Anti-CMET antibodies and methods of use thereof

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 the first antigen-binding domain does not compete with the second antigen-binding domain. The present disclosure also provides uses of the antibodies or multispecific antibodies for treating diseases such as cancer.

Description

[Technical Field]

[0001] Disclosed herein are antibodies that specifically bind to human cMET, multispecific antibodies that specifically bind to two distinct epitopes on human cMET, multispecific antibodies or antigen-binding fragments thereof that specifically bind to human EGFR and human cMET, 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 technology]

[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 important roles in multiple cellular processes, stimulating cell proliferation, survival, invasion, and angiogenesis.

[0003] cMET consists of an extracellular α subunit and a transmembrane β subunit linked by disulfide bonds. The extracellular region consists 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 the dimerization of cMET, which allows its intracellular kinase domain (KD) to undergo autophosphorylation, thereby promoting its dimerization. 1 Active binding sites are formed for proteins that mediate activation of downstream signaling pathways, such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT pathways.

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

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

[0006] Activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) occur in a significant proportion of patients with non-small cell lung cancer (NSCLC) 4.5 Their presence is associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite the initial efficacy of TKIs in treating EGFR mutations harbored in NSCLC, most patients inevitably experience acquired resistance approximately 1 year after initial treatment. 6.7 .

[0007] Mechanisms of acquired resistance are generally classified into several categories, including EGFR mutations, gene amplification, MAPK-PI3K mutations, oncogene fusions, and cell cycle gene mutations. The evolution of EGFR kinase inhibitors has overcome emerging EGFR mutation mechanisms. However, given that the majority of resistance is caused by non-EGFR mutational alterations, overcoming treatment resistance remains a major challenge. Among these, hepatocyte growth factor receptor (cMET) amplification is one of the major alterations leading to resistance after EGFR-TKI treatment. For example, this has been identified in 5–50% of patients who developed resistance to second-line osimertinib treatment and in 7–15% of patients after first-line treatment. 8 .

[0008] Mechanistically, because both EGFR and cMET signal through the ERK and AKT pathways, activation of cMET signaling compensates for the loss of EGFR-driven signaling when EGFR is inhibited. This makes a strategy that combines targeting of EGFR and cMET particularly attractive for overcoming cMET amplification-driven compensatory resistance. This strategy has been applied to the EGFR × c-MET bispecific antibody JNJ-61186372 (amivantamab, or abbreviated JNJ-372). 9 .

[0009] Considering the above reasons, there remains an unmet medical need for therapeutic agents that target EGFR and / or cMET. Summary of the Invention

[0010] The present disclosure includes antibodies or antibody fragments thereof that specifically bind to human cMET, and multispecific antibodies or antibody fragments thereof that specifically bind to two distinct (e.g., non-overlapping) epitopes of human cMET. In addition, the antibodies and antibody fragments thereof disclosed herein can be used to construct multispecific antibodies that include other modalities, such as a second tumor-associated antigen (TAA), immune checkpoint, or immunostimulatory agent, or to construct antibody-drug conjugates (ADCs), or to form fusion proteins. cMET antibodies can potentially be used, alone or in combination with other therapeutic agents, for the treatment or prevention of cancer.

[0011] The present disclosure includes multispecific antibodies or antibody fragments thereof that specifically bind to two distinct (e.g., non-overlapping) epitopes of human EGFR and human cMET. The multispecific antibodies or antibody fragments thereof can potentially be used, alone or in combination with other therapeutic agents, 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, (1) a heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 94; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 8, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 11, (b) an HCDR2 of SEQ ID NO: 12, (c) an HCDR3 of SEQ ID NO: 13, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 56, (b) an HCDR2 of SEQ ID NO: 57, (c) an HCDR3 of SEQ ID NO: 58, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 16, (b) an HCDR2 of SEQ ID NO: 17, (c) an HCDR3 of SEQ ID NO: 18, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 21, (b) an HCDR2 of SEQ ID NO: 22, (c) an HCDR3 of SEQ ID NO: 23, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 26, (b) an HCDR2 of SEQ ID NO: 27, (c) an HCDR3 of SEQ ID NO: 28, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 31, (b) an HCDR2 of SEQ ID NO: 32, (c) an HCDR3 of SEQ ID NO: 33, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (9) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 36, (b) an HCDR2 of SEQ ID NO: 37, (c) an HCDR3 of SEQ ID NO: 38, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (10) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 41, (b) an HCDR2 of SEQ ID NO: 42, (c) an HCDR3 of SEQ ID NO: 43, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (11) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 46, (b) an HCDR2 of SEQ ID NO: 47, (c) an HCDR3 of SEQ ID NO: 48, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (12) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 51, (b) an HCDR2 of SEQ ID NO: 52, (c) an HCDR3 of SEQ ID NO: 53, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (13) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 61, (b) an HCDR2 of SEQ ID NO: 62, (c) an HCDR3 of SEQ ID NO: 63, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (14) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 84, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (15) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 86, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (16) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 88, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (17) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 90, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; or (18) The antibody or antigen-binding fragment thereof, comprising 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: 92, 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.

[0014] Embodiment 2: (1) a heavy chain variable region (VH) comprising an amino acid sequence 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64; or (15) The antibody or antigen-binding fragment thereof according to embodiment 1, comprising a heavy chain variable region (VH) comprising an amino acid sequence 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 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 of any one of the preceding embodiments, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids are inserted, deleted, or substituted in 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:64.

[0016] Embodiment 4: (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) The antibody or antigen-binding fragment thereof of any one of the preceding embodiments, comprising 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.

[0017] Embodiment 5: The antibody or antigen-binding fragment thereof of any one of the preceding embodiments, 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.

[0018] Embodiment 6: 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; a multispecific antibody or antigen-binding fragment thereof, wherein the first epitope is different from the second epitope, or the first antigen-binding domain is different from the second antigen-binding domain, or the first antigen-binding domain does not compete with the second antigen-binding domain.

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

[0020] Embodiment 8: 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64; or (12) The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 7, comprising a heavy chain variable region (VH) comprising an amino acid sequence 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 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 according to embodiment 8, wherein in the first antigen-binding domain that specifically binds to a first epitope of human cMET, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids are inserted, deleted or substituted in 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:64.

[0022] Embodiment 10: 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) The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 9, comprising 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.

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

[0024] Embodiment 12: The second antigen-binding domain that specifically binds to a second epitope of human cMET is: (1) a heavy chain variable region (VH) comprising an amino acid sequence 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 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 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64; or (3) The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 11, comprising a heavy chain variable region (VH) comprising an amino acid sequence 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 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 of embodiment 12, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises an insertion, deletion, or substitution of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids 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 second antigen-binding domain that specifically binds to a second epitope of human cMET is (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) The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 13, comprising 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.

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

[0028] Embodiment 16: 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 a second epitope of human cMET is 16. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 15, comprising 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 first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 94; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 8, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 11, (b) an HCDR2 of SEQ ID NO: 12, (c) an HCDR3 of SEQ ID NO: 13, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 16, (b) an HCDR2 of SEQ ID NO: 17, (c) an HCDR3 of SEQ ID NO: 18, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 21, (b) an HCDR2 of SEQ ID NO: 22, (c) an HCDR3 of SEQ ID NO: 23, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 26, (b) an HCDR2 of SEQ ID NO: 27, (c) an HCDR3 of SEQ ID NO: 28, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 31, (b) an HCDR2 of SEQ ID NO: 32, (c) an HCDR3 of SEQ ID NO: 33, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 36, (b) an HCDR2 of SEQ ID NO: 37, (c) an HCDR3 of SEQ ID NO: 38, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 41, (b) an HCDR2 of SEQ ID NO: 42, (c) an HCDR3 of SEQ ID NO: 43, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (10) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 46, (b) an HCDR2 of SEQ ID NO: 47, (c) an HCDR3 of SEQ ID NO: 48, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (11) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 51, (b) an HCDR2 of SEQ ID NO: 52, (c) an HCDR3 of SEQ ID NO: 53, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (12) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 84, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (13) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 86, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (14) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 88, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (15) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 90, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; or (16) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 92, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68, and The second antigen-binding domain that specifically binds to a second epitope of human cMET is 15. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 14, comprising a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 61, (b) an HCDR2 of SEQ ID NO: 62, (c) an HCDR3 of SEQ ID NO: 63, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68.

[0030] Embodiment 18: 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 a second epitope of human cMET is 18. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 14 and 17, comprising 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 according to any one of Embodiments 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.

[0032] Embodiment 20: 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, and 20. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 19, wherein 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 according to any one of embodiments 6 to 20, wherein the multispecific antibody is a bispecific antibody or a trispecific antibody.

[0034] Embodiment 22: 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 22. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 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: 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.

[0035] Embodiment 23: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 6 to 22, further comprising 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 embodiments 23, wherein said TAA is EGFR.

[0037] Embodiment 25: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 6 to 24, further comprising an amino acid linker, wherein said amino acid linker is any sequence among SEQ ID NOs: 97 to 139.

[0038] Embodiment 26: The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding 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 kappa or lambda type.

[0039] Embodiment 27: The antibody, multispecific antibody or antigen-binding fragment thereof of any one of the preceding 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 kappa type.

[0040] Embodiment 28: The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding 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 of any one of the preceding embodiments, wherein the antibody or antigen-binding fragment thereof has reduced glycosylation, no glycosylation, or is hypofucosylated.

[0042] Embodiment 30: The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding embodiments, wherein the antibody or antigen-binding fragment thereof is defucosylated.

[0043] Embodiment 31: The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding embodiments, wherein the antibody or antigen-binding fragment thereof comprises increased bisecting GlcNAc structures.

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

[0045] Embodiment 33: The antibody, multispecific antibody, or antigen-binding fragment thereof of any one of the preceding 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 of any one of the preceding 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 of any one of the preceding embodiments, and a pharmaceutically acceptable carrier.

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

[0049] Embodiment 37: The method of embodiment 36, wherein the cancer has a cMET gene mutation 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 gene mutation is cMET overexpression, genomic amplification, and / or mutation resulting in constitutively active cMET signaling.

[0053] Embodiment 41: The method of any one of embodiments 36 to 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 to 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 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; 1. A multispecific antibody or antigen-binding fragment thereof, wherein the first epitope is different from the second epitope or the first antigen-binding domain does not compete with the second antigen-binding domain.

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

[0064] Embodiment 52: 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64; or (12) The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 51, comprising a heavy chain variable region (VH) comprising an amino acid sequence 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64.

[0065] Embodiment 53: A multispecific antibody or antigen-binding fragment thereof according to embodiment 52, wherein in the first antigen-binding domain that specifically binds to a first epitope of human cMET, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids are inserted, deleted or substituted in 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:64.

[0066] Embodiment 54: 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) The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 53, comprising 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.

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

[0068] Embodiment 56: The second antigen-binding domain that specifically binds to a second epitope of human cMET is: (1) a heavy chain variable region (VH) comprising an amino acid sequence 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 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 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64; or (3) The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 55, comprising a heavy chain variable region (VH) comprising an amino acid sequence 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 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 of embodiment 56, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids 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 second antigen-binding domain that specifically binds to a second epitope of human cMET is: (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) The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 57, comprising 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.

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

[0072] Embodiment 60: The third antigen-binding domain that specifically binds to human EGFR is 60. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 24 and 50 to 59, comprising 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 first antigen-binding domain that specifically binds to the first epitope of human cMET is (1) a heavy chain variable region (VH) comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 94; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 8, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 11, (b) an HCDR2 of SEQ ID NO: 12, (c) an HCDR3 of SEQ ID NO: 13, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 16, (b) an HCDR2 of SEQ ID NO: 17, (c) an HCDR3 of SEQ ID NO: 18, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 21, (b) an HCDR2 of SEQ ID NO: 22, (c) an HCDR3 of SEQ ID NO: 23, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 26, (b) an HCDR2 of SEQ ID NO: 27, (c) an HCDR3 of SEQ ID NO: 28, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 31, (b) an HCDR2 of SEQ ID NO: 32, (c) an HCDR3 of SEQ ID NO: 33, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 36, (b) an HCDR2 of SEQ ID NO: 37, (c) an HCDR3 of SEQ ID NO: 38, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 41, (b) an HCDR2 of SEQ ID NO: 42, (c) an HCDR3 of SEQ ID NO: 43, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (10) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 46, (b) an HCDR2 of SEQ ID NO: 47, (c) an HCDR3 of SEQ ID NO: 48, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (11) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 51, (b) an HCDR2 of SEQ ID NO: 52, (c) an HCDR3 of SEQ ID NO: 53, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (12) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 84, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (13) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 86, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (14) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 88, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (15) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 90, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; or (16) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; The second antigen-binding domain that specifically binds to a second epitope of human cMET is (a) a heavy chain variable region comprising an HCDR1 of SEQ ID NO: 56, (b) an HCDR2 of SEQ ID NO: 57, (c) an HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; and The third antigen-binding domain that specifically binds to human EGFR is 61. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 24 and 50 to 60, comprising a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 155, (b) an HCDR2 of SEQ ID NO: 156, (c) an HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 158, (e) an LCDR2 of SEQ ID NO: 159, and (f) an LCDR3 of SEQ ID NO: 160.

[0074] Embodiment 62: The first antigen-binding domain that specifically binds to the first epitope of human cMET is (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 is 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 is 62. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 24 and 50 to 61, comprising 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 first antigen-binding domain that specifically binds to the first epitope of human cMET is (1) a heavy chain variable region (VH) comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 94; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 8, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 11, (b) an HCDR2 of SEQ ID NO: 12, (c) an HCDR3 of SEQ ID NO: 13, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 16, (b) an HCDR2 of SEQ ID NO: 17, (c) an HCDR3 of SEQ ID NO: 18, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 21, (b) an HCDR2 of SEQ ID NO: 22, (c) an HCDR3 of SEQ ID NO: 23, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 26, (b) an HCDR2 of SEQ ID NO: 27, (c) an HCDR3 of SEQ ID NO: 28, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 31, (b) an HCDR2 of SEQ ID NO: 32, (c) an HCDR3 of SEQ ID NO: 33, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 36, (b) an HCDR2 of SEQ ID NO: 37, (c) an HCDR3 of SEQ ID NO: 38, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 41, (b) an HCDR2 of SEQ ID NO: 42, (c) an HCDR3 of SEQ ID NO: 43, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (10) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 46, (b) an HCDR2 of SEQ ID NO: 47, (c) an HCDR3 of SEQ ID NO: 48, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (11) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 51, (b) an HCDR2 of SEQ ID NO: 52, (c) an HCDR3 of SEQ ID NO: 53, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (12) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 84, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (13) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 86, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (14) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 88, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (15) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 90, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; or (16) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; The second antigen-binding domain that specifically binds to a second epitope of human cMET is (a) a heavy chain variable region comprising an HCDR1 of SEQ ID NO: 61, (b) an HCDR2 of SEQ ID NO: 62, (c) an HCDR3 of SEQ ID NO: 63, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; and The third antigen-binding domain that specifically binds to human EGFR is 61. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 24 and 50 to 60, comprising a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 155, (b) an HCDR2 of SEQ ID NO: 156, (c) an HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 158, (e) an LCDR2 of SEQ ID NO: 159, and (f) an LCDR3 of SEQ ID NO: 160.

[0076] Embodiment 64: The first antigen-binding domain that specifically binds to the first epitope of human cMET is (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 is 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 is 64. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 24, 50 to 60, and 63, comprising 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 first antigen-binding domain that specifically binds to the first epitope of human cMET comprises a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an 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) an HCDR1 of SEQ ID NO: 56, (b) an HCDR2 of SEQ ID NO: 57, (c) an HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; and The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 24 and 50 to 64, wherein the third antigen-binding domain that specifically binds to human EGFR comprises a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 155, (b) an HCDR2 of SEQ ID NO: 156, (c) an HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 158, (e) an LCDR2 of SEQ ID NO: 159, and (f) an LCDR3 of SEQ ID NO: 160.

[0078] Embodiment 66: 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 multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 24 and 50 to 65, 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.

[0079] Embodiment 67: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 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 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 multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 24 and 50 to 66, wherein 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 third antigen-binding domain that specifically binds to human EGFR comprises an scFv comprising a VH having the amino acid sequence of SEQ ID NO: 142 and a VL having the amino acid sequence of SEQ ID NO: 143; optionally, said VH and said VL are connected via a first amino acid linker; Optionally, the first amino acid linker is any sequence among SEQ ID NOs: 97 to 139; The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 24 and 50 to 68, wherein the first amino acid linker is preferably SEQ ID NO: 139.

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

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

[0084] Embodiment 72: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 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 kappa or lambda type.

[0085] Embodiment 73: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 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.

[0086] Embodiment 74: The multispecific antibody or antigen-binding fragment thereof of any one of embodiments 50 to 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 according to any one of embodiments 50 to 74, wherein the multispecific antibody or antigen-binding fragment thereof has reduced glycosylation, no glycosylation or is hypofucosylated.

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

[0089] Embodiment 77: The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 76, wherein the multispecific antibody or antigen-binding fragment thereof comprises increased bisecting GlcNAc structures.

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

[0091] Embodiment 79: 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 79. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 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: 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.

[0092] Embodiment 80: 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, said first light chain constant region and said second light chain constant region are different, or 80. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 79, wherein optionally the first light chain constant region and the second light chain constant region are the same.

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

[0094] Embodiment 82: A method comprising the steps of: (1) the VL of the third antigen-binding domain that specifically binds to human EGFR, optionally the first amino acid linker, the VH of the third antigen-binding domain that specifically binds to human EGFR, optionally the second amino acid linker, the VH of the second antigen-binding domain that specifically binds to a second epitope of human cMET, and the 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; or the VL of the third antigen-binding domain that specifically binds to human EGFR, optionally the first amino acid linker, the VH of the third antigen-binding domain that specifically binds to human EGFR, optionally the second amino acid linker, the VH of the first antigen-binding domain that specifically binds to a 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; 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 said first antigen-binding domain and the VL of said second antigen-binding domain are the same; Optionally, said first light chain constant region and said second light chain constant region are the same; 82. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 81, wherein optionally the third polypeptide and the fourth polypeptide are the same.

[0095] Embodiment 83: A method comprising the steps of: (1) the VL of the third antigen-binding domain that specifically binds to human EGFR, optionally the first amino acid linker, the VH of the third antigen-binding domain that specifically binds to human EGFR, optionally the second amino acid linker, the VH of the first antigen-binding domain that specifically binds to a first epitope of human cMET, and the first heavy chain constant region are arranged in an N-terminal to C-terminal direction in the first polypeptide; (2) the VH of the second antigen-binding domain that specifically binds to the second epitope of human cMET and the second heavy chain constant region are arranged in an N-terminal to C-terminal direction in the second polypeptide; or the VL of the third antigen-binding domain that specifically binds to human EGFR, optionally the first amino acid linker, the VH of the third antigen-binding domain that specifically binds to human EGFR, optionally the second amino acid linker, the VH of the second antigen-binding domain that specifically binds to a second epitope of human cMET, and the second heavy chain constant region are arranged in an 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 an 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 an 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 said first antigen-binding domain and the VL of said second antigen-binding domain are the same; Optionally, said first light chain constant region and said second light chain constant region are the same; 83. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 82, wherein optionally the third polypeptide and the fourth polypeptide are the same.

[0096] Embodiment 84: A method comprising the steps of: (1) the VL of the third antigen-binding domain that specifically binds to human EGFR, optionally the first amino acid linker, the VH of the third antigen-binding domain that specifically binds to human EGFR, optionally the second amino acid linker, the VH of the second antigen-binding domain that specifically binds to a second epitope of human cMET, and the 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; 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 said first antigen-binding domain and the VL of said second antigen-binding domain are the same; Optionally, said first light chain constant region and said second light chain constant region are the same; 84. The multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 83, wherein optionally the third polypeptide and the fourth polypeptide are the same.

[0097] Embodiment 85: A method comprising the steps of: (1) 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: 150, and the third polypeptide has the 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 multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 84, wherein 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: 150, and the third polypeptide has the amino acid sequence of SEQ ID NO: 148.

[0098] Embodiment 86: 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 multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 85, comprising 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 to 86, and a pharmaceutically acceptable carrier.

[0100] Embodiment 88: A method for treating cancer, comprising administering a therapeutically effective amount of the multispecific antibody or antigen-binding fragment thereof according to any one of embodiments 50 to 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 has a cMET gene mutation 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 gene mutation is cMET overexpression, genomic amplification, and / or mutation resulting in constitutively active cMET signaling.

[0105] Embodiment 93: The method of embodiment 88, wherein the cancer has an EGFR activating mutation and / or the growth of the cancer cells is driven by EGFR signaling, and optionally the EGFR activating mutation is a deletion or 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 to 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 to 100, wherein said 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 to 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 process for producing an antibody, multispecific antibody or antigen-binding fragment thereof, comprising culturing the host cell of 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 distinct epitopes of human cMET (e.g., non-overlapping), or whose 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) It can block ligand-independent signal transduction; (2) It can inhibit cancer cell proliferation. (3) It can 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 distinct (e.g., non-overlapping) epitopes 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 (e.g., an EGFR×cMET biparatopic antibody or antigen-binding fragment thereof) and has high binding affinity to human cMET and human EGFR.

[0124] In some embodiments, the present disclosure provides EGFR×cMET biparatopic trispecific antibodies or antigen-binding fragments thereof that have high or excellent 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 an EGFR×cMET biparatopic trispecific antibody or antigen-binding fragment thereof that has high 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 EGFRxcMET biparatopic trispecific antibodies or antigen-binding fragments thereof that significantly block EGFR signaling and / or cMET signaling by downregulating receptors on the cell surface (e.g., by internalization). In addition, the EGFRxcMET biparatopic trispecific antibodies or antigen-binding fragments thereof of the present disclosure have high anti-proliferative activity against EGFR mutation / signaling-driven cancer cells and / or excellent anti-proliferative activity against cMET amplification / signaling-driven cancer cells.

[0127] In some embodiments, the present disclosure provides EGFR×cMET biparatopic trispecific antibodies or antigen-binding fragments thereof that exhibit high or excellent killing efficacy against cancer cells, including EGFR mutation / signaling-driven cancer cells, and particularly cMET amplification / signaling-driven cancer cells.

[0128] In some embodiments, the present disclosure provides EGFRxcMET biparatopic trispecific antibodies or antigen-binding fragments thereof that exhibit high tumor growth inhibition in EGFR mutation / signaling-driven tumors and / or that exhibit 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 better safety.

[0130] In some embodiments, the present disclosure provides a multispecific antibody or antigen-binding fragment thereof that specifically binds to two distinct (e.g., non-overlapping) epitopes 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 EGFRxcMET biparatopic antibody or antigen-binding fragment thereof), and has any one or more of the following characteristics: (1) High or excellent ADCC activity against cancer cells, including EGFR mutation / signaling-driven cancer cells and / or cMET amplification / signaling-driven cancer cells; (2) High ADCP activity against cancer cells, including EGFR mutation / signaling-driven cancer cells and / or cMET amplification / signaling-driven cancer cells. (3) substantial blockage of EGFR signaling and / or cMET signaling by downregulating receptors on the cell surface (e.g., by internalization); (4) High anti-proliferative activity against EGFR mutation / signaling-driven cancer cells and / or excellent anti-proliferative activity against cMET amplification / signaling-driven cancer cells; (5) high or excellent killing effect against cancer cells, including EGFR mutation / signaling-driven cancer cells, and especially cMET amplification / signaling-driven cancer cells; (6) high tumor growth inhibition in EGFR mutation / signaling-driven tumors and / or excellent tumor growth inhibition in cMET amplification / signaling-driven tumors; and (7) Less toxicity and / or better safety.

[0131] In some embodiments, the present disclosure provides EGFR×cMET biparatopic trispecific antibodies or antigen-binding fragments thereof that exhibit superior killing efficacy / tumor growth inhibition against both EGFR mutation / signaling-driven tumors and cMET amplification / signaling-driven tumors, and thus can overcome cMET amplification-driven compensatory resistance or EGFR mutation-driven compensatory resistance. [Brief explanation of the drawings]

[0132] [Figure 1A] 1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody 063Ab10910. [Figure 1B] 1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody 061Ab15310. [Figure 1C] 1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody 063Ab16010. [Figure 1D] 1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody, 063Ab02110. [Figure 1E] 1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody 063Ab15210. [Figure 1F] 1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody 062Ab16310. [Figure 1G] 1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody 063Ab05510. [Figure 1H] 1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody 063Ab07710. [Figure 1I] 1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody 063Ab14710. [Figure 1J] 1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody 061Ab05110. [Figure 1K]1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody, 063Ab03210. [Figure 1L] 1 shows the SPR binding kinetics curve of a representative monoclonal anti-cMET antibody, 063Ab16720. [Figure 2] 1 shows a comparison of the ligand-induced signaling blocking activity of representative monoclonal anti-cMET antibodies. [Figure 3] Representative epitope binning results of monoclonal anti-cMET antibodies are shown. [Figure 4] 1 shows inhibition of ligand-independent signaling by bispecific anti-cMET antibodies in Hs746T cells. [Figure 5] 1 shows the anti-proliferative activity of bispecific anti-cMET antibodies on Hs746T cells. [Figure 6] 1 shows ligand-induced signaling blockade of bispecific anti-cMET antibodies in H596 cells. [Figure 7] 1 shows various EGFRxcMETxcMET trispecific antibody formats that differ in valency of the EGFR scFv and orientation relative to the cMET arms. [Figure 8A] 1 shows the ADCC activity of EGFR×cMET×cMET trispecific antibody against serum-free H1975 cells. [Figure 8B] 1 shows the ADCC activity of the EGFR×cMET×cMET trispecific antibody against H1975 cells in the presence of serum. [Figure 8C] 1 shows the ADCC activity of EGFR×cMET×cMET trispecific antibody against serum-free Hs746T cells. [Figure 8D] 1 shows the ADCC activity of the EGFR×cMET×cMET trispecific antibody against Hs746T cells in the presence of serum. [Figure 9A] 1 shows the ADCP activity of EGFR×cMET×cMET trispecific antibody against serum-free H1975 cells. [Figure 9B] 1 shows the ADCP activity of the EGFR×cMET×cMET trispecific antibody against H1975 cells in the presence of serum. [Figure 9C] 1 shows the ADCP activity of EGFR×cMET×cMET trispecific antibody against serum-free Hs746T. [Figure 9D] 1 shows the ADCP activity of EGFR×cMET×cMET trispecific antibody against Hs746T in the presence of serum. [Figure 10A] 1 shows the anti-proliferative activity of the EGFR×cMET×cMET trispecific antibody against the EGFR signaling-dependent cancer cell line H1975. [Figure 10B] 1 shows the anti-proliferative activity of the EGFR×cMET×cMET trispecific antibody against the EGFR signaling-dependent cancer cell line H2073. [Figure 10C] 1 shows the anti-proliferative activity of the EGFR×cMET×cMET trispecific antibody against the cMET signaling-dependent cancer cell line Hs746T. [Figure 10D] 1 shows the anti-proliferative activity of EGFR×cMET×cMET trispecific antibody against the cMET signaling-dependent cancer cell line EBC-1. [Figure 11] 1 shows the anti-proliferative activity of EGFRxcMETxcMET trispecific antibodies on HEKn cells. [Figure 12] 1 shows that the EGFRxcMETxcMET trispecific antibody TE-642 showed lower TGI and CR rates compared to JNJ-372 in an HCC827 xenograft model (EGFR mutation-driven model). [Figure 13] 1 shows that the EGFRxcMETxcMET trispecific antibody TE-647 exhibited comparable tumor growth inhibition to JNJ-372 in an HCC827 xenograft model (an EGFR mutation-driven model). [Figure 14] 1 shows that the EGFRxcMETxcMET trispecific antibodies TE-642 and TE-646 exhibited tumor growth inhibition in the H1975 xenograft model (EGFR mutation-driven model). [Figure 15]1 shows that the EGFRxcMETxcMET trispecific antibody TE-647 exhibited comparable tumor growth inhibition to JNJ-372 in the H1975 xenograft model (an EGFR mutation-driven model). [Figure 16] We show that the EGFRxcMETxcMET trispecific antibody TE-647 exhibits better tumor growth inhibition than JNJ-372 in the Hs746T xenograft model (cMET amplification-driven model), and the effect is dose-dependent. [Figure 17] We show that the EGFRxcMETxcMET antibody TE-647 exhibits better in vivo activity than JNJ-372 in the EBC-1 (cMET amplification-driven model) xenograft model, and that the effect is dose-dependent. DETAILED DESCRIPTION OF THE INVENTION

[0133] 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 distinct (e.g., non-overlapping) epitopes on human cMET, or whose first antigen-binding domain targeting human cMET does not compete with its second antigen-binding domain targeting human cMET. The present disclosure also provides antibodies with desirable binding affinity and desirable blocking activity against ligand-independent and / or ligand-induced signaling. The antibodies can be used to construct multispecific antibodies with other modalities, such as a second tumor-associated antigen (TAA), immune checkpoint, or immunostimulatory substance, or to construct antibody-drug conjugates (ADCs), or fused with other domains to form fusion proteins. Furthermore, the antibodies and constructs thereof can be used to reduce the likelihood of or treat cancer and related disorders.

[0134] The present disclosure provides multispecific antibodies or antibody fragments thereof that specifically bind to two distinct (e.g., non-overlapping) epitopes on human EGFR and human cMET, or multispecific antibodies or antigen-binding fragments thereof that specifically bind to human EGFR and human cMET, wherein a first antigen-binding domain targeting human cMET does not compete with a second antigen-binding domain targeting human cMET. The present disclosure also provides multispecific antibodies or antibody fragments thereof that have desirable binding affinity, desirable ADCC activity, desirable ADCP activity, desirable blocking activity against EGFR signaling and cMET signaling, desirable antiproliferative activity, and killing effect against EGFR signaling-driven cancer cells and cMET signaling-driven cancer cells. Furthermore, multispecific antibodies and constructs thereof can be used to reduce the likelihood of or treat cancer and related disorders.

[0135] I. Anti-cMET antibody 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.

[0136] 1.1 Group 1 anti-cMET antibodies [Table 1]

[0137] The present disclosure provides an antibody or antigen-binding fragment that specifically binds to human cMET, wherein the antibody or antibody fragment (e.g., antigen-binding fragment) comprises a VH domain having 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 (Table 1). The present disclosure also provides an antibody or antigen-binding fragment that specifically binds to human cMET, wherein the antibody or antigen-binding fragment comprises an HCDR having the amino acid sequence of any one of the HCDRs listed in Table 1. In one aspect, the present disclosure provides an antibody or antigen-binding fragment that specifically binds to human cMET, wherein the antibody comprises one, two, three or more HCDRs having the amino acid sequence of any of the HCDRs listed in Table 1.

[0138] The present disclosure provides an antibody or antigen-binding fragment that specifically binds 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 an antibody or antigen-binding fragment that specifically binds to human cMET, wherein the antibody or antigen-binding fragment comprises an LCDR having the amino acid sequence of any one of the LCDRs listed in Table 1. In one aspect, the present disclosure provides an antibody or antigen-binding fragment that specifically binds to human cMET, wherein the antibody comprises one, two, three or more LCDRs having the amino acid sequence of any of the LCDRs listed in Table 1.

[0139] In one embodiment, an 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: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.

[0140] In another embodiment, an antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises (a) a heavy chain variable region (HCDR) comprising one or more complementarity determining regions 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: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 (LCDR) comprising one or more complementarity determining regions comprising an amino acid sequence selected from the group consisting of SEQ ID NO:66, SEQ ID NO:67, and SEQ ID NO:68.

[0141] In another embodiment, an antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises (a) 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; 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 HCDR3 comprising the amino acid sequence of SEQ ID NO:8, SEQ ID NO:94, SEQ ID NO:104, SEQ ID NO:116, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:221, SEQ ID NO:26, SEQ ID NO:311, SEQ ID NO:36, SEQ ID NO:411, SEQ ID NO:46, or SEQ ID NO:511, SEQ ID NO:120, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO and / or (b) a heavy chain variable region (HCDR) comprising three complementarity determining regions, wherein LCDR1 comprises the amino acid sequence of SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ 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 (LCDR) comprising three complementarity determining regions, wherein LCDR1 comprises the amino acid sequence of SEQ ID NO: 66, LCDR2 comprises the amino acid sequence of SEQ ID NO: 67, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 68.

[0142] In another embodiment, an antibody or antigen-binding fragment thereof that specifically binds to human cMET has one or more of: (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 6, HCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; or (b) HCDR1 comprising the amino acid sequence of SEQ ID NO: 6, HCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 94; or (c) HCDR1 comprising the amino acid sequence of SEQ ID NO: 6, HCDR2 comprising the amino acid sequence of SEQ ID NO: 7, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 84. or HCDR1 comprises the amino acid sequence of SEQ ID NO: 6, HCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 86, or HCDR1 comprises the amino acid sequence of SEQ ID NO: 6, HCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 88, or HCDR1 comprises the amino acid sequence of SEQ ID NO: 6, HCDR2 comprises the amino acid sequence of SEQ ID NO: 7, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 90, or HCDR1 comprises the amino acid sequence of SEQ ID NO: 6 and HCDR2 comprises SEQ ID NO: 7, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 92; or HCDR1 comprises the amino acid sequence of SEQ ID NO: 11, HCDR2 comprises the amino acid sequence of SEQ ID NO: 12, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 13; or HCDR1 comprises the amino acid sequence of SEQ ID NO: 16, HCDR2 comprises the amino acid sequence of SEQ ID NO: 17, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 18; or HCDR1 comprises the amino acid sequence of SEQ ID NO: 21, HCDR2 comprises the amino acid sequence of SEQ ID NO: 22, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 23. or HCDR1 comprises the amino acid sequence of SEQ ID NO: 26, HCDR2 comprises the amino acid sequence of SEQ ID NO: 27, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 28, or HCDR1 comprises the amino acid sequence of SEQ ID NO: 31, HCDR2 comprises the amino acid sequence of SEQ ID NO: 32, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 33, or HCDR1 comprises the amino acid sequence of SEQ ID NO: 36, HCDR2 comprises the amino acid sequence of SEQ ID NO: 37, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 38, or HCDR1 comprises the amino acid sequence of SEQ ID NO: 41,a heavy chain variable region (HCDR) comprising three complementarity determining regions, wherein HCDR2 comprises the amino acid sequence of SEQ ID NO: 42, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 43, or wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 46, HCDR2 comprises the amino acid sequence of SEQ ID NO: 47, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 48, or wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 51, HCDR2 comprises the amino acid sequence of SEQ ID NO: 52, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 53, and / or (b) a light chain variable region (LCDR) comprising three complementarity determining regions, wherein LCDR1 comprises the amino acid sequence of SEQ ID NO: 66, LCDR2 comprises the amino acid sequence of SEQ ID NO: 67, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 68.

[0143] In one embodiment, an 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. HCDR1, HCDR2, and HCDR3, (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 HCDR from the heavy chain variable region (VH) set forth in SEQ ID NO: 34 or SEQ ID NO: 78. 3, (13) HCDR1, HCDR2, and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO: 39 or SEQ ID 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) comprising LCDR1 (light chain complementarity-determining region 1), LCDR2, and LCDR3 from the light chain variable region (VL) set forth in SEQ ID NO: 64.

[0144] In one embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET is (1) a heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 94; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 84; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 86; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (4) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 88, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (5) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 90, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; or (6) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 92, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 8, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (8) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 11, (b) an HCDR2 of SEQ ID NO: 12, (c) an HCDR3 of SEQ ID NO: 13, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (9) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 16, (b) an HCDR2 of SEQ ID NO: 17, (c) an HCDR3 of SEQ ID NO: 18, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (10) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 21, (b) an HCDR2 of SEQ ID NO: 22, (c) an HCDR3 of SEQ ID NO: 23, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (11) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 26, (b) an HCDR2 of SEQ ID NO: 27, (c) an HCDR3 of SEQ ID NO: 28, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (12) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 31, (b) an HCDR2 of SEQ ID NO: 32, (c) an HCDR3 of SEQ ID NO: 33, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (13) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 36, (b) an HCDR2 of SEQ ID NO: 37, (c) an HCDR3 of SEQ ID NO: 38, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (14) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 41, (b) an HCDR2 of SEQ ID NO: 42, (c) an HCDR3 of SEQ ID NO: 43, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (15) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 46, (b) an HCDR2 of SEQ ID NO: 47, (c) an HCDR3 of SEQ ID NO: 48, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; or (16) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 51, (b) an HCDR2 of SEQ ID NO: 52, (c) an HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68 (all according to the Kabat definition).

[0145] In one embodiment, the antibody or antigen-binding fragment thereof of the disclosure comprises (a) an antibody or antigen-binding fragment thereof comprising: (a) 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; and / or (b) a heavy chain variable region comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of 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 the amino acid sequence of SEQ ID NO:64, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:64.

[0146] In one embodiment, the antibody or antigen-binding fragment thereof (1) a heavy chain variable region (VH) comprising an amino acid sequence 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64.

[0147] In one embodiment, the disclosure provides an antibody or antigen-binding fragment thereof, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids are inserted, deleted, or substituted (optionally by conservative amino acid substitution) in 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:64, while retaining therapeutic activity / binding specificity / affinity, and optionally, the corresponding sequences of the CDRs are not altered.

[0148] In one embodiment, the 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:64, SEQ ID NO:34 and SEQ ID NO:78 and SEQ ID NO:64, SEQ ID NO:39 and 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 have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids inserted, deleted or substituted (optionally by conservative amino acid substitution) in the sequence of SEQ ID NO:144 and SEQ ID NO:64, while retaining therapeutic activity / binding specificity / affinity, and optionally the corresponding sequences of the CDRs are not altered.

[0149] In one embodiment, the antibody or antigen-binding fragment thereof (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) 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.

[0150] Other antibodies or antigen-binding fragments of the disclosure have been altered but still comprise amino acids with at least 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity within the CDR regions compared to the CDR regions disclosed in Table 1. In some embodiments, other antibodies or antigen-binding fragments of the disclosure comprise amino acid alterations (insertions, deletions, or substitutions, optionally conservative amino acid substitutions) where no more than 1, 2, 3, 4, or 5 amino acids have been altered within the CDR regions compared to the CDR regions set forth in the sequences set forth in Table 1, while maintaining binding specificity and affinity.

[0151] Other antibodies of the disclosure include those in which the amino acids or nucleic acids encoding the amino acids have been altered in the variable regions (e.g., framework regions of the variable regions) but still retain binding specificity / affinity while having 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% percent identity with the variable region sequences set forth in Table 1, and optionally, the corresponding sequences of the CDRs are not altered. In some embodiments, other antibodies of the disclosure comprise amino acid sequence alterations in which 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 altered in the variable regions (e.g., framework regions of the variable regions) compared to the variable regions set forth in the sequences in Table 1, while retaining binding specificity / affinity, and optionally, the corresponding sequences of the CDRs are not altered. The alterations may be insertions, deletions, or substitutions, optionally conservative amino acid substitutions.

[0152] In another embodiment, the present disclosure provides a method for the treatment of human cMET with 1×10 -6 M~1×10 -11 Binding affinity (K DIn another embodiment, the anti-cMET antibody or antigen-binding fragment thereof specifically binds to human cMET at about 1 x 10 -6 M, about 1 x 10 -7 M, about 1 x 10 -8 M, about 1 x 10 -9 M, about 1 x 10 -10 M, or approximately 1 x 10 -11 Binding affinity (K D ) to join them.

[0153] The present disclosure also provides nucleic acid sequences encoding the VH or VL of an antibody that specifically binds human cMET. Such nucleic acid sequences can be optimized for expression in mammalian cells.

[0154] 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. Accordingly, additional antibodies and antigen-binding fragments thereof can be identified based on their ability to cross-compete with the antibodies described in Table 1 in binding assays (e.g., competitively inhibit the binding of the antibodies in a statistically significant manner). The ability of a test antibody to inhibit the binding of an antibody and 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 a related (e.g., structurally similar or spatially proximal) epitope on human cMET as the antibody or antigen-binding fragment thereof with which it competes. In certain embodiments, 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 human or humanized monoclonal antibodies can be prepared and isolated as described herein.

[0155] 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.

[0156] In one embodiment, the antibody or antigen-binding fragment thereof is in an scFv format comprising, from N-terminal to C-terminal, a VH-VL or, from N-terminal to C-terminal, a VL-VH. In some embodiments, the VH and VL are connected via an amino acid linker 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 listed in Table 1. In some embodiments, the VL is any one of the VLs listed 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.

[0157] 1.2 Group 2 anti-cMET antibodies [Table 2]

[0158] 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 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 (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 an HCDR having the 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 the amino acid sequence of any of the HCDRs listed in Table 2.

[0159] The present disclosure provides an antibody or antigen-binding fragment that specifically binds 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 an antibody or antigen-binding fragment that specifically binds to human cMET, wherein the antibody or antigen-binding fragment comprises an LCDR having the amino acid sequence of any one of the LCDRs listed in Table 2. In one aspect, the present disclosure provides an antibody or antigen-binding fragment that specifically binds to human cMET, wherein the antibody comprises one, two, three or more LCDRs having the amino acid sequence of any of the LCDRs listed in Table 2.

[0160] 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.

[0161] In another embodiment, an antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises (a) a heavy chain variable region (HCDR) comprising one or more complementarity determining regions 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, and SEQ ID NO: 63, and / or (b) a light chain variable region (LCDR) comprising one or more complementarity determining regions comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 66, SEQ ID NO: 67, and SEQ ID NO: 68.

[0162] In another embodiment, an antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises (a) a heavy chain variable region (HCDR) comprising three complementarity determining regions, in which HCDR1 comprises the amino acid sequence of SEQ ID NO: 56 or SEQ ID NO: 61, HCDR2 comprises the amino acid sequence of SEQ ID NO: 57 or SEQ ID NO: 62, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 58 or SEQ ID NO: 63, and / or (b) a light chain variable region (LCDR) comprising three complementarity determining regions, in which LCDR1 comprises the amino acid sequence of SEQ ID NO: 66, LCDR2 comprises the amino acid sequence of SEQ ID NO: 67, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 68.

[0163] In another embodiment, an antibody or antigen-binding fragment thereof that specifically binds to human cMET comprises: (a) a heavy chain variable region (HCDR) comprising three complementarity determining regions, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, HCDR2 comprises the amino acid sequence of SEQ ID NO: 57, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 58, or wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 61, HCDR2 comprises the amino acid sequence of SEQ ID NO: 62, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 63; and / or (b) a light chain variable region (LCDR) comprising three complementarity determining regions, wherein LCDR1 comprises the amino acid sequence of SEQ ID NO: 66, LCDR2 comprises the amino acid sequence of SEQ ID NO: 67, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 68.

[0164] In one embodiment, an 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: 54, SEQ ID NO: 82, or SEQ ID NO: 145, (2) HCDR1, HCDR2, and HCDR3 from the heavy chain variable region (VH) set forth 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) set forth in SEQ ID NO: 64.

[0165] In one embodiment, the antibody or antigen-binding fragment thereof that specifically binds to human cMET is (1) a heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 56, (b) an HCDR2 of SEQ ID NO: 57, and (c) an HCDR3 of SEQ ID NO: 58; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (2) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 61, (b) an HCDR2 of SEQ ID NO: 62, and (c) an HCDR3 of SEQ ID NO: 63, and a light chain variable region comprising (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68 (all according to the Kabat definition).

[0166] 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 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 at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:64.

[0167] In one embodiment, the antibody or antigen-binding fragment thereof (1) a heavy chain variable region (VH) comprising an amino acid sequence 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 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 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 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 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64.

[0168] In one embodiment, the disclosure provides an antibody or antigen-binding fragment thereof, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids are inserted, deleted, or substituted (optionally, conservative amino acid substitutions) in 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, and optionally, the corresponding sequences of the CDRs are not altered.

[0169] In one embodiment, the disclosure provides an antibody or antigen-binding fragment thereof, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids are inserted, deleted, or substituted (optionally, conservative amino acid substitutions) in 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, and optionally the corresponding sequences of the CDRs are not altered.

[0170] In one embodiment, the antibody or antigen-binding fragment thereof (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) 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.

[0171] Other antibodies or antigen-binding fragments of the disclosure have been altered but still comprise amino acids with at least 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity within the CDR regions compared to the CDR regions disclosed in Table 2. In some embodiments, other antibodies or antigen-binding fragments of the disclosure comprise amino acid alterations (insertions, deletions, or substitutions, optionally conservative amino acid substitutions) where no more than 1, 2, 3, 4, or 5 amino acids have been altered within the CDR regions compared to the CDR regions set forth in the sequences set forth in Table 2, while maintaining binding specificity and affinity.

[0172] Other antibodies of the disclosure include those in which the amino acids or nucleic acids encoding the amino acids have been altered in the variable regions (e.g., framework regions of the variable regions) but still retain binding specificity / affinity while having 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% percent identity with the variable region sequences set forth in Table 2, and optionally, the corresponding sequences of the CDRs are not altered. In some embodiments, other antibodies of the disclosure comprise amino acid sequence alterations in which 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 altered in the variable regions (e.g., framework regions of the variable regions) compared to the variable regions set forth in the sequences set forth in Table 2, while retaining binding specificity / affinity, and optionally, the corresponding sequences of the CDRs are not altered. The alterations may be insertions, deletions, or substitutions, optionally conservative amino acid substitutions.

[0173] In another embodiment, the present disclosure provides a method for the treatment of human cMET with 1×10 -6 M~1×10 -11 Binding affinity (K DIn another embodiment, the anti-cMET antibody or antigen-binding fragment thereof specifically binds to human cMET at about 1 x 10 -6 M, about 1 x 10 -7 M, about 1 x 10 -8 M, about 1 x 10 -9 M, about 1 x 10 -10 M, or approximately 1 x 10 -11 Binding affinity (K D ) to join them.

[0174] The present disclosure also provides nucleic acid sequences encoding the VH or VL of an antibody that specifically binds human cMET. Such nucleic acid sequences can be optimized for expression in mammalian cells.

[0175] 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. Accordingly, additional antibodies and antigen-binding fragments thereof can be identified in binding assays based on their ability to cross-compete with the antibodies described in Table 2 (e.g., competitively inhibit the binding of the antibodies in a statistically significant manner). The ability of a test antibody to inhibit the binding of an antibody and 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 a related (e.g., structurally similar or spatially proximal) epitope on human cMET as the antibody or antigen-binding fragment thereof with which it competes. In certain embodiments, 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 human or humanized monoclonal antibodies can be prepared and isolated as described herein.

[0176] 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.

[0177] In one embodiment, the antibody or antigen-binding fragment thereof is in an scFv format comprising, from N-terminal to C-terminal, VH-VL or VL-VH. In some embodiments, the VH and VL are connected via an amino acid linker 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 listed in Table 2. In some embodiments, the VL is any one of the VLs listed 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 one of SEQ ID NOs:97-139.

[0178] II. Anti-EGFR antibody The present disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to human EGFR. In one embodiment, the anti-EGFR antibody or antigen-binding fragment thereof binds to human EGFR at a concentration of 1×10 -6 M~1×10 -10 Binding affinity (K D In another embodiment, the anti-EGFR antibody or antigen-binding fragment thereof specifically binds to human EGFR at about 1 x 10 -6 M, about 1 x 10 -7 M, about 1 x 10 -8 M, about 1 x 10 -9 M, or approximately 1 x 10 -10 Binding affinity (K D ) to join them.

[0179] In one embodiment, the anti-EGFR antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising (a) an HCDR1 of SEQ ID NO: 155, (b) an HCDR2 of SEQ ID NO: 156, (c) an HCDR3 of SEQ ID NO: 157, and a light chain variable region (VL) comprising (d) an LCDR1 of SEQ ID NO: 158, (e) an LCDR2 of SEQ ID NO: 159, and (f) an LCDR3 of SEQ ID NO: 160 (according to Kabat numbering).

[0180] In another embodiment, the anti-EGFR antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, and HCDR3 from the heavy chain variable region (VH) set forth in SEQ ID NO: 142, and LCDR1, LCDR2, and LCDR3 from the light chain variable region (VL) set forth in SEQ ID NO: 143.

[0181] In another embodiment, the anti-EGFR antibody or antigen-binding fragment thereof further comprises deletions, insertions, or substitutions of no more than 1, 2, 3, 4, or 5 amino acids within the CDRs, preferably wherein the amino acid substitutions are conservative amino acid substitutions while maintaining binding specificity and affinity.

[0182] In another embodiment, the anti-EGFR antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence 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 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: 143. In another embodiment, 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 in SEQ ID NO: 142 or SEQ ID NO: 143 have been inserted, deleted, or substituted (optionally, conservative amino acid substitutions). In another embodiment, such variations are within the framework regions of the variable regions. In another embodiment, an anti-EGFR antibody or antigen-binding fragment thereof having such variations retains binding specificity and affinity.

[0183] 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.

[0184] In one embodiment, the anti-EGFR antibody or antigen-binding fragment thereof is in an scFv format comprising, from N-terminal to C-terminal, VH-VL or VL-VH. In some embodiments, the VH and VL are connected via an amino acid linker 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 sequence from SEQ ID NOs: 97-139. In one embodiment, the amino acid linker is SEQ ID NO: 139.

[0185] In one embodiment, the antibody or antigen-binding fragment thereof comprises an scFv having the amino acid sequence of SEQ ID NO: 161. In another embodiment, the antibody or antigen-binding fragment thereof comprises an scFv of SEQ ID NO:161.

[0186] III. Multispecific antibodies 3.1 Anti-cMET bispecific antibody The present disclosure provides a bispecific antibody or antigen-binding fragment that specifically binds 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.

[0187] In one embodiment, the first epitope is different from (eg, non-overlapping with) the second epitope, or the first antigen-binding domain does not compete with the second antigen-binding domain.

[0188] In one aspect, the first antigen-binding domain that specifically binds to a first epitope of human cMET and the second antigen-binding domain that specifically binds to a second epitope of human cMET are selected from any of the anti-cMET antibodies described in Section I and are different from each other.

[0189] In one aspect, the first antigen-binding domain that specifically binds to a first epitope of human cMET and the second antigen-binding domain that specifically binds to a second epitope of human cMET are selected from any of the anti-cMET antibodies described in Section I and do not compete with each other.

[0190] In another embodiment, the first antigen-binding domain that specifically binds to a first epitope of human cMET can be any antibody or antigen-binding fragment selected from those described in Section 1.1 "First Group of Anti-cMET Antibodies," including Table 1. The second antigen-binding domain that specifically binds to a second epitope of human cMET can be any antibody or antigen-binding fragment selected from those described in Section 1.2 "Second Group of Anti-cMET Antibodies," including Table 2.

[0191] In some embodiments, the bispecific antibody comprises an antigen-binding fragment, where the antigen-binding fragment can be a Fab, F(ab')2, Fv, single-chain Fv (scFv), or single-domain antibody.

[0192] In one embodiment, the bispecific antibody of the present disclosure is administered to human cMET at a concentration of 1 x 10 -6 M~1×10 -10 M, or even 1×10 -11 Binding affinity (K D In another embodiment, the bispecific antibody of the present disclosure binds to human cMET at about 1 x 10 -6 M, about 1 x 10 -7 M, about 1 x 10 -8 M, about 1 x 10 -9 M, about 1 x 10 -10 M, or approximately 1 x 10 -11 Binding affinity (K D ) to join them.

[0193] In some embodiments, bispecific antibodies of the present disclosure that specifically bind to two distinct epitopes of human cMET (e.g., non-overlapping or non-competing) exhibit better blocking activity against ligand-independent and / or ligand-induced signaling compared to antibodies that comprise only one antigen-binding domain that specifically binds to human cMET.

[0194] In one embodiment, the present disclosure provides a bispecific antibody or antigen-binding fragment thereof, wherein a first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 94; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 8, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 11, (b) an HCDR2 of SEQ ID NO: 12, (c) an HCDR3 of SEQ ID NO: 13, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (4) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 16, (b) an HCDR2 of SEQ ID NO: 17, (c) an HCDR3 of SEQ ID NO: 18, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (5) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 21, (b) an HCDR2 of SEQ ID NO: 22, (c) an HCDR3 of SEQ ID NO: 23, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (6) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 26, (b) an HCDR2 of SEQ ID NO: 27, (c) an HCDR3 of SEQ ID NO: 28, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (7) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 31, (b) an HCDR2 of SEQ ID NO: 32, (c) an HCDR3 of SEQ ID NO: 33, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (8) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 36, (b) an HCDR2 of SEQ ID NO: 37, (c) an HCDR3 of SEQ ID NO: 38, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (9) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 41, (b) an HCDR2 of SEQ ID NO: 42, (c) an HCDR3 of SEQ ID NO: 43, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (10) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 46, (b) an HCDR2 of SEQ ID NO: 47, (c) an HCDR3 of SEQ ID NO: 48, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; or (11) A heavy chain variable region comprising an HCDR1 of SEQ ID NO: 51, (b) an HCDR2 of SEQ ID NO: 52, (c) an HCDR3 of SEQ ID NO: 53, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; and The second antigen-binding domain that specifically binds to a second epitope of human cMET is It comprises a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 56, (b) an HCDR2 of SEQ ID NO: 57, (c) an HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68.

[0195] In one embodiment, the present disclosure provides a bispecific antibody or antigen-binding fragment thereof, wherein a first antigen-binding domain that specifically binds to a first epitope of human cMET comprises: (1) a heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 84; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 86; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 88; and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (4) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, and (c) an HCDR3 of SEQ ID NO: 90, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68, or (5) A heavy chain variable region (VH) comprising (a) an HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 92, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; and The second antigen-binding domain that specifically binds to a second epitope of human cMET is It comprises a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 56, (b) an HCDR2 of SEQ ID NO: 57, (c) an HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68.

[0196] In one embodiment, the present disclosure provides a bispecific antibody or antigen-binding fragment thereof, wherein a 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 a second epitope of human cMET is It 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.

[0197] In one embodiment, the present disclosure provides a bispecific antibody or antigen-binding fragment thereof, wherein a 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 a second epitope of human cMET is It 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.

[0198] In some embodiments, in the above-described bispecific antibodies or antigen-binding fragments thereof, the second antigen-binding domain that specifically binds to a second epitope of human cMET may be altered.

[0199] In one embodiment, the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: It comprises a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 61, (b) an HCDR2 of SEQ ID NO: 62, (c) an HCDR3 of SEQ ID NO: 63, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68.

[0200] In one embodiment, the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises: It 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.

[0201] 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.

[0202] 3.2 Anti-cMET x antigen multispecific antibody In one embodiment, the anti-cMET antibodies disclosed herein (including Section I, "Anti-cMET Antibodies," and Section 3.1, "Anti-cMET Bispecific Antibodies") can be used to construct multispecific antibodies that include other modalities, such as human tumor-associated antigens (TAAs), immune checkpoints, or immunostimulatory agents.

[0203] In one embodiment, an anti-cMET antibody as disclosed herein can be incorporated into an anti-cMETxTAA multispecific antibody, where 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, e.g., comprises at least two antigen-binding domains, where at least one antigen-binding domain sequence specifically binds to a first epitope, cMET, and a second antigen-binding domain sequence specifically binds to a second epitope, TAA.

[0204] In another embodiment, the two antigen-binding domain sequences specifically bind to two distinct epitopes (e.g., non-overlapping or non-competing) of human cMET, the first epitope and the second epitope, respectively, and the third antigen-binding domain sequence specifically binds to a TAA, 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.

[0205] In one embodiment, a multispecific antibody is a bispecific antibody. As used herein, a bispecific antibody specifically binds to only two antigens. A bispecific antibody comprises a first antigen-binding domain that specifically binds to human cMET and a second antigen-binding domain that specifically binds to a TAA. This includes bispecific antibodies comprising a second heavy chain variable domain and a second light chain variable domain that specifically bind to a TAA, and a first heavy chain variable domain and a first light chain variable domain that specifically bind to human cMET. In some embodiments, a bispecific antibody comprises an antigen-binding fragment, where the antigen-binding fragment can be a Fab, F(ab'), Fv, single-chain Fv (scFv), or single-domain antibody.

[0206] In one embodiment, a multispecific antibody is a trispecific antibody. As used herein, a trispecific antibody specifically binds to at least three antigens or epitopes. A 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 a TAA. This includes trispecific antibodies comprising a third heavy chain variable domain and a third light chain variable domain that specifically bind to a 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, a trispecific antibody comprises an antigen-binding fragment, where the antigen-binding fragment can be a Fab, F(ab'), Fv, single-chain Fv (scFv), or single-domain antibody.

[0207] In one embodiment, the multispecific antibodies of the disclosure are administered to human TAA and / or human cMET at a concentration of 1×10 -6 M~1×10 -10 M, or even 1×10 -11 Binding affinity (K DIn another embodiment, the multispecific antibody of the disclosure binds to at least one epitope on human TAA and human cMET at a concentration of about 1 x 10 -6 M, about 1 x 10 -7 M, about 1 x 10 -8 M, about 1 x 10 -9 M, about 1 x 10 -10 M, or approximately 1 x 10 -11 Binding affinity (K D ) to join them.

[0208] Previous work (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 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, which can be readily produced by recombinant expression of nucleic acids encoding antibody polypeptide chains. The multivalent antibodies herein contain three to eight, preferably three or four, antigen-binding domains that specifically bind to at least two antigens.

[0209] 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.

[0210] 3.3 EGFR×cMET multispecific antibody 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.

[0211] In one embodiment, the first epitope is different from the second epitope or the first antigen-binding domain does not compete with the second antigen-binding domain.

[0212] In one embodiment, the EGFRxcMET multispecific antibody further comprises, in addition to the anti-cMET bispecific antibody described in Section 3.1, a third antigen-binding domain that specifically binds to human EGFR.

[0213] In one embodiment, in the anti-cMET x antigen multispecific antibody described in section 3.2, the additional antigen (TAA) is human EGFR.

[0214] In one embodiment, the first antigen-binding domain that specifically binds to a first epitope of human cMET is selected from any of the anti-cMET antibodies described in Section 1.1.

[0215] In one embodiment, the second antigen-binding domain that specifically binds to a second epitope of human cMET is selected from any of the anti-cMET antibodies described in Section 1.2.

[0216] 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.

[0217] In one embodiment, in the EGFR×cMET multispecific antibody or antigen-binding fragment thereof, a first antigen-binding domain that specifically binds to a first epitope of human cMET comprises a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; and a second antigen-binding domain that specifically binds to a second epitope of human cMET comprises (a) an HCDR1 of SEQ ID NO: 56, (b) an HCDR2 of SEQ ID NO: 57. and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68, and the third antigen-binding domain specifically binds to human EGFR. The third antigen-binding domain comprises a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 155, (b) an HCDR2 of SEQ ID NO: 156, (c) an HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 158, (e) an LCDR2 of SEQ ID NO: 159, and (f) an LCDR3 of SEQ ID NO: 160.

[0218] In one embodiment, in the EGFRxcMET multispecific antibody or antigen-binding fragment thereof, a 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; a 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 a 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.

[0219] 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.

[0220] In one embodiment, the EGFRxcMET 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.

[0221] In one embodiment, the EGFRxcMET 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.

[0222] In one embodiment, the EGFRxcMET multispecific antibody or antigen-binding fragment thereof has antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC).

[0223] In one embodiment, the EGFRxcMET multispecific antibody or antigen-binding fragment thereof has reduced glycosylation, no glycosylation, or is hypofucosylated, hi another embodiment, the multispecific antibody or antigen-binding fragment thereof is defucosylated.

[0224] In one embodiment, the EGFRxcMET multispecific antibody or antigen-binding fragment thereof comprises increased bisecting GlcNAc structures.

[0225] In one embodiment, the EGFRxcMET multispecific antibody or antigen-binding fragment thereof comprises an Fc domain, wherein the Fc domain is an IgG1 Fc with extended half-life.

[0226] In one embodiment, the EGFRxcMET multispecific antibody or antigen-binding fragment thereof adopts a knob into a hole (KIH) to form a heterodimer.

[0227] In one embodiment, a 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 a 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.

[0228] In another embodiment, a 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 a 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.

[0229] In another embodiment, the first antigen-binding domain that specifically binds to a first epitope of human cMET and the second antigen-binding domain that specifically binds to a second epitope of human cMET share a common light chain.

[0230] In one embodiment, the first light chain constant region and the second light chain constant region are different, hi another embodiment, the first light chain constant region and the second light chain constant region are the same.

[0231] 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.

[0232] In one embodiment, the first light chain variable region and the second light chain variable region are different, hi another embodiment, the first light chain variable region and the second light chain variable region are the same.

[0233] In one embodiment, the EGFRxcMET multispecific antibody or antigen-binding fragment thereof further comprises an amino acid linker as described herein.

[0234] In one embodiment, the EGFRxcMET multispecific antibody or antigen-binding fragment thereof can be in a variety of formats that differ in the valency and orientation of the EGFR scFv relative to the cMET arm, and can be any of the formats shown in Figure 7, designated TE-644, TE-645, TE-646, TE-647, TE-648, or TE-642.

[0235] In one embodiment, the EGFRxcMET multispecific antibody or antigen-binding fragment thereof comprises a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein (1) the VL of the third antigen-binding domain that specifically binds human EGFR, optionally a first amino acid linker, the VH of the third antigen-binding domain that specifically binds human EGFR, optionally a second amino acid linker, the VH of the second antigen-binding domain that specifically binds a second epitope of human cMET, and the second heavy chain constant region are arranged in an N-terminal to C-terminal direction in the first polypeptide, and (2) the VH of the first antigen-binding domain that specifically binds a 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 a second epitope of human cMET and a 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 a first epitope of human cMET and a first light chain constant region are arranged in an N-terminal to C-terminal direction in the fourth polypeptide.

[0236] In one embodiment, the EGFRxcMET multispecific antibody or antigen-binding fragment thereof comprises a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide, wherein (1) the VL of the third antigen-binding domain that specifically binds human EGFR, optionally a first amino acid linker, the VH of the third antigen-binding domain that specifically binds human EGFR, optionally a second amino acid linker, the VH of the second antigen-binding domain that specifically binds to a second epitope of human cMET, and the second heavy chain constant region are arranged in the first polypeptide, from N-terminus to C-terminus. (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.

[0237] 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.

[0238] 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.

[0239] In one embodiment, the VL of the first antigen-binding domain and the VL of the second antigen-binding domain are the same.

[0240] In another embodiment, the first light chain constant region and the second light chain constant region are the same. In another embodiment, the first light chain constant region and the second light chain constant region are SEQ ID NO: 71.

[0241] In one embodiment, the third polypeptide and the fourth polypeptide are the same.

[0242] In another embodiment, the position of a first antigen-binding domain that specifically binds to a first epitope of human cMET (e.g., BGA-109) and the position of a second antigen-binding domain that specifically binds to a second epitope of human cMET (e.g., BGA-032) may be swapped.

[0243] 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 the amino acid sequence of SEQ ID NO: 153, 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: 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 the amino acid sequence of SEQ ID NO: 146, 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: 148.

[0244] In another embodiment, the multispecific antibody or antigen-binding fragment thereof comprises: (1) a first polypeptide of SEQ ID NO: 153, a second polypeptide of SEQ ID NO: 150, and a third polypeptide of SEQ ID NO: 148; (2) a first polypeptide of SEQ ID NO: 146, a second polypeptide of SEQ ID NO: 147, and a third polypeptide of SEQ ID NO: 148; (3) a first polypeptide of SEQ ID NO: 149, a second polypeptide of SEQ ID NO: 150, and a third polypeptide of SEQ ID NO: 151; (4) a first polypeptide of SEQ ID NO: 149, a second polypeptide of SEQ ID NO: 150, and a third polypeptide of SEQ ID NO: 152; (5) a first polypeptide of SEQ ID NO: 153, a second polypeptide of SEQ ID NO: 154, and a third polypeptide of SEQ ID NO: 148, or (6) A first polypeptide of SEQ ID NO: 146, a second polypeptide of SEQ ID NO: 150, and a third polypeptide of SEQ ID NO: 148.

[0245] IV. Anti-human cMET antibodies conjugated to cytotoxins The anti-human cMET antibodies disclosed herein (Section I, "Anti-cMET Antibodies," and Section III, "Multispecific Antibodies," e.g., the anti-cMET bispecific antibodies of Section 3.1, the anti-cMET x antigen multispecific antibodies of Section 3.2, or the EGFR x cMET multispecific antibodies of Section 3.3) 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 cytotoxin linker.

[0246] cytotoxin Cytotoxins or cytotoxic agents include any agent detrimental to cell growth, viability, or proliferation, 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-(2chloroethyl)-1,2-dimethanesulfonylhydrazide, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-13-one, 1-dehydrotestosterone, 5-fluorouracil, 6-mercaptopurine, 6-thioguanine, 9-aminocamptothecin, actinomycin D, amanitin, aminopterin, anguidine, anthracyclines, anthracyclines, and anthracyclines. Antimycin (AMC), auristatins, bleomycin, busulfan, butyric acid, calicheamicin (e.g., calicheamicin γ1), camptothecin, carminomycin, carmustine, cemadotin, cisplatin, colchicine, combretastatin, cyclophosphamide, cytarabine, cytochalasin B, dactinomycin, daunorubicin, dacarbazine, diacetoxypentyldoxorubicin, dibromomannitol, dihydroxyanthracindione, disorazole, dolastatins (e.g., dolastatins Rastatin 10), doxorubicin, duocarmycin, echinomycin, eleutherobin, emetine, epothilone, esperamicin, estramustine, ethidium bromide, etoposide, fluorouracil, geldanamycin, gramicidin D, glucocorticoids, irinotecan, kinesin spindle protein (KSP) inhibitors, leptomycin, leurosine, lidocaine, lomustine (CCNU), maytansinoids, mechlorethamine, melphalan, mercaptopurine, methopterin, methotrexate Examples of antihistamines include acetaminophen, ...

[0247] Cytotoxin Linker A cytotoxin linker, or a linker for an ADC, is any group or moiety that links, connects, or binds an antibody or antigen-binding protein described herein to a therapeutic moiety, such as a cytotoxic drug. 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.

[0248] In general, suitable binding agent or cytotoxin linkers for the antibody conjugates described herein are sufficiently stable to take advantage of the circulating half-life of the antibody while simultaneously being able to release their payload after antigen-mediated internalization of the conjugate. The linker may be cleavable or non-cleavable. Cleavable linkers include those that are cleaved after internalization by intracellular metabolism, such as hydrolysis, reduction, or enzymatic cleavage. Non-cleavable linkers include those that release the attached payload after internalization by lysosomal degradation of the antibody. Suitable linkers include, but are not limited to, acid-labile linkers, hydrolytically unstable linkers, enzymatically cleavable linkers, reduction-labile linkers, self-immolative linkers, and non-cleavable linkers. Suitable linkers also include, but are not limited to, those that are or include peptides, glucuronides, succinimide-thioethers, polyethylene glycol (PEG) units, hydrazones, malcaproyl units, dipeptide units, valine-citrulline units, and para-aminobenzyl (PAB) units.

[0249] Any cytotoxin linker molecule or linker technology known in the art can be used to make or construct the ADC of the present disclosure.In certain embodiments, the cytotoxin 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, for example, linkers comprising or consisting of GGFC, MC (6-maleimidocaproyl), MP (maleimidopropanoyl), val-cit (valine-citrulline), val-ala (valine-alanine), a dipeptide moiety in a protease-cleavable linker, ala-phe (alanine-phenylalanine), a dipeptide moiety 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. Further examples of linkers that can be used in the context of the present disclosure are provided, for example, in US 7,754,681 and Ducry, Bioconjugate Chem., 2010, 27:5-13, and the references cited therein, the contents of which are incorporated herein by reference in their entireties.

[0250] In certain embodiments, the cytotoxin linker is stable under physiological conditions. In certain embodiments, the linker is cleavable, e.g., capable of releasing at least the payload portion in the presence of an enzyme or at a particular pH range or value. In some embodiments, the linker comprises an enzyme-cleavable moiety. Exemplary enzyme-cleavable moieties include, but are not limited to, peptide bonds, ester bonds, hydrazones, and disulfide bonds. In some embodiments, the linker comprises a cathepsin-cleavable linker.

[0251] In some embodiments, the cytotoxin linker comprises a non-cleavable moiety.

[0252] Suitable cytotoxin linkers also include, but are not limited to, those chemically bonded to a single linking agent, such as two cysteine ​​residues of an antibody, which can serve to mimic the disulfide bonds of an antibody that are disrupted as a result of the conjugation process.

[0253] In some embodiments, the cytotoxin linker comprises one or more amino acids. Suitable amino acids include natural, non-natural, standard, non-standard, proteinogenic, non-proteinogenic, and L- 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, derivatives thereof, or combinations thereof. In certain embodiments, one or more side chains of the amino acids are attached to a 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.

[0254] V. Fusion Proteins Targeting Human cMET Anti-human cMET antibodies can be used to fuse with other proteins or other functional domains to form fusion or chimeric proteins.

[0255] VI. Other Modifications Constant region and Fc region The heavy chain constant region can be the wild-type sequence of a heavy chain constant region derived from the IgG1, IgG2, IgG3, or IgG4 subclass. The light chain constant region can be the wild-type sequence of a light chain derived from the kappa or lambda subclass. In one embodiment, the heavy chain constant region is the wild-type sequence of a constant region derived from IgG1. The light chain constant region is the wild-type sequence of a light chain derived from a kappa 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 the wild-type Fc region of the IgG1, IgG2, IgG3, or IgG4 subclass.

[0256] In one embodiment, the antibody or antigen-binding fragment thereof comprises an IgG1 or IgG4 Fc domain with reduced effector function, hi another embodiment, the heavy chain constant region comprises the mutations E233P, L234A, L235A, G236del, and P329A.

[0257] In one embodiment, the antibody or antigen-binding fragment thereof comprises an Fc domain with extended half-life. In another embodiment, the antibody or antigen-binding fragment thereof comprises an IgG1 Fc domain, in which YTE mutations (M252Y / S254T / T256E, EU numbering as described in US7658921, which is incorporated by reference in its entirety) located in CH2 of the IgG Fc region have been introduced.

[0258] In another embodiment, the antibodies of the disclosure have potent Fc-mediated effector function, wherein the antibodies mediate antibody-dependent cellular cytotoxicity (ADCC) against target cells.

[0259] In yet another embodiment, the Fc region is altered by substituting at least one amino acid residue with a different amino acid residue to alter the effector function of the antibody. For example, one or more amino acids can be substituted with a different amino acid residue so that the antibody has altered affinity for an 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 approach is described, for example, in U.S. Patent Nos. 5,624,821 and 5,648,260, both by Winter et al., each of which is incorporated by reference in its entirety.

[0260] In another embodiment, one or more amino acid residues can be substituted 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 by Idusogie et al., which is incorporated by reference in its entirety.

[0261] In yet another embodiment, one or more amino acid residues are altered to thereby alter the antibody's ability to fix complement. This approach is described, for example, in Publication WO 94 / 29351 by Bodmer et al. In certain embodiments, one or more amino acids of an antibody or antigen-binding fragment thereof of the present disclosure are replaced with one or more allotypic amino acid residues for the IgG1 subclass and the kappa isotype. Also, as described by Jefferis et al., MAbs. 1:332-338 (2009) (incorporated by reference in its entirety), allotypic amino acid residues include, but are not limited to, those found in the heavy chain constant regions of the IgG1, IgG2, and IgG3 subclasses and the light chain constant region of the kappa isotype.

[0262] In another aspect, the Fc region is modified by modifying one or more amino acids to enhance the ability of the antibody to mediate antibody-dependent cellular cytotoxicity (ADCC) and / or to increase the affinity of the antibody for an Fcγ receptor. This approach is described, for example, in Publication WO 00 / 42072 by Presta. Furthermore, the binding sites on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn have been mapped, and mutants 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.

[0263] In yet another embodiment, the glycosylation of the antibody is modified. For example, an aglycosylated antibody can be made (i.e., the antibody lacks or has reduced glycosylation). Altering glycosylation can, for example, increase the affinity of the antibody for its antigen. Such sugar modifications can be achieved, for example, by altering one or more glycosylation sites within the antibody sequence. For example, one or more amino acid substitutions can be made to remove one or more variable region framework glycosylation sites, thereby eliminating glycosylation at those sites. Such aglycosylation can increase the affinity of the antibody for its antigen. Such techniques are described, for example, in U.S. Patent Nos. 5,714,350 and 6,350,861 by Co et al., which are incorporated by reference in their entireties.

[0264] Additionally or alternatively, antibodies can be made with altered types of glycosylation (e.g., hypofucosylated antibodies with reduced amounts of fucosyl residues or antibodies with increased bisecting GlcNAc structures). Such altered glycosylation patterns have previously been demonstrated to enhance the ADCC ability of antibodies. Such glycosylation can be achieved, for example, by expressing the antibody in a host cell with an altered glycosylation pathway. Cells with altered glycosylation pathways have previously been described in the art and can be used as host cells for expressing modified antibodies, thereby producing antibodies with altered glycosylation. For example, EP 1,176,195 by Hang et al., incorporated by reference in its entirety, describes a cell line in which the FUT8 gene, encoding fucosyltransferase, has been functionally disrupted such that antibodies expressed in such cell lines exhibit hypofucosylation. Publication WO 03 / 035835 by Presta, which is incorporated by reference in its entirety, describes a mutant CHO cell line, Lecl3 cells, that has a reduced ability to add fucose to the Asn(297)-linked sugar, which also results in hypofucosylation of antibodies expressed in the host cells (see also Shields et al., (2002) J. Biol. Chem. 277:26733-26740, which is incorporated by reference in its entirety). WO 99 / 54342 by Umana et al., which is incorporated by reference in its entirety, describes cell lines that have been engineered to express a glycoprotein-modifying glycosyltransferase (e.g., beta(1,4)-N-acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures, which results in increased ADCC activity of the antibodies (see also Umana et al., Nat. Biotech. 17:176-180, 1999, which is incorporated by reference in its entirety).

[0265] WO2003085107A1 by Naoko Ohnuki et al. describes modified CHO cell lines that have reduced or absent α1,6-fucosyltransferase activity, resulting in defucosylated antibodies or antigen-binding fragments thereof produced.

[0266] In another aspect, when reduced ADCC is desired, human antibody subclass IgG4 has been shown in many previous reports to have only moderate ADCC and little CDC effector function (Moore GL, et al., 2010 MAbs, 2:181-189, the entire contents of which are incorporated by reference). However, native IgG4 has been found to be less stable under stress conditions such as in acidic buffers or at elevated temperatures (Angal, S. 1993 Mol Immunol, 30:105-108; Dall'Acqua, W. et al., 1998 Biochemistry, 37:9266-9273; Aalberse et al., 2002 Immunol, 105:9-19, the entire contents of which are incorporated by reference). Reduced ADCC can be achieved by operably linking an antibody to an IgG4 Fc that has been engineered with a combination of changes that reduce FcγR binding or C1q binding activity, thereby reducing or eliminating ADCC and CDC effector functions. Considering the physicochemical properties of antibodies as biologics, one of the more undesirable intrinsic properties of IgG4 is the dynamic separation of its two heavy chains in solution to form antibody halves, which generates bispecific antibodies in vivo via a process called "Fab arm exchange" (Van der Neut Kolfschoten M, et al., 2007 Science, 317:1554-157, incorporated by reference in its entirety). A serine to proline mutation at position 228 (EU numbering system) appeared to inhibit IgG4 heavy chain separation (Angal, S. 1993 Mol Immunol, 30:105-108; Aalberse et al., 2002 Immunol, 105:9-19, each incorporated by reference in its entirety).Some amino acid residues in the hinge and gamma Fc region have been reported to affect antibody interaction with Fcγ 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). Furthermore, some IgG4 isoforms that occur rarely in the human population may also result in different physicochemical properties (Brusco, A. et al., 1998 Eur J Immunogenet, 25:349-55; Aalberse et al., 2002 Immunol, 105:9-19, each of which is incorporated by reference in its entirety). To generate multispecific antibodies with low ADCC and CDC but good stability, it is possible to modify the hinge and Fc regions of human IgG4 and introduce a number of changes. These modified IgG4 Fc molecules can be found in SEQ ID NOs: 83-88 of U.S. Patent No. 8,735,553 by Li et al. (each of which is incorporated by reference in its entirety).

[0267] In another embodiment, an antibody of the disclosure comprises a human IgG4 Fc domain with an S228P and / or R409K substitution (according to the EU numbering system).

[0268] "Knob-into-hole" mutations can be incorporated into the Fc:Fc binding interface. In some embodiments, the knob-into-hole ensures the correct pairing of two different heavy chains together during the production 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.

[0269] In another embodiment, the first heavy chain constant region or 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 second Fc of the multispecific antibody herein comprises a variant of the human IgG1 constant region comprising T366S, L368A, and Y407V (EU numbering).

[0270] In another embodiment, the first heavy chain constant region or 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 second Fc of the multispecific antibody herein comprises a variant of the human IgG1 constant region comprising T366W (EU numbering).

[0271] Amino Acid Linker It is also understood that the domains and / or regions of the polypeptide chains of an antibody or protein can be separated by linker regions of various lengths. In some embodiments, antigen-binding domains are separated from each other, from the CL, CH1, hinge, CH2, CH3, or the entire Fc region by linker regions. For example, VL1-CL-(linker)VH2-CH1. Such linker regions can comprise randomly assorted amino acids or a limited set of amino acids. Such linker regions can be flexible or rigid (see, e.g., US2009 / 0155275, incorporated by reference in its entirety).

[0272] Multispecific antibodies have been synthesized through dimerization devices such as leucine zippers (Kostelny et al., J. Immunol. 1992 148:1547-53; de Kruifetal J. Biol. Chem. 1996 271:7630-4) and Ig C / CH1 domains (Muller et al., FEBS Lett. 422:259-64), with or without the use of flexible linkers, 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 (Packet (Mallender et al., J. Biol. Chem. 1994 269:199-206; Mackett et al., Proc. Natl. Acad. Sci. USA 1995 92:7021-5; Zapata et al., Protein Eng. 1995 8:1057-62). Each reference cited in this paragraph is incorporated herein by reference in its entirety.

[0273] 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 of their 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 included in the linker region.In another embodiment, the linker is 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), GGGSGGGGSGGGGS (SEQ ID NO:109), AKTTPKL EEGEFSEAR (SEQ ID NO: 110), AKTTPKLEEGEFSEARV (SEQ ID NO: 111), AKTTPKLGG (SEQ ID NO: 112), SAKTTPKLGG (SEQ ID 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), RADAAAAAGGPGS (SEQ ID NO: 119), RADAAAA(G4S)4 (SEQ ID NO: 120). 20), 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 ID NO: 128), QPKAAPSVTLFPP (SEQ ID NO: 129), AKTTPP (SEQ ID NO: 130), AKTTPPSVTPLAP (SEQ ID NO: 131), AKTT AP (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 WO2007 / 024715).

[0274] Dimerization-specific amino acids In one embodiment, the multivalent antibody comprises at least one dimerization-specific amino acid modification. The dimerization-specific amino acid modification results in "knobs-into-holes" interactions, increasing the likelihood of correct multivalent antibody assembly. The dimerization-specific amino acid can be in the CH1 domain or the CL domain, or a combination thereof. The dimerization-specific amino acid is used to pair a CH1 domain with another CH1 domain (CH1-CH1) and a CL domain with another CL domain (CL-CL), and can be found in at least WO2014082179, WO2015181805 family, and WO2017059551, each of which is incorporated by reference in its entirety. The dimerization-specific amino acid can also be in the Fc domain. Alternatively, a dimerization-specific amino acid in the Fc domain can be combined with a dimerization-specific amino acid in the CH1 or CL domain. In one embodiment, the present disclosure provides a multispecific antibody comprising at least one dimerization-specific amino acid pair.

[0275] antibody production Antibodies and antigen-binding fragments thereof can be produced by any means 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 a mammalian host cell, a bacterial host cell, a yeast host cell, an insect host cell, etc.

[0276] The present disclosure further provides polynucleotides encoding the antibodies or proteins described herein, e.g., polynucleotides encoding heavy chain variable regions or light chain variable regions comprising the complementarity determining regions described herein. In some embodiments, 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 embodiments, 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.

[0277] The present disclosure also provides polynucleotides encoding the scFvs described herein.

[0278] The polynucleotides of the present disclosure can encode the variable region sequences of the multispecific antibodies described herein. They can also encode both 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.

[0279] In some embodiments, the polynucleotides described herein can be codon-optimized for expression in a host cell, for example, a eukaryotic cell, more particularly a mammalian cell (e.g., a CHO cell).

[0280] In some embodiments, the disclosure provides polynucleotides encoding the polypeptides of the multispecific antibodies herein, e.g., the EGFRxcMET multispecific antibodies described herein (e.g., all of the polypeptides listed in Table 21 and Table 22).

[0281] In one embodiment, the polynucleotide encoding the first polypeptide of the EGFRxcMET 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, and the polynucleotide encoding the second polypeptide of the EGFRxcMET 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 EGFRxcMET 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.

[0282] In one embodiment, a polynucleotide encoding a first polypeptide of the EGFRxcMET 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, and a polynucleotide encoding a second polypeptide of the EGFRxcMET 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 EGFRxcMET 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.

[0283] In one embodiment, a first polynucleotide encoding a first polypeptide of the EGFRxcMET multispecific antibody comprises the DNA sequence having SEQ ID NO: 164, a second polynucleotide encoding a second polypeptide of the EGFRxcMET multispecific antibody comprises the DNA sequence having SEQ ID NO: 165, and a third polynucleotide encoding a third polypeptide of the EGFRxcMET multispecific antibody comprises the DNA sequence having SEQ ID NO: 166.

[0284] In one embodiment, a first polynucleotide encoding a first polypeptide of the EGFRxcMET multispecific antibody comprises the DNA sequence of SEQ ID NO: 164, a second polynucleotide encoding a second polypeptide of the EGFRxcMET multispecific antibody comprises the DNA sequence of SEQ ID NO: 165, and a third polynucleotide encoding a third polypeptide of the EGFRxcMET multispecific antibody comprises the DNA sequence of SEQ ID NO: 166.

[0285] In some embodiments, the polynucleotides described herein can be codon-optimized for expression in a host cell, for example, a eukaryotic cell, more particularly a mammalian cell (e.g., a CHO cell).

[0286] In one embodiment, 2F-Peracetyl-Fucose (Sigma-Aldrich), a fucosyltransferase inhibitor for inhibiting fucosylation, is added to the production system to enhance effector function.

[0287] In one embodiment, a modified CHO cell line is used that has reduced or eliminated α1,6-fucosyltransferase activity, resulting in defucosylated antibodies or antigen-binding fragments thereof. For further details, see WO2003085107A1.

[0288] The present disclosure also provides expression vectors and host cells for producing the antibodies herein. The choice of expression vector depends on the intended host cell in which the vector will be expressed. Typically, expression vectors contain a promoter and other regulatory sequences (e.g., enhancers) operably linked to the polynucleotide encoding the antibody chain or antigen-binding fragment. In some embodiments, an inducible promoter is used to prevent expression of the inserted sequence except under the control of inducing conditions. Inducible promoters include, for example, arabinose, lacZ, metallothionein promoters, or heat shock promoters. Cultures of transformed organisms can be grown under non-inducing conditions without biasing the population toward coding sequences whose expression products are better tolerated by the host cell. In addition to promoters, other regulatory elements may be required or desired for efficient expression of antibodies or antigen-binding fragments. These elements typically include an ATG initiation codon and adjacent ribosome binding site or other sequences. Furthermore, the efficiency of expression can be increased by incorporating enhancers appropriate for the cell system being used (see, e.g., Scharf et al., Results Probl. Cell Differ. 20:125, 1994, and Bittner et al., Meth. Enzymol., 153:516, 1987, each incorporated by reference in its entirety). For example, the SV40 enhancer or CMV enhancer can be used to increase expression in mammalian host cells.

[0289] Host cells for harboring and expressing antibody chains can be prokaryotic or eukaryotic. E. coli is one prokaryotic host useful for cloning and expressing the polynucleotides of the present disclosure. Other suitable microbial hosts include bacilli, such as Bacillus subtilis, and other Enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species. In these prokaryotic hosts, expression vectors can also be made, typically containing expression control sequences (e.g., an origin of replication) compatible with the host cell. Additionally, a variety of well-known promoters are available, such as the lactose promoter system, the tryptophan (trp) promoter system, the beta-lactamase promoter system, or promoter systems derived from phage lambda. Promoters typically control expression (optionally with operator sequences) and contain ribosome binding site sequences for initiating and completing transcription and translation. Other microbes, such as yeast, can also be used to express antibodies. Insect cells can also be used in conjunction with baculovirus vectors. In another embodiment, 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 harboring exogenous expression vectors. These include any normal mortal, or normal or abnormal immortal, animal or human cells. For example, several suitable host cell lines capable of secreting intact immunoglobulins have been developed, including CHO cell lines, various COS cell lines, HEK293 cells, myeloma cell lines, transformed B cells, and hybridomas. The use of mammalian tissue cell culture to express polypeptides is reviewed, for example, in Winnacker, From Genes to Clones, VCH Publishers, NY, NY, 1987, each of which is 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, an enhancer (see, e.g., Queen et al., Immunol. Rev. 89:49-68, 1986, incorporated by reference in its entirety), as well as necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcription terminator sequences. These expression vectors usually contain promoters derived from mammalian genes or mammalian viruses. Suitable promoters can be constitutive, cell type-specific, stage-specific, and / or tunable or regulatable. 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 pol III 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.

[0290] Methods of detection and diagnosis The antibodies or antigen-binding fragments of the present disclosure are useful in a variety of applications, including, but not limited to, methods for detecting cMET / EGFR (i.e., cMET and / or EGFR). In one embodiment, the antibodies or antigen-binding fragments are useful for detecting the presence of cMET / EGFR in a biological sample. As used herein, the term "detecting" includes quantitative or qualitative detection. In certain embodiments, the biological sample comprises cells or tissues. In other embodiments, such tissues include normal and / or cancerous tissues that express cMET / EGFR at higher levels than other tissues.

[0291] In one aspect, the present disclosure provides a method 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 that allow binding of the antibody to the antigen, and detecting whether a complex is formed between the antibody and the antigen. Biological samples include, but are not limited to, urine, tissue, sputum, or blood samples.

[0292] Also included are methods for diagnosing disorders associated with cMET / EGFR expression. In certain embodiments, the methods comprise contacting a test cell with an anti-cMET / EGFR antibody, determining (quantitatively or qualitatively) the level of expression of cMET / EGFR expressed in the test cell by detecting binding of the anti-cMET / EGFR antibody to the cMET / EGFR polypeptide, and comparing the level of expression in the test cell with the level of cMET / EGFR expression in a control cell (e.g., a normal cell of the same tissue origin as the test cell or a non-cMET / EGFR-expressing cell), wherein a higher level of cMET / EGFR expression in the test cell compared to the control cell indicates the presence of a disorder associated with cMET / EGFR expression.

[0293] Treatment method In some embodiments, the antibodies or antigen-binding fragments of the present disclosure are useful in a variety of applications, including, but not limited to, methods for treating cMET-related disorders or diseases. In one aspect, the cMET-related disorder or disease is cancer. In some embodiments, the cancer is cMET-positive.

[0294] The antibodies or antigen-binding fragments of the present disclosure are useful in a variety of applications, including, but not limited to, methods for treating an EGFR / cMET-associated disorder or disease. In one aspect, the EGFR / cMET-associated disorder or disease is cancer. In some embodiments, the cancer is EGFR / cMET-positive.

[0295] 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 cMET antibody containing a multispecific antibody to a patient in need thereof. In another aspect, the present disclosure provides an anti-cMET antibody or antigen-binding fragment, or a multispecific antibody, or a pharmaceutical composition for use in 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.

[0296] In one aspect, the present disclosure provides a method of 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 herein, or a pharmaceutical composition, for use in treating cancer. In another aspect, the present disclosure provides use of a multispecific antibody or antigen-binding fragment thereof, or a pharmaceutical composition in the manufacture of a medicament for treating cancer.

[0297] In one embodiment, the cancer has a cMET gene mutation, and / or the cMET gene mutation results in constitutively active cMET signaling. In one embodiment, the cancer growth is driven by cMET signaling. In one embodiment, the cancer has a cMET gene mutation, and the cancer growth is driven by cMET signaling.

[0298] In one embodiment, cMET signaling is ligand-dependent. In another embodiment, cMET signaling is ligand-independent.

[0299] In another embodiment, the cMET gene mutation comprises cMET overexpression, genomic amplification, mutation, and / or alternative splicing that results in constitutively active cMET signaling.

[0300] In another embodiment, the cancer has an activating EGFR mutation and / or the growth of the cancer cells is driven by EGFR signaling, hi another embodiment, the activating EGFR mutation is a deletion or point mutation, including EGFR exon 19 deletion (E19del) and / or EGFR L858R / T790M.

[0301] In another embodiment, EGFR signaling is ligand-independent. In another embodiment, EGFR signaling is ligand-dependent.

[0302] In another embodiment, the EGFRxcMET multispecific antibodies herein induce internalization of the EGFR and / or cMET receptor, thereby reducing the receptor on the cell surface. Thus, the treatment with EGFRxcMET multispecific antibodies is not limited to a specific EGFR mutation or cMET amplification. The cell lines used in the examples are used only as illustrative examples and do not limit the scope of the treatments herein.

[0303] The 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.

[0304] 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.

[0305] The antibodies or antigen-binding fragments disclosed herein can be administered by any suitable means, for example, parenteral, intrapulmonary, and intranasal administration, as well as intralesional administration if localized therapy is desired. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing may be by any suitable route, for example, injection, such as intravenous or subcutaneous injection, depending in part on whether administration is short-term or long-term. Various dosing schedules are contemplated herein, including, but not limited to, single administration or multiple administrations over various time periods, bolus administration, and pulse infusion.

[0306] The antibodies or antigen-binding fragments of the present disclosure can be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the schedule of administration, and other factors known to medical professionals. The antibodies are optionally, but need not be, formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents will vary depending on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above.

[0307] For the prevention or treatment of disease, the appropriate dosage of an antibody or antigen-binding fragment of the disclosure will vary depending on the type of disease being treated, the type of antibody, the severity and course of the disease, whether the antibody is administered prophylactically or therapeutically, previous treatments, the patient's clinical history and response to the antibody, and the judgment of the attending physician.

[0308] Combination therapy In one aspect, the antibodies of the disclosure (including anti-cMET bispecific antibodies and EGFRxcMET multispecific antibodies) can be used in combination with other therapeutic agents.

[0309] The antibodies of the present disclosure can be used in combination with other therapeutic agents, such as other immune checkpoint antibodies. Such immune checkpoint antibodies may include anti-PD1 antibodies. Anti-PD1 antibodies include, but are not limited to, tislelizumab, pembrolizumab, or nivolumab. Tislelizumab (SEQ ID NOs: 140 and 141 in Table 3) is disclosed in US 8,735,553. Pembrolizumab (formerly known as MK-3475), disclosed in US 8,354,509 and US 8,900,587, is a humanized IgG4-K immunoglobulin that targets the PD1 receptor and inhibits the binding of the PD1 receptor ligands PD-L1 and PD-L2. Nivolumab (disclosed by Bristol-Meyers Squibb) is a fully human IgG4-K monoclonal antibody. Nivolumab (clone 5C4) is disclosed in U.S. Patent No. US8,008,449 and WO2006 / 121168. [Table 3]

[0310] In one embodiment, the disclosure provides for the use of an antibody of the disclosure in combination with an anti-PD-1 antibody (such as tislelizumab or another anti-PD-1 antibody described above) in the manufacture of a medicament for the treatment of cancer, such as those described above. In another embodiment, the disclosure provides for a combination of an antibody of the disclosure (including anti-cMET bispecific antibodies and EGFRxcMET multispecific antibodies) with an anti-PD-1 antibody (such as tislelizumab or another anti-PD-1 antibody described above) for use in the treatment of cancer, such as those described above.

[0311] Combination therapy is intended to mean, refer to, and include any one of the following: - simultaneous administration of such combination therapy to a patient in need of such treatment (where such components are formulated together in a single dosage form that releases said components substantially simultaneously to said patient); - substantially simultaneous administration of such combination to a patient in need of treatment (where such components are formulated separately from one another in separate dosage forms which are taken by the patient at substantially the same time, at the same time that the components are released to the patient at substantially the same time); - sequential administration of such combination therapy to a patient in need of treatment, where such components are formulated separately from one another in separate dosage forms which are taken sequentially by the patient with a substantial time interval between each administration, while the components are released to the patient at substantially different times; and - Sequential administration of such combination to a patient in need of treatment (where such components are formulated together into a single dosage form which releases such components in a controlled manner, whereby the components are released to the patient simultaneously and / or at different times, simultaneously, sequentially and / or overlappingly, and each part may be administered by either the same or different routes).

[0312] Pharmaceutical Composition Also provided are compositions, such as pharmaceutical preparations, comprising the antibodies or multispecific antibodies herein, or polynucleotides comprising 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 comprising sequences encoding one or more antibodies or antigen-binding fragments. These compositions can further comprise suitable carriers, for example, pharmaceutically acceptable excipients such as buffers, which are well known in the art.

[0313] The compositions disclosed herein may be in a variety of forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes, and suppositories. Suitable forms depend on the intended mode of administration and therapeutic application. Typical suitable compositions are in the form of injectable and infusible solutions. One suitable mode of administration is parenteral administration (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.

[0314] definition Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by those of ordinary skill in the art.

[0315] As used in this specification, including the appended claims, singular terms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0316] The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless the context clearly dictates otherwise.

[0317] As used herein, the term "anti-cancer agent" refers to any agent that can be used to treat a cell proliferative disorder, such as cancer, including, but not limited to, cytotoxic agents, chemotherapeutic agents, radiation therapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.

[0318] 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.

[0319] 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. EGFR amino acid sequence of SEQ ID NO: 167

[0320] The term "cMET biparatopic antibody or antigen-binding fragment thereof" means a multispecific antibody or antigen-binding fragment thereof, a first antigen-binding domain thereof that targets human cMET and a second antigen-binding domain thereof that targets a non-overlapping epitope recognized by human cMET on human cMET, or a first antigen-binding domain thereof that targets human cMET that does not compete with the second antigen-binding domain thereof that targets human cMET.

[0321] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, or diagnostic agent or composition with such animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with the cell and, when a fluid is in contact with the cell, contact of a reagent with a fluid. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatments, e.g., of a cell, with a reagent, diagnostic agent, binding compound, or with another cell. The term "subject," as used herein, includes any organism, preferably an animal, more preferably a mammal (e.g., a rat, mouse, dog, cat, rabbit), and most preferably a human. In one aspect, treating any disease or disorder refers to ameliorating the disease or disorder (i.e., delaying, preventing, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat," "treating," or "treatment" refers to modulating a disease or disorder, either physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In yet another embodiment, "treat," "treating," or "treatment" refers to preventing or delaying the onset or development or progression of a disease or disorder.

[0322] The term "subject" in the context of this disclosure is a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having or at risk of having a disorder described herein).

[0323] The term "affinity" as used herein refers to the strength of the interaction between an antibody and an antigen. Within the antigen, the variable region of the antibody interacts with the antigen at multiple sites through non-covalent forces. Generally, the more interactions, the stronger the affinity.

[0324] The term "antibody," as used herein, refers to a polypeptide of the immunoglobulin family that can bind to a corresponding antigen in a reversible and specific manner other than by covalent bonds. For example, naturally occurring IgG antibodies are tetramers containing at least two heavy (H) chains and two light (L) chains interconnected 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 consists 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 consists of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability 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 the amino terminus to the 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 can 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 (C1q) of the classical complement system.

[0325] 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. Antibodies can be of 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 binding to another agent (another drug or antibody) or by forming a complex with another agent.

[0326] The term "chimeric antibody" refers to a molecule composed of domains derived from different species, i.e., in which the variable domains of an antibody derived from one host species (e.g., mouse, rabbit, llama, etc.) are fused with the constant domains of an antibody derived from a different species (e.g., human).

[0327] In some embodiments, the anti-cMET antibody comprises at least one antigen-binding site, at least the 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 also includes multispecific antibodies that target 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 also includes multispecific antibodies that target cMET as at least one arm (e.g., two arms, each targeting a distinct epitope) and other antigen(s) as another arm(s).

[0328] As used herein, the term "monoclonal antibody" or "mAb" or "Mab" refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules within the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a large number of different antibodies with different amino acid sequences within the variable domains, particularly the complementarity-determining regions (CDRs), which are often specific for different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a population of substantially homogeneous antibodies and is not to be construed as requiring production of the antibody by any particular method. Monoclonal antibodies (mAbs) can be obtained by methods known to those skilled in the art. See, for example, Kohler et al., Nature 1975 256:495-497; U.S. Patent No. 4,376,110; Ausubel et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY 1992; Harlow et al., ANTIBODIES: A LABORATORY 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, such as IgG, IgM, IgD, IgE, IgA, and any subclass thereof, e.g., IgG1, IgG2, IgG3, IgG4. Hybridomas producing monoclonal antibodies can be cultivated in vitro or in vivo. High-titer monoclonal antibodies can be obtained by in vivo production, where cells from individual hybridomas are injected intraperitoneally into mice, such as pristine-primed Balb / c mice, to produce ascites fluid containing high concentrations of the desired antibody. Monoclonal antibodies of the IgM or IgG isotype can be purified from such ascites fluid or from the culture supernatant using column chromatography methods well known to those skilled in the art.

[0329] Generally, the basic structural unit of an antibody comprises a tetramer. Each tetramer contains two identical pairs of polypeptide chains, each pair having one "light chain" (approximately 25 kDa) and one "heavy chain" (approximately 50-70 kDa). The amino-terminal portion of each chain contains a variable region of approximately 100-110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function. Human light chains are typically classified as kappa and lambda light chains. Human heavy chains are further classified as α, δ, ε, γ, or μ, and the antibody isotype is defined 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 approximately 12 or more amino acids, and heavy chains also contain a "D" region of approximately 10 amino acids.

[0330] The variable regions of each light / heavy chain (VL / VH) pair form the antibody binding site. Thus, an intact antibody generally has two binding sites. Except for bifunctional or bispecific antibodies, the two binding sites generally have the same primary sequence.

[0331] Typically, both heavy and light chain variable domains contain three hypervariable regions, also called "complementarity-determining regions (CDRs)," which are located between relatively conserved framework regions (FRs). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. Generally, from the N-terminus to the C-terminus, both light chain variable domains 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 locations of CDRs and framework regions can be determined using various definitions well known in the art, such as Kabat, Chothia, AbM, and IMGT (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 Immunologist, 7, 132-136 (1999); Lefranc, M.-P. et al., Dev. Comp. Immunol., 27, 55-77 (2003) (see "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, Oxford, 141-172 (1996). For example, in 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). In Chothia, the CDR amino acids in the VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3), and the amino acid residues in the VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). Combining the Kabat and Chothia CDR definitions, 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.In IMGT, the CDR amino acid residues in the VH are numbered approximately 26-35 (HCDR1), 51-57 (HCDR2), and 93-102 (HCDR3), and the CDR amino acid residues in the VL are numbered approximately 27-32 (LCDR1), 50-52 (LCDR2), and 89-97 (LCDR3) (numbering according to Kabat). In IMGT, the CDR regions of an antibody can be determined using the program IMGT / DomainGapAlign.

[0332] The term "hypervariable region" refers to the amino acid residues of an antibody that are involved in antigen binding. A hypervariable region comprises amino acid residues from a "CDR" (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, Md., which define antibody CDR regions by sequence. See also Chothia and Lesk (1987) J. Mol. Biol. 196:901-917, which define antibody CDR regions by structure. The term "framework" or "FR" residues refers to variable domain residues other than the hypervariable region residues defined herein as CDR residues.

[0333] 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 bound by the full-length antibody, 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'), and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules such as single-chain Fv (ScFv), nanobodies formed from antibody fragments, and multispecific antibodies.

[0334] As used herein, an antibody "specifically binds" to a target protein means that the antibody exhibits preferential binding to that target relative to other proteins, although this specificity does not require absolute binding specificity. The terms "specifically bind" or "selectively bind" an antibody are used in the context of describing the interaction between an antigen (e.g., a protein) and an antibody or antigen-binding antibody fragment, and refer to a binding reaction that determines the presence of the antigen in a heterogeneous population of proteins and other biologics, such as a biological sample, blood, serum, plasma, or tissue sample. Thus, under certain designated immunoassay conditions, an antibody or antigen-binding fragment thereof specifically binds to a particular antigen at least twice as much as background levels and does not specifically bind in significant amounts to other antigens present in the sample. In one embodiment, under designated immunoassay conditions, an antibody or antigen-binding fragment thereof specifically binds to a particular antigen at least 10 times as much as background levels of binding and does not specifically bind in significant amounts to other antigens present in the sample.

[0335] As used herein, "antigen-binding domain" refers to the portion 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 for single-domain antibodies). The "antigen-binding domain" 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, trispecific, tetraspecific, etc., with an antigen-binding domain directed to each specific epitope. Multispecific antibodies can be multivalent (e.g., a bispecific tetravalent antibody) comprising multiple antigen-binding domains, e.g., two, three, four, or more antigen-binding domains that specifically bind to a first epitope and two, three, four, or more antigen-binding domains that specifically bind to a second epitope.

[0336] The term "human antibody" herein refers to an antibody that contains only human immunoglobulin protein sequences. A human antibody may contain mouse glycosylation if produced in a mouse, a mouse cell, or a mouse cell-derived hybridoma. Similarly, a "mouse antibody" or a "rat antibody" refers to an antibody that contains only mouse immunoglobulin protein sequences or only rat immunoglobulin protein sequences, respectively.

[0337] The terms "humanized" or "humanized antibody" refer to forms of antibodies that contain sequences from non-human (e.g., mouse, rabbit, llama, etc.) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. A humanized antibody will also optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically at least a portion of a human immunoglobulin constant region (Fc). Where necessary to distinguish a humanized antibody from a rodent parent antibody, the name of the antibody clone will be prefixed with "hum," "hu," "Hu," or "h." Humanized forms of rodent / camelid antibodies generally contain the same CDR sequences of the rodent parent antibody, but may contain certain amino acid substitutions to increase affinity, increase the stability of the humanized antibody, remove post-translational modifications, or for other reasons.

[0338] The term "corresponding human germline sequence" refers to a nucleic acid sequence encoding a human variable region amino acid sequence or subsequence that shares the highest amino acid sequence identity, as determined with 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. 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 with 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 framework regions only, complementarity determining regions only, framework and complementarity determining regions, variable segments (as defined above), or other combinations of sequences or subsequences that comprise variable regions. Sequence identity can be determined using methods described herein, such as aligning two sequences using BLAST, ALIGN, or another alignment algorithm known in the art. The 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 the nucleic acid or amino acid sequence of the reference variable region. Furthermore, if the antibody contains a constant region, the constant region also is derived from such a human sequence, e.g., a human germline sequence, or a mutated version of a human germline sequence, or an antibody containing a consensus framework sequence derived from human framework sequence analysis, e.g., as described in Knappik et al., J. Mol. Biol. 296:57-86, 2000.

[0339] “Equilibrium dissociation constant (K D The term "dissociation rate constant (kd, time -1 ) as the binding rate constant (ka, time -1 , M -1 ) The equilibrium dissociation constant can be measured using any method known in the art. Antibodies of the present disclosure generally have an equilibrium dissociation constant of about 10 -7 Less than or equal to 10 -8 Less than m, e.g., about 10 -9Less than M or 10 -10 M or less, and in some embodiments, about 10 -11 Under M, 10 -12 Less than M or 10 -13 It is less than M.

[0340] The terms "cancer" or "tumor" as used herein have the broadest meaning understood in the art and refer to a physiological condition in mammals that is typically characterized by uncontrolled cell growth. In the context of this disclosure, cancer is not limited to any particular type or location.

[0341] In the context of the present disclosure, when referring to an amino acid sequence, the term "conservative substitution" means a substitution of an original amino acid with a new amino acid that does not substantially alter the chemical, physical, and / or functional properties of the antibody or fragment, e.g., its binding affinity to cMET. In particular, common conservative changes of amino acids are well known in the art.

[0342] As used herein, the term "knob-into-hole" technology refers to amino acids that direct the pairing of two polypeptides together, either in vitro or in vivo, by introducing a spatial protuberance (knob) in one polypeptide and a socket or cavity (hole) in the other polypeptide at the interface where they interact. For example, knob-into-hole technology can be used to ... L :C H Interface, or V H / V LIn some embodiments, knob-into-hole amino acids have been introduced into the VH or VL region to ensure proper pairing of two different heavy chains together during the production of multispecific antibodies. For example, multispecific antibodies with knob-into-hole amino acids in their Fc region may further comprise a single variable domain linked to each Fc region, or may further comprise a different heavy chain variable domain paired with a similar or different light chain variable domain. The knob-into-hole technology can also be used with the VH or VL region to ensure proper pairing.

[0343] As used herein, the term "knob," in the context of "knob-into-hole" technology, refers to an amino acid modification that introduces a knob into a polypeptide at the interface where the polypeptide interacts with another polypeptide. In some embodiments, the other polypeptide has a hole mutation.

[0344] As used herein, the term "hole," in the context of "knob-into-hole," refers to an amino acid modification that introduces a socket or cavity in a polypeptide at the interface where the polypeptide interacts with another polypeptide. In some embodiments, the other polypeptide has a knob mutation.

[0345] An example of a suitable algorithm for determining percent sequence identity and sequence similarity is the BLAST algorithm, 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 analyses is publicly available through the National Center for Biotechnology Information. This algorithm involves first identifying high-scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence that match or meet a positive threshold score T when aligned with words of the same length in a database sequence. T is referred to as the neighborhood word score threshold. These initial neighborhood word hits serve as starting points for searches to find longer HSPs containing them. Word hits are extended outward along each end of each sequence as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, 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 hits in each direction is halted if the cumulative alignment score falls by an amount X from the maximum achieved value, if the cumulative score falls below zero due to the accumulation of one or more negative-scoring residue alignments, or if either end of the 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 as defaults a word length (W) of 11, an expectation (E) of 10, M=5, N=-4, and both strands are compared.For amino acid sequences, the BLAST program uses as defaults a word length of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff, (1989) Proc. Natl. Acad. Sci. USA 89:10915) of 50. Alignment (B), expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[0346] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, for example, 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 sequences of nucleotides or amino acids will occur by chance. For example, a nucleic acid is considered to be similar to a reference sequence if the smallest sum probability when comparing the test nucleic acid with 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.

[0347] 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 a PAM120 weight remainder table, a gap length penalty of 12, and a gap penalty of 4. Additionally, 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 a BLOSUM62 matrix or a PAM250 matrix, and gap weights of 16, 14, 12, 10, 8, 6, or 4 and length weights of 1, 2, 3, 4, 5, or 6.

[0348] The term "nucleic acid" is used interchangeably herein with the term "polynucleotide" to refer to deoxyribonucleotides or ribonucleotides and polymers thereof in either single-stranded or double-stranded form. The term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, including synthetic, naturally occurring, and non-naturally occurring nucleic acids, which have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to the reference nucleotide. Examples of such analogs include, but are not limited to, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, and peptide nucleic acids (PNAs).

[0349] The term "operably linked," in the context of nucleic acids, refers to a functional relationship between two or more polynucleotide (e.g., DNA) segments. Typically, this refers to the functional relationship between a transcriptional regulatory sequence and a transcriptional sequence. For example, a promoter or enhancer sequence is operably linked to a coding sequence if it stimulates or regulates the transcription of the coding sequence in an appropriate host cell or other expression system. Generally, promoter transcriptional regulatory sequences operably linked to a transcriptional sequence are physically contiguous to the transcriptional sequence, i.e., they are cis-acting. However, some transcriptional regulatory sequences, such as enhancers, need not be physically contiguous to or located in close proximity to the coding sequence whose transcription they enhance.

[0350] 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 all solvents, dispersion media, isotonic and absorption delaying agents, and the like that are physiologically compatible. The excipient may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal, or epidermal administration (e.g., by injection or infusion).

[0351] As used herein, the term "therapeutically effective amount" refers to the amount of an antibody that, when administered to a subject to treat a disease or at least one of the clinical symptoms of a disease or disorder, is sufficient to effect such treatment for the disease, disorder, or condition. A "therapeutically effective amount" may vary depending on the antibody, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case will be apparent to one of ordinary skill in the art and can also be determined by routine experimentation. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combined components for effective treatment of the disease, disorder, or condition.

[0352] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder 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) for each active ingredient. The powders and / or liquids may be reconstituted or diluted to the desired dosage prior to administration. Furthermore, such administration also encompasses the use of various therapeutic agents in a sequential manner, either at about the same time or at different times. In either case, the treatment regimen provides the beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0353] As used herein, the term "in combination with" means that the anti-cMET antibody is administered to a subject simultaneously with, immediately before, or immediately after the administration of an additional therapeutic agent. In certain embodiments, the anti-cMET antibody is administered as a co-formulation with the additional therapeutic agent.

[0354] equivalent While the present invention has been described with reference to its detailed description, it should be understood that the foregoing description is intended to be illustrative and not limiting of the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. It is understood that one, some, any, or all of the features of the various embodiments described herein may be combined to form additional embodiments of the present disclosure. These and other aspects of the present disclosure will be apparent to those skilled in the art. [Example]

[0355] Example 1. Generation of anti-cMET antibodies Immunization of mice To generate anti-cMET antibodies, genetically engineered mice (RenLite®, Biocytogen) were immunized with the human cMET extracellular domain (amino acids 1-932 of SEQ ID NO: 69, representing full-length human cMET) fused to a his-tag or mouse Fc (in-house production, 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 two or three times weekly. The mice used contained DNA encoding different human immunoglobulin heavy chains and one common human light chain variable region.

[0356] 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 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[0357] Plasma cell screening using the Beacon Optofluidic System Three to five days after the final boost, spleens were harvested and mashed into a single cell suspension. Plasma cells were isolated using a mouse CD138 positive selection kit (STEMCELL™) according to the manufacturer's instructions. Plasma cells were isolated at a density of 6.25 x 10 6 1 / ml of enriched plasma cells were introduced into the channel and placed in the NanoPen chamber of an OptoSelect 14K Chip™ (Berkeley Lights) according to the manufacturer's instructions. To screen for human cMET-specific plasma cells, human cMET protein (MET-H82E1, Acrobiosystems)-conjugated beads (520-00053, Berkeley Lights) and Alexa Fluor 488 goat anti-mouse IgG secondary antibody (Jackson ImmunoResearch) were introduced into the channel at a concentration of 5 μg / ml. After introduction, the freeze valve was turned on, and the exposure time of the FITC channel for the Alexa Fluor 488 fluorophore was set to 1000 ms. Positive signals were captured by time-lapse imaging at a setting of 3 min and 10 cycles. After completing the human cMET-specific plasma cell screening, cynomolgus monkey cMET-specific plasma cells were screened using cynomolgus monkey cMET-ECD-his (in-house produced, SEQ ID NO: 3)-conjugated beads. An assay to remove nonspecific binding signals using irrelevant His-tagged protein-conjugated beads was performed as a counterscreen. Human and cynomolgus monkey cMET-positive plasma cells were individually transferred to a 96-well plate filled with lysis buffer.

[0358] Example 2. Antibody VH and VL Gene Cloning, Sequencing, and Expression First-strand cDNA was synthesized, and the entire cDNA was amplified using the Opto Plasma B Discovery cDNA Synthesis Kit™ (Berkeley Lights) according to the manufacturer's instructions. Antibody VH and VL genes were amplified using the Opto Plasma B Discovery Sanger Prep Kit™ (Berkeley Lights) according to the manufacturer's instructions. The amplified VH and VL genes were cloned into mammalian expression vectors containing the human IgG1 constant region (SEQ ID NO: 70) and human kappa chain constant region (SEQ ID NO: 71) genes, respectively, and sequenced. The amino acid sequences of the three HCDRs, three LCDRs, VH and VL, and the DNA sequences of the VH and VL of representative antibodies are listed in Tables 5 and 6 as SEQ ID NOs: 4-68. Antibodies were expressed in Expi293™ cells and purified by affinity chromatography. [Table 5] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14] [Table 6-15] [Table 6-16] [Table 6-17] [Table 6-18] [Table 6-19]

[0359] Example 3. Determination of binding affinity and specificity of anti-cMET antibodies The binding affinity and specificity of purified anti-cMET antibodies were determined by ELISA and FACS. Briefly, 2 μg / ml of human or cynomolgus monkey monomeric cMET fusion proteins, human cMET-ECD-his or cynomolgus monkey cMET-ECD-his (produced in-house, SEQ ID NOs: 1 and 3), or human dimeric cMET protein formed by human cMET-ECD-mFc (produced in-house, SEQ ID NO: 2), was coated onto a 96-well ELISA plate. 50 μL of serially diluted antibodies were co-incubated for 30–60 min, washed, and then 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. Positive candidates from ELISA binding were serially diluted and incubated with Hs746T cells, a human gastric cancer cell line harboring a putative oncogenic mutation with cMET amplification resulting in high cMET expression, for 30 minutes at 4°C. After two washes with FACS buffer, diluted Alexa Fluor 647 goat anti-human IgG secondary antibody was added and incubated with Hs746T cells in the dark for 30 minutes at 4°C. After two washes with FACS buffer, cells were resuspended in FACS buffer and read using a Becton Dickinson LSR Fortessa™ cell analyzer. Nonspecific binding of these antibodies was assessed by FACS binding to Jurkat cells (cMET-negative cells). Titration curves were generated using a sigmoidal dose-response nonlinear fit with GraphPad™ Software from Dotmatics.

[0360] As shown in Tables 7 and 8, all selected candidates specifically bind to cMET monomer and dimer proteins with high affinity, and all of them specifically bind to human cMET-expressing cancer cells and cross-link to cynomolgus monkey cMET. [Table 7] [Table 8]

[0361] Example 4. Binding kinetics of anti-cMET antibodies The binding affinity and kinetics of purified anti-cMET antibodies were determined at room temperature by surface plasmon resonance (Biacore 8K, GE Life Sciences). Briefly, mouse anti-human IgG Fc antibodies were immobilized on an activated CM5 biosensor chip (catalog no. BR100530, GE Life Sciences) via 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 over the surface-captured antibody, and the changes in surface plasmon resonance signal were analyzed to determine the association rate (k ) using a one-to-one Langmuir binding model (BIA Evaluation Software™, GE Life Sciences). on ) and dissociation rate (k off The equilibrium dissociation constant (K D ) as the ratio k off / k on The binding affinity and kinetic profiles of selected monoclonal anti-cMET antibodies are listed in Table 9 below, and detailed binding curves of selected candidates are presented in Figures 1A-1L. [Table 9]

[0362] Example 5. Blocking activity of monoclonal anti-cMET antibodies against ligand-induced signaling To assess the activity of anti-cMET antibodies in disrupting HGF-cMET interaction and inhibiting downstream signaling, we used the inhibition of HGF-induced ERK phosphorylation in T202 / Y204 cells by antibody treatment 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 and 5% CO2. After 24 hours, the cells were starved with FBS-free medium for 4 hours. A dilution series of anti-cMET antibodies was 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 1x lysis buffer was added to the assay plate and incubated at room temperature for 30 minutes. Cellular phosphorylated ERK was measured using the ERK Phosphorylation T202 / Y204 Kit (PerkinElmer). IC50 values ​​were determined by fitting the dose-response data to a 4-parameter logistic model using GraphPad Prism. Imax was calculated using the 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, which is the background signal. The IC50 and Imax of monoclonal anti-cMET antibodies are shown in Table 10 and Figure 2. [Table 10]

[0363] Example 6. Agonist activity of monoclonal anti-cMET antibodies To evaluate the transient agonistic activity of anti-cMET antibodies, activation of cMET downstream signaling, i.e., upregulation of ERK phosphorylation T202 / Y204, was measured upon antibody treatment. Briefly, H596 cells were seeded into 96-well assay plates and incubated at 37°C and 5% CO2. After 24 hours, the cells were starved with FBS-free medium for 4 hours. Next, 50 nM anti-cMET antibody was added to each well and incubated at 37°C for 2 hours. The medium was then discarded, and 1x lysis buffer was added to the assay plate and incubated at room temperature for 30 minutes. Cellular phosphorylated ERK was measured using the ERK Phosphorylation T202 / Y204 Kit (PerkinElmer). Fold stimulation was determined by comparing the p-ERK signal in the presence of 50 nM antibody with the p-ERK signal in the presence of vehicle (PBS buffer). The agonistic activity of monoclonal anti-cMET antibodies is shown in Table 11. [Table 11]

[0364] Example 7. Anti-cMET antibodies that bind to different epitopes To assess whether anti-cMET antibodies compete with each other, we performed an epitope binning assay using surface plasmon resonance (Biacore 8K, GE Life Sciences) at room temperature. Briefly, human cMET-his (produced in-house, SEQ ID NO: 1) was captured on the sensor surface of an anti-his antibody-immobilized CM5 chip (catalog no. 29234602, GE Life Sciences). 300 nM of primary antibody was injected to saturate antigen binding, followed by injection of the secondary antibody. Data were analyzed using Biacore Insight Epitope Binning Extension. Representative epitope binning results for monoclonal antibodies are listed in Figure 3. Based on Figure 3 , the anti-cMET antibodies were divided into two non-competing groups: (1) 063Ab10910, 061Ab15310, 063Ab16010, 063Ab02110, 063Ab15210, 062Ab16310, 063Ab05510, 063Ab07710, 063Ab14710, or 061Ab05110, and (2) 063Ab03210 or 063Ab16720.

[0365] Example 8. Construction of a bispecific antibody with two distinct antigen-binding domains directed against distinct epitopes of cMET To generate biparatopic antibodies against cMET, we constructed a bispecific antibody containing two distinct arms (arm 1 and arm 2), which are derived from different anti-cMET monospecific antibodies that bind to distinct epitopes and are non-competing.

[0366] Individual anti-cMET monospecific antibodies were derived from the candidates described in Examples 1-7 herein. All anti-cMET antibodies described herein share a common light chain (SEQ ID NO: 64). Bispecific antibodies were expressed in Expi293™ cells and purified by MabSelect™ SuRe affinity chromatography. Representative selected antibodies are listed in Table 12, which shows the pairing algorithm and bispecific antibody SEQ ID NOs. [Table 12]

[0367] Example 9. Inhibition of Ligand-Independent Signaling by Bispecific Anti-cMET Antibodies In cancer cell lines with cMET amplification, such as Hs746T (human gastric cancer cells), cMET signaling is constitutively active, supporting cell proliferation without the need for ligand engagement. To evaluate the activity of anti-cMET bispecific antibodies in inhibiting ligand-independent cMET signaling, we measured the inhibition of ERK phosphorylation (T202 / Y204) in Hs746T cells by anti-cMET bispecific antibody treatment. Briefly, Hs746T cells were seeded into 96-well assay plates and incubated at 37°C and 5% CO2. After 24 hours, the cells were treated with 10 nM anti-cMET bispecific antibody and incubated at 37°C for 18 hours. Next, the medium was discarded, and 1x lysis buffer was added to the assay plate and incubated at room temperature for 30 minutes. Cellular phosphorylated ERK was measured using the ERK Phosphorylation T202 / Y204 Kit (PerkinElmer). The percentage of inhibition was calculated using the 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 Hs746T and PBS alone. MIN is the signal in the presence of medium alone, which is the background signal. As shown in Table 13, all pairs of bispecific antibodies showed inhibitory activity against ligand-independent cMET signaling at 10 nM. [Table 13]

[0368] Example 10. Inhibitory activity of ligand-independent signaling and antiproliferative activity of bispecific anti-cMET antibodies The ligand-independent signaling inhibitory activity of anti-cMET bispecific antibodies was measured by the method described in Example 9. Briefly, Hs746T cells were seeded into a 96-well assay plate, treated with serial dilutions of anti-cMET antibodies, and incubated at 37°C for 18 hours. Cellular phosphorylated ERK was then measured using the ERK Phosphorylation T202 / Y204 Kit (PerkinElmer). IC50 values ​​were determined by fitting the dose-response data to a four-parameter logistic model using GraphPad Prism. As shown in Table 14 and Figure 4, all bispecific antibodies tested below, 06BS01 to 06BS14, exhibited po...

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds to human cMET, (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 (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) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 8, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 11, (b) an HCDR2 of SEQ ID NO: 12, (c) an HCDR3 of SEQ ID NO: 13, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (4) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 56, (b) an HCDR2 of SEQ ID NO: 57, (c) an HCDR3 of SEQ ID NO: 58, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (5) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 16, (b) an HCDR2 of SEQ ID NO: 17, (c) an HCDR3 of SEQ ID NO: 18, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (6) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 21, (b) an HCDR2 of SEQ ID NO: 22, (c) an HCDR3 of SEQ ID NO: 23, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (7) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 26, (b) an HCDR2 of SEQ ID NO: 27, (c) an HCDR3 of SEQ ID NO: 28, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (8) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 31, (b) an HCDR2 of SEQ ID NO: 32, (c) an HCDR3 of SEQ ID NO: 33, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (9) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 36, (b) an HCDR2 of SEQ ID NO: 37, (c) an HCDR3 of SEQ ID NO: 38, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (10) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 41, (b) an HCDR2 of SEQ ID NO: 42, (c) an HCDR3 of SEQ ID NO: 43, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (11) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 46, (b) an HCDR2 of SEQ ID NO: 47, (c) an HCDR3 of SEQ ID NO: 48, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (12) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 51, (b) an HCDR2 of SEQ ID NO: 52, (c) an HCDR3 of SEQ ID NO: 53, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (13) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 61, (b) an HCDR2 of SEQ ID NO: 62, (c) an HCDR3 of SEQ ID NO: 63, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (14) (a) a heavy chain variable region (VH) comprising HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) a HCDR2 of SEQ ID NO: 7, (c) a HCDR3 of SEQ ID NO: 84, and (d) a light chain variable region comprising LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) a LCDR2 of SEQ ID NO: 67, and (f) a LCDR3 of SEQ ID NO: 68; (15) (a) 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 (d) a light chain variable region comprising 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; (16) (a) a heavy chain variable region (VH) comprising HCDR1 (heavy chain complementarity determining region 1) of SEQ ID NO: 6, (b) a HCDR2 of SEQ ID NO: 7, (c) a HCDR3 of SEQ ID NO: 88, and (d) a light chain variable region comprising LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) a LCDR2 of SEQ ID NO: 67, and (f) a LCDR3 of SEQ ID NO: 68; (17) (a) a heavy chain variable region (VH) comprising 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: 90, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; or (18) The antibody or antigen-binding fragment thereof, comprising 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: 92, and (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. (1) A heavy chain variable region (VH) comprising an amino acid sequence 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64; or (15) The antibody or antigen-binding fragment thereof according to claim 1, comprising a heavy chain variable region (VH) comprising an amino acid sequence 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO:

64.

3. 10. The antibody or antigen-binding fragment thereof of any one of the preceding claims, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids are inserted, deleted, or substituted in 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:

64.

4. (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) An antibody or antigen-binding fragment thereof according to any one of the preceding claims, comprising 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.

5. 10. The antibody or antigen-binding fragment thereof of 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 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; a multispecific antibody or antigen-binding fragment thereof, wherein the first epitope is different from the second epitope, or the first antigen-binding domain is different from the second antigen-binding domain, or the first antigen-binding domain does not compete with the second antigen-binding domain.

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

8. 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64; or (12) The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 7, comprising a heavy chain variable region (VH) comprising an amino acid sequence 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO:

64.

9. 9. The multispecific antibody or antigen-binding fragment thereof according to claim 8, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET comprises an insertion, deletion or substitution of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids in 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:

64.

10. 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) The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 9, comprising 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.

11. the second antigen-binding domain that specifically binds to a second epitope of human cMET is (1) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 56, (b) an HCDR2 of SEQ ID NO: 57, (c) an HCDR3 of SEQ ID NO: 58, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; or (2) The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 10, comprising 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 second antigen-binding domain that specifically binds to a second epitope of human cMET is (1) a heavy chain variable region (VH) comprising an amino acid sequence 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 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 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64; or (3) The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 11, comprising a heavy chain variable region (VH) comprising an amino acid sequence 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO:

64.

13. 13. The multispecific antibody or antigen-binding fragment thereof of claim 12, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises an insertion, deletion, or substitution of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids 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.

14. the second antigen-binding domain that specifically binds to a second epitope of human cMET is (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) The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 13, comprising 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.

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

68.

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

68.

18. 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 a second epitope of human cMET is 18. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 14 and 17, comprising 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 according to 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 an F(ab')2 fragment.

20. 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 multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 19, wherein 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.

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

22. 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 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: 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.

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

25. 25. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 6 to 24, further comprising an amino acid linker, wherein said amino acid linker is any sequence selected from SEQ ID NOs: 97 to 139.

26. 10. 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. 10. 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 subclass and a light chain constant region of the kappa type.

28. 10. 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, no glycosylation or is hypofucosylated.

30. 10. 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 defucosylated.

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 increased bisecting GlcNAc structures.

32. 10. 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 Fc domain, and the Fc domain is an IgG1 Fc with extended half-life.

33. 10. 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. 10. 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. 10. A pharmaceutical composition comprising the antibody, multispecific antibody or antigen-binding fragment thereof of any one of the preceding claims and a pharmaceutically acceptable carrier.

36. 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 of any one of claims 1 to 34, or the pharmaceutical composition of claim 35.

37. 37. The method of claim 36, wherein the cancer has a cMET gene mutation and / or the growth of the cancer cells is driven by cMET signaling.

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

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

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

41. 41. The method of any one of claims 36 to 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. 42. The method of claim 41, wherein the lung cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

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

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

45. 42. 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 to 45, wherein the antibody or antigen-binding fragment thereof is administered in combination with another therapeutic agent.

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

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

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

50. 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; 1. A multispecific antibody or antigen-binding fragment thereof, wherein the first epitope is different from the second epitope or the first antigen-binding domain does not compete with the second antigen-binding domain.

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

68.

52. 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO: 64; or (12) The multispecific antibody or antigen-binding fragment thereof according to any one of claims 50 to 51, comprising a heavy chain variable region (VH) comprising an amino acid sequence 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 at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO:

64.

53. 53. The multispecific antibody or antigen-binding fragment thereof of claim 52, wherein the first antigen-binding domain that specifically binds to a first epitope of human cMET has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids inserted, deleted, or substituted in 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:

64.

54. 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) The multispecific antibody or antigen-binding fragment thereof according to any one of claims 50 to 53, comprising 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.

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

68.

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

64.

57. 57. The multispecific antibody or antigen-binding fragment thereof of claim 56, wherein the second antigen-binding domain that specifically binds to a second epitope of human cMET comprises an insertion, deletion, or substitution of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids 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.

58. the second antigen-binding domain that specifically binds to a second epitope of human cMET is (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) The multispecific antibody or antigen-binding fragment thereof according to any one of claims 50 to 57, comprising 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.

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

160.

60. The third antigen-binding domain that specifically binds to human EGFR is 60. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 24 and 50 to 59, comprising 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 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 of SEQ ID NO: 6, (b) HCDR2 of SEQ ID NO: 7, (c) HCDR3 of SEQ ID NO: 94, and (d) an LCDR1 (light chain complementarity determining region 1) of SEQ ID NO: 66, (e) LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (2) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 8, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (3) a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 11, (b) an HCDR2 of SEQ ID NO: 12, (c) an HCDR3 of SEQ ID NO: 13, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (4) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 16, (b) an HCDR2 of SEQ ID NO: 17, (c) an HCDR3 of SEQ ID NO: 18, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (5) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 21, (b) an HCDR2 of SEQ ID NO: 22, (c) an HCDR3 of SEQ ID NO: 23, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (6) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 26, (b) an HCDR2 of SEQ ID NO: 27, (c) an HCDR3 of SEQ ID NO: 28, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (7) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 31, (b) an HCDR2 of SEQ ID NO: 32, (c) an HCDR3 of SEQ ID NO: 33, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (8) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 36, (b) an HCDR2 of SEQ ID NO: 37, (c) an HCDR3 of SEQ ID NO: 38, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (9) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 41, (b) an HCDR2 of SEQ ID NO: 42, (c) an HCDR3 of SEQ ID NO: 43, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (10) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 46, (b) an HCDR2 of SEQ ID NO: 47, (c) an HCDR3 of SEQ ID NO: 48, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (11) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 51, (b) an HCDR2 of SEQ ID NO: 52, (c) an HCDR3 of SEQ ID NO: 53, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (12) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 84, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (13) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 86, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (14) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 88, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; (15) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 90, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; or (16) A heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 92, and (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; the second antigen-binding domain that specifically binds to a second epitope of human cMET is (a) a heavy chain variable region comprising an HCDR1 of SEQ ID NO: 56, (b) an HCDR2 of SEQ ID NO: 57, (c) an HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; and The third antigen-binding domain that specifically binds to human EGFR is 61. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 24 and 50 to 60, comprising a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 155, (b) an HCDR2 of SEQ ID NO: 156, (c) an HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 158, (e) an LCDR2 of SEQ ID NO: 159, and (f) an LCDR3 of SEQ ID NO:

160.

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

160.

64. 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; the second antigen-binding domain that specifically binds to a second epitope of human cMET is 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 is 64. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 24 and 50 to 60 and 63, comprising 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 first antigen-binding domain that specifically binds to a first epitope of human cMET comprises a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 6, (b) an HCDR2 of SEQ ID NO: 7, (c) an HCDR3 of SEQ ID NO: 92, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an 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) an HCDR1 of SEQ ID NO: 56, (b) an HCDR2 of SEQ ID NO: 57, (c) an HCDR3 of SEQ ID NO: 58, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 66, (e) an LCDR2 of SEQ ID NO: 67, and (f) an LCDR3 of SEQ ID NO: 68; and 65. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 24 and 50 to 64, wherein the third antigen-binding domain that specifically binds to human EGFR comprises a heavy chain variable region comprising (a) an HCDR1 of SEQ ID NO: 155, (b) an HCDR2 of SEQ ID NO: 156, (c) an HCDR3 of SEQ ID NO: 157, and a light chain variable region comprising (d) an LCDR1 of SEQ ID NO: 158, (e) an LCDR2 of SEQ ID NO: 159, and (f) an LCDR3 of SEQ ID NO:

160.

66. 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 66. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 24 and 50 to 65, 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.

67. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 50 to 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 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 67. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 24 and 50 to 66, wherein 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 an F(ab')2 fragment.

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

139.

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

161.

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

72. 72. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 50 to 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 kappa or lambda type.

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

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

77. The multispecific antibody or antigen-binding fragment thereof according to any one of claims 50 to 76, wherein the multispecific antibody or antigen-binding fragment thereof comprises increased bisecting GlcNAc structures.

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

79. 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 79. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50 to 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: 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.

80. 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, said first light chain constant region and said second light chain constant region are different; or 80. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50 to 79, wherein optionally the first light chain constant region and the second light chain constant region are the same.

81. 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 said second amino acid linker is any sequence of SEQ ID NOs: 97 to 139, preferably said second amino acid linker is SEQ ID NO:

139.

82. a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide; (1) the VL of the third antigen-binding domain that specifically binds to human EGFR, optionally the first amino acid linker, the VH of the third antigen-binding domain that specifically binds to human EGFR, optionally the second amino acid linker, the VH of the second antigen-binding domain that specifically binds to a second epitope of human cMET, and the 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; or the VL of the third antigen-binding domain that specifically binds to human EGFR, optionally the first amino acid linker, the VH of the third antigen-binding domain that specifically binds to human EGFR, optionally the second amino acid linker, the VH of the first antigen-binding domain that specifically binds to a 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; 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, said second amino acid linker is SEQ ID NO: 139; Optionally, the VL of said first antigen-binding domain and the VL of said second antigen-binding domain are the same; Optionally, the first light chain constant region and the second light chain constant region are the same; 82. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50 to 81, wherein optionally the third polypeptide and the fourth polypeptide are the same.

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

84. a first polypeptide, a second polypeptide, a third polypeptide, and a fourth polypeptide; (1) the VL of the third antigen-binding domain that specifically binds to human EGFR, optionally the first amino acid linker, the VH of the third antigen-binding domain that specifically binds to human EGFR, optionally the second amino acid linker, the VH of the second antigen-binding domain that specifically binds to a second epitope of human cMET, and the 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; 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, said second amino acid linker is SEQ ID NO: 139; Optionally, the VL of said first antigen-binding domain and the VL of said second antigen-binding domain are the same; Optionally, the first light chain constant region and the second light chain constant region are the same; 84. The multispecific antibody or antigen-binding fragment thereof of any one of claims 50 to 83, wherein optionally the third polypeptide and the fourth polypeptide are the same.

85. comprising a first polypeptide, a second polypeptide, and a third polypeptide; (1) 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: 150, and the third polypeptide has the 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 multispecific antibody or antigen-binding fragment thereof according to any one of claims 50 to 84, wherein 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: 150, and the third polypeptide has the amino acid sequence of SEQ ID NO:

148.

86. 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 multispecific antibody or antigen-binding fragment thereof according to any one of claims 50 to 85, comprising 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. 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 to 86, or the pharmaceutical composition of claim 87.

89. 89. The method of claim 88, wherein the cancer has a cMET gene mutation and / or the growth of the cancer cells is driven by cMET signaling.

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

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

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

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

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

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

96. 96. The method of any one of claims 88 to 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. 97. The method of claim 96, wherein the lung cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC).

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

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

100. 97. 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 to 100, wherein the multispecific antibody or antigen-binding fragment thereof is administered in combination with another therapeutic agent.

102. 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. 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 to 86.

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

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

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

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