Anti-CMET antibodies and methods of use

CN120603850APending Publication Date: 2025-09-05BEIGENE GUANGZHOU BIOLOGICS MFG CO LTD
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Patent Information

Application Number
CN202480008442.2
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Priority Date
2023-06-28
Filing Date
2024-01-18
Publication Date
2025-09-05

AI Technical Summary

Technical Problem

Existing therapeutic drugs targeting EGFR and cMET are difficult to effectively overcome the drug resistance caused by EGFR mutations, especially the compensatory drug resistance driven by cMET amplification, resulting in poor treatment effects.

Method used

Develop multispecific antibodies or antigen-binding fragments thereof that specifically bind to human EGFR and human cMET, and construct multispecific antibodies or antibody-drug conjugates by simultaneously targeting different epitopes of EGFR and cMET for combination with other therapeutic agents to enhance the anti-cancer effect.

Benefits of technology

It enhances the therapeutic effect against EGFR-mutated cancers, overcomes drug resistance, and improves the therapeutic response against cMET amplification-driven cancers.

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Abstract

The present disclosure provides antibodies, or antigen-binding fragments thereof, that specifically bind to human cMET and multispecific antibodies, or antigen-binding fragments thereof, comprising a first antigen-binding domain that specifically binds to a first epitope of human cMET; a second antigen binding domain that specifically binds to a second epitope of human cMET; and a third antigen binding domain that specifically binds to human EGFR; wherein the first epitope is different from the second epitope, or wherein the first antigen binding domain does not compete with the second antigen binding domain. The present disclosure also provides the use of an antibody or multispecific antibody for the treatment of a disease, such as cancer.
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Description

Technical Field

[0001] Disclosed herein are antibodies that specifically bind to human cMET, multispecific antibodies that specifically bind to two different epitopes of human cMET, multispecific antibodies that specifically bind to human EGFR and human cMET, or antigen-binding fragments thereof, as well as isolated nucleic acids, vectors, and host cells. Finally, the antibodies or antigen-binding fragments thereof disclosed herein can be used to treat various cancers. Background Art

[0002] The receptor tyrosine kinase mesenchymal-epithelial transition factor (c-MET, also known as cMET or MET, hepatocyte growth factor receptor, or HGFR) and its ligand hepatocyte growth factor (HGF) play key roles in multiple cellular processes that stimulate cell proliferation, survival, invasion, and angiogenesis.

[0003] cMET is composed of an extracellular α subunit and a transmembrane β subunit connected by disulfide bonds. The extracellular region is composed of a semaphorin (SEMA) domain, a plexin-semaphorin-integrin (PSI) domain, and four consecutive immunoglobulin-plexin-transcription factor (IPT1-4) domains. HGF binding to cMET induces dimerization of cMET, causing autophosphorylation of its intracellular kinase domain (KD). 1 , which in turn creates active docking sites for proteins that mediate activation of downstream signaling pathways, such as the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT pathways.

[0004] Dysregulated HGF-cMET signaling has been observed in a variety of solid cancer types, including gastric cancer, colorectal cancer, lung cancer, liver cancer, head and neck cancer, breast cancer, brain cancer, etc. Aberrant cMET activation in an HGF-independent manner can be induced by multiple mechanisms, including cMET overexpression, genomic amplification, mutation, and alternative splicing. 2 Given its important roles in cellular processes, tumorigenesis, and cancer progression, c-MET is considered a promising target for cancer therapy.

[0005] Small molecules and antibodies targeting cMET have been developed and evaluated in clinical trials. However, in most trials, cMET inhibitors have not yielded promising results. 3 .

[0006] Activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) occur in a substantial proportion of patients with non-small cell lung cancer (NSCLC). 4.5Their presence is associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Although TKIs have initial efficacy in treating NSCLC harboring EGFR mutations, most patients inevitably develop acquired resistance within approximately one year after initial treatment. 6.7

[0007] Acquired resistance mechanisms are generally categorized into several categories: EGFR mutations, gene amplification, MAPK-PI3K mutations, oncogene fusions, and cell cycle gene alterations. The development of EGFR kinase inhibitors has overcome emerging EGFR mutational mechanisms. However, overcoming treatment resistance remains a major challenge, as the majority of resistance is caused by non-EGFR mutational alterations. Among these, hepatocyte growth factor receptor (cMET) amplification is one of the primary alterations leading to resistance after EGFR TKI treatment. For example, 5%-50% of patients develop resistance to second-line osimertinib treatment, compared to 7%-15% with first-line treatment. 8

[0008] Mechanistically, both EGFR and cMET signal through the ERK and AKT pathways, so when EGFR is inhibited, cMET signaling activation compensates for the loss of EGFR-driven signaling. This makes strategies combining EGFR and cMET targeting particularly attractive for overcoming compensatory drug resistance driven by cMET amplification. This strategy has been applied to JNJ-61186372 (Amivantamab, or JNJ-372), an EGFR x c-MET bispecific antibody. 9

[0009] Given the above reasons, there is still an unmet medical need for therapeutic drugs targeting EGFR and / or cMET. Summary of the Invention

[0010] The present disclosure includes antibodies or antibody fragments thereof that specifically bind to human cMET, as well as multispecific antibodies or antibody fragments thereof that specifically bind to two different epitopes (e.g., non-overlapping) of human cMET. In addition, the antibodies and antibody fragments thereof disclosed herein can be used to construct multispecific antibodies with other modes, such as a second tumor-associated antigen (TAA), an immune checkpoint or an immune stimulator, or to construct an antibody drug conjugate (ADC) or form a fusion protein. The cMET antibody can potentially be used to treat or prevent cancer alone or in combination with other therapeutic agents.

[0011] The present disclosure includes multispecific antibodies or antibody fragments thereof that specifically bind to two different epitopes (e.g., non-overlapping) of human EGFR and human cMET. Multispecific antibodies or antibody fragments thereof, alone or in combination with other therapeutic agents, can potentially be used to treat or prevent cancer.

[0012] The present disclosure encompasses the following embodiments.

[0013] Embodiment 1: An antibody or antigen-binding fragment thereof that specifically binds to human cMET, the antibody or antigen-binding fragment thereof comprising: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, and (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 61, (b) HCDR2 of SEQ ID NO: 62, (c) HCDR3 of SEQ ID NO: 63, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (16) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (17) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (18) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68.

[0014] Embodiment 2: The antibody or antigen-binding fragment thereof according to embodiment 1, wherein the antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91 or SEQ ID NO:93, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:4 or SEQ ID NO:72, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:54 or SEQ ID NO:82, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (5) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:34 or SEQ ID NO:78, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (10) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:39 or SEQ ID NO:79, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (11) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:44 or SEQ ID NO:80, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (12) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:49 or SEQ ID NO:81, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (13) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (14) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 144, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; or (15) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 145, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64.

[0015] Embodiment 3: The antibody or antigen-binding fragment thereof as described in any one of the above embodiments, wherein SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, SEQ ID NO: 4, SEQ ID NO: 72, SEQ ID NO: 9, SEQ ID NO: 73, SEQ ID NO: 54, SEQ ID NO: 82, SEQ ID NO: 14, SEQ ID NO: 74, SEQ ID NO: 19, SEQ ID NO: 75, SEQ ID NO: 24, SEQ ID NO: 76, SEQ ID NO: 29, SEQ ID NO: 77, SEQ ID NO: 34, SEQ ID NO: 78, SEQ ID NO: 39, SEQ ID NO: 79, SEQ ID NO: 44, SEQ ID NO: 80, SEQ ID NO: 49, SEQ ID NO: 81, SEQ ID NO: 59, SEQ ID NO: 83, SEQ ID NO: 144, SEQ ID NO: 145 or SEQ ID NO: 86. One, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted in NO:64.

[0016] Embodiment 4: The antibody or antigen-binding fragment thereof according to any one of the above embodiments, wherein the antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54 or SEQ ID NO: 82, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (12) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (13) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (14) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (15) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 145, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO: 64.

[0017] Embodiment 5: The antibody or antigen-binding fragment thereof as described in any one of the above embodiments, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment or a F(ab')2 fragment.

[0018] Embodiment 6: A multispecific antibody or antigen-binding fragment thereof, comprising a first antigen-binding domain that specifically binds to a first epitope of human cMET, and a second antigen-binding domain that specifically binds to a second epitope of human cMET, wherein the first epitope is different from the second epitope, or wherein the first antigen binding domain is different from the second antigen binding domain, or wherein the first antigen binding domain does not compete with the second antigen binding domain.

[0019] Embodiment 7: The multispecific antibody or antigen-binding fragment thereof according to embodiment 6, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68.

[0020] Embodiment 8: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6-7, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91 or SEQ ID NO:93, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:4 or SEQ ID NO:72, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:24 or SEQ ID NO:76, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (7) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:34 or SEQ ID NO:78, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (9) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:39 or SEQ ID NO:79, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (10) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:44 or SEQ ID NO:80, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (11) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:49 or SEQ ID NO:81, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; or (12) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 144, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64.

[0021] Embodiment 9: The multispecific antibody or antigen-binding fragment thereof of embodiment 8, wherein in the first antigen-binding domain that specifically binds to the first epitope of human cMET, SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:4, SEQ ID NO:72, SEQ ID NO:9, SEQ ID NO:73, SEQ ID NO:14, SEQ ID NO:74, SEQ ID NO:19, SEQ ID NO:75, SEQ ID NO:24, SEQ ID NO:76, SEQ ID NO:29, SEQ ID NO:77, SEQ ID NO:34, SEQ ID NO:78, SEQ ID NO:39, SEQ ID NO:79, SEQ ID NO:44, SEQ ID NO:80, SEQ ID NO:49, SEQ ID NO:81, SEQ ID NO:144, or SEQ ID NO:155. One, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted in NO:64.

[0022] Embodiment 10: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 9, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO: 64.

[0023] Embodiment 11: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 10, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO:61, (b) HCDR2 of SEQ ID NO:62, (c) HCDR3 of SEQ ID NO:63, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO:66, (e) LCDR2 of SEQ ID NO:67, and (f) LCDR3 of SEQ ID NO:68.

[0024] Embodiment 12: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 11, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:54 or SEQ ID NO:82, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:59 or SEQ ID NO:83, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; or (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 145, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64.

[0025] Embodiment 13: The multispecific antibody or antigen-binding fragment thereof as described in embodiment 12, wherein in the second antigen-binding domain that specifically binds to the second epitope of human cMET, one, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted in SEQ ID NO:54, SEQ ID NO:82, SEQ ID NO:59, SEQ ID NO:83, SEQ ID NO:145 or SEQ ID NO:64.

[0026] Embodiment 14: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 6-13, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54 or SEQ ID NO: 82, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (3) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 145, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO: 64.

[0027] Embodiment 15: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 14, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68.

[0028] Embodiment 16: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 15, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 82 or SEQ ID NO: 145, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64.

[0029] Embodiment 17: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 6-14, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO:61, (b) HCDR2 of SEQ ID NO:62, (c) HCDR3 of SEQ ID NO:63, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO:66, (e) LCDR2 of SEQ ID NO:67, and (f) LCDR3 of SEQ ID NO:68.

[0030] Embodiment 18: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 6-14 and 17, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64.

[0031] Embodiment 19: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 6-18, wherein the multispecific antibody or antigen-binding fragment thereof is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment or a F(ab')2 fragment.

[0032] Embodiment 20: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 6-19, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment; and The second antigen-binding domain that specifically binds to the second epitope of human cMET is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

[0033] Embodiment 21: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 6-20, wherein the multispecific antibody is a bispecific antibody or a trispecific antibody.

[0034] Embodiment 22: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 6-21, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises a first heavy chain constant region comprising SEQ ID NO: 95, and the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises a second heavy chain constant region comprising SEQ ID NO: 96; or wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises a first heavy chain constant region comprising SEQ ID NO: 96, and the second antigen-binding domain that specifically binds to the second epitope of human cMET comprises a second heavy chain constant region comprising SEQ ID NO: 95.

[0035] Embodiment 23: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 6-22, wherein the multispecific antibody or antigen-binding fragment thereof further comprises a third antigen-binding domain that specifically binds to a human tumor-associated antigen (TAA).

[0036] Embodiment 24: The multispecific antibody or antigen-binding fragment thereof of any one of Embodiment 23, wherein the TAA is EGFR.

[0037] Embodiment 25: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 6-24, further comprising an amino acid linker, wherein the amino acid linker is any sequence of SEQ ID NO: 97 to SEQ ID NO: 139.

[0038] Embodiment 26: The antibody, multispecific antibody or antigen-binding fragment thereof as described in any one of the above embodiments, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain constant region of the IgG1, IgG2, IgG3 or IgG4 subclass and / or a light chain constant region of the κ or λ type.

[0039] Embodiment 27: The antibody, multispecific antibody or antigen-binding fragment thereof as described in any one of the above embodiments, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain constant region of the IgG1 subclass and a light chain constant region of the κ type.

[0040] Embodiment 28: The antibody, multispecific antibody or antigen-binding fragment thereof as described in any one of the above embodiments, wherein the antibody or antigen-binding fragment thereof has antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement-dependent cytotoxicity (CDC).

[0041] Embodiment 29: The antibody, multispecific antibody, or antigen-binding fragment thereof as described in any one of the above embodiments, wherein the antibody or antigen-binding fragment thereof has reduced glycosylation or no glycosylation or low fucosylation.

[0042] Embodiment 30: The antibody, multispecific antibody, or antigen-binding fragment thereof as described in any one of the above embodiments, wherein the antibody or antigen-binding fragment thereof is afucosylated.

[0043] Embodiment 31: The antibody, multispecific antibody, or antigen-binding fragment thereof as described in any of the above embodiments, wherein the antibody or antigen-binding fragment thereof comprises an added bisecting GlcNac structure.

[0044] Embodiment 32: The antibody, multispecific antibody, or antigen-binding fragment thereof as described in any of the above embodiments, wherein the antibody or antigen-binding fragment thereof comprises an Fc domain, and wherein the Fc domain is an IgG1 Fc with extended half-life.

[0045] Embodiment 33: The antibody, multispecific antibody, or antigen-binding fragment thereof as described in any of the above embodiments, wherein the antibody or antigen-binding fragment thereof is conjugated to a cytotoxin.

[0046] Embodiment 34: The antibody, multispecific antibody, or antigen-binding fragment thereof as described in any of the above embodiments, wherein the antibody or antigen-binding fragment thereof is conjugated to a cytotoxin via a cytotoxin linker.

[0047] Embodiment 35: A pharmaceutical composition comprising the antibody, multispecific antibody, or antigen-binding fragment thereof according to any one of the above embodiments, and a pharmaceutically acceptable carrier.

[0048] Embodiment 36: A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the antibody, multispecific antibody, or antigen-binding fragment thereof according to any one of embodiments 1-34, or the pharmaceutical composition according to embodiment 35.

[0049] Embodiment 37: The method of embodiment 36, wherein the cancer carries a cMET gene alteration and / or the growth of the cancer cells is driven by cMET signaling.

[0050] Embodiment 38: The method of embodiment 37, wherein the cMET signaling is ligand-independent.

[0051] Embodiment 39: The method of embodiment 37, wherein the cMET signaling is ligand-dependent.

[0052] Embodiment 40: The method of embodiment 37, wherein the cMET genetic alteration is cMET overexpression, genomic amplification and / or mutation, which results in constitutively active cMET signaling.

[0053] Embodiment 41: The method of any one of Embodiments 36-40, wherein the cancer is gastric cancer, colorectal cancer, lung cancer, liver cancer, head and neck cancer, kidney cancer, breast cancer, or brain cancer.

[0054] Embodiment 42: The method of embodiment 41, wherein the lung cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

[0055] Embodiment 43: The method of embodiment 42, wherein the non-small cell lung cancer is squamous non-small cell lung cancer.

[0056] Embodiment 44: The method of embodiment 41, wherein the liver cancer is hepatocellular carcinoma.

[0057] Embodiment 45: The method of embodiment 41, wherein the head and neck cancer is head and neck squamous cell carcinoma.

[0058] Embodiment 46: The method of any one of embodiments 36-45, wherein the antibody or antigen-binding fragment thereof is administered in combination with another therapeutic agent.

[0059] Embodiment 47: The method of embodiment 46, wherein the therapeutic agent is an immune checkpoint inhibitor.

[0060] Embodiment 48: The method of embodiment 46, wherein the therapeutic agent is an anti-PD-1 antibody.

[0061] Embodiment 49: The method of embodiment 48, wherein the anti-PD1 antibody is Tislelizumab.

[0062] Embodiment 50: A multispecific antibody or antigen-binding fragment thereof, comprising a first antigen-binding domain that specifically binds to a first epitope of human cMET; a second antigen-binding domain that specifically binds to a second epitope of human cMET; and The third antigen-binding domain specifically binds to human EGFR; wherein the first epitope is different from the second epitope, or wherein the first antigen binding domain does not compete with the second antigen binding domain.

[0063] Embodiment 51: The multispecific antibody or antigen-binding fragment thereof of embodiment 50, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68.

[0064] Embodiment 52: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50-51, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91 or SEQ ID NO:93, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:4 or SEQ ID NO:72, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:24 or SEQ ID NO:76, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (7) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:34 or SEQ ID NO:78, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (9) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:39 or SEQ ID NO:79, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (10) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:44 or SEQ ID NO:80, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (11) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:49 or SEQ ID NO:81, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; or (12) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 144, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64.

[0065] Embodiment 53: The multispecific antibody or antigen-binding fragment thereof of embodiment 52, wherein in the first antigen-binding domain that specifically binds to the first epitope of human cMET, SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:4, SEQ ID NO:72, SEQ ID NO:9, SEQ ID NO:73, SEQ ID NO:14, SEQ ID NO:74, SEQ ID NO:19, SEQ ID NO:75, SEQ ID NO:24, SEQ ID NO:76, SEQ ID NO:29, SEQ ID NO:77, SEQ ID NO:34, SEQ ID NO:78, SEQ ID NO:39, SEQ ID NO:79, SEQ ID NO:44, SEQ ID NO:80, SEQ ID NO:49, SEQ ID NO:81, SEQ ID NO:144, or SEQ ID NO: One, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted in NO:64.

[0066] Embodiment 54: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50-53, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO: 64.

[0067] Embodiment 55: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50-54, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO:61, (b) HCDR2 of SEQ ID NO:62, (c) HCDR3 of SEQ ID NO:63, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO:66, (e) LCDR2 of SEQ ID NO:67, and (f) LCDR3 of SEQ ID NO:68.

[0068] Embodiment 56: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50-55, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:54 or SEQ ID NO:82, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:59 or SEQ ID NO:83, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; or (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 145, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64.

[0069] Embodiment 57: The multispecific antibody or antigen-binding fragment thereof as described in embodiment 56, wherein in the second antigen-binding domain that specifically binds to the second epitope of human cMET, one, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted in SEQ ID NO:54, SEQ ID NO:82, SEQ ID NO:59, SEQ ID NO:83, SEQ ID NO:145 or SEQ ID NO:64.

[0070] Embodiment 58: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50-57, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54 or SEQ ID NO: 82, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (3) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 145, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO: 64.

[0071] Embodiment 59: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 24 and 50-58, wherein the third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 155, (b) HCDR2 of SEQ ID NO: 156, (c) HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 158, (e) LCDR2 of SEQ ID NO: 159, and (f) LCDR3 of SEQ ID NO: 160.

[0072] Embodiment 60: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 24 and 50-59, wherein the third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 142, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 143.

[0073] Embodiment 61: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 24 and 50-60, wherein The first antigen binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; The second antigen binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 155, (b) HCDR2 of SEQ ID NO: 156, (c) HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 158, (e) LCDR2 of SEQ ID NO: 159, and (f) LCDR3 of SEQ ID NO: 160.

[0074] Embodiment 62: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 24 and 50-61, wherein The first antigen binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; The second antigen binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 82, or SEQ ID NO: 145, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 142, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 143.

[0075] Embodiment 63: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 24 and 50-60, wherein The first antigen binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; The second antigen binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 61, (b) HCDR2 of SEQ ID NO: 62, (c) HCDR3 of SEQ ID NO: 63, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 155, (b) HCDR2 of SEQ ID NO: 156, (c) HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 158, (e) LCDR2 of SEQ ID NO: 159, and (f) LCDR3 of SEQ ID NO: 160.

[0076] Embodiment 64: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 24, 50-60 and 63, wherein The first antigen binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; The second antigen binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 142, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 143.

[0077] Embodiment 65: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 24 and 50-64, wherein The first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; The second antigen binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The third antigen binding domain that specifically binds to human EGFR comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 155, (b) HCDR2 of SEQ ID NO: 156, (c) HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 158, (e) LCDR2 of SEQ ID NO: 159, and (f) LCDR3 of SEQ ID NO: 160.

[0078] Embodiment 66: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 24 and 50-65, wherein The first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; The second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 145, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The third antigen-binding domain that specifically binds to human EGFR comprises: a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 142, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO: 143.

[0079] Embodiment 67: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 50-66, wherein the multispecific antibody or antigen-binding fragment thereof is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment or a F(ab')2 fragment.

[0080] Embodiment 68: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 24 and 50-66, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment; The second antigen-binding domain that specifically binds to a second epitope of human cMET is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment; and The third antigen-binding domain that specifically binds to human EGFR is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

[0081] Embodiment 69: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 24 and 50-68, wherein the third antigen-binding domain that specifically binds to human EGFR comprises an scFv comprising a VH having amino acids of SEQ ID NO: 142 and a VL having amino acids of SEQ ID NO: 143; Optionally, the VH and VL are joined via a first amino acid linker; Optionally, the first amino acid linker is any sequence of SEQ ID NO: 97 to SEQ ID NO: 139; Preferably, the first amino acid linker is SEQ ID NO:139.

[0082] Embodiment 70: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 24 and 50-69, wherein the third antigen-binding domain that specifically binds to human EGFR comprises a scFv having the amino acid sequence of SEQ ID NO: 161.

[0083] Embodiment 71: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 24 and 50-70, wherein the multispecific antibody is a trispecific antibody.

[0084] Embodiment 72: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 50-71, wherein the multispecific antibody or antigen-binding fragment thereof comprises a heavy chain constant region of the IgG1, IgG2, IgG3 or IgG4 subclass and / or a light chain constant region of the κ or λ type.

[0085] Embodiment 73: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 50-72, wherein the multispecific antibody or antigen-binding fragment thereof comprises a heavy chain constant region of the IgG1 subclass and a light chain constant region of the κ type.

[0086] Embodiment 74: A multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 50-73, wherein the multispecific antibody or antigen-binding fragment thereof has antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement-dependent cytotoxicity (CDC).

[0087] Embodiment 75: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50-74, wherein the multispecific antibody or antigen-binding fragment thereof has reduced glycosylation or no glycosylation or low fucosylation.

[0088] Embodiment 76: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50-75, wherein the multispecific antibody or antigen-binding fragment thereof is afucosylated.

[0089] Embodiment 77: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50-76, wherein the multispecific antibody or antigen-binding fragment thereof comprises an added bisecting GlcNac structure.

[0090] Embodiment 78: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50-77, wherein the multispecific antibody or antigen-binding fragment thereof comprises an Fc domain, and wherein the Fc domain is an IgG1 Fc with extended half-life.

[0091] Embodiment 79: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50-78, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises a first heavy chain constant region comprising SEQ ID NO: 95, and the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises a second heavy chain constant region comprising SEQ ID NO: 96; or wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises a first heavy chain constant region comprising SEQ ID NO: 96, and the second antigen-binding domain that specifically binds to the second epitope of human cMET comprises a second heavy chain constant region comprising SEQ ID NO: 95.

[0092] Embodiment 80: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50-79, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises a first light chain constant region, and the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises a second light chain constant region; Optionally, the first light chain constant region and the second light chain constant region are different; or Optionally, the first light chain constant region and the second light chain constant region are identical.

[0093] Embodiment 81: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 50-80, further comprising a second amino acid linker, wherein the second amino acid linker is any sequence from SEQ ID NO: 97 to SEQ ID NO: 139, preferably, the second amino acid linker is SEQ ID NO: 139.

[0094] Embodiment 82: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50-81, comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein (1) a VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to the second epitope of human cMET, and a second heavy chain constant region arranged in the N-terminal to C-terminal direction in the first polypeptide; (2) the VH and first heavy chain constant regions of the first antigen-binding domain that specifically bind to the first epitope of human cMET are arranged in the N-terminal to C-terminal direction in the second polypeptide, or A VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to the first epitope of human cMET, and a first heavy chain constant region are arranged in the N-terminal to C-terminal direction in the second polypeptide; (3) the VL of the second antigen-binding domain that specifically binds to the second epitope of human cMET and the second light chain constant region are arranged in the N-terminal to C-terminal direction in the third polypeptide; and (4) the VL of the first antigen-binding domain that specifically binds to the first epitope of human cMET and the first light chain constant region are arranged in the N-terminal to C-terminal direction in the fourth polypeptide; Optionally, the second heavy chain constant region is SEQ ID NO: 95, and the first heavy chain constant region is SEQ ID NO: 96; or the second heavy chain constant region is SEQ ID NO: 96, and the first heavy chain constant region is SEQ ID NO: 95; Optionally, the first amino acid linker is SEQ ID NO: 139; Optionally, the second amino acid linker is SEQ ID NO: 139; Optionally, the VL of the first antigen binding domain and the VL of the second antigen binding domain are identical; Optionally, the first light chain constant region and the second light chain constant region are identical; Optionally, the third polypeptide and the fourth polypeptide are identical.

[0095] Embodiment 83: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50-82, comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein (1) a VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to the first epitope of human cMET, and a first heavy chain constant region arranged in the direction from N-terminus to C-terminus in the first polypeptide; (2) the VH and the second heavy chain constant region of the second antigen-binding domain that specifically bind to the second epitope of human cMET are arranged in the N-terminal to C-terminal direction in the second polypeptide, or A VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to a second epitope of human cMET, and a second heavy chain constant region are arranged in the N-terminal to C-terminal direction in the second polypeptide; (3) the VL of the first antigen-binding domain that specifically binds to the first epitope of human cMET and the first light chain constant region are arranged in the N-terminal to C-terminal direction in the third polypeptide; and (4) the VL of the second antigen-binding domain that specifically binds to the second epitope of human cMET and the second light chain constant region are arranged in the N-terminal to C-terminal direction in the fourth polypeptide; Optionally, the second heavy chain constant region is SEQ ID NO: 95, and the first heavy chain constant region is SEQ ID NO: 96; or the second heavy chain constant region is SEQ ID NO: 96, and the first heavy chain constant region is SEQ ID NO: 95; Optionally, the first amino acid linker is SEQ ID NO: 139; Optionally, the second amino acid linker is SEQ ID NO: 139; Optionally, the VL of the first antigen binding domain and the VL of the second antigen binding domain are identical; Optionally, the first light chain constant region and the second light chain constant region are identical; Optionally, the third polypeptide and the fourth polypeptide are identical.

[0096] Embodiment 84: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50-83, comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein (1) a VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to the second epitope of human cMET, and a second heavy chain constant region arranged in the N-terminal to C-terminal direction in the first polypeptide; (2) the VH of the first antigen-binding domain that specifically binds to the first epitope of human cMET and the first heavy chain constant region are arranged in the N-terminal to C-terminal direction in the second polypeptide; (3) the VL of the second antigen-binding domain that specifically binds to the second epitope of human cMET and the second light chain constant region are arranged in the N-terminal to C-terminal direction in the third polypeptide; and (4) the VL of the first antigen-binding domain that specifically binds to the first epitope of human cMET and the first light chain constant region are arranged in the N-terminal to C-terminal direction in the fourth polypeptide; Optionally, the second heavy chain constant region is SEQ ID NO: 95, and the first heavy chain constant region is SEQ ID NO: 96; or the second heavy chain constant region is SEQ ID NO: 96, and the first heavy chain constant region is SEQ ID NO: 95; Optionally, the first amino acid linker is SEQ ID NO: 139; Optionally, the second amino acid linker is SEQ ID NO: 139; Optionally, the VL of the first antigen binding domain and the VL of the second antigen binding domain are identical; Optionally, the first light chain constant region and the second light chain constant region are identical; Optionally, the third polypeptide and the fourth polypeptide are identical.

[0097] Embodiment 85: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50-84, comprising a first polypeptide, a second polypeptide, and a third polypeptide, wherein (1) the first polypeptide has an amino acid sequence of SEQ ID NO: 153, the second polypeptide has an amino acid sequence of SEQ ID NO: 150, and the third polypeptide has an amino acid sequence of SEQ ID NO: 148; (2) the first polypeptide has the amino acid sequence of SEQ ID NO: 146, the second polypeptide has the amino acid sequence of SEQ ID NO: 147, and the third polypeptide has the amino acid sequence of SEQ ID NO: 148; (3) the first polypeptide has the amino acid sequence of SEQ ID NO: 149, the second polypeptide has the amino acid sequence of SEQ ID NO: 150, and the third polypeptide has the amino acid sequence of SEQ ID NO: 151; (4) the first polypeptide has the amino acid sequence of SEQ ID NO: 149, the second polypeptide has the amino acid sequence of SEQ ID NO: 150, and the third polypeptide has the amino acid sequence of SEQ ID NO: 152; (5) the first polypeptide has the amino acid sequence of SEQ ID NO: 153, the second polypeptide has the amino acid sequence of SEQ ID NO: 154, and the third polypeptide has the amino acid sequence of SEQ ID NO: 148; or (6) The first polypeptide has an amino acid sequence of SEQ ID NO: 146, the second polypeptide has an amino acid sequence of SEQ ID NO: 150, and the third polypeptide has an amino acid sequence of SEQ ID NO: 148.

[0098] Embodiment 86: The multispecific antibody or antigen-binding fragment thereof as described in any one of embodiments 50-85, wherein the multispecific antibody or antigen-binding fragment thereof comprises (1) the first polypeptide of SEQ ID NO: 153, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO: 148; (2) the first polypeptide of SEQ ID NO: 146, the second polypeptide of SEQ ID NO: 147, and the third polypeptide of SEQ ID NO: 148; (3) the first polypeptide of SEQ ID NO: 149, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO: 151; (4) the first polypeptide of SEQ ID NO: 149, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO: 152; (5) the first polypeptide of SEQ ID NO: 153, the second polypeptide of SEQ ID NO: 154, and the third polypeptide of SEQ ID NO: 148; or (6) The first polypeptide of SEQ ID NO: 146, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO: 148.

[0099] Embodiment 87: A pharmaceutical composition comprising the multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50-86, and a pharmaceutically acceptable carrier.

[0100] Embodiment 88: A method of treating cancer, comprising administering a therapeutically effective amount of the multispecific antibody or antigen-binding fragment thereof according to any one of Embodiments 50-86, or the pharmaceutical composition according to Embodiment 87, to a patient in need thereof.

[0101] Embodiment 89: The method of embodiment 88, wherein the cancer carries a cMET gene alteration and / or the growth of the cancer cells is driven by cMET signaling.

[0102] Embodiment 90: The method of embodiment 89, wherein the cMET signaling is ligand-independent.

[0103] Embodiment 91: The method of embodiment 89, wherein the cMET signaling is ligand-dependent.

[0104] Embodiment 92: The method of embodiment 89, wherein the cMET genetic alteration is cMET overexpression, genomic amplification and / or mutation, which results in constitutively active cMET signaling.

[0105] Embodiment 93: The method of embodiment 88, wherein the cancer carries an EGFR activating mutation and / or the growth of the cancer cell is driven by EGFR signaling; optionally, the EGFR activating mutation is a deletion or a point mutation.

[0106] Embodiment 94: The method of embodiment 93, wherein the EGFR signaling is ligand-independent.

[0107] Embodiment 95: The method of embodiment 93, wherein the EGFR signaling is ligand-dependent.

[0108] Embodiment 96: The method of any one of embodiments 88-95, wherein the cancer is gastric cancer, colorectal cancer, lung cancer, liver cancer, head and neck cancer, kidney cancer, breast cancer, or brain cancer.

[0109] Embodiment 97: The method of embodiment 96, wherein the lung cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

[0110] Embodiment 98: The method of embodiment 97, wherein the non-small cell lung cancer is squamous non-small cell lung cancer.

[0111] Embodiment 99: The method of embodiment 96, wherein the liver cancer is hepatocellular carcinoma.

[0112] Embodiment 100: The method of embodiment 96, wherein the head and neck cancer is head and neck squamous cell carcinoma.

[0113] Embodiment 101: The method of any one of embodiments 88-100, wherein the multispecific antibody or antigen-binding fragment thereof is administered in combination with another therapeutic agent.

[0114] Embodiment 102: The method of embodiment 101, wherein the therapeutic agent is an immune checkpoint inhibitor.

[0115] Embodiment 103: The method of embodiment 101, wherein the therapeutic agent is an anti-PD-1 antibody.

[0116] Embodiment 104: The method of embodiment 103, wherein the anti-PD1 antibody is tislelizumab.

[0117] Embodiment 105: An isolated nucleic acid encoding the antibody, multispecific antibody, or antigen-binding fragment thereof of any one of embodiments 1 to 34 and 50-86.

[0118] Embodiment 106: A vector comprising the nucleic acid of embodiment 105.

[0119] Embodiment 107: A host cell comprising the nucleic acid of embodiment 105 or the vector of embodiment 106.

[0120] Embodiment 108: A method for producing an antibody, a multispecific antibody, or an antigen-binding fragment thereof, the method comprising culturing the host cell as described in embodiment 107, and recovering the antibody, multispecific antibody, or antibody fragment from the culture.

[0121] In some embodiments, the present disclosure provides anti-human cMET antibodies or antigen-binding fragments thereof that have high binding affinity to human cMET and / or are capable of blocking ligand-dependent signaling.

[0122] In some embodiments, the present disclosure provides a multispecific antibody or antigen-binding fragment thereof that binds to two different epitopes of human cMET (e.g., non-overlapping), or wherein its first antigen-binding domain that targets human cMET does not compete with its second antigen-binding domain that targets human cMET. Such a multispecific antibody or antigen-binding fragment thereof has any one or more of the following characteristics: (1) Ability to block ligand-independent signal transduction; (2) can inhibit the proliferation of cancer cells; and (3) Able to block ligand-induced signal transduction.

[0123] In some embodiments, the present disclosure provides a multispecific antibody or antigen-binding fragment thereof that specifically binds to two different epitopes (e.g., non-overlapping) of human EGFR and human cMET, or a multispecific antibody or antigen-binding fragment thereof that specifically binds to human EGFR and human cMET, wherein a first antigen-binding domain thereof that targets human cMET does not compete with a second antigen-binding domain thereof that targets human cMET (e.g., an EGFR x cMET biparatopic antibody or antigen-binding fragment thereof that has high binding affinity for human cMET and human EGFR).

[0124] In some embodiments, the present disclosure provides EGFRxcMET biparatopic trispecific antibodies or antigen-binding fragments thereof that have potent or superior ADCC activity against cancer cells, including EGFR mutation / signaling driven cancer cells and / or cMET amplification / signaling driven cancer cells.

[0125] In some embodiments, the present disclosure provides EGFR x cMET biparatopic trispecific antibodies or antigen-binding fragments thereof that have potent ADCP activity against cancer cells, including EGFR mutation / signaling driven cancer cells and / or cMET amplification / signaling driven cancer cells.

[0126] In some embodiments, the present disclosure provides EGFR x cMET biparatopic trispecific antibodies or antigen-binding fragments thereof that significantly block EGFR signaling and / or cMET signaling by downregulating cell surface receptors (e.g., by internalization). In addition, the EGFR x cMET biparatopic trispecific antibodies or antigen-binding fragments thereof of the present disclosure have significant anti-proliferative activity against cancer cells driven by EGFR mutation / signaling, and / or have superior anti-proliferative activity against cancer cells driven by cMET amplification / signaling.

[0127] In some embodiments, the present disclosure provides EGFRxcMET biparatopic trispecific antibodies or antigen-binding fragments thereof that exhibit potent or superior killing of cancer cells, including EGFR mutation / signaling driven cancer cells and, in particular, cMET amplification / signaling driven cancer cells.

[0128] In some embodiments, the present disclosure provides EGFR x cMET biparatopic trispecific antibodies or antigen-binding fragments thereof that exhibit substantial tumor growth inhibition in EGFR mutation / signaling driven tumors, and / or superior tumor growth inhibition in cMET amplification / signaling driven tumors.

[0129] In some embodiments, the present disclosure provides EGFRxcMET biparatopic trispecific antibodies or antigen-binding fragments thereof that exhibit less toxicity and / or a better safety profile.

[0130] In some embodiments, the present disclosure provides a multispecific antibody or antigen-binding fragment thereof that specifically binds to two different epitopes (e.g., non-overlapping) of human EGFR and human cMET, or a multispecific antibody or antigen-binding fragment thereof that specifically binds to human EGFR and human cMET, wherein a first antigen-binding domain thereof that targets human cMET does not compete with a second antigen-binding domain thereof that targets human cMET (e.g., an EGFR x cMET biparatopic antibody or antigen-binding fragment thereof having any one or more of the following characteristics): (1) having substantial or superior ADCC activity against cancer cells, including EGFR mutation / signaling-driven cancer cells and / or cMET amplification / signaling-driven cancer cells; (2) possesses substantial ADCP activity against cancer cells, including EGFR mutation / signaling-driven cancer cells and / or cMET amplification / signaling-driven cancer cells; (3) blocking EGFR signaling and / or cMET signaling by downregulating receptors on the cell surface (e.g., through internalization); (4) have substantial antiproliferative activity against EGFR mutation / signaling-driven cancer cells, and / or have superior antiproliferative activity against cMET amplification / signaling-driven cancer cells; (5) have a significant or superior killing effect on cancer cells, including EGFR mutation / signaling-driven cancer cells and especially cMET amplification / signaling-driven cancer cells; (6) have a substantial tumor growth inhibitory effect in EGFR mutation / signaling driven tumors, and / or have a superior tumor growth inhibitory effect in cMET amplification / signaling driven tumors; and (7) Less toxicity and / or better safety.

[0131] In some embodiments, the present disclosure provides EGFR x cMET biparatopic trispecific antibodies or antigen-binding fragments thereof that exhibit excellent killing / tumor growth inhibition effects on EGFR mutation / signaling driven tumors and cMET amplification / signaling driven tumors, thereby overcoming cMET amplification-driven compensated resistance or EGFR mutation-driven compensated resistance. BRIEF DESCRIPTION OF THE DRAWINGS

[0132] Figures 1A-1L Shown are SPR binding kinetic curves of representative monoclonal anti-cMET antibodies. Figure 1A :063Ab10910; Figure 1B :061Ab15310; Figure 1C :063Ab16010; Figure 1D :063Ab02110; Figure 1E :063Ab15210; Figure 1F :062Ab16310; Figure 1G :063Ab05510; Figure 1H :063Ab07710; Figure 1I :063Ab14710; Figure 1J :061Ab05110; Figure 1K :063Ab03210; Figure 1L :063Ab16720.

[0133] Figure 2 Shown is a comparison of ligand-induced signaling blocking activities of representative monoclonal anti-cMET antibodies.

[0134] Figure 3 Shown are the epitope binning results of representative monoclonal anti-cMET antibodies.

[0135] Figure 4Inhibitory effects of bispecific anti-cMET antibodies on ligand-independent signaling in Hs746T cells are shown.

[0136] Figure 5 The anti-proliferative activity of the bispecific anti-cMET antibody on Hs746T cells was shown.

[0137] Figure 6 Ligand-induced signaling blockade by bispecific anti-cMET antibodies in H596 cells is shown.

[0138] Figure 7 Different EGFR x cMET x cMET trispecific antibody formats with different EGFR scFv valencies and cMET arm orientations.

[0139] Figure 8. EGFR x cMET x cMET trispecific antibody in the absence of serum ( Figure 8A ) and serum ( Figure 8B ) in H1975 cells and in the absence of serum ( Figure 8C ) and serum ( Figure 8D ) under the condition of ADCC activity against Hs746T cells.

[0140] Figure 9. EGFR x cMET x cMET trispecific antibody in the absence of serum ( Figure 9A ) and serum ( Figure 9B ) in H1975 cells and in the absence of serum ( Figure 9C ) and serum ( Figure 9D ) under the condition of ADCP activity against Hs746T.

[0141] Figure 10. EGFR x cMET x cMET trispecific antibody against EGFR signaling-dependent cancer cell line H1975 ( Figure 10A ) and H2073( Figure 10B ) and the cMET signaling-dependent cancer cell line Hs746T ( Figure 10C ) and EBC-1( Figure 10D )'s antiproliferative activity.

[0142] Figure 11 .Antiproliferative activity of the EGFR x cMET x cMET trispecific antibody against HEKn cells.

[0143] Figure 12 .The EGFR x cMET x cMET trispecific antibody TE-642 showed lower TGI and CR rates in the HCC827 xenograft model (an EGFR mutation-driven model) compared to JNJ-372.

[0144] Figure 13 TE-647, an EGFR x cMET x cMET trispecific antibody, demonstrated comparable tumor growth inhibition to JNJ-372 in the HCC827 xenograft model (an EGFR mutation-driven model).

[0145] Figure 14 .The EGFR x cMET x cMET trispecific antibodies TE-642 and TE-646 showed tumor growth inhibition in the H1975 xenograft model (a model driven by EGFR mutations).

[0146] Figure 15 TE-647, an EGFR x cMET x cMET trispecific antibody, demonstrated comparable tumor growth inhibition to JNJ-372 in the H1975 xenograft model (an EGFR mutation-driven model).

[0147] Figure 16 .The EGFR x cMET x cMET trispecific antibody TE-647 showed better tumor growth inhibition than JNJ-372 in the Hs746T xenograft model (a model driven by cMET amplification), and this effect was dose-dependent.

[0148] Figure 17 The EGFR x cMET x cMET antibody TE-647 showed better in vivo activity than JNJ-372 in the EBC-1 (cMET amplification-driven) xenograft model, and this effect was dose-dependent. DETAILED DESCRIPTION

[0149] The present disclosure provides anti-human cMET antibodies or antigen-binding fragments thereof and multispecific antibodies or antigen-binding fragments thereof that bind to two different epitopes of human cMET (e.g., non-overlapping), or wherein the first antigen-binding domain thereof that targets human cMET does not compete with the second antigen-binding domain thereof that targets human cMET. In addition, the present disclosure provides antibodies with desired binding affinity and desired blocking activity for ligand-independent signaling and / or ligand-induced signaling. Antibodies can be used to construct multispecific antibodies with other modes, such as a second tumor-associated antigen (TAA), an immune checkpoint or an immunostimulatory substance, or to construct an antibody drug conjugate (ADC) or to fuse with other domains to form a fusion protein. In addition, antibodies and their constructs can be used to reduce the likelihood of cancer and related disorders or to treat cancer and related disorders.

[0150] The present disclosure also provides a multispecific antibody or antibody fragment thereof that specifically binds to two different epitopes (e.g., non-overlapping) of human EGFR and human cMET, or a multispecific antibody or antigen-binding fragment thereof that specifically binds to human EGFR and human cMET, wherein its first antigen-binding domain that targets human cMET does not compete with its second antigen-binding domain that targets human cMET. In addition, the present disclosure provides a multispecific antibody or antibody fragment thereof having a desired binding affinity, desired ADCC activity, desired ADCP activity, desired blocking activity for EGFR signaling and cMET signaling, and desired anti-proliferative activity and killing effect on cancer cells driven by EGFR signaling and cancer cells driven by cMET signaling. In addition, multispecific antibodies and constructs thereof can be used to reduce the likelihood of cancer and related disorders or to treat cancer and related disorders. I. Anti-cMET Antibodies

[0151] The present disclosure provides antibodies or antigen-binding fragments thereof that specifically bind to human cMET. The antibodies or antigen-binding fragments of the present disclosure include, but are not limited to, antibodies or antigen-binding fragments thereof generated as described below. 1.1 The first group of anti-cMET antibodies Table 1. Anti-cMET monoclonal antibody list 1

[0152] The present disclosure provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody or antibody fragment (e.g., antigen-binding fragment) comprises a VH domain having an amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 72, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, SEQ ID NO: 9, SEQ ID NO: 73, SEQ ID NO: 14, SEQ ID NO: 74, SEQ ID NO: 19, SEQ ID NO: 75, SEQ ID NO: 24, SEQ ID NO: 76, SEQ ID NO: 29, SEQ ID NO: 77, SEQ ID NO: 34, SEQ ID NO: 78, SEQ ID NO: 39, SEQ ID NO: 79, SEQ ID NO: 44, SEQ ID NO: 80, SEQ ID NO: 49, SEQ ID NO: 81, or SEQ ID NO: 144 (Table 1). The present disclosure also provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody or antigen-binding fragment comprises a HCDR having the amino acid sequence of any one of the HCDRs listed in Table 1. In one aspect, the present disclosure provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody comprises one, two, three or more HCDRs having the amino acid sequence of any one of the HCDRs listed in Table 1.

[0153] The present disclosure provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody or antibody fragment (e.g., antigen-binding fragment) comprises a VL domain having the amino acid sequence of SEQ ID NO: 64 (Table 1). The present disclosure also provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody or antigen-binding fragment comprises a LCDR having the amino acid sequence of any one of the LCDRs listed in Table 1. In one aspect, the present disclosure provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody comprises one, two, three or more LCDRs having the amino acid sequence of any one of the LCDRs listed in Table 1.

[0154] In one embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises one or more complementarity determining regions (CDRs) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 94, SEQ ID NO: 84; SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45 ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:66, SEQ ID NO:67 and SEQ ID NO:68.

[0155] In another embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises: (a) a heavy chain variable region comprising one or more complementarity determining regions (HCDRs) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 94, SEQ ID NO: 84; SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45; NO:42, SEQ ID NO:43, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:51, SEQ ID NO:52 and SEQ ID NO:53, and / or (b) a light chain variable region comprising one or more complementarity determining regions (LCDRs) comprising an amino acid sequence selected from the group consisting of SEQ ID NO:66, SEQ ID NO:67 and SEQ ID NO:68.

[0156] In another embodiment, an antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises: (a) a heavy chain variable region comprising three complementarity determining regions (HCDRs), wherein the complementarity determining regions are HCDR1 comprising the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 11, SEQ ID NO: 16, SEQ ID NO: 21, SEQ ID NO: 26, SEQ ID NO: 31, SEQ ID NO: 36, SEQ ID NO: 41, SEQ ID NO: 46, or SEQ ID NO: 51; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 12, SEQ ID NO: 17, SEQ ID NO: 22, SEQ ID NO: 27, SEQ ID NO: 32, SEQ ID NO: 37, SEQ ID NO: 42, SEQ ID NO: 47, or SEQ ID NO: 52; and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 94, SEQ ID NO: 84; SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93; ID NO:92, SEQ ID NO:13, SEQ ID NO:18, SEQ ID NO:23, SEQ ID NO:28, SEQ ID NO:33, SEQ ID NO:38, SEQ ID NO:43, SEQ ID NO:48 or SEQ ID NO:53; and / or (b) a light chain variable region comprising three complementarity determining regions (LCDRs), which are LCDR1 comprising the amino acid sequence of SEQ ID NO:66; LCDR2 comprising the amino acid sequence of SEQ ID NO:67; and LCDR3 comprising the amino acid sequence of SEQ ID NO:68.

[0157] In another embodiment, an antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises: (a) a heavy chain variable region comprising three complementarity determining regions (HCDRs), the complementarity determining regions being: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; a HCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 94; a HCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 84; a HCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 86; a HCDR1 comprising the amino acid sequence of SEQ ID NO: 6, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 87; NO:7, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:88; a HCDR1 comprising the amino acid sequence of SEQ ID NO:6, a HCDR2 comprising the amino acid sequence of SEQ ID NO:7, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:90; a HCDR1 comprising the amino acid sequence of SEQ ID NO:6, a HCDR2 comprising the amino acid sequence of SEQ ID NO:7, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:92; a HCDR1 comprising the amino acid sequence of SEQ ID NO:11, a HCDR2 comprising the amino acid sequence of SEQ ID NO:12, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:13; a HCDR1 comprising the amino acid sequence of SEQ ID NO:16, a HCDR2 comprising the amino acid sequence of SEQ ID NO:17, and a HCDR3 comprising the amino acid sequence of SEQ ID NO:18; a HCDR1 comprising the amino acid sequence of SEQ ID NO:21, a HCDR2 comprising the amino acid sequence of SEQ ID NO:22, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: NO: 23; HCDR1 comprising the amino acid sequence of SEQ ID NO: 26, HCDR2 comprising the amino acid sequence of SEQ ID NO: 27, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 28;a HCDR1 comprising the amino acid sequence of SEQ ID NO: 31, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 32, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 33; a HCDR1 comprising the amino acid sequence of SEQ ID NO: 36, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 37, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; a HCDR1 comprising the amino acid sequence of SEQ ID NO: 41, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 42, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 43; a HCDR1 comprising the amino acid sequence of SEQ ID NO: 46, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 47, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 48; or a HCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 52, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: NO: 53, and / or (b) a light chain variable region comprising three complementarity determining regions (LCDRs), wherein the complementarity determining regions are LCDR1 comprising the amino acid sequence of SEQ ID NO: 66, LCDR2 comprising the amino acid sequence of SEQ ID NO: 67, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.;

[0158] In one embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises: (1) HCDR1 (heavy chain complementarity determining region 1), HCDR2, and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:4 or SEQ ID NO:72; (2) HCDR1, HCDR2, and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:85; (3) HCDR1, HCDR2, and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:87; (4) HCDR1, HCDR2, and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:89; (5) HCDR1, HCDR2, and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:91; (6) HCDR1, HCDR2, and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:93; (7) HCDR1, HCDR2, and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:9 or SEQ ID NO:73; (8) HCDR1, HCDR2 and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:14 or SEQ ID NO:74; (9) HCDR1, HCDR2 and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:19 or SEQ ID NO:75; (10) HCDR1, HCDR2 and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:24 or SEQ ID NO:76; (11) HCDR1, HCDR2 and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:29 or SEQ ID NO:77; (12) HCDR1, HCDR2 and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:34 or SEQ ID NO:78; (13) HCDR1, HCDR2 and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:39 or SEQ ID NO: NO:79; (14) HCDR1, HCDR2 and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:44 or SEQ ID NO:80; (15) HCDR1, HCDR2 and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:49 or SEQ ID NO:81; or (16) HCDR1, HCDR2 and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO:144;and / or (1) LCDR1 (light chain complementary determining region 1), LCDR2, and LCDR3 from the light chain variable region (VL) shown in SEQ ID NO: 64. ;

[0159] In one embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (6) a heavy chain variable region (VH), which comprises (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO:6, (b) HCDR2 of SEQ ID NO:7, (c) HCDR3 of SEQ ID NO:92, and a light chain variable region, which comprises: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO:66, (e) LCDR2 of SEQ ID NO:67, and (f) LCDR3 of SEQ ID NO:68. (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, and (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO:51, (b) HCDR2 of SEQ ID NO:52, (c) HCDR3 of SEQ ID NO:53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO:66, (e) LCDR2 of SEQ ID NO:67, and (f) LCDR3 of SEQ ID NO:68, according to the Kabat definition.

[0160] In one embodiment, the antibodies or antigen-binding fragments thereof of the present disclosure comprise: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4, SEQ ID NO:72, SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:9, SEQ ID NO:73, SEQ ID NO:14, SEQ ID NO:74, SEQ ID NO:19, SEQ ID NO:75, SEQ ID NO:24, SEQ ID NO:76, SEQ ID NO:29, SEQ ID NO:77, SEQ ID NO:34, SEQ ID NO:78, SEQ ID NO:39, SEQ ID NO:79, SEQ ID NO:44, SEQ ID NO:80, SEQ ID NO:49, SEQ ID NO:81, or SEQ ID NO:144; or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4, SEQ ID NO:72, SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:9, SEQ ID NO:73, SEQ ID NO:14, SEQ ID NO:74, SEQ ID NO:19, SEQ ID NO:75, SEQ ID NO:24, SEQ ID NO:76, SEQ ID NO:29, SEQ ID NO:77, SEQ ID NO:34, SEQ ID NO:78, SEQ ID NO:39, SEQ ID NO:79, SEQ ID NO:44, SEQ ID NO:80, SEQ ID NO:49, SEQ ID NO:81, or SEQ ID NO:144; NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:9, SEQ ID NO:73, SEQ ID NO:14, SEQ ID NO:74, SEQ ID NO:19, SEQ ID NO:75, SEQ ID NO:24, SEQ ID NO:76, SEQ ID NO:29, SEQ ID NO:77, SEQ ID NO:34, SEQ ID NO:78, SEQ ID NO:39, SEQ ID NO:79, SEQ ID NO:44, SEQ ID NO:80, SEQ ID NO:49, SEQ ID NO:81, or SEQ ID NO:144, and / or (b) a light chain variable region comprising an amino acid sequence of SEQ ID NO:64, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73 NO:64 is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence.

[0161] In one embodiment, the antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91 or SEQ ID NO:93, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:4 or SEQ ID NO:72, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:24 or SEQ ID NO:76, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (7) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:34 or SEQ ID NO:78, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (9) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:39 or SEQ ID NO:79, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (10) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:44 or SEQ ID NO:80, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (11) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:49 or SEQ ID NO:81, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; or (12) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 144, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64.

[0162] In one embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof, wherein SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:4, SEQ ID NO:72, SEQ ID NO:9, SEQ ID NO:73, SEQ ID NO:14, SEQ ID NO:74, SEQ ID NO:19, SEQ ID NO:75, SEQ ID NO:24, SEQ ID NO:76, SEQ ID NO:29, SEQ ID NO:77, SEQ ID NO:34, SEQ ID NO:78, SEQ ID NO:39, SEQ ID NO:79, SEQ ID NO:44, SEQ ID NO:80, SEQ ID NO:49, SEQ ID NO:81, SEQ ID NO:144, or SEQ ID NO:155. One, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted (optionally conservative amino acid substitutions) within NO:64 while retaining therapeutic activity / binding specificity / affinity, optionally without altering the corresponding sequence of the CDRs.

[0163] In one embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof, wherein SEQ ID NO: 85 and SEQ ID NO: 64, SEQ ID NO: 87 and SEQ ID NO: 64, SEQ ID NO: 89 and SEQ ID NO: 64, SEQ ID NO: 91 and SEQ ID NO: 64, SEQ ID NO: 93 and SEQ ID NO: 64, SEQ ID NO: 4 and SEQ ID NO: 64, SEQ ID NO: 72 and SEQ ID NO: 64, SEQ ID NO: 9 and SEQ ID NO: 64, SEQ ID NO: 73 and SEQ ID NO: 64, SEQ ID NO: 14 and SEQ ID NO: 64, SEQ ID NO: 74 and SEQ ID NO: 64, SEQ ID NO: 19 and SEQ ID NO: 64, SEQ ID NO: 75 and SEQ ID NO: 64, SEQ ID NO: 24 and SEQ ID NO: 64, SEQ ID NO: 76 and SEQ ID NO: 64, SEQ ID NO: 29 and SEQ ID NO: 64, SEQ ID NO: 77 and SEQ ID NO: NO:64, SEQ ID NO:34 and SEQ ID NO:64, SEQ ID NO:78 and SEQ ID NO:64, SEQ ID NO:39 and SEQ ID NO:64, SEQ ID NO:79 and SEQ ID NO:64, SEQ ID NO:44 and SEQ ID NO:64, SEQ ID NO:80 and SEQ ID NO:64, SEQ ID NO:49 and SEQ ID NO:64, SEQ ID NO:81 and SEQ ID NO:64, or SEQ ID NO:144 and SEQ ID NO:64, while retaining therapeutic activity / binding specificity / affinity, optionally without altering the corresponding sequence of the CDRs.

[0164] In one embodiment, an antibody or antigen-binding fragment thereof comprising: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO: 64.

[0165] Other antibodies or antigen-binding fragments thereof of the present disclosure include amino acids that have been altered but have a percent identity of at least 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% in the CDR regions compared to the CDR regions disclosed in Table 1. In some aspects, they include amino acid alterations (insertions, deletions or substitutions, optionally conservative amino acid substitutions) wherein no more than 1, 2, 3, 4 or 5 amino acids are altered in the CDR regions when compared to the CDR regions depicted in the sequences described in Table 1 while maintaining binding specificity and affinity.

[0166] Other antibodies of the present disclosure include those in which amino acids or nucleic acids encoding amino acids have been altered in the variable region (e.g., the framework region of the variable region); but have at least 60%, 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%, 95%, 96%, 97%, 98% or 99% identity to the variable region sequences set forth in Table 1 while retaining binding specificity / affinity, optionally without altering the corresponding sequences of the CDRs. In some aspects, it includes changes in the amino acid sequence, wherein no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 amino acids are changed in the variable region (e.g., the framework region of the variable region) when compared to the variable region depicted in the sequence described in Table 1, while retaining binding specificity / affinity, optionally without changing the corresponding sequence of the CDR. These changes can be insertions, deletions or substitutions, optionally conservative amino acid substitutions.

[0167] In another embodiment, the present disclosure provides a 1×10 -6 M to 1×10 -11 The binding affinity (K D) an antibody or antigen-binding fragment thereof that specifically binds to human cMET. In another embodiment, the anti-cMET antibody or antigen-binding fragment thereof is present at about 1×10 -6 M, about 1×10 -7 M, about 1×10 -8 M, about 1×10 -9 M, about 1×10 -10 M or about 1×10 -11 The binding affinity (K D ) binds to human cMET.

[0168] The present disclosure also provides nucleic acid sequences encoding VH or VL of antibodies that specifically bind to human cMET. Such nucleic acid sequences can be optimized for expression in mammalian cells.

[0169] The present disclosure also provides antibodies and antigen-binding fragments thereof that bind to the same epitope as the anti-cMET antibodies described in Table 1. Thus, additional antibodies and antigen-binding fragments thereof can be identified based on their ability to cross-compete with (e.g., competitively inhibit their binding in a statistically significant manner) the antibodies described in Table 1 in a binding assay. The ability of a test antibody to inhibit the binding of an antibody or antigen-binding fragment thereof of the present disclosure to human cMET demonstrates that the test antibody can compete with the antibody or antigen-binding fragment thereof for binding to human cMET. Without being bound by any one theory, such an antibody may bind to the same or related (e.g., structurally similar or spatially adjacent) epitope on human cMET as the antibody or antigen-binding fragment thereof that it competes with. In certain aspects, an antibody that binds to the same epitope on human cMET as an antibody or antigen-binding fragment thereof of the present disclosure is a human or humanized monoclonal antibody. Such a human or humanized monoclonal antibody can be prepared and isolated as described herein.

[0170] In some embodiments, the antibody or antigen-binding fragment thereof is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

[0171] In one embodiment, the antibody or antigen-binding fragment thereof is in the form of an scFv comprising VH-VL in an N-terminal to C-terminal direction or VL-VH in an N-terminal to C-terminal direction. In some embodiments, VH and VL are linked via an amino acid linker as described herein. In some embodiments, the VH comprises the amino acid sequence of any one of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, SEQ ID NO: 4, SEQ ID NO: 72, SEQ ID NO: 9, SEQ ID NO: 73, SEQ ID NO: 14, SEQ ID NO: 74, SEQ ID NO: 19, SEQ ID NO: 75, SEQ ID NO: 24, SEQ ID NO: 76, SEQ ID NO: 29, SEQ ID NO: 77, SEQ ID NO: 34, SEQ ID NO: 78, SEQ ID NO: 39, SEQ ID NO: 79, SEQ ID NO: 44, SEQ ID NO: 80, SEQ ID NO: 49, SEQ ID NO: 81, or SEQ ID NO: 144. In some embodiments, the VL comprises the amino acid sequence of any one of SEQ ID NO: 64. In some embodiments, the VH is any one of the VHs described in Table 1. In some embodiments, the VL is any one of the VLs described in Table 1. In some embodiments, the amino acid linker has an amino acid sequence comprising any one of SEQ ID NOs: 97-139. In some embodiments, the amino acid linker is any sequence of SEQ ID NOs: 97-139. 1.2 Second group of anti-cMET antibodies Table 2. Anti-cMET monoclonal antibody list 2

[0172] The present disclosure provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody or antibody fragment (e.g., antigen-binding fragment) comprises a VH domain having an amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 82, SEQ ID NO: 145, SEQ ID NO: 59, or SEQ ID NO: 83 (Table 2). The present disclosure also provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody or antigen-binding fragment comprises a HCDR having an amino acid sequence of any one of the HCDRs listed in Table 2. In one aspect, the present disclosure provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody comprises one, two, three, or more HCDRs having an amino acid sequence of any one of the HCDRs listed in Table 2.

[0173] The present disclosure provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody or antibody fragment (e.g., antigen-binding fragment) comprises a VL domain having the amino acid sequence of SEQ ID NO: 64 (Table 2). The present disclosure also provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody or antigen-binding fragment comprises a LCDR having the amino acid sequence of any one of the LCDRs listed in Table 2. In one aspect, the present disclosure provides antibodies or antigen-binding fragments that specifically bind to human cMET, wherein the antibody comprises one, two, three or more LCDRs having the amino acid sequence of any one of the LCDRs listed in Table 2.

[0174] In one embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises one or more complementarity determining regions (CDRs) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62; SEQ ID NO: 63, SEQ ID NO: 66, SEQ ID NO: 67, and SEQ ID NO: 68.

[0175] In another embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises: (a) a heavy chain variable region comprising one or more complementarity determining regions (HCDRs) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 61, SEQ ID NO: 62; SEQ ID NO: 63, and / or (b) a light chain variable region comprising one or more complementarity determining regions (LCDRs) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 66, SEQ ID NO: 67, and SEQ ID NO: 68.

[0176] In another embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises: (a) a heavy chain variable region comprising three complementarity determining regions (HCDRs), which are HCDR1 comprising the amino acid sequence of SEQ ID NO: 56 or SEQ ID NO: 61; HCDR2 comprising the amino acid sequence of SEQ ID NO: 57 or SEQ ID NO: 62; and HCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or SEQ ID NO: 63; and / or (b) a light chain variable region comprising three complementarity determining regions (LCDRs), which are LCDR1 comprising the amino acid sequence of SEQ ID NO: 66; LCDR2 comprising the amino acid sequence of SEQ ID NO: 67; and LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0177] In another embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises: (a) a heavy chain variable region comprising three complementarity determining regions (HCDRs), which are: HCDR1 comprising the amino acid sequence of SEQ ID NO: 56, HCDR2 comprising the amino acid sequence of SEQ ID NO: 57, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 58; or a HCDR1 comprising the amino acid sequence of SEQ ID NO: 61, HCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 63, and / or (b) a light chain variable region comprising three complementarity determining regions (LCDRs), which are LCDR1 comprising the amino acid sequence of SEQ ID NO: 66, LCDR2 comprising the amino acid sequence of SEQ ID NO: 67, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 68.

[0178] In one embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises: (1) HCDR1 (heavy chain complementarity determining region 1), HCDR2, and HCDR3 from the heavy chain variable region (VH) shown in SEQ ID NO:54, SEQ ID NO:82, or SEQ ID NO:145; (2) HCDR1, HCDR2, and HCDR3 from the heavy chain variable region (VH) shown in SEQ ID NO:59 or SEQ ID NO:83; and / or (1) LCDR1 (light chain complementarity determining region 1), LCDR2, and LCDR3 from the light chain variable region (VL) shown in SEQ ID NO:64.

[0179] In one embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO:61, (b) HCDR2 of SEQ ID NO:62, (c) HCDR3 of SEQ ID NO:63, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO:66, (e) LCDR2 of SEQ ID NO:67, and (f) LCDR3 of SEQ ID NO:68; according to the Kabat definition.

[0180] In one embodiment, an antibody or antigen-binding fragment thereof of the present disclosure comprises: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 82, SEQ ID NO: 145, SEQ ID NO: 59, or SEQ ID NO: 83, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO: 54, SEQ ID NO: 82, SEQ ID NO: 145, SEQ ID NO: 59, or SEQ ID NO: 83, and / or (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 64, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 64.

[0181] In one embodiment, the antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:54 or SEQ ID NO:82, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:59 or SEQ ID NO:83, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; or (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 145, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64.

[0182] In one embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof, wherein one, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted (optionally conservative amino acid substitutions) within SEQ ID NO: 54, SEQ ID NO: 82, SEQ ID NO: 145, SEQ ID NO: 59, or SEQ ID NO: 83, or SEQ ID NO: 64, while retaining therapeutic activity / binding specificity / affinity, optionally without altering the corresponding sequence of the CDRs.

[0183] In one embodiment, the present disclosure provides an antibody or antigen-binding fragment thereof, wherein one, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted (optionally conservative amino acid substitutions) within SEQ ID NO: 54 and SEQ ID NO: 64, SEQ ID NO: 82 and SEQ ID NO: 64, SEQ ID NO: 145 and SEQ ID NO: 64, SEQ ID NO: 59 and SEQ ID NO: 64, or SEQ ID NO: 83 and SEQ ID NO: 64, while retaining therapeutic activity / binding specificity / affinity, optionally without altering the corresponding sequence of the CDRs.

[0184] In one embodiment, an antibody or antigen-binding fragment thereof comprising: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54 or SEQ ID NO: 82, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (3) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 145, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO: 64.

[0185] Other antibodies or antigen-binding fragments thereof of the present disclosure include amino acids that have been altered but have a percent identity of at least 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% in the CDR regions compared to the CDR regions disclosed in Table 2. In some aspects, they include amino acid alterations (insertions, deletions or substitutions, optionally conservative amino acid substitutions) wherein no more than 1, 2, 3, 4 or 5 amino acids are altered in the CDR regions when compared to the CDR regions depicted in the sequences described in Table 2 while maintaining binding specificity and affinity.

[0186] Other antibodies of the present disclosure include those in which amino acids or nucleic acids encoding amino acids have been altered in the variable region (e.g., the framework region of the variable region); but have at least 60%, 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%, 95%, 96%, 97%, 98% or 99% identity to the variable region sequences set forth in Table 2 while retaining binding specificity / affinity, optionally without altering the corresponding sequences of the CDRs. In some aspects, it includes changes in the amino acid sequence, wherein no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 amino acids are changed in the variable region (e.g., the framework region of the variable region) when compared to the variable region depicted in the sequence described in Table 2, while retaining binding specificity / affinity, optionally without changing the corresponding sequence of the CDR. These changes can be insertions, deletions or substitutions, optionally conservative amino acid substitutions.

[0187] In another embodiment, the present disclosure provides a 1×10 -6 M to 1×10 -11 The binding affinity (K D ) an antibody or antigen-binding fragment thereof that specifically binds to human cMET. In another embodiment, the anti-cMET antibody or antigen-binding fragment thereof is present at about 1×10 -6 M, about 1×10 -7 M, about 1×10 -8 M, about 1×10 -9 M, about 1×10 -10 M or about 1×10 -11 The binding affinity (K D ) binds to human cMET.

[0188] The present disclosure also provides nucleic acid sequences encoding VH or VL of antibodies that specifically bind to human cMET. Such nucleic acid sequences can be optimized for expression in mammalian cells.

[0189] The present disclosure also provides antibodies and antigen-binding fragments thereof that bind to the same epitope as the anti-cMET antibodies described in Table 2. Thus, additional antibodies and antigen-binding fragments thereof can be identified based on their ability to cross-compete with (e.g., competitively inhibit their binding in a statistically significant manner) the antibodies described in Table 2 in a binding assay. The ability of a test antibody to inhibit the binding of an antibody or antigen-binding fragment thereof of the present disclosure to human cMET demonstrates that the test antibody can compete with the antibody or antigen-binding fragment thereof for binding to human cMET. Without being bound by any one theory, such an antibody may bind to the same or related (e.g., structurally similar or spatially adjacent) epitope on human cMET as the antibody or antigen-binding fragment thereof that it competes with. In certain aspects, an antibody that binds to the same epitope on human cMET as an antibody or antigen-binding fragment thereof of the present disclosure is a human or humanized monoclonal antibody. Such a human or humanized monoclonal antibody can be prepared and isolated as described herein.

[0190] In some embodiments, the antibody or antigen-binding fragment thereof is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

[0191] In one embodiment, the antibody or antigen-binding fragment thereof is in the form of an scFv comprising a VH-VL in an N-terminal to C-terminal direction or a VL-VH in an N-terminal to C-terminal direction. In some embodiments, the VH and VL are linked via an amino acid linker as described herein. In some embodiments, the VH comprises the amino acid sequence of any one of SEQ ID NO: 54, SEQ ID NO: 82, SEQ ID NO: 145, SEQ ID NO: 59, or SEQ ID NO: 83. In some embodiments, the VL comprises the amino acid sequence of any one of SEQ ID NO: 64. In some embodiments, the VH is any one of the VHs described in Table 2. In some embodiments, the VL is any one of the VLs described in Table 2. In some embodiments, the amino acid linker has an amino acid sequence comprising any one of SEQ ID NOs: 97-139. In some embodiments, the amino acid linker is any sequence of SEQ ID NOs: 97-139. II. Anti-EGFR Antibodies

[0192] The present disclosure provides antibodies or antigen-binding fragments thereof that specifically bind to human EGFR. In one embodiment, the anti-EGFR antibody or antigen-binding fragment thereof is 1×10 -6 M to 1×10 -10The binding affinity (K D ) specifically binds to human EGFR. In another embodiment, the anti-EGFR antibody or antigen-binding fragment thereof is present at about 1×10 -6 M, about 1×10 -7 M, about 1×10 -8 M, about 1×10 -9 M or about 1×10 -10 The binding affinity (K D ) binds to human EGFR.

[0193] In one embodiment, the anti-EGFR antibody or antigen-binding fragment thereof comprises: a heavy chain variable region (VH) comprising (a) HCDR1 of SEQ ID NO: 155, (b) HCDR2 of SEQ ID NO: 156, (c) HCDR3 of SEQ ID NO: 157; and a light chain variable region (VL) comprising (d) LCDR1 of SEQ ID NO: 158, (e) LCDR2 of SEQ ID NO: 159, (f) LCDR3 of SEQ ID NO: 160, according to Kabat numbering.

[0194] In another embodiment, the anti-EGFR antibody or antigen-binding fragment thereof comprises: HCDR1, HCDR2 and HCDR3 from the heavy chain variable region (VH) shown in SEQ ID NO: 142; and LCDR1, LCDR2 and LCDR3 from the light chain variable region (VL) shown in SEQ ID NO: 143.

[0195] In another embodiment, the anti-EGFR antibody or antigen-binding fragment thereof further comprises no more than one, two, three, four or five amino acid deletions, insertions or substitutions in the CDR, preferably the amino acid substitutions are conservative amino acid substitutions while maintaining binding specificity and affinity.

[0196] In another embodiment, the anti-EGFR antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 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%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 142, and a light chain variable region (VL) comprising an amino acid sequence that is at least 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%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 142. In another embodiment, SEQ ID NO: 142 or SEQ ID NO: 143 has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 amino acids inserted, deleted or substituted (optionally conservative amino acid substitutions) therein. In another embodiment, such variation is in the framework region of the variable region.In another embodiment, the anti-EGFR antibody or antigen-binding fragment thereof having such variation retains binding specificity and affinity.

[0197] In another embodiment, the anti-EGFR antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising SEQ ID NO: 142 and a light chain variable region (VL) comprising SEQ ID NO: 143.

[0198] In one embodiment, the anti-EGFR antibody or antigen-binding fragment thereof is in the form of an scFv comprising a VH-VL in an N-terminal to C-terminal direction or a VL-VH in an N-terminal to C-terminal direction. In some embodiments, the VH and VL are linked via an amino acid linker as described herein. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 142. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 143. In some embodiments, the amino acid linker has an amino acid sequence comprising any one of SEQ ID NOs: 97-139. In some embodiments, the amino acid linker is any of SEQ ID NOs: 97-139. In one embodiment, the amino acid linker is SEQ ID NO: 139.

[0199] In one embodiment, the antibody or antigen-binding fragment thereof comprises a scFv having the amino acid sequence of SEQ ID NO: 161. In another embodiment, the antibody or antigen-binding fragment thereof comprises a scFv of SEQ ID NO: 161. III. Multispecific Antibodies 3.1 Anti-cMET Bispecific Antibodies

[0200] The present disclosure provides bispecific antibodies or antigen-binding fragments that specifically bind to human cMET, comprising a first antigen-binding domain that specifically binds to a first epitope of human cMET, and a second antigen-binding domain that specifically binds to a second epitope of human cMET, wherein the first antigen-binding domain is different from the second antigen-binding domain.

[0201] In one embodiment, the first epitope is different from the second epitope (eg, non-overlapping), or the first antigen binding domain does not compete with the second antigen binding domain.

[0202] In one aspect, the first antigen binding domain that specifically binds a first epitope of human cMET and the second antigen binding domain that specifically binds a second epitope of human cMET are selected from any anti-cMET antibodies described in Section I and are different from each other.

[0203] In one aspect, the first antigen binding domain that specifically binds a first epitope of human cMET and the second antigen binding domain that specifically binds a second epitope of human cMET are selected from any anti-cMET antibodies described in Section I and do not compete with each other.

[0204] In another aspect, the first antigen-binding domain that specifically binds to the first epitope of human cMET can be any antibody or antigen-binding fragment selected from those described in Section 1.1, “The First Group of Anti-cMET Antibodies” (including Table 1). The second antigen-binding domain that specifically binds to the second epitope of human cMET can be any antibody or antigen-binding fragment selected from those described in Section 1.2, “The Second Group of Anti-cMET Antibodies” (including Table 2).

[0205] In some embodiments, the bispecific antibody comprises an antigen-binding fragment, wherein the antigen-binding fragment can be Fab, F(ab')2, Fv, single-chain Fv (scFv), or a single-domain antibody.

[0206] In one embodiment, the bispecific antibodies of the present disclosure are expressed in 1×10 -6 M to 1×10 -10 M, or even 1×10 -11 The binding affinity (K D) binds to human cMET. In another embodiment, the bispecific antibodies of the present disclosure are present at about 1×10 -6 M, about 1×10 -7 M, about 1×10 -8 M, about 1×10 -9 M, about 1×10 -10 M or about 1×10 -11 The binding affinity (K D ) binds to human cMET.

[0207] In some embodiments, the bispecific antibodies of the present disclosure that specifically bind to two different epitopes of human cMET (e.g., non-overlapping or non-competing) exhibit better blocking activity on ligand-independent signaling and / or ligand-induced signaling compared to antibodies comprising only one antigen-binding domain that specifically binds to human cMET.

[0208] In one embodiment, the present disclosure provides a bispecific antibody or antigen-binding fragment thereof, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68.

[0209] In one embodiment, the present disclosure provides a bispecific antibody or antigen-binding fragment thereof, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (5) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68.

[0210] In one embodiment, the present disclosure provides a bispecific antibody or antigen-binding fragment thereof, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 82 or SEQ ID NO: 145, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64.

[0211] In one embodiment, the present disclosure provides a bispecific antibody or antigen-binding fragment thereof, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, or SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 82 or SEQ ID NO: 145, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64.

[0212] In some embodiments, in the above-mentioned bispecific antibody or antigen-binding fragment thereof, the second antigen-binding domain that specifically binds to the second epitope of human cMET can be changed.

[0213] In one embodiment, the second antigen binding domain that specifically binds to a second epitope of human cMET comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO:61, (b) HCDR2 of SEQ ID NO:62, (c) HCDR3 of SEQ ID NO:63, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO:66, (e) LCDR2 of SEQ ID NO:67, and (f) LCDR3 of SEQ ID NO:68.

[0214] In one embodiment, the second antigen binding domain that specifically binds to a second epitope of human cMET comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64.

[0215] In another embodiment, the bispecific antibody further comprises an amino acid linker as described herein. In some embodiments, the amino acid linker has an amino acid sequence comprising any one of SEQ ID NOs: 97-139. In some embodiments, the amino acid linker is any sequence of SEQ ID NOs: 97-139. 3.2 Anti-cMET x antigen multispecific antibodies

[0216] In one embodiment, the anti-cMET antibodies disclosed herein (including Section 1 "Anti-cMET Antibodies" and Section 3.1 "Anti-cMET Bispecific Antibodies") can be used to construct multispecific antibodies with other modalities, such as human tumor-associated antigens (TAAs), immune checkpoints, or immune stimulants.

[0217] In one embodiment, the anti-cMET antibodies disclosed herein can be incorporated into anti-cMET x TAA multispecific antibodies, wherein the anti-TAA is an antibody or fragment thereof directed against any human tumor-associated antigen (TAA) other than cMET. The antibody molecule is a multispecific antibody molecule, for example, comprising at least two antigen-binding domains, wherein at least one antigen-binding domain sequence specifically binds to cMET as a first epitope, and the second antigen-binding domain sequence specifically binds to a TAA as a second epitope.

[0218] In another embodiment, the two antigen binding domain sequences specifically bind to two different epitopes (e.g., non-overlapping or non-competing) of human cMET as the first and second epitopes, respectively, and the third antigen binding domain sequence specifically binds to TAA as the third epitope. In one embodiment, the multispecific antibody comprises a third, fourth, or fifth antigen binding domain. In one embodiment, the multispecific antibody is a bispecific antibody, a trispecific antibody, or a tetraspecific antibody.

[0219] In one embodiment, the multispecific antibody is a bispecific antibody. As used herein, a bispecific antibody specifically binds only to two antigens. The bispecific antibody comprises a first antigen-binding domain that specifically binds to human cMET and a second antigen-binding domain that specifically binds to TAA. This includes a bispecific antibody that comprises a second heavy chain variable domain and a second light chain variable domain that specifically bind to TAA and a first heavy chain variable domain and a first light chain variable domain that specifically bind to human cMET. In some embodiments, the bispecific antibody comprises an antigen-binding fragment, wherein the antigen-binding fragment can be Fab, F(ab')2, Fv, single-chain Fv (scFv) or a single-domain antibody.

[0220] In one embodiment, the multispecific antibody is a trispecific antibody. As used herein, a trispecific antibody specifically binds to at least three antigens or epitopes. The trispecific antibody comprises a first antigen-binding domain that specifically binds to a first epitope of human cMET, a second antigen-binding domain that specifically binds to a second epitope of human cMET, and a third antigen-binding domain that specifically binds to TAA. This includes a trispecific antibody comprising a third heavy chain variable domain and a third light chain variable domain that specifically bind to TAA, a first heavy chain variable domain and a first light chain variable domain that specifically bind to a first epitope of human cMET, and a second heavy chain variable domain and a second light chain variable domain that specifically bind to a second epitope of human cMET. In some embodiments, the trispecific antibody comprises an antigen-binding fragment, wherein the antigen-binding fragment can be a Fab, F(ab')2, Fv, a single-chain Fv (scFv), or a single-domain antibody.

[0221] In one embodiment, the multispecific antibodies of the present disclosure are expressed in 1×10 -6 M to 1×10 -10 M, or even 1×10 -11 The binding affinity (K D ) binds to human TAA and / or human cMET. In another embodiment, the multispecific antibodies of the present disclosure are present at about 1×10 -6 M, about 1×10 -7 M, about 1×10 -8 M, about 1×10-9 M, about 1×10 -10 M or about 1×10 -11 The binding affinity (K D ) binds to at least one epitope on human TAA and human cMET.

[0222] Previous experiments (Coloma and Morrison Nature Biotech. 15: 159-163 (1997), incorporated by reference in its entirety) described tetravalent bispecific antibodies engineered by fusing DNA encoding a single-chain anti-dansyl antibody Fv (scFv) to the C-terminus (CH3-scFv) or to the hinge (hinge-scFv) of an IgG3 anti-dansyl antibody. The present disclosure provides multivalent antibodies (e.g., tetravalent antibodies) having at least two antigen-binding domains that can be readily produced by recombinant expression of nucleic acids encoding antibody polypeptide chains. The multivalent antibodies herein comprise three to eight, but preferably three or four, antigen-binding domains that specifically bind to at least two antigens.

[0223] In one embodiment, the multispecific antibody is a bispecific antibody, a trispecific antibody, or a tetraspecific antibody. In another embodiment, the multispecific antibody further comprises an amino acid linker as described herein. In some embodiments, the amino acid linker has an amino acid sequence comprising any one of SEQ ID NOs: 97-139. In some embodiments, the amino acid linker is any sequence of SEQ ID NOs: 97-139. 3.3EGFR x cMET multispecific antibody

[0224] In one aspect, the present disclosure provides a multispecific antibody or antigen-binding fragment thereof, comprising a first antigen-binding domain that specifically binds to a first epitope of human cMET; a second antigen-binding domain that specifically binds to a second epitope of human cMET; and a third antigen-binding domain that specifically binds to human EGFR.

[0225] In one embodiment, the first epitope is different from the second epitope, or wherein the first antigen binding domain does not compete with the second antigen binding domain.

[0226] In one aspect, the EGFR x cMET multispecific antibody further comprises a third antigen-binding domain that specifically binds to human EGFR on top of the anti-cMET bispecific antibody described in Section 3.1.

[0227] In one aspect, in the anti-cMET x antigen multispecific antibody described in Section 3.2, the other antigen (TAA) is human EGFR.

[0228] In one embodiment, the first antigen binding domain that specifically binds to the first epitope of human cMET is selected from any anti-cMET antibody described in Section 1.1.

[0229] In one embodiment, the second antigen binding domain that specifically binds a second epitope of human cMET is selected from any of the anti-cMET antibodies described in Section 1.2.

[0230] In one embodiment, the third antigen binding domain that specifically binds to human EGFR is selected from any of the anti-EGFR antibodies described in Section II.

[0231] In one embodiment, in the EGFR x cMET multispecific antibody or antigen-binding fragment thereof, the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region comprising: (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68. NO:67 LCDR2, and (f) LCDR3 of SEQ ID NO:68; and a third antigen binding domain that specifically binds to human EGFR comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO:155, (b) HCDR2 of SEQ ID NO:156, (c) HCDR3 of SEQ ID NO:157, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO:158, (e) LCDR2 of SEQ ID NO:159, and (f) LCDR3 of SEQ ID NO:160.

[0232] In one embodiment, in the EGFR x cMET multispecific antibody or antigen-binding fragment thereof, the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 145, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and the third antigen-binding domain that specifically binds to human EGFR comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 142, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 143.

[0233] In one embodiment, the first antigen binding domain that specifically binds to a first epitope of human cMET is a monoclonal antibody, a human engineered antibody, a single chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment; the second antigen binding domain that specifically binds to a second epitope of human cMET is a monoclonal antibody, a human engineered antibody, a single chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment; and the third antigen binding domain that specifically binds to human EGFR is a monoclonal antibody, a human engineered antibody, a single chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

[0234] In one embodiment, the EGFR x cMET multispecific antibody or antigen-binding fragment thereof comprises a heavy chain constant region of the IgG1, IgG2, IgG3, or IgG4 subclass and / or a light chain constant region of the kappa or lambda type.

[0235] In one embodiment, the EGFR x cMET multispecific antibody or antigen-binding fragment thereof comprises a heavy chain constant region of the IgG1 subclass and a light chain constant region of the kappa type.

[0236] In one embodiment, the EGFR x cMET multispecific antibody or antigen-binding fragment thereof has antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC).

[0237] In one embodiment, the EGFR x cMET multispecific antibody or antigen-binding fragment thereof has reduced glycosylation, is aglycosylated, or is hypofucosylated. In another embodiment, the multispecific antibody or antigen-binding fragment thereof is afucosylated.

[0238] In one embodiment, the EGFR x cMET multispecific antibody or antigen-binding fragment thereof comprises an added bisecting GlcNac structure.

[0239] In one embodiment, the EGFR x cMET multispecific antibody or antigen-binding fragment thereof comprises an Fc domain, and wherein the Fc domain is an IgG1 Fc with extended half-life.

[0240] In one embodiment, the EGFR x cMET multispecific antibody or antigen-binding fragment thereof uses a knob-in-hole (KIH) structure to form heterodimers.

[0241] In one embodiment, the first antigen binding domain that specifically binds to a first epitope of human cMET comprises a first heavy chain constant region comprising SEQ ID NO: 95, and the second antigen binding domain that specifically binds to a second epitope of human cMET comprises a second heavy chain constant region comprising SEQ ID NO: 96.

[0242] In another embodiment, the first antigen binding domain that specifically binds to a first epitope of human cMET comprises a first heavy chain constant region comprising SEQ ID NO:96, and the second antigen binding domain that specifically binds to a second epitope of human cMET comprises a second heavy chain constant region comprising SEQ ID NO:95.

[0243] In another embodiment, the first antigen binding domain that specifically binds a first epitope of human cMET and the second antigen binding domain that specifically binds a second epitope of human cMET share a common light chain.

[0244] In one embodiment, the first light chain constant region and the second light chain constant region are different. In another embodiment, the first light chain constant region and the second light chain constant region are identical.

[0245] In one embodiment, the light chain constant region has the amino acid sequence of SEQ ID NO: 71. In one embodiment, the light chain constant region is SEQ ID NO: 71.

[0246] In one embodiment, the first light chain variable region and the second light chain variable region are different. In another embodiment, the first light chain variable region and the second light chain variable region are identical.

[0247] In one embodiment, the EGFR x cMET multispecific antibody or antigen-binding fragment thereof further comprises an amino acid linker described herein.

[0248] In one embodiment, the EGFR x cMET multispecific antibody or antigen-binding fragment thereof can be in different formats, with different EGFR scFv valencies and cMET arm orientations. The formats can be Figure 7 Any of the forms shown in , represented by TE-644, TE-645, TE-646, TE-647, TE-648 or TE-642.

[0249] In one embodiment, the EGFR x cMET multispecific antibody or antigen-binding fragment thereof comprises a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein (1) a VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to the second epitope of human cMET, and a second heavy chain constant region are arranged in an N-terminal to C-terminal direction in the first polypeptide; (2) a VH that specifically binds to the first epitope of human cMET and a first heavy chain constant region are arranged in an N-terminal to C-terminal direction in the second polypeptide; or a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to the second epitope of human cMET and a first heavy chain constant region are arranged in an N-terminal to C-terminal direction in the second polypeptide; The VL of the third antigen-binding domain of FR, optionally a first amino acid linker, the VH of the third antigen-binding domain that specifically binds to human EGFR, optionally a second amino acid linker, the VH of the first antigen-binding domain that specifically binds to the first epitope of human cMET, and the first heavy chain constant region are arranged in the N-terminal to C-terminal direction in the second polypeptide; (3) the VL of the second antigen-binding domain that specifically binds to the second epitope of human cMET and the second light chain constant region are arranged in the N-terminal to C-terminal direction in the third polypeptide; and (4) the VL of the first antigen-binding domain that specifically binds to the first epitope of human cMET, and the first light chain constant region are arranged in the N-terminal to C-terminal direction in the fourth polypeptide.

[0250] In one embodiment, the EGFR x cMET multispecific antibody or antigen-binding fragment thereof comprises a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein (1) a VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to a second epitope of human cMET, and a second heavy chain constant region are arranged in an N-terminal to C-terminal direction in the first polypeptide; (2) the VH of the first antigen-binding domain that specifically binds to the first epitope of human cMET and the first heavy chain constant region are arranged in an N-terminal to C-terminal direction in the second polypeptide; (3) the VL of the second antigen-binding domain that specifically binds to the second epitope of human cMET and the second light chain constant region are arranged in an N-terminal to C-terminal direction in the third polypeptide; and (4) the VL of the first antigen-binding domain that specifically binds to the first epitope of human cMET and the first light chain constant region are arranged in an N-terminal to C-terminal direction in the fourth polypeptide.

[0251] In one embodiment, the second heavy chain constant region is SEQ ID NO:95 and the first heavy chain constant region is SEQ ID NO:96; or the second heavy chain constant region is SEQ ID NO:96 and the first heavy chain constant region is SEQ ID NO:95.

[0252] In one embodiment, the first amino acid linker is SEQ ID NO: 139. In another embodiment, the second amino acid linker is SEQ ID NO: 139.

[0253] In one embodiment, the VL of the first antigen binding domain and the VL of the second antigen binding domain are identical.

[0254] In another embodiment, the first light chain constant region and the second light chain constant region are identical.In another embodiment, the first light chain constant region and the second light chain constant region are SEQ ID NO:71.

[0255] In one embodiment, the third polypeptide and the fourth polypeptide are identical.

[0256] In another embodiment, the positions of the first antigen-binding domain that specifically binds to a first epitope of human cMET (eg, BGA-109) and the second antigen-binding domain that specifically binds to a second epitope of human cMET (eg, BGA-032) can be swapped.

[0257] In one embodiment, the multispecific antibody or antigen-binding fragment thereof comprises a first polypeptide, a second polypeptide, and a third polypeptide, wherein (1) the first polypeptide has an amino acid sequence of SEQ ID NO: 153, the second polypeptide has an amino acid sequence of SEQ ID NO: 150, and the third polypeptide has an amino acid sequence of SEQ ID NO: 148; (2) the first polypeptide has the amino acid sequence of SEQ ID NO: 146, the second polypeptide has the amino acid sequence of SEQ ID NO: 147, and the third polypeptide has the amino acid sequence of SEQ ID NO: 148; (3) the first polypeptide has the amino acid sequence of SEQ ID NO: 149, the second polypeptide has the amino acid sequence of SEQ ID NO: 150, and the third polypeptide has the amino acid sequence of SEQ ID NO: 151; (4) the first polypeptide has the amino acid sequence of SEQ ID NO: 149, the second polypeptide has the amino acid sequence of SEQ ID NO: 150, and the third polypeptide has the amino acid sequence of SEQ ID NO: 152; (5) the first polypeptide has the amino acid sequence of SEQ ID NO: 153, the second polypeptide has the amino acid sequence of SEQ ID NO: 154, and the third polypeptide has the amino acid sequence of SEQ ID NO: 148; or (6) The first polypeptide has an amino acid sequence of SEQ ID NO: 146, the second polypeptide has an amino acid sequence of SEQ ID NO: 150, and the third polypeptide has an amino acid sequence of SEQ ID NO: 148.

[0258] In another embodiment, the multispecific antibody or antigen-binding fragment thereof comprises (1) the first polypeptide of SEQ ID NO: 153, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO: 148; (2) the first polypeptide of SEQ ID NO: 146, the second polypeptide of SEQ ID NO: 147, and the third polypeptide of SEQ ID NO: 148; (3) the first polypeptide of SEQ ID NO: 149, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO: 151; (4) the first polypeptide of SEQ ID NO: 149, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO: 152; (5) the first polypeptide of SEQ ID NO: 153, the second polypeptide of SEQ ID NO: 154, and the third polypeptide of SEQ ID NO: 148; or (6) The first polypeptide of SEQ ID NO: 146, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO: 148. IV. Anti-human cMET Antibodies Conjugated to Cytotoxins

[0259] The anti-human cMET antibodies disclosed herein (including Section I "Anti-cMET Antibodies" and Section III "Multispecific Antibodies, e.g., Section 3.1 Anti-cMET Bispecific Antibodies, Section 3.2 Anti-cMET x Antigen Multispecific Antibodies, or Section 3.3 EGFR xcMET Multispecific Antibodies) can be used to construct antibody drug conjugates (ADCs). In one embodiment, the antibody or antigen-binding fragment thereof is conjugated to a cytotoxin. In another embodiment, the antibody or antigen-binding fragment thereof is conjugated to a cytotoxin via a cytotoxic linker. Cytotoxins

[0260] Cytotoxins or cytotoxic agents include any agents that are detrimental to cell growth, viability, or reproduction, including but not limited to tubulin-interacting agents and DNA-damaging agents. Examples of suitable cytotoxic and chemotherapeutic agents that can be conjugated to the antibodies of the present disclosure include, for example, 1-(2-chloroethyl)-1,2-dimethanesulfonylhydrazide, 1,8-dihydroxy-bicyclo[7.3.1]tridec-4,9-diene-2,6-diyn-13-one, 1-dehydrotestosterone, 5-fluorouracil, 6-mercaptopurine, 6-thioguanine, 9-aminocamptothecin, actinomycin D, amanitins, aminopterin, anguidine, anthracycline, anthramycin (AMC), auristatins, bleomycin, busulfan, butyric acid, calicheamicins calicheamicins (e.g., calicheamicin gamma 1), camptothecin, carmine, carmustine, cemadotin, cisplatin, colchicine, combretastatins, cyclophosphamide, cytarabine, cytochalasin B, dactinomycin, daunorubicin, decarbazine, diacetoxypentyldoxorubicin, dibromomannitol, dihydroxyanthracin dione, disorazoles, dolastatins (e.g., dolastatin 10), doxorubicin, duocarmycin, echinocycin, eleutherobins, emetine, epothilones, esperamicin, estramustine, ethidium bromidebromide), etoposide, fluorouracil, geldanamycins, gramicidin D, glucocorticoids, irinotecans, kinesin spindle protein (KSP) inhibitors, leptomycins, leurosines, lidocaine, lomustine (CCNU), maytansinoids, nitrogen mustards, melphalan, mercaptopurines, methotrexate

[00145] The present invention also includes but is not limited to the following: hopterins, methotrexate, mithramycin, mitomycin, mitoxantrone, N8-acetylspermidine, podophyllotoxins, procaine, propranolol, pteridines, puromycin, pyrrolobenzodiazepines (PBD), rhizoxins, streptozotocin, tallysomycins, paclitaxel, tenoposide, tetracaine, thioepa chlorambucil, tomaymycins, topotecans, tubulysin, vinblastine, vincristine, vindesine, vinorelbine, and derivatives of any of the foregoing. Cytotoxic linkers

[0261] Cytotoxic linkers or linkers for use in ADCs are any group or moiety that links, connects, or bonds an antibody or antigen-binding protein described herein to a therapeutic moiety (e.g., a cytotoxic agent). Suitable linkers can be found, for example, in Antibody-Drug Conjugates and Immunotoxins; Phillips, GL, ed.; Springer-Verlag: New York, 2013; Antibody-Drug Conjugates; Ducry, L, ed.; Humana Press, 2013; Antibody-Drug Conjugates; Wang, J., Shen, W.-C, and Zaro, JL, eds.; Springer International Publishing, 2015, the contents of each of which are incorporated herein by reference in their entirety.

[0262] Typically, suitable binding agents or cytotoxic linkers for antibody conjugates described herein are sufficiently stable to utilize the circulating half-life of the antibody while being able to release its payload after antigen-mediated conjugate internalization. The linker can be cleavable or non-cleavable. Cleavable linkers include linkers that are cleaved by intracellular metabolism after internalization, for example, by hydrolysis, reduction, or enzymatic reaction cleavage. Non-cleavable linkers include linkers that release the payload of the connection by lysosomal degradation of the antibody after internalization. Suitable linkers include, but are not limited to, acid-labile linkers, hydrolytically unstable linkers, enzymatically cleavable linkers, reduction-unstable linkers, self-immolative linkers, and non-cleavable linkers. Suitable linkers also include, but are not limited to, those that are or comprise peptides, glucuronides, succinimide-thioethers, polyethylene glycol (PEG) units, hydrazones, maleic-hexanoyl units, dipeptide units, valine-citrulline units, and para-aminobenzyl (PAB) units.

[0263] Any cytotoxic linker molecule or linker technology known in the art can be used to create or construct the ADC of the present disclosure. In certain embodiments, the cytotoxic linker is a cleavable linker. According to other embodiments, the linker is a non-cleavable linker. Exemplary linkers that can be used in the context of the present disclosure include, but are not limited to, linkers comprising or consisting of, for example, GGFG, MC (6-maleimidocaproyl), MP (maleimidopropionyl), val-cit (valine-citrulline), val-ala (valine-alanine), a dipeptide site in a protease-cleavable linker, ala-phe (alanine-phenylalanine), a dipeptide site in a protease-cleavable linker, PAB (p-aminobenzyloxycarbonyl), SPP (N-succinimidyl 4-(2-pyridylthio) pentanoate), SMCC (N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1 carboxylate), SIAB (N-succinimidyl (4-iodo-acetyl) aminobenzoate) and variants and combinations thereof. Additional examples of linkers useful in the context of the present disclosure are provided in, for example, US 7,754,681 and Ducry, Bioconjugate Chem., 2010, 27:5-13, and references cited therein, the contents of which are incorporated herein by reference in their entireties.

[0264] In certain embodiments, the cytotoxic linker is stable under physiological conditions. In certain embodiments, the linker is cleavable, for example, capable of releasing at least a portion of the payload in the presence of an enzyme or at a specific pH range or value. In some embodiments, the linker comprises an enzyme-cleavable moiety. Illustrative enzyme-cleavable moieties include, but are not limited to, peptide bonds, ester bonds, hydrazone bonds, and disulfide bonds. In some embodiments, the linker comprises a cathepsin-cleavable linker.

[0265] In some embodiments, the cytotoxic linker comprises a non-cleavable portion.

[0266] Suitable cytotoxic linkers also include, but are not limited to, those that chemically bond to two cysteine ​​residues of a single binding agent (e.g., an antibody). Such linkers can be used to mimic the disulfide bonds of antibodies, which are disrupted by the conjugation process.

[0267] In some embodiments, the cytotoxin linker comprises one or more amino acids. Suitable amino acids include natural, non-natural, standard, non-standard, protein, non-protein and L-amino acids or D-amino acids. In some embodiments, the cytotoxin linker comprises alanine, valine, glycine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine or citrulline, its derivatives or combinations thereof. In certain embodiments, one or more side chains of amino acids are connected to the side chain group, as described below. In some embodiments, the linker comprises valine and citrulline. In some embodiments, the cytotoxin linker comprises lysine, valine and citrulline. In some embodiments, the linker comprises lysine, valine and alanine. In some embodiments, the linker comprises valine and alanine. V. Fusion Protein Targeting Human cMET

[0268] Anti-human cMET antibodies can be used to fuse with other proteins or other functional domains to form fusion proteins or chimeric proteins. VI. Other modifications Constant region and Fc region

[0269] The heavy chain constant region can be a wild-type sequence of a heavy chain constant region from the IgG1, IgG2, IgG3, or IgG4 subclass. The light chain constant region can be a wild-type sequence of a light chain from the κ or λ class. In one embodiment, the heavy chain constant region is a wild-type sequence of a constant region from IgG1. The light chain constant region is a wild-type sequence of a light chain from a κ chain. In one embodiment, the heavy chain constant region has the amino acid sequence of SEQ ID NO: 70 and the light chain constant region has the amino acid sequence of SEQ ID NO: 71. In one embodiment, the Fc region can be a wild-type Fc region of the IgG1, IgG2, IgG3, or IgG4 subclass.

[0270] In one embodiment, the antibody or antigen-binding fragment thereof comprises an Fc domain of IgG1 or IgG4 with reduced effector function. In another embodiment, the heavy chain constant region comprises the mutations E233P, L234A, L235A, G236del and P329A.

[0271] In one embodiment, the antibody or its antigen-binding fragment comprises an Fc domain with an extended half-life. In another embodiment, the antibody or its antigen-binding fragment comprises an Fc domain of IgG1, wherein a YTE mutation (M252Y / S254T / T256E, EU numbering, as described in US 7658921, incorporated by reference in its entirety) is introduced into the CH2 of the IgG Fc region.

[0272] In another embodiment, the antibodies of the present disclosure have potent Fc-mediated effector function, and the antibodies mediate antibody-dependent cellular cytotoxicity (ADCC) against target cells.

[0273] In other aspects, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to change the effector function of the antibody. For example, one or more amino acids can be replaced with different amino acid residues so that the antibody has a changed affinity for the effector ligand, but retains the antigen binding ability of the parent antibody. The effector ligand with altered affinity can be, for example, an Fc receptor or the C1 component of complement. This method is described, for example, in U.S. Patent Nos. 5,624,821 and 5,648,260 to Winter et al., each of which is incorporated by reference in its entirety.

[0274] In another aspect, one or more amino acid residues can be replaced with one or more different amino acid residues such that the antibody has altered C1q binding and / or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described, for example, in U.S. Patent No. 6,194,551 to Idusogie et al., which is incorporated by reference in its entirety.

[0275] On the other hand, one or more amino acid residues are changed so as to change the ability of the antibody to fix complement. This method is described in, for example, the disclosure WO 94 / 29351 of Bodmer et al. In a specific aspect, one or more amino acids of an antibody of the present disclosure or its antigen-binding fragment are replaced by one or more allotypic amino acid residues of IgG1 subclass and κ isotype. Allotypic amino acid residues also include but are not limited to the heavy chain constant region of IgG1, IgG2 and IgG3 subclasses and the light chain constant region of κ isotype, as described in Jefferis et al., MAbs [monoclonal antibodies] 1: 332-338 (2009), which are incorporated by reference in their entirety.

[0276] In another aspect, the Fc region is modified by modifying one or more amino acids to increase the ability of the antibody to mediate antibody-dependent cellular cytotoxicity (ADCC) and / or to increase the affinity of the antibody for Fcγ receptors. This approach is described, for example, in publication WO 00 / 42072 by Presta. In addition, the binding sites for FcγRI, FcγRII, FcγRIII, and FcRn on human IgG1 have been mapped, and variants with improved binding have been described (see Shields et al., J. Biol. Chem. 276: 6591-6604, 2001), which is incorporated by reference in its entirety.

[0277] On the other hand, the glycosylation of the antibody is modified. For example, aglycosylated antibodies (i.e., antibodies lacking or having reduced glycosylation) can be prepared. For example, glycosylation can be changed to increase the affinity of the antibody to the antigen. This carbohydrate modification can be achieved by, for example, changing one or more glycosylation sites within the antibody sequence. For example, one or more amino acid substitutions can be made that result in the elimination of one or more variable region framework glycosylation sites, thereby eliminating the glycosylation at the site. This aglycosylation can increase the affinity of the antibody to the antigen. This method is described in, for example, U.S. Patent Nos. 5,714,350 and 6,350,861 to Co et al., which are incorporated by reference in their entirety.

[0278] Additionally or alternatively, antibodies with altered glycosylation patterns can be prepared, such as hypofucosylated antibodies with reduced amounts of fucosyl residues or antibodies with increased bisecting GlcNac structures. Such altered glycosylation patterns have been shown to increase the ADCC ability of antibodies. Such carbohydrate modifications can be achieved, for example, by expressing the antibody in a host cell with an altered glycosylation pathway. Cells with altered glycosylation pathways have been described in the art and can be used as host cells in which recombinant antibodies are expressed to produce antibodies with altered glycosylation. For example, EP 1,176,195 to Hang et al., incorporated by reference in its entirety, describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyltransferase, such that antibodies expressed in such a cell line exhibit hypofucosylation. Publication WO 03 / 035835 by Presta, incorporated by reference in its entirety, describes a variant CHO cell line, Lec13 cells, which have a reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in this host cell (see also Shields et al., (2002) J. Biol. Chem. 277:26733-26740), incorporated by reference in its entirety. WO 99 / 54342 to Umana et al., incorporated by reference in its entirety, describes a cell line engineered to express a glycoprotein-modifying glycosyltransferase (e.g., β(1,4)-N-acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell line exhibit increased bisecting GlcNac structures, which results in increased ADCC activity of the antibody (see also Umana et al., Nat. Biotech. 17:176-180, 1999, incorporated by reference in its entirety).

[0279] WO 2003085107 A1 by Naoko Ohnuki et al. describes an engineered CHO cell line in which the activity of α1,6-fucosyltransferase is reduced or abolished, thereby producing antibodies or antigen-binding fragments thereof that are afucosylated.

[0280] On the other hand, if reduction of ADCC is desired, many previous reports have shown that human antibody subclass IgG4 has only moderate ADCC and almost no CDC effector function (Moore GL et al. 2010 MAbs [monoclonal antibodies], 2: 181-189, incorporated by reference in its entirety). However, native IgG4 has been found to be less stable under stress conditions (such as in acidic buffer or at elevated temperatures) (Angal, S. 1993 Mol Immunol [molecular immunology], 30: 105-108; Dall'Acqua, W. et al. 1998 Biochemistry [biochemistry], 37: 9266-9273; Aalberse et al. 2002 Immunol [molecular immunology], 105: 9-19, each incorporated by reference in its entirety). Reduced ADCC can be achieved by operably linking the antibody to an IgG4 Fc engineered with a combination of alterations that reduce FcγR binding or C1q binding activity, thereby reducing or eliminating ADCC and CDC effector function. Considering the physicochemical properties of antibodies as biopharmaceuticals, one of the less desirable inherent properties of IgG4 is that its two heavy chains dynamically separate in solution to form half antibodies, which leads to the generation of bispecific antibodies in vivo through a process called "Fab arm exchange" (Van der Neut Kolfschoten M et al., 2007 Science, 317: 1554-157, incorporated by reference in its entirety). Mutation of serine at position 228 (EU numbering system) to proline inhibits the separation of IgG4 heavy chains (Angal, S. 1993 Mol Immunol, 30: 105-108; Aalberse et al., 2002 Immunol, 105: 9-19, each incorporated by reference in its entirety). It has been reported that some amino acid residues in the hinge region and the gamma Fc region have an influence on the interaction of antibodies with Fc gamma receptors (Chappel SM et al., 1991 Proc. Natl. Acad. Sci. USA, 88:9036-9040; Mukherjee, J. et al., 1995 FASEB J, 9:115-119; Armour, KL et al., 1999 Eur J Immunol, 29:2613-2624; Clynes, RA et al., 2000 Nature Medicine, 6:443-446; Arnold JN, 2007 Annu Rev immunol, 25:21-50, each of which is incorporated by reference in its entirety).In addition, some rare IgG4 isotypes in the human population may also give rise to different physicochemical properties (Brusco, A. et al., 1998 Eur J Immunogenet [European Journal of Immunogenetics], 25: 349-55; Aalberse et al., 2002 Immunol [Molecular Immunology], 105: 9-19, each of which is incorporated by reference in its entirety). In order to generate multispecific antibodies with low ADCC and CDC but good stability, the hinge and Fc regions of human IgG4 can be modified and many changes can be introduced. These modified IgG4 Fc molecules can be found in SEQ ID NOs: 83-88 of U.S. Patent No. 8,735,553 to Li et al., each of which is incorporated by reference in its entirety.

[0281] In another embodiment, an antibody of the disclosure comprises an Fc domain of human IgG4 having an S228P and / or R409K substitution (according to the EU numbering system).

[0282] "Knob-in-hole" mutations can be incorporated into the Fc:Fc binding interface. In some embodiments, the knob-in-hole ensures that the two different heavy chains are properly paired together during the manufacture of the multispecific antibody. In one embodiment, the first heavy chain constant region or first Fc of the multispecific antibody herein comprises SEQ ID NO: 95, and the second heavy chain constant region or second Fc of the multispecific antibody herein comprises SEQ ID NO: 96. In another embodiment, the first heavy chain constant region or first Fc of the multispecific antibody herein comprises SEQ ID NO: 96, and the second heavy chain constant region or second Fc of the multispecific antibody herein comprises SEQ ID NO: 95.

[0283] In another embodiment, the first heavy chain constant region or the first Fc of the multispecific antibody herein comprises a variant of the human IgG1 constant region comprising T366W, and the second heavy chain constant region or the second Fc of the multispecific antibody herein comprises a variant of the human IgG1 constant region comprising T366S, L368A and Y407V (EU numbering).

[0284] In another embodiment, the first heavy chain constant region or the first Fc of the multispecific antibody herein comprises a variant of the human IgG1 constant region comprising T366S, L368A and Y407V, and the second heavy chain constant region or the second Fc of the multispecific antibody herein comprises a variant of the human IgG1 constant region comprising T366W (EU numbering). Amino acid linker

[0285] It should also be understood that the domains and / or regions of the polypeptide chains of antibodies or proteins can be separated by linker regions of various lengths. In some embodiments, the antigen binding domains are separated from each other by linker regions, CL, CH1, hinge, CH2, CH3 or the entire Fc region. For example, VL1-CL-(linker) VH2-CH1. Such linker regions can comprise randomly sorted amino acids, or a group of restricted amino acids. Such linker regions can be flexible or rigid (see, for example, US2009 / 0155275, incorporated by reference in its entirety).

[0286] Multispecific antibodies have been constructed by genetically fusing two single-chain Fv (scFv) or Fab fragments with or without a flexible linker (Mallender et al., J. Biol. Chem. 1994 269:199-206; Mack et al., Proc. Natl. Acad. Sci. USA. 1995 92:7021-5; Zapata et al., Protein Eng. 1995 8:1057-62), through dimerization devices such as leucine zippers (Kostelny et al., J Immunol. 1992 148:1547-53; de Kruife et al., J Biol Chem. 1996 271:7630-4) and Ig C / CH1 domains (Muller et al., FEBS [FEBS Letters] 422:259-64); by diabodies (Holliger et al., (1993) Proc. Nat. Acad. Sci. USA. 1998 90:6444-8; Zhu et al., Bio / Technology (NY) 1996 14:192-6); Fab-scFv fusions (Schoonjans et al., J. Immunol. 2000 165:7050-7); and miniantibody formats (Pack et al., Biochemistry 1992. 31:1579-84; Pack et al., Bio / Technology 1993 11:1271-7). Each of the references mentioned in this paragraph is incorporated by reference in its entirety.

[0287] The antibodies or proteins disclosed herein comprise an amino acid linker region of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or more amino acid residues between one or more antigen binding domains, CL domains, CH1 domains, hinge regions, CH2 domains, CH3 domains or Fc regions. In some embodiments, the amino acids glycine and serine are contained within the linker region. In another embodiment, the linker can be GS (SEQ ID NO:97), GGS (SEQ ID NO:98), GSG (SEQ ID NO:99), SGG (SEQ ID NO:100), GGG (SEQ ID NO:101), GGGS (SEQ ID NO:102), SGGG (SEQ ID NO:103), GGGGS (SEQ ID NO:104), GGGGSGS (SEQ ID NO:105), GGGGSGS (SEQ ID NO:106), GGGGSGGS (SEQ ID NO:107), GGGGSGGGGS (SEQ ID NO:108), GGGGSGGGGSGGGGS (SEQ ID NO:109), AKTTPKLEEGEFSEAR (SEQ ID NO:110), AKTTPKLEEGEFSEARV (SEQ ID NO:111), AKTTPKLGG (SEQ ID NO:112), SAKTTPKLGG (SEQ ID NO:113), or SAKTTPKLGG (SEQ ID NO:114). NO:113), AKTTPKLEEGEFSEARV (SEQ ID NO:114), SAKTTP (SEQ ID NO:115), SAKTTPKLGG (SEQ ID NO:116), RADAAP (SEQ ID NO:117), RADAAPTVS (SEQ ID NO:118), RADAAAAGGPGS (SEQ ID NO:119), RADAAAA (G4S)4 (SEQ ID NO:120), SAKTTP (SEQ ID NO:121), SAKTTPKLGG (SEQ ID NO:122), SAKTTPKLEEGEFSEARV (SEQ ID NO:123), ADAAP (SEQ ID NO:124), ADAAPTVSIFPP (SEQ ID NO:125), TVAAP (SEQ ID NO:126), TVAAPSVFIFPP (SEQ ID NO:127), QPKAAP(SEQ IDNO: 128), QPKAAPSVTLFPP (SEQ ID NO: 129), AKTTPP (SEQ ID NO: 130), AKTTPPSVTPLAP (SEQ ID NO: 131), AKTTAP (SEQ ID NO: 132), AKTTAPSVYPLAP (SEQ ID NO: 133), ASTKGP (SEQ ID NO: 134), ASTKGPSVFPLAP (SEQ ID NO: 135), GENKVEYAPALMALS (SEQ ID NO: 136), GPAKELTPLKEAKVS (SEQ ID NO: 137), and GHEAAAVMQVQYPAS (SEQ ID NO: 138), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 139), or any combination thereof (see WO 2007 / 024715). Dimerization-specific amino acids

[0288] In one embodiment, the multivalent antibody comprises at least one dimerization-specific amino acid change. The dimerization-specific amino acid change causes a "protrusion into the hole" interaction and increases the assembly of the correct multivalent antibody. The dimerization-specific amino acid can be in the CH1 domain or the CL domain or a combination thereof. The dimerization-specific amino acids for pairing the CH1 domain with other CH1 domains (CH1-CH1) and the CL domain with other CL domains (CL-CL) can be found at least in the disclosures of WO2014082179, WO 2015181805 family, and WO 2017059551, each of which is incorporated by reference as a whole. The dimerization-specific amino acid can also be in the Fc domain. In addition, the dimerization-specific amino acids in the Fc domain can also be combined with the dimerization-specific amino acids in the CH1 or CL domains. In one embodiment, the present disclosure provides a multispecific antibody comprising at least one dimerization-specific amino acid pair. Antibody production

[0289] Antibodies and antigen-binding fragments thereof can be produced by any method known in the art, including but not limited to recombinant expression of antibody tetramers, chemical synthesis, and enzymatic digestion, while full-length monoclonal antibodies can be obtained, for example, by hybridoma or recombinant production. Recombinant expression can be from any suitable host cell known in the art, such as mammalian host cells, bacterial host cells, yeast host cells, insect host cells, etc.

[0290] The present disclosure also provides polynucleotides encoding antibodies or proteins described herein, e.g., polynucleotides encoding heavy chain variable regions or light chain variable regions comprising complementarity determining regions as described herein. In some aspects, the polynucleotide encoding the heavy chain variable region has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity to a polynucleotide selected from SEQ ID NO: 5, SEQ ID NO: 162, SEQ ID NO: 10, SEQ ID NO: 15, SEQ ID NO: 20, SEQ ID NO: 25, SEQ ID NO: 30, SEQ ID NO: 35, SEQ ID NO: 40, SEQ ID NO: 45, SEQ ID NO: 50, SEQ ID NO: 55, SEQ ID NO: 163 or SEQ ID NO: 60. In some aspects, the polynucleotide encoding the light chain variable region has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity to a polynucleotide selected from SEQ ID NO:65.

[0291] The present disclosure also provides polynucleotides encoding the scFvs described herein.

[0292] The polynucleotides of the present disclosure can encode the variable region sequences of the multispecific antibodies described herein. They can also encode the variable and constant regions of the multispecific antibodies. In another embodiment, the polynucleotides of the present disclosure can encode the amino acid sequences of the fusion proteins described herein.

[0293] In some embodiments, the polynucleotides described herein can be codon-optimized for expression in host cells, eg, eukaryotic cells, more particularly, mammalian cells (eg, CHO cells).

[0294] In some embodiments, the disclosure provides polynucleotides encoding polypeptides of the multispecific antibodies herein (e.g., all of the polypeptides described in Table 21 and Table 22), e.g., the EGFR x cMET multispecific antibodies described herein.

[0295] In one embodiment, the polynucleotide encoding the first polypeptide of the EGFR x cMET multispecific antibody has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity to the polynucleotide having SEQ ID NO: 164, the polynucleotide encoding the second polypeptide of the EGFR x cMET multispecific antibody has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity to the polynucleotide having SEQ ID NO: 165, and the polynucleotide encoding the third polypeptide of the EGFR x cMET multispecific antibody has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity to the polynucleotide having SEQ ID NO: 166. The polynucleotide of NO:166 has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity.

[0296] In one embodiment, the polynucleotide encoding the first polypeptide of the EGFR x cMET multispecific antibody has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity to the polynucleotide of SEQ ID NO: 164, the polynucleotide encoding the second polypeptide of the EGFR x cMET multispecific antibody has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity to the polynucleotide of SEQ ID NO: 165, and the polynucleotide encoding the third polypeptide of the EGFR x cMET multispecific antibody has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity to the polynucleotide of SEQ ID NO: 166. The polynucleotide of NO:166 has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity.

[0297] In one embodiment, the first polynucleotide encoding the first polypeptide of the EGFR x cMET multispecific antibody comprises a DNA sequence having SEQ ID NO: 164, the second polynucleotide encoding the second polypeptide of the EGFR x cMET multispecific antibody comprises a DNA sequence having SEQ ID NO: 165, and the third polynucleotide encoding the third polypeptide of the EGFR x cMET multispecific antibody comprises a DNA sequence having SEQ ID NO: 166.

[0298] In one embodiment, the first polynucleotide encoding the first polypeptide of the EGFR x cMET multispecific antibody comprises the DNA sequence of SEQ ID NO: 164, the second polynucleotide encoding the second polypeptide of the EGFR x cMET multispecific antibody comprises the DNA sequence of SEQ ID NO: 165, and the third polynucleotide encoding the third polypeptide of the EGFR x cMET multispecific antibody comprises the DNA sequence of SEQ ID NO: 166.

[0299] In some embodiments, the polynucleotides described herein can be codon-optimized for expression in host cells, eg, eukaryotic cells, more particularly, mammalian cells (eg, CHO cells).

[0300] In one embodiment, the fucosyltransferase inhibitor 2F-peracetyl-fucose (Sigma-Aldrich) for inhibiting fucosylation is added to the production system for effector function enhancement.

[0301] In one embodiment, an engineered CHO cell line is used in which the activity of α1,6-fucosyltransferase is reduced or abolished, thereby producing an antibody or antigen-binding fragment thereof that is afucosylated. For more details, see WO2003085107 A1.

[0302] The present disclosure also provides expression vectors and host cells for producing antibodies herein. The selection of expression vectors depends on the expected host cell of the expression vector. Generally, the expression vector contains a promoter and other regulatory sequences (e.g., enhancer) that are operably connected to the polynucleotide encoding the antibody chain or Fab. In some aspects, except under the control of inducing conditions, an inducible promoter is used to prevent the expression of the inserted sequence. Inducible promoters include, for example, arabinose, lacZ, metallothionein promoters or heat shock promoters. The culture of the transformed organism can be expanded under non-inducing conditions and not in the case of a colony of the coding sequence that is biased towards the host cell to better tolerate its expression product. In addition to the promoter, other regulatory elements can also be required or desired for effective expression of the antibody or Fab. These elements typically include an ATG start codon and adjacent ribosome bind site or other sequences. In addition, expression efficiency can be increased by including an enhancer appropriate for the cell system in use (see, e.g., Scharf et al., Results Probl. Cell Differ. 20:125, 1994; and Bittner et al., Meth. Enzymol. 153:516, 1987), each of which is incorporated by reference in its entirety. For example, the SV40 enhancer or the CMV enhancer can be used to increase expression in mammalian host cells.

[0303] The host cell for carrying and expressing the antibody chain can be prokaryotic or eukaryotic. Escherichia coli is a prokaryotic host that can be used for cloning and expressing the polynucleotides of the present disclosure. Other applicable microbial hosts include bacillus, such as Bacillus subtilis, and other enterobacteriaceae, such as Salmonella, Serratia and various Pseudomonas species. In these prokaryotic hosts, expression vectors can also be prepared, which typically contain expression control sequences (such as replication origins) compatible with the host cell. In addition, there will be any number of various well-known promoters, such as lactose promoter systems, tryptophan (trp) promoter systems, beta-lactamase promoter systems or promoter systems from bacteriophage lambda. Promoters are typically optionally expressed with operator sequences and have ribosome binding site sequences, etc., for initiating and completing transcription and translation. Other microorganisms such as yeast can also be used to express antibodies. A combination of insect cells and baculovirus vectors can also be used. In other aspects, mammalian host cells are used to express and produce the antibodies of the present disclosure. For example, they can be hybridoma cell lines expressing endogenous immunoglobulin genes or mammalian cell lines carrying exogenous expression vectors. These include any normal death or normal or abnormal immortalized animal or human cells. For example, several suitable host cell lines capable of secreting complete immunoglobulins have been developed, including CHO cell lines, various COS cell lines, HEK 293 cells, myeloma cell lines, transformed B cells and hybridomas. The use of mammalian tissue cell cultures to express polypeptides is generally discussed in, for example, Winnacker, From Genes to Clones, VCH Publishers, New York, NY, 1987, each incorporated by reference in its entirety. Expression vectors for mammalian host cells can include expression control sequences, such as an origin of replication, a promoter, and an enhancer (see, e.g., Queen et al., Immunol. Rev. 89:49-68, 1986, incorporated by reference in its entirety) and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcription terminator sequences. These expression vectors typically contain promoters derived from mammalian genes or mammalian viruses. Suitable promoters can be constitutive, cell type-specific, stage-specific, and / or regulatable or controllable.Useful promoters include, but are not limited to, the metallothionein promoter, the constitutive adenovirus major late promoter, the dexamethasone-inducible MMTV promoter, the SV40 promoter, the MRP polIII promoter, the constitutive MPSV promoter, the tetracycline-inducible CMV promoter (such as the human immediate-early CMV promoter), the constitutive CMV promoter, and promoter-enhancer combinations known in the art. Detection and diagnostic methods

[0304] The antibodies or antigen-binding fragments disclosed herein can be used in a variety of applications, including but not limited to methods for detecting cMET / EGFR (i.e., cMET and / or EGFR). In one aspect, the antibodies or antigen-binding fragments can be used to detect the presence of cMET / EGFR in a biological sample. As used herein, the term "detection" includes quantitative or qualitative detection. In certain aspects, the biological sample includes cells or tissues. In other aspects, such tissues include normal and / or cancerous tissues that express cMET / EGFR at higher levels relative to other tissues.

[0305] In one aspect, the present disclosure provides methods for detecting the presence of cMET in a biological sample. In certain aspects, the method comprises contacting the biological sample with an anti-cMET / EGFR antibody under conditions permissive for binding of the antibody to the antigen, and detecting whether a complex forms between the antibody and the antigen. The biological sample may include, but is not limited to, urine, tissue, sputum, or blood samples.

[0306] Also included are methods for diagnosing a condition associated with cMET / EGFR expression. In certain aspects, the method includes contacting a test cell with an anti-cMET / EGFR antibody; determining the expression level (quantitative or qualitative) of cMET / EGFR expressed by the test cell by detecting binding of the anti-cMET / EGFR antibody to a cMET polypeptide / EGFR polypeptide; and comparing the expression level of the test cell with the expression level of cMET / EGFR in a control cell (e.g., a normal cell of the same tissue origin as the test cell or a cell that does not express cMET / EGFR), wherein a higher level of cMET / EGFR expression in the test cell compared to the control cell indicates the presence of a condition associated with cMET / EGFR expression. Treatment

[0307] In some embodiments, the antibodies or antigen-binding fragments of the present disclosure can be used in a variety of applications, including but not limited to methods for treating cMET-related conditions or diseases. In one aspect, the cMET-related condition or disease is cancer. In some embodiments, the cancer is cMET-positive.

[0308] The antibodies or antigen-binding fragments disclosed herein can be used in a variety of applications, including but not limited to methods for treating EGFR / cMET-related conditions or diseases. In one aspect, the EGFR / cMET-related condition or disease is cancer. In some embodiments, the cancer is EGFR / cMET-positive.

[0309] In one aspect, the present disclosure provides a method for treating cancer. In certain aspects, the method comprises administering an effective amount of an anti-cMET antibody or antigen-binding fragment or a multispecific antibody comprising a cMET antibody to a patient in need thereof. In another aspect, the present disclosure provides an anti-cMET antibody or antigen-binding fragment or multispecific antibody or pharmaceutical composition for treating cancer. In another aspect, the present disclosure provides the use of an anti-cMET antibody or antigen-binding fragment, a multispecific antibody or antigen-binding fragment thereof, or a pharmaceutical composition in the manufacture of a medicament for treating cancer.

[0310] In one aspect, the present disclosure provides a method for treating cancer. In certain aspects, the method comprises administering an effective amount of a multispecific antibody herein (e.g., a multispecific antibody described in Section 3) to a patient in need thereof. In another aspect, the present disclosure provides a multispecific antibody or pharmaceutical composition herein for use in treating cancer. In another aspect, the present disclosure provides the use of a multispecific antibody or antigen-binding fragment thereof or pharmaceutical composition in the manufacture of a medicament for treating cancer.

[0311] In one embodiment, the cancer carries a cMET gene alteration and / or the cMET gene alteration results in constitutively active cMET signaling. In one embodiment, the growth of the cancer is driven by cMET signaling. In one embodiment, the cancer carries a cMET gene alteration and the growth of the cancer is driven by cMET signaling.

[0312] In one embodiment, cMET signaling is ligand-dependent. In another embodiment, cMET signaling is ligand-independent.

[0313] In another embodiment, the cMET genetic alteration comprises cMET overexpression, genomic amplification, mutation, and / or alternative splicing, which results in constitutively active cMET signaling.

[0314] In another embodiment, the cancer carries an EGFR activating mutation and / or the growth of the cancer cell is driven by EGFR signaling. In another embodiment, the EGFR activating mutation is a deletion or point mutation, including EGFR exon 19 deletion (E19del) and / or EGFR L858R / T790M.

[0315] In another embodiment, EGFR signaling is ligand-independent. In another embodiment, EGFR signaling is ligand-dependent.

[0316] In another embodiment, the EGFR x cMET multispecific antibodies herein induce internalization of EGFR and / or cMET receptors, thereby reducing the receptors on the cell surface. Therefore, therapies using the EGFR x cMET multispecific antibodies are not limited to specific EGFR mutations or cMET amplifications. The cell lines used in the Examples section are illustrative only and should not limit the scope of the treatments described herein.

[0317] Cancer may include, but is not limited to, gastric cancer, colorectal cancer, lung cancer, liver cancer, head and neck cancer, kidney cancer, breast cancer, or brain cancer.

[0318] In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). In another embodiment, the non-small cell lung cancer is squamous non-small cell lung cancer. In another embodiment, the liver cancer is hepatocellular carcinoma. In another embodiment, the head and neck cancer is head and neck squamous cell carcinoma. In another embodiment, the gastric cancer is alpha-fetoprotein positive (AFP+) gastric cancer.

[0319] Antibodies or antigen-binding fragments disclosed herein can be administered in any suitable manner, including parenteral, intrapulmonary and intranasal, and if desired for local treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. Administration can be by any suitable route, for example, by injection, such as intravenous or subcutaneous injection, depending in part on whether administration is short-lived or long-term. Various dosing regimens are contemplated herein, including but not limited to single administration or multiple administrations at different time points, push injection administration and pulse infusion.

[0320] The antibodies or antigen-binding fragments of the present disclosure can be formulated, dosed, and used in a manner consistent with good medical practice. Factors to be considered in this regard include the specific condition being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the condition, the delivery site of the agent, the method of administration, the administration regimen, and other factors known to medical practitioners. The antibodies need not but are optionally formulated with one or more agents currently used to prevent or treat the condition being studied. The effective amount of such other agents depends on the amount of the antibody present in the formulation, the type of condition or treatment, and other factors discussed above.

[0321] For the prevention or treatment of disease, the appropriate dosage of the antibodies or antigen-binding fragments of the disclosure will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is being administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the judgment of the attending physician. Combination therapy

[0322] In one aspect, the antibodies of the present disclosure (including anti-cMET bispecific antibodies and EGFR x cMET multispecific antibodies) can be used in combination with other therapeutic agents.

[0323] The antibodies disclosed herein can be used in combination with other therapeutic agents (e.g., other immune checkpoint antibodies). Such immune checkpoint antibodies may include anti-PD1 antibodies. Anti-PD1 antibodies may include, but are not limited to, tislelizumab, pembrolizumab (Pembrolizumab) or nivolumab (Nivolumab). Tislelizumab (SEQ ID No: 140 and 141 in Table 3) is disclosed in US 8,735,553. Pembrolizumab (formerly known as MK-3475) is disclosed in US 8,354,509 and US8,900,587 and is a humanized IgG4-K immunoglobulin that targets PD1 receptors and inhibits the combination of PD1 receptor ligands PD-L1 and PD-L2. Nivolumab (as disclosed by Bristol-Meyers Squibb) is a fully human IgG4-K monoclonal antibody. Nivolumab (clone 5C4) is disclosed in U.S. Patent No. 8,008,449 and WO 2006 / 121168. Table 3. Tislelizumab sequence

[0324] In one embodiment, the present disclosure provides the use of a combination of an antibody herein and an anti-PD-1 antibody (such as tislelizumab or other anti-PD-1 antibodies described above) in the manufacture of a medicament for treating cancer (such as the cancers described above). In another embodiment, the present disclosure provides a combination of an antibody herein (including an anti-cMET bispecific antibody and an EGFR x cMET multispecific antibody) and an anti-PD-1 antibody (such as tislelizumab or other anti-PD-1 antibodies described above) for treating cancer (such as the cancers described above).

[0325] Combination therapy is intended to mean, and does mean and include, any of the following: - administering this combination therapy simultaneously to a patient in need of treatment, where the components are formulated together in a single dosage form that releases the components to the patient substantially simultaneously, - administering this combination to a patient in need of treatment at substantially the same time, where the components are formulated separately from one another into separate dosage forms to be taken by said patient at substantially the same time, so that said components are released to said patient at substantially the same time, - sequential administration of this combination therapy to a patient in need of treatment, where the components are formulated separately from one another into separate dosage forms to be taken sequentially by said patient with significant intervals between each administration, so that the components are released to said patient at substantially different times; and - sequential administration of such a combination to a patient in need of treatment, where the components are formulated together in a single dosage form that releases the components in a controlled manner so that they are released to the patient simultaneously, successively and / or overlappingly at the same and / or different times, wherein each part can be administered by the same or different routes. Pharmaceutical composition

[0326] Also provided are compositions, including pharmaceutical formulations, comprising the antibodies or multispecific antibodies herein or polynucleotides containing sequences encoding the antibodies or antigen-binding fragments herein. In certain embodiments, the compositions comprise one or more antibodies or multispecific antibodies or antigen-binding fragments, or one or more polynucleotides containing sequences encoding one or more antibodies or antigen-binding fragments. These compositions may also comprise a suitable carrier, such as pharmaceutically acceptable excipients well known in the art, including buffers.

[0327] Compositions disclosed herein can be in various forms. These include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories. The appropriate form depends on the intended mode of administration and therapeutic application. Typical suitable compositions are in the form of injectable or infusible solutions. A suitable mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In some embodiments, the antibody is administered by intravenous infusion or injection. In certain embodiments, the antibody is administered by intramuscular or subcutaneous injection. definition

[0328] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0329] As used herein, including the appended claims, singular forms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0330] Unless the context clearly indicates otherwise, the term "or" means and is used interchangeably with the term "and / or."

[0331] As used herein, the term "anti-cancer agent" refers to any agent useful in treating a cell proliferative disorder such as cancer, including but not limited to cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.

[0332] The term "human cMET" refers to the receptor tyrosine kinase mesenchymal-epithelial transition factor in humans. The amino acid sequence of human cMET (SEQ ID NO: 69) can also be found in GenBank: AAI30421.1.

[0333] The term "human EGFR" refers to the epidermal growth factor receptor in humans. The amino acid sequence of human EGFR (SEQ ID NO: 167) can be found at https: / / www.uniprot.org / uniprotkb / P00533 / entry#sequences. SEQ ID NO: 167 EGFR amino acid sequence

[0334] The term "cMET biparatopic antibody or antigen-binding fragment thereof" means that in the multispecific antibody or antigen-binding fragment thereof, its first antigen-binding domain that targets human cMET and its second antigen-binding domain that targets human cMET recognize non-overlapping epitopes on human cMET, or its first antigen-binding domain that targets human cMET does not compete with its second antigen-binding domain that targets human cMET.

[0335] As used herein, the terms "administration / administering" and "treating / treatment" refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent or composition with an animal, a human, a subject, a cell, a tissue, an organ or a biological fluid when applied to an animal, a human, a subject, a cell, a tissue, an organ or a biological fluid. The treatment of cells encompasses the contact of an agent with a cell and the contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatments, for example, treatment of a cell by a reagent, a diagnostic agent, a binding compound or by another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., a rat, a mouse, a dog, a cat, a rabbit), and most preferably a human. On the one hand, treating any disease or condition refers to improving the disease or condition (i.e., slowing down or preventing or reducing the development of a disease or at least one clinical symptom thereof). On the other hand, "treat / treating / treatment" refers to alleviating or improving at least one physical parameter, including those that the patient may not be able to discern. In yet another aspect, "treat," "treating," or "treatment" refers to modulating a disease or condition physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of a physical parameter), or both. In yet another aspect, "treat," "treating," or "treatment" refers to preventing or delaying the onset, development, or progression of a disease or condition.

[0336] In the context of the present disclosure, the term "subject" is a mammal, eg, a primate, preferably a higher primate, such as a human (eg, a patient having or at risk of having a disorder described herein).

[0337] As used herein, the term "affinity" refers to the strength of the interaction between an antibody and an antigen. Within an antigen, the variable region of an antibody interacts with the antigen at many sites through non-covalent forces. Generally, the more interactions there are, the stronger the affinity.

[0338] As used herein, the term "antibody" refers to a polypeptide of the immunoglobulin family that can non-covalently, reversibly, and specifically bind to a corresponding antigen. For example, a naturally occurring IgG antibody is a tetramer comprising at least two heavy (H) chains and two light (L) chains bound to each other by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL or Vκ) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). Each VH and VL is composed of three CDRs and four framework regions (FRs), arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of antibodies mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.

[0339] The term "antibody" includes, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies and anti-idiotypic (anti-Id) antibodies, human engineered antibodies, single-chain antibodies (scFv), single domain antibodies, Fab fragments, Fab' fragments or F(ab')2 fragments. The antibody can be any isotype / class (e.g., IgG, IgE, IgM, IgD, IgA and IgY) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2). In addition, antibodies include derivatives thereof, such as fusion proteins, multispecific antibodies or antibody-drug conjugates (ADCs). In addition, antibodies include derivatives thereof, by directly or indirectly connecting to or forming a complex with another agent (e.g., other drugs or antibodies).

[0340] The term "chimeric antibody" refers to a molecule composed of domains from different species, i.e., the variable domains of an antibody from one host species (e.g., mouse, rabbit, llama, etc.) are fused to the constant domains of an antibody from a different species (e.g., human).

[0341] In some embodiments, the anti-cMET antibody comprises at least one antigen binding site and at least one variable region. In some embodiments, the anti-cMET antibody comprises an antigen binding fragment from a cMET antibody described herein. In some embodiments, the anti-cMET antibody is isolated or recombinant. In some embodiments, the anti-cMET antibody further comprises a multispecific antibody that targets a first epitope of cMET as a first arm and a second epitope of cMET as a second arm. In some embodiments, the anti-cMET antibody further comprises a multispecific antibody that targets cMET as at least one arm (e.g., two arms that target different epitopes, respectively) and another arm that targets another antigen.

[0342] The term "monoclonal antibody" or "mAb" or "Mab" herein refers to a colony of substantially homogeneous antibodies, that is, the antibody molecules included in the colony are identical in amino acid sequence except for the possible naturally occurring mutations that may be present in a small amount. In contrast, conventional (polyclonal) antibody preparations typically include a variety of different antibodies with different amino acid sequences in their variable domains, particularly their complementary determining regions (CDRs), which are typically specific for different epi-positions. The modifier "monoclonal" indicates the characteristic of an antibody obtained from a substantially homogeneous antibody colony and should not be construed as requiring antibody production by any ad hoc method. Monoclonal antibodies (mAb) can be obtained by methods well known to those skilled in the art. See, e.g., Kohler et al., Nature 1975 256:495-497; U.S. Pat. No. 4,376,110; Ausubel et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY 1992; Harlow et al., ANTIBODIES: ALABORATORY MANUAL, Cold Spring Harbor Laboratory 1988; and Colligan et al., CURRENT PROTOCOLS IN IMMUNOLOGY 1993. The antibodies disclosed herein can be of any immunoglobulin class (including IgG, IgM, IgD, IgE, IgA), and any subclass thereof (e.g., IgG1, IgG2, IgG3, IgG4). Hybridomas producing monoclonal antibodies can be cultured in vitro or in vivo. High titers of monoclonal antibodies can be obtained in vivo by injecting cells from a single hybridoma intraperitoneally into mice, such as primary primed Balb / c mice, to produce ascites fluid containing high concentrations of the desired antibody. Monoclonal antibodies of the isotype IgM or IgG can be purified from such ascites fluid, or from culture supernatants, using column chromatography methods well known to those skilled in the art.

[0343] Typically, the basic antibody structural unit comprises a tetramer. Each tetramer comprises two pairs of identical polypeptide chains, each pair having one "light chain" (about 25 kDa) and one "heavy chain" (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids that is primarily responsible for antigen recognition. The carboxyl-terminal portion of the heavy chain can be defined as a constant region that is primarily responsible for effector function. Typically, human light chains are classified as kappa and lambda light chains. In addition, human heavy chains are typically classified as alpha, delta, epsilon, gamma, or mu, and define the isotype of the antibody as IgA, IgD, IgE, IgG, and IgM, respectively. Within the light and heavy chains, the variable and constant regions are connected by a "J" region of about 12 or more amino acids, and the heavy chain also includes a "D" region of about 10 or more amino acids.

[0344] The variable regions of each light chain / heavy chain (VL / VH) pair form an antibody binding site. Thus, in general, a complete antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are typically identical in primary sequence.

[0345] Typically, the variable domains of the heavy and light chains contain three hypervariable regions, also referred to as "complementarity determining regions (CDRs)," which are located between relatively conserved framework regions (FRs). The CDRs are typically aligned by the framework regions, enabling binding to specific epitopes. In general, from N-terminus to C-terminus, both the light and heavy chain variable domains contain FR-1 (or FR1), CDR-1 (or CDR1), FR-2 (FR2), CDR-2 (CDR2), FR-3 (or FR3), CDR-3 (CDR3), and FR-4 (or FR4). The positions of the CDRs and framework regions can be determined using various definitions well known in the art, such as Kabat, Chothia, AbM, and IMGT (see, e.g., Johnson et al., Nucleic Acids Res., 29:205-206 (2001); Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987); Chothia et al., Nature, 342:877-883 (1989); Chothia et al., J. Mol. Biol., 227:799-817 (1992); Al-Lazikani et al., J. Mol. Biol., 273:927-748 (1997)), ImMunoGenTics (IMGT) numbering (Lefranc, M.-P., The J. Mol. Biol., 294:101-103 (1997)), and ImMunoGenTics (IMGT) numbering. Immunologist, 7, 132-136 (1999); Lefranc, M.-P. et al., Dev. Comp. Immunol., 27, 55-77 (2003) ("IMGT" numbering scheme).The definition of antigen binding sites is also described in Ruiz et al., Nucleic Acids Res., 28:219-221 (2000); and Lefranc, MP, Nucleic Acids Res., 29:207-209 (2001); MacCallum et al., J. Mol. Biol., 262:732-745 (1996); and Martin et al., Proc. Natl. Acad. Sci. USA, 86:9268-9272 (1989); Martin et al., Methods Enzymol., 203:121-153 (1991); and Rees et al., in Sternberg MJE (ed.), Protein Structure Prediction, Oxford University Press. Press [Oxford University Press], Oxford, 141-172 (1996). For example, according to Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). According to Chothia, the CDR amino acid residues in VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of Kabat and Chothia, the CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL. According to IMGT, the CDR amino acid residues in VH are numbered as approximately 26-35 (HCDR1), 51-57 (HCDR2), and 93-102 (HCDR3), and the CDR amino acid residues in VL are numbered as approximately 27-32 (LCDR1), 50-52 (LCDR2), and 89-97 (LCDR3) (numbering according to Kabat). According to IMGT, the CDR regions of an antibody can be determined using the program IMGT / DomainGap Align.

[0346] The term "hypervariable region" refers to the amino acid residues in an antibody that are responsible for antigen binding. The hypervariable region comprises amino acid residues from "CDRs" (e.g., LCDR1, LCDR2, and LCDR3 in the light chain variable domain and HCDR1, HCDR2, and HCDR3 in the heavy chain variable domain). See Kabat et al., (1991) Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, Maryland (defining the CDR regions of antibodies by sequence); see also Chothia and Lesk (1987) J. Mol. Biol. 196: 901-917 (defining the CDR regions of antibodies by structure). The term "framework" or "FR" residues refers to those variable domain residues other than the hypervariable region residues defined herein as CDR residues.

[0347] Unless otherwise indicated, "antigen-binding fragment" refers to an antigen-binding fragment of an antibody, i.e., an antibody fragment that retains the ability to specifically bind to the antigen to which the full-length antibody binds, e.g., a fragment that retains one or more CDR regions. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules (e.g., single-chain Fv (ScFv)); nanobodies, and multispecific antibodies formed from antibody fragments.

[0348] As used herein, an antibody "specifically binds" a target protein, meaning that the antibody exhibits preferential binding to the target protein compared to other proteins, but such specificity does not require absolute binding specificity. "Specific binding" or "selective binding" of an antibody, as used in the context of describing an interaction between an antigen (e.g., a protein) and an antibody or antigen-binding antibody fragment, refers to a binding reaction that determines the presence of the antigen in a heterogeneous population of proteins and other biological agents (e.g., in a biological sample, blood, serum, plasma, or tissue sample). Thus, under certain specified immunoassay conditions, the antibody or its antigen-binding fragment specifically binds to a particular antigen at least twice the background level and does not specifically bind to other antigens present in the sample in significant amounts. In one aspect, under specified immunoassay conditions, the antibody or its antigen-binding fragment specifically binds to a particular antigen at least ten (10) times the background binding level and does not specifically bind to other antigens present in the sample in significant amounts.

[0349] As used herein, "antigen binding domain" refers to the part of an antibody that specifically binds to an antigen. In some embodiments, it comprises at least six CDRs and specifically binds to an epitope (or three CDRs, with respect to single-domain antibodies). The "antigen binding fragment" of a multispecific antibody (e.g., a bispecific antibody) comprises a first antigen binding domain that specifically binds to a first epitope and a second antigen binding domain that specifically binds to a second epitope. Multispecific antibodies can be bispecific antibodies, trispecific antibodies, tetraspecific antibodies, etc., having antigen binding domains for each specific epitope. Multispecific antibodies can be multivalent antibodies (e.g., bispecific tetravalent antibodies), which comprise multiple antigen binding domains, such as 2, 3, 4 or more antigen binding domains that specifically bind to a first epitope and 2, 3, 4 or more antigen binding domains that specifically bind to a second epitope.

[0350] The term "human antibody" as used herein means an antibody that comprises only human immunoglobulin protein sequences. If produced in a mouse, mouse cell, or hybridoma derived from a mouse cell, a human antibody may contain murine carbohydrate chains. Similarly, a "mouse antibody" or a "rat antibody" means an antibody that comprises only mouse or rat immunoglobulin protein sequences, respectively.

[0351] The term "humanization" or "humanized antibody" means an antibody form containing sequences from non-human (e.g., mouse, rabbit, llama, etc.) antibodies and human antibodies. Such antibodies contain the minimum sequence derived from non-human immunoglobulins. Typically, a humanized antibody will comprise substantially all of at least one and typically two variable domains, all or substantially all of its hypervariable loops corresponding to those of non-human immunoglobulins, and all or substantially all of FRs are those of human immunoglobulin sequences. Humanized antibodies will also optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically at least a portion of a human immunoglobulin. When it is necessary to distinguish a humanized antibody from a parent rodent antibody, the prefix "hum," "hu," "Hu," or "h" is added to the antibody clone name. The rodent / camelid antibody of a humanized form will typically comprise the identical CDR sequence of the parent rodent antibody, but may include certain amino acid substitutions to increase affinity, increase the stability of the humanized antibody, remove post-translational modifications, or for other reasons.

[0352] The term "corresponding human germline sequence" refers to a nucleic acid sequence encoding a human variable region amino acid sequence or subsequence that has the highest determined amino acid sequence identity to a reference variable region amino acid sequence or subsequence compared to all other known variable region amino acid sequences encoded by human germline immunoglobulin variable region sequences. A corresponding human germline sequence can also refer to a human variable region amino acid sequence or subsequence that has the highest amino acid sequence identity to a reference variable region amino acid sequence or subsequence compared to all other evaluated variable region amino acid sequences. The corresponding human germline sequence can be only the framework region, only the complementarity determining regions, the framework and complementarity determining regions, the variable segment (as defined above), or other combinations of sequences or subsequences comprising a variable region. Sequence identity can be determined using the methods described herein, for example, by aligning two sequences using BLAST, ALIGN, or another alignment algorithm known in the art. A corresponding human germline nucleic acid or amino acid sequence can have at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a reference variable region nucleic acid or amino acid sequence. Furthermore, if the antibody contains a constant region, the constant region is also derived from such human sequences, e.g., human germline sequences, or mutated forms of human germline sequences or antibodies containing consensus framework sequences derived from analysis of human framework sequences, e.g., as described in Knappik et al., J. Mol. Biol. 296:57-86, 2000.

[0353] The term "equilibrium dissociation constant (K D , M)" refers to the dissociation rate constant (kd, time- 1 ) divided by the association rate constant (ka, time- 1 , M -l The equilibrium dissociation constant can be measured using any method known in the art. The antibodies of the present disclosure will typically have a dissociation constant of less than about 10 -7 or 10 -8 M, for example, less than about 10 -9 M or 10 -10 M, in some aspects, is less than about 10 -11 M, 10 -12 M or 10 -13 The equilibrium dissociation constant of M.

[0354] The term "cancer" or "tumor" herein has the broadest meaning as understood in the art and refers to the physiological condition in mammals that is typically characterized by unregulated cell growth. In the context of this disclosure, cancer is not limited to a certain type or location.

[0355] In the context of the present disclosure, when referring to an amino acid sequence, the term "conservative substitution" means replacing an original amino acid with a new amino acid that does not substantially change the chemical, physical and / or functional properties of the antibody or fragment, such as its binding affinity to cMET. In particular, common conservative substitutions of amino acids are well known in the art.

[0356] As used herein, the term "knob-into-hole" refers to the use of amino acids to guide the pairing of two polypeptides together in vitro or in vivo by introducing a steric protrusion (knob) into one polypeptide and a hole or cavity (hole) into the other polypeptide at their interactive interface. For example, knobs and holes have been introduced into the Fc:Fc binding interface of antibodies, C L :C H Interface, or V H / V L The knob-in-hole interface (see, e.g., US 2011 / 0287009, US 2007 / 0178552, WO 96 / 027011, WO 98 / 050431, and Zhu et al., 1997, Protein Science 6:781-788). In some embodiments, the knob-in-hole ensures that two different heavy chains are correctly paired together during multispecific antibody production. For example, a multispecific antibody having knob-in-hole amino acids in its Fc region can also comprise a single variable domain attached to each Fc region, or further comprise different heavy chain variable domains paired with similar or different light chain variable domains. Knob-in-hole technology can also be used in the VH or VL region to ensure correct pairing.

[0357] The term "knob" as used herein in the context of "knob-to-hole" technology refers to an amino acid change that introduces a protrusion (knob) into a polypeptide at the interface where the polypeptide interacts with another polypeptide. In some embodiments, the other polypeptide has a hole mutation.

[0358] The term "hole" as used herein in the context of a "knob-hole" refers to an amino acid change that introduces a pocket or cavity (hole) into a polypeptide at the interface where the polypeptide interacts with another polypeptide. In some embodiments, the other polypeptide has a knob mutation.

[0359] An example of an algorithm suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al., Nuc. Acids Res. 25:3389-3402, 1977; and Altschul et al., J. Mol. Biol. 215:403-410, 1990, respectively. Software for performing BLAST analysis is publicly available through the National Center for Biotechnology Information. This algorithm involves first identifying high-scoring sequence pairs (HSPs) by identifying short word lengths W in the query sequence that, when aligned with the same word length in the database sequence, match or satisfy some positive-valued threshold score T. T is referred to as the neighborhood word score threshold. These initial neighborhood word hits serve as values ​​for starting a search to find longer HSPs containing them. The word hits are extended along each sequence in both directions until the cumulative alignment score can be increased. For nucleotide sequences, the cumulative score is calculated using the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is ​​used to calculate the cumulative score. Extension of the word hit in each direction is stopped when: the cumulative alignment score drops by the amount X from its maximum achieved value; the cumulative score approaches zero or lower due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses a word length (W) of 11, an expectation (E) of 10, M=5, N=-4 by default and compares both chains. For amino acid sequences, the BLAST program uses as defaults a wordlength of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff, (1989) Proc. Natl. Acad. Sci. USA 89:10915), alignments (B) 50, expectation (E) 10, M=5, N=-4, and a comparison of both strands.

[0360] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873-5787, 1993). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability that a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[0361] The percent identity between two amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller, Comput. Appl. Biosci. 4: 11-17, (1988), which has been incorporated into the ALIGN program (version 2.0), using the PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the algorithm of Needleman and Wunsch, J. Mol. Biol. 48: 444-453 (1970), which has been incorporated into the GAP program in the GCG software package, using either the BLOSUM62 matrix or the PAM250 matrix, a gap weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2, 3, 4, 5, or 6.

[0362] The term "nucleic acid" is used interchangeably with the term "polynucleotide" herein and refers to deoxyribonucleotides or ribonucleotides and polymers thereof in single-stranded or double-stranded form. The term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages that are synthetic, naturally occurring, and non-naturally occurring, that have similar binding properties to a reference nucleic acid, and that are metabolized in a manner similar to a reference nucleotide. Examples of such analogs include, but are not limited to, phosphorothioates, phosphoramidates, methylphosphonates, chiral methylphosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs).

[0363] In the context of nucleic acid, the term "operably connected" refers to the functional relationship between two or more polynucleotide (e.g., DNA) segments. Typically, it refers to the functional relationship between a transcriptional regulatory sequence and a transcribed sequence. For example, a promoter or enhancer sequence is operably connected to a coding sequence if it stimulates or regulates the transcription of a coding sequence in a suitable host cell or other expression system. Typically, the promoter transcriptional regulatory sequence operably connected to a transcribed sequence is physically adjacent to the transcribed sequence, i.e., they are cis-acting. However, some transcriptional regulatory sequences (e.g., enhancers) do not need to be physically adjacent to or next to the coding sequence that they enhance their transcription.

[0364] In some aspects, the present disclosure provides compositions, e.g., pharmaceutically acceptable compositions, comprising an anti-cMET multispecific antibody described herein formulated with at least one pharmaceutically acceptable excipient. As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, isotonicity agents, and absorption delaying agents that are physiologically compatible. The excipient can be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal, or epidermal administration (e.g., by injection or infusion).

[0365] As used herein, the term "therapeutically effective amount" refers to an amount of an antibody that, when administered to a subject to treat a disease, or at least one clinical symptom of a disease or condition, is sufficient to affect the treatment of the disease, condition or symptom. A "therapeutically effective amount" can vary with the antibody, disease, condition, and / or symptoms of the disease or condition, the severity of the disease, condition, and / or symptoms of the disease or condition, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled in the art or can be determined by routine experimentation. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination subject used to effectively treat the disease, condition or condition.

[0366] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner. Such administration also encompasses co-administration in multiple containers or in separate containers (e.g., capsules, powders, and liquids) of each active ingredient. The powder and / or liquid can be reconstituted or diluted to the desired dose prior to administration. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner at approximately the same time or at different times. In any case, the therapeutic regimen will provide the beneficial effects of the drug combination in terms of treating the conditions or disorders described herein.

[0367] As used herein, the phrase "in combination with" means that the anti-cMET antibody is administered to the subject simultaneously with, just before, or just after administration of the additional therapeutic agent. In certain embodiments, the anti-cMET antibody is administered as a co-formulation with the additional therapeutic agent. equivalent

[0368] It should be understood that although the invention has been described in conjunction with the detailed description, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims. It should be understood that one, some, any or all of the features of the various embodiments described herein can be combined to form additional embodiments of the present disclosure. These and other aspects of the present disclosure will become apparent to those skilled in the art. Example Example 1. Generation of anti-cMET antibodies Mouse immunization

[0369] To produce anti-cMET antibodies, genetically engineered mice ( Biocytogen immunized mice with either the human cMET extracellular domain (amino acids 1-932 of SEQ ID NO: 69, which is full-length human cMET) fused to a his-tag or mouse Fc (generated in-house, SEQ ID NOs: 1 and 2) mixed with adjuvants: complete Freund's adjuvant (F5881, Sigma) for the primary immunization and incomplete Freund's adjuvant (F5506, Sigma) for subsequent immunizations. Animals were injected intraperitoneally and subcutaneously every two or three weeks. The mice used contained DNA encoding different human immunoglobulin heavy chains and a shared human light chain variable region.

[0370] Serum titers against cMET protein were determined by ELISA to monitor humoral immune responses. Animals with sufficient cMET-specific antibody titers were administered a final boost of cMET protein for antibody screening. Table 4. Antigen sequence list Plasma cell screening using the Beacon Optofluidic system

[0371] 3-5 days after the final boost immunization, spleens were harvested and mashed into single cell suspensions. Mouse CD138 positive selection kit (STEMCELL) was used according to the manufacturer's instructions. TM ) to separate plasma cells. According to the manufacturer's instructions, a density of 6.25 x 10 6 / ml of enriched plasma cells were introduced into the channel and injected into the OptoSelect 14K Chip TM(Berkeley Light Life Sciences). In order to screen for human cMET-specific plasma cells, human cMET protein (MET-H82E1, Acrobiosystems) conjugated beads (520-00053, Berkeley Light Life Sciences) and Alexa Fluor 488 goat anti-mouse IgG secondary antibody (Jackson ImmunoResearch) at a concentration of 5 μg / ml were introduced into the channel. After introduction, the freezing valve was opened and the exposure time of the FITC channel of the Alexa Fluor 488 fluorophore was set to 1000 ms. Bloom-like positive signals were captured by setting a time period of 3 minutes and 10 cycles of time-lapse imaging. After completing the human cMET-specific plasma cell screening, cynomolgus monkey cMET-specific plasma cells were screened using cyno cMET-ECD-his (generated in-house, SEQ ID NO: 3) conjugated beads. An assay using irrelevant His-tagged protein-conjugated beads to remove nonspecific binding signals was performed as a counterscreen. Plasma cells showing human and cynomolgus monkey cMET-specific positive signals were individually exported to 96-well plates filled with lysis buffer. Example 2. Antibody VH and VL gene cloning, sequencing and expression

[0372] First-strand cDNA was synthesized using the Opto Plasma B Discovery cDNA Synthesis Kit according to the manufacturer's instructions. TM Total cDNA was amplified using the OptoPlasma B Discovery Sanger Prep Kit (Beckley Life Sciences) according to the manufacturer's instructions. TM (Beckley Light Life Sciences, Inc.) amplified the antibody VH and VL genes. The amplified VH and VL genes were cloned into mammalian expression vectors containing human IgG1 constant region (SEQ ID NO: 70) and human kappa chain constant region (SEQ ID NO: 71) genes and sequenced. The three HCDRs, three LCDRs, VH and VL amino acid sequences of representative antibodies and the DNA sequences of VH and VL are listed in Tables 5 and 6 as SEQ ID NOs: 4 to 68. The antibodies were cloned by Expi293 TM expressed in cells and purified by affinity chromatography. Table 5. List of anti-cMET monoclonal antibodies Table 6. Anti-cMET monoclonal antibody sequence list Example 3. Determination of binding affinity and specificity of anti-cMET antibodies

[0373] The binding affinity and specificity of the purified anti-cMET antibodies were determined by ELISA and FACS. Briefly, 2 μg / ml of human or cynomolgus monkey monomeric cMET fusion protein human cMET-ECD-his or cynomolgus monkey cMET-ECD-his (generated in-house, SEQ ID No: 1 and 3) or human cMET-ECD-mFc formed human dimeric cMET protein (generated in-house, SEQ ID NO: 2) was coated in a 96-well ELISA plate, and 50 μL of serially diluted antibodies were incubated for 30-60 minutes, washed, and incubated with a goat anti-human IgG secondary antibody conjugated to HRP (Abcam, ab98624). After incubation and washing, the plate was developed with HRP substrate and the absorbance was measured. Candidates that were positive for ELISA binding were serially diluted and incubated with Hs746T cells (a human gastric cancer cell line with a putative oncogenic mutation that undergoes cMET amplification leading to high cMET expression) at 4°C for 30 minutes. After washing twice with FACS buffer, diluted Alexa Fluor 647 goat anti-human IgG secondary antibody was added and incubated with Hs746T cells in the dark at 4°C for 30 minutes. After washing twice with FACS buffer, the cells were resuspended in FACS buffer and detected using a BectonDickinson LSR Fortessa TM The nonspecific binding of these antibodies was assessed by FACS binding to Jurkat cells (cMET negative cells). TMThe titration curve was generated by nonlinear fitting of the sigmoidal dose response.

[0374] As shown in Tables 7 and 8, all selected candidates specifically bound to cMET monomer and dimer proteins with high affinity, and they all specifically bound to cancer cells expressing human cMET and cross-bound to cynomolgus monkey cMET. Table 7. Binding affinity of anti-cMET antibodies to human and cynomolgus monkey cMET proteins Table 8. Binding affinity of anti-cMET antibodies to Hs746T cells and Jurkat cells nd: Not detected Example 4. Binding kinetics of anti-cMET antibodies

[0375] The binding affinity and kinetics of the purified anti-cMET antibodies were determined by surface plasmon resonance (Biacore 8K, GE Life Sciences) at room temperature. Briefly, mouse anti-human IgG Fc antibodies were immobilized on activated CM5 biosensor chips (Cat. No. BR100530, GE Life Sciences) by amine coupling. Purified monoclonal antibody candidates were flowed over the chip surface and captured by anti-human IgG antibodies. Serial dilutions of soluble monomeric human cMET fusion protein with a his tag (generated in-house, SEQ ID NO: 1) were then injected onto the antibody-captured surface and the binding affinity and kinetics were determined by using a one-to-one Langmuir binding model (BIA Evaluation Software TM , General Life Sciences) analyzed the changes in surface plasmon resonance signals to calculate the association rate (k on ) and dissociation rate (k off ). The equilibrium dissociation constant (K D ) is calculated as the ratio k off / k on The binding affinity and kinetic curves of the selected monoclonal anti-cMET antibodies are shown in Table 9 below. The detailed binding curves of the selected candidates are shown in Figures 1A-1L shown. Table 9. Binding kinetics of anti-cMET antibodies to monomeric cMET protein Example 5. Blocking activity of monoclonal anti-cMET antibodies on ligand-induced signaling

[0376] To assess the activity of anti-cMET antibodies in interfering with HGF-cMET interactions and inhibiting downstream signaling, inhibition of HGF-induced ERK phosphorylation at T202 / Y204 following antibody treatment was used as a cellular readout. Briefly, H596 cells (an epithelial-like cell line isolated from human lung cancer) were seeded into a 96-well assay plate and incubated at 37°C, 5% CO2. After 24 hours, the cells were starved for 4 hours with FBS-free medium. Serial dilutions of anti-cMET antibodies were then added to each well and incubated at 37°C for 1 hour. 100 pM human HGF was added to each well and incubated at 37°C for 15 minutes. The medium was then discarded, and 1× lysis buffer was added to the assay plate and incubated at room temperature for 30 minutes. Cellular phospho-ERK was measured using the ERK Phospho-T202 / Y204 Kit (PerkinElmer). IC50 values ​​were determined by fitting the dose-response data to a four-parameter logistic model using GraphPad Prism. Imax was calculated using the following formula: % inhibition = 100*[1-(X-MIN) / (MAX-MIN)]. X is the FRET signal at a given compound concentration. MAX is the signal in the presence of H596 cells and 100 pM hHGF. MIN is the signal in the presence of starvation medium as background signal. IC50 and Imax of monoclonal anti-cMET antibodies are sho...

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds to human cMET, the antibody or antigen-binding fragment thereof comprising: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, and (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 61, (b) HCDR2 of SEQ ID NO: 62, (c) HCDR3 of SEQ ID NO: 63, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (16) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (17) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (18) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO:

68.

2. The antibody or antigen-binding fragment thereof according to claim 1, comprising: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91 or SEQ ID NO:93, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:4 or SEQ ID NO:72, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:54 or SEQ ID NO:82, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (5) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:34 or SEQ ID NO:78, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (10) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:39 or SEQ ID NO:79, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (11) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:44 or SEQ ID NO:80, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (12) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:49 or SEQ ID NO:81, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (13) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (14) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 144, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; or (15) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 145, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:

64.

3. The antibody or antigen-binding fragment thereof of any one of the preceding claims, wherein SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, SEQ ID NO: 4, SEQ ID NO: 72, SEQ ID NO: 9, SEQ ID NO: 73, SEQ ID NO: 54, SEQ ID NO: 82, SEQ ID NO: 14, SEQ ID NO: 74, SEQ ID NO: 19, SEQ ID NO: 75, SEQ ID NO: 24, SEQ ID NO: 76, SEQ ID NO: 29, SEQ ID NO: 77, SEQ ID NO: 34, SEQ ID NO: 78, SEQ ID NO: 39, SEQ ID NO: 79, SEQ ID NO: 44, SEQ ID NO: 80, SEQ ID NO: 49, SEQ ID NO: 81, SEQ ID NO: 59, SEQ ID NO: 83, SEQ ID NO: 144, SEQ ID NO: 145 or SEQ ID NO: 86 is selected from the group consisting of: One, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted in NO:

64.

4. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, comprising: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54 or SEQ ID NO: 82, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (12) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (13) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (14) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (15) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 145, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO:

64.

5. The antibody or antigen-binding fragment thereof according to any one of the preceding claims, which is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment or a F(ab')2 fragment.

6. A multispecific antibody or antigen-binding fragment thereof, comprising a first antigen-binding domain that specifically binds to a first epitope of human cMET, and a second antigen-binding domain that specifically binds to a second epitope of human cMET, wherein the first epitope is different from the second epitope, or wherein the first antigen binding domain is different from the second antigen binding domain, or wherein the first antigen binding domain does not compete with the second antigen binding domain.

7. The multispecific antibody or antigen-binding fragment thereof according to claim 6, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO:

68.

8. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 7, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91 or SEQ ID NO:93, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:4 or SEQ ID NO:72, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:24 or SEQ ID NO:76, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (7) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:34 or SEQ ID NO:78, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (9) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:39 or SEQ ID NO:79, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (10) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:44 or SEQ ID NO:80, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (11) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:49 or SEQ ID NO:81, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; or (12) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 144, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:

64.

9. The multispecific antibody or antigen-binding fragment thereof of claim 8, wherein in the first antigen-binding domain that specifically binds to the first epitope of human cMET, SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:4, SEQ ID NO:72, SEQ ID NO:9, SEQ ID NO:73, SEQ ID NO:14, SEQ ID NO:74, SEQ ID NO:19, SEQ ID NO:75, SEQ ID NO:24, SEQ ID NO:76, SEQ ID NO:29, SEQ ID NO:77, SEQ ID NO:34, SEQ ID NO:78, SEQ ID NO:39, SEQ ID NO:79, SEQ ID NO:44, SEQ ID NO:80, SEQ ID NO:49, SEQ ID NO:81, SEQ ID NO:144, or SEQ ID NO: One, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted in NO:

64.

10. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 9, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO:

64.

11. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 10, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO:61, (b) HCDR2 of SEQ ID NO:62, (c) HCDR3 of SEQ ID NO:63, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO:66, (e) LCDR2 of SEQ ID NO:67, and (f) LCDR3 of SEQ ID NO:

68.

12. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 11, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:54 or SEQ ID NO:82, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:59 or SEQ ID NO:83, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; or (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 145, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:

64.

13. The multispecific antibody or antigen-binding fragment thereof of claim 12, wherein in the second antigen-binding domain that specifically binds to a second epitope of human cMET, one, two, three, four, five, six, seven, eight, nine, or ten amino acids have been inserted, deleted, or substituted within SEQ ID NO: 54, SEQ ID NO: 82, SEQ ID NO: 59, SEQ ID NO: 83, SEQ ID NO: 145, or SEQ ID NO:

64.

14. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 13, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54 or SEQ ID NO: 82, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (3) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 145, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO:

64.

15. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 14, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO:

68.

16. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 15, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 82 or SEQ ID NO: 145, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:

64.

17. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 14, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementary determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 (light chain complementary determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO:61, (b) HCDR2 of SEQ ID NO:62, (c) HCDR3 of SEQ ID NO:63, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO:66, (e) LCDR2 of SEQ ID NO:67, and (f) LCDR3 of SEQ ID NO:

68.

18. The multispecific antibody or antigen-binding fragment thereof of any one of claims 6 to 14 and 17, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The second antigen-binding domain that specifically binds to the second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:

64.

19. The multispecific antibody or antigen-binding fragment thereof of any one of claims 6 to 18, wherein the multispecific antibody or antigen-binding fragment thereof is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

20. The multispecific antibody or antigen-binding fragment thereof of any one of claims 6 to 19, wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment; and The second antigen-binding domain that specifically binds to the second epitope of human cMET is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

21. The multispecific antibody or antigen-binding fragment thereof of any one of claims 6 to 20, wherein the multispecific antibody is a bispecific antibody or a trispecific antibody.

22. The multispecific antibody or antigen-binding fragment thereof of any one of claims 6 to 21, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises a first heavy chain constant region comprising SEQ ID NO: 95, and the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises a second heavy chain constant region comprising SEQ ID NO: 96; or wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises a first heavy chain constant region comprising SEQ ID NO: 96, and the second antigen-binding domain that specifically binds to the second epitope of human cMET comprises a second heavy chain constant region comprising SEQ ID NO:

95.

23. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 22, further comprising a third antigen-binding domain that specifically binds to a human tumor-associated antigen (TAA).

24. The multispecific antibody or antigen-binding fragment thereof of any one of claim 23, wherein the TAA is EGFR.

25. The multispecific antibody or antigen-binding fragment thereof of any one of claims 6-24, further comprising an amino acid linker, wherein the amino acid linker is any sequence of SEQ ID NO: 97 to SEQ ID NO:

139.

26. The antibody, multispecific antibody, or antigen-binding fragment thereof according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain constant region of the IgG1, IgG2, IgG3, or IgG4 subclass and / or a light chain constant region of the kappa or lambda type.

27. The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain constant region of the IgG1 subclass and a light chain constant region of the kappa type.

28. The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof has antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC).

29. The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof has reduced glycosylation or is aglycosylated or is hypofucosylated.

30. The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is afucosylated.

31. The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises an added bisecting GlcNac structure.

32. The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the above claims, wherein the antibody or antigen-binding fragment thereof comprises an Fc domain, and wherein the Fc domain is an IgG1 Fc with extended half-life.

33. The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the antibody, or antigen-binding fragment thereof, is conjugated to a cytotoxin.

34. The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding claims, wherein the antibody, or antigen-binding fragment thereof, is conjugated to a cytotoxin via a cytotoxin linker.

35. A pharmaceutical composition comprising the antibody, multispecific antibody, or antigen-binding fragment thereof according to any one of the preceding claims, and a pharmaceutically acceptable carrier.

36. A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the antibody, multispecific antibody, or antigen-binding fragment thereof according to any one of claims 1 to 34, or the pharmaceutical composition according to claim 35.

37. The method of claim 36, wherein the cancer carries a cMET gene alteration and / or the growth of the cancer cell is driven by cMET signaling.

38. The method of claim 37, wherein the cMET signaling is ligand-independent.

39. The method of claim 37, wherein the cMET signaling is ligand-dependent.

40. The method of claim 37, wherein the cMET genetic alteration is cMET overexpression, genomic amplification and / or mutation, which results in constitutively active cMET signaling.

41. The method of any one of claims 36-40, wherein the cancer is gastric cancer, colorectal cancer, lung cancer, liver cancer, head and neck cancer, kidney cancer, breast cancer, or brain cancer.

42. The method of claim 41, wherein the lung cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

43. The method of claim 42, wherein the non-small cell lung cancer is squamous non-small cell lung cancer.

44. The method of claim 41, wherein the liver cancer is hepatocellular carcinoma.

45. The method of claim 41, wherein the head and neck cancer is head and neck squamous cell carcinoma.

46. ​​The method of any one of claims 36-45, wherein the antibody or antigen-binding fragment thereof is administered in combination with another therapeutic agent.

47. The method of claim 46, wherein the therapeutic agent is an immune checkpoint inhibitor.

48. The method of claim 46, wherein the therapeutic agent is an anti-PD-1 antibody.

49. The method of claim 48, wherein the anti-PD1 antibody is tislelizumab.

50. A multispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding domain that specifically binds to a first epitope of human cMET; a second antigen-binding domain that specifically binds to a second epitope of human cMET; and The third antigen-binding domain specifically binds to human EGFR; wherein the first epitope is different from the second epitope, or wherein the first antigen binding domain does not compete with the second antigen binding domain.

51. The multispecific antibody or antigen-binding fragment thereof of claim 50, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO:

68.

52. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-51, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91 or SEQ ID NO:93, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:4 or SEQ ID NO:72, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:24 or SEQ ID NO:76, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (7) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:34 or SEQ ID NO:78, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (9) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:39 or SEQ ID NO:79, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (10) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:44 or SEQ ID NO:80, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (11) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:49 or SEQ ID NO:81, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; or (12) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 144, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:

64.

53. The multispecific antibody or antigen-binding fragment thereof of claim 52, wherein in the first antigen-binding domain that specifically binds to the first epitope of human cMET, SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:4, SEQ ID NO:72, SEQ ID NO:9, SEQ ID NO:73, SEQ ID NO:14, SEQ ID NO:74, SEQ ID NO:19, SEQ ID NO:75, SEQ ID NO:24, SEQ ID NO:76, SEQ ID NO:29, SEQ ID NO:77, SEQ ID NO:34, SEQ ID NO:78, SEQ ID NO:39, SEQ ID NO:79, SEQ ID NO:44, SEQ ID NO:80, SEQ ID NO:49, SEQ ID NO:81, SEQ ID NO:144, or SEQ ID NO: One, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted in NO:

64.

54. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-53, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO:

64.

55. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-54, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO:61, (b) HCDR2 of SEQ ID NO:62, (c) HCDR3 of SEQ ID NO:63, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO:66, (e) LCDR2 of SEQ ID NO:67, and (f) LCDR3 of SEQ ID NO:

68.

56. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-55, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:54 or SEQ ID NO:82, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; (2) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:59 or SEQ ID NO:83, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64; or (3) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 145, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:

64.

57. The multispecific antibody or antigen-binding fragment thereof of claim 56, wherein in the second antigen-binding domain that specifically binds to a second epitope of human cMET, one, two, three, four, five, six, seven, eight, nine or ten amino acids have been inserted, deleted or substituted within SEQ ID NO: 54, SEQ ID NO: 82, SEQ ID NO: 59, SEQ ID NO: 83, SEQ ID NO: 145 or SEQ ID NO:

64.

58. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-57, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54 or SEQ ID NO: 82, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (3) a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 145, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO:

64.

59. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24 and 50-58, wherein the third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 155, (b) HCDR2 of SEQ ID NO: 156, (c) HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 158, (e) LCDR2 of SEQ ID NO: 159, and (f) LCDR3 of SEQ ID NO:

160.

60. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24 and 50-59, wherein the third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 142, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:

143.

61. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24 and 50-60, wherein The first antigen binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; The second antigen binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 155, (b) HCDR2 of SEQ ID NO: 156, (c) HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 158, (e) LCDR2 of SEQ ID NO: 159, and (f) LCDR3 of SEQ ID NO:

160.

62. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24 and 50-61, wherein The first antigen binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; The second antigen binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 82, or SEQ ID NO: 145, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 142, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:

143.

63. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24 and 50-60, wherein The first antigen binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and a light chain variable region comprising: (d) LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 8, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 11, (b) HCDR2 of SEQ ID NO: 12, (c) HCDR3 of SEQ ID NO: 13, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 16, (b) HCDR2 of SEQ ID NO: 17, (c) HCDR3 of SEQ ID NO: 18, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 21, (b) HCDR2 of SEQ ID NO: 22, (c) HCDR3 of SEQ ID NO: 23, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 26, (b) HCDR2 of SEQ ID NO: 27, (c) HCDR3 of SEQ ID NO: 28, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 31, (b) HCDR2 of SEQ ID NO: 32, and (c) HCDR3 of SEQ ID NO: 33, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 36, (b) HCDR2 of SEQ ID NO: 37, (c) HCDR3 of SEQ ID NO: 38, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 41, (b) HCDR2 of SEQ ID NO: 42, (c) HCDR3 of SEQ ID NO: 43, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (10) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 46, (b) HCDR2 of SEQ ID NO: 47, (c) HCDR3 of SEQ ID NO: 48, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (11) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 51, (b) HCDR2 of SEQ ID NO: 52, (c) HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (12) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 84, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (13) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 86, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (14) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 88, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; (15) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 90, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; or (16) a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; The second antigen binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 61, (b) HCDR2 of SEQ ID NO: 62, (c) HCDR3 of SEQ ID NO: 63, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 155, (b) HCDR2 of SEQ ID NO: 156, (c) HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 158, (e) LCDR2 of SEQ ID NO: 159, and (f) LCDR3 of SEQ ID NO:

160.

64. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24, 50-60, and 63, wherein The first antigen binding domain that specifically binds to the first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 72, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (2) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 73, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (3) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO: 74, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (4) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 75, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (5) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 24 or SEQ ID NO: 76, and a light chain variable region (VL) of SEQ ID NO: 64; (6) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 77, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (7) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 34 or SEQ ID NO: 78, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (8) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 39 or SEQ ID NO: 79, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (9) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 44 or SEQ ID NO: 80, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (10) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 49 or SEQ ID NO: 81, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; (11) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, or SEQ ID NO: 93, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; or (12) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; The second antigen binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 59 or SEQ ID NO: 83, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The third antigen-binding domain that specifically binds to human EGFR comprises: A heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 142, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:

143.

65. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24 and 50-64, wherein The first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; The second antigen binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 56, (b) HCDR2 of SEQ ID NO: 57, (c) HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) LCDR3 of SEQ ID NO: 68; and The third antigen binding domain that specifically binds to human EGFR comprises: a heavy chain variable region comprising (a) HCDR1 of SEQ ID NO: 155, (b) HCDR2 of SEQ ID NO: 156, (c) HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising: (d) LCDR1 of SEQ ID NO: 158, (e) LCDR2 of SEQ ID NO: 159, and (f) LCDR3 of SEQ ID NO:

160.

66. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24 and 50-65, wherein The first antigen-binding domain that specifically binds to the first epitope of human cMET comprises: a heavy chain variable region (VH), the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 144, and a light chain variable region (VL), the light chain variable region comprising the amino acid sequence of SEQ ID NO: 64; The second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 145, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 64; and The third antigen-binding domain that specifically binds to human EGFR comprises: a heavy chain variable region (VH), which comprises the amino acid sequence of SEQ ID NO: 142, and a light chain variable region (VL), which comprises the amino acid sequence of SEQ ID NO:

143.

67. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-66, wherein the multispecific antibody or antigen-binding fragment thereof is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

68. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24 and 50-66, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment; The second antigen-binding domain that specifically binds to a second epitope of human cMET is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment; and The third antigen-binding domain that specifically binds to human EGFR is a monoclonal antibody, a human engineered antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or a F(ab')2 fragment.

69. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24 and 50-68, wherein the third antigen-binding domain that specifically binds to human EGFR comprises a scFv comprising a VH having amino acids of SEQ ID NO: 142 and a VL having amino acids of SEQ ID NO: 143; Optionally, the VH and VL are joined via a first amino acid linker; Optionally, the first amino acid linker is any sequence of SEQ ID NO: 97 to SEQ ID NO: 139; Preferably, the first amino acid linker is SEQ ID NO:

139.

70. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24 and 50-69, wherein the third antigen-binding domain that specifically binds to human EGFR comprises a scFv having the amino acid sequence of SEQ ID NO:

161.

71. The multispecific antibody or antigen-binding fragment thereof of any one of claims 24 and 50-70, wherein the multispecific antibody is a trispecific antibody.

72. The multispecific antibody or antigen-binding fragment thereof as described in any one of claims 50-71, wherein the multispecific antibody or antigen-binding fragment thereof comprises a heavy chain constant region of the IgG1, IgG2, IgG3 or IgG4 subclass and / or a light chain constant region of the κ or λ type.

73. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-72, wherein the multispecific antibody or antigen-binding fragment thereof comprises a heavy chain constant region of the IgG1 subclass and a light chain constant region of the kappa type.

74. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-73, wherein the multispecific antibody or antigen-binding fragment thereof has antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC).

75. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-74, wherein the multispecific antibody or antigen-binding fragment thereof has reduced glycosylation or is aglycosylated or is hypofucosylated.

76. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-75, wherein the multispecific antibody or antigen-binding fragment thereof is afucosylated.

77. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-76, wherein the multispecific antibody or antigen-binding fragment thereof comprises an added bisecting GlcNac structure.

78. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-77, wherein the multispecific antibody or antigen-binding fragment thereof comprises an Fc domain, and wherein the Fc domain is an IgG1 Fc with extended half-life.

79. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-78, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises a first heavy chain constant region comprising SEQ ID NO: 95, and the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises a second heavy chain constant region comprising SEQ ID NO: 96; or wherein the first antigen-binding domain that specifically binds to the first epitope of human cMET comprises a first heavy chain constant region comprising SEQ ID NO: 96, and the second antigen-binding domain that specifically binds to the second epitope of human cMET comprises a second heavy chain constant region comprising SEQ ID NO:

95.

80. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-79, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises a first light chain constant region, and the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises a second light chain constant region; Optionally, the first light chain constant region and the second light chain constant region are different; or Optionally, the first light chain constant region and the second light chain constant region are identical.

81. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 50 to 80, further comprising a second amino acid linker, wherein the second amino acid linker is any sequence of SEQ ID NO: 97 to SEQ ID NO: 139, preferably, the second amino acid linker is SEQ ID NO:

139.

82. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50 to 81, comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein (1) a VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to the second epitope of human cMET, and a second heavy chain constant region arranged in the N-terminal to C-terminal direction in the first polypeptide; (2) the VH and first heavy chain constant regions of the first antigen-binding domain that specifically bind to the first epitope of human cMET are arranged in the N-terminal to C-terminal direction in the second polypeptide, or A VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to the first epitope of human cMET, and a first heavy chain constant region are arranged in the N-terminal to C-terminal direction in the second polypeptide; (3) the VL of the second antigen-binding domain that specifically binds to the second epitope of human cMET and the second light chain constant region are arranged in the N-terminal to C-terminal direction in the third polypeptide; and (4) the VL of the first antigen-binding domain that specifically binds to the first epitope of human cMET and the first light chain constant region are arranged in the N-terminal to C-terminal direction in the fourth polypeptide; Optionally, the second heavy chain constant region is SEQ ID NO: 95, and the first heavy chain constant region is SEQ ID NO: 96; or the second heavy chain constant region is SEQ ID NO: 96, and the first heavy chain constant region is SEQ ID NO: 95; Optionally, the first amino acid linker is SEQ ID NO: 139; Optionally, the second amino acid linker is SEQ ID NO: 139; Optionally, the VL of the first antigen binding domain and the VL of the second antigen binding domain are identical; Optionally, the first light chain constant region and the second light chain constant region are identical; Optionally, the third polypeptide and the fourth polypeptide are identical.

83. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50 to 82, comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein (1) a VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to the first epitope of human cMET, and a first heavy chain constant region arranged in the direction from N-terminus to C-terminus in the first polypeptide; (2) the VH and the second heavy chain constant region of the second antigen-binding domain that specifically bind to the second epitope of human cMET are arranged in the N-terminus to C-terminus direction in the second polypeptide, or A VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to a second epitope of human cMET, and a second heavy chain constant region are arranged in the N-terminal to C-terminal direction in the second polypeptide; (3) the VL of the first antigen-binding domain that specifically binds to the first epitope of human cMET and the first light chain constant region are arranged in the N-terminal to C-terminal direction in the third polypeptide; and (4) the VL of the second antigen-binding domain that specifically binds to the second epitope of human cMET and the second light chain constant region are arranged in the N-terminal to C-terminal direction in the fourth polypeptide; Optionally, the second heavy chain constant region is SEQ ID NO: 95, and the first heavy chain constant region is SEQ ID NO: 96; or the second heavy chain constant region is SEQ ID NO: 96, and the first heavy chain constant region is SEQ ID NO: 95; Optionally, the first amino acid linker is SEQ ID NO: 139; Optionally, the second amino acid linker is SEQ ID NO: 139; Optionally, the VL of the first antigen binding domain and the VL of the second antigen binding domain are identical; Optionally, the first light chain constant region and the second light chain constant region are identical; Optionally, the third polypeptide and the fourth polypeptide are identical.

84. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50 to 83, comprising a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein (1) a VL that specifically binds to the third antigen-binding domain of human EGFR, optionally a first amino acid linker, a VH that specifically binds to the third antigen-binding domain of human EGFR, optionally a second amino acid linker, a VH that specifically binds to the second epitope of human cMET, and a second heavy chain constant region arranged in the N-terminal to C-terminal direction in the first polypeptide; (2) the VH of the first antigen-binding domain that specifically binds to the first epitope of human cMET and the first heavy chain constant region are arranged in the N-terminal to C-terminal direction in the second polypeptide; (3) the VL of the second antigen-binding domain that specifically binds to the second epitope of human cMET and the second light chain constant region are arranged in the N-terminal to C-terminal direction in the third polypeptide; and (4) the VL of the first antigen-binding domain that specifically binds to the first epitope of human cMET and the first light chain constant region are arranged in the N-terminal to C-terminal direction in the fourth polypeptide; Optionally, the second heavy chain constant region is SEQ ID NO: 95, and the first heavy chain constant region is SEQ ID NO: 96; or the second heavy chain constant region is SEQ ID NO: 96, and the first heavy chain constant region is SEQ ID NO: 95; Optionally, the first amino acid linker is SEQ ID NO: 139; Optionally, the second amino acid linker is SEQ ID NO: 139; Optionally, the VL of the first antigen binding domain and the VL of the second antigen binding domain are identical; Optionally, the first light chain constant region and the second light chain constant region are identical; Optionally, the third polypeptide and the fourth polypeptide are identical.

85. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-84, comprising a first polypeptide, a second polypeptide, and a third polypeptide, wherein (1) the first polypeptide has an amino acid sequence of SEQ ID NO: 153, the second polypeptide has an amino acid sequence of SEQ ID NO: 150, and the third polypeptide has an amino acid sequence of SEQ ID NO: 148; (2) the first polypeptide has the amino acid sequence of SEQ ID NO: 146, the second polypeptide has the amino acid sequence of SEQ ID NO: 147, and the third polypeptide has the amino acid sequence of SEQ ID NO: 148; (3) the first polypeptide has the amino acid sequence of SEQ ID NO: 149, the second polypeptide has the amino acid sequence of SEQ ID NO: 150, and the third polypeptide has the amino acid sequence of SEQ ID NO: 151; (4) the first polypeptide has the amino acid sequence of SEQ ID NO: 149, the second polypeptide has the amino acid sequence of SEQ ID NO: 150, and the third polypeptide has the amino acid sequence of SEQ ID NO: 152; (5) the first polypeptide has the amino acid sequence of SEQ ID NO: 153, the second polypeptide has the amino acid sequence of SEQ ID NO: 154, and the third polypeptide has the amino acid sequence of SEQ ID NO: 148; or (6) The first polypeptide has an amino acid sequence of SEQ ID NO: 146, the second polypeptide has an amino acid sequence of SEQ ID NO: 150, and the third polypeptide has an amino acid sequence of SEQ ID NO:

148.

86. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50-85, wherein the multispecific antibody or antigen-binding fragment thereof comprises (1) the first polypeptide of SEQ ID NO: 153, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO: 148; (2) the first polypeptide of SEQ ID NO: 146, the second polypeptide of SEQ ID NO: 147, and the third polypeptide of SEQ ID NO: 148; (3) the first polypeptide of SEQ ID NO: 149, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO: 151; (4) the first polypeptide of SEQ ID NO: 149, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO: 152; (5) the first polypeptide of SEQ ID NO: 153, the second polypeptide of SEQ ID NO: 154, and the third polypeptide of SEQ ID NO: 148; or (6) The first polypeptide of SEQ ID NO: 146, the second polypeptide of SEQ ID NO: 150, and the third polypeptide of SEQ ID NO:

148.

87. A pharmaceutical composition comprising the multispecific antibody or antigen-binding fragment thereof according to any one of claims 50 to 86, and a pharmaceutically acceptable carrier.

88. A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the multispecific antibody or antigen-binding fragment thereof according to any one of claims 50-86, or the pharmaceutical composition according to claim 87.

89. The method of claim 88, wherein the cancer carries a cMET gene alteration and / or the growth of the cancer cell is driven by cMET signaling.

90. The method of claim 89, wherein the cMET signaling is ligand-independent.

91. The method of claim 89, wherein the cMET signaling is ligand-dependent.

92. The method of claim 89, wherein the cMET genetic alteration is cMET overexpression, genomic amplification and / or mutation, which results in constitutively active cMET signaling.

93. The method of claim 88, wherein the cancer carries an EGFR activating mutation and / or the growth of the cancer cell is driven by EGFR signaling; optionally, the EGFR activating mutation is a deletion or a point mutation.

94. The method of claim 93, wherein the EGFR signaling is ligand-independent.

95. The method of claim 93, wherein the EGFR signaling is ligand-dependent.

96. The method of any one of claims 88-95, wherein the cancer is gastric cancer, colorectal cancer, lung cancer, liver cancer, head and neck cancer, kidney cancer, breast cancer, or brain cancer.

97. The method of claim 96, wherein the lung cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

98. The method of claim 97, wherein the non-small cell lung cancer is squamous non-small cell lung cancer.

99. The method of claim 96, wherein the liver cancer is hepatocellular carcinoma.

100. The method of claim 96, wherein the head and neck cancer is head and neck squamous cell carcinoma.

101. The method of any one of claims 88-100, wherein the multispecific antibody or antigen-binding fragment thereof is administered in combination with another therapeutic agent.

102. The method of claim 101, wherein the therapeutic agent is an immune checkpoint inhibitor.

103. The method of claim 101, wherein the therapeutic agent is an anti-PD-1 antibody.

104. The method of claim 103, wherein the anti-PD1 antibody is tislelizumab.

105. An isolated nucleic acid encoding the antibody, multispecific antibody, or antigen-binding fragment thereof of any one of claims 1 to 34 and 50-86.

106. A vector comprising the nucleic acid of claim 105.

107. A host cell comprising the nucleic acid of claim 105 or the vector of claim 106.

108. A method for producing an antibody, a multispecific antibody, or an antigen-binding fragment thereof, the method comprising culturing the host cell of claim 107, and recovering the antibody, multispecific antibody, or antibody fragment from the culture.

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