (S) chiral designation for a chiral carbon in the name of the compound, it is understood that both the (R) and (S) configurations of each chiral carbon are present, and thus each enantiomer or diastereomer and mixtures thereof are included in the formula or name.

[0503] The present disclosure includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers, such as mixtures of enantiomers and / or diastereomers present in various proportions. Therefore, the enantiomers disclosed herein include enantiomerically pure products, left-handed enantiomers and right-handed enantiomers, racemates, and mixtures of two enantiomers in various proportions. If it is a cis / trans isomer, it includes cis and trans and mixtures in various proportions. If necessary, each stereoisomer can be prepared by separating the mixture by conventional methods, such as chromatography or crystallization, by synthesizing using stereochemically uniform raw materials or by stereoselective synthesis. Optionally, derivatization can be performed before the separation of stereoisomers. The separation of stereoisomer mixtures can be performed in an intermediate step of compound synthesis or on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallographic analysis of the crystalline product or crystalline intermediate, and if necessary, the crystalline intermediate can be derivatized using a reagent containing a stereocenter of known configuration. In addition, the absolute stereochemical structure can also be determined by vibrational circular dichroism (VCD) spectroscopy.

[0504] Unless otherwise stated, structures described herein also include compounds that differ only in the presence of one or more isotopically enriched atoms, in other words, compounds in which one or more atoms are replaced by atoms having the same atomic number, but with an atomic mass or mass number different from the atomic mass or mass number that predominates in nature. Such compounds are termed "isotopic variants". The present disclosure is intended to include all pharmaceutically acceptable isotopic variants of the compounds of the invention or any formula depicting and describing the compounds. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2 H (i.e. D) and 3 H; carbon, such as 11 C. 13 C. and 14 C; chlorine, such as 36 Cl; fluorine, such as 18 F; iodine, such as 123 I and 125 I; Nitrogen, such as 13 N and 15 N; oxygen, such as 15 O. 17 O and 18 O; phosphorus, such as 32 P; and sulfur, such as 35S. Certain isotopic variants of the disclosed compounds or any formula depicting and describing the compounds, such as those containing radioactive isotopes, may be useful for drug and / or substrate tissue distribution studies. In particular, compounds having the described structures, which differ only in the replacement of heavier isotopes, such as the replacement of hydrogen with deuterium (2H or D), may provide certain therapeutic advantages, such as greater metabolic stability, extended in vivo half-life or reduced dosage requirements, and therefore, may be used in certain specific situations. Isotopic variants of the disclosed compounds or any formula depicting and describing the compounds can generally be prepared by techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples, and synthesized using appropriate isotopically labeled reagents instead of previously used non-labeled reagents.

[0505] The compounds provided herein are described with reference to general formulae and specific compounds. In addition, the compounds of the present disclosure may exist in a variety of different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, pharmaceutically acceptable salts, tautomers, stereoisomers, racemic mixtures, regioisomers, prodrugs, solvated forms, different crystalline forms or polymorphs, and active metabolites, etc.

[0506] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acid / base form of a particular compound and do not have adverse effects biologically or otherwise. Pharmaceutically acceptable salts may include salts formed with inorganic bases or acids and organic bases or acids. In the case where the compounds of the present disclosure contain one or more acidic or basic groups, the present disclosure also includes its corresponding pharmaceutically acceptable salts. Therefore, the compounds of the present invention containing acidic groups (such as carboxyl groups) may exist in the form of salts and may be used according to the present invention, such as alkali metal salts, alkaline earth metal salts, aluminum salts or ammonium salts. More non-limiting examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine or amino acids. These salts are easily obtained, for example, by reacting a compound with 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 alkali salts of the disclosed compounds include, but are not limited to, copper (I), copper (II), iron (II), iron (III), manganese (II) and zinc salts. The disclosed compounds contain one or more basic groups, such as protonable groups, which can exist in the form of salts and can be used in the form of addition salts with inorganic or organic acids according to the disclosure. Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic 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, pamoic 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 salt formed includes hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methyl sulfonate (mesylate), toluene sulfonate, carbonate, bicarbonate, formates, acetate, sulfoacetate, trifluoromethanesulfonate, oxalate, malonate, maleate, succinate, tartrate, malate, pamoate, mandelate, fumarate, lactate, citrate, glutarate, stearate, aspartate and glutamate. In addition, the stoichiometric ratio of the salt formed by the compounds of the present invention can be an integer multiple or non-integer multiple of 1.

[0507] Compounds of the present disclosure containing basic nitrogen-containing groups can be quaternized using the following agents: C1-4 alkyl halides, such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; diC1-4 alkyl sulfates, such as dimethyl sulfate, diethyl sulfate and diamyl sulfate; C10-18 alkyl halides, such as decyl, dodecyl, lauryl, tetradecyl and octadecanoyl chlorides, bromides and iodides; and aryl C1-4 alkyl halides, such as benzyl chloride and phenethyl bromide.

[0508] If the compounds of the present disclosure contain both acidic and basic groups in the molecule, the present disclosure also includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned. The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these salts with organic or inorganic acids or bases 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, which are not suitable for direct use in medicines due to low physiological compatibility, but can be used as, for example, intermediates for chemical reactions or for preparing pharmaceutically acceptable salts. For a review of more suitable salts, please refer to Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0509] The compounds of the present disclosure or any formula depicting and describing the compounds and their pharmaceutically acceptable salts may exist in both non-dissolved and dissolved forms. The term "solvate" as used herein 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.

[0510] Pharmaceutically acceptable solvates according to the present disclosure may include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, d6-acetone, d6-DMSO.

[0511] Linker (Linker Compound)

[0512] In some embodiments, the therapeutic agent is conjugated via a linker (or linker compound). As used herein, the term "linker" or "linker compound" refers to a compound that can react with groups of a ligand compound and a therapeutic compound, respectively, by, for example, a coupling reaction, to link a ligand (such as an antibody, an antigen-binding fragment thereof, or an antigen-binding protein construct (such as a bispecific antibody) described herein) and a therapeutic agent (such as any therapeutic agent described herein) together to form a ligand-drug conjugate.

[0513] In some embodiments, a linker described herein is a compound having the formula:

[0514]

[0515] or a pharmaceutically acceptable salt, solvate, stereoisomer or isotopic variant thereof, wherein Q represents a linker moiety capable of coupling to a ligand through a bond selected from a carbonyl, a thioether, an amide, a disulfide and a hydrazone bond; and L represents a linker moiety capable of connecting Q to a therapeutic agent.

[0516] In some embodiments, the linking moiety (Q in Formula (I)) has the following structure:

[0517]

[0518] In some embodiments, the linking moiety (L in formula (I)) has the following structure:

[0519]

[0520] Wherein L1 is a polypeptide residue consisting of 3 to 8 amino acid residues, the polypeptide residue includes at least one amino acid residue with a side chain carboxyl group, such as a glutamic acid residue or an aspartic acid residue, wherein "-COOH" represents the carboxyl group of the amino acid residue at the C-terminal end of the polypeptide residue;

[0521] L2 is a monodentate, bidentate or tridentate hydrophilic group that is absent or attached to the side chain carboxyl group of the amino acid residue of the polypeptide residue L1, and L2 has NHC(R L2a )(R L2b )(R L2c ) structure, where R L2a , R L2b , and R L2c Each independently selected from H, -(CH2O)(CH2CH2O) m (CH2) p C(O)OH, and -(CH2O)(CH2CH2O) m (CH2) p C(O)NHR L2d The group consisting of R L2d is H or C1-6 alkyl optionally substituted by 1 to 6 hydroxyl groups, each m is independently an integer from 0 to 10, preferably from 0 to 4, such as 0, 1, 2, 3 or 4, particularly preferably m is 0, each p is independently an integer from 1 to 4, such as 1, 2, 3 or 4; and

[0522] represents the N-terminal side of the polypeptide residue covalently linked to the linking moiety Q.

[0523] In some embodiments, polypeptide residue L1 isNH -Glutamic acid-Valine-Alanine- COOH In some embodiments, the hydrophilic group L2 has the following structure:

[0524]

[0525] Wherein "*" indicates the site of covalent attachment to polypeptide residue L1, e.g. NH -Glutamic acid-Valine-Alanine- COOH Side chain of glutamic acid residue in .

[0526] In some embodiments, the linker described herein is a compound having the following structure:

[0527]

[0528] In some embodiments, the linker is a VC linker. For detailed information on linkers used in ADCs, see 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.

[0529] Therapeutic agents

[0530] In some embodiments, the therapeutic agents conjugated to the antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs (eg, bispecific antibodies) described herein are discussed below.

[0531] In some embodiments, the therapeutic agent described herein is a cytotoxic agent. 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:

[0532]

[0533] wherein X is selected from the group consisting of -CH2-, O and S; and Y is selected from the group consisting of H, D and F.

[0534] 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:

[0535]

[0536] 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:

[0537]

[0538] In some embodiments, the therapeutic agent is CPT3. The structure of CPT-3 is shown below:

[0539]

[0540] 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:

[0541]

[0542] In some embodiments, the therapeutic agent is an auristatin, such as auristatin E (also known in the art as a derivative of dolastatin-10) or a derivative thereof. For example, the auristatin can be an ester formed between auristatin E and a ketoacid. For example, auristatin E can be reacted with acetylbenzoic acid or benzoylvaleric acid to generate AEB and AEVB, respectively. Other typical auristatins include AFP, MMAF, and MMAE. The synthesis and structure of exemplary auristatins are described in U.S. Patent Application Publication No. 2003-0083263, International Patent Publication No. WO 04 / 010957, International Patent Publication No. WO 02 / 088172 and U.S. Patent 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; 5,530,09 7; 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, the entire text of each of which is incorporated herein by reference and for all purposes.

[0543] Studies have shown that auristatins can interfere with microtubule dynamics as well as nuclear and cell division and have anticancer activity. Auristatins bind to tubulin and can produce cytotoxic or cytostatic effects on cancer cells. There are many different detection methods known in the art that can be used to determine whether auristatins or antibody-drug conjugates produced therefrom produce cytostatic or cytotoxic effects on desired cells.

[0544] In certain embodiments, the therapeutic agent is a chemotherapeutic agent. Examples of chemotherapeutic agents include alkylating agents (such as thiotepa and cyclophosphamide (CYTOXAN TM)); alkyl sulfonates (such as busulfan, improsulfan, and piposulfan); aziridines (such as benzodopa, carboquinone, meturedopa, and uredopa); ethyleneimines and methylmelamines (including hexamethylmelamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide, and trimethylolomelamine); nitrogen mustards (such as chlorambucil, naphthyl mustard, cholophosphamide, estramustine, ifosfamide, phenylalanine mustard, mechlorethamine oxide, mechlorethamine oxide hydrochloride, and chlorambucil). hydrochloride), new nitrogen mustard, phenylephrine, prednimustine, trofosamide, uracil nitrogen mustard); nitrosoureas (such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine); antibiotics (such as aclarubicin, actinomycin, anthramycin, azaserine, actinomycin C, calicheamicin, calabikine, carminomycin, carmomycin, chromomycin, actinomycin D, daunorubicin, detoximum, 6-diazo-5-oxo-L-norleucine azathioprine, oxadiazine, oxadiazine, idarubicin, mexicocycline, mitomycin, mycophenolic acid, norgamycin, olivomycin, peplomycin, potfiromycin, puromycin, triferric doxorubicin, rhodorubicin, streptozotocin, streptozotocin, tuberculocidin, ubenimex, nistatin, daunorubicin); antimetabolites (such as methotrexate and 5-fluorouracil (5-FU)); folic acid analogs (such as folinic acid, methotrexate, pteropterin, trimetrexate ); purine analogs (such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine); pyrimidine analogs (such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU); androgens (such as calutosterone, drostanolone propionate, cyclothiodine, melastosane, testolactone); antiadrenal drugs (such as aminoglutethimide, mitotane, trilostane); folic acid supplements (such as folinic acid); aceglucuronolide; aldophosphamideglycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; colcemid; diazocone; eflornithine; elitrilonium acetate; etoglu; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguanidine; mitoxantrone; mopidarol; diamine nitracrine; pentostatin;phenamet; pirarubicin; podophylloic acid; 2-ethylhydrazide; procarbazine; PSK7; razoxane; sizoran; spirogermanamine; tricosporic acid; triazoquinone; 2',2',2'-trichlorotriethylamine; ethyl carbamate; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulanol; pipobroman; cytosine; arabinoside ("Ara-C"); cyclophosphamide; taxanes (e.g., paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel ( Rhone-Poulenc Rorer, Antoni, France); chlorambucil; gemcitabine; 6-thioguanine; platinum analogs (such as cisplatin and carboplatin); vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; mitoxantrone (Novantrone); teniposide; daunorubicin; aminopterin; Xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above substances. The definition also includes anti-hormonal agents that regulate or inhibit the effect of hormones on tumors, such as anti-estrogens, including, for example, tamoxifen, raloxifene, aromatase inhibitory 4 (5) -imidazoles, 4-hydroxytamoxifen, trioxifene, raloxifene, LY117018, onapristone and toremifene (Falutone); and anti-androgens, such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above substances. A detailed description of chemotherapeutic agents can be found in, for example, US20180193477A1, which is incorporated herein by reference in its entirety.

[0545] Linker-Therapeutic Agent Compounds

[0546] In some embodiments, a linker (such as any linker described herein) and a therapeutic agent (such as any therapeutic agent described herein) can be linked to form a "linker-therapeutic agent" compound.

[0547] In some embodiments, the linker-therapeutic agent compound has the structure:

[0548]

[0549] In some embodiments, the linker-therapeutic agent compound has the structure:

[0550]

[0551] In some embodiments, an antibody ("Ab"), such as any antibody described herein, an antigen-binding fragment thereof, or an antigen-binding protein construct (such as a bispecific antibody), can be linked to a linker-therapeutic compound (such as any linker-therapeutic compound described herein) to generate an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate has the following structure:

[0552]

[0553] wherein n=1, 2, 3, 4, 5, 6, 7 or 8.

[0554] Antibody and ADC characterization

[0555] The anti-EGFR / MET antigen binding protein construct (eg, an antibody, a bispecific antibody, or an antibody fragment thereof) may include an antigen binding region derived from any anti-EGFR antibody or any antigen binding fragment thereof as described herein.

[0556] The present disclosure provides antibodies and antigen-binding fragments thereof that can specifically bind to EGFR. The antibodies and antigen-binding fragments described herein can bind 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, anti-EGFR antibodies can inhibit EGFR-related signaling pathways, thereby treating cancer (such as NSCLC). In some embodiments, anti-EGFR antibodies or antigen-binding fragments thereof can initiate CDC or ADCC.

[0557] The affinity of an antibody for an antigen can be measured using common techniques, including, for example, ELISA, RIA, and surface plasmon resonance (SPR). Affinity can be derived from the quotient of kinetic rate constants (KD = koff / kon). In some embodiments, an antibody, an antigen-binding fragment thereof, or an antigen-binding protein construct (e.g., a bispecific antibody) can be measured at a rate of less than 0.1 s -1 , less than 0.01s -1 , less than 0.001s -1 , less than 0.0001s -1 or less than 0.00001s -1 The dissociation rate (koff) of the antibody binds 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 0.001s-1 , greater than 0.0001s -1 , greater than 0.00001s -1 or greater than 0.000001s -1 .

[0558] In some embodiments, the kinetic binding 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 kinetic binding rate (kon) is less than 1×10 5 / Ms, less than 1×10 6 / Ms or less than 1×10 7 / Ms.

[0559] In some embodiments, an antibody, antigen-binding fragment thereof, or antigen-binding protein construct (e.g., a bispecific antibody) can be expressed at a density of 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 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.

[0560] Anti-EGFR / MET antigen binding protein constructs (e.g., bispecific antibodies) may include an antigen binding region derived from any anti-MET antibody or any antigen binding fragment thereof as described herein. The anti-EGFR antibody or antigen binding fragment thereof described herein can block the binding between MET and HGF. In some embodiments, by binding to MET, the antibody can inhibit MET-related signaling pathways, thereby inhibiting cell proliferation, differentiation and / or metastasis. Therefore, 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.

[0561] In some embodiments, an antibody, antigen-binding fragment thereof, or antigen-binding protein construct (eg, a bispecific antibody) can be expressed in less than 0.1 s. -1 , less than 0.01s -1 , less than 0.001s -1 , less than 0.0001s -1 or less than 0.00001s -1 In some embodiments, the dissociation rate (koff) is greater than 0.01 s -1 , greater than 0.001s -1 , greater than 0.0001s -1 , greater than 0.00001s -1 or greater than 0.000001s -1 .

[0562] In some embodiments, the kinetic binding 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 kinetic binding rate (kon) is less than 1×10 5 / Ms, less than 1×10 6 / Ms or less than 1×10 7 / Ms.

[0563] Affinity can be derived from the quotient of the kinetic rate constants (KD = koff / kon). In some embodiments, KD is 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 In some embodiments, the 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, 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.

[0564] Since the antigen binding protein construct (e.g., bispecific antibody) binds both MET and EGFR, for cells expressing both MET and EGFR, the antigen binding protein construct has a higher binding affinity to these cells. Avidity can be used to measure the binding affinity of the antigen binding protein construct to these cells. Avidity is the cumulative strength of multiple affinities of various types of non-covalent binding interactions.

[0565] Thermal stability can also be determined. Antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs (e.g., bispecific antibodies) as described herein may have a Tm greater 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. Since IgG can be described as a multi-domain protein, a dissolution curve is sometimes shown to have two transitions, showing a first denaturation temperature Tm D1 and a second denaturation temperature Tm D2. The presence of these two peaks typically represents the denaturation of the Fc domain (Tm D1) and the Fab domain (Tm D2), respectively. When there are two peaks, Tm typically refers to Tm D2. Thus, in some embodiments, the antibodies or antigen-binding fragments as described herein have a Tm D1 of greater 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. In some embodiments, the antibodies or antigen binding fragments as described herein have a Tm D2 of greater 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. In some embodiments, Tm, Tm Dl, Tm D2 is 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.

[0566] In some embodiments, the antibody, its antigen binding fragment, antigen binding protein construct (such as bispecific antibody) can bind to human EGFR or monkey EGFR. In some embodiments, the antibody, its antigen binding fragment, antigen binding protein construct (such as bispecific antibody) does not bind to human EGFR or monkey EGFR. In some embodiments, the antibody, its antigen binding fragment, antigen binding protein construct (such as bispecific antibody) can bind to human MET or monkey MET. In some embodiments, the antibody, its antigen binding fragment, antigen binding protein construct (such as bispecific antibody) does not bind to human MET or monkey MET.

[0567] In some embodiments, the antibody, antigen-binding fragment thereof, antigen-binding protein construct (e.g., an anti-MET antibody, an anti-EGFR antibody, or a bispecific antibody) has a purity 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%, for example, as measured by HPLC. In some embodiments, the antibody 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% pure, e.g., as measured by HPLC.

[0568] In some embodiments, the antibody, antigen-binding fragment thereof, antigen-binding protein construct (e.g., anti-MET antibody, anti-EGFR antibody, or bispecific antibody) has a tumor growth inhibition percentage (TGI%) greater 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 percentage of less than 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150%. TGI% can be determined, for example, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, or 24 days after the start of treatment. As used herein, tumor growth inhibition percentage (TGI%) is calculated using the following formula:

[0569] TGI(%)=[1-(Ti-T0) / (Vi-V0)]×100%

[0570] Ti is the mean tumor volume in the treatment group at day i. T0 is the mean tumor volume in the treatment group at day zero. Vi is the mean tumor volume in the control group at day i. V0 is the mean tumor volume in the control group at day zero.

[0571] In some embodiments, antibodies, antigen binding fragments thereof, or antigen binding protein constructs (e.g., bispecific antibodies) have functional Fc regions. In some embodiments, the effector function of the functional Fc region is antibody-dependent cell-mediated 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.

[0572] In some embodiments, antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs (e.g., bispecific antibodies) do not have a functional Fc region. For example, antibodies or antigen-binding fragments are Fab, Fab', F(ab')2, and Fv fragments. In some embodiments, protein constructs as described herein have an Fc region without effector function. In some embodiments, Fc is human IgG4 Fc. In some embodiments, Fc does not have a functional Fc region. For example, the Fc region has a LALA mutation (L234A and L235A mutations of EU numbering), or a LALA-PG mutation (L234A, L235A, P329G mutations of EU numbering).

[0573] Some other modifications may be made to the Fc region. For example, cysteine ​​residues may be introduced into the Fc region, thereby allowing interchain disulfide bonds to form in this region. The homodimeric fusion protein thus produced may have any increased in vitro and / or in vivo half-life.

[0574] In some embodiments, the IgG4 has an S228P mutation (EU numbering). The S228P mutation prevents IgG4 Fab arm exchange in vivo and in vitro.

[0575] In some embodiments, antibody variants are provided, which have a carbohydrate structure lacking fucose (directly or indirectly) connected to the Fc region. For example, the amount of fucose in such antibodies can be 1% to 80%, 1% to 65%, 5% to 65% or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the sugar chain at Asn297 relative to the sum of all sugar structures (e.g., complex, hybrid and high mannose structures) connected to Asn297, as measured by MALDI-TOF mass spectrometry (e.g., as described in WO 2008 / 077546). Asn297 refers to an asparagine residue located at approximately position 297 in the Fc region (Eu numbering of Fc region residues; or position 314 in Kabat numbering); however, due to minor sequence variations in antibodies, Asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. Such fucosylation variants may have improved ADCC function.In some embodiments, to reduce glycan heterogeneity, the Fc region of the antibody may be further engineered to replace the asparagine at position 297 with alanine (N297A).

[0576] In some embodiments, the major peak by HPLC-SEC after purification by Protein A-based affinity chromatography and / or size exclusion chromatography accounts for at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5% of the protein complex described herein.

[0577] In some embodiments, the ADC described herein has 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 in killing cancer cells (e.g., lung cancer cell line NCI-H1975) in vitro.

[0578] 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 terituzumab analogs. In some embodiments, the bispecific antibodies described herein have a higher endocytosis rate than ervantuzumab analogs.

[0579] Methods for preparing antibodies, antigen-binding fragments and antigen-binding protein constructs

[0580] Can use separated human protein fragment as immunogen, use polyclonal and monoclonal antibody preparation standard technology to produce antibody.Polyclonal antibody can be produced in animal by multiple injection (for example, subcutaneous or intraperitoneal injection) antigen peptide or protein.In some embodiments, antigen peptide or protein is injected together with at least one adjuvant.In some embodiments, antigen peptide or protein can be conjugated to the medicament with immunogenicity in the species to be immunized.Antigen peptide or protein can be injected more than once (for example twice, three times or four times) animal.

[0581] Full-length polypeptides or proteins can be used, or alternatively antigenic peptide fragments thereof can be selected as immunogens. The antigenic peptide of a protein includes at least 8 (e.g., at least 10, 15, 20, or 30) amino acid residues of the amino acid sequence of the protein, and encompasses the epitope of the protein, so that antibodies generated against the peptide form specific immune complexes with the protein.

[0582] Immunogens are typically used to prepare antibodies by immunizing a suitable subject (e.g., a human or transgenic animal expressing at least one human immunoglobulin locus). Suitable immunogenic preparations may contain, for example, recombinantly expressed or chemically synthesized polypeptides. The preparations may also include an adjuvant (such as Freund's complete or incomplete adjuvant) or a similar immunostimulant.

[0583] Polyclonal antibodies can be prepared as described above by immunizing a suitable subject with a polypeptide or its antigenic peptide (e.g., a portion of a protein) as an immunogen. Antibody titers in immunized subjects can be monitored over time by standard techniques, such as enzyme-linked immunosorbent assay (ELISA) using immobilized polypeptides or peptides. If necessary, antibody molecules can be isolated from mammals (e.g., from blood) and further purified by well-known techniques (such as protein A or protein G chromatography) to obtain the IgG portion. At an appropriate time after immunization, for example, when specific antibody titers are highest, antibody-producing cells can be 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 (trioma technique). The techniques for producing hybridomas are well known (see generally Current Protocols in Immunology, 1994, Coligan et al. (Eds.), John Wiley & Sons, Inc., New York, NY). Hybridoma cells producing monoclonal antibodies are detected by screening hybridoma culture supernatants for antibodies that bind the polypeptide or epitope of interest, for example, using a standard ELISA assay.

[0584] Variants of antibodies or antigen-binding fragments described herein can be prepared by introducing appropriate nucleotide changes into DNA encoding people, humanized or chimeric antibodies or their antigen-binding fragments described herein, or by peptide synthesis. These variants include, for example, deletions, insertions or substitutions of residues in the amino acid sequence constituting the antigen-binding site of the antibody or antigen-binding domain. In the population of these variants, some antibodies or antigen-binding fragments will have increased affinity for the target protein. Any combination of deletions, insertions and / or combinations can be performed to obtain antibodies or their antigen-binding fragments with increased binding affinity for the target. The amino acid changes introduced into antibodies or antigen-binding fragments can also change or introduce new post-translational modifications to antibodies or antigen-binding fragments, such as changing (for example, increasing or decreasing) the number of glycosylation sites, changing the type of glycosylation sites (for example, changing the amino acid sequence so that different sugars are connected by enzymes present in the cell), or introducing new glycosylation sites.

[0585] The antibodies disclosed herein can be derived from animals of any species, including mammals. Non-limiting examples of natural antibodies include antibodies derived from humans, primates (e.g., monkeys and apes), cattle, 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).

[0586] Phage display (panning) can be used to optimize antibody sequences with desired binding affinity. In this technology, genes encoding single-chain Fv (including VH or VL) can be inserted into phage coat protein genes, so that the phage "displays" scFv on its outside, and contains the gene of the protein inside, thereby generating a connection between genotype and phenotype. These display phages can then be screened for target antigens to detect the interaction between the displayed antigen binding site and the target antigen. Therefore, large protein libraries can be screened and amplified in a process called in vitro selection, and antibody sequences with desired binding affinity can be obtained.

[0587] Human and humanized antibodies include antibodies having variable and constant regions derived from human germline immunoglobulin sequences (or having the same amino acid sequence as antibodies derived from human germline immunoglobulin sequences). Human antibodies may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or somatic mutations in vivo), such as in CDRs.

[0588] Humanized antibodies generally have a human framework (FR) grafted with non-human CDRs. Therefore, humanized antibodies have one or more amino acid sequences introduced therein from non-human sources. Therefore, "humanized" antibodies are chimeric antibodies in which a small portion of a complete human V domain is replaced by a corresponding sequence from a non-human species. In fact, humanized antibodies are generally mouse antibodies in which some CDR residues and some FR residues are replaced by residues from similar sites in human antibodies.

[0589] More importantly, the antibody humanization retains high specificity and affinity to antigen and other favorable biological properties.In order to achieve this goal, humanized antibodies can be prepared by using the three-dimensional model analysis of parental sequence and various conceptual humanized products of parental and humanized sequences.Three-dimensional immunoglobulin model is usually available and familiar to those skilled in the art.The computer program of the possible three-dimensional conformational structure of the candidate immunoglobulin sequence of explanation and display selection can be obtained.The inspection of these displays allows the analysis of the possible effect of residues in the function of the candidate immunoglobulin sequence, i.e., analyzes the residues that affect the ability of the candidate immunoglobulin to bind its antigen.By this method, can select and combine FR residues from receptor and imported sequence, so as to obtain desired antibody characteristics, such as the affinity to the target antigen increased.

[0590] In some embodiments, a mouse (e.g., RenMab) having a humanized heavy chain immunoglobulin locus and a humanized kappa chain immunoglobulin locus is used. TM Mouse) produces antibodies. The heavy chain immunoglobulin locus is a region on the chromosome that contains antibody heavy chain genes. 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. The κ chain immunoglobulin locus is a region on the chromosome that contains genes encoding antibody light chains (κ chains). The κ chain immunoglobulin locus can include, for example, human IGKV (variable) genes, human IGKJ (joining) genes, and mouse light chain constant domain genes. About RenMab TM A detailed description of mice can be found in PCT / CN2020 / 075698 or US20200390073A1, the entire contents of which are incorporated herein by reference.

[0591] In some embodiments, mice (e.g., RenLite TM Mouse) produces antibodies. The heavy chain immunoglobulin locus is a region on the chromosome that contains antibody heavy chain genes. 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. The κ chain immunoglobulin locus is a region on the chromosome that contains genes encoding common light chains. The κ chain immunoglobulin locus can include, for example, human IGKV (variable) genes, human IGKJ (joining) genes, and mouse light chain constant domain genes. About RenLite TM A detailed description of mice can be found in PCT / CN2021 / 097652, which is incorporated herein by reference in its entirety.

[0592] Identity or homology relative to a native sequence is typically the percentage of amino acid residues present in a candidate sequence that are identical to the sequence present in a human, humanized or chimeric antibody or fragment, after aligning the candidate sequence with the native sequence and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity.

[0593] In some embodiments, antibodies, antigen-binding fragments thereof, or antigen-binding protein constructs (e.g., bispecific antibodies) may be covalently modified. These covalent modifications may be performed by chemical or enzymatic synthesis, or by enzymatic or chemical cleavage. Other types of covalent modifications of antibodies or antibody fragments are introduced into the molecule by reacting the targeted amino acid residues of the antibody or fragment with an organic derivatizing agent that is capable of reacting with the selected side chain or N-terminal or C-terminal residues.

[0594] In some embodiments, antibody variants are provided, which have a carbohydrate structure lacking fucose (directly or indirectly) connected to the Fc region. For example, the amount of fucose in such antibodies can be 1% to 80%, 1% to 65%, 5% to 65% or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the sugar chain at Asn297 relative to the sum of all sugar structures (e.g., complex, hybrid and high mannose structures) connected to Asn297, as measured by MALDI-TOF mass spectrometry (e.g., as described in WO 2008 / 077546). Asn297 refers to an asparagine residue located at approximately position 297 in the Fc region (Eu numbering of Fc region residues; or position 314 in Kabat numbering); however, due to minor sequence variations in antibodies, Asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. Such fucosylation variants may have improved ADCC function.In some embodiments, to reduce glycan heterogeneity, the Fc region of the antibody may be further engineered to replace the asparagine at position 297 with alanine (N297A).

[0595] In some embodiments, to promote production efficiency by avoiding Fab arm exchange, the Fc region of the antibody is further engineered to replace the serine (S228P) at position 228 (EU numbering) of IgG4 with proline. For a detailed description of the S228 mutation, see, for example, 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.

[0596] In some embodiments, the methods described herein are designed to prepare bispecific antibodies. Bispecific antibodies can be prepared by engineering the interface between a pair of antibody molecules to maximize the ratio of heterodimers recovered from recombinant cell culture. For example, the interface can include at least a portion of the CH3 domain of an antibody constant domain. In this method, one or more small amino acid side chains at the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). By replacing the large amino acid side chains with smaller amino acid side chains (e.g., alanine or threonine), a compensation "cavity" identical or similar to the large side chain size is produced on the interface of the second antibody molecule. This provides a mechanism that can make the yield of heterodimers higher than other unwanted end products (such as homodimers). The method is described in, for example, WO 96 / 27011, which is incorporated herein by reference in its entirety.

[0597] In some embodiments, the knob-into-hole (KIH) technology can be used, which includes engineering the CH3 domain to create a "knob" or "hole" in each heavy chain to promote heterodimerization. The KIH technology is described in, for example, 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 T366W and / or S354C (knob) substitutions (EU numbering), while the other heavy chain has Y349C, T366S, L368A and / or Y407V (hole) substitutions (EU numbering). In some embodiments, one heavy chain has one or more of the following substitutions: Y349C and T366W (EU numbering). The other heavy chain may have one or more of the following substitutions: E356C, T366S, L368A and Y407V (EU numbering). In addition, substitutions may be introduced in the hinge region of both substituted IgGs (-ppcpScp->-ppcpPcp-).

[0598] Bispecific antibodies may also include, for example, cross-linked or "heteroconjugate" antibodies. For example, one of the antibodies in the heteroconjugate may be coupled to avidin and the other antibody may be coupled to biotin. Heteroconjugate antibodies may also be prepared 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. Pat. No. 4,676,980, which is incorporated herein by reference in its entirety.

[0599] Methods for producing bispecific antibodies from antibody fragments are also known in the art. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al. (Science 229:81, 1985) described a method in which intact antibodies are cleaved by proteolytic cleavage to produce F(ab')2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize adjacent dithiols and prevent intermolecular disulfide formation. The resulting Fab' fragments are then converted into thionitrobenzoate (TNB) derivatives. One of the Fab'TNB derivatives is then converted into a Fab' thiol by reduction with mercaptoethylamine, and mixed with another Fab'TNB derivative in an equimolar amount to form a bispecific antibody.

[0600] Recombinant vector

[0601] 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 these recombinant vectors are introduced (i.e., such that these host cells contain the polynucleotides and / or vectors comprising the polynucleotides), and recombinant antibody polypeptides or fragments thereof produced by recombinant technology.

[0602] As used herein, "vector" is any construct capable of delivering one or more polynucleotides of interest to a host cell when the vector is introduced into the host cell. "Expression vector" can deliver one or more polynucleotides of interest and express them as encoded polypeptides in a host cell that has been introduced into the expression vector. Therefore, in the expression vector, by being operably connected with a regulatory element (such as a promoter, enhancer and / or poly-A tail) at or near or on both sides of the integration site of the polynucleotide of interest in the vector or in the genome of the host cell, the polynucleotide of interest is positioned in the vector for expression so that the polynucleotide of interest will be translated in the host cell introduced into the expression vector.

[0603] The vector can be introduced into the host cell by methods known in the art, such as electroporation, chemical transfection (e.g., DEAE-dextran), transformation, transfection and infection and / or transduction (e.g., with a recombinant virus). Therefore, non-limiting examples of vectors include viral vectors (which can be used to produce recombinant viruses), naked DNA or RNA, plasmids, cosmids, phage vectors, and DNA or RNA expression vectors associated with cationic condensing agents.

[0604] In some embodiments, a polynucleotide disclosed herein (e.g., a polynucleotide encoding a polypeptide disclosed herein) is introduced using a viral expression system (e.g., vaccinia or other poxvirus, retrovirus, or adenovirus), which may involve the use of non-pathogenic (defective), replication-competent viruses, or replication-defective viruses may be used. In the latter case, viral propagation typically occurs only in complementing virus packaging cells. Suitable systems are disclosed, for example, in Fisher-Hoch et al., 1989, Proc. Natl. Acad. Sci. USA 86:317-321; Flexner et al., 1989, Ann. NY Acad Sci. 569:86-103; Flexner et al., 1990, Vaccine, 8:17-21; U.S. Pat. Nos. 4,603,112, 4,769,330 and 5,017,487; WO 89 / 01973; U.S. Pat. No. 4,777,127; GB 2,200,651; EP 0,345,242; WO 91 / 02805; Berkner-Biotechniques, 6:616-627, 1988; Rosenfeld et al. 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 ordinary skill in the art. The DNA can also be "naked," as described, for example, in Ulmer et al., 1993, Science, 259: 1745-1749, and Cohen, 1993, Science, 259: 1691-1692. Uptake of naked DNA can be increased by coating the DNA on biodegradable beads that are efficiently transported into cells.

[0605] For expression, the DNA insert comprising the polynucleotide encoding the antibody or polypeptide disclosed herein can be operably linked to a suitable promoter (e.g., a heterologous promoter), such as the bacteriophage λPL promoter, E. coli (E. coli) lac, trp and tac promoters, SV40 early and late promoters, and promoters of retroviral LTRs, etc. Other suitable promoters are known to those skilled in the art. The expression construct may also contain transcription initiation and termination sites, and a ribosome binding site for translation in the transcribed region. The coding portion of the mature transcript expressed by the construct may include a translation initiation codon at the start of the polypeptide to be translated and a termination codon (UAA, UGA or UAG) at an appropriate position at the end of the polypeptide to be translated.

[0606] As described above, the expression vector may include at least one selectable marker. Such markers include dihydrofolate reductase or neomycin resistance genes for eukaryotic cell culture and tetracycline or ampicillin resistance genes for culture in Escherichia coli and other bacteria. Representative examples of suitable hosts include, but are not limited to, bacterial cells, such as Escherichia coli, Streptomyces, and Salmonella typhimurium cells; fungal cells, such as yeast cells; insect cells, such as Drosophila S2 and Spodoptera frugiperda Sf9 cells; animal cells, such as CHO, COS, Bowes melanoma, and HK 293 cells; and plant cells. Suitable culture media and conditions for host cells described herein are known in the art.

[0607] Non-limiting vectors for bacteria include pQE70, pQE60, and pQE-9 from Qiagen; pBS vectors, Phagescript vectors, Bluescript vectors, pNH8A, pNH16a, pNH18A, pNH46A from Stratagene; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 from Pharmacia. Non-limiting eukaryotic vectors include pWLNEO, pSV2CAT, pOG44, pXT1, and pSG from Stratagene; and pSVK3, pBPV, pMSG, and pSVL from Pharmacia. Other suitable vectors will be apparent to those skilled in the art.

[0608] Suitable non-limiting bacterial promoters include E. coli lacI and lacZ promoters, T3 and T7 promoters, gpt promoter, lambda PR and PL promoters and trp promoter. Suitable eukaryotic promoters include CMV immediate early promoter, HSV thymidine kinase promoter, early and late SV40 promoter, retroviral LTR promoter (such as Rous sarcoma virus (Roussarcoma virus, RSV) promoter) and metallothionein promoter (such as mouse metallothionein-I promoter).

[0609] In Saccharomyces cerevisiae, a number of vectors containing constitutive or inducible promoters are available, such as alpha factor, alcohol oxidase, and PGH. For review, see Ausubel et al. (1989) Current Protocols in Molecular Biology, John Wiley & Sons, New York, NY, and Grant et al., Methods Enzymol., 153:516-544 (1997).

[0610] The constructs can be introduced into host cells by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid mediated transfection, electroporation, transduction, infection or other methods. These methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986), which is incorporated herein by reference in its entirety.

[0611] The transcription of the DNA encoding the antibodies of the present disclosure by higher eukaryotes can be increased by inserting an enhancer sequence into the vector. An enhancer is a cis-acting element of DNA, usually about 10-300 bp, that acts to increase the transcriptional activity of a promoter in a given host cell type. Examples of enhancers include the SV40 enhancer located on the late side of the replication origin at base pairs 100-270, the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and the adenovirus enhancer.

[0612] In order to secrete the translated protein into 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 an endogenous signal of the polypeptide or a heterologous signal.

[0613] Polypeptides (e.g., antibodies) can be expressed in a modified form, such as a fusion protein (e.g., a GST fusion protein) or with a histidine tag, and can include not only a secretion signal, but also additional heterologous functional regions. For example, a region of additional amino acids (particularly charged amino acids) can be added to the N-terminus of the polypeptide to improve stability and durability in a host cell, during purification, or during subsequent processing and storage. In addition, peptide moieties can be added to the polypeptide to promote purification. These regions can be removed before the final preparation of the polypeptide. Adding peptide moieties to a polypeptide to cause secretion or excretion, improve stability, and promote purification, etc., is a conventional technique well known in the art.

[0614] 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 of the nucleotide sequences described herein. The present invention also provides the present invention relates to any amino acid sequence as 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 as described herein.

[0615] 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% homology to any of the nucleotide sequences described herein. The present invention also provides the present invention relates to 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% homology to any amino acid sequence as described herein.

[0616] In some embodiments, the disclosure relates to a nucleotide sequence encoding any peptide described herein or any amino acid sequence encoded by any nucleotide sequence as 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.

[0617] 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.

[0618] 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.

[0619] In order to determine the percent identity of two amino acid sequences or two nucleic acid sequences, these sequences are compared for the purpose of optimal comparison (e.g., a gap can be introduced in one or both of the first and second amino acid or nucleic acid sequences for optimal comparison, and non-homologous sequences can be ignored for comparison purposes). The amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are then compared. When the 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 identical at that position (as used herein, amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology"). Taking into account the number of gaps that need to be introduced to achieve the best comparison of the two sequences and the length of each gap, the percent identity between the two sequences is a function of the number of identical positions shared by the sequences. For example, the comparison of sequences and the determination of the percent identity between the two sequences can be completed using the Blossum 62 scoring matrix, with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5.

[0620] The percentage of sequence homology (e.g., amino acid sequence homology or nucleic acid homology) can also be determined. How to determine the percentage of sequence homology is known in the art. In some embodiments, conservative amino acid residues (homology percentage) with similar physicochemical properties, such as leucine and isoleucine, can be used to measure sequence similarity. Families of amino acid residues with similar physicochemical properties have been defined in the art. These families include, for example, amino acids with basic side chains (e.g., lysine, arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), amino acids with uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), amino acids with non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amino acids with β-branched side chains (e.g., threonine, valine, isoleucine) and amino acids with aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). In many cases, the percent homology is higher than the percent identity.

[0621] The present disclosure provides one or more nucleic acids encoding any one of the polypeptides as described herein. In some embodiments, nucleic acids (e.g., cDNA) include polynucleotides encoding heavy chain polypeptides as described herein. In some embodiments, nucleic acids include polynucleotides encoding light chain polypeptides as described herein. In some embodiments, nucleic acids include polynucleotides encoding scFv polypeptides as described herein.

[0622] In some embodiments, the vector may have two of the nucleic acids as described herein, wherein the vector encodes a VL region and a VH region that jointly bind to EGFR. In some embodiments, a pair of vectors is provided, wherein each vector includes one of the nucleic acids as described herein, wherein the pair of vectors jointly encodes a VL region and a VH region that jointly bind to EGFR.

[0623] In some embodiments, the vector comprises two of the nucleic acids as described herein, wherein the vector encodes a VL region and a VH region that jointly bind MET. In some embodiments, a pair of vectors is provided, wherein each vector comprises one of the nucleic acids as described herein, wherein the pair of vectors jointly encodes a VL region and a VH region that jointly bind MET.

[0624] The vector can also be constructed to express specific antibodies or polypeptides. In some embodiments, the vector can be constructed to co-express anti-EGFR antibody light chain (EGFR-K) and heavy chain (EGFR-H). In some embodiments, the vector may contain sequences of cytomegalovirus promoter (CMV), EGFR-K, polyadenylation (PolyA), CMV, EGFR-H, PolyA, simian vacuolating virus 40 terminator (SV40), and glutamine synthetase marker (GS) from 5' to 3' end. In some embodiments, the vector can be constructed to co-express anti-MET antibody light chain (MET-K) and anti-MET antibody heavy chain (MET-H). In some embodiments, the vector may contain sequences of CMV, MET-K, PolyA, CMV, MET-H, SV40, and GS from 5' to 3' end. In some embodiments, the vector can be constructed to express anti-MET antibody scFv polypeptide chain. In some embodiments, a first vector expressing an antibody heavy chain (e.g., any heavy chain described herein) and a second vector expressing an antibody light chain (e.g., any light chain described herein) are used to co-transfect cells (e.g., CHO cells) to produce a monoclonal antibody or antigen-binding fragment thereof described herein. In some embodiments, a first vector expressing an anti-EGFR antibody heavy chain (e.g., any anti-EGFR antibody heavy chain described herein), a second vector expressing an anti-MET antibody heavy chain (e.g., any anti-MET antibody heavy chain described herein) and a third vector expressing a common light chain (e.g., any common light chain described herein) are used to co-transfect cells (e.g., CHO cells) to produce an antigen-binding protein construct described herein (e.g., any anti-EGFR / MET bispecific antibody described herein).

[0625] Treatment

[0626] The methods described herein include methods for treating a disorder associated with cancer. Typically, the method includes administering a therapeutically effective amount of an engineered antibody, an antigen-binding fragment thereof, an antigen-binding protein construct (e.g., a bispecific antibody) as described herein to a subject in need or determined to need such treatment.

[0627] As used herein, "treating" means improving at least one symptom of a condition associated with cancer. Typically, cancer leads to death; therefore, treatment can increase life expectancy (e.g., at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or at least 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years). Administration of a therapeutically effective amount of an agent described herein to treat a condition associated with cancer will reduce the number of cancer cells and / or alleviate symptoms.

[0628] As used herein, the term "cancer" refers to cells with autonomous growth capacity, i.e., an abnormal state or condition characterized by rapid proliferation of cell growth. The term is intended to include all types of cancerous growth or carcinogenic processes, metastatic tissues, or malignantly transformed cells, tissues, or organs, regardless of their histopathological type or invasion stage. As used herein, the term "tumor" refers to a cancer cell, such as a cancer cell mass. Cancers that can be treated or diagnosed using the methods described herein include malignant tumors of various organ systems, such as malignant tumors affecting the lungs, breasts, thyroids, lymphatics, gastrointestinal tracts, and urogenital tracts; and adenocarcinomas, which include malignant tumors, such as most colon cancers, renal cell carcinomas, prostate cancers, and / or testicular tumors, non-small cell lung cancers, small intestine cancers, and esophageal cancers. In some embodiments, the agents described herein are designed to treat or diagnose cancer in a subject. The term "cancer" is recognized in the art and refers to malignant tumors of epithelial or endocrine tissues, including respiratory cancers, gastrointestinal cancers, urogenital cancers, testicular cancers, breast cancers, prostate cancers, endocrine system cancers, and melanomas. In some embodiments, the cancer is renal cancer or melanoma. Exemplary cancers include cancers formed by tissues of the cervix, lung, prostate, breast, head and neck, colon, and ovary. The term also includes carcinosarcoma, for example, which includes malignant tumors composed of carcinoma and sarcoma tissue. "Adenocarcinoma" refers to a cancer derived from glandular tissue or in which the tumor cells form a recognizable glandular structure. The term "sarcoma" is recognized in the art and refers to a mesenchymal derived malignant tumor.

[0629] In some embodiments, the cancer is a chemotherapy-resistant cancer.

[0630] In one aspect, the present disclosure also provides methods for treating cancer in a subject, methods for reducing the rate of increase of tumor volume over time in a subject, methods for reducing the risk of forming metastases, or methods for reducing the risk of forming additional metastases in a subject. In some embodiments, treatment may terminate, slow, delay, or inhibit the progression of cancer. In some embodiments, treatment may reduce the number, severity, and / or duration of one or more symptoms of cancer in a subject.

[0631] In one aspect, the methods of the present disclosure comprise administering a therapeutically effective amount of an antibody, antigen-binding fragment thereof, antigen-binding protein construct (e.g., a bispecific antibody), or antibody drug conjugate described herein to a subject in need thereof, e.g., a subject having, or identified or diagnosed as having, a cancer, e.g., a solid tumor, lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, or lung cancer), gastric cancer (e.g., gastric cancer), skin cancer (e.g., skin cancer), colorectal cancer, breast cancer, head and neck cancer, ovarian cancer, prostate cancer, thyroid cancer, pancreatic cancer, central nervous system cancer, liver cancer, nasopharyngeal cancer, ampullary cancer, or brain cancer.

[0632] As used herein, the terms "subject" and "patient" are used interchangeably throughout the specification, and describe an animal, human or non-human for which treatment is provided according to the method of the present invention. Veterinary and non-veterinary applications are contemplated by the present invention. Human patients can be adults or adolescents (e.g., people 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. Including, for example, non-human primates (e.g., monkeys, chimpanzees, gorillas, etc.), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, rabbits), lagomorphs, pigs (e.g., pigs, mini-pigs), horses, dogs, cats, cattle and other domestic animals, farm animals and zoo animals. In some embodiments, the subject is a human. In some embodiments, the subject is a dog.

[0633] In some embodiments, the compositions and methods disclosed herein can be used to treat patients at risk for cancer.Cancer patients can be identified using various methods known in the art.

[0634] As used herein, "effective amount" refers to an amount or dosage sufficient to achieve beneficial or desired results, including terminating, slowing, delaying or inhibiting the progression of a disease (e.g., 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, antibody encoding polynucleotide, vector comprising the polynucleotide and / or a composition thereof is to be administered, the severity of the symptoms, and the route of administration, and therefore can be determined on an individual basis.

[0635] The effective amount can be applied in one or more administrations. For example, the effective amount of an antibody, an Fab or an antibody drug conjugate is enough to improve, terminate, stabilize, reverse, inhibit, slow down and / or delay the amount of the progress of an autoimmune disease or cancer in a patient, or is enough to improve, terminate, stabilize, reverse, slow down and / or delay the amount of a cell (e.g., a biopsy cell, any one of the cancer cells described herein or a cell line (e.g., a cancer cell line)) in vitro propagation. As understood in the art, the effective amount of an antibody, an Fab or an antibody drug conjugate can be based on, especially the patient's medical history and other factors (such as the type (and / or dosage) of the antibody used) change.

[0636] The effective amount and dosing regimen of the antibodies, polynucleotides encoding the antibodies, antibody drug conjugates and / or compositions disclosed herein can be determined empirically, and making such determinations is within the skill of the art. It will be appreciated by those skilled in the art that the dosage that must be administered will vary depending on, for example, the mammal to which the antibodies, polynucleotides encoding the antibodies, antibody drug conjugates and / or compositions disclosed herein will be administered, the route of administration, the specific type of antibodies, polynucleotides encoding the antibodies, antigen-binding fragments, antibody drug conjugates and / or compositions disclosed herein used, and other drugs administered to the mammal. Guidance for selecting appropriate doses of antibodies or antigen-binding fragments can be found in the literature on the therapeutic use of antibodies and antigen-binding fragments, such as Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge, NJ, 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.

[0637] The typical daily dose of an effective amount of an antibody, an antigen-binding fragment thereof, an antigen-binding protein construct (e.g., a bispecific antibody) is 0.01 mg / kg to 100 mg / kg. In some embodiments, the dosage may 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 may 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 dose 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.

[0638] In any of the methods described herein, at least one antibody, antigen-binding fragment thereof, or antigen-binding protein construct (e.g., bispecific antibody), antibody drug conjugate, or 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 may 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 with the same composition (e.g., liquid composition). In some embodiments, at least one antibody, antigen-binding fragment thereof, antigen-binding protein construct (e.g., bispecific antibody), or antibody drug conjugate and at least one additional therapeutic agent are administered with the same composition (e.g., liquid composition). In some embodiments, at least one antibody or antigen-binding fragment and at least one additional therapeutic agent are administered with 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 in the form of a pill, tablet, or capsule. In some embodiments, at least one additional therapeutic agent is administered in a sustained release oral formulation.

[0639] In some embodiments, one or more additional therapeutic agents may be administered to a subject before or after administration of 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, one or more additional therapeutic agents and 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 a subject such that there is overlap in the biological activity period of the one or more additional therapeutic agents and at least one antibody or antigen-binding fragment (e.g., any of the antibodies or antigen-binding fragments described herein) in the subject.

[0640] In some embodiments, 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) may be administered to a subject over 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). A skilled medical professional can diagnose or track the effectiveness of treatment using any of the methods described herein to determine the length of the treatment period (e.g., observing at least one symptom of cancer). As described herein, a skilled medical professional can also change the type and amount (e.g., increase or decrease) of the antibody or antigen-binding antibody fragment, antibody drug conjugate (and / or one or more additional therapeutic agents) administered to a subject, and can also adjust (e.g., increase or decrease) the dosage or frequency of at least one antibody or antigen-binding antibody fragment (and / or one or more additional therapeutic agents) administered to a subject based on an assessment of therapeutic effectiveness (e.g., using any of the methods described herein and known in the art).

[0641] In some embodiments, one or more additional therapeutic agents may be administered to the subject. The additional therapeutic agent may include one or more inhibitors, and the one or more inhibitors are selected from the group consisting of: B-Raf inhibitors, EGFR inhibitors, MEK inhibitors, ERK inhibitors, K-Ras inhibitors, c-Met inhibitors, anaplastic lymphoma kinase (ALK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, Akt inhibitors, mTOR inhibitors, PI3K / mTOR dual inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, and isocitrate dehydrogenase 1 (IDH1) and / or isocitrate dehydrogenase 2 (IDH2) inhibitors. In some embodiments, the additional therapeutic agent is an indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor (e.g., epacadostat).

[0642] In some embodiments, the additional therapeutic agent may include one or more inhibitors selected from the group consisting of: a HER3 inhibitor, a LSD1 inhibitor, a MDM2 inhibitor, a BCL2 inhibitor, a CHK1 inhibitor, an inhibitor of activated hedgehog signaling pathway, and an agent that selectively degrades estrogen receptors.

[0643] In some embodiments, the additional therapeutic agent may include one or more therapeutic agents selected from the group consisting of trabectedin, nab-paclitaxel, trebananib, pazopanib, cediranib, palbociclib, everolimus, fluoropyrimidine, IFL, regorafenib, Reolysin, Alimta, zykadia, sutent, temsirolimus, axitinib ), sorafenib, Votrient, IMA-901, AGS-003, cabozantinib, vinflunine, Hsp90 inhibitors, Ad-GM-CSF, temazolomide, IL-2, IFNa, vinblastine, thalomid, dacarbazine, cyclophosphamide, lenalidomide, azacytidine, bortezomid, amrubicine, carfilzomib, pralatrexate, and enzastaurin.

[0644] In some embodiments, the additional therapeutic agent may include one or more therapeutic agents selected from the group consisting of an adjuvant, a TLR agonist, a 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 CX3CL1-targeted therapy, a CXCL9-targeted therapy, a CXCL10-targeted therapy, a CCL5-targeted therapy, an LFA-1 agonist, an ICAM1 agonist, and a selectin agonist.

[0645] In some embodiments, the subject is administered carboplatin, nab-paclitaxel, paclitaxel, cisplatin, pemetrexed, gemcitabine, FOLFOX, or FOLFIRI.

[0646] 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-CTLA4 antibody, an anti-CD40 antibody, an anti-OX40 antibody, an anti-4-1BB antibody, an anti-TIM3 antibody, or an anti-GITR antibody.

[0647] Pharmaceutical compositions and routes of administration

[0648] Also provided herein are pharmaceutical compositions containing at least one (e.g., one, two, three, or four) of the antigen-binding protein constructs, antibodies (e.g., bispecific antibodies), antigen-binding fragments, or antibody drug conjugates described herein. Two or more (e.g., two, three, or four) of any antigen-binding protein constructs, antibodies, antigen-binding fragments, or antibody drug conjugates described herein may be present in any combination in a pharmaceutical composition. The pharmaceutical composition may be formulated in any manner known in the art.

[0649] Pharmaceutical compositions are formulated to be compatible with their intended routes of administration (e.g., intravenous, intra-arterial, intramuscular, intradermal, subcutaneous or peritoneal). Compositions may include sterile diluents (e.g., sterile water or saline), fixed oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents, antibacterial or antifungal agents (such as benzyl alcohol or methyl paraben, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.), antioxidants (such as ascorbic acid or sodium bisulfite), chelating agents (such as ethylenediaminetetraacetic acid), buffers (such as acetate, citrate or phosphate) and isotonic agents (such as sugars (e.g., glucose), polyols (e.g., mannitol or sorbitol) or salts (e.g., sodium chloride)), or any combination thereof. Liposomal suspensions may also be used as pharmaceutically acceptable carriers (see, e.g., U.S. Patent No. 4,522,811). The preparation of the composition may be formulated and encapsulated in ampoules, disposable syringes or multi-dose vials. When necessary (as, for example, in injectable formulations), appropriate fluidity can be maintained by, for example, using a coating (such as lecithin) or a surfactant. 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, controlled release can be achieved by implants and microencapsulated delivery systems, which can include biodegradable, biocompatible polymers (e.g., ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid; Alza and Nova Pharmaceuticals).

[0650] Compositions containing one or more of any of the antigen binding protein constructs, antibodies, antigen binding fragments, antibody drug conjugates described herein can be formulated for parenteral (e.g., intravenous, intraarterial, intramuscular, intradermal, subcutaneous, or intraperitoneal) administration in dosage unit form (i.e., physically discrete units containing predetermined quantities of active compound to facilitate administration and uniformity of dosage).

[0651] The toxicity and therapeutic efficacy of the composition can be determined by standard pharmaceutical methods in cell culture or experimental animals (e.g., monkeys). The LD50 (the dose that is lethal to 50% of the population) and the ED50 (the dose that is therapeutically effective to 50% of the population) can be determined: the therapeutic index is the ratio of LD50:ED50. Agents that exhibit high therapeutic indices are preferred. When an agent exhibits undesirable side effects, care should be taken to minimize potential damage (i.e., reduce undesirable side effects). Toxicity and therapeutic efficacy can be determined by other standard pharmaceutical methods.

[0652] The data obtained from cell culture assays and animal studies can be used to formulate any given agent for a subject (e.g., a person) in an appropriate dose. The therapeutically effective amount of one or more (e.g., one, two, three, or four) antigen-binding protein constructs, antibodies, or antigen-binding fragments thereof (e.g., any antibody or antibody fragment described herein) will be a therapeutic subject (e.g., a human subject identified as having cancer) or a subject identified as having a risk of illness (e.g., a subject previously suffering from cancer but now cured) in a disease (e.g., killing cancer cells), reducing the severity, frequency, and / or duration of one or more symptoms of the disease in a subject (e.g., a person). The effectiveness and dosage of any antigen-binding protein construct, antibody, or antigen-binding fragment described herein can be determined by a health care professional or veterinary professional using methods known in the art and by observing one or more symptoms of the disease in a subject (e.g., a person). Certain factors can affect the dosage and time required for the effective treatment of a subject (e.g., the severity of the disease or condition, previous treatment, the general health status and / or age of the subject, and the presence of other diseases).

[0653] Exemplary dosages include milligram or microgram amounts of any antigen binding protein construct, antibody or antigen binding fragment or antibody drug conjugate described herein per kilogram of subject 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 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 these dosages cover a wide range, it will be appreciated by those of ordinary skill in the art that the efficacy of therapeutic agents (including antigen binding protein constructs, antibodies and antigen binding fragments thereof) varies, and that effective amounts can be determined by methods known in the art. Typically, a relatively low dose is first administered, after which the attending healthcare professional or veterinary professional (in the case of therapeutic applications) or researcher (when still working in the development phase) can gradually increase the dose until an appropriate response is obtained. Furthermore, it should be understood that the specific dosage level for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health, sex and diet of the subject, the time of administration, the route of administration, the rate of excretion and the half-life of the antibody or antibody fragment in vivo.

[0654] The pharmaceutical composition may be contained in a container, pack, or dispenser together with instructions for administration. The present disclosure also provides methods for preparing antibodies or antigen-binding fragments thereof or antibody drug conjugates for various uses as described herein.

[0655] Example

[0656] The presen...

Claims

1. An antibody or antigen-binding fragment thereof that binds to EGFR (epidermal growth factor receptor), the antibody or antigen-binding fragment thereof comprising: 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 a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; 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 a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR3 amino acid sequence, wherein the selected VH CDR1, 2 and 3 amino acid sequence and the selected VL CDR1, 2 and 3 amino acid sequence are one of the following: (1) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 4-6, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (2) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 7-9, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (3) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 10-12, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (4) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 13-15, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (5) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 16-18, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (6) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 34-36, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (7) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 37-39, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (8) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 40-42, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (9) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 43-45, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (10) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 46-48, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (11) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 82-84, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (12) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 85-87, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (13) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 88-90, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (14) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 91-93, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (15) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 94-96, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (16) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 97-99, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (17) the selected VH CDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 100-102, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; and (18) The selected VH CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 103-105, respectively, and the selected VLCDR1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

20. An antibody or antigen-binding fragment thereof that binds to EGFR, the antibody or antigen-binding fragment thereof comprising: A heavy chain variable region (VH), the VH comprising an amino acid sequence that is at least 90% identical to a selected VH sequence, and a light chain variable region (VL), the VL comprising an amino acid sequence that is at least 90% identical to a selected VL sequence, wherein 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.

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

61.

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

61.

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

61.

30. An antibody or antigen-binding fragment thereof that binds to EGFR, the antibody or antigen-binding fragment thereof comprising: A heavy chain variable region (VH), comprising a VH CDR1, a VH CDR2 and a VH and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3 identical to the VL CDR1, VL CDR2, and VL CDR3 of the selected VL sequence. CDR3, wherein 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.

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

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

33. The antibody or antigen-binding fragment thereof according to any one of claims 1-32, 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 1-33, wherein the antibody or antigen-binding fragment thereof is a multispecific antibody (eg, a bispecific antibody) or an antigen-binding fragment thereof.

35. The antibody or antigen-binding fragment thereof of claim 34, wherein the antibody or antigen-binding fragment thereof further specifically binds 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 1-35.

37. A nucleic acid comprising a polynucleotide encoding a polypeptide comprising: (1) an immunoglobulin heavy chain or a fragment thereof, comprising a heavy chain variable region (VH), wherein the VH comprises complementarity determining regions (CDRs) 1, 2 and 3, wherein the CDRs 1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 4-6, respectively, and 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; (2) an immunoglobulin light chain or a fragment thereof, comprising a light chain variable region (VL), wherein the VL comprises complementarity determining regions (CDRs) 1, 2, and 3, wherein CDRs 1, 2, and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and 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; (3) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 7-9, respectively, and wherein the VH binds to EGFR 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, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 63; (5) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 10-12, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (6) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 64; (7) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 13-15, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (8) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 65; (9) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 16-18, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (10) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 66; (11) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 34-36, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (12) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 37-39, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (13) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 40-42, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (14) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 43-45, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (15) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 46-48, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (16) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 82-84, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (17) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 106; (18) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 85-87, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (19) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 107; (20) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 88-90, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (21) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 108; (22) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 91-93, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (23) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and wherein the VL binds to EGFR when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 109; (24) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 94-96, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (25) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 97-99, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (26) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 100-102, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; and (27) An immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO:103-105, respectively, and wherein the VH binds to EGFR when paired with a VL comprising the amino acid sequence shown in SEQ ID NO:

61.

38. The nucleic acid of claim 37, wherein the VH specifically binds to human or monkey EGFR when paired with the VL.

39. The nucleic acid of claim 37 or 38, wherein the immunoglobulin heavy chain or fragment thereof is a human or humanized immunoglobulin heavy chain or fragment thereof.

40. The nucleic acid of any one of claims 37-39, wherein the nucleic acid encodes a single-chain variable fragment (scFv).

41. The nucleic acid of any one of claims 37-40, wherein the nucleic acid is cDNA.

42. An antibody or antigen-binding fragment thereof that binds to MET (tyrosine protein kinase Met), the antibody or antigen-binding fragment thereof comprising: 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 a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; 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 a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR3 amino acid sequence, wherein the selected VH CDR1, 2 and 3 amino acid sequence and the selected VL CDR1, 2 and 3 amino acid sequence are one of the following: (1) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 19-21, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (2) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 22-24, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (3) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 25-27, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (4) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 28-30, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (5) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 49-51, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (6) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 52-54, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (7) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 55-57, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (8) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 58-60, respectively, and the selected VLCDR1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (9) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 112-114, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (10) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 115-117, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (11) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 118-120, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (12) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 121-123, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (13) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 124-126, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (14) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 127-129, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (15) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 130-132, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (16) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 133-135, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (17) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 136-138, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (18) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 139-141, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; (19) the selected VH CDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 142-144, respectively, and the selected VLCDR 1, 2, 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively; and (20) The selected VH CDR 1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 145-147, respectively, and the selected VLCDR 1, 2, and 3 amino acid sequences are shown in SEQ ID NOs: 1-3, respectively.

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

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

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

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

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

48. The antibody or antigen-binding fragment thereof of claim 42, wherein the VH comprises CDR1, 2, 3 having amino acid sequences as shown in SEQ ID NOs: 52-54, respectively, and the VL comprises CDR1, 2, 3 having amino acid sequences as shown in SEQ ID NOs: 1-3, respectively.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

63. An antibody or antigen-binding fragment thereof that binds to MET, the antibody or antigen-binding fragment thereof comprising: A heavy chain variable region (VH), the VH comprising an amino acid sequence that is at least 90% identical to a selected VH sequence, and a light chain variable region (VL), the VL comprising an amino acid sequence that is at least 90% identical to a selected VL sequence, wherein 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.

64. The antibody or antigen-binding fragment thereof of 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 of 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 of 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 of 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 of 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 of 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 of 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 of 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 of 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 of 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, the antibody or antigen-binding fragment thereof comprising: a heavy chain variable region (VH), the VH comprising VHCDR1, VH CDR2 and VH CDR3 identical to the VH CDR1, VH CDR2 and VH CDR3 of a selected VH sequence; and a light chain variable region (VL), the VL comprising VL CDR1, VL CDR2 and VL CDR3 identical to the 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: (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.

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

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

77. The antibody or antigen-binding fragment thereof according to any one of claims 42-76, 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 42-77, wherein the antibody or antigen-binding fragment thereof is a multispecific antibody (e.g., a bispecific antibody) or an antigen-binding fragment thereof.

79. The antibody or antigen-binding fragment thereof of claim 78, wherein the antibody or antigen-binding fragment thereof 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 42-79.

81. A nucleic acid comprising a polynucleotide encoding a polypeptide comprising: (1) an immunoglobulin heavy chain or a fragment thereof, comprising a heavy chain variable region (VH), wherein the VH comprises complementarity determining regions (CDRs) 1, 2, and 3, wherein CDRs 1, 2, and 3 comprise the amino acid sequences shown in SEQ ID NOs: 19-21, respectively, and 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; (2) an immunoglobulin light chain or a fragment thereof, comprising a light chain variable region (VL), wherein the VL comprises complementarity determining regions (CDRs) 1, 2, and 3, wherein CDRs 1, 2, and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and 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; (3) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 22-24, respectively, and wherein 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, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 68; (5) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 25-27, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (6) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 69; (7) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 28-30, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (8) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 1-3, respectively, and wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 70; (9) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 49-51, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (10) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 52-54, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (11) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 55-57, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (12) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 58-60, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (13) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 112-114, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (14) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 148; (15) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 115-117, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (16) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 149; (17) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 118-120, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (18) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 150; (19) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 121-123, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (20) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 151; (21) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 124-126, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (22) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 152; (23) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 127-129, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (24) an immunoglobulin light chain or a fragment thereof, comprising a VL, wherein the VL comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO: 1-3, respectively, and wherein the VL binds to MET when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 153; (25) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 130-132, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (26) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 133-135, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (27) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 136-138, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (28) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 139-141, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; (29) an immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NOs: 142-144, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 61; and (30) An immunoglobulin heavy chain or a fragment thereof, comprising a VH, wherein the VH comprises CDR1, 2 and 3, wherein the CDR1, 2 and 3 comprise the amino acid sequences shown in SEQ ID NO:145-147, respectively, and wherein the VH binds to MET when paired with a VL comprising the amino acid sequence shown in SEQ ID NO:

61.

82. The nucleic acid of claim 81, wherein the VH specifically binds human, monkey or canine MET when paired with a VL.

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

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

85. A nucleic acid according to any one of claims 81-84, wherein the nucleic acid is cDNA.

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

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

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

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

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

61.

92. An antigen-binding protein construct according to any one of claims 87-90, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:62, the first light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:61, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:69, and the second light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:

61.

93. An antigen-binding protein construct according to any one of claims 87-90, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:62, the first light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:61, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:70, and the second light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:

61.

94. An antigen-binding protein construct according to any one of claims 87-90, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:63, the first light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:61, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:69, and the second light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:

61.

95. An antigen-binding protein construct according to any one of claims 87-90, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:63, the first light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:61, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:70, and the second light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:

61.

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

61.

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

61.

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

61.

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

61.

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

61.

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

61.

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

61.

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

61.

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

61.

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

61.

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

61.

107. An antigen-binding protein construct according to any one of claims 87-90, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:66, the first light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:61, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:70, and the second light chain variable region comprises a sequence at least 80%, 85%, 90% or 95% identical to SEQ ID NO:

61.

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

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

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

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

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

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

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

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

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

117. The antibody drug conjugate of claim 116, wherein the therapeutic agent is a cytotoxic agent or a cytostatic agent.

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

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

121. The antibody drug conjugate of any one of claims 116, 119 and 120, wherein the linker has the following structure:

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

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

124. The method of claim 123, wherein the subject has a cancer that expresses EGFR and / or MET.

125. The method of claim 123, wherein the cancer is a solid tumor, a lung cancer (such as non-small cell lung cancer, lung adenocarcinoma, or lung cancer), a stomach cancer (such as gastric cancer), a skin cancer (such as skin cancer), a cancer of the ampullary region (such as ampullary cancer), a colorectal cancer, a breast cancer, a head and neck cancer, an ovarian cancer, a prostate cancer, a thyroid cancer, a pancreatic cancer, a central nervous system (CNS) cancer, a liver cancer, a nasopharyngeal cancer, or a brain cancer.

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

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

128. The method of any one of claims 123-127, wherein the method further comprises administering chemotherapy to the subject.

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

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

131. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) the 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 (c) The antibody drug conjugate according to any one of claims 116-122.

132. An antibody drug conjugate (ADC) comprising a therapeutic agent covalently bound to a bispecific antibody or 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.

133. The antibody drug conjugate (ADC) of claim 132, wherein the drug to antibody ratio (DAR) is about 4 or 8.

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