WO2018069851A2

WO2018069851A2 - C-met antibody drug conjugate

Info

Publication number: WO2018069851A2
Application number: PCT/IB2017/056295
Authority: WO
Inventors: Tong Zhu; Gang Chen; Alisher Khasanov
Original assignee: Sorrento Therapeutics, Inc.
Priority date: 2016-10-11
Filing date: 2017-10-11
Publication date: 2018-04-19
Also published as: WO2018069851A3

Abstract

Described are antibody drug conjugates (ADCs) having an IgG antibody (A) that binds to a c-Met target, conjugated through a conjugation component at both Cys sites in the hinge region of the IgG antibody and to disulfide bonds linking heavy and light chains of the IgG class human antibody, to a drug (D). More specifically, the present disclosure relates to the drug component (D) of the ADC.

Description

C-MET ANTIBODY DRUG CONJUGATE

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/406,746, filed October 11, 2016, which is incorporated by reference herein in its entirety.

TECHNICAL FIELD

The present disclosure provides antibody drug conjugates (ADCs) having an IgG antibody (A) that binds to a c-Met target, the antibody conjugated through a conjugation component at both Cys sites in the hinge region of the IgG antibody and to disulfide bonds linking heavy and light chains of the IgG class human antibody, to a drug component (D). The present disclosure further provides a combination therapeutic composition comprising the cMet ADC disclosed herein combined with an anti-EGFR antibody.

BACKGROUND

HGF is a mesenchyme-derived pleiotrophic factor with mitogenic, motogenic and morphogenic activities on a number of different cell types. HGF effects are mediated through a specific tyrosine kinase, c- Met, and aberrant HGF and c-Met expression are frequently observed in a variety of tumors. (Maulik et al., Cytokine & Growth Factor Reviews (2002), 13:41-59; Danilkovitch-Miagkova & Zbar, J. Clin. Invest. (2002), 109(7):863-867). Regulation of the HGF/c-Met signaling pathway is implicated in tumor progression and metastasis. (Trusolino & Comoglio, Nature Rev. (2002), 2:289-300).

HGF binds the extracellular domain of the Met receptor tyrosine kinase (RTK) and regulates diverse biological processes such as cell scattering, proliferation, and survival. HGF-Met signaling is essential for normal embryonic development especially in migration of muscle progenitor cells and development of the liver and nervous system (Bladt et al., Nature 376, 768-771. 1995; Hamanoue et al. J. Neurosci. Res. 43, 554-564. 1996; Schmidt et al., Proc. Natl. Acad. Sci. USA 94, 11445-11450, 1995; Uehara et al., Nature 373, 702-705, 1995). Developmental phenotypes of Met and HGF knockout mice are very similar suggesting that HGF is the cognate ligand for the Met receptor (Schmidt et al., Proc. Natl. Acad. Sci. USA 94, 11445-11450, 1995; Uehara et al., Nature 373, 702-705, 1995). HGF-Met also plays a role in liver regeneration, angiogenesis, and wound healing (Bussolino et al., J. Cell Biol. 119, 629-641 1992; Nusrat et al., J. Clin. Invest. 93, 2056-2065 1994). The precursor Met receptor undergoes proteolytic cleavage into an extracellular subunit and membrane spanning subunit linked by disulfide bonds (Tempest et al., Br. J.

Cancer 58, 3-7 1988). The subunit contains the cytoplasmic kinase domain and harbors a multi-substrate docking site at the C-terminus where adapter proteins bind and initiate signaling. Upon HGF binding, activation of Met leads to tyrosine phosphorylation and downstream signaling through Gabl and Grb2/Sos mediated PI3 -kinase and Ras/MAPK activation respectively, which drives cell motility and proliferation (Furge et al., Oncogene 19, 5582-5589 2000; Hartmann et al., J. Biol. Chem. 269, 21936-21939 1994;

Ponzetto et al., Cell 87, 531-542 1996; and Royal and Park, J. Biol. Chem. 270, 27780-27787 1995). Met overexpression or gene-amplification has been observed in a variety of human cancers. For example, Met protein is overexpressed at least 5 -fold in colorectal cancers and reported to be gene-amplified in liver metastasis (Di Renzo et al., Clin. Cancer Res. 1, 147-154, 1995; Liu et al., Oncogene 7, 181-185 1992). Met protein is also reported to be overexpressed in oral squamous cell carcinoma, hepatocellular carcinoma, renal cell carcinoma, breast carcinoma, and lung carcinoma (Jin et al., Cancer 79, 749-760 1997; Morello et al., J. Cell Physiol. 189, 285-290 2001; Natali et al., Int. J. Cancer 69, 212-217. 1996; Olivero et al., Br. J. Cancer 74, 1862-1868 1996; Suzuki et al., Hepatology 20, 1231-1236 1994). In addition, overexpression of mRNA has been observed in hepatocellular carcinoma, gastric carcinoma, and colorectal carcinoma (Boix et al., Hepatology 19, 88-91 1994; Kuniyasu et al., Int. J. Cancer 55, 72-75 1993; Liu et al., Oncogene 7, 181-185 1992).

A number of mutations in the kinase domain of Met have been found in renal papillary carcinoma which leads to constitutive receptor activation (Olivero et al., Int. J. Cancer 82, 640-643 1999; Schmidt et al., Nat. Genet. 16, 68-73 1997; Schmidt et al., Oncogene 18, 2343-2350 1999). These activating mutations confer constitutive Met tyrosine phosphorylation and result in MAPK activation, focus formation, and tumorigenesis (Jeffers et al., Proc. Natl. Acad. Sci. USA 94, 11445-11450 1997). In addition, these mutations enhance cell motility and invasion (Giordano et al., 2000; Lorenzato et al., Cancer Res. 62, 7025-7030 2002). HGF-dependent Met activation in transformed cells mediates increased motility, scattering, and migration which eventually leads to invasive tumor growth and metastasis (Jeffers et al., Mol. Cell Biol. 16, 1115-1125 1996; Meiners et al., Oncogene 16, 9-20 1998).

The disclosed ADCs contains the same A (antibody) component and conjugation components of prior filed USSN 14/963,900 filed 08 December 2015, the disclosure of which is incorporated by reference herein.

SUMMARY

In one aspect, the present disclosure provides antibody drug conjugates (ADCs) having an IgG antibody that binds to a c-Met target conjugated through a conjugation component at both Cys sites in the hinge region of an IgG antibody to a drug or "D" component of the ADC, the ADCs comprising a structure of Formula I:

or a pharmaceutically acceptable salt thereof. Ab is an anti c-Met antibody. In some embodiments, n is an integer from 1 to 4, reflecting a DAR (drug: antibody ratio) of from 1: 1 to 4: 1. L¹ - L² taken together represent a linking moiety

wherein the wavy lines indicate a point of attachment to the Ab. In some embodiments, L² is a linker selected from the group consisting of one or more amino acids, -(CH₂)_m-, -(CH₂CH₂0)_m-, - [C(0)NHCH₂CH₂OCH₂CH₂OCH₂CH₂C(0)]_m-, PAB, Val-Cit-PAB, Val-Ala-PAB, Ala- Ala- Asn-PAB , and combinations thereof. In some embodiments, m is an integer from 1 to 8. D represents a calicheamicin analog according to Formula II:

(II).

In some embodiments, Rj is selected from the group consisting of C1-C8 alkyl, -(CH₂CH₂0)_p-, isopropyl, glucose, galactose, mannose, glucosamine, and C1-C8 alkyl-OH. In some embodiments, p is an integer from 1 to 24. In some embodiments, Rj is a hydrophilic group (e.g., PEG4). Without wishing to be bound by theory, it is believed that incorporation of a hydrophilic group via the disulfide bond may improve the solubility in aqueous buffer and may mitigate possible aggregation.

In certain embodiments, Rj is selected from the group consisting of

The point of attachment to the calicheamicin disulfide is indicated by the wavy lines. One skilled in the art will recognize that some of these structures may be combined. Therefore, in some embodiments, Ri may represent a combination of any two or more of the aforementioned structures.

In particular embodiments, the structure of Formula II is

In another aspect, the present disclosure further provides a method for treating a cancer comprising providing an effective amount of a c-Met ADC as disclosed herein. In some embodiments, the cancenr is breast cancer.

In yet another aspect is provided a composition comprising a c-Met ADC as disclosed herein in combination with an effective amount of an anti-EGFR antibody. In one embodiment, the anti-EGFR antibody is Erbitux. In a final aspect is provided a method of treating a cancer with an effective amount of a c-MET ADC as disclosed herein in combination with an effective amount of an anti-EGFR antibody. In one embodiment, the anti-EGFR antibody is Erbitux. In one embodiment, the cancer is breast cancer.

BRIEF DESCRIPTION OF THE FIGURES

Figures 1 A-E show the in vivo tumor growth inhibition efficacy of one disclosed c-Met ADC (c- Met ADC 1 from drug linker conjugate compound 8) in mice xenograft models bearing various cancer cell lines.

Figure 2 shows a comparison of single dose of c-Met ADC1 (present invention) at 3 mg/kg, d eight doses of Erbitux (anti-EGFR antibody) at 0.5 mg/kg, and the combination of a single dose of c-Met ADC1 at 3 mg/kg and eight doses of Erbitux at 0.5 mg/kg. Figure 2 provides these comparative data and demonstrates a significant synergistic effect when combining c-Met ADC1 with an anti-EGFR antibody.

Figures 3A-C show the in vivo tumor growth inhibition efficacy with c-Met ADC1 in mice PDX models.

DETAILED DESCRIPTION

We generated antibody drug conjugates containing a novel human anti-c-Met antibody (STI-0602) (described in United States Patent application serial number 13/924,492 filed 21 June 2013, the disclosure of which is incorporated by reference herein) with a calicheamicin "D" component. The ADC conjugates retained binding affinity and showed potent cell killing in a variety of c-Met positive cell lines and showed surprisingly better results than a prior cMet ADC with the same antibody and a tubulin binder as the drug component.

The present disclosure provides antibody drug conjugate (ADC) compositions comprising an IgG antibody (A) that binds to c-Met, a conjugation linker component (C) that binds to both Cys residues in the hinge region of the IgG antibody and a drug moiety (D). In preferred embodiments, the antibody is an IgG antibody from the H8 (heavy/light SEQ ID NOs 19/20) family or is a B 12 (heavy/light SEQ ID NOs 7/8), wherein the H8 antibody family is selected from the group consisting of H8-A2, H8-9, H8-9EE8L3, H8-C1, H8-D4, H8-D5, H8-D6, H8-D10, H8-E5, H8-G7, H8-H6, H8-2A2, H8-2B 1, H8-2B2, H8-2B4, H8-2B7, H8- A7P, H8-9EH11L, H8-9EH11L, and H8-6AG2H3.

Antibody Component

The present disclosure provides a fully human antibody of an IgG class that binds to a c-Met epitope with a binding affinity of at least 10^"6M, which has a heavy chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 37, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 74, SEQ ID NO. 75, SEQ ID NO. 76, SEQ ID NO. 79, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, and combinations thereof, and that has a light chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 35, SEQ ID NO. 38, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 67, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 73, SEQ ID NO. 77, SEQ ID NO. 78, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, and combinations thereof. Preferably, the fully human antibody has both a heavy chain and a light chain wherein the antibody has a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2 (called Al herein), SEQ ID NO. 3/SEQ ID NO. 4 (called A2 herein), SEQ ID NO. 5/SEQ ID NO. 6 (called A8 herein), SEQ ID NO. 7/SEQ ID NO. 8 (called B 12 herein), SEQ ID NO. 9/SEQ ID NO. 10 (called D6 herein), SEQ ID NO. 11/SEQ ID NO. 12 (called El herein), SEQ ID NO. 13/SEQ ID NO. 14 (called E6 herein), SEQ ID NO. 15/SEQ ID NO. 16 (called F3 herein), SEQ ID NO. 17/SEQ ID NO. 18 (called H6 herein), SEQ ID NO. 19/SEQ ID NO. 20 (called H8 herein), SEQ ID NO. 21/SEQ ID NO. 22 (called H8-9 herein), SEQ ID NO. 21/SEQ ID NO. 23 (called H8-9EE8L3 herein), SEQ ID NO. 24/SEQ ID NO. 22 (called H8-G3S herein), SEQ ID NO. 25/SEQ ID NO. 26 (called H8-A2 herein), SEQ ID NO. 27/SEQ ID NO. 28 (called H8-B6 herein), SEQ ID NO. 29/SEQ ID NO. 23 (called H8-C1 herein), SEQ ID NO. 24/SEQ ID NO. 30 (called H8-D4 herein), SEQ ID NO. 31/SEQ ID NO. 23 (called H8-D5 herein), SEQ ID NO. 24/SEQ ID NO. 23 (called H8-D6 herein), SEQ ID NO. 32/SEQ ID NO. 23 (called H8-D10 herein), SEQ ID NO. 33/SEQ ID NO. 22 (called H8-E5 herein), SEQ ID NO. 34/SEQ ID NO. 22 (called H8-G7 herein), SEQ ID NO. 24/SEQ ID NO. 35 (called H8-G9 herein), SEQ ID NO. 36/SEQ ID NO. 26 (called H8-H6 herein), SEQ ID NO. 29/SEQ ID NO. 22 (called H8-2A2 herein), SEQ ID NO. 37/SEQ ID NO. 38 (called H8-2B 1 herein), SEQ ID NO. 34/SEQ ID NO. 23 (called H8-2B2 herein), SEQ ID NO. 37/SEQ ID NO. 23 (called H8-2B4 herein), SEQ ID NO. 32/SEQ ID NO. 39 (called H8-2B7 herein), SEQ ID NO. 32/SEQ ID NO. 22 (called H8-A7P herein), SEQ ID NO. 40/SEQ ID NO. 41 (called GCE-A10 herein), SEQ ID NO. 42/SEQ ID NO. 43 (called GCE-A11 herein), SEQ ID NO. 44/SEQ ID NO. 41 (called GCE-A13 herein), SEQ ID NO. 45/SEQ ID NO. 46 (called GCE-A14 herein), SEQ ID NO. 47/SEQ ID NO. 48 (called GCE-A16 herein), SEQ ID NO. 49/SEQ ID NO. 50 (called GCE-A18 herein), SEQ ID NO. 51/SEQ ID NO. 52 (called GCE-B2 herein), SEQ ID NO.

53/SEQ ID NO. 54 (called GCE-B9 herein), SEQ ID NO. 45/SEQ ID NO. 55 (called GCE-B11 herein), SEQ ID NO. 56/SEQ ID NO. 57 (called GCE-B13 herein), SEQ ID NO. 58/SEQ ID NO. 57 (called GCE- B19 herein), SEQ ID NO. 59/SEQ ID NO. 60 (called GCE-BR1 herein), SEQ ID NO. 61/SEQ ID NO. 62 (called GCE-B20 herein), SEQ ID NO. 63/SEQ ID NO. 64 (called GCE-A19 herein), SEQ ID NO. 65/SEQ ID NO. 66 (called GCE-B10 herein), SEQ ID NO. 58/SEQ ID NO. 67 (called GCE-B5 herein), SEQ ID NO. 61/SEQ ID NO. 68 (called GCE-B4 herein), SEQ ID NO. 69/SEQ ID NO. 70 (called GCE-A26 herein),

SEQ ID NO. 71/SEQ ID NO. 72 (called GCE-LlA-9 herein), SEQ ID NO. 49/SEQ ID NO. 73 (called GCE- H34-36 herein), SEQ ID NO. 74/SEQ ID NO. 73 (called GCE-H13-1 herein), SEQ ID NO. 61/SEQ ID NO. 73 (called GCE-H13-2 herein), SEQ ID NO. 44/SEQ ID NO. 73 (called GCE-H13-3 herein), SEQ ID NO. 40/SEQ ID NO. 73 (called GCE-H13-4 herein), SEQ ID NO. 75/SEQ ID NO. 73 (called GCE-H13-5 herein), SEQ ID NO. 69/SEQ ID NO. 73 (called GCE-H13-6 herein), SEQ ID NO. 76/SEQ ID NO. 73 (called GCE-H13-8 herein), SEQ ID NO. 21/SEQ ID NO. 77 (called H8-9EH11L herein), SEQ ID NO. 21/SEQ ID NO. 78 (called H8-9EG11L herein), SEQ ID NO. 79/SEQ ID NO. 20 (called H8-6AG2H3 herein), SEQ ID NO. 80/SEQ ID NO. 81 (called Al-2 herein), SEQ ID NO. 82/SEQ ID NO. 83 (called Al-4 herein), SEQ ID NO. 84/SEQ ID NO. 85 (called Al-6 herein), SEQ ID NO. 86/SEQ ID NO. 87 (called Al-8 herein), SEQ ID NO. 88/SEQ ID NO. 89 (called Al-9 herein), SEQ ID NO. 90/SEQ ID NO. 91 (called Al- 24 herein), SEQ ID NO. 92/SEQ ID NO. 93 (called Al-32 herein), and combinations thereof.

The present disclosure provides a fully human antibody Fab fragment, having a variable domain region from a heavy chain and a variable domain region from a light chain, wherein the heavy chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 37, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 74, SEQ ID NO. 75, SEQ ID NO. 76, SEQ ID NO. 79, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, and combinations thereof, and that has a light chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 35, SEQ ID NO. 38, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 67, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 73, SEQ ID NO. 77, SEQ ID NO. 78, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, and combinations thereof. Preferably, the fully human antibody Fab fragment has both a heavy chain variable domain region and a light chain variable domain region wherein the antibody has a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 21/SEQ ID NO. 23, SEQ ID NO. 24/SEQ ID NO. 22, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO.

29/SEQ ID NO. 23, SEQ ID NO. 24/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 23, SEQ ID NO.

24/SEQ ID NO. 23, SEQ ID NO. 32/SEQ ID NO. 23, SEQ ID NO. 33/SEQ ID NO. 22, SEQ ID NO.

34/SEQ ID NO. 22, SEQ ID NO. 24/SEQ ID NO. 35, SEQ ID NO. 36/SEQ ID NO. 26, SEQ ID NO.

29/SEQ ID NO. 22, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 34/SEQ ID NO. 23, SEQ ID NO.

37/SEQ ID NO. 23, SEQ ID NO. 32/SEQ ID NO. 39, SEQ ID NO. 32/SEQ ID NO. 22, SEQ ID NO.

40/SEQ ID NO. 41, SEQ ID NO. 42/SEQ ID NO. 43, SEQ ID NO. 44/SEQ ID NO. 41, SEQ ID NO.

45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO.

51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO. 45/SEQ ID NO. 55, SEQ ID NO.

56/SEQ ID NO. 57, SEQ ID NO. 58/SEQ ID NO. 57, SEQ ID NO. 59/SEQ ID NO. 60, SEQ ID NO.

61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO.

58/SEQ ID NO. 67, SEQ ID NO. 61/SEQ ID NO. 68, SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO.

71/SEQ ID NO. 72, SEQ ID NO. 49/SEQ ID NO. 73, SEQ ID NO. 74/SEQ ID NO. 73, SEQ ID NO.

61/SEQ ID NO. 73, SEQ ID NO. 44/SEQ ID NO. 73, SEQ ID NO. 40/SEQ ID NO. 73, SEQ ID NO.

75/SEQ ID NO. 73, SEQ ID NO. 69/SEQ ID NO. 73, SEQ ID NO. 76/SEQ ID NO. 73, SEQ ID NO.

21/SEQ ID NO. 77, SEQ ID NO. 21/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 20, SEQ ID NO.

80/SEQ ID NO. 81, SEQ ID NO. 82/SEQ ID NO. 83, SEQ ID NO. 84/SEQ ID NO. 85, SEQ ID NO.

86/SEQ ID NO. 87, SEQ ID NO. 88/SEQ ID NO. 89, SEQ ID NO. 90/SEQ ID NO. 91, SEQ ID NO.

92/SEQ ID NO. 93, and combinations thereof.

The present disclosure provides a single chain human antibody, having a variable domain region from a heavy chain and a variable domain region from a light chain and a peptide linker connection the heavy chain and light chain variable domain regions, wherein the heavy chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 32, SEQ ID NO. 33, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 37, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 74, SEQ ID NO. 75, SEQ ID NO. 76, SEQ ID NO. 79, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, and combinations thereof, and that has a light chain variable domain sequence that is at least 95% identical to the amino acid sequences selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 35, SEQ ID NO. 38, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 67, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 73, SEQ ID NO. 77, SEQ ID NO. 78, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, and combinations thereof. Preferably, the fully human single chain antibody has both a heavy chain variable domain region and a light chain variable domain region, wherein the single chain fully human antibody has a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO.

19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 21/SEQ ID NO. 23, SEQ ID NO.

24/SEQ ID NO. 22, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO.

92/SEQ ID NO. 93, and combinations thereof. Linker/Conjugation Component and Drug Component

EXAMPLES

Example 1

Preparation of compound 8

To calicheamicin γΐ (1) (880 mg, 0.54 mmol) in 25 mL of dimethylformamide (DMF) was added (9H-fluoren-9-yl)methyl (2-chloro-2-oxoethyl)carbamate (256 mg, 0.81 mmol) and diisopropylethylamine (DIEA, 173 μί, 1 mmol). The mixture was stirred for 2 h, then evaporated and purified by HPLC to give compound 2 (300 mg). MS m/z 1647.3 (M+H).

To compound 2 (100 mg, 0.06 mmol) in 4 mL of acetonitrile and 0.3 mL of DMF was added compound 3 (75 mg, 0.24 mmol). The mixture was stirred for 16 h, then 120 μί of piperidine was added. After 30 min the mixture was purified by HPLC to give compound 4 (60 mg). MS m/z 1654.4 (M+H).

To compound 4 (20 mg, 12 μπιοΐ) in 2 mL of DMF was added compound 5 (11 mg, 14 μπιοΐ), N- Hydroxybenzotriazole (HOBt, 2 mg), and 5 μΐ_^ of DIEA. The mixture was stirred for 1 h, then 40 μΐ_^ of piperidine was added. After 10 min the mixture was purified by HPLC to give compound 6 (21 mg). MS m/z 2059.6 (M+H).

To compound 6 (21 mg, 10 μπιοΐ) in 2 mL of dichloromethane (DCM) was added compound 7 (13 mg, 13 μπιοΐ), and 3 μί of DIEA. The mixture was stirred for 20 min, then evaporated and purified by HPLC to give compound 8 (11 mg). MS m/z 2558.6 (M+H).

Preparation of compound 12

To compound 2 (100 mg, 0.06 mmol) in 4 mL of acetonitrile and 0.3 mL of DMF was added compound 9 (118 mg, 0.57 mmol). The mixture was stirred for 16 h, then 120 μΐ_^ of piperidine was added. After 30 min the mixture was purified by HPLC to give compound 10 (40 mg). MS m/z 1552.4 (M+H).

To compound 10 (28 mg, 18 mmol) in 1 mL of DMF was added compound 5 (17 mg, 22 mmol), HOBt (2 mg), and 5 μΐ_^ of DIEA. The mixture was stirred for 1 h, then 20 μΐ_^ of piperidine was added. After 10 min the mixture was purified by HPLC to give compound 11 (23 mg). MS m/z 1957.6 (M+H).

To compound 11 (23 mg, 12 μπιοΐ) in 2 mL of DCM was added compound 7 (17 mg, 17 μπιοΐ), and 3 μΐ_^ of DIEA. The mixture was stirred for 20 min, then evaporated and purified by HPLC to give compound 12 (16 mg). MS m/z 2558.6 (M+H). Example 2

Preparation of cMet-ADC 1

Anti-cMet antibody was reduced by TCEP (tris(2-carboxyethyl)phosphine), up to 20 mM. The excess of TCEP was removed by gel-filtration chromatography or centrifugal filtration. Added organic solvent (up to 50%) to antibody solution. Drug-linker (compound 8) was dissolved in Acetonitrile/water solution and added to the reduced antibody with Toxin/antibody ratio from 3.5 to 6. After few hours' incubation at room temperature, the unconjugated Toxin-linker was removed by gel-filtration

chromatography or centrifugal filtration. The resulting cMet-ADC (compound ADC 1) was characterized by HPLC. The drug antibody ratio (DAR) was calculated based on UV-VIS or HIC-HPLC.

Example 3

This example (Figure 1) is an experiment showing in vivo tumor growth inhibition efficacy of one c-

Met ADC disclosed herein (c-Met ADC 1 from drug linker conjugate compound 8) in mice xenograft models bearing various cancer cell lines. ADC or vehicle control was administered iv to the tail.

Tumor cells were maintained in vitro as a monolayer culture. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. Each mouse was inoculated subcutaneously with appropriate amount of tumor cells in 0.2 mL of serum-free medium. The treatments were started when the average tumor volume reached about 100-200 mm³ (QW x 3 for H1993; single dose for the rest tumor models). The testing article was administrated to the mice at indicated arrangement via iv route. Tumor size was measured twice weekly in two dimensions using a caliper, and the volume was expressed in mm³ using the formula: V = 0.5 a x b² where a and b are the long and short diameters of the tumor, respectively.

Example 4

This example is an experiment using disclosed c-Met ADC 1 in vivo with mice having tumor developed with H292 non-small cell lung cancer line. ADC or vehicle control was administered iv to the tail in one weekly dose. Erbitux (anti-EGFR antibody) was administered at biweekly doses for 4 weeks. Figure 2 shows comparison of single dose of c-Met ADC 1 at 3 mg/kg, eight doses of Erbitux at 0.5mg/kg, and the combination of single of c-Met-ADC 1 at 3 mg/kg and eight doses of Erbitux at 0.5 mg/kg. Figure 2 provides these comparative data and it shows a significant synergistic effect when combining a c-Met-ADC with an anti-EGFR antibody. Example 5

This example is an in vivo tumor growth inhibition efficacy study with c-Met ADC 1 in mice PDX models.

Tumor fragments from stock mice inoculated with selected primary human tumor tissues were harvested and used for inoculation into BALB/c nude mice. Each mouse was inoculated subcutaneously at the right flank with primary human lung models LU2503 (P8); LU1868 (P8) or LU1429 (P7) fragment (2-4 mm in diameter) for tumor development. The treatments were started when the average tumor size reached around 227 mm³; 226 mm³ or 207 mm³, respectively. The test article was administered once to the tumor- bearing mice in 0.3 ml solution buffer. Figure 3 provides these comparative data and it shows significant tumor growth inhibition from c-Met ADC1 in mice PDX models. Sequence Listing

QAVLTQPASVSGSPGQSITISCTGT

QVQLQQWGAGLLKPSETLSLTCAVYGGS RSDVGGYNYVSWYQQHPGKAPKL FSGYYWSWIRQPPGKGLEWIGEINHSGS LVYDVSNRPSGVSNRFSGSQSGN TNYNPSLKSRVTISVDTSKNQFSLKLSSVT TASLTISGLQTEDEADYYCSSYTDN AADTAVYYCARGGRVYSNYYMDVWGKG SALVVFGGGTKVTVL SEQ ID NO.

E6 TTVTVSS SEQ ID NO. 13 14

QSVLTQPASVSGSPGQSITISCTGT

QVQLVESGPGLVKPSGTLSLTCAVSGGSI SSDVGGYNYVSWYQQHPGKAPKL SSSNWWSWVRQPPGKGLEWIGEIYHSG LIYDVDSRPSGVSNRFSGSKSGNT STNYNPSLKSRVTISVDKSKNQFSLKLSS ASLTISGLQAEDEADYYCSSFTSSS VTAADTAVYYCARSAYGDYFLDYWGQGT TLVVFGGGTKVTVL SEQ ID NO.

F3 LVTVSS SEQ I D NO. 15 16

EVQLLESGGGLVQPGGSLRLSCAASGFT AIRMTQSPAFMSATPGDKVNISYKA FSSYEMNWVRQAPGKGLEWVSYISSSGS SQDVDDDMTWCQEKPGEAAIFIFQ TIYYADSVKGRFTISRDNAKNSLYLQMNS EAATLVPG IPPRLSGSGNGTD FTLT LRAEDTAVYYCARDGAATGDQIDYWGQG INNMESEDAAYYFCLQQDNFPLTF

H6 TLVTVSS SEQ ID NO. 17 GQGTKVDIK SEQ ID NO. 18

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FSSYYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGYAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDYWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8 TLVTVSS SEQ ID NO. 19 AGVFGGGTKLTVL SEQ ID NO. 20

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSYYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGYAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-9 TLVTVSS SEQ ID NO. 21 AWVFGGGTKLTVL SEQ ID NO. 22

H8-9EE8L3 TLVTVSS SEQ ID NO. 21 AWLFGGGTKLTVL SEQ ID NO. 23

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSEYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGYAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT

H8-G3S SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS TLVTVSS SEQ ID NO. 24 AWVFGGGTKLTVL SEQ ID NO. 22

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSEYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGVAPKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-A2 TLVTVSS SEQ ID NO. 25 AWAFGGGTKLTVL SEQ ID NO. 26

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSEYMHWVRQAPGQGLEWMGWINPNS SNSFTDNTYVSWYHHLPGTAPKLLI GNTGYAQKFQGRVTMTRNTSISTAYMEL YDTNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-B6 TLVTVSS SEQ ID NO. 27 AWVFGGGTKLTVL SEQ ID NO. 28

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSEYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGLAPKFQGRVTMTRNTSISTAYMELS YDNNKRPSGIPDRFSGSKSGTSAT SLRSEDTAVYYCARRGTTVSFDTWGQGT LGITGLQPGDEAHYYCGTWDSTLS

H8-C1 LVTVSS SEQ I D NO. 29 AWLFGGGTKLTVL SEQ ID NO. 23

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSEYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGYAQKFQGRVTMTRNTSISTAYMEL YDNNKRQSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-D4 TLVTVSS SEQ ID NO. 24 AWVFGGGTKLTVL SEQ ID NO. 30

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSYYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGVAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-D5 TLVTVSS SEQ ID NO. 31 AWLFGGGTKLTVL SEQ ID NO. 23

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSEYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGYAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-D6 TLVTVSS SEQ ID NO. 24 AWLFGGGTKLTVL SEQ ID NO. 23

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSEYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI

H8-D10 GNTGLAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS TLVTVSS SEQ ID NO. 32 AWLFGGGTKLTVL SEQ ID NO. 23

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSEYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGYAPKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-E5 TLVTVSS SEQ ID NO. 33 AWVFGGGTKLTVL SEQ ID NO. 22

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSEYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGVAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-G7 TLVTVSS SEQ ID NO. 34 AWVFGGGTKLTVL SEQ ID NO. 22

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSEYMHWVRQAPGQGLEWMGWINPNS SNSFSSNNYVSWYHHLPGTAPKLLI GNTGYAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-G9 TLVTVSS SEQ ID NO. 24 AWVFGGGTKLTVL SEQ ID NO. 35

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSYYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGLAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-H6 TLVTVSS SEQ ID NO. 36 AWAFGGGTKLTVL SEQ ID NO. 26

H8-2A2 LVTVSS SEQ I D NO. 29 AWVFGGGTKLTVL SEQ ID NO. 22

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSYYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGLAPKFQGRVTMTRNTSISTAYMELS YDTNKRPSGIPDRFSGSKSGTSAT SLRSEDTAVYYCARRGTTVSFDTWGQGT LGITGLQPGDEAHYYCGTWDSTLS

H8-2B1 LVTVSS SEQ I D NO. 37 AWAFGGGTKLTVL SEQ ID NO. 38

H8-2B2 GNTGVAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS TLVTVSS SEQ ID NO. 34 AWLFGGGTKLTVL SEQ ID NO. 23

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSYYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGLAPKFQGRVTMTRNTSISTAYMELS YDNNKRPSGIPDRFSGSKSGTSAT SLRSEDTAVYYCARRGTTVSFDTWGQGT LGITGLQPGDEAHYYCGTWDSTLS

H8-2B4 LVTVSS SEQ I D NO. 37 AWLFGGGTKLTVL SEQ ID NO. 23

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSAS FYSEYMHWVRQAPGQGLEWMGWINPNS NSNIGNNYVSWYHHLPGTAPKLLIY GNTGLAQKFQGRVTMTRNTSISTAYMEL DNNKRPSGIPDRFSGSKSGTSATL SSLRSEDTAVYYCARRGTTVSFDTWGQG GITGLQPGDEAHYYCGTWDSTLSA

H8-2B7 TLVTVSS SEQ ID NO. 32 WVFGGGTKLTVL SEQ ID NO. 39

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSEYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGLAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-A7P TLVTVSS SEQ ID NO. 32 AWVFGGGTKLTVL SEQ ID NO. 22

QSVVTQPPSVSGAPGQRVTISCLG

QVQLVQSGAEVKKPGASVKVSCKASGYT SASNIGAGHDVHWYQQLPGTAPKL FSGDYMHWVRQAPGQGLEWMGWINPN LIYGNSNRPSGVPDRFSGSKSGTS SGGTNYAQKFQGRVTMTRDTSISTAYME ASLAITGLQAEDEADYYCQSYSSSL LSRLRSDDTAVYYCAREPARDYYYYDGL SAYVFGTGTKVTVL SEQ ID NO.

GCE-A10 DVWGQGTTVTVSS SEQ ID NO. 40 41

QVQLVQSGAEVKKPGASVKVSCKASGFT QSVVTQPPSVSGAPGQRVTISCLG FSGDYIHWVRQAPGQGLEWMGWINPNS SSSNIGAGHDVHWYQQLPGTAPKL GGTNYAQKFQGRVTMTRDTSISTAYMEL LIYGNSNRISGVPDRFSGSKSGTSA SRLRSDDTAVYYCAREPARDYYYYDGLD SLAITGLQAEDEADYYCQSYSSSLS

GCE-A1 1 VWGQGTTVTVSS SEQ ID NO. 42 AYLFGTGTKVTVL SEQ I D NO. 43

QSVVTQPPSVSGAPGQRVTISCLG

QVQLVQSGAEVKKPGASVKVSCKASGYT SASNIGAGHDVHWYQQLPGTAPKL FSGDYLHWVRQAPGQGLEWMGWINPNS LIYGNSNRPSGVPDRFSGSKSGTS GGTNYAQKFQGRVTMTRDTSISTAYMEL ASLAITGLQAEDEADYYCQSYSSSL SRLRSDDTAVYYCAREPARDYYYYDGLD SAYVFGTGTKVTVL SEQ ID NO.

GCE-A13 VWGQGTTVTVSS SEQ ID NO. 44 41 QSVVTQPPSVSGAPGQRVTISCIG

QVQLVQSGAEVKKPGASVKVSCKASGYT SSSNIGAGHDVHWYQQLPGTAPKL FSGDYIHWVRQAPGQGLEWMGWINPNS LIYGNSNRPSGVPDRFSGSKSGTS GGTNYAQKFQGRVTMTRDTSISTAYMEL ASLAITGLQAEDEADYYCQSYSSSL SRLRSDDTAVYYCAREPARDYYYYDGLD SAYVFGTGTKVTVL SEQ ID NO.

GCE-A14 VWGQGTTVTVSS SEQ ID NO. 45 46

QSVVTQPPSVSGAPGQRVTISCIG

QVQLVQSGAEVKKPGASVKVSCKASGYT SSSNIGAGYDVHWYQQLPGTAPKL FSGDYLHWVRQAPGQGLEWMGWINPNT LIYGNSNLPSGVPDRFSGSKSGTS GGTNYAQKFQGRVTMTRDTSISTAYMEL ASLAITGLQAEDEADYYCQSYESSL SRLRSDDTAVYYCAREPARDYYYYDGLD SAYVFGTGTKVTVL SEQ ID NO.

GCE-A16 VWGQGTTVTVSS SEQ ID NO. 47 48

QSVVTQPPSVSGAPGQRVTISCIG

QVQLVQSGAEVKKPGASVKVSCKASGYT SASNIGAGHDVHWYQQLPGTAPKL FSGDYMHWVRQAPGQGLEWMGWINPN LIYGNSNRPSGVPDRFSGSKSGTS SGGTNYAQKFQGRVTMTRDTSISTAYME ASLAITGLQAEDEADYYCQSYSSSL LSRLRSDDTAVYYCAREPGRDYYYYDGL SAYVFGTGTKVTVL SEQ ID NO.

GCE-A18 D VWGQGTTVTVSS SEQ ID NO. 49 50

QSVVTQPPSVSGAPGQRVTISCLG

QVQLVQSGAEVKKPGASVKVSCKASGYT SASNIGAGYDVHWYQQLPGTAPKL FSGDYMHWVRQAPGQGLEWMGWINPN LIYGNSNRPSGVPDRFSGSKSGTS TGGTNYAQKFQGRVTMTRDTSISTAYME ASLAITGLQAEDEADYYCQSYSSSL LSRLRSDDTAVYYCAREPARDYYYYDGL SAYVFGTGTKVTVL SEQ ID NO.

GCE-B2 D VWGQGTTVTVSS SEQ ID NO. 51 52

QVQLVQSGAEVKKPGASVKVSCKASGFT QSVVTQPPSVSGAPGQRVTISCLG FSGDYMHWVRQAPGQGLEWMGWINPN SSSNIGAGHDVHWYQQLPGTAPKL SGGTNYAQKFQGRVTMTRDTSISTAYME LIYGNSNLPSGVPDRFSGSKSGTS LSRLRSDDTAVYYCAREPARDYYYYDGL ASLAITGLQAEDEADYYCQSYSSSL

GCE-B9 D VWGQGTTVTVSS SEQ ID NO. 53 SAVLFGTGTKVTVL SEQ ID NO. 54

QVQLVQSGAEVKKPGASVKVSCKASGYT QSVVTQPPSVSGAPGQRVTISCIG FSGDYIHWVRQAPGQGLEWMGWINPNS SSSNIGAGYDVHWYQQLPGTAPKL GGTNYAQKFQGRVTMTRDTSISTAYMEL LIYGNSNRISGVPDRFSGSKSGTSA SRLRSDDTAVYYCAREPARDYYYYDGLD SLAITGLQAEDEADYYCQSYSSSLS

GCE-B1 1 VWGQGTTVTVSS SEQ ID NO. 45 AVLFGTGTKVTVL SEQ I D NO. 55 QVQLVQSGAEVKKPGASVKVSCKASGST QSVVTQPPSVSGAPGQRVTISCLG FSGDYIHWVRQAPGQGLEWMGWINPNS SASNIGAGHDVHWYQQLPGTAPKL GGTNYAQKFQGRVTMTRDTSISTAYMEL LIYGNSNRPSGVPDRFSGSKSGTS SRLRSDDTAVYYCAREPARDYYYYDGLD ASLAITGLQAEDEADYYCQSYSSSL

GCE-B13 VWGQGTTVTVSS SEQ ID NO. 56 SAVLFGTGTKVTVL SEQ ID N0.57

QVQLVQSGAEVKKPGASVKVSCKASGFT QSVVTQPPSVSGAPGQRVTISCLG FSGDYIHWVRQAPGQGLEWMGWINPNS SASNIGAGHDVHWYQQLPGTAPKL GGTNYAQKFQGRVTMTRDTSISTAYMEL LIYGNSNRPSGVPDRFSGSKSGTS SRLRSDDTAVYYCAREPGRDYYYYDGLD ASLAITGLQAEDEADYYCQSYSSSL

GCE-B19 VWGQGTTVTVSS SEQ ID NO. 58 SAVLFGTGTKVTVL SEQ ID NO. 57

QVQLVQSGAEVKKPGASVKVSCKASGST QSVVTQPPSVSGAPGQRVTISCLG FSGDYLHWVRQAPGQGLEWMGWINPNS SASNIGAGYDVHWYQQLPGTAPKL GGTNYAQKFQGRVTMTRDTSISTAYMEL LIYGNSNRPSGVPDRFSGSKSGTS SRLRSDDTAVYYCAREPARDYYYYDGLD ASLAITGLQAEDEADYYCQSYSSSL

GCE-BR1 VWGQGTTVTVSS SEQ ID NO. 59 SAVLFGTGTKVTVL SEQ ID NO. 60

QVQLVQSGAEVKKPGASVKVSCKASGYT QSVVTQPPSVSGAPGQRVTISCLG FSGDYLHWVRQAPGQGLEWMGWINPNS SASNIGAGHDVHWYQQLPGTAPKL GGTNYAQKFQGRVTMTRDTSISTAYMEL LIYGNSNRISGVPDRFSGSKSGTSA SRLRSDDTAVYYCAREPARDYYYYDGMD SLAITGLQAEDEADYYCQSYSSSLS

GCE-B20 VWGQGTTVTVSS SEQ ID NO. 61 AVLFGTGTKVTVL SEQ I D NO. 62

QVQLVQSGAEVKKPGASVKVSCKASGFT QSVVTQPPSVSGAPGQRVTISCLG FSGDYLHWVRQAPGQGLEWMGWINPNS SSSNIGAGHDVHWYQQLPGTAPKL GGTNYAQKFQGRVTMTRDTSISTAYMEL LIYGNSNRISGVPDRFSGSKSGTSA SRLRSDDTAVYYCAREPARDYYYYYGLD SLAITGLQAEDEADYYCQSYSSSLS

GCE-A19 VWGQGTTVTVSS SEQ ID NO. 63 AYVFGTGTKVTVL SEQ ID NO. 64

QSVVTQPPSVSGAPGQRVTISCLG

QVQLVQSGAEVKKPGASVKVSCKASGFT SSSNIGAGHDVHWYQQLPGTAPKL FSGDYLHWVRQAPGQGLEWMGWINPNT LIYGNSNLPSGVPDRFSGSKSGTS GGTNYAQKFQGRVTMTRDTSISTAYMEL ASLAITGLQAEDEADYYCQSYSSSL SRLKSDDTAVYYCAREPARDYYYYDGLD SAYVFGTGTKVTVL SEQ ID NO.

GCE-B10 VWGQGTTVTVSS SEQ ID NO. 65 66

QSVVTQPPSVSGAPGQRVTISCLG

QVQLVQSGAEVKKPGASVKVSCKASGFT SASNIGAGHDVHWYQQLPGTAPKL FSGDYIHWVRQAPGQGLEWMGWINPNS LIYGNSNRPSGVPDRFSGSKSGTS GGTNYAQKFQGRVTMTRDTSISTAYMEL ASLAITGLQAEDEADYYCQSYSSSL SRLRSDDTAVYYCAREPGRDYYYYDGLD SAVVFGTGTKVTVL SEQ ID NO.

GCE-B5 VWGQGTTVTVSS SEQ ID NO. 58 67 QVQLVQSGAEVKKPGASVKVSCKASGYT QSVVTQPPSVSGAPGQRVTISCIG FSGDYLHWVRQAPGQGLEWMGWINPNS SASNIGAGHDVHWYQQLPGTAPKL GGTNYAQKFQGRVTMTRDTSISTAYMEL LIYGNSNRISGVPDRFSGSKSGTSA SRLRSDDTAVYYCAREPARDYYYYDGMD SLAITGLQAEDEADYYCQSYSSSLS

GCE-B4 VWGQGTTVTVSS SEQ ID NO. 61 AVLFGTGTKVTVL SEQ I D NO. 68

QVQLVQSGAEVKKPGASVKVSCKASGFT QSVVTQPPSVSGAPGQRVTISCLG FSGDYLHWVRQAPGQGLEWMGWINPNS SSSNIGAGHDVHWYQQLPGTAPKL GGTNYAQKFQGRVTMTRDTSISTAYMEL LIYGNSNRPSGVPDRFSGSKSGTS SRLRSDDTAVYYCAREPARDYYYYDGLD ASLAITGLQAEDEADYYCQSYSSSL

GCE-A26 VWGQGTTVTVSS SEQ ID NO. 69 SAYLFGTGTKVTVL SEQ ID NO. 70

QSVVTQPPSVSGAPGQRVTISCLG

QVQLVQSGAEVKKPGASVKVSCKASGYT SSSNIGAGYDVHWYQQLPGTAPKL FSGDYMHWVRQAPGQGLEWMGWINPN LIYGNSNRPSGVPDRFSGSKSGTS SGGTNYAQKFQGRVTMTRDTSISTAYME ASLAITGLQAEDEADYYCQSYSSSL LSRLRSDDTAVYYCAREPGRDYYYYDGM SAYVFGTGTKVTVL SEQ ID NO.

GCE-L1 A-9 D VWGQGTTVTVSS SEQ ID NO. 71 72

QVQLVQSGAEVKKPGASVKVSCKASGYT QSVVTQPPSVSGAPGQRVTISCTG FSGDYMHWVRQAPGQGLEWMGWINPN SSSNIGAGYDVHWYQQLPGTAPKL SGGTNYAQKFQGRVTMTRDTSISTAYME LIYGNSNRPSGVPDRFSGSKSGTS

GCE-H3B- LSRLRSDDTAVYYCAREPGRDYYYYDGL ASLAITGLQAEDEADYYCQSYSSSL 36 D VWGQGTTVTVSS SEQ ID NO. 49 SAYVFGTGTKVTVL SEQ ID N0.73

QSVVTQPPSVSGAPGQRVTISCTG

QVQLVQSGAEVKKPGASVKVSCKASGST SSSNIGAGYDVHWYQQLPGTAPKL FSGDYLHWVRQAPGQGLEWMGWINPNS LIYGNSNRPSGVPDRFSGSKSGTS GGTNYAQKFQGRVTMTRDTSISTAYMEL ASLAITGLQAEDEADYYCQSYSSSL SRLRSDDTAVYYCAREPGRDYYYYDGLD SAYVFGTGTKVTVL SEQ ID NO.

GCE-H13-1 VWGQGTTVTVSS SEQ ID NO. 74 73

QSVVTQPPSVSGAPGQRVTISCTG

QVQLVQSGAEVKKPGASVKVSCKASGYT SSSNIGAGYDVHWYQQLPGTAPKL FSGDYLHWVRQAPGQGLEWMGWINPNS LIYGNSNRPSGVPDRFSGSKSGTS GGTNYAQKFQGRVTMTRDTSISTAYMEL ASLAITGLQAEDEADYYCQSYSSSL SRLRSDDTAVYYCAREPARDYYYYDGMD SAYVFGTGTKVTVL SEQ ID NO.

GCE-H13-2 VWGQGTTVTVSS SEQ ID NO. 61 73

QVQLVQSGAEVKKPGASVKVSCKASGYT QSVVTQPPSVSGAPGQRVTISCTG FSGDYLHWVRQAPGQGLEWMGWINPNS SSSNIGAGYDVHWYQQLPGTAPKL GGTNYAQKFQGRVTMTRDTSISTAYMEL LIYGNSNRPSGVPDRFSGSKSGTS

GCE-H13-3 SRLRSDDTAVYYCAREPARDYYYYDGLD ASLAITGLQAEDEADYYCQSYSSSL VWGQGTTVTVSS SEQ ID NO. 44 SAYVFGTGTKVTVL SEQ ID NO.

73

QSVVTQPPSVSGAPGQRVTISCTG

QVQLVQSGAEVKKPGASVKVSCKASGYT SSSNIGAGYDVHWYQQLPGTAPKL FSGDYMHWVRQAPGQGLEWMGWINPN LIYGNSNRPSGVPDRFSGSKSGTS SGGTNYAQKFQGRVTMTRDTSISTAYME ASLAITGLQAEDEADYYCQSYSSSL LSRLRSDDTAVYYCAREPARDYYYYDGL SAYVFGTGTKVTVL SEQ ID NO.

GCE-H13-4 D VWGQGTTVTVSS SEQ ID NO. 40 73

QSVVTQPPSVSGAPGQRVTISCTG

QVQLVQSGAEVKKPGASVKVSCKASGFT SSSNIGAGYDVHWYQQLPGTAPKL FSGDYLHWVRQAPGQGLEWMGWINPNS LIYGNSNRPSGVPDRFSGSKSGTS GGTNYAQKFQGRVTMTRDTSISTAYMEL ASLAITGLQAEDEADYYCQSYSSSL SRLRSDDTAVYYCAREPARDYYYYDGMD SAYVFGTGTKVTVL SEQ ID NO.

GCE-H13-5 VWGQGTTVTVSS SEQ ID NO. 75 73

QSVVTQPPSVSGAPGQRVTISCTG

QVQLVQSGAEVKKPGASVKVSCKASGFT SSSNIGAGYDVHWYQQLPGTAPKL FSGDYLHWVRQAPGQGLEWMGWINPNS LIYGNSNRPSGVPDRFSGSKSGTS GGTNYAQKFQGRVTMTRDTSISTAYMEL ASLAITGLQAEDEADYYCQSYSSSL SRLRSDDTAVYYCAREPARDYYYYDGLD SAYVFGTGTKVTVL SEQ ID NO.

GCE-H13-6 VWGQGTTVTVSS SEQ ID NO. 69 73

QSVVTQPPSVSGAPGQRVTISCTG

QVQLVQSGAEVKKPGASVKVSCKASGYT SSSNIGAGYDVHWYQQLPGTAPKL FSGDYLHWVRQAPGQGLEWMGWINPNS LIYGNSNRPSGVPDRFSGSKSGTS GGTNYAQKFQGRVTMTRDTSISTAYMEL ASLAITGLQAEDEADYYCQSYSSSL SRLRSDDTAVYYCAREPGRDYYYYDGLD SAYVFGTGTKVTVL SEQ ID NO.

GCE-H13-8 VWGQGTTVTVSS SEQ ID NO. 76 73

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSYYMHWVRQAPGQGLEWMGWINPNS SNSFIGNNYVSWYHHLPGTAPKLLI GNTGYAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS

H8-9EH1 1 L TLVTVSS SEQ ID NO. 21 AWVFGGGTKLTVL SEQ ID NO. 77

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FYSYYMHWVRQAPGQGLEWMGWINPNS SNSNIGNTYVSWYHHLPGTAPKLLI

H8- GNTGYAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT

9EG1 1 L SSLRSEDTAVYYCARRGTTVSFDTWGQG LGITGLQPGDEAHYYCGTWDSTLS TLVTVSS SEQ ID NO. 21 AWVFGGGTKLTVL SEQ ID NO. 78

EVQLVQSGAEVKKPGASVKVSCKASGYT QLVLTQSPSVSVAPGQRVTISCSG FSDYYMHWVRQAPGQGLEWMGWINPNS SNSNIGNNYVSWYHHLPGTAPKLLI GNTGYAQKFQGRVTMTRNTSISTAYMEL YDNNKRPSGIPDRFSGSKSGTSAT

H8- SSLRSEDTAVYYCARRATTVSFDYWGQG LGITGLQPGDEAHYYCGTWDSTLS

6AG2H3 TLVTVSS SEQ ID NO. 79 AGVFGGGTKLTVL SEQ I D NO. 20

LPVLTQPASVSGSPGQSITISCTGT

QVQLQESGPGLVKPSQTLSLTCTVSGGSI SFDVGGYNYVSWYQQHPGKAPKL SSGGYYWSWIRQHPGKGLEWIGESTHS MIYDVSDRPSGVSTRFSGSKSGNT GSTNYNPSLKSRVTISVDTSKNQFSLKLS ASLTISGLQAEDEADYYCSSFRSSS SVTAADTAVYYCARGRDGYDFDAWGQG ALVVFGGGTKLTVL SEQ I D NO.

A1 -2 TLVTVSS SEQ ID NO. 80 81

LPVLTQPASVSGSPGQSITISCTGT

QVQLQESGPGLVKPSQTLSLTCTVSGGSI SSDVGGYPYVSWYQQHPGKAPKL SSGGYYWSWIRQHPGKGLEWIGESSHS MIYVVSDRPSGVSTRFSGSKSGNT GSTNYNPSLKSRVTISVDTSKNQFSLKLS ASLTISGLQAEDEADYYCSSYRSSS SVTAADTAVYYCARGRDGYYFDAWGQG ALVVFGGGTQLTVL SEQ ID NO.

A1 -4 TLVTVSS SEQ ID NO. 82 83

LPVLTQPASVSGSPGQSITISCTGT

QVQLQESGPGLVKPSQTLSLTCTVSGGSI SWDVGGYPYVSWYQQHPGKAPKL SSGGYYWSWIRQHPGKGLEWIGEITHSG MIYDVSDRPSGVSTRFSGSKSGNT STNYNPSLKSRVTISVDTSKNQFSLKLSSV ASLTISGLQAEDEADYYCSSYRSVS TAADTAVYYCARGRDGYDIDAWGQGTLV ALVVFGGGTKLTVL SEQ I D NO.

A1 -6 TVSS SEQ ID NO. 84 85

LPVLTQPASVSGSPGQSITISCTGT

QVQLQESGPGLVKPSQTLSLTCTVSGGSI SSDVGGYPYVSWYQQHPGKAPKL SSGGYYWSWIRQHPGKGLEWIGEISHSG MIYRVSDRPSGVSTRFSGSKSGNT STNYNPSLESRVTISVDTSKNQFSLKLSSV ASLTISGLQAEDEADYYCSSYRSSA TAADTAVYYCARGRDGYDLDRWGQGTL ALVVFGGGTKLTVL SEQ I D NO.

A1 -8 VTVSS SEQ ID NO. 86 87

QVQLQESGPGLVKPSQTLSLTCTVSGGSI LPVLTQPASVSGSPGQSITISCTGT SSGGYYWSWIRQHPGKGLEWIGEISHSG SSDVGGYNYVSWYQQHPGKAPKL STNYNPSLKSRVTISVDTSKNQFSLKLSSV MIYNVSDRPSGVSTRFSGSKSGNT

A1 -9 TAADTAVYYCARGRDGYYLDQWGQGTL ASLTISGLQAEDEADYYCSSFRSSS VTVSS SEQIDNO.88 ALVVFGGGTKLTVL SEQIDNO.

89

LPVLTQPASVSGSPGQSITISCTGT

QVQLQESGPGLVKPSQTLSLTCTVSGGSI SFDVGGYNYVSWYQQHPGKAPKL SSGGYYWSWIRQHPGKGLEWIGESTHS MIYDVSDRPSGVSTRFSGSKSGNT GSTNYNPSLESRVTISVDTSKNQFSLKLS ASLTISGLQAEDEADYYCSSFRSSA SVTAADTAVYYCARGRDSYDFDAWGQG ALVVFGGGTKLTVL SEQIDNO.

A1-24 TL VTVSS SEQIDNO.90 91

LPVLTQPASVSGSPGQSITISCTGT

QVQLQESGPGLVKPSQTLSLTCTVSGGSI SFDVGGYPYVSWYQQHPGKAPKL SSGGYYWSWIRQHPGKGLEWIGESTHS MIYDVSDRPSGVSTRFSGSKSGNT GSTNYNPSLDSRVTISVDTSKNQFSLKLS ASLTISGLQAEDEADYYCSSFRSSA S VTA A DTA V YYC A RG R D G YYL DQ WG QG ALVVFGGGTKLTVL SEQIDNO.

A1-32 TL VTVSS SEQIDNO.92 93

Claims

An ADC comprising a structure of Formula I,

(I)

or a pharmaceutically acceptable salt thereof, wherein:

Ab is an anti c-Met antibody;

n is 1, 2, 3, or 4,

- L² taken together is a linking moiety

wherein the wavy lines indicate a point of attachment to the Ab; and wherein L is a linker selected from the group consisting of one or more amino acids, -(CH₂)_m-, -(CH₂CH₂0)_m-, -[C(0)NHCH₂CH₂OCH₂CH₂OCH₂CH₂C(0)]_m-, PAB, Val-Cit-PAB, Val-Ala-PAB, Ala-Ala-Asn-PAB, and combinations thereof, wherein m is an integer from 1 to 8; and D is calicheamicin analog according to Formula II,

(Π)

wherein Rj is selected from the group consisting of C1-C8 alkyl, -(CH₂CH₂0)_p-, isopropyl, glucose, galactose, mannose, glucosamine, C1-C8 alkyl-OH,

and combinations thereof, and wherein the wavy line indicates a point of attachment and wherein p is an integer from 1-24.

2. The ADC of claim 1, wherein the structure of Formula II is:

wherein n is 1, 2, 3, or 4.

3. A method for treating a cancer, the method comprising providing an effective amount of the c-Met ADC of claim 1.

4. The method of claim 3, wherein the cancer is breast cancer.

5. A therapeutic composition comprising the c-Met ADC of claim 1 with an effective amount of an anti- EGFR antibody.

6. The composition of claim 5, wherein the anti-EGFR antibody is Erbitux.

7. A method for treating a cancer, the method comprising providing an effective amount of the composition of claim 5.

8. The method of claim 7, wherein the cancer is breast cancer.