USE OF ANTI-MET ANTIBODIES AND BI-SPECIFIC ANTIGEN-BINDING MOLECULES THAT BIND TO MET IN THE TREATMENT OF OCULAR CANCER.

Abstract

The present invention relates to an antibody-drug conjugate (ADC) comprising a bispecific antigen-binding molecule and a cytotoxin, wherein the bispecific antigen-binding molecule comprises: a first antigen-binding domain (D1); and a second antigen-binding domain (D2); wherein D1 binds specifically to a first human MET epitope; wherein D2 binds specifically to a second human MET epitope; wherein D1 comprises the amino acid sequence of SEQ ID NO: 60; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 62; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 64; a light chain complementarity-determining region (LCDR1) comprising the amino acid sequence of SEQ ID NO: 140; and an LCDR2 comprising the amino acid sequence of SEQ ID NO: 142. and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 144;and wherein D2 comprises: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 84; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 86; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 88; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 140; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 142; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 144; for use in the treatment, reduction of tumor growth and / or regression of c-MET-expressing uveal melanoma in a subject in need, wherein the ADC formulated for administration to the subject results in the destruction of c-Met-expressing uveal melanoma cells;

Description

METHODS FOR TREATING EYE CANCER USING ANTI-MET ANTIBODIES AND BISPECIFIC ANTIGEN-BINDING MOLECULES THAT BIND MET field of invention The present invention relates to the use of antibodies, bispecific antibodies and antigen-binding fragments thereof, as well as antibody-drug conjugates of said antibodies, which specifically bind to the hepatocyte growth factor receptor (c-Met or MET) and modulate MET signal transduction, to treat ocular cancer, including uveal melanoma. Sequence listing information An official copy of the sequence listing is submitted together with the description electronically via EFS-Web as an ASCII-format sequence listing with a file name of 10548W001_SEQ_LIST_ST25.TXT, a creation date of February 20, 2020 and a size of approximately 140 kilobytes. The sequence listing contained herein in ASCII format is part of the description and is incorporated herein by reference in its entirety. Background of the invention Uveal melanoma is the most common primary infraocular malignancy in adults, accounting for 79-81% of ocular melanomas. Incidence rates in the United States are estimated at 5 / million inhabitants, while incidence rates in Europe range from 2 to 8 / million inhabitants, depending on latitude with a decrease in incidence from north to south. . Uveal melanoma has a high tendency to metastasize, resulting in a poor long-term prognosis, with death occurring in more than 50% of cases. Hepatocyte growth factor (HGF) (also known as scatter factor [SF]) is a heterodimeric paracrine growth factor that exerts its activity by interacting with the HGF receptor (HGFR). HGFR is the product of the c-Met oncogene and is also known as MET. MET is a receptor tyrosine kinase consisting of a transmembrane beta chain disulfide-linked to an extracellular alpha chain. HGF binding to MET activates the catalytic activity of MET kinase resulting in the phosphorylation of Tyr 1234 and Tyr 1235 of the beta chain and subsequent activation of downstream signaling pathways. Tumor cell lines that have amplification of the MET gene are highly dependent on MET for growth and survival. Several monovalent MET-blocking antibodies are in clinical development for the treatment of various cancers (see US Patent Nos. 5,686,292; 5,646,036; 6,099,841; 7,476,724; 9,260,531; and 9,328,173; and US Patent Application Publications , No. 2014 / 0349310 and 2005 / 0233960). Those antibodies include onartuzumab (MetMab) and emibetuzumab, (Xiang et al., Clin. Cancer Res. 19(18):5068-78, 2013 and Rosen et al., Clin. Cancer Res., Published Oct 10, 2016, doi : 10.1158 / 1078-0432.CCR-16-1418). ΜΛ / t / ZUZ I / UOÓ4OÓ Some of these antibodies block ligand-dependent MET signaling, but are not as effective in blocking ligand-independent MET activation. Uveal melanoma tumors are characterized by mutations in G proteins (GNAQ and GNA11) and high expression of c-Met. Targeting c-Met in uveal melanoma results in inhibition of cell invasion and metastasis, however it does not suppress tumor growth. The rate of local tumor control and globe recovery has improved over time, but the survival rate remains relatively unchanged. Antibody-drug conjugates (ADCs) have advanced in recent years, several of which are approved for use by the FDA, but so far none have been developed for uveal melanoma. There remains a significant unmet medical need for improved anticancer drugs for use in the treatment of eye cancer, including uveal melanoma, that potently block ligand-independent and dependent MET signaling. Brief description of the invention Methods for treating ocular cancer such as uveal melanoma, orbital lymphoma, retinoblastoma and medulloepithelioma are provided herein. Methods include treatment with antibodies, antigen-binding antibody fragments, combinations of bivalent monospecific antibodies, or bispecific antibodies that bind to the human c-Met (MET x MET) receptor protein. Anti-MET antibodies, and antigen-binding portions thereof, can be used alone in unmodified form, or can be included as part of an antibody-drug conjugate (ADC) or bispecific antibody. Antibodies and ADC are useful, inter alia, for targeting MET-expressing tumor cells and are therefore useful in methods for treating ocular cancer as described herein. Other embodiments will become apparent upon review of the following detailed description of the invention. Brief description of the figures Figure 1 is a matrix illustrating the components of 272 exemplary MET x MET bispecific antibodies described herein. Each numbered cell in the array identifies a unique bispecific antibody comprising a D1 antigen-binding domain and a D2 antigen-binding domain, wherein the D1 antigen-binding domain comprises the immunoglobulin variable domain (pair of amino acid sequences of HCVR / LCVR) or CDR of the corresponding anti-MET antibody numbered along the Y-axis, and wherein the D2 antigen-binding domain comprises the immunoglobulin variable domain (HCVR / LCVR amino acid sequence pair) or CDR of the corresponding anti-MET antibody numbered along the X axis. Figure 2 is a schematic of a luciferase-based reporter assay used to assess antibody-induced MET pathway activation or antibody blockade of HGF-induced pathway activation in HEK293T cells containing an SRE reporter gene construct. -Luciferase. Figures 3A and 3B are line graphs depicting relative luminance units (RLUs) representing SRE-luciferase expression as a function of antibody concentration in log moles per liter. Filled squares () represent the parental bivalent monospecific antibody H4H13306P2, filled pyramids (A) represent the parental bivalent monospecific antibody H4H13312P2, filled circles ( ) represent a monovalent antibody, filled diamonds (♦) represent isotype control, and filled inverted pyramids (▼) do not represent ligand. Figure 3A depicts the antibody alone without HGF ligand. Figure 3B depicts antibodies plus HGF ligand. Figures 4A and 4B are a line graph depicting relative light units (RLUs) representing SRE-luciferase expression as a function of antibody concentration in log moles per liter. Filled squares () represent a monovalent anti-MET antibody, filled circles (·) represent a MET x MET bispecific antibody, and filled diamonds (♦) represent the parental antibody H4H13312P2. Figure 4A depicts the antibody alone without HGF ligand. Figure 4B depicts antibodies plus HGF ligand. Figure 5 is a bar graph depicting the relative cell growth of MET-amplified gastric cancer SNU5 cells as a function of treatment with human bivalent monospecific anti-MET antibodies 1-18, a control antibody, and a monovalent anti-human anti-MET antibody. MET. For comparison purposes, antibody 8 (abscissa) is the parent antibody H4H13306P2 and antibody 11 (abscissa) is the parent antibody H4H13312P2. Figures 6A and 6B contain bar graphs depicting the relative cell growth of MET-amplified cells as a function of treatment with a MET x MET bispecific antibody, a control antibody, and a monovalent anti-MET antibody. Figure 6A depicts the relative growth of SNU5 cells as a function of control antibody treatment, a monovalent antibody at 0.1, 1, and 10 pg / mL, and a MET x MET bispecific antibody at 0.1, 1, and 10 pg / mL. Figure 6B depicts the relative growth of EBC-1 cells as a function of treatment with control antibody and a MET x MET bispecific antibody at 0.1 and 1 pg / mL. Figures 7A and 7B depict immunoblots of pMET (phosphorylated MET), MET, pErk (phosphorylated Erk), and tubulin (for loading control) extracted from Hs746T cells after treatment with a control antibody and a MET x MET bispecific antibody (Figure 7A) and MET expression (and tubulin as loading control) in Hs746T cells after treatment with the MET x MET bispecific antibody for 0, 2 and 6 hours (Figure 7B). Figure 8 depicts an immunoblot of pMET, MET, pErk and tubulin (for loading control) extracted from Hs746T cells after treatment with a control antibody, a MET x MET bispecific antibody, an anti-MET 1 monospecific bivalent parental antibody , a monospecific anti-MET 2 bivalent parental antibody and a combination of parental 1 and 2 antibodies. Figure 9 depicts an immunoblot of MET expression (and tubulin as loading control) in Hs746T cells after treatment with a control antibody and a MET x MET bispecific antibody for 2, 6 and 18 hours. Figures 10A and 10B depict immunoblots of pMET, MET, pErk, and tubulin (for loading control) extracted from SNU5 cells after treatment with a control antibody and a MET x MET bispecific antibody (Figure 10A); and MET expression (and tubulin as loading control) in SNU5 cells after treatment with a control antibody and a monovalent anti-MET antibody (Figure 10B). Figure 11 depicts an immunoblot of pMET, MET, pErk and tubulin (for loading control) extracted from EBC-1 cells after treatment with a control antibody and a MET x MET bispecific antibody. Figure 12 is a line graph depicting the change in EBC-1 tumor volume in cubic millimeters as a function of time in days after EBC-1 cell implantation in control antibody-treated animals (filled square ), MET monovalent antibody (filled circle ♦), or MET x MET bispecific antibody (filled diamond ♦). Figures 13A and 13B contain bar graphs depicting the relative cell growth of MET-amplified cells as a function of treatment with a MET x MET bispecific antibody, a control antibody, and a monovalent anti-MET antibody. Figure 13A depicts the relative growth of Hs746T cells as a function of treatment with control antibody, MET x MET bispecific antibody, MET x MET parental monospecific antibody 1, MET x MET parental monospecific antibody 2, and a combination of antibodies. parents 1 and 2. Figure 13B depicts the relative growth of Hs746T cells as a function of control antibody treatment, a monovalent antibody at 1, 10, and 25 pg / mL, and a MET x MET bispecific antibody at 1, 10, and 25 pg / mL. pg / mL. Figure 14 is a bar graph depicting the relative cell growth of NCI-H596 cells as a function of treatment with control antibody (C), MET x MET bispecific antibody (MM), parental monospecific antibody 1 (M1 ) of MET x MET, the parental monospecific antibody 2 (M2) MET x MET, a combination of parental antibodies 1 and 2 (Μ1M2), and MET agonist hepatocyte growth factor (HGF). Figure 15 is a line graph depicting the change in Hs746T tumor volume in cubic millimeters as a function of time in days after implantation of the Hs746T cells in animals treated with control antibody (filled square), monovalent MET antibody. (filled circle·), or MET x MET bispecific antibody (filled diamond ♦). Figure 16A is a line graph depicting the change in SNU5 tumor volume in cubic millimeters as a function of time in days after implantation of SNU5 cells in animals treated with control antibody (filled square), MET monovalent antibody at 1 mg / mL (filled circle), 10 mg / mL MET monovalent antibody (open circleO), 1 mg / mL MET x MET bispecific antibody (filled diamond ♦), or 10 mg / mL MET x MET bispecific antibody mL (open diamond O). Figure 16B is an immunoblot of pMET, MET and tubulin (loading control) extracted from a SNU5 tumor extracted from a mouse xenograft model after treatment with a control antibody, 10 mg / kg of a monovalent anti-MET antibody. and 10 mg / kg of a MET x bispecific antibody ΜΛ / t / ZUZ I / UOO4OO ΜΕΤ. Figure 17 is a line graph depicting the change in U87-MG tumor volume in cubic millimeters as a function of time in days after U87-MG cell implantation in control antibody-treated animals (filled square). , MET monovalent antibody (filled circle ♦), or MET x MET bispecific antibody (filled diamond ♦). Figure 18 is a line graph depicting the change in U118-MG tumor volume in cubic millimeters as a function of time in days after LJ118-MG cell implantation in control antibody-treated animals (filled square ), MET monovalent antibody (filled circle), or MET x MET bispecific antibody (open diamond ^). Figure 19 is a schematic illustrating the synthesis of maytansinoid 6. Figure 20 is a schematic illustrating the synthesis of intermediate maytansinoid 1. Figure 21A, Figure 21B, Figure 21C and Figure 21D are line graphs depicting the change in cell viability in four c-Met-expressing uveal melanoma cells treated with two different concentrations of Maitansinoid B-conjugated c-Met bispecific antibody. (filled circle ·) compared to the maytansinoid B-conjugated antibody isotype (filled triangle a ) for 7 days. Figure 22A and Figure 22B are line graphs depicting the change in cell viability in c-Met-expressing OMM1.3 cells vs. c-Met-negative OCM3 cells when treated with maytansinoid B-conjugated c-Met bispecific antibody. (0.3 to 10 nM) (cross line) or Maytansinoid B-conjugated antibody isotype (filled square) for 7 days. Figure 23 and Figure 24 are bar graphs depicting the percentage of apoptosis resulting from treatment of uveal melanoma cells treated with two different concentrations (1.25 nM, Figure 23; 2.5 nM, Figure 24) of c-Met-conjugated bispecific antibody. Maytansinoid B compared to the Maytansinoid B-conjugated antibody isotype. Figure 25, Figure 26 and Figure 27 are histograms (with inset side scatter plots) depicting cell distribution in each of the growth phases after treatment with Maytansinoid B conjugated c-Met bispecific antibody compared to isotype. of Maytansinoid B-conjugated antibody. Two c-Met positive cell lines, OMM1.3 (Figure 25) and Mel202 (Figure 26), were tested and compared with a c-Met negative cell line, OCM3 (Figure 27). . Figure 28 is an image of a Western blot showing the expression levels of c-Met from various uveal melanoma cell lines, as well as from SNU-5, a positive control gastric carcinoma cell line known to express highly c-Met, and A549, a lung carcinoma cell line that also express c-Met. Figure 29 is an image of a Western blot demonstrating PARP cleavage and histone H3 phosphorylation in three uveal melanoma cell lines after 24 hours of treatment with a Maitansinoid B-conjugated c-Met bispecific antibody compared with an isotype antibody conjugated to Maytansinoid B. M A / E / ZUZ I / UOÓ4OÓ Figure 30 is an image of a Western blot showing the time-dependent induction of PARP cleavage, c-Met protein expression, and histone H3 phosphorylation in a c-Met-positive cell line, OMM1. .3, compared with a c-Met-negative cell line, OCM3, after treatment with a Maitansinoid B-conjugated c-Met bispecific antibody compared with a Maitansinoid B-conjugated isotype antibody. Figure 31 illustrates an H-NMR spectrum of Maytansine-3-N-methyl-L-alanine-propanamidyl-3-thio-3-succinimidyl-N-methylcyclohexyl-4-trans-carboxysuccinamate. The spectrum is not complicated by resonances attributable to a mixture and is consistent with a single diasteromer present in at least 95% diasteromeric excess. Figure 32 provides images demonstrating inhibition of cell invasion in OMM1.3 cells treated with increasing doses of control, control-ADC, MET x MET and MET x METADC antibody while using 50 ng / mL HGF as chemotactic agent. The MET x MET and MET x MET-ADC antibody potently inhibited cell invasion at picomolar doses where cell viability is not affected. Figure 33 illustrates the dose-dependent decrease in cell viability of uveal melanoma cells treated with a Maytansinoid B-conjugated c-Met bispecific antibody compared to the Maytansinoid B-conjugated antibody isotype. Detailed description of the invention Before describing the present invention, it should be understood that this description is not limited to the particular experimental methods and conditions described, as these methods and conditions may vary. Furthermore, it is to be understood that the terminology used in the present description is solely for the purpose of describing particular embodiments, and is not intended to be limiting, as the scope of the present description shall only be limited by the claims. Unless otherwise defined, all technical and scientific terms used in the present description have the same meaning as is commonly understood by a person skilled in the art to which this technology pertains. As used herein, the term approximately, when used in reference to a particular mentioned numerical value, means that the value may vary from the mentioned value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​in between (eg, 99.1, 99.2, 99.3, 99.4, etc.). Although any of the methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, preferred methods and materials will be described below. All patents, applications and non-patent publications mentioned in this description are incorporated herein by reference in their entirety. MET protein The terms MET, c-Met and the like, as used herein, refer to the ΜΛ / t / ZUZ I / UOÓ4OÓ human membrane-spanning receptor tyrosine kinase comprising (1) the amino acid sequence as set forth in SEQ ID NO: 145, and / or having the amino acid sequence as set forth in NCBI accession number NM_001127500.2, representing the unprocessed preproprotein of isoform a, (2) the amino acid sequence as set forth in SEQ ID NO: 146, and / or having the amino acid sequence as set forth in the NCBI accession number NM_000236.2, representing the unprocessed preproprotein of isoform b, (3) the amino acid sequence as set forth in SEQ ID NO: 147, and / or having the amino acid sequence as set forth in NCBI accession number NM_001311330.1, which represents the unprocessed preproprotein of isoform c, and / or (3) the mature protein comprising the cytoplasmic alpha subunit (SEQ ID NO: 148) shared by all three isoforms and the beta transmembrane subunit (SEQ ID NO: 149,150 or 151 of isoform a, b and c, respectively). The term MET includes both monomeric and multimeric MET molecules. As used herein, the term "monomeric human MET" means a MET protein or a portion thereof that does not contain or possess any multimerization domain and that exists under normal conditions as a single MET molecule without a direct physical connection to another molecule. MET. An illustrative monomeric MET molecule is the molecule referred to herein as hMET.mmh comprising the amino acid sequence of SEQ ID NO: 152 (see, for example, Example 3, herein). As used herein, the term "dimeric human MET" means a construct comprising two MET molecules connected to each other through a linker, covalent binding, non-covalent binding, or through a multimerization domain such as a Fe domain. antibody. An exemplary dimeric MET molecule is the molecule designated herein as hMET.mFc comprising the amino acid sequence of SEQ ID NO: 153 (see, eg, Example 3, herein). All references to proteins, polypeptides and protein fragments in the present description are intended to refer to the human version of the respective protein, polypeptide or protein fragment unless explicitly specified as being from a non-human species. Thus, the term MET means human MET unless it is specified to be from a non-human species, eg, mouse MET, monkey MET, and so on. As used herein, the term "cell surface expressed MET" means one or more MET protein(s), or the extracellular domain thereof, that are expressed on the surface of a cell in vitro or in vivo, in a manner that at least a portion of a MET protein is exposed to the extracellular side of the cell membrane and is accessible to an antigen-binding portion of an antibody. A cell surface expressed MET may comprise or consist of a MET protein expressed on the surface of a cell that normally expresses the MET protein. Alternatively, cell surface expressed MET may comprise or consist of the surface expressed MET protein of a cell that does not normally express human MET on its surface but has been artificially engineered to express MET on its surface. Therapeutic methods to treat eye cancer Provided herein are methods for treating ocular cancer such as, for example, uveal melanoma, orbital lymphoma, retinoblastoma, and medulloepithelioma. In some aspects, the method comprises administering to a subject in need thereof a therapeutic composition comprising an anti-MET antibody or a MET x MET bispecific antigen-binding molecule (eg, an anti-MET comprising any of the sequences of HCVR / LCVR or CDR as set forth in Table 1 of the present disclosure, or a MET x MET bispecific antigen-binding molecule comprising any of components D1 and D2 as set forth in Table 5 of the present disclosure, or an anti-MET antibody selected from the group consisting of onartuzumab, emibetuzumab, telisotuzumab, SAIT301, ARGX-111, Sym015, HuMax-cMet, and CE-355621). In some embodiments, the anti-MET antibody or a MET x MET bispecific antigen binding molecule is conjugated to a cytotoxic compound such as a maytansinoid, as described in detail below. The therapeutic composition may comprise any of the anti-MET antibodies or MET x MET bispecific antigen binding molecules described herein, including anti-MET ADCs or MET x MET bispecific antigen binding molecule conjugated to a cytotoxic agent, and a pharmaceutically acceptable carrier or diluent. Uveal melanoma is the most common malignant primary infraocular tumor in adults. These tumors can occur in the choroid, iris, and ciliary body and are sometimes called iris or ciliary body melanomas. Uveal melanoma is highly metastatic. Other ocular cancers include orbital lymphoma, retinoblastoma, and medulloepithelioma, the latter of which can occur in the ciliary body and uvea. The methods described herein are contemplated to be useful for treating ocular cancers such as orbital lymphoma, retinoblastoma, and medulloepithelioma. In some aspects, treatment includes inhibiting or mitigating the invasion and / or metastasis of the primary tumor. Anti-MET antibodies and MET x MET bispecific antigen binding molecules, and drug conjugates thereof, are useful, inter alia, for the treatment, prevention and / or amelioration of any disease or disorder associated with or mediated by MET expression, signaling, or activity, or tractable by blocking the interaction between MET and HGF, or by otherwise inhibiting MET activity and / or signaling, and / or promoting receptor internalization and / or decreasing receptor number from the cell surface. In particular, anti-MET antibodies and MET x MET bispecific antigen-binding molecules, and drug conjugates of these, are useful for treating uveal melanoma. Treatment includes reducing the growth of the uveal melanoma tumor and / or causing the regression of a uveal melanoma in a subject. Treatment also includes inhibiting or mitigating uveal melanoma cell invasion, or inhibiting or mitigating uveal melanoma metastasis of the primary tumor. For example, the anti-MET antibodies and MET x MET bispecific antigen binding molecules of the present disclosure are useful for the treatment of uveal melanoma tumors that express (or overexpress) MET. For example, anti-MET antibodies and MET x MET bispecific antigen binding molecules can be used to treat primary and / or metastatic tumors arising in the eye. As such, provided herein is a method for treating eye cancer, reducing the growth of an eye cancer, inhibiting or mitigating invasion and / or metastasis, and / or causing regression of eye cancer. ΜΛ / t / ZUZ I 7UOO4OO an eye cancer in a subject. For example, provided herein is a method of treating a uveal melanoma, reducing the growth of a uveal melanoma tumor, inhibiting or mitigating invasion and / or metastasis, and / or causing regression of a uveal melanoma in a subject. In some aspects, eye cancer, eg uveal melanoma, expresses MET. In some aspects, the method comprises administering to a subject in need thereof an antibody-drug conjugate (ADC) comprising a bispecific antigen-binding molecule and a cytotoxin, wherein the bispecific antigen-binding molecule comprises: a first domain of antigen binding (D1); and a second antigen-binding domain (D2); wherein D1 specifically binds to a first human MET epitope; and wherein D2 specifically binds to a second epitope of human MET. Further provided herein is a method for inhibiting proliferation, inhibiting invasion, causing apoptosis, and / or decreasing viability of a uveal melanoma cell. In some embodiments, the method comprises contacting the cell with an antibody-drug conjugate (ADC) comprising a bispecific antigen-binding molecule and a cytotoxin. In some embodiments, the bispecific antigen-binding molecule comprises: a first antigen-binding domain (D1); and a second antigen-binding domain (D2); wherein D1 specifically binds to a first human MET epitope; and wherein D2 specifically binds to a second epitope of human MET. Further provided herein is a method for inducing mitotic arrest of a uveal melanoma cell. In some embodiments, the method comprises contacting the cell with an antibody-drug conjugate (ADC) comprising a bispecific antigen-binding molecule and a cytotoxin, wherein the bispecific antigen-binding molecule comprises: a first binding domain to antigen (D1); and a second antigen-binding domain (D2); wherein D1 specifically binds to a first human MET epitope; and wherein D2 specifically binds to a second epitope of human MET. Also provided herein is a method of treating eye cancer in a subject suffering from a c-Met-expressing tumor. In some embodiments, the method comprises administering to the subject a bispecific antigen-binding molecule comprising: a first antigen-binding domain (D1); and a second antigen-binding domain (D2); wherein D1 specifically binds to a first human MET epitope; and wherein D2 specifically binds to a second epitope of human MET. In some aspects, the bispecific antigen-binding molecule is conjugated to a cytotoxin to form an antibody-drug conjugate (ADC). In some aspects, the cytotoxin is a maytansinoid. Various aspects of the bispecific antigen-binding molecule and various aspects of the cytotoxin are provided in the following paragraphs, although they are described in greater detail elsewhere in the present disclosure. In some respects, D1 and D2 do not compete with each other to join the human MET. In some aspects, the first epitope of human MET comprises amino acids 192-204 of SEQ ID NO: 155. In some aspects, the second epitope of human MET comprises amino acids 305-315 and 421-455 of SEQ ID NO: 155. In some aspects, the first human MET epitope comprises amino acids 192-204 of SEQ ID NO: 155; and the second epitope of human MET comprises amino acids 305-315 and 421-455 of SEQ ID NO: 155. In some embodiments, D1 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 58 or SEQ ID NO : 18 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138. In some embodiments, D2 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 82 and three light chain complementarity determining regions ( LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138. In some embodiments, the bispecific antigen-binding molecule comprises the CDRs within the D1-HCVR amino acid sequence of SEQ ID NO: 58 and the CDRs within the D2-HCVR amino acid sequence of SEQ ID NO: 82. In some In other embodiments, the bispecific antigen-binding molecule comprises the CDRs within the D1-HCVR amino acid sequence of SEQ ID NO: 18 and the CDRs within the D2-HCVR amino acid sequence of SEQ ID NO: 82. In some aspects, the bispecific antigen binding molecule D1 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical to itself and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical thereto. In some aspects, the D1 HCDR1 comprises the amino acid sequence of SEQ ID NO: 60; HCDR2 comprises the amino acid sequence of SEQ ID NO: 62; HCDR3 comprises the amino acid sequence of SEQ ID NO: 64; LCDR1 comprises the amino acid sequence of SEQ ID NO: 140; LCDR2 comprises the amino acid sequence of SEQ ID NO: 142; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 144. In some aspects, the D1 bispecific antigen-binding molecule comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical thereto; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical thereto. In some aspects, the D1 bispecific antigen binding molecule comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 58; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138. In some aspects, the bispecific antigen binding molecule D2 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO : 82 or an amino acid sequence that is at least 95% identical thereto and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the sequence amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical thereto. In some aspects, the bispecific antigen-binding molecule D2 HCDR1 comprises the amino acid sequence of SEQ ID NO: 84; HCDR2 comprises the amino acid sequence of SEQ ID NO: 86; HCDR3 comprises the amino acid sequence of SEQ ID NO: 88; LCDR1 comprises the amino acid sequence of SEQ ID NO: 140; LCDR2 comprises the amino acid sequence of SEQ ID NO: 142; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 144. In some aspects, the D2 bispecific antigen binding molecule comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical thereto; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical thereto. In some aspects, the D2 bispecific antigen-binding molecule comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 82; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138. In some embodiments of the methods provided herein, the cytotoxin is selected from the group consisting of biotoxins, chemotherapeutic agents, and radioisotopes. For example, the cytotoxin can be selected from the group consisting of maytansinoids, auristatins, thomamycins, duocarmycins, 225Ac, 227Th and derivatives thereof. In some aspects, the cytotoxin is conjugated to the bispecific antigen-binding molecule via a linker. An illustrative cytotoxin is: M A / Ε / ΖυΖΊ / UOO4OO i____ where the is the binding to a linker. In some aspects, the linker is: ΜΛ / t / ZUZ I / UOÓ4OÓ where binding indicated by 2 represents binding to the bispecific antigen-binding molecule and binding indicated by 2 represents binding to the cytotoxin. Yet another illustrative cytotoxin is: where the is the union with the linker. In some aspects, the linker is where binding denoted by 2 represents binding to the bispecific antigen-binding molecule f and the binding indicated with 2 represents binding to the cytotoxin. The methods provided in the present disclosure are useful for treating ocular cancer or eye cancer. In some modalities, the eye cancer is selected from the group consisting of melanoma M A / uveal, orbital lymphoma, retinoblastoma and medulloepithelioma. In the context of the methods of treatment described herein, anti-MET antibodies and MET x MET bispecific antigen-binding molecules, and drug conjugates thereof, can be administered as a monotherapy (i.e., as the only therapeutic agent) or in combination with one or more additional therapeutic agents (examples of which are described elsewhere in the present disclosure). Anti-MET antibodies and antigen-binding fragments thereof In more detail, and in accordance with one aspect, the anti-MET antibodies useful in accordance with the methods provided herein are listed in Tables 1 and 2 of the present disclosure. Table 1 sets forth the amino acid sequence identifiers of the heavy chain variable regions (HCVR), light chain variable regions (LCVR), heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and the light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of illustrative anti-MET antibodies from which bispecific antigen-binding molecules (used interchangeably herein with binding protein) can be derived to bispecific antigen) described in the present description. Table 2 sets forth the nucleic acid sequence identifiers of the HCVR, LCVR, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of illustrative anti-MET antibodies. Also useful in accordance with the methods provided herein are anti-MET antibodies selected from the group consisting of onartuzumab, emibetuzumab, telisotuzumab, SAIT301, ARGX-111, Sym015, HuMax-cMet and CE-355621. Also useful according to the methods provided herein are antibodies or antigen-binding fragments thereof that specifically bind to MET and agonize (eg, activate) the MET signaling pathway in cells, as well as the use of such antibodies in therapeutic settings where activation of MET signaling would be beneficial or therapeutically useful. Non-limiting examples of such agonist anti-MET antibodies include the antibody referred to herein as H4H14636D, as well as antibodies and antigen-binding fragments thereof comprising the heavy and light chain CDRs (SEQ ID NO: 28, 30, 32,140,142,144) and / or heavy and light chain variable domains (SEQ ID NO: 26 / 138) thereof. Useful herein are antibodies or antigen-binding fragments thereof that specifically bind to MET, comprising an HCVR comprising an amino acid sequence selected from any of the HCVR amino acid sequences mentioned in Table 1, or a sequence substantially similar to these having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto. Useful herein are antibodies or antigen-binding fragments thereof that specifically bind to MET, comprising an LCVR comprising an amino acid sequence selected from any of the LCVR amino acid sequences mentioned in Table 1, or a sequence substantially similar to these having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith. Useful herein are antibodies or antigen-binding fragments thereof that specifically bind to MET, comprising a pair of HCVR and LCVR amino acid sequences (HCVR / LCVR) comprising either amino acid sequence of HCVR mentioned in Table 1 paired with any of the LCVR amino acid sequences mentioned in Table 1. According to certain embodiments, the antibodies or antigen-binding fragments thereof, comprise a pair of HCVR / LCVR contained within any of the illustrative anti-MET antibodies listed in Table 1. In certain embodiments, the HCVR / LCVR amino acid sequence pair is selected from the group consisting of: SEQ ID NO: 2 / 138, 10 / 138, 18 / 138, 26 / 138, 34 / 138, 42 / 138, 50 / 138, 58 / 138, 66 / 138, 74 / 138, 82 / 138, 90 / 138, 98 / 138, 106 / 138, 114 / 138, 122 / 138 and 130 / 138. Also useful are antibodies or antigen-binding fragments thereof, which specifically bind to MET, comprising a heavy chain CDR1 (HCDR1) comprising an amino acid sequence selected from any of the HCDR1 amino acid sequences mentioned in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. Also useful are antibodies or antigen-binding fragments thereof, which specifically bind to MET, comprising a heavy chain CDR2 (HCDR2) comprising an amino acid sequence selected from any of the HCDR2 amino acid sequences mentioned in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. Also useful are antibodies or antigen-binding fragments thereof, which specifically bind to MET, comprising a heavy chain CDR3 (HCDR3) comprising an amino acid sequence selected from any of the HCDR3 amino acid sequences mentioned in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. Also useful are antibodies or antigen-binding fragments thereof, which specifically bind to MET, comprising a light chain CDR1 (LCDR1) comprising an amino acid sequence selected from any of the LCDR1 amino acid sequences mentioned in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. Also useful are antibodies or antigen-binding fragments thereof that specifically bind to MET, comprising a pair of HCDR1 and LCDR1 amino acid sequences (HCDR1 / LCDR1) comprising any of the HCDR1 amino acid sequences mentioned in Table 1 paired with any of the LCDR1 amino acid sequences mentioned in Table 1. According to certain embodiments, the antibodies, or antigen-binding fragments thereof, comprise a pair of HCDR3 / LCDR3 amino acid sequences contained within either of the illustrative anti-MET antibodies listed in Table 1. In certain embodiments, the pair of ΜΛ / t / ZUZ I / UOÓ4OÓ amino acid sequences HCDR1 / LCDR1 is selected from the group consisting of: SEQ ID NO: 4 / 140, 12 / 140, 20 / 140, 28 / 140, 36 / 140, 44 / 140, 52 / 140, 60 / 140, 68 / 140, 76 / 140, 84 / 140, 92 / 140, 100 / 140, 108 / 140, 116 / 140, 124 / 140 and 132 / 140. Also useful are antibodies or antigen-binding fragments thereof, which specifically bind to MET, comprising a light chain CDR2 (LCDR2) comprising an amino acid sequence selected from any of the LCDR2 amino acid sequences mentioned in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. Also useful are antibodies or antigen-binding fragments thereof that specifically bind to MET, comprising a pair of HCDR2 and LCDR2 amino acid sequences (HCDR2 / LCDR2) comprising any of the HCDR2 amino acid sequences mentioned in Table 1 paired with any of the LCDR2 amino acid sequences mentioned in Table 1. According to certain embodiments, the antibodies, or antigen-binding fragments thereof, comprise a pair of HCDR2 / LCDR2 amino acid sequences contained within either of the illustrative anti-MET antibodies listed in Table 1. In certain embodiments, the HCDR2 / LCDR2 amino acid sequence pair is selected from the group consisting of: SEQ ID NO: 6 / 142, 14 / 142, 22 / 142, 30 / 142, 38 / 142, 46 / 142, 54 / 142, 62 / 142, 70 / 142, 78 / 142, 86 / 142, 94 / 142, 102 / 142, 110 / 142, 118 / 142, 126 / 142 and 134 / 142. Also useful are antibodies or antigen-binding fragments thereof, which specifically bind to MET, comprising a light chain CDR3 (LCDR3) comprising an amino acid sequence selected from any of the LCDR3 amino acid sequences mentioned in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. Also useful herein are antibodies or antigen-binding fragments thereof that specifically bind to MET, comprising a pair of HCDR3 and LCDR3 amino acid sequences (HCDR3 / LCDR3) comprising either of the sequences of HCDR3 amino acid sequences mentioned in Table 1 paired with any of the LCDR3 amino acid sequences mentioned in Table 1. According to certain embodiments, the antibodies, or antigen-binding fragments thereof, comprise a pair of HCDR3 amino acid sequences / LCDR3 contained within any of the illustrative anti-MET antibodies mentioned in Table 1. In certain embodiments, the HCDR3 / LCDR3 amino acid sequence pair is selected from the group consisting of SEQ ID NO: 8 / 144, 16 / 144, 24 / 144, 32 / 144, 40 / 144, 48 / 144, 56 / 144, 64 / 144, 72 / 144, 80 / 144, 88 / 144, 96 / 144, 104 / 144, 112 / 144 , 120 / 144, 128 / 144 and 136 / 144. Also useful herein are antibodies or antigen-binding fragments thereof that specifically bind to MET, which comprise a set of six CDRs (i.e., HCDR1 HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within of any of the illustrative anti-MET antibodies listed in Table 1. In certain embodiments, the set of amino acid sequences of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 is selected from the group consisting of: SEQ ID NO: M A / E / ZUZ I / UOÓ4OÓ 4-6-8-140-142-144, 12-14-16-140-142-144, 20-22-24-140-142-144, 28-30-32-140-142-144, 36- 38-40-140142-144, 44-44-48-140-142-144, 52-54-56-140-142-144, 60-62-64-140-142-144, 68-70-72- 140-142-144, 7678-80-140-142-144, 84-86-88-140-142-144, 92-94-96-140-142-144, 100-102-104-140-142- 144, 108-1 ΙΟΙ 12-140-142-144, 116-118-120-140-142-144, 124-126-128-140-142-144 and 132-134-136-140-142-144. In a related embodiment, antibodies or antigen-binding fragments thereof that specifically bind to MET and that are useful in the methods described herein comprise a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3- LCDR1-LCDR2-LCDR3) contained within an HCVR / LCVR amino acid sequence pair as defined by any of the illustrative anti-MET antibodies listed in Table 1. For example, antibodies or antigen-binding fragments of these that specifically bind to MET, comprise the set of amino acid sequences HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 contained within a pair of HCVR / LCVR amino acid sequences selected from the group consisting of: SEQ ID NO: 4- 6-8140-142-144, 12-14-16-140-142-144, 20-22-24-140-142-144, 28-30-32-140-142-144, 36-38-40- 140-142144, 44-44-48-140-142-144, 52-54-56-140-142-144, 60-62-64-140-142-144, 68-70-72-140-142- 144, 76-7880-140-142-144, 84-86-88-140-142-144, 92-94-96-140-142-144, 100-102-104-140-142-144, 108- 110-112-140-142-144, 116-118-120-140-142-144, 124-126-128-140-142-144 and 132-134-136-140-142-144. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within specified HCVR and / or LCVR amino acid sequences described herein. Illustrative conventions that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Broadly speaking, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, eg, Kabat, Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md. (1991); Al-Lazikan¡ et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. nati. Acad. Sci. USA 36:9268-9272 (1989). Public databases are also available to identify CDR sequences within an antibody. Also useful according to the methods provided herein are anti-MET antibodies having a modified glycosylation pattern. In some embodiments, modification to remove undesirable glycosylation sites may be useful, or an antibody that lacks a fucose moiety present in the oligosaccharide chain, for example, to enhance antibody-dependent cellular cytotoxicity (ADCC) function. (see Shield et al. (2002) JBC 277:26733). In other applications, modification of galactosylation may occur to modify complement-dependent cytotoxicity (CDC). MET x MET bispecific antigen-binding molecules The present inventors have observed that certain monospecific anti-MET antigen-binding molecules that block HGF binding to MET tend to potently activate MET signaling (an undesirable consequence for a therapeutic molecule). The present inventors have ΜΛ / t / ZUZ I / UOÓ4OÓ surprisingly discovered, however, that bispecific antigen-binding molecules that simultaneously bind to two separate epitopes on the extracellular domain of the MET protein are effective in blocking ligand binding to MET while causing poor agonism of MET signaling. Furthermore, the present inventors have surprisingly found that bispecific antigen binding molecules are uniquely suitable for treating ocular cancer such as uveal melanoma, orbital lymphoma, retinoblastoma and medulloepithelioma, and / or inhibiting or mitigating metastasis. Accordingly, bispecific antigen-binding molecules comprising a first antigen-binding domain (further referred to herein as D1), and a second antigen-binding domain, are useful in accordance with the methods described herein. binding to an antigen (further referred to herein as D2). Simultaneous binding of the two separate MET epitopes by the bispecific antigen-binding molecule results in effective ligand blockade with minimal activation of MET signalling. Bispecific antigen-binding molecules, comprising a first antigen-binding domain (D1) that specifically binds to a first human MET epitope and a second antigen-binding domain (D2) that specifically binds to a second epitope of human MET, may be referred to herein as MET x MET, MET x MET bispecific antibodies or other related terminology. In some embodiments, the first human MET epitope comprises amino acids 192-204 of SEQ ID NO: 155. In some embodiments, the second human MET epitope comprises amino acids 305-315 and 421-455 of SEQ ID NO: 155. In some embodiments, the first human MET epitope comprises amino acids 192-204 of SEQ ID NO: 155; and the second human MET epitope comprises amino acids 305-315 and 421-455 of SEQ ID NO: 155. In certain embodiments, the D1 and D2 domains of a MET x MET bispecific antibody are not competitive with each other. The non-competition between D1 and D2 for binding to MET means that the respective monospecific antigen-binding proteins from which D1 and D2 were derived do not compete with each other for binding to human MET. Illustrative antigen-binding protein competition assays are known in the art, non-limiting examples of which are described elsewhere in this disclosure. In certain embodiments, D1 and D2 bind to different (eg, non-overlapping or partially overlapping) epitopes on MET, as described elsewhere in this disclosure. MET x MET bispecific antigen binding molecules can be constructed by using the antigen binding domains of two separate monospecific anti-MET antibodies. For example, a library of monoclonal monospecific anti-MET antibodies can be produced using standard methods known in the art. The individual antibodies thus produced can be tested in pairs with each other for cross-competition with a MET protein. If two different anti-MET antibodies can bind to MET at the same time (i.e., they do not compete with each other), then the antigen-binding domain of the first anti-MET antibody and the antigen-binding domain of the second anti-MET antibody noncompetitive can be engineered into a single MET x MET bispecific antibody in accordance with the present disclosure. In accordance with the present disclosure, a bispecific antigen-binding molecule can be M A / t / ZUZ I / UOO4OO a single multifunctional polypeptide, or it can be a multimeric complex of two or more polypeptides covalently or non-covalently associated with each other. As will be apparent from the present disclosure, any antigen-binding construct that has the ability to simultaneously bind to two separate non-identical epitopes of the MET molecule is considered to be a bispecific antigen-binding molecule. Any of the bispecific antigen-binding molecules described herein, or variants thereof, can be constructed using standard molecular biology techniques (eg, recombinant DNA and protein expression technology), as will be known to one skilled in the art. The technique. Antigen-binding domains Bispecific antigen-binding molecules useful in the methods described herein comprise two separate antigen-binding domains (D1 and D2). As used herein, the term "antigen-binding domain" means any peptide, polypeptide, nucleic acid molecule, scaffold molecule, peptide-presenting molecule, or polypeptide-containing construct that is capable of specifically binding to an antigen. of particular interest (eg, human MET). The term "specifically binding" or the like, as used herein, means that the antigen-binding domain forms a complex with a particular antigen characterized by a dissociation constant (Kd) of 500 pM or less, and does not bind. to other unrelated antigens under normal test conditions. Unrelated antigens are proteins, peptides, or polypeptides that have less than 95% amino acid identity with each other. Illustrative categories of antigen-binding domains that may be used in the context of the present disclosure include antibodies, antigen-binding portions of antibodies, peptides that specifically interact with a particular antigen (eg, peptibodies), receptor molecules that interact specifically with a particular antigen, proteins that comprise a ligand-binding portion of a receptor that specifically binds a particular antigen, antigen-binding scaffolds (e.g., DARPin, HEAT repeat proteins, ARM repeat proteins, tetratricopeptide repeat proteins, and other naturally occurring repeat protein-based scaffolds, etc., [see, for example, Boersma and Pluckthun, 2011, Curr Opin Biotechnol 22:849-857, and references cited in the same]), and aptamers or portions thereof. Methods for determining whether two molecules specifically bind to each other are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antigen-binding domain, as used in the context of the present disclosure, includes polypeptides that bind to a particular antigen (eg, a target molecule [T] or an effector protein with internalization [E ]) or a portion thereof with a Kd of less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, less than about 10 pM, less than M A / Ε / ΖυΖΊ / UOO4OO about 5 pM, less than about 4 pM, less than about 2 pM, less than about 1 pM, less than about 0.5 pM, less than about 0.2 pM, less than about 0.1 pM, or less than approximately 0.05 pM, as measured in a surface plasmon resonance assay. The term surface plasmon resonance, as used in the present description, refers to an optical phenomenon that allows analysis of interactions in real time by detection of alterations in protein concentrations within a biosensor array, for example , using the BIAcore™ system (Biacore Life Sciences Division of GE Healthcare, Piscataway, NJ). The term Kd, as used herein, refers to the equilibrium dissociation constant of a particular protein-protein interaction (eg, antibody-antigen interaction). Unless otherwise indicated, the Kd values ​​described herein refer to the Kd values ​​determined by a surface plasmon resonance assay at 25SC. As indicated above, an antigen-binding domain (D1 and / or D2) can comprise or consist of an antibody or antigen-binding fragment of an antibody. The term "antibody", as used herein, means any antigen-binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen (eg, MET human). The term antibody includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) and two light (L) chains interconnected by disulfide bonds, as well as multimers of these (eg, IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or Vh) and a heavy chain constant region. The heavy chain constant region comprises three domains, Ch1, Ch2 and Ch3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or Vl) and a light chain constant region. The constant region of the light chain comprises a domain (Cl1). The Vh and Vl regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Each Vh and Vl is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of the antibodies provided herein (or the antigen-binding portion thereof) may be identical to human germline sequences, or may be naturally or artificially modified. A consensus amino acid sequence can be defined based on a side-by-side analysis of two or more CDRs. Components D1 and / or D2 of the bispecific antigen-binding molecules provided herein may comprise or consist of antigen-binding fragments of whole antibody molecules. The terms antigen-binding portion of an antibody, antigen-binding fragment of an antibody, and the like, as used herein, include any naturally occurring polypeptide or glycoprotein, which may be obtained enzymatically, synthetically, or genetically modified cells that specifically bind to an antigen to form a complex. Antigen-binding fragments of an antibody can be derived, for example, from whole antibody molecules using any suitable standard technique such as proteolytic digestion or recombinant genetic modification techniques involving manipulation and expression of the encoding DNA. the variable and optionally constant domains of an antibody. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, antibody and phage libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or through the use of molecular biological techniques, for example, to arrange one or more variable and / or constant domains in a suitable configuration, or to introduce codons, create cysteine ​​residues, modify, add or remove amino acids, etc. Non-limiting examples of antigen binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (ii) Fd fragments; (iv) Fv fragments; (v) single chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (for example, an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a FR3-CDR3-peptide. FR4 restricted. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies , etc.), small modular immunopharmaceutical domains (SMIPs), and shark variable IgNARs, are also included within the term antigen-binding fragment, as used herein. An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain can be of any size or amino acid composition and will generally comprise at least one CDR that is adjacent to, or in-frame with, one or more framework sequences. In antigen-binding fragments having a Vh domain associated with a Vl domain, the Vh and Vl domains may be positioned relative to each other in any suitable arrangement. For example, the variable region can be dimeric and contain Vh-Vh, Vh-Vl or Vl-Vl dimers. Alternatively, the antigen-binding fragment of an antibody may contain a Vh or Vl monomeric domain. In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Illustrative non-limiting configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present disclosure include: (i) Vh-Ch1 ; (ii) Vh-Ch2; (iii) Vh-Ch3; (iv) VhCh1-Ch2; (v) Vh-Ch1-Ch2-Ch3; (vi) Vh-Ch2-Ch3; (vii) Vh-Cl; (viii) Vl-Ch1; (¡x) Vl-Ch2; (x) Vl-Ch3; (x¡) Vl-Ch1Ch2; (x¡¡) Vl-Ch1-Ch2-Ch3; (xiii) Vl-Ch2-Ch3; and (xiv) Vl-Cl. In any configuration of variable and constant domains, including any of the illustrative configurations mentioned above, the variable and constant domains may be joined directly to one another or may be joined by a full or partial hinge or linker region. A hinge region may consist of at least 2 (eg, 5, 10, 15, 20, 40, 60 or more) amino acids that result in a flexible or semi-flexible link between adjacent variable and / or constant domains in a single molecule. polypeptide. In addition, a fragment binding to ΜΛ / t / ZUZ I / UOO4OO antigen may comprise a homodimer or heterodimer (or other multimers) of any of the aforementioned constant and variable domain configurations in non-covalent association with each other and / or with one or more Vh or Vl monomeric domains (eg, by disulfide bond(s). Bispecific antigen binding molecules useful in the methods provided herein may comprise or consist of human antibodies and / or recombinant human antibodies or fragments thereof. The term human antibody, as used herein, includes antibodies having variable and constant regions derived from human germ-line immunoglobulin sequences. Human antibodies may, however, include amino acid residues not encoded by human germline immunoglobulin sequences (for example, mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDR and in particular CDR3. However, the term human antibody, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto sequences of the human frame. Bispecific antigen-binding molecules useful in the methods provided herein may comprise or consist of recombinant human antibodies or antigen-binding fragments thereof. The term recombinant human antibody, as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described in more detail below), antibodies isolated from a combinatorial, recombinant, human antibody library (described in more detail below), antibodies isolated from an animal (for example, a mouse) that is transgenic for human immunoglobulin genes (see, for example, Taylor et al. (1992) Nucí. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created, or isolated by any other means involving sequence splicing of human immunoglobulin genes with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germ line immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using a transgenic animal for human Ig sequences, in vivo somatic mutagenesis) and thus the amino acid sequences of the Vh and Vl regions of recombinant antibodies are sequences which, while derived from and related to human germline Vh and Vl sequences, may not naturally exist within the human germline repertoire of antibodies in vivo. Methods for preparing bispecific antibodies are known in the art and can be used to construct bispecific antigen-binding molecules described herein. Illustrative bispecific formats that may be used in the context of the present disclosure include, without limitation, for example, scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-lg, quadroma, button on buttonhole (knobs-into-holes), common light chain (for example, common light chain with buttonhole, etc.), CrossMab, CrossFab, body(SEED), leucine zipper, Duobody, IgG 1 / lgG2, Dual Action Fab (DAF)-lgG, and Mab2 bispecific formats (see, eg, Klein et al. 2012, mAbs 4:6, 1-11, and references cited therein, for a revision of previous formats). Illustrative antigen-binding domains (D1 and D2) that can be included in the MET x MET bispecific antigen-binding molecules provided herein include antigen-binding domains derived from any of the anti-MET antibodies described herein. description. For example, MET x MET bispecific antigen binding molecules comprising a D1 or D2 antigen binding domain comprising an HCVR comprising an amino acid sequence selected from any of the HCVR amino acid sequences listed in Table 1, or a substantially similar sequence thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith, are useful in methods of treating uveal melanoma as described in present description. Also useful, according to the methods provided herein, are MET x MET bispecific antigen binding molecules comprising a D1 or D2 antigen binding domain comprising an LCVR comprising an amino acid sequence selected from any of the LCVR amino acid sequences recited in Table 1, or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto. Also useful, according to the methods provided herein, are MET x MET bispecific antigen-binding molecules comprising a D1 or D2 antigen-binding domain comprising a pair of amino acid sequences from an HCVR and an LCVR. (HCVR / LCVR) comprising any of the HCVR amino acid sequences mentioned in Table 1 paired with any of the LCVR amino acid sequences mentioned in Table 1. According to certain embodiments, MET bispecific antigen-binding molecules x Useful METs comprising a D1 or D2 antigen-binding domain comprising a pair of HCVR / LCVR amino acid sequences contained within any of the illustrative anti-MET antibodies mentioned in Table 1. Also useful, according to the methods provided herein, are MET x MET bispecific antigen-binding molecules comprising a D1 or D2 antigen-binding domain comprising a heavy chain CDR1 (HCDR1) comprising a amino acid sequence selected from any of the HCDR1 amino acid sequences listed in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity . Also useful, according to the methods provided herein, are MET x MET bispecific antigen-binding molecules comprising a D1 or D2 antigen-binding domain comprising a heavy chain CDR2 (HCDR2) comprising a amino acid sequence selected from any of the HCDR2 amino acid sequences listed in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity . Also useful, according to the methods provided herein, are MET x MET bispecific antigen-binding molecules comprising a D1 or D2 antigen-binding domain comprising a heavy chain CDR3 (HCDR3) comprising a amino acid sequence selected from any of the HCDR3 amino acid sequences listed in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity . Also useful, according to the methods provided herein, are MET x MET bispecific antigen-binding molecules comprising a D1 or D2 antigen-binding domain comprising a light chain CDR1 (LCDR1) comprising a sequence amino acid sequence selected from any of the LCDR1 amino acid sequences mentioned in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. Also useful, according to the methods provided herein, are MET x MET bispecific antigen-binding molecules comprising a D1 or D2 antigen-binding domain comprising a light chain CDR2 (LCDR2) comprising a sequence amino acid sequence selected from any of the LCDR2 amino acid sequences mentioned in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. Also useful, according to the methods provided herein, are MET x MET bispecific antigen-binding molecules comprising a D1 or D2 antigen-binding domain comprising a light chain CDR3 (LCDR3) comprising a sequence amino acid sequence selected from any of the LCDR3 amino acid sequences mentioned in Table 1 or a sequence substantially similar thereto that has at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. Also useful, according to the methods provided herein, are MET x MET bispecific antigen-binding molecules comprising a D1 or D2 antigen-binding domain comprising a pair of HCDR3 and LCDR3 (HCDR3 / LCDR3) amino acid sequences. LCDR3) comprising any of the HCDR3 amino acid sequences mentioned in Table 1 paired with any of the LCDR3 amino acid sequences mentioned in Table 1. According to certain embodiments, the present disclosure provides antigen-binding antibodies or fragments of these, comprising a pair of HCDR3 / LCDR3 amino acid sequences contained within any of the illustrative anti-MET antibodies mentioned in Table 1. Also useful, according to the methods provided herein, are MET x MET bispecific antigen-binding molecules comprising a D1 or D2 antigen-binding domain comprising a set of six CDRs (i.e., HCDR1-HCDR2 -HCDR3-LCDR1-LCDR2LCDR3) contained within any of the illustrative anti-MET antibodies mentioned in Table 1. Also useful, according to the methods provided herein, are MET x MET bispecific antigen-binding molecules comprising an antigen-binding domain. ΜΛ / t / ZUZ I / UO0400 D1 or D2 comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2LCDR3) contained within a pair of HCVR / LCVR amino acid sequences as defined by any of the aforementioned illustrative anti-MET antibodies in Table 1. MET x MET bispecific antigen binding molecules useful in the methods provided herein may comprise a D1 antigen binding domain derived from any of the anti-MET antibodies in Table 1, and a D2 antigen binding domain. derived from any other anti-MET antibody in Table 1. Non-limiting examples of MET x MET bispecific antibodies are depicted in Figure 1. Figure 1 is a matrix illustrating the components of 272 illustrative MET x MET bispecific antibodies. Each numbered cell of the array (numbered 1 to 272) identifies a unique bispecific antibody comprising a D1 antigen-binding domain and a D2 antigen-binding domain, wherein the D1 antigen-binding domain comprises the D1 antigen-binding domain. immunoglobulin (HCVR / LCVR amino acid sequence pair) or CDR of the corresponding anti-MET antibody numbered along the Y-axis, and wherein the D2 antigen-binding domain comprises the variable domain of immunoglobulin (HCVR / LCVR amino acid sequence pair). LCVR) or CDR of the corresponding mentioned anti-MET antibody along the X-axis. Thus, for example, the MET x MET bispecific antigen-binding molecule number 10 shown in the matrix comprises a D1 antigen-binding domain comprising an HCVR / LCVR pair, or 6-CDR pool, from the illustrative anti-MET antibody H4H13290P2 and an antigen-binding domain D2 comprising an HCVR / LCVR pair, or 6-CDR pool, from the illustrative anti-MET antibody H4H13321P2. Additional examples of MET x MET bispecific antibodies provided herein are described in Example 4. An illustrative MET x MET bispecific antigen binding molecule useful, according to the methods provided herein, comprises a D1 antigen binding domain and a D2 antigen binding domain, wherein the D1 antigen binding domain comprises a pair of HCVR / LCVR amino acid sequences of SEQ ID NO: 58 / 138, or a set of heavy and light chain CDRs (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3), comprising SEQ ID NO : 60-6264-140-142-144, and wherein the D2 antigen-binding domain comprises a pair of HCVR / LCVR amino acid sequences of SEQ ID NO: 82 / 138, or a set of CDRs from the heavy chains and light (HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3), comprising SEQ ID NO: 84-86-88-140-142-144. An illustrative MET x MET bispecific antibody having these sequence characteristics is the bispecific antibody designated H4H14639D, also referred to as bispecific antibody No. 122, comprising a D1 derived from H4H13306P2 and a D2 derived from H4H13312P2 (see Example 4, Table 5 in the present description). As illustrative non-limiting examples, MET x MET bispecific antigen binding molecules useful herein comprise a D1 antigen binding domain and a D2 antigen binding domain, wherein the D1 antigen binding domain comprises a HCVR / LCVR amino acid sequence pair of SEQ ID NO: 18 / 138, or a set of heavy and light chain CDRs (HCDR1-HCDR2HCDR3-LCDR1-LCDR2-LCDR3), comprising SEQ ID NO: 20-22 -24-140-142-144, and wherein the D2 antigen-binding domain comprises a pair of HCVR / LCVR amino acid sequences of SEQ ID ΜΛ / t / ZUZ I / UOO4OO NO: 82 / 138, or a set of CDRs of the heavy and light chains (HCDR1-HCDR2-HCDR3-LCDR1LCDR2-LCDR3), comprising SEQ ID NO: 84-86-88-140-142-144. An illustrative MET x MET bispecific antibody having these sequence characteristics is the bispecific antibody designated H4H14635D, also referred to as bispecific antibody No. 42, comprising a D1 derived from H4H13295P2 and a D2 derived from H4H13312P2 (see Example 4, Table 5 in the present description). multimerization components Bispecific antigen binding molecules useful in accordance with the provided methods may, in certain embodiments, further comprise one or more multimerization component(s). The multimerization components may function to maintain the association between the antigen-binding domains (D1 and D2). As used herein, a multimerization component is any macromolecule, protein, polypeptide, peptide, or amino acid that has the ability to associate with a second multimerization component of the same or similar structure or constitution. For example, a multimerization component can be a polypeptide comprising a Ch3 immunoglobulin domain. A non-limiting example of a multimerization component is an Fe moiety of an immunoglobulin, for example, an Fe domain of an IgG selected from the IgG1, IgG2, IgG3, and IgG4 isotypes, as well as any allotype within each group of isotype. In certain embodiments, the multimerization component is an Fe fragment or an amino acid sequence from 1 to about 200 amino acids in length that contains at least one cysteine ​​residue. In other embodiments, the multimerization component is a cysteine ​​residue, or a short cysteine-containing peptide. Other multimerization domains include peptides or polypeptides that comprise or consist of a leucine zipper, a helix-loop motif, or a coiled-coil motif. In certain embodiments, bispecific antigen-binding molecules comprise two multimerization domains, M1 and M2, where D1 binds M1 and D2 binds M2, and where association of M1 with M2 facilitates physical binding of D1 and D2 with each other in a single bispecific antigen-binding molecule. In certain embodiments, M1 and M2 are identical to each other. For example, M1 can be an Fe domain having a particular amino acid sequence, and M2 is an Fe domain with the same amino acid sequence as M1. Alternatively, M1 and M2 may differ from each other at one or more amino acid positions. For example, M1 may comprise a first Ch3 immunoglobulin (Ig) domain and M2 may comprise a second Ch3 Ig domain, where the first and second Ch3 Ig domains differ from each other by at least one amino acid, and where at least one difference of one amino acid reduces the binding of the targeting construct to Protein A compared to a reference construct having identical M1 and M2 sequences. In one embodiment, the Ig Ch3 domain of M1 binds Protein A and the Ig Ch3 domain of M2 contains a mutation that reduces or abolishes binding to Protein A such as an H95R modification (for IMGT exon numbering; H435R by the EU numbering). M2 Ch3 may further comprise a Y96F (for IMGT; Y436F for EU) modification. Other modifications that can be found within Ch3 of M2 Include: D16E, L18M, N44S, K52N, V57M and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M and V422I by EU) in the case of an Fe domain IgG1; N44S, K52N and V82I (IMGT; EU N384S, K392N and V422I) in the case of an lgG2 Fe domain; and Q15R, N44S, K52N, V57M, R69K, E79Q and M A / E / ZUZ I / UOO4OO V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q and V422I by EU) in the case of an lgG4 Fe domain. Bispecific antigen binding molecules useful in accordance with the methods provided herein can be isolated. An isolated bispecific antigen-binding molecule, as used herein, means a bispecific antigen-binding molecule that has been identified and separated and / or recovered from at least one component of its natural environment. For example, a bispecific antibody that has been separated or extracted from at least one component of an organism, or from a tissue or cell in which the antibody is produced, is an isolated bispecific antibody for the purposes of this disclosure. An isolated bispecific antigen binding molecule further includes molecules in situ within a recombinant cell. Isolated bispecific antigen-binding molecules are molecules that have undergone at least one purification or isolation step. According to certain embodiments, an isolated bispecific antigen-binding molecule may be substantially free of other cellular material and / or chemicals. Bispecific antigen-binding molecules useful according to the methods provided herein, or the antigen-binding domains thereof (D1 and / or D2) may comprise one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antigen-binding proteins or antigen-binding domains were derived. Such mutations can be readily determined by comparing the amino acid sequences described herein with germline sequences available from, for example, public antibody sequence databases. Bispecific antigen-binding molecules or antigen-binding domains thereof (D1 and / or D2), are derived from any of the amino acid sequences described herein, where one or more amino acids within one or more framework and / or CDR regions were mutated to the corresponding residue(s) of the germline sequence(s) from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence(s), or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are collectively referred to herein as germline mutations). Beginning with the heavy and light chain variable region sequences described herein, one skilled in the art can readily produce numerous bispecific antigen-binding molecules, or antigen-binding domains thereof (D1 and / or D2) comprising one or more individual germline mutations or combinations thereof. In certain embodiments, all framework and / or CDR residues within the Vh and / or Vl domains are mutated back to residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues were mutated back to the original germline sequence, for example, only mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only mutated residues. found within CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). In addition, the bispecific antigen-binding molecules or antigen-binding domains thereof (D1 and / or D2) useful herein may contain any combination of two or more germline mutations within the framework and / or framework regions. or CDRs, for example, where certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or mutated to the corresponding residue of a sequence of the different germ line. Once obtained, bispecific antigen-binding molecules, or the antigen-binding domains thereof (D1 and / or D2) containing one or more germline mutations can be readily assayed for one or more desired properties such as, better binding specificity, higher binding affinity, improved or enhanced agonist or antagonist biological properties (as appropriate on a case-by-case basis), lower immunogenicity, etc. Bispecific antigen-binding molecules, or antigen-binding domains thereof (D1 and / or D2), obtained in this general manner are contemplated as useful in the present disclosure. variants Also useful herein are anti-MET antibodies, and bispecific antigen binding molecules comprising variants of any of the HCVR, LCVR and / or CDR amino acid sequences described herein. Illustrative variants included in this aspect include variants of any of the HCVR, LCVR, and / or CDR amino acid sequences described herein that have one or more conservative substitutions. For example, the present disclosure includes anti-MET antibodies and MET x MET bispecific antigen-binding molecules having HCVR, LCVR and / or CDR amino acid sequences with, for example, 10 or less, 8 or less, 6 or less , 4 or less, etc. conservative amino acid substitutions with respect to any of the HCVR, LCVR and / or CDR amino acid sequences set forth in Table 1 of the present disclosure. Illustrative variants include variants that have substantial sequence identity to any of the HCVR, LCVR, and / or CDR amino acid sequences described herein. As used herein in the context of amino acid sequences, the term "Substantially Identity" or "Substantially Identical" means that two amino acid sequences, when optimally aligned, such as by the GAP or BESTFIT programs through the use of weights of Default break, share at least 95%, 98%, or 99% sequence identity. In certain embodiments, residue positions, which are not identical, differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which one amino acid residue is substituted for another amino acid residue having a side chain (R group) with similar chemical properties (eg, charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity can be adjusted upward to correct for the nature of the sequence. ΜΛ / t / ZUZ I / UO0400 conservative substitution. Means for making this adjustment are well known to those skilled in the art. See, for example, Pearson (1994) Methods Mol. BioL 24: 307-331, is incorporated herein by reference. Examples of groups of amino acids that have side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) aliphatic hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains are cysteine ​​and methionine. Preferred conservative amino acid substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change that has a positive value in the PAM250 log-likelihood matrix described in Gonnet et al. (1992) Science 256:1443-1445, incorporated herein by reference. A moderately conservative replacement is any change that has a non-negative value in the PAM250 log-likelihood matrix. Sequence identity between two different amino acid sequences is typically measured using a sequence analysis computer program. The sequence analysis computer program searches for matches between similar sequences using similarity measures assigned to various substitutions, deletions, and other modifications, including conservative amino acid substitutions. For example, the GCG software contains programs such as GAP and BESTFIT that can be used with predetermined parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a protein from wild type and a mutein thereof. See, for example, GCG Version 6.1. Polypeptide sequences can also be compared using FASTA with default or recommended parameters; a program in GCG Version 6.1. FASTA (eg, FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence provided herein with a database containing a large number of sequences from different organisms is the BLAST computer program, especially BLASTP or TBLASTN, using predetermined parameters. See, for example, Altschul et al. (1990) J. Mol. BioL 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402, each of which is incorporated herein by reference. Anti-MET antibodies and MET x MET bispecific antigen-binding molecules comprising Fe variants According to certain embodiments provided herein, anti-MET antibodies and MET x MET bispecific antigen-binding proteins useful herein comprise an Fc domain comprising one or more mutations that enhance or decrease binding of the antibody to the receptor. FcRn, for example, at acidic pH compared to neutral pH. For example, such variants include anti-MET antibodies and MET x MET bispecific antigen-binding proteins that comprise a mutation in the Ch2 or Ch3 region of the Fe domain, wherein the mutation(s) increases the affinity of the Fe domain to FcRn in an acidic environment (for example, in an endosome where the pH ranges from about 5.5 to about 6.0). Such mutations may result in an increased serum half-life of the antibody when administered to an animal. Non-limiting examples of such Fe modifications include, for example, a modification at position 250 (eg, E or Q); 250 and 428 (eg, L or F); 252 (for example, UY / F / \N or T), 254 (for example, S or T), and 256 (for example, S / R / Q / E / D or T); or a modification at position 428 and / or 433 (eg H / L / R / S / P / Q or K) and / or 434 (eg H / F or Y); or a modification at position 250 and / or 428; or a modification at position 307 or 308 (eg, 308F, V308F) and 434. In one embodiment, the modification comprises a 428L (eg, M428L) and 434S modification (eg, N434S); a 428L, 259I (eg V259I) and 308F modification (eg V308F); a 433K (eg H433K) and a 434 modification (eg 434Y); a 252, 254, and 256 modification (eg, 252Y, 254T, and 256E); a modification 250Q and 428L (for example, T250Q and M428L); and a 307 and / or 308 modification (eg, 308F or 308P). Accordingly, anti-MET antibodies and MET x MET bispecific antigen-binding proteins comprising an Fc domain comprising one or more pairs or groups of mutations selected from the group consisting of: 250Q and 248L are useful herein. (for example, T250Q and M248L); 252Y, 254T and 256E (for example M252Y, S254T and T256E); 428L and 434S (for example, M428L and N434S); and 433K and 434F (for example, H433K and N434F). All possible combinations of the above Fe domain mutations, and other mutations within the antibody variable domains described herein, are contemplated within the scope of this description. Biological Characteristics of the Antigen-Binding Molecules Useful of the Present Disclosure Useful according to the methods provided herein are antibodies and antigen-binding fragments thereof, as well as ADCs comprising the antibodies and antigen-binding fragments, which inhibit proliferation, inhibit invasion, cause apoptosis and / or decrease the viability of a uveal melanoma cell. Also useful, according to the methods provided herein, are antibodies and antigen-binding fragments thereof, as well as ADCs comprising the antibodies and antigen-binding fragments, which affect the cell cycle of a cell. uveal melanoma cell. In some aspects, the cell undergoes mitotic arrest. In some aspects, the cell remains in a SubG1 phase, indicating that the cell is undergoing apoptosis. Also useful, according to the methods provided herein, are antibodies and antigen-binding fragments thereof, as well as ADCs comprising the antibodies and antigen-binding fragments, which cause apoptosis in a cell. uveal melanoma. In some aspects, the uveal melanoma cell exhibits PARP cleavage. In some aspects, the uveal melanoma cell shows histone H3 phosphorylation. Also useful, in accordance with the methods provided herein, are antibodies and antigen-binding fragments thereof that bind to monomeric human MET with high ΜΛ / t / ZUZ I / UOO4OO affinity. For example, the present disclosure includes anti-MET antibodies that bind to monomeric human MET (eg, hMET.mmh) with a Kd of less than about 230 nM as measured by surface plasmon resonance at 25SC or 37SC, eg, by using an assay format as defined in Example 3 herein or a substantially similar assay. According to certain embodiments, anti-MET antibodies are provided that bind to monomeric human MET at 37°C with a Kd of less than about 230 nM, less than about 200 nM, less than about 150 nM, less than about 100 nM, less less than about 50 nM, less than about 25 nM, less than about 20 nM, less than about 10 nM, less than about 8 nM, less than about 6 nM, or less than about 5 nM, less than about 4 nM, or less of about 3 nM, as measured by surface plasmon resonance, eg, using an assay format as defined in Example 3 herein or a substantially similar assay. Such antibodies and antigen-binding fragments thereof that bind to monomeric human MET (eg, hMET.mmh) with a dissociative half-life (1½) greater than about 1 minute as measured by surface plasmon resonance at 25°C or 378°C, for example, by use of an assay format as defined in Example 3 herein or a substantially similar assay. Such anti-MET antibodies that bind to monomeric human MET at 37SC with a 1½ greater than about 1 minute, greater than about 2 minutes, greater than about 4 minutes, greater than about 6 minutes, greater than about 8 minutes, greater than about 10 minutes, greater than about 12 minutes, greater than about 14 minutes, greater than about 16 minutes, greater than about 18 minutes, or greater than about 20 minutes or more, as measured by surface plasmon resonance, for example, using a assay format as defined in Example 3 herein or a substantially similar assay. Such antibodies and antigen-binding fragments thereof bind to dimeric human MET (eg, hMET.mFc) with high affinity. For example, anti-MET antibodies that bind dimeric human MET with a Kd of less than about 3 nM as measured by surface plasmon resonance at 25SC or 37SC, eg, using an assay format as defined in Example 3 in the present description or a substantially similar test. According to certain embodiments, anti-MET antibodies that bind dimeric human MET to 37SC with a Kd of less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 0.9 nM , less than about 0.8 nM, less than about 0.7 nM, less than about 0.6 nM, less than about 0.5 nM, less than about 0.4 nM, less than about 0.3 nM, or less than about 0.25 nM, as measured by surface plasmon resonance, eg, using an assay format as defined in Example 3 herein or a substantially similar assay. Such antibodies and antigen-binding fragments thereof that bind dimeric human MET (eg, hMET.mFc) with a dissociative half-life (1½) greater than about 4 minutes measured ΜΛ / t / ZUZ I / UOÓ4OÓ by surface plasmon resonance at 25SC or 37SC, eg, using an assay format as defined in Example 3 herein or a substantially similar assay. According to certain embodiments, anti-MET antibodies can bind to dimeric human MET at 37°C with a t1 / z greater than about 4 minutes, greater than about 5 minutes, greater than about 10 minutes, greater than about 20 minutes, greater than about 30 minutes, greater than about 40 minutes, greater than about 50 minutes, greater than about 60 minutes, greater than about 70 minutes, greater than about 80 minutes, greater than about 90 minutes, greater than about 100 minutes, greater than about 105 minutes or more, as measured by surface plasmon resonance, for example, using an assay format as defined in Example 3 herein or a substantially similar assay. Also useful, according to the methods provided herein, are MET x MET bispecific antigen-binding molecules that bind to dimeric human MET (eg, hMET.mFc) with a dissociative half-life (1½) greater than about 10 minutes, as measured by surface plasmon resonance at 25SC or 37SC, eg, using an assay format as defined in Example 5 herein or a substantially similar assay. According to certain embodiments, bispecific antibody-binding proteins that bind to human MET at 37SC with a t1 / 2 greater than about 10 minutes, greater than about 20 minutes, greater than about 30 minutes, greater than about 40 minutes, greater greater than approximately 50 minutes, greater than approximately 60 minutes, greater than approximately 70 minutes, greater than approximately 80 minutes, greater than approximately 90 minutes, greater than approximately 100 minutes, greater than approximately 200 minutes, greater than approximately 300 minutes, greater than approximately 400 minutes, greater than approximately 500 minutes, greater than approximately 600 minutes, greater than approximately 700 minutes, greater than approximately 800 minutes, greater than approximately 900 minutes, greater than approximately 1000 minutes, greater than approximately 1100, or more, as measured by resonance of surface plasmons, for example, by using an assay format as defined in Example 5 of the present disclosure or a substantially similar assay. Also in accordance with the methods provided herein are anti-MET antibodies and MET x MET bispecific antigen binding proteins that block the interaction between HGF and MET, eg, in an in vitro ligand binding assay. In accordance with certain embodiments provided herein, MET x MET bispecific antigen-binding proteins block HGF binding to cells expressing human MET and induce minimal or no MET activation in the absence of HGF signalling. For example, MET x MET bispecific antigen-binding proteins exhibit a degree of MET agonist activity in a cell-based MET activity indicator assay that is less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, less than 2%, or less than 1% of the MET agonist activity observed in an equivalent activity indicator assay using a monospecific antibody ΜΛ / t / ZUZ I / UOÓ4OÓ comprising D1 or D2 alone. Antibodies and antigen-binding proteins useful in accordance with the present disclosure may possess one or more of the aforementioned biological characteristics, or any combination thereof. The above list of biological characteristics of antibodies is not intended to be exhaustive. Other biological characteristics of the antibodies provided herein will be apparent to one skilled in the art from a review of the present disclosure including the working examples of the present disclosure. Antibody-drug conjugates (ADC) In accordance with the methods provided herein, antibody-drug conjugates (ADCs) comprising an anti-MET antibody or a MET x MET bispecific antigen-binding protein conjugated to a therapeutic moiety such as a cytotoxic agent, are useful. a chemotherapeutic drug or a radioisotope. Cytotoxic agents include any agent that is detrimental to the growth, viability, or propagation of cells, including, but not limited to, agents that interact with tubulin and agents that damage DNA. Examples of suitable cytotoxic agents and chemotherapeutic agents that can be conjugated to anti-MET antibodies in accordance with this aspect of the disclosure include, for example, 1-(2chloroethyl)-1,2-dimethanesulfonylhydrazide, 1,8-dihydroxy-bicyclo[ 7.3.1 ]trideca-4,9diene-2,6-diin-13-one, 1-dehydrotestosterone, 5-fluorouracil, 6-mercaptopurine, 6-thioguanine, 9-aminocamptothecin, actinomycin D, amanitins, aminopterin, anguidin, anthracycline, anthramycin (AMO), auristatins, bleomycin, busulfan, butyric acid, calicheamicins (e.g. calicheamicin yi), camptothecin, carminomycins, carmustine, cemadotins, cisplatin, colchicine, combretastatins, cyclophosphamide, cytarabine, cytochalasin B, dactinomycin, daunorubicin, decarbazine, diacetoxypentyldoxorubicin, dibromomannitol, dihydroxy anthracin dione, disorazoles, dolastatin (for example, dolastatin 10), doxorubicin, duocarmycin, echinomycins, eleutherobins, emetine, epothilones, esperamycin, estramustines, ethidium bromide, etoposide, fluorouracils, geldanamycins, gramicidin D, Glucocorticoids, irinotecycins, kinesin protein (KSP) inhibitors, leptomycins, leurosins, lidocaine, lomustine (CCNU), maytansinoids, mechlorethamine, melphalan, mercatopurines, metopterins, methotrexate, mithramycin, mitomycin, mitoxantrone, N8-acetyl spermidine, podophyllotoxins, procaine, propranolol, pteridins, puromycin, pterinsodlazidines, pterinsodiazirines, puromycin, plrrolobenzodiazepines (PBDs), rhizoxins, streptozotocin, tallisomycins, taxol, tenoposide, tetracaine, tloepa chlorambucil, thomamycins, topotecans, tubulisin, vlnblastin, vincris vat, vindesine, vinorelbines and derivatives of any of the previous ones. According to certain embodiments, the cytotoxic agent that is conjugated to an anti-MET antibody is a maytansinoid such as DM1 or DM4, a thomamycin derivative, or a dolastatin derivative. According to certain embodiments, the cytotoxic agent that is conjugated to an anti-MET antibody is an auristatin such as MMAE, MMAF, or derivatives thereof. Other cytotoxic agents known in the art are contemplated within the scope of the present disclosure, including, for example, protein toxins such as ricin, C. difficile toxin, pseudomonas exotoxin, ricin, diphtheria toxin, botulinum toxin, bryodin, saporin, pokeweed toxins (i.e., phytolaccatoxin and M A / t / ZUZ I / UO0400 phytolaccigenin), and others such as those set forth in Sapra et al., Pharmacol. & Therapeutics, 2013, 138:452-469. In certain embodiments, the cytotoxic agent is a maytansinoid, eg, maytansine derivative. Suitable maytansinoids include DM1, DM4 or derivatives, stereoisomers or isotopologues thereof. Suitable maytansinoids also include, but are not limited to, those described in WO 2014 / 145090A1, WO 2015 / 031396A1, US 2016 / 0375147A1 and US 2017 / 0209591A1, incorporated herein by reference in their entirety. In some embodiments, the maytansinoid has the following structure: wherein A is an optionally substituted arylene or heteroarylene. In some embodiments, the maytansinoid has the following structure: wherein A is an optionally substituted arylene or heteroarylene. In some embodiments, the maytansinoid has the following structure: where n is an integer from 1-12 and R1 is alkyl. In some embodiments, the maytansinoid is: MA / E / ZUZ! / UOO4OO ΜΑ / Ε / ΖυΖΊ / UO 0400 ΜΑ / Ε / ΖυΖΊ / UO 0400 In some embodiments, the maytansinoid is: In some embodiments, the maytansinoid is: either Also useful, according to the methods provided herein, are antibody-radionuclide conjugates (ARCs) comprising anti-MET antibodies conjugated to one or more radionuclides. Illustrative radionuclides that may be used in the context of this aspect of the disclosure include, but are not limited to, for example, 225Ac,212Bi,213B¡,1311,186Re, 227Th, 222Rn,223Ra,224Ra, and 90Y. In certain embodiments, ADCs comprise an anti-MET antibody or a MET x MET bispecific antigen-binding protein conjugated to a cytotoxic agent (eg, any of the cytotoxic agents described above) via a linker molecule. Linkers are any group or moiety that binds, connects, or binds the antibody or antigen-binding proteins described herein to a therapeutic moiety, eg, cytotoxic agent. Suitable linkers can be found, for example, in Antibody-Drug Conjugales and Immunotoxins; Phillips, G.L, Ed.; Springer Verlag: New York, 2013; Antibody-Drug Conjugales·, Ducry, L., Ed.; Human Press, 2013; Antibody-Drug Conjugal; Wang, J., Shen, W.-C. and Zaro, JL, Eds.; Springer International Publishing, 2015, the content of each is incorporated herein in its entirety by reference. Generally, suitable binding agent linkers for the antibody conjugates described herein are those that are stable enough to exploit the circulating half-life of the antibody and, at the same time, capable of releasing their payload after internalization of the antibody. antigen-mediated conjugate. The linkers may be cleavable or non-cleavable. Cleavable linkers include linkers that are cleaved by intracellular metabolism after internalization, eg, cleavage by hydrolysis, reduction, or enzymatic reaction. Non-cleavable linkers include linkers that release a bound payload through lysosomal degradation of the antibody after internalization. Suitable linkers include, but are not limited to, acid-labile linkers, hydrolysis-labile linkers, enzymatically cleavable linkers, reduction-labile linkers, autoimmolative linkers, and non-cleavable linkers. Suitable linkers also include, but are not limited to, those that are or comprise peptides, glucuronides, succinimide thioethers, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, dipeptide units, valine-citrulline units, and para-aminobenzyl (PAB) units. Any linker molecule or linker technology known in the art can be used to create or construct a useful ADC in accordance with the present disclosure. In certain embodiments, the linker is a split linker. According to other embodiments, the linker is a non-cleaved linker. Illustrative linkers that may be used in the context of the present disclosure include linkers comprising or consisting of, for example, MC (6-maleimidocaproyl), MP (maleimidopropanoyl), val-cit (valine-citrulline), val-ala (valine -alanine), dipeptide site in linker cleaved by protease, ala-phe (alanine-phenylalanin), dipeptide site in linker cleaved by protease, PAB (p-aminoencyloxycaroonyl), SPP (N-succinimidyl 4-(2- plrld¡lt¡o)pentanoate), SMCC (N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-caroxylate), SIAB (Succinimidyl N-(4-iodo-acetyl)aminooenzoate), and variants and combinations thereof. Additional examples of linkers are provided. M A / E / ZUZ I / UOÓ4OÓ that can be used in the context of the present description, for example, in US 7,754,681 and in Ducry, Bioconjugate Chem., 2010, 21:5-13, and the references cited there, the content of which is incorporated herein by reference in its entirety. In certain embodiments, the linkers are stable under physiological conditions. In certain embodiments, the linkers are cleavable, eg, 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, a linker comprises an enzyme cleaved moiety. Illustrative 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-cleaved linker. In some embodiments, the linker comprises a non-cleaved moiety. Suitable linkers also include, but are not limited to, those that are chemically linked to two cysteine ​​residues of a single binding agent, eg, antibody. Such linkers can serve to mimic antibody disulfide bonds that are broken as a result of the conjugation process. In some embodiments, the linker comprises one or more amino acids. Suitable amino acids include natural, non-natural, standard, non-standard, proteinogenic, non-proteinogenic, and ίο D- α-amino acids. In some embodiments, the 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. , a derivative thereof or a combination thereof. In certain embodiments, one or more amino acid side chains are attached to a side chain group, which is described below. In some embodiments, the linker comprises valine and citrulline. In some embodiments, the linker comprises usine, valine, and citrulline. In some embodiments, the linker comprises lysine, valine, and alanine. In some embodiments, the linker comprises valine and alanine. In some embodiments, the linker comprises a self-immolating group. The self-immolating group can be any group known to those skilled in the art. In particular embodiments, the autoimmolative group is p-aminobenzyl (PAB), or a derivative thereof. Useful derivatives include p-aminobenzyloxycarbonyl (PABC). Those skilled in the art will recognize that a self-immolating group is capable of carrying out a chemical reaction that releases the remaining atoms of a linker from a payload. In some embodiments, the linker is: ; Α where * is binding to the antibody or antigen-binding protein (eg, via the lysine residue) and ¿ is binding to the cytotoxic agent (eg, DM1). In some embodiments, the linker is: to or M A / Ε / ΖυΖΊ / UO 0400 where 5 is binding to the antibody or antigen-binding protein (eg, via ^lysine residue) and ¿ is binding to the cytotoxic agent (eg, DM1). In certain embodiments, the linker is: In certain embodiments, the linker is: In some embodiments, the linker is derived from maleimidylmethyl-4-transcyclohexanecarboxysuccinamate: In some embodiments, the linker is: M A / IZ / ΖυΖΊ / UOÓ4OÓ where 5 is binding to the antibody or antigen-binding protein (eg, via the Usin residue) and ¿ is binding to the cytotoxic agent (eg, a compound having the following formula: Molecules useful according to the described methods comprise ADCs in which a linker connects an anti-MET antibody or MET x MET bispecific antigen-binding protein to a drug or cytotoxin through binding to a particular amino acid within the antibody. or antigen-binding molecule. Illustrative amino acid linkages that can be used in the context of this aspect, for example, lysine (see, for example, US 5,208,020; US 2010 / 0129314; Hollander et al., Bioconjugate Chem., 2008, 19:358-361; WO 2005 / 089808; US 5,714,586; US 2013 / 0101546; and US 2012 / 0585592), cysteine ​​(see, for example, US 2007 / 0258987; WO 2013 / 055993; WO 2013 / 055990; WO 2013 / 053873; WO 2013 / 053872; WO 2011 / 130598; US 2013 / 0101546; and US 7,750,116), selenocysteine ​​(see, for example, WO 2008 / 122039; and Hofer et al., Proc. Nati. Acad. Sci., USA, 2008, 105:12451-12456 ), formyl glycine (see, for example, Carneo et al., Nat. Chem. Biol., 2007, 3:321-322; Agarwal et al., Proc. Nati. Acad. Sci., USA, 2013, 170:46- 51 and Rabuka et al., Nat. Protocols, 2012, 70:1052-1067), unnatural amino acids (see, for example, WO 2013 / 068874 and WO 2012 / 166559) and acidic amino acids (see, for example, WO 2012 / 05982 ). Linkers can also be conjugated to an antigen-binding protein through carbohydrate binding (see, for example, US 2008 / 0305497, WO 2014 / 065661 and Ryan et al., Food & Agriculture Immunol., 2001, 73: 127-130) and disulfide linkers (see, for example, WO 2013 / 085925, WO 2010 / 010324, WO 2011 / 018611 and Shaunak et al., Nat. Chem. Biol., 2006, 2:312-313). Site-specific conjugation techniques can also be employed to direct conjugation to particular residues of the antibody or antigen-binding protein (see, eg, Schumacher et al., J Clin Immunol (2016) 36 (Suppl 1): 100). . Site-specific conjugation techniques include, but are not limited to, glutamine conjugation via transglutaminase (see eg, Schibli, Angew Chemie Inter Ed. 2010, 49, 9995). According to certain embodiments, ADCs useful in accordance with the methods provided herein comprise an anti-MET antibody or a MET x MET bispecific antigen-binding protein conjugated to a linker-drug composition as set forth in the publication of international patent WO2014 / 145090, (for example, compound 7, also referred to in the present description as M0026 and shown below), the disclosure of which is incorporated herein by reference in its entirety: ΜΛ / t / ZUZ I / UO0400 O^NH Also useful according to the methods provided herein are antibody-drug conjugates comprising the monospecific anti-MET antibodies and MET x MET bispecific antibodies, wherein said anti-MET antibody or MET x MET bispecific antibody is conjugated to a cytotoxic agent. . In certain embodiments, the cytotoxic agent is a maytansinoid. In certain embodiments, the maytansinoid is a compound having the following formula: 1HR1—N-(CH2)n Or CH3 where n is an integer from 1-12 and R1 is alkyl. In certain embodiments, the maytansinoid either ΜΛ / t / ZUZ I / UO0400 In certain embodiments, the cytotoxic agent is a maytansinoid and the maytansinoid is covalently attached to the antibody through a non-cleavable linker. In certain embodiments, the cytotoxic agent is a maytansinoid and the maytansinoid is covalently attached to the antibody through a cleavable linker. In one embodiment, the antibody is conjugated to: where 5 is a binding to the antibody. In one embodiment, the antibody is conjugated to: where * is a binding to the antibody. In one embodiment, the antibody is conjugated to: either ΜΛ / t / ZUZ I / UOÓ4OÓ where 5 is a binding to the antibody. In one embodiment, the antibody is conjugated to: where * is a binding to the antibody. In one embodiment, the antibody is conjugated to a diastereoisomer of a compound having the following structure where the diastereoisomer is characterized by a 1H NMR characterized by delta shifts of (300 MHz, CDChjó 6.85 (d, 1H, J= 4 Hz), 6.72 (m, 1H), 6.65 (d, 1H, J = 4 Hz ), 6.44 (dd, 1H, J= 15 Hz, 11 Hz), 6.25 (s, 1H), 5.67 (dd, 1H, J= 16 Hz, 9 Hz), 5.41 (m, 1 H), 4.79 (day , 1H, J= 11 Hz), 4.30 (t, 1H, J= 11 Hz), 3.72 (m, 2H), 3.51 (d, 1H, J= 9 Hz), 3.37 (m, 4H), 3.27 (m, 1H), 3.23 (s, 3H), 3.16 - 2.99 (m, 4H), 2.85 (m, 7H), 2.62 (m, 3H), 2.39 (ddd, 1H, J= 19 Hz, 12 Hz, 4 Hz), 2.18 (brm, 2H), 1.77 (br m, 3H), 1.66 (s, 3H), 1.60 -1.47 (m, 4H), 1.31 (m, 6H), 1.05 (m , 2H) and 0.82 (s, 3H). In one embodiment, the antibody is conjugated to a diastereoisomer of a compound having the following structure wherein the diastereoisomer is characterized by a 1H NMR substantially as shown in Figure 31. In one embodiment, the antibody is conjugated to a compound that has the following structure: prepared through a process that includes the steps of contacting: (i) a compound of Formula III: (ii) a compound of Formula IV: (iii) silica gel; and (iv) a diluent comprising an organic solvent and water. In some modalities, the conjugates have the following structure: Ab-[L-Pay]n where: Ab is an anti-MET antibody or a MET x MET bispecific antigen-binding protein as described herein; L is a linker; Pay is a cytotoxic agent; and n is an integer from 1 -10. In some embodiments, Ab is an anti-MET antibody comprising the CDRs within the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 82 / 138. In some embodiments, Ab is an anti-MET antibody comprising the HCVR amino acid sequence of SEQ ID NO: 82 and the LCVR amino acid sequence of SEQ ID NO: 138. In some embodiments, Ab is a MET x MET bispecific antigen-binding protein comprising the CDRs within the D1-HCVR amino acid sequence of SEQ ID NO: 58 and the CDRs within the D2-HCVR amino acid sequence of SEQ ID NO: 82. In some aspects, the MET x MET bispecific antigen-binding protein further comprises the CDRs within the LCVR amino acid sequence of SEQ ID NO: 138. In some embodiments, Ab is a MET bispecific antigen-binding protein x MET comprising the D1-HCVR amino acid sequence of SEQ ID NO: 58 and the D2-HCVRde SEQ ID NO: 82 amino acid sequence. In some aspects, the MET x MET bispecific antigen-binding protein further comprises the amino acid sequence LCVR of SEQ ID NO: 138. In some embodiments, Ab is a MET x MET bispecific antigen-binding protein comprising the CDRs within the D1-HCVR amino acid sequence of SEQ ID NO: 18 and the CDRs within the D2-HCVR amino acid sequence of SEQ ID NO: 82. In some aspects, the MET x MET bispecific antigen-binding protein further comprises the CDRs within the LCVR amino acid sequence of SEQ ID NO: 138. In some embodiments, Ab is a MET bispecific antigen-binding protein x MET comprising the D1-HCVR amino acid sequence of SEQ ID NO: 18 and the D2-HCVR amino acid sequence of SEQ ID NO: 82. In some embodiments, L is a cleavable linker. In some embodiments, L is a non-cleavable linker. In some embodiments, L comprises a dipeptide. In some embodiments, L comprises a PAB moiety. In some embodiments, L comprises a remainder having the following structure: In some embodiments, L comprises a remainder having the following structure: ΜΛ / t / ZUZ I / UO0400 In some embodiments, L comprises a remainder having the following structure: In some embodiments, L comprises a remainder having the following structure: In some embodiments, Pay is a maytansinoid. In some modalities, Pay is: where R1 is alkyl. In some modalities, Pay is: In some modalities, Pay is: In some embodiments, n is an integer from 2 to 5. In some modalities, -L-Pay is: where * is a binding to the antibody. where * is a binding to the antibody. In some modalities, -L-Pay is or ί>Αwhere * is a binding to the antibody. In some modalities, -L-Pay is: In some modalities, the conjugates have the following structure: Ab-[L-Pay]n where: Ab is an anti-MET antibody comprising the HCVR amino acid sequence of SEQ ID NO: 82 and the LCVR amino acid sequence of SEQ ID NO: 138; L Pay is ^A where έ is a binding to the antibody; and n is an integer from 2-5. In some modalities, the conjugates have the following structure: Ab-[L-Pay]nen where: Ab is an anti-MET antibody comprising the HCVR amino acid sequence of SEQ ID NO: 82 and the LCVR amino acid sequence of SEQ ID NO: 138; L Pay is where * is a binding to the antibody; and n is an integer from 2-5. In some modalities, the conjugates have the following structure: Ab-[L-Pay]n M A / Ε / ΖυΖΊ / UOÓ4OÓ where: Ab is an anti-MET antibody comprising the HCVR amino acid sequence of SEQ ID NO: 82 and the LCVR amino acid sequence of SEQ ID NO: 138; L Pay is where * is a binding to the antibody; and n is an integer from 2-5. In some modalities, the conjugates have the following structure: Ab-[L-Pay]n where: Ab is an anti-MET antibody comprising the HCVR amino acid sequence of SEQ ID NO: 82 and the LCVR amino acid sequence of SEQ ID NO: 138; L Pay is >A where 5 is antibody binding; and n is an integer from 2-5. In some modalities, the conjugates have the following structure: Ab-[L-Pay]n where: Ab is a MET x MET bispecific antigen-binding protein comprising the D1-HCVR amino acid sequence of SEQ ID NO: 58 and the D2-HCVR amino acid sequence of SEQ ID NO: 82; L Pay is where is a binding to the antigen binding protein; and n is an integer from 2-5. In some modalities, the conjugates have the following structure: Ab-[L-Pay]n where: Ab is a MET x MET bispecific antigen-binding protein comprising the D1-HCVR amino acid sequence of SEQ ID NO: 58 and the D2-HCVR amino acid sequence of SEQ ID NO: 82; L Pay is >A where * is a binding antigen binding protein; and n is an integer from 2-5. In some modalities, the conjugates have the following structure: Ab-[L-Pay]n where: Ab is a MET x MET bispecific antigen-binding protein comprising the D1-HCVR amino acid sequence of SEQ ID NO: 58 and the D2-HCVR amino acid sequence of SEQ ID NO: 82; L Pay is or wherein 5 is a binding to the antigen binding protein; and n is an integer from 2-5. In some modalities, the conjugates have the following structure: Ab-[L-Pay]nen where: Ab is a MET x MET bispecific antigen-binding protein comprising the D1-HCVR amino acid sequence of SEQ ID NO: 58 and the D2-HCVR amino acid sequence of SEQ ID NO: 82; L Pay is ΜΛ / t / ZUZ I / UO0400 where * is a binding to antigen binding protein; and n is an integer from 2-5. In some modalities, the conjugates have the following structure: Ab-[L-Pay]n where: Ab is a MET x MET bispecific antigen-binding protein comprising the D1-HCVR amino acid sequence of SEQ ID NO: 18 and the D2-HCVR amino acid sequence of SEQ ID NO: 82; L Pay is >A where * is a binding antigen binding protein; and n is an integer from 2-5. In some modalities, the conjugates have the following structure: Ab-[L-Pay]nen where: Ab is a MET x MET bispecific antigen-binding protein comprising the D1-HCVR amino acid sequence of SEQ ID NO: 18 and the D2-HCVR amino acid sequence of SEQ ID NO: 82; L Pay is EITHER M A / E / ZUZ I / UOO4OO where is a binding to antigen binding protein; and n is an integer from 2-5. In some modalities, the conjugates have the following structure: Ab-[L-Pay]n where: Ab is a MET x MET bispecific antigen-binding protein comprising the D1-HCVR amino acid sequence of SEQ ID NO: 18 and the D2-HCVR amino acid sequence of SEQ ID NO: 82; L Pay is >A where * is a binding antigen binding protein; and n is an integer from 2-5. In some modalities, the conjugates have the following structure: Ab-[L-Pay]n where: Ab is a MET x MET bispecific antigen-binding protein comprising the D1-HCVR amino acid sequence of SEQ ID NO: 18 and the D2-HCVR amino acid sequence of SEQ ID NO: 82; L Pay is ί>Αwhere * is a binding to the antigen binding protein; and n is an integer from 2-5. Antibody-drug conjugates useful herein can be prepared using conjugation conditions known to those skilled in the art (see, for example, Doronina et al., Nature Biotechnology 2003, 21,7, 778, which is incorporated herein by reference in its entirety). In some embodiments, an anti-MET antibody or a MET x MET bispecific antigen-binding protein antibody drug conjugate is prepared by contacting an anti-MET antibody or a MET x MET bispecific antigen-binding protein described in present disclosure with a compound comprising the desired linker and cytotoxic agent, wherein said linker possesses a moiety that is reactive with the antibody or antigen-binding protein, for example, at the desired residue of the antibody or antigen-binding protein . In some embodiments, processes for preparing an antibody-drug conjugate useful in accordance with the methods provided herein comprise contacting an anti-MET antibody or a MET x MET bispecific antigen-binding protein described herein with a compound having the following formula A1: A1y dilute me watery. In some embodiments, the compound of formula A1 is present in stoichiometric excess. In some embodiments, the compound of formula A1 is present in a 5-6 fold stoichiometric excess. In some embodiments, the aqueous diluent comprises HEPES. In some embodiments, the aqueous diluent comprises DMA. In some embodiments, the compound of formula A1 is a compound of formula A2 or A3: ΜΛ / t / ZUZ I / UOO4OO In some embodiments, the compound of formula A2 or A3 is stereometrically pure. In some embodiments, the compound of formula A1 comprises a compound of formula A2 or A3, wherein the compound of A2 or A3 is present in greater than 50% diastereomeric excess. In certain embodiments, the diastereomeric excess is greater than 70%. In certain embodiments, the diastereomeric excess is greater than 90%. In certain embodiments, the diastereomeric excess is greater than 95%. The term "diastereoisomeric excess" refers to the difference between the mole fraction of the desired single diastereoisomer as compared to the remaining diastereoisomers in a composition. The diastereomeric excess is calculated as follows: (amount of individual diastereoisomer) (amount of other diastereomers) / 1. For example, a composition containing 90% of 1 and 10% of 2, 3, 4 or a mixture of these has a diastereomeric excess of 80% [(90-10) / 1]. A composition containing 95% of 1 and 5% of 2, 3, 4 or a mixture of these has a diastereomeric excess of 90% [(95-5) / 1]. A composition containing 99% of 1 and 1% of 2, 3, 4 or a mixture of these has a diastereomeric excess of 98% [(99-1) / 1]. The diastereomeric excess can be similarly calculated for any of 1,2, 3, or 4. In some embodiments, the compound of formula A1 is prepared by contacting a compound of Formula (a): with a compound of Formula (b) Or (b) in the presence of silica gel and diluent. In some embodiments, the diluent comprises an organic solvent and water. Also provided herein is the product prepared by the process of: (i) contacting a compound of Formula (a): with a compound of Formula (b): (b) in the presence of silica gel and diluent to synthesize an intermediate; and (ii) contacting an anti-MET antibody or a MET x MET bispecific antigen-binding protein described herein with the aqueous intermediate and diluent. In some embodiments, provided herein are processes for preparing an antibody-drug conjugate comprising contacting an anti-MET antibody or a MET x MET bispecific antigen-binding protein described herein with a compound having the following formula B: ΜΛ / t / ZUZ I / UOÓ4OÓ where LG is a leaving group and an aqueous solvent. In some embodiments, the compound of formula B is present in stoichiometric excess. In some embodiments, the compound of formula B is present in a 5-6 fold stoichiometric excess. In some embodiments, the aqueous diluent comprises HEPES. In some embodiments, the aqueous diluent comprises DMA. In some embodiments, the -C(O)-LG is an ester, eg, NHS or trifluorophenyl ester. In some embodiments, the compound of formula B is a compound of formula B1: In some embodiments, the compound of formula B1 is prepared by contacting a compound of formula C: C with N-hydroxysuccinimide (NHS), a peptide coupling reagent, and an organic diluent. Suitable peptide coupling reagents include those that activate, ie, supply reactive carboxylic acid moieties for reaction with a nucleophile. In certain embodiments, the peptide coupling reagent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDO) hydrochloride. In some embodiments, the organic solvent is dichloromethane. In some embodiments, the compound of formula C is prepared by contacting a compound of formula D: with adipic acid, a peptide coupling agent and an organic solvent. In certain embodiments, the peptide coupling agent is 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ). In certain embodiments, the organic solvent comprises dichloromethane. Compound D can be prepared as described in WO2014 / 145090. Epitope mapping and related technologies The antibody-binding epitope and antigen-binding domains may consist of a single contiguous sequence of 3 or more (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) amino acids of a MET protein. Alternatively, the relevant epitope may consist of a plurality of non-contiguous amino acids (or amino acid sequences) from METs. In some embodiments, the epitope is located in or near the ligand-binding domain of MET. In other embodiments, the epitope is located outside the MET ligand-binding domain, for example, at a site on the MET surface where an antibody, when bound to such an epitope, does not interfere with the binding of MET. HGF to MET. As described elsewhere in this disclosure, the individual antigen-binding domains (D1 and D2) of MET x MET bispecific antigen-binding molecules can bind to distinct, non-overlapping or partially overlapping epitopes, each other. As used herein, partially overlapping epitopes means that the first and second epitopes share less than 5, less than 4, less than 3, or only one common amino acid as determined by any epitope mapping methodology known in the art. technique (eg, X-ray crystallography, alanine scanning mutagenesis, hydrogen / deuterium exchange [HDX], domain exchange, etc.). Domains D1 and D2 may not be competitive with each other. For example, in certain embodiments, binding of a D1 domain of a particular MET x MET bispecific antigen-binding molecule to its epitope on MET does not (or only minimally) inhibit the binding of the D2 domain of the antigen-binding molecule. MET x MET bispecific to its epitope on MET. Due to the non-overlapping (or at most partially overlapping) nature of the respective epitopes of the D1 and D2 components, MET x MET bispecific antigen-binding molecules can bind to a single MET molecule on the cell surface. Various techniques known to those skilled in the art can be used to determine the epitope on MET with which the antibodies and antigen-binding domains useful herein interact. Illustrative techniques that can be used to determine an epitope or binding domain of a particular antibody or antigen-binding domain include, for example, point mutagenesis (eg, alanine scanning mutagenesis, arginine scanning mutagenesis, etc.), peptide blot analysis (Reineke, 2004, Methods Mol Biol 248:443-463), protease protection and peptide cleavage analysis. In addition, methods such as epitope cleavage, epitope extraction and chemical modification of antigens can be employed (Tomer, 2000, Protein Science 9:487496). Another method that can be used to identify the amino acids within a polypeptide with which an antibody interacts is hydrogen / deuterium exchange detected by mass spectrometry. Broadly speaking, the deuterium / hydrogen exchange method involves deuterium labeling of the protein of interest, followed by binding of the antibody to the deuterium labeled protein. The protein / antibody complex is then transferred to water to allow hydrogen-deuterium exchange to occur at all residues except antibody-protected residues (which remain deuterium-labeled). After dissociation of the antibody, the target protein is subjected to protease cleavage and mass spectrometry analysis, thereby revealing deuterium-labeled residues that correspond to the specific amino acids with which the antibody interacts. See, for example, Ehring (1999) Analytical Biochemistry 267(2):252-259; Engen and Smith (2001) Anal. Chem. 73:256A265A. X-ray crystal structure analysis can also be used to identify the amino acids within a polypeptide with which an antibody interacts. In accordance with the methods provided herein, anti-MET antibodies (including bispecific antibodies) that bind to the same epitope as any of the illustrative specific antibodies or antigen-binding domains described herein ( for example, antibodies comprising any of the amino acid sequences as set forth in Table 1 of the present disclosure). Likewise, the present disclosure also provides anti-MET antibodies that compete for binding to MET with any of the illustrative specific antibodies described herein (for example, antibodies comprising any of the amino acid sequences as set forth in Table 1 in the present description). In some embodiments, the human MET epitope to which anti-MET antibodies bind comprises amino acids 192-204, amino acids 305-315, and / or amino acids 421-455 of SEQ ID NO: 155. In some embodiments, the first human MET epitope comprises amino acids 192-204 of SEQ ID NO: 155; and the second human MET epitope comprises amino acids 305-315 and 421-455 of SEQ ID NO: 155. Whether an antibody binds to the same epitope as, or competes for binding with, a reference anti-MET antibody can be readily determined using routine methods known in the art and exemplified herein. For example, to determine whether a test antibody binds to the same epitope as a reference anti-MET antibody provided herein, the reference antibody is allowed to bind to a MET protein. Next, the ability of a test antibody to bind to the MET molecule is assessed. If the test antibody is able to bind MET after saturation binding with the reference anti-MET antibody, it can be concluded that the test antibody binds a different epitope than the reference anti-MET antibody. Besides, ΜΛΖ t / ZUZ IZUO0400 if the test antibody cannot bind to the MET molecule after saturation binding with the reference anti-MET antibody, then the test antibody can bind to the same epitope as the epitope bound by the anti-MET antibody -MET reference. Additional routine experimentation (eg, binding and peptide mutation analysis) can be carried out to confirm whether the observed lack of binding of the test antibody is indeed due to binding to the same epitope as the reference antibody or whether steric blockade (or other phenomenon) is responsible for the observed non-binding. Experiments of this type can be performed using ELISA, RIA, Biacore, flow cytometry, or any other quantitative or qualitative antibody binding assay available in the art. According to certain embodiments, two antibodies bind to the same (or overlapping) epitope if, for example, a 1-, 5-, 10-, 20-, or 100-fold excess of one antibody inhibits the binding of the other by at least 50%, but preferably 75%, 90% or even 99%, as measured in a competitive binding assay (see, for example, Junghans et al., Cancer Res. 1990:50:1495-1502). Alternatively, two antibodies are considered to bind to the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies are considered to have overlapping epitopes if only a subset of the amino acid mutations that reduce or eliminate the binding of one antibody reduce or eliminate the binding of the other. To determine whether an antibody competes for binding (or cross-competes for binding) with a reference anti-MET antibody, the binding methodology described above is performed in two orientations: In a first orientation, the antibody is allowed to reference binds to a MET protein under saturation conditions followed by assessment of the binding of the test antibody to the MET molecule. In a second orientation, the test antibody is allowed to bind to a MET molecule under saturation conditions followed by an assessment of the binding of the reference antibody to the MET molecule. If, in both orientations, only the first antibody (in saturation) is capable of binding to the MET molecule, then it is concluded that the test antibody and the reference antibody compete for binding to MET. As will be appreciated by one skilled in the art, an antibody that competes for binding to a reference antibody does not necessarily bind to the same epitope as the reference antibody, but may spherically block the reference antibody from binding to an epitope. adjacent or overlapping. Preparation of human antibodies Anti-MET antibodies and MET x MET bispecific antibodies useful according to the methods provided herein may be fully human antibodies. Methods for generating monoclonal antibodies, including fully human monoclonal antibodies, are known in the art. Any such known methods can be used in the context of the present disclosure to produce human antibodies that specifically bind to human MET. Using the VELOCIMMUNE™ technology, for example, or any other similar method known to generate fully human monoclonal antibodies, high affinity chimeric antibodies to METs having a human variable region and a mouse constant region are initially isolated. As in the experimental section below, antibodies are characterized and screened for desirable characteristics, including affinity, ligand-blocking activity, selectivity, epitope, and so on. If necessary, the mouse constant regions are replaced with a desired human constant region, eg, modified or wild-type IgG1 or IgG4, to generate a fully human anti-MET antibody. While the selected constant region may vary according to its specific use, antigen-binding characteristics with high affinity and target specificity reside in the variable region. In certain instances, fully human anti-MET antibodies are isolated directly from antigen-positive B cells. bioequivalent Anti-MET antibodies and antibody fragments useful in accordance with the methods provided herein encompass proteins that have amino acid sequences that vary from those of the disclosed antibodies, but retain the ability to bind MET. Such antibody variants and antibody fragments comprise one or more amino acid additions, deletions, or substitutions compared to the parental sequence, but exhibit biological activity that is essentially equivalent to that of the disclosed antibodies. Similarly, the DNA sequences encoding anti-MET antibodies of the present disclosure encompass sequences that comprise one or more nucleotide additions, deletions, or substitutions compared to the described sequence, but that encode an anti-MET antibody or antibody fragment. which is essentially bioequivalent to an anti-MET antibody or antibody fragment of the disclosure. Examples of such variant amino acid and DNA sequences are discussed above. Two antigen-binding proteins, or antibodies, are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and degree of absorption do not show a significant difference when administered at the same molar dose under similar experimental conditions, either in single or multiple doses. Some antibodies will be considered equivalent or pharmaceutical alternatives if they are equivalent in the degree of their absorption but not in their rate of absorption and may still be considered bioequivalent because such differences in rate of absorption are intentional and reflected on the label, they are not essential for obtaining effective body concentrations of drugs in, for example, chronic use, and are considered medically insignificant for the particular drug product studied. In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically significant differences in their safety, purity, and potency. In one embodiment, two antigen-binding proteins are bioequivalent if a patient can be switched one or more times between the reference product and the biologic without an expected increase in the risk of adverse effects, including a clinically significant change in the immunogenicity, or decreased efficacy, compared to continued therapy without such a change. In one embodiment, two antigen-binding proteins are bioequivalent if they both act by a common mechanism(s) of action for the condition(s) of use, to the extent such mechanisms are known. Bioequivalence can be demonstrated by in vivo and in vitro methods. The measurements of M A / IZ / ZUZI / UOÓ4OÓ bioequivalence includes, for example, (a) an in vivo test in humans or other mammals, in which the concentration of the antibody or its metabolites is measured in blood, plasma, serum or other biological fluid in function of time; (b) an in vitro test that has been correlated with and is reasonably predictive of in vivo human bioavailability data; (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the antibody (or its target) is measured as a function of time; and (d) in a well-controlled clinical trial that establishes the safety, efficacy, or bioavailability or bioequivalence of an antibody. Bioequivalent variants of the anti-MET antibodies provided herein can be constructed, for example, by making multiple residue or sequence substitutions or terminal deletion or internal residues or sequences that are not required for biological activity. For example, cysteine ​​residues that are not essential for biological activity can be removed or replaced with other amino acids to avoid unnecessary or incorrect intramolecular disulfide bond formation upon renaturation. In other contexts, bioequivalent antibodies can include variants of anti-MET antibodies that comprise amino acid changes, which modify the glycosylation characteristics of the antibodies, eg, mutations that abolish or remove glycosylation. Species selectivity and cross-species reactivity The present disclosure, in accordance with certain embodiments, provides anti-MET antibodies (and antigen-binding molecules comprising anti-MET antigen-binding domains) that bind human MET but not MET from other species, and are useful. in the treatment of ocular cancers such as uveal melanoma, orbital lymphoma, retinoblastoma and medulloepithelioma. The present disclosure also includes anti-MET antibodies (and antigen-binding molecules comprising anti-MET antigen-binding domains) that bind to human MET and MET from one or more non-human species, and are useful in the treatment of ocular cancers such as uveal melanoma, orbital lymphoma, retinoblastoma and medulloepithelioma. For example, anti-MET antibodies antigen-binding molecules can bind human MET and may or may not bind, as the case may be, one or more mouse, rat, guinea pig, hamster, gerbil, pig, cat, or other METs. , dog, rabbit, goat, sheep, cow, horse, camel, crab-eating macaque, marmoset, rhesus or chimpanzee. Anti-MET antibodies and antigen-binding molecules which specifically bind to human MET and crab-eating macaque (eg, Macaca fascicularis) MET are provided, according to certain illustrative embodiments. Other anti-MET antibodies and antigen-binding molecules bind human MET but do not bind, or bind only weakly, to crab-eating macaque MET. Multispecific antibodies As described elsewhere in the present disclosure, bispecific antigen-binding molecules comprising two different antigen-binding domains are useful according to the present disclosure, wherein the first antigen-binding domain (D1) binds to a first epitope on MET and wherein the second antigen-binding domain (D2) binds to a second epitope on MET. In certain embodiments, the first and second epitopes on METs to which the D1 and D2 domains bind are distinct, do not overlap, or partially overlap. According to this aspect, the D1 domain can ΜΛ / t / ZUZ I / UOÓ4OÓ comprise any of the HCVR / LCVR or CDR amino acid sequences as set forth in Table 1 herein, and the D2 domain may comprise any other of the HCVR / LCVR amino acid sequences or CDR as set forth in Table 1 of the present disclosure (provided that the binding specificity of the D1 domain is different from the binding specificity of the D2 domain, and / or the antigen-binding protein from which D1 was derived is not compete for binding to MET with the antigen-binding protein from which D2 was derived). In some embodiments, the human MET epitope to which anti-MET antibodies bind comprises amino acids 192-204, amino acids 305-315, and / or amino acids 421-455 of SEQ ID NO: 155. In some embodiments, the first human MET epitope comprises amino acids 192-204 of SEQ ID NO: 155; and the second human MET epitope comprises amino acids 305-315 and 421-455 of SEQ ID NO: 155. According to a separate aspect, conventional bispecific antibodies are also provided as useful herein wherein one arm of the bispecific antibody binds to an epitope on human MET and the other arm of the bispecific antibody binds to a second antigen other than MET. The MET binding arm may comprise any of the HCVR / LCVR or CDR amino acid sequences as set forth in Table 1 herein. In certain embodiments, the MET-binding arm binds to human MET and blocks the binding of HGF to MET. In other embodiments, the MET-binding arm binds human MET but does not block HGF from binding to MET. An illustrative bispecific antibody format that can be used in the context of the present disclosure involves the use of a first Ch3 immunoglobulin (Ig) domain and a second Ch3 Ig domain, wherein the first and second Ch3 Ig domains differ from each other. by at least one amino acid, and wherein the at least one amino acid difference decreases the binding of the bispecific antibody to Protein A as compared to a bispecific antibody lacking the amino acid difference. In one embodiment, the first Ch3 Ig domain binds Protein A and the second Ch3 Ig domain contains a mutation that decreases or abolishes Protein A binding such as an H95R modification (based on IMGT exon numbering; H435R according to EU numbering). The second Ch3 can also comprise a modification Y96F (according to IMGT; Y436F according to EU). Other modifications that can be found within the second Ch3 include: D16E, L18M, N44S, K52N, V57M and V82I (according to IMGT; D356E, L358M, N384S, K392N, V397M and V422I according to EU) in the case of lgG1 antibodies; N44S, K52N and V82I (IMGT; EU N384S, K392N and V422I) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q and V422I according to EU) in the case of lgG4 antibodies. Variations in the bispecific antibody format described above are contemplated within the scope of the present disclosure. Other illustrative bispecific formats that may be used in the context of the present disclosure include, without limitation, for example, scFv-based or diabody bispecific formats, IgGscFv fusions, Ig dual variable domain (DVD), quadroma, buttonhole, knobs -into-holes, common light chain (for example, common light chain with buttonhole, etc.), CrossMab, CrossFab, SEED, leucine zipper, Duobody, lgG1 / lgG2, Dual Action Fab (DAF)- lgG, and Mab2 bispecific formats (see, eg, Klein et al. 2012, mAbs 4:6,1-11, and references cited therein, for a review of earlier formats). Bispecific antibodies can also be constructed through the use of peptide / nucleic acid conjugation, for example, where unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates that then self-assemble into multimeric complexes with defined composition, valence and geometry. (See, eg, Kazane et al., J. Am. Chem. Soc. [Epub: Dio. 4, 2012\). Therapeutic formulation and administration Provided herein are pharmaceutical compositions comprising the anti-MET antibodies or MET x MET bispecific antigen binding molecules useful in accordance with the methods described herein. Pharmaceutical compositions can be formulated with suitable carriers, excipients, and other agents that provide improved transfer, delivery, tolerability, and the like. In some aspects, pharmaceutical compositions comprising anti-MET antibodies or MET x MET bispecific antigen binding molecules are formulated for administration to the eye to treat eye cancer, such as uveal melanoma, orbital lymphoma, retinoblastoma or medulloepithelioma. Provided herein are methods in which anti-MET antibodies or MET x MET bispecific antigen binding molecules that are administered to the patient are contained in a pharmaceutical formulation. The pharmaceutical formulation may comprise the anti-MET antibody or the MET x MET bispecific antigen binding molecule together with at least one inactive ingredient such as, for example, a pharmaceutically acceptable carrier. Other agents may be incorporated into the pharmaceutical composition to provide improved transfer, administration, tolerability, and the like. The term "pharmaceutically acceptable" means approved by a regulatory agency of the Public Administration or state government or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia, for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the antibody is administered. A multitude of suitable formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15aed, Mack Publishing Company, Easton, Pennsylvania, 1975), in particular Chapter 87 of this by Blaug, Seymour. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid-containing vesicles (cationic or anionic) (such as LIPOFECTIN.TM.), DNA conjugates, anhydrous absorption pastes, emulsions of oil-in-water and water-in-oil, carbowax emulsions (polyethylene glycols of various molecular weights), semisolid gels, and semisolid mixtures containing carbowax. Any of the above mixtures may be appropriate in the context of the methods of the present disclosure, provided that the anti-MET antibody or MET x MET bispecific antigen-binding molecule is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Powel et al. PDA (1998) J Pharm Sci Technol. 52: 238-311 and citations thereto for additional information related to excipients and carriers well known to pharmaceutical chemists. Pharmaceutical formulations useful for administration by injection in the context of M A / E / ZUZ I / UOO4OO present disclosure can be prepared by dissolving, suspending or emulsifying an anti-MET antibody or a MET x MET bispecific antigen binding molecule in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, isotonic solution containing glucose and other auxiliary agents, etc., which can be used in combination with an appropriate solubilizing agent such as alcohol (for example, ethanol), a polyol (eg, propylene glycol, polyethylene glycol), a nonionic surfactant [eg, polysorbate 80, HCO-50 (polyoxyethylene adduct (50 mol) of hydrogenated castor oil)], and so on. As the oily medium, for example, sesame oil, soybean oil, etc. can be used, which can be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared can be filled into a suitable ampoule if desired. Modes of administration The anti-MET antibodies and the MET x MET bispecific antigen binding molecules (or the pharmaceutical formulation comprising the anti-MET antibodies and the MET x MET bispecific antigen binding molecules) can be administered to the patient by any system of delivery and / or known method of administration. In certain embodiments, anti-MET antibodies and MET x MET bispecific antigen-binding molecules are administered to the patient by ocular, infraocular, intravitreal, or subconjunctival injection. In other embodiments, the anti-MET antibodies and MET x MET bispecific antigen-binding molecules may be administered to the patient by topical administration, for example, by eye drops or other liquid, gel, ointment, or fluid containing the anti-MET antibodies. anti-MET antibodies and MET x MET bispecific antigen-binding molecules and can be applied directly to the eye. Other possible routes of administration include, for example, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral. Combination therapies and formulations Provided herein are therapeutic compositions and formulations comprising any of the anti-MET antibodies and MET x MET bispecific antigen binding molecules described herein in combination with one or more additional therapeutically active components, and methods of treatment that comprise administering such combinations to subjects in need thereof. Anti-MET antibodies and MET x MET bispecific antigen-binding molecules may be co-formulated and / or administered in combination with one or more additional therapeutically active components selected from the group consisting of: a MET antagonist (e.g., an antibody anti-MET [for example, onartuzumab, emibetuzumab, telisotuzumab, SAIT301, ARGX-111, Sym015, HuMaxcMet, CE-355621, and H4H14639D] or small molecule MET inhibitor), an EGFR antagonist (for example, an anti-EGFR antibody (for example, cetuximab or panitumumab] or small molecule EGFR inhibitor [for example, gefitinib or erlotinib]), an antagonist of another EGFR family member such as Her2 / ErbB2, ErbB3, or ErbB4 (for example, anti-ErbB2 [ for example, trastuzumab or T-DM1 {KADCYLA®}], anti-ErbB3 or anti-ErbB4 antibody, or small molecule inhibitor of ErbB2, ErbB3, or ErbB4 activity), an EGFRvIll antagonist (for example, an anti-EGFRvIII antibody ), an IGF1R antagonist (for MA / t / ZUZ I / UO0400 example, an anti-IGF1R antibody), a B-raf inhibitor (for example, vemurafenib, sorafenib, GDC-0879, PLX-4720), a PDGFR-α inhibitor (for example, an anti-PDGFR-α antibody), a PDGFR-β inhibitor (for example, an anti-PDGFR-β antibody or a small molecule kinase inhibitor such as imatinib mesylate or sunitinib malate), an inhibitor of PDGF ligand (eg, anti-PDGF-A, -B, -C or -D antibody, aptamer, siRNA, etc.), a VEGF antagonist (eg, a VEGF-Trap such as aflibercept, see, eg, US 7,087,411 (also referred to herein as a VEGF inhibitor fusion protein), anti-VEGF antibody (eg, bevacizumab), a VEGF receptor small molecule kinase inhibitor (eg, sunitinib, sorafenib, or pazopanib )), a DLL4 antagonist (for example, an anti-DLL4 antibody described in US 2009 / 0142354 such as REGN421), an Ang2 antagonist (for example, an anti-Ang2 antibody described in US 2011 / 0027286 as H1H685P), a FOLH1 antagonist (for example, an anti-FOLH1 antibody), a STEAP1 or STEAP2 antagonist (for example, an anti-STEAP1 antibody or an anti-STEAP2 antibody), a TMPRSS2 antagonist (for example, an anti- TMPRSS2), an MSLN antagonist (eg, an anti-MSLN antibody), a CA9 antagonist (eg, an anti-CA9 antibody), a uroplakin antagonist (eg, an anti-uroplakin [eg, anti-UPK3A] antibody), a MUC16 antagonist (for example, an anti-MUC16 antibody), a Tn antigen antagonist (for example, an anti-Tn antibody), a CLEC12A antagonist (for example, an anti-CLEC12A antibody), a TNFRSF17 antagonist (for example, an anti-TNFRSF17 antibody), an LGR5 antagonist (for example, an anti-LGR5 antibody), a monovalent CD20 antagonist (for example, a monovalent anti-CD20 antibody such as rituximab), a bispecific CD20 x CD3, a PD-1 blocking agent (eg, an anti-PD-1 antibody such as pembrolizumab or nivolumab), etc. Other agents that may be beneficially administered in combination with the antibodies provided herein include, for example, tamoxifen, aromatase inhibitors, and cytokine inhibitors, including small molecule cytokine inhibitors and antibodies that bind to cytokines such such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-11, IL-12, IL-13, IL-17, IL -18 or their respective receivers. Illustratively, a PD-1 inhibitor such as an anti-PD-1 antibody can be combined with an anti-Met antibody-drug conjugate as described herein. The target patient population specifically includes those patients with tumors that overexpress the cMet mutation, such as a patient with a c-Met-expressing uveal melanoma or a c-Met-expressing non-small cell lung cancer. Provided herein are therapeutic compositions and formulations comprising any of the anti-MET antibodies and MET x MET bispecific antigen binding molecules described herein in combination with one or more chemotherapeutic agents. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (Cytoxan™); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, colophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterin, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycins, actinomycin, autramycin, azaserin, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophyllin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxyno-L-norleucin, doxorubicin, epidirubicin, esorubicin, idarubicin, marcelomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folleo acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purin analogues such as fludarabine, 6-mercaptopurine, thiamiprine, tloguanine; pyrimidine analogues such as ancitabine, azacltidine, 6-azauridine, carmofur, cytarabin, dideoxyuridine, doxlfluridine, enocitabin, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid booster such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisanthrene; edatraxate; defofamine; demecolcine; Diaziquone; elforntina; elliptinium acetate; ethoglycide; gallium nitrate; hydroxylurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet; pyrarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK™; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2-trichlorothiethylamin; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxanes, eg, paclitaxel (Taxol™, Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (Taxotere™; Aventis Antony, France); chlorambucil; gemeitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbina; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; RFS 2000 topoisomerase inhibitor; difluoromethylornithine (DMFO); Retinoic acid; esperamycins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing. Also included in this definition are anti-hormonal agents that act to regulate or inhibit hormonal action in tumors such as antiestrogens, including for example, tamoxifen, raloxifene, 4(5)-imidazoles aromatase inhibitors, 4-hydroxytamoxifen, trioxifen, keoxlfene, LY 117018, onapristone and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing. Anti-MET antibodies and MET x MET bispecific antigen-binding molecules can also be administered and / or co-formulated with antivirals, antibiotics, analgesics, corticosteroids, steroids, oxygen, antioxidants, COX inhibitors, cardioprotectants, metal chelators, IFNs -gamma and / or NSAIDs. The additional therapeutically active component(s), eg, any of the agents listed above or derivatives thereof, may be administered just before, at the same time, or shortly after administration of an anti-MET antibody or MET bispecific antigen-binding molecule. x ΜΛ / t / ZUZ I / UO0400 MET; (For the purposes of the present description, such administration regimens are considered the administration of an antibody in combination with an additional therapeutically active component). The present disclosure includes pharmaceutical compositions in which an anti-MET antibody or bispecific antigen binding molecule is formulated together with one or more additional therapeutically active components as described elsewhere in the present disclosure. Administration regimes According to certain embodiments, multiple doses of an anti-MET antibody or MET x MET bispecific antigen-binding molecule (or a pharmaceutical composition comprising an anti-MET antibody or MET x MET bispecific antigen-binding molecule combination and any of the additional therapeutically active agents mentioned herein) may be administered to a subject over a defined time course. Methods according to this aspect comprise sequentially administering to a subject multiple doses of an anti-MET antibody or MET x MET bispecific antigen binding molecule provided herein. As used herein, sequential administration means that each dose of the antibody is administered to the subject at a different point in time, for example, on different days separated by a predetermined interval (for example, hours, days, weeks, or months). ). The present disclosure includes methods comprising sequentially administering to the patient a single initial dose of an anti-MET antibody or MET x MET bispecific antigen-binding molecule, followed by one or more secondary doses of the anti-MET antibody or antigen-binding molecule. bispecific MET x MET, and optionally followed by one or more tertiary doses of anti-MET antibody or a bispecific MET x MET antigen-binding molecule. The terms initial dose, secondary doses, and tertiary doses refer to the temporal sequence of administration of the anti-MET antibody or MET x MET bispecific antigen-binding molecule. Thus, the starting dose is the dose given at the beginning of the treatment regimen (also called the baseline dose); secondary doses are the doses given after the initial dose; and the tertiary doses are the doses that are administered after the secondary doses. Initial, secondary, and tertiary doses may all contain the same amount of anti-MET antibody or MET x MET bispecific antigen-binding molecule, but may generally differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of antibody contained in the initial, secondary, and / or tertiary doses varies from one another (eg, adjusted up or down as appropriate) during the course of treatment. In certain modalities, two or more (eg, 2, 3, 4, or 5) doses are administered at the start of the treatment regimen as a loading dose followed by subsequent doses that are administered on a less frequent basis (eg, loading doses). maintenance). Diagnostic Uses of Antibodies The anti-MET antibody or MET x MET bispecific antigen binding molecule of the present disclosure can further be used to detect and / or measure MET or MET-expressing cells in a sample, eg, for diagnostic purposes. For example, an anti-MET antibody, or fragment thereof, can be used to diagnose a condition or disease characterized by aberrant expression (for ΜΛ / t / ZUZ I / UOÓ4OÓ example, overexpression, underexpression, lack of expression, etc.) of MET. Illustrative diagnostic assays for MET may comprise, for example, contacting a sample, obtained from a patient, with an anti-MET antibody or a MET x MET bispecific antigen-binding molecule wherein the anti-MET antibody is labeled with a detectable label or reporter molecule. Alternatively, an anti-MET antibody or an unlabeled MET x MET bispecific antigen binding molecule can be used in diagnostic applications in combination with a detectably labeled secondary antibody. The detectable marker or reporter molecule can be a radioisotope, such as 3H14C, 32P, 35S, or 1251; a fluorescent or chemiluminescent moiety such as fluorescein or rhodamine; or an enzyme such as alkaline phosphatase, deta-galactosidase, horseradish peroxidase or luciferase. Illustrative specific assays that can be used to detect or measure MET in a sample include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immuno-PET (eg, 89Zr, 64Cu, etc), and cell sorting. fluorescence activated (FACS). Samples that can be used in MET diagnostic assays in accordance with the present disclosure include any tissue or fluid sample that can be obtained from a patient, particularly tissue or fluid found in the eye or eye socket. Generally, MET levels in a particular sample obtained from a healthy patient (eg, a patient not suffering from a disease or disorder associated with abnormal MET levels or activity) will be measured to initially establish a baseline or standard MET level. This initial MET level can then be compared to MET levels measured in samples obtained from individuals suspected of having a MET-related disease or disorder. examples The following examples are intended to provide those skilled in the art with a complete description of how to make and use the methods and compositions provided herein, and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure accuracy with respect to the numbers used (eg amounts, temperature, etc.) but some experimental errors and deviations must be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Example 1. Generation of anti-MET antibodies Anti-MET antibodies were obtained by immunizing a genetically engineered mouse comprising DNA encoding variable regions of the human immunoglobulin kappa light and heavy chain with an immunogen comprising the extracellular domain of recombinant human MET fused to human Fe (R&D Systems , Catalog #358-MT, Minneapolis, MN). The mice used for the immunizations express a universal light chain. That is, the antibodies produced in this mouse have different heavy chain variable regions but essentially identical light chain variable domains. The antibody immune response was monitored by a specific immunoassay for MET. When a desired immune response was achieved, the splenocytes were harvested and fused with mouse myeloma cells to preserve their viability and form hybridoma cell lines. Hybridoma cell lines were screened and selected to identify cell lines that produce MET-specific antibodies. A number of chimeric anti-MET antibodies (ie, antibodies possessing human variable domains and mouse constant domains) were obtained using this technique. In addition, several fully human anti-MET antibodies were isolated directly from antigen-positive B cells without fusion with myeloma cells, as described in US 2007 / 0280945A1. Certain biological properties of illustrative anti-MET antibodies generated according to the methods of this Example, and bispecific antibodies constructed therefrom, are described in detail in the Examples set forth below. Example 2. Amino Acid and Nucleic Acid Sequences of the Variable Regions of the Heavy and Light Chain Table 1 sets forth the amino acid sequence identifiers of the heavy and light chain variable regions and CDRs of selected anti-MET antibodies described herein. (As indicated above, all of the antibodies generated in Example 1 possess the same light chain variable region and thus the same light chain CDR sequences as well). The corresponding nucleic acid sequence identifiers are set forth in Table 2. M A / I / UOÓ4OÓ Table 1: Amino Acid Sequence Identifiers SEQ ID NO: Antibody Designation HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 H4H13290P2 2 4 6 8 138 140 142 144 H4H13291P2 10 12 14 16 138 140 142 144 H4H13295P2 18 20 22 24 138 140 142 144 H4H13299P2 26 28 30 32 138 140 142 144 H4H13300P2 34 36 38 40 138 140 142 144 H4H13301P2 42 44 46 48 138 140 142 144 H4H13302P2 50 52 54 56 138 140 142 144 H4H1 3306P2 58 60 62 64 138 140 142 144 H4H13309P2 66 68 70 72 138 140 142 144 H4H13311P2 74 76 78 80 138 140 142 144 H4H13312P2 82 84 86 88 138 140 142 144 SEQ ID NO: Antibody Designation HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 H4H13313P2 90 92 94 96 138 140 142 144 H4H13316P2 98 100 102 104 138 140 142 144 H4H1331 8P2 106 108 110 112 138 140 142 144 H4H13319P2 114 116 118 120 138 140 142 144 H4H13325P2 122 124 126 128 138 140 142 144 H4H13331P2 130 132 134 136 138 140 142 144 ΜΛ / t / ZUZ I / UO0400 Table 2: Nucleic Acid Sequence Identifiers SEQ ID NO: Antibody Designation HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 H4H13290P2 1 3 5 7 137 139 141 143 H4H13291P2 9 11 13 15 137 139 141 143 H4H13295P2 17 1 9 21 23 137 139 141 143 H4H13299P2 25 27 29 31 137 139 141 143 H4H13300P2 33 35 37 39 137 139 141 143 H4H13301P2 41 43 45 47 137 139 141 143 H4H13302P2 49 51 53 55 137 139 141 143 H4H1 3306P2 57 59 61 63 137 139 141 143 H4H13309P2 65 67 69 71 137 139 141 143 H4H13311P2 73 75 77 79 137 139 141 143 H4H13312P2 81 83 85 87 137 139 141 143 H4H13313P2 89 91 93 95 137 139 141 143 H4H13316P2 97 99 101 103 13 7 139 141 143 H4H13318P2 105 107 109 111 137 139 141 143 H4H13319P2 113 115 117 119 137 139 141 143 H4H13325P2 121 123 125 127 137 139 141 143 H4H13331P2 129 131 133 135 137 139 141 143 Antibodies are typically referred to herein according to the following nomenclature: Fe prefix (eg H4H), followed by a numerical identifier (eg 13290, 13291, 13295, etc.), followed by a P2 suffix, as shown in Tables 1 and 2. Therefore, according to this nomenclature, an antibody may be referred to herein as, for example, Ή4Η13290Ρ2,” Ή4Η13291Ρ2,” Ή4Η13295Ρ2,” etc. The Fe prefixes in the antibody designations used herein indicate the particular isotype of the Fe region of the antibody, in particular, a Ή4Η antibody has an Fe of human lgG4, (all variable regions are fully human as indicated by the first H in the antibody designation). As will be appreciated by one skilled in the art, an antibody having a particular Fe isotype can be converted to an antibody with a different Fe isotype (for example, an antibody with a mouse IgG4 Fe can be converted to an antibody with a different Fe isotype). human lgG1, etc.), but in any case, the variable domains (including CDRs), which are indicated by the numerical identifiers shown in Tables 1 and 2, will be the same, and it is expected that the properties binding sites are identical or substantially similar regardless of the nature of the Fe domain. Example 3. Binding affinities derived from surface plasmon resonance and kinetic constants of human anti-MET monoclonal antibodies (monospecific) Binding affinities and kinetic constants of human anti-MET antibodies were determined by surface plasmon resonance (Biacore 4000 or T-200) at 37°C. The anti-Met antibodies tested in this example were bivalent monospecific binders of MET. Antibodies, expressed as human IgG4 (designated Ή4Η), were captured on a derivatized CM4 or CM5 Biacore sensor surface via amine coupling with a mouse monoclonal anti-human Fe antibody (GE, BR-1008-39). Various concentrations Met proteins, soluble monomeric Met.mmh (human (h); SEQ ID NO: 152; macaca fascicularis (mf) Met.mmh; SEQ ID NO: 154) or dimeric (hMet.mFc; SEQ ID NO: 153) they were injected onto the captured surface with anti-MET antibody at a flow rate of 30 or 50 pL / minute. The association of hMET.mmh or hMET.mFc to the captured monoclonal antibody was monitored for 4 or 5 min and dissociation was monitored in running buffer of hMET.mmh or hMET.mFc in HBS-ET (0.01 M HEPES pH 7.4, 0.15 M NaCI, 3 mM EDTA, 0.05% v / v surfactant P20) or PBS-P (0.01 M sodium phosphate pH 7.4, 0.15 M NaCI, 0.05% v / v surfactant P20) for 10 min. Kinetic association (ka) and dissociation (ko) rate constants were determined by fitting the real-time sensorgrams to a 1:1 binding model using Scrubber 2.0c curve-fitting software. The equilibrium binding dissociation constant (Kd) and dissociative half-life (t1 / 2) were calculated from the kinetic rate constants as: ^¢)1)=^,,^(^) = ^ Binding kinetic parameters for monospecific anti-Met antibodies for monomeric and dimeric Met protein are shown below in Table 3. ΜΛ / t / ZUZ I / UOÓ4OÓ Table 3: Biacore binding affinities of monospecific anti-MET mAbs to 37SC ΜΛ / t / ZUZ I / UOO4OO 37sC Binding / Antibody Capture Format Antibody Analyte ka (Ms-1) kd (s-1) KD (Molar) t1 / 2 (min) H4H13290P2 hMet.mmh 2.53E+05 8.03E-04 3.17E-09 14.4 hMET.mFc 6.15E+05 3.15E -04 5.13E-10 36.6 mfMet.mmh 1.23E+05 6.33E-04 5.16E-09 18.2 H4H13291P2 hMet.mmh 2.55E+04 2.38E-03 9.34E-08 4.8 hMET.mFc 3.33E+05 3. 39E- 04 1.02E-09 34 mfMet.mmh 3.70E+04 1.39E-03 3.76E-08 8.3 H4H13295P2 hMet.mmh 1.67E+04 5.40E-04 3.24E-08 21.4 hMET.mFc 2.28E+05 2.64 E-04 1.16E-09 43.8 mfMet.mmh 1.65E+04 9.79E-04 5.93E-08 11.8 H4H13299P2 hMet.mmh 9.10E+04 7.80E-04 8.57E-09 14.8 hMET.mFc 3.57E+05 3.14 E-04 8.78 E-10 36.8 mfMet.mmh 1.13E+05 8.84E-04 7.86E-09 13.1 H4H13300P2 hMet.mmh 3.35E+04 2.43E-03 7.25E-08 4.8 hMET.mFc 2.65E+05 2.95E-04 1 .12E -09 39.1 mfMet.mmh 5.13E+04 1.94E-03 3.77E-08 6.0 H4H13301P2 hMet.mmh 7.57E+04 6.22E-03 8.22 E-08 1.9 hMET.mFc 7.05E+05 1.14E-03 1.6 2E- 09 10.1 mfMet.mmh 6.85E+04 5.30E-03 7.74 E-08 2.2 H4H13302P2 hMet.mmh 5.24E+04 2.46E-03 4.70E-08 4.7 hMET.mFc 2.51 E+05 5.84E-04 2.3 3E-09 19.8 mfMet.mmh 3.56E+04 2.92E-03 8.20E-08 4.0 H4H13306P2 hMet.mmh 1.52E+05 1.66E-02 1.09E-07 0.7 hMET.mFc 1.21E+06 2.60E-03 2.15E- 09 4.4 mfMet.mmh 1.21E+06 3.11E-02 2.58E-08 0.4 H4H13309P2 hMet.mmh 9.20E+04 5.87E-04 6.38E-09 19.7 hMET.mFc 4.06E+05 2.67E-04 6.57E-10 4 3.3 mfMet .mmh 1.23E+05 6.33E-04 5.16E-09 18.2 H4H13311P2 hMet.mmh 4.48E+04 5.19E-03 1.16E-07 2.2 hMET.mFc 3.02E+05 4.68E-04 1.55E-09 24.7 mfMet. mmh 7.61 E+04 6.04E-03 7.94 E-08 1.9 H4H13312P2 hMet.mmh 7.19E+04 1.63E-02 2.27E-07 0.7 hMET.mFc 6.14E+05 1.71E-03 2.79 E-09 6.7 379C Binding / Antibody Capture Format Antibody Analyte ka (Ms-1) kd (s-1) KD (Molar) t1 / 2 (min) mfMet.mmh 1.47E+05 7.72E-03 5.24E-08 1.5 H4H13313P2 hMet.mmh 8.78E+04 5.70E -03 6.49E-08 2 hMET.mFc 7.50E+05 8.93E-04 1.19E-09 12.9 mfMet.mmh 5.10E+04 4.08E-03 8.00E-08 2.8 H4H13316P2 hMet.mmh 7.82E+04 1.51E - 03 1.93 E-08 7.6 hMET.mFc 2.93E+05 1.08E-04 3.67E-10 107.4 mfMet.mmh NB NB NB NB H4H13318P2 hMet.mmh 3.30E+04 2.92E-03 8.83 E-08 4 hMET.mF c 3.52 E+05 1.65E-04 4.67E-10 70.2 mfMet.mmh NB NB NB NB H4H13319P2 hMet.mmh 3.11E+04 2.38E-03 7.65E-08 4.9 hMET.mFc 3.82E+05 5.42E-04 1.42E- 09 21.3 mfMet.mmh 2.66E+04 1.15E-03 4.33 E-08 10.0 H4H13325P2 hMet.mmh 9.53E+04 2.36E-03 2.48 E-08 4.9 hMET.mFc 3.06E+05 1.85E-04 6. 05E-10 62.4 mfMet.mmh NB NB NB NB H4H13331P2 hMet.mmh 2.61 E+05 8.73E-04 3.35E-09 13.2 hMET.mFc 6.39E+05 1.56E-04 2.44E-10 74.1 mfMet.mmh 1.61 E+0 5 1.04E -03 6.47E-09 11.1 NB = No binding observed under conditions used M A / t / ZUZ I / UO0400 As shown in Table 3, several antibodies showed high affinity binding to human and monkey MET protein. Example 4. Anti-Met antibodies bind to different epitopes on the Met receptor To assess whether two anti-Met antibodies are capable of competing with each other to bind to their respective epitopes on MET, a binding competition assay was performed using real-time labelless biofilm interferometry (BLI) on an OCTET biosensor. ® HTX (ForteBlo Corp., Menlo Park, CA). In summary, approximately 0.25 nM of human MET extracellular domain expressed with a myc-myc-hexahistidine tag at the C-terminus (hMet.mmh) was first captured on OCTET® biosensors coated with anti-penta-His antibody (FortéBio Corp. , #18-5079) by immersing the biosensors for 5 minutes in wells containing a 20 pg / mL solution of hMET.mmh. The antigen-captured biosensors were then saturated with a first anti-MET antibody (subsequently referred to as mAb-1) by immersing them in wells containing a 50 pg / mL solution of mAb-1 for 5 minutes. The biosensors were then immersed in wells containing a 50 pg / mL solution of a second anti-MET antibody (subsequently referred to as mAb-2) for 3 minutes. All biosensors were washed in OCTET® HEPES-buffered EDTA-saline polysorbate 20 buffer (HBS-EP) between each step of the experiment. The real-time binding response was monitored during the course of the experiment and the binding response was recorded at the end of each step. The binding response of mAb-2 to the anti-MET precomplex was compared with mAb-1 and the competitive / non-competitive behavior of different anti-MET monoclonal antibodies was determined using a 50% inhibition threshold. Table 4 explicitly defines the ratios of competing antibodies in both directions, regardless of binding order. M A / E / ZUZ I / UOO4OO Table 4: Cross competition of anti-MET antibodies to bind hMET.mmh First mAb (mAb-1) captured using anti-penta-his byte biosensors mAb-2 antibodies competing with mAb-1 First mAb (mAb-1) captured using anti-penta-his byte biosensors Competing mAb-2 antibodies with mAb-1 H4H13301P2 H4H13302P2 H4H13300P2 H4H13291P2 H4H13302P2 H4H13301P2 H4H13295P2 H4H13290P2 H4H13306P2 H4H13311P2 H4H13316P2 H4H133 18P2 H4H13306P2 H4H13290P2 H4H13319P2 H4H13316P2 H4H13311P2 H4H13291P2 H4H13316P2 H4H13290P2 H4H13295P2 H4H13306P2 H4H13300P2 H4H13325P 2 H4H13318P2 H4H13331P2 H4H13319P2 H4H13325P2 H4H13316P2 H4H13318P2 H4H13291P2 H4H13331P2 H4H13295P2 H4H13312P2 H4H13331P2 H4H13300P2 H4 H13291P2 H4H13295P2 H4H13311P2 H4H13300P2 H4H13319P2 H4H13311P2 H4H13319P2 H4H13291P2 H4H13318P2 H4H13295P2 First mAb (mAb-1) captured using anti-penta-his byte biosensors mAb-2 antibodies that compete with mAb-1 H4H13319P2 First mAb (mAb-1) captured using anti-penta-his byte biosensors mAb-2 antibodies that Race mAb-1 H4H13300P2 H4H13295P2 H4H13291P2 H4H13311P2 H4H13300P2 H4H13318P2 H4H13311P2 H4H13331P2 H4H13316P2 H4H13318P2 H4H13325P2 H4H1 3319P2 H4H13312P2 Example 5. Construction of Bispecific Antibodies Having Two Different Antigen-Binding Domains Specific for Different MET Epitopes This example describes the construction of bispecific antibodies comprising two different antigen-binding domains (D1 and D2), where D1 and D2 are derived from different anti-MET antibodies and consequently bind separate epitopes on the extracellular domain. of Met. The individual anti-MET antigen binding domains used to construct the bispecific antibodies of this Example were derived from various bivalent monospecific anti-MET antibodies described in Examples 1 to 3, herein. All anti-MET antibodies described herein comprise the same (common) light chain (comprising the light chain variable region [LCVR] amino acid sequence of SEQ ID NO:138, and the amino acid sequences of the CDR of the light chain [LCDR1, LCDR2 and LCDR3] of SEQ ID NO: 140, 142 and 144). Furthermore, all of the bispecific antibodies illustrated in this example contain a D2 arm derived from the illustrative anti-MET antibody H4H13312P2. Thus, both antigen-binding domains (D1 and D2) of all bispecific antibodies described in this example comprise this common light chain variable region, and all D2-binding arms comprise the heavy chain variable region of D2. H4H13312P2; however, bispecific antibodies differ from each other in terms of their heavy chain D1 variable regions (HCVR) and heavy chain CDR (HCDR). The components of the bispecific antibodies of this Example are summarized in Table 5. Table 5: Summary of MET x MET bispecific antibody components SEQ ID NO: (Amino acid sequences) Bispecific Antibody First antigen-binding domain (D1) Second antigen-binding domain (D2) D1HCVR D1HCDR1 D1HCDR2 D1HCDR3 D2HCVR D2HCDR1 D2HCDR2 D2HCDR3 H4H14634D (No. 10) H4H13290P2 H4H13312P2 2 4 6 8 82 84 86 88 H4H14635D (No. 42) H4H13295P2 H4H13312P2 18 20 22 24 82 84 86 88 H4H14636D (No. 74) H4H13299P2 H4H13312P2 26 28 30 32 82 8 4 86 88 H4H14637D (No. 90) H4H13301P2 H4H13312P2 42 44 46 48 82 84 86 88 H4H14638D (No. 106) H4H13302P2 H4H13312P2 50 52 54 56 82 84 86 88 H4H14639D (No. 122) H4H13306P2 H4H13312P2 58 60 62 64 82 84 86 88 H4H14640D (No. 138) H4H13309P2 H4H13312P2 66 68 70 72 82 84 86 88 H4H14641D (No. 187) H4H13313P2 H4H13312P2 90 92 94 96 82 84 86 88 H4H16445D (No. 26) H4H13291P2 H4H13312P2 10 12 14 16 82 84 86 88 H4H16446D ( No. 58) H4H13300P2 H4H13312P2 34 36 38 40 82 84 86 88 H4H16447D (No. 154) H4H13311P2 H4H13312P2 74 76 78 80 82 84 86 88 H4H16448D (No. 219) H4H13318P2 H4H13312P2 106 108 110 112 82 84 86 88 M A / IZ / ZUZI / UOÓ4OÓ SEQ ID NO: (Amino acid sequences) Antibody First antigen-binding domain (D1) Second antigen-binding domain (D2) Bispecific D1HCVR D1HCDR1 D1HCDR2 D1HCDR3 D2HCVR D2HCDR1 D2HCDR2 D2HCDR3 H4H16449D H4H13319P2 H4H13312P2 (No. 235) 114 11 6 118 120 82 84 86 88 * The number designation in parentheses below the bispecific antibody identifiers (e.g., No. 10”) indicates the bispecific antibody number represented in the MET x MET bispecific antibody matrix of Figure 1. ΜΛ / t / ZUZ I / UOÓ4OÓ Example 6. Binding Affinities Derived from Surface Plasmon Resonance and Kinetic Constants of MET x MET Human Bispecific Monoclonal Antibodies The binding affinities and kinetic constants of the MET x MET bispecific antibodies constructed according to Example 4 of the present disclosure were determined by surface plasmon resonance (Biacore 4000 or T-200) at 37 SC. Bispecific antibodies, expressed as human lgG4 (referred to as Ή4Η), were captured on a derivatized CM4 or CM5 Biacore sensor surface via amine coupling with a mouse anti-human Fc monoclonal antibody (GE, BR-1008-39). . Various concentrations of soluble monomeric MET protein (hMet.mmh, SEQ ID NO: 152) were injected onto the surface captured with anti-MET x MET bispecific antibody at a flow rate of 30 or 50 pL / min. The association of the analyte with the captured bispecific antibody was monitored for 4 or 5 minutes and the dissociation of the analyte in HBS-ET (0.01 M HEPES pH 7.4, 0.15 M NaCI, 3 mM EDTA, 0.05% v / v Surfactant P20) or PBS-P (0.01 M sodium phosphate pH 7.4, 0.15 M NaCI, 0.05% v / v surfactant P20) was monitored for 10 min. The kinetic association (ka) and dissociation (kd) rate constants were determined as described in Example 3. Binding kinetic parameters for bispecific anti-Met antibodies to monomeric Met protein (hMET.mmh) are shown in Table 6. Table 6: Biacore binding affinities of bispecific anti-MET mAbs to 37SC Binding to 37 2C / Antibody Capture Format Bispecific Antibody Analyte ka (Ms1) kd (s1) Kd (Molar) t1 / 2 (min) H4H14634D hMet.mmh N / A < 1E-5 N / A > 1155 H4H14635D hMet. mmh N / A 8.21 E-05 N / A 140.6 H4H14636D hMet.mmh N / A < 1E-5 N / A > 1155 H4H14637D hMet.mmh N / A 3.26E-04 N / A 35.4 H4H14638D hMet.mmh N / A 1.65E-04 N / A 70.2 H4H14639D hMet.mmh N / A 1.63E-04 N / A 70.8 H4H14640D hMet.mmh N / A < 1E-5 N / A > 1155 H4H14641D hMet.mmh N / A 3.27E-04 N / A 35.3 H4H16445D hMet.mmh N / A 3.93E-04 N / A 29.4 H4H16446D hMet.mmh N / A 1.03E-04 N / A 111.8 H4H16447D hMet.mmh N / A 8.48E-04 N / A 13.6 H4H16448D hMet.mmh N / A 5.92E -04 N / A 19.5 H4H16449D hMet.mmh N / A 2.94E-04 N / A 39.3 As shown in Table 6, the "MET x MET" bispecific antibodies described herein exhibited T1 / α values ​​up to more than 1155 minutes. ΜΛ / t / ZUZ I / UOÓ4OÓ As shown in Table 7, the dissociation rate for the bispecific antibody H4H14639D is significantly less than the dissociation rates of each of its parent antibodies, H4H13306P2 and H4H13312P2. Table 7: Biacore binding affinities of bispecific anti-MET mAbs and monospecific parents at 372C Binding to 37 2C / Antibody Capture Format Antibody Analyte kd (s-1) t1 / 2 (min) H4H13306P2 hMet.mmh 1.66E-02 0.7 H4H13312P2 hMet.mmh 8.40E-03 1.4 H4H14639D hMet.mmh 1.63E-04 70.8 Example 7. Anti-Met Antibodies Block HFG-Mediated Met Activation in the SRE-Luciferase Reporter Bioassay The ability of anti-MET antibodies to block hepatocyte growth factor (HGF)-mediated activation of MET was examined in a luciferase-based reporter assay. Growth factor HGF binds to the extracellular domain of its c-Met (MET) receptor, triggering rapid homodimerization and activating several downstream signaling cascades. The anti-MET antibodies tested in this example were bivalent monospecific MET binders, or anti-MET bispecific, in which each arm of the bispecific antibody bound a different and distinct epitope on MET. A cell-based luciferase reporter assay (Figure 2) was used to determine the ability of anti-MET antibodies to activate MET signaling (Figure 3A; Table 8, columns 3 and 4) and to block MET-mediated activation. MET ligand (Figure 3B; Table 8, columns 1 and 2). Briefly, the CIGNAL™ Lenti SRE Reporter (luc) Kit (SABiosciences, Hilden, DE) was used to generate HEK293 / SRE-Luc cells. HEK293 (human embryonic kidney) cells were selected because they endogenously express c-Met. HEK293 / SRE-Luc cells stably incorporated the serum response element (SRE)-dependent reporter luciferase (Luc) (see Dinter et al., PLoS ONE 10(2): eO117774, 2015). HEK293 / SRE-Luc cells were grown in DMEM supplemented with 10% fetal bovine serum (FBS), penicillin / streptomycin / glutamine, and 1 pg / mL puromycin. Next, 2.0 x 105 HEK293 / SRE-Luc cells were seeded in luciferase assay medium in 96-well plates and incubated overnight at 37°C in 5% CO2. Hepatocyte growth factor (HGF) dose-response curves were generated by adding serially diluted HGF (0.01 pM to 1.0 nM) to the cells and recording the luciferase signal after incubation at 37 °C for four to six hours in the absence of antibodies. To generate antibody inhibition curves, cells were pre-incubated for one hour at 37SC with serially diluted (1.1 pM to 200 nM) anti-human MET antibodies. HGF was then added at a concentration of 73 pM or 100 pM for an additional four to six hours before recording the signal. Separately, the ability of the antibodies to activate c-Met in the absence of ligand was also assessed. Luciferase activity was detected using the ONE-Glo™ Luciferase Assay System (Promega, Madison, WI) and emitted light was measured on a Victor or Envision luminometer (Perkin Elmer, Shelton, CT) and expressed as units of relative light (RLU). EC50 / IC50 values ​​were determined from a four-parameter logistic equation on a 12-point response curve using GRAPHPAD PRISM®. HGF percent blockade and MET fold activation (mAbs alone) were reported for the highest antibody dose. The results are shown in Table 8. Table 8: Anti-Met antibody blockade of HGF-mediated signaling and activation of ΜΛ / t / ZUZ I / UOÓ4OÓ SRE-Luc in the absence of ligand HEK293 / SRELuc blocking activity (1 h prior binding to mAb) Ligand (HGF)- HEK293 / SRE-Luc independent activation Antibody ID % inhibition IC50 (M) Doubling ECso response (M) Anti-MET bivalent monospecific antibodies Antibodies expressed with a hlgG1-Fc H1H13301P2 42 3.3E-09 1.4 ND H1H13316P2 86 4.0E-11 1.7 ND Antibodies expressed with a hlgG4-Fc H4H13312P2 48 7.7E-11 10.9 1.2E-10 H4H13325P2 69 1.3E-11 4.3 1.9E -10 H4H13316P2 74 7.8E-12 2.3 4.7E-11 H4H13302P2 45 1.6E-09 1.8 NA H4H13313P2 47 2.3E-09 1.2 NA H4H13301P2 40 1.5E-09 1.6 NA H4H13 295P2 70 5.5E-11 2.8 3.0E-10 HEK293 / SRELuc blocking activity (1 h prior binding to mAb) Ligand (HGF)- HEK293 / SRE-Luc independent activation Antibody ID % inhibition ICso (NI) Doubling ECso response (M) H4H13306P2 67 ND 9.8 1.3E -11 H4H13291P2 61 1.3E-10 2.7 3.9E-10 H4H13319P2 67 5.2E-11 4.8 1.8E-10 H4H13309P2 77 2.0E-10 9.2 3.9E-10 H4H13318P2 77 1.0E-1 0 3.1 NA H4H13300P2 69 1.2E-10 2.8 4.8E-10 H4H13290P2 56 <2.0E-12 9.8 <2.0E-12 H4H13311P2 62 3.5E-11 5.2 3.0E-10 H4H13331P2 75 < 1.0E-11 7.1 2.3E-12 H4H13299P2 51 NA 14.4 3.7E-12 Anti-MET bispecific antibodies (hlgG4-Fc) H4H14639D 95 2.4E-11 1.8 5.7E-11 H4H14640D 89 5.2E-10 2.5 6.8E-09 H4H14634D 85 9.7E-12 3.4 9.0E-11 H4H14635D 85 1.9E-10 2.2 1 .4E-09 H4H14638D 79 1.1E-09 2.6 5.9E-09 H4H14641D 75 2.7E-09 4.4 8.4E-08 H4H14636D 74 NA 2.8 2.8E-10 H4H14637D 73 NA 2.1 4.1E-09 H4H16445D 81 5.2E-10 4.3 1 .0E-09 H4H16446D 83 1.0E-09 4.0 1.4E-09 H4H16447D 76 8.6E-10 5.8 1.4E-09 H4H16448D 87 6.2E-10 4.3 9.1 E-10 H4H16449D 85 3.2E-10 4.2 4.2E-10 NT = not tested; ND = EC50 / IC50 not determined due to non-sigmoid curves or incomplete block. As summarized in Table 8, most antibodies inhibited SRE reporter activation, with IC50 values ​​ranging from <2.0 pM to approximately 1.0 nM. Several illustrative monospecific bivalent anti-MET antibodies, such as H4H13306P2 and H4H13309P2, were potent inhibitors of SRE-luc activation, with percent inhibition values ​​of 67% and 77%, respectively. Anti-MET bispecific antibodies (MET x MET) showed greater inhibition of SRE-luc activation overall. For example, the MET x MET bispecific antibody H4H14639D showed 95 percent inhibition. In addition, several blocking antibodies were weakly activated in the absence of ligand with activation responses ranging from 0.8 to 14.4 fold above control levels. Also as shown in Figures 3A and 3B, the bivalent monospecific antibodies H41413306P2 and H4H13312P2 each activate the Met pathway in the absence of HGF ligand (Figure 3A) and also block HGF activation of Met (Figure 3B). The effect of a bispecific MET x MET antibody (eg H4H14639D) on HGF-dependent and independent MET activation was also evaluated using the HEK293 / SRELuc system. SRE-driven luciferase activity was measured in HEK293T cells treated with MET antibodies H4H14639D (the MET x MET bispecific antibody), a monovalent anti-MET antibody, and the parental antibody H4H14639D H4H13312P2 at various concentrations to determine the level of MET independent of the agonism to HGF. While the parental anti-MET monospecific bivalent antibody showed MET agonist activity, neither the monovalent nor the MET x MET bispecific antibody showed MET agonist activity (Figure 4A). SRE-driven luciferase activity was measured in HEK293T cells treated with MET antibodies H4H14639D (the MET x MET bispecific antibody), a monovalent anti-MET antibody, and the parental antibody H4H14639D H4H13312P2 at various concentrations to determine the level of inhibition or blockage. of HGF-dependent MET agonism. While the parental anti-MET monospecific bivalent antibody showed some HGF blocking activity, both the monovalent antibody and the MET x MET bispecific antibody showed greater HGF blocking (Figure 4B). The MET x MET bispecific antibody blocks HGF signaling and exhibits low MET agonist activity. Example 8. Anti-Met antibodies inhibit the growth of cells amplified with Met Selected anti-Met antibodies were then tested for their ability to inhibit the growth of MET-amplified SNU5 cells. Briefly, 2.5 x 103 human gastric carcinoma cells (SNU5) were seeded in complete growth medium in the presence of anti-MET antibodies at concentrations ranging from 1.5 pM to 100 nM. SNU5 complete growth medium contained Iscove's modified Dulbecco's medium, 10% FBS and penicillin / streptomycin / glutamine. Cells were incubated for 5 days and the number of viable cells was determined using the CELLTITER-GLO® Luminescent Cell Viability Assay Kit (Promega, Madison, WI) according to the manufacturer's instructions. As summarized in Table 9, several anti-MET antibodies, such as H4H13312P2 and H4H13325P2 blocked SNU5 growth by more than 50%, with total IC50 values ​​ranging from 44 pM to 780 pM. Figure 5 depicts the relative cell growth of SNU5 cells treated with various anti-MET bivalent monospecific antibodies (ie, standard antibodies). A subset of conventional MET antibodies inhibits the growth of SNU5 MET-amplified gastric cancer cells (Figure 5). SNU5 cells in 96-well plates were treated with each antibody at 10 pg / mL and ΜΛ / t / ZUZ I / UOÓ4OÓ Cell growth was determined after 5 days by reduction of ALAMARBLUE® reagent (Thermo Fisher Scientific, Waltham, MA). The monovalent MET antibody (lane 2, Figure 5) was generated using the MetMab heavy and light chain variable sequences as set forth in US Patent 7,892,550 B2, which is incorporated herein by reference at its entirety. Standard antibody 8 is H4H13306P2 and standard antibody 11 is H4H13312P2, which were used to construct the MET x MET bispecific antibody H4H14639D. In a separate growth assay, the blocking activity of a MET x MET bispecific antibody (i.e., H4H14639D) was assessed in both SNU5 and the non-small cell lung cancer (NSCLC) cell line EBC-1, which it also displays the amplified Met gene and overexpresses MET (Lutterbach et al., Cancer Res. 67(5):2081-2088, 2007). Complete growth medium for EBC-1 cells contained Earle's salts of MEM, 10% fetal bovine serum (FBS), penicillin / streptomycin / glutamine, and non-essential amino acids for MEM. H4H14369D exhibited the highest percent inhibition in MET activity according to the SRE-Luciferase reading. In the current experiment, 3.0 x 103 SNU5 or EBC-1 cells were seeded in complete growth medium in the presence of H4H14639D at concentrations ranging from 15 pM to 100 nM. Cells were incubated for 3 days at 37 °C in 5% CO2. Cells were then fixed in 4% formaldehyde and stained with 3 pg / mL Hoechst 33342 to label nuclei. Images were acquired on IMAGEXPRESS® Micro XL (Molecular Devices, Sunnyvale, CA) and nuclear counts were determined using METAXPRESS® image analysis software (Molecular Devices, Sunnyvale, CA). Nuclear background counts from cells treated with 40 nM digitonin were subtracted from all wells and viability was expressed as a percentage of untreated controls. IC50 values ​​were determined from a four-parameter logistic equation on a 10-point response curve (GRAPHPAD PRISM®). IC50 values ​​and percent cell death are shown in Table 9. M A / E / ZUZ I / UOÓ4OÓ Table 9: Anti-MET antibody blocking of SNU5 growth Antibody % Growth Inhibition IC50 (M) Antibody % Growth Inhibition IC50 (M) H4H13312P2 69 7.8E-10 H4H13291P2 24 NA H4H13325P2 57 4.4E-11 H4H13319P2 23 1.0E-10 H4H13316 P2 53 1.0E-10 H4H13309P2 22 1.0 E-10 H4H13302P2 40 1.1E-10 H4H13318P2 18 5.1 E-11 H4H13313P2 34 4.4E-11 H4H13300P2 16 NA H4H13301P2 33 7.4E-11 H4H13290P2 12 NA H1H1 3301P2 33 1.0E-10 H4H13311P2 8 NA H1H13316P2 30 2.0E-10 H4H13331P2 5 NA H4H13295P2 30 NA H4H13299P2 -8 NA H4H13306P2 28 7.1E-11 ND = IC50 not determined due to non-sigmoid curves or incomplete block As summarized in Table 10, below, the MET x MET bispecific antibody H4H14639D inhibited the growth of EBC-1 and SNU5 cells by 37 and 40 percent, and with IC50s of 0.82 nM and 0.3 nM, respectively. ΜΛ / I / UO0400 Table 10: Anti-Met bispecific antibody blocks the growth of EBC-1 and SNU5 mAb IC50 (nM) % Growth Inhibition EBC-1 SNU5 EBC-1 SNU5 H4H14639D 0.82 0.30 37 40 SNU5 (gastric) cells in 96-well plates were treated with a control antibody, a monovalent MET antibody, or a MET x MET bispecific antibody at 0.1 pg / mL, 1 pg / mL, or 10 pg / mL. Cell growth was determined after 5 days by reduction in ALAMARBLUE® reagent (Thermo Fisher Scientific, Waltham, MA). The MET x MET bispecific antibody significantly reduced the relative cell growth of SNU5 cells compared to control and monovalent antibody (Figure 6A). Likewise, the effect of the MET x MET bispecific antibody on the growth of EBC-1 cells was evaluated. 2,500 EBC-1 cells were seeded in a 96-well plate and cultured in Dulbecco's medium supplemented with 10% FBS. Cells were treated with a control antibody or a MET x MET bispecific antibody at 0.1 pg / mL or 1 pg / mL, and subsequently incubated with 5% CO2 at 37 °C. After 5 days, relative cell growth was determined by measuring the reduction of the ALAMARBLUE ® reporter dye to its highly fluorescent form on a SPECTRAMAX ® M3 Plate Reader (Molecular Devices, LLC, Sunnyvale, CA). The results are shown in Table 11 and Figure 6B. The MET x MET bispecific antibody (H4H14639D) significantly reduced the relative cell growth of EBC-1 cells compared to the control antibody (Figure 6B). Several anti-MET antibodies, both monospecific bivalent and MET x MET bivalent, are potent inhibitors of SRE-Luc activation and inhibit the growth of Met-amplifying and MET-overexpressing cell lines. Table 11: Anti-Met Bispecific Antibody Blocks EBC-1 Cell Growth Relative Cell Growth (n = 3) Standard Deviation Control 1.000 0.045 0.1 pg / mL of H4H14639D 0.397 0.032 1 pg / mL of H4H14639D 0.462 0.028 Example 9. A MET x MET Bispecific Antibody Induces Modest and Transient MET Pathway Activity in NCI-H596 NSCLC Cells The effect of a MET x MET bispecific antibody on the MET pathway in human lung adenosquamous carcinoma cells was evaluated in vitro. 250,000 NCI-H596 cells were seeded in a 12-well plate and cultured in RPMI medium supplemented with 10% FBS. Cells were treated with hepatocyte growth factor (HGF) at 50 ng / mL or the MET x MET bispecific antibody H4H14639D at 10 pg / mL in duplicate. Subsequently, the cells were incubated in 5% CO2 at 37 °C. After 0, 2, 6, or 18 hours, cell counts were prepared, protein content normalized, and immunoblot analysis performed. MET phosphorylation and ERK phosphorylation were quantified with the ImageJ imaging program (T. Collins, BioTechniques 43: S25-S30, 2007). Phosphorylation levels were normalized relative to tubulin loading control and expressed as fold change relative to control treatment. The results are summarized in Table 12. M A / E / ZUZf / UO 0400 Table 12: Phosphorylation of MET and ERK Treatment (hours) Phospho-MET (mean ± SD) Phospho-ERK (mean ± SD) Control (hFc) (18) 1.0 ±0.5 1.0 ±0.3 HGF (2) 202.3 ±38.7 16.7 ±1.6 HGF (6) 38.9 ±4.9 12.4 ±3.9 HGF (18) 59.2 ±24.4 12.4 ±0.9 H4H14639D (2) 69.7 ±7.0 2.2 ±0.9 H4H14639D (6) 9.9 ±7.4 0.3 ±0.4 H4H14639D (18) 1.4 ±0.1 0.1 ±0.1 HGF treatment of NCI-H596 cells induced strong MET and ERK activation that peaked at 2 hours and was sustained after 18 hours. Modest phosphorylation of MET and ERK was detected with H4H14636D bispecific antibody treatment, returning to baseline levels at 18 or 6 hours, respectively. Example 10. A MET x MET bispecific antibody induces MET degradation and inhibits pathway activity more potently than monospecific antibodies in Hs746T gastric cancer cells The effect of a MET x MET bispecific antibody on the MET activity of human gastric carcinoma cells was evaluated in vitro. 250,000 Hs746T human gastric carcinoma cells (H. Smith, J. Nati. Cancer Inst. 62(2): 225-230, 1979) were seeded in a 12-well plate and cultured in modified Dulbecco's medium supplemented with FBS at 10%. Cells were treated with (1) 5 pg / mL of the hFc control molecule, (2) 5 pg / mL of the parental bivalent monospecific anti-MET antibody H4H13306P2, (3) 5 pg / mL of the monospecific anti-MET antibody. parental bivalent H4H13312P2, (4) the combination of 2.5 pg / mL H4H13306P2 and 2.5 pg / mL H4H13312P2, or (5) 5 pg / mL MET x MET bispecific antibody H4H14639D. Subsequently, the cells were incubated with 5% CO2 at 37 °C. After 18 hours, cell counts were prepared, protein content normalized, and immunoblot analysis performed. MET expression, MET phosphorylation, and ERK phosphorylation were quantified with the ImageJ imaging program (T. Collins, BioTechniques 43: S2586 S30, 2007). The results are summarized in Table 13 and Figure 7A, which represents the crude immunoblot data. Figure 7B depicts the expression of MET protein in cells that were treated with MET x MET bispecific antibody at 10 pg / mL for 0, 2, or 6 hours. Total MET levels in Hs747T cells decreased over time following treatment with the MET x MET bispecific antibody. Similar results were obtained for the MET-amplified human papillary adenocarcinoma cell line NCI-H820 (Bean et al., MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to getfitnib or erlotinib,, Proc. Nati. Acad Sci. 2007 Dec 26, 104(52):20932-20937). Table 13: Relative levels of MET protein and activation of the MET / ERK pathway Molecule Relative MET protein level (mean ± SD) Relative phosphoMET level (mean ± SD) Relative phospho-ERK level (mean ± SD) Control (hFc) 1.00 ±0.06 1.00 ±0.06 1.00 ±0.03 H4H13306P2 0.61 ±0.09 0.57 ±0.02 0.41 ±0.03 H4H13312P2 1.15 ±0.19 0.93 ±0.04 0.39 ±0.11 H4H13306P2+H4H13312P2 1.06 ±0.02 1.07 ±0.10 1.04 ±0.23 H4H14639D 0.41 ±0. 02 0.20 ±0.01 0.04 ±0.01 The bispecific antibody, H4H14639D, induced MET degradation more potently than its parental standard antibodies. Both MET and ERK phosphorylation were more effectively inhibited by treatment with H4H14636D than by the parental antibodies or the combination of the parental antibodies. Hs746T gastric cancer cells were treated with control antibody, MET x MET bispecific antibody H4H14639D, anti-MET parental antibody H4H13306P2, anti-MET parental antibody H4H13312P2, and parental antibody combination 1 and 2, each antibody at 10 pg / mL or the combination of parental antibodies at 5 pg / mL each, for 18 hours. MET expression (MET) and pathway activation (pMET and pErk) were determined by immunoblotting with the indicated antibodies (Figure 8). The MET x MET bispecific antibody inhibits the activation of the MET pathway more effectively than its parent antibodies in Hs746T gastric cancer cells. Example 11. A MET x MET bispecific antibody induces MET degradation with greater potency than monospecific antibodies in NCI-H596 lung cancer cells The effect of a MET x MET bispecific antibody and the parental bivalent monospecific anti-MET antibodies on hepatocyte growth factor receptor (HGFR or MET) expression levels in human lung adenosquamous carcinoma cells was evaluated. 250,000 NCI-H596 human lung adenosquamous carcinoma cells were seeded in a 12-well plate and cultured in RPMI medium supplemented with 10% FBS. Cells were treated with (1) 5 pg / mL of the hFc control molecule, (2) 5 pg / mL of the parental bivalent monospecific anti-MET antibody H4H13306P2, (3) 5 pg / mL of the monospecific anti-MET antibody. parental bivalent H4H13312P2, (4) the combination of 2.5 pg / mL H4H13306P2 and 2.5 pg / mL H4H13312P2, or (5) 5 pg / mL MET x MET bispecific antibody H4H14639D. Subsequently, the cells were incubated with 5% CO2 at 37 °C. After 18 hours, cell counts were prepared, protein content normalized, and immunoblot analysis performed. MET expression was quantified with the ImageJ image processing program (T. Collins, BioTechniques 43: S25-S30, 2007). The results are summarized in Table 14. ΜΛ / t / ZUZ I / UOÓ4OÓ Table 14: Relative level of MET protein Molecule Relative MET Level Control (hFc) 1 ± 0.03 H4H13306P2 0.50 ±0.01 H4H13312P2 0.35 ±0.04 H4H13306P2+H4H13312P2 0.61 ±0.04 H4H14639D 0.24 ±0.01 NCI-H596 (MET exon14 skipping mutation) lung cancer cells were also treated with control or MET x MET bispecific antibodies at 10 pg / mL for 2, 6, or 18 hours. MET expression was determined by immunoblotting (Figure 9), which shows MET degradation induced by MET x MET bispecific antibodies with increasing treatment time. The bispecific antibody, H4H14636D, induces MET degradation more potently than its parental conventional antibodies in NCI-H596 lung cancer cells. Example 12. MET x MET Bispecific Antibodies Induce MET Degradation and Inhibit Pathway Activity More Potently Than Monospecific Antibodies in SNU5 Gastric Cancer Cells The effect of a bivalent monospecific anti-MET antibody and several MET x MET bispecific antibodies on hepatocyte growth factor receptor (HGFR or MET) expression levels in gastric carcinoma cells was evaluated. Human gastric carcinoma SNU5 cells were seeded in Iscove medium containing 20% ​​FBS plus penicillin-streptomycin-glutamine. 24 hours after seeding, cells were treated with control hFc, the parental anti-MET bivalent monospecific antibody H4H13312P2, or the MET x MET bispecific antibodies (H4H14634D, H4H14635D, H4H14636D, H4H14637D, H4H14638D, H4H14639D, H4H 14640D, H4H14641D) for 18 h. Cellular cells were then prepared and analyzed by Western blotting. Western blots were probed for MET and tubulin. The expression level of the MET protein was quantified and normalized relative to the tubulin loading control. The results are presented in Table 15 and Figure 10B. Table 15: Relative level of MET protein Molecule Relative MET Level Molecule Relative MET Level Control (hFc) 1 H4H14637D 0.49 H4H13312P2 0.62 H4H14638D 0.35 H4H14634D 0.45 H4H14639D 0.27 H4H14635D 0.27 H4H14640D 0.1 8 H4H14636D 0.50 H4H14641D 0.31 SNU5 cancer cells were treated with control antibody or MET x MET bispecific antibody or monovalent MET antibody at 10 pg / mL for 18 h as described above. MET expression (Figure 10A and 10B) and pathway activation (ie, pMET and pERK; Figure 10A) were determined by immunoblotting with the indicated antibodies. Immunoblots are shown in Figures 10A and 10B. Treatment of SNU5 cells with MET x MET bispecific antibodies induced more potent MET degradation than treatment with bivalent monospecific anti-MET antibody (H4H13312P2) (Figure 10B), monovalent MET antibody, or control hFc. Treatment of SNU5 cells with the MET x MET bispecific antibody inhibited the downstream effectors of the MET pathway. Similar results were obtained for the MET-amplified non-small cell lung cancer adenocarcinoma cell line NCI-H1993 (Kubo et al., “MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors,” Int J. Cancer 2009 Apr 15;124(8):17781784). Example 13. A MET x MET bispecific antibody induces MET degradation, inhibits pathway activity, and inhibits tumor growth more potently than monospecific antibodies in EBC-1 cells MET-amplified human lung squamous cell carcinoma EBC-1 cells (Lutterbach et al., “Lung cancer cell lines harboring MET gene amplification are dependent on Metforgrowth and survival,” Cancer Res. 2007 Mar 1;67(5):2081 -8) were treated with a control antibody or 10 pg / mL of a MET x MET bispecific antibody for 18 h as described above. MET expression and MET pathway activation determined by pMET and pErk expression were determined by immunoblotting with the indicated antibodies. Western blots are shown in Figure 11. Treatment of EBC-1 cells, harboring amplification of the MET gene, with MET x MET bispecific antibodies induced more potent degradation of MET than treatment with the control antibody. Treatment of EBC-1 cells with the MET x MET bispecific antibody inhibited the d effectors of the MET pathway. In another experiment, 5 million EBC-1 cells were implanted subcutaneously in the flank of CB-17 SCID mice. Once tumor volumes reached approximately 150 mm3, mice were randomized into groups of 6 and treated twice weekly with either a control antibody at 25 mg / kg or the MET x MET H4H14639D bispecific antibody at 25 mg / kg. Tumor growth was monitored for 30 days after implantation and tumor volume (mm 3 ) was measured for each experimental group over time. The results are shown in Table 16 and Figure 12, which show that the MET x MET bispecific antibody significantly inhibits the growth of EBC-1 tumors. ΜΛ / t / ZUZ I / UOÓ4OÓ Table 16: Relative EBC-1 Tumor Growths Treatment Tumor growth (mm3) since the start of treatment (mean ± SEM) 25 mg / kg control 1394 ± 226 25 mg / kg H4H14639D 89 ±47 Example 14. A MET x MET bispecific antibody inhibits the in vitro growth of Hs746T gastric cancer cells more potently than monospecific antibodies The effect of a MET x MET bispecific antibody on the growth of human gastric carcinoma cells in vitro was evaluated. 2,500 Hs746T human gastric carcinoma cells (H. Smith, J. Nat'l. Cancer Inst. 62(2): 225-230, 1979) were seeded in a 96-well plate and cultured in modified Dulbecco's medium supplemented with 10% FBS. Cells were treated with (1) single bivalent monospecific anti-MET antibodies (H4H13306P2 or H4H13312P2) at 5 pg / mL, (2) a combination of the two parental bivalent monospecific anti-MET antibodies (H4H13306P2 and H4H13312P2) at 2.5 pg / mL. mL each, or (3) the bispecific antibody containing one arm binding to H4H13306P2 and the other arm binding to H4H13312P2 (H4H14639D) at 5 pg / mL. Subsequently, the cells were incubated with 5% CO2 at 37 °C. After 5 days, relative cell growth was determined by measuring the reduction of the reporter dye, ALAMAR BLUE® (ThermoFischer Scientific, Waltham, MA), to its highly fluorescent form on an M3SPECTRAMAX® plate reader (Molecular Devices, Sunnyvale, CA). . The increase in fluorescence correlates with cell growth. Table 17 represents relative Hs746T cell growth for each antibody treatment normalized to control Hs746T cell growth (no treatment). The bispecific antibody, H4H14639D, inhibits Hs746T cell proliferation more potently than its parent monospecific antibodies individually or in combination. Table 17: Normalized cell growth of Hs746T Relative cell growth (n = 3) Standard deviation Control 1 0.133497801 H4H14639D 0.647408139 0.019090432 H4H13306P2 1.623312821 0.189647479 H4H13312P2 0.852680493 0.0 1728527 H4H13306P2+H4H13312P2 1.767720125 0.077445717 Hs746T gastric cancer cells were treated with control antibody, MET x MET bispecific antibody H4H14639D, anti-MET parental antibody H4H13306P2, anti-MET parental antibody H4H13312P2, and parental antibody combination 1 and 2, each antibody at 2 pg / mL. Cell growth was determined after 5 days by reduction of the ALAMAR BLUE® reagent (Figure 13A). The MET x MET bispecific antibody inhibited cell growth relative to parental antibodies alone or in combination, and inhibited MET pathway activation more effectively than its parent antibodies in Hs746T gastric cancer cells. Hs746T gastric cancer cells in 96-well plates were treated with 25 pg / mL control antibody, 1 pg / mL, 10 pg / mL, or 25 pg / mL monovalent MET antibody, or 1 pg / mL, 10 pg / mL. mL or 25 pg / mL MET x MET bispecific antibody. The growth of Hs746T gastric cancer cells was determined after 5 days by reduction of the ALAMARBLUE® reagent (Figure 13B). The MET x MET bispecific antibody potently inhibits the growth of MET-amplified cells. Example 15. A MET x MET bispecific antibody does not induce the growth of NCI-H596 lung cancer cells in vitro The effect of a MET x MET bispecific antibody on the growth of human non-small cell lung cancer (NSCLC) cells (NCI-H596) was evaluated in vitro. 10,000 NCI-H596 lung adenosquamous carcinoma cells (Nair et al., J. Nat'l. Cancer Inst. 86(5): 378383, 1994) were seeded in 96-well plates on a 0.66% agar layer in medium supplemented with 1% fetal bovine serum (FBS). Cells were grown in RPMI 1640 medium supplemented with 1% FBS with 0.3% agarose. Cells were treated with (1) individual parental bivalent monospecific anti-MET antibodies (H4H13306P2 or H4H13312P2) at 5 pg / mL, (2) a combination of the two parental bivalent monospecific anti-MET antibodies (H4H13306P2 and H4H13312P2) at 2.5 pg / mL each, (3) a bispecific antibody containing one binding arm of H4H13306P2 and the other binding arm of H4H13312P2 (H4H14639D) at 5 pg / mL, or (4) 100 ng / mL hepatocyte growth factor (HGF). Subsequently, the cells were incubated with COaal 5% at 37 °C. After two weeks, relative cell growth was determined by measuring the reduction of the reporter dye, ALAMAR BLUE® (Thermo Fischer Scientific, Waltham, MA), to its highly fluorescent form on an M3 plate reader. SPECTRAMAX® (Molecular Devices, Sunnyvale, CA). The increase in fluorescence correlates with cell growth. Table 18 and Figure 14 depict the relative growth of NCI-H596 cells for each antibody treatment standardized to control NCI-H596 cell growth (no treatment). Treatment of NCI-H596 lung cancer cells with HGF resulted in a potent induction of growth in soft agar. The MET x MET bispecific antibody (MM in Figure 14) H4H14639D did not significantly alter growth relative to control treated cells. A modest induction of cell growth was observed with each parental bivalent monospecific antibody H4H13306P2 (M1) or H4H13312P2 (M2) individually, or in combination (H4H13306P2 and H4H13312P2) (M1M2). ΜΛ / t / ZUZ I / UOÓ4OÓ Table 18: Normalized cell growth of NCI-H596 Relative Cell Growth (n = 3) Standard Deviation Control 1 0.030074808 H4H14639D 1.070339237 0.075103746 H4H13306P2 2.9593578 0.337877264 H4H13312P2 1.686580346 0.145 670753 H4H13306P2+H4H13312P2 1.693724668 0.168651046 HGF 7.87655937 0.46057617 Example 16. A MET x MET bispecific antibody inhibits the in vitro growth of SNU5 gastric cancer cells more potently than monospecific antibodies The effect of a MET x MET bispecific antibody on the growth of human gastric carcinoma cells in vitro was evaluated. 2,500 SNU5 human gastric carcinoma cells (Ku and Park, Cancer Res. Treat. 37(1): 1-19, 2005) were seeded in a 96-well plate and cultured in Iscove's modified Dulbecco's medium supplemented with FBS at twenty %. Cells were treated with (1) single bivalent monospecific anti-MET antibodies (H4H13306P2 or H4H13312P2) at 5 pg / mL, (2) a combination of the two bivalent monospecific anti-MET antibodies (H4H13306P2 and H4H13312P2) at 2.5 pg / mL each, or (3) a bispecific antibody containing one binding arm from H4H13306P2 and the other binding arm from H4H13312P2 (H4H14639D) at 5 pg / mL. Subsequently, the cells were incubated with 5% CO salt at 37 °C. After 5 days, relative cell growth was determined by measuring the reduction of the reporter dye, ALAMAR BLUE® (Thermo Fischer Scientific, Waltham, MA), to its highly fluorescent form on a M3SPECTRAMAX® plate reader (Molecular Devices, Sunnyvale, CA ). The increase in fluorescence correlates with cell growth. Table 19 represents the relative growth of SNU5 cells for each antibody treatment standardized to control SNU5 cell growth (no treatment). The bispecific antibody, H4H14639D, inhibits SNU5 cell proliferation more potently than its parental monospecific antibodies. Table 19: Normalized cell growth of SNU5 Relative Cell Growth (n = 3) Standard Deviation Control 1 0.070814765 H4H14639D 0.271100069 0.01324024 H4H13306P2 0.766317547 0.061930288 H4H13312P2 0.431990234 0.03 3183065 H4H13306P2+H4H13312P2 0.331287005 0.012042949 ΜΛ / t / ZUZ I / UOÓ4OÓ Example 17. A MET x MET bispecific antibody induces the regression of the Hs746T tumor xenograft The effect of a MET x MET bispecific antibody on a human gastric carcinoma tumor was evaluated in an immunocompromised mouse model. Three million Hs746T human gastric carcinoma cells were implanted subcutaneously in the flank of CB-17 SCID mice (Bancroft et al., J. ImmunoL 137(1):4-9,1986). Once tumor volumes reached approximately 200 mm3, mice were randomized into groups of six and treated twice weekly with either a control antibody at 25 mg / kg or a MET x MET (H4H14639D) bispecific antibody at 25 mg. / kg. Tumor growth was monitored for 16 days post-implantation for the control group, when control-treated tumors reached protocol size limits. Tumor growth was monitored for 30 days after implantation for the H4H14639-treated group. Treatment of tumors with the MET x MET bispecific antibody induced regression of tumor size over 21 days relative to the start of treatment. Control-treated tumors showed a mean increase in volume of approximately 12-fold during 16 days of growth (Table 20). Tumor volume over time, showing Hs746T tumor regression due to MET x MET bispecific antibody, is shown in Figure 15. Table 20: Growth of the gastric tumor Hs746T Antibody (mg / kg) Tumor growth (mm3) since start of treatment (mean ± SEM) Control (10) 1164 ±138 H4H14639D (25) -215 ±8.3 Example 18. A MET x MET bispecific antibody induces regression of the tumor xenograft SNU5 The effect of a MET x MET bispecific antibody on a human gastric carcinoma tumor was evaluated in an immunocompromised mouse model. Ten million SNU5 human gastric carcinoma cells were implanted subcutaneously in the flank of CB-17 SCID mice. Once tumor volumes reached approximately 500 mm3, mice were randomized into groups of five and treated twice weekly with either a control antibody at 10 mg / kg or a MET x MET (H4H14639D) bispecific antibody at 1 mg. / kg or 10mg / kg. Tumor growth was monitored for 81 days after implantation when control-treated tumors reached protocol size limits. Tumors from mice treated with 1 mg / kg or 10 mg / kg of the MET x MET antibody demonstrated a mean reduction in size of approximately 95% or 98%, respectively. Control-treated tumors showed a mean volume increase of approximately 12-fold from the start of treatment (Table 21). M A / t / ZUZ I 7UOO4OO Table 21: SNU5 gastric tumor growth Antibody (mg / kg) Tumor growth (mm3) since the start of treatment (mean ± SEM) Control (10) 1123 ±194 H4H14639D (1) -477 ± 43 H4H14639D (10) -492 ± 18 Subcutaneously implanted SNU5 tumors were treated twice weekly with control antibody, monovalent MET antibody at 1 mg / kg or 10 mg / kg, or MET x MET bispecific antibody at 1 mg / kg or 10 mg / kg. Potent and sustained regression of MET-amplified SNU5 tumors (ie, reduction in tumor volume) was observed over time in mice treated with MET x MET bispecific antibody (Figure 16A). Protein was extracted from the tumors at the end of the study and MET expression and activation of the pathway indicated by MET phosphorylation (pMET expression) were determined by immunoblotting. MET x MET (tumors) treated mice showed reduced expression of MET and pMET relative to controls (Figure 16B). The MET x MET bispecific antibody is a potent inhibitor of tumors harboring MET amplification. Example 19. A MET x MET bispecific antibody induces the regression of the U87-MG tumor xenograft The effect of a MET x MET bispecific antibody on a human glioblastoma tumor was evaluated in an immunocompromised mouse model. Five million U87-MG human glioblastoma cells (Vordermark and Brown, Int. J. Radiation Biol. 56(4): 1184-1193, 2003) were implanted subcutaneously into the flank of CB-17 SCID mice. U87-MG glioblastoma xenograft models are driven by autocrine signaling from HGF. Once tumor volumes reached approximately 100 mm3, mice were randomized into groups of six and treated with either a control antibody or the MET x MET bispecific antibody (H4H14639D). 25 mg / kg of antibody (control or MET x MET) was administered to each mouse twice a week. Tumor growth was monitored for 29 days after implantation when control-treated tumors reached protocol size limits. Tumors from mice treated with the MET x MET antibody demonstrated a mean reduction in size of approximately 38%, while control-treated tumors showed a mean increase in volume of approximately 19-fold over 29 days of growth (Table 22). Tumor volume over time, showing U87-MG tumor regression due to MET x MET bispecific antibody, is shown in Figure 17. Table 22: Glioblastoma tumor growth Antibody (mg / kg) Tumor growth (mm3) since start of treatment (mean ± SEM) Control (25) 1777 ±98 H4H14639D (25) -38 ±18 Example 20. A MET x MET bispecific antibody inhibits the growth of the U118-MG tumor xenograft The effect of a MET x MET bispecific antibody on a human glioblastoma tumor was evaluated in an immunocompromised mouse model. U118-MG glioblastoma xenograft models are driven by autocrine signaling from HGF. Five million U118MG human glioblastoma cells (Olopade et al., Cancer Research 52:2523-2529,1992) were implanted subcutaneously in the flank of CB-17 SCID mice. Once tumor volumes reached approximately 100 mm3, mice were randomized into groups of six and treated with either a control antibody or the MET x MET bispecific antibody (H4H14639D). 25 mg / kg of antibody (control or MET x MET) was administered to each mouse twice a week. Tumor growth was monitored for 72 days after implantation. The MET antibody inhibited tumor growth by 99% over the 72 day period (Table 23). Table 23: Glioblastoma tumor growth Antibody (mg / kg) Tumor growth (mm3) since start of treatment (mean ± SEM) % decrease in tumor growth vs. control Control (25) 1228 ±123 - H4H14639D (25) 11 ±18 99.1 In another experiment, subcutaneously implanted U118-MG glioblastoma tumors in mice were treated twice weekly with 25 mg / kg control antibody, monovalent MET antibody, or MET x MET bispecific antibody. Tumor volume (mm3) was measured for each experimental group over time. The results are shown in Figure 18, which shows that the MET x MET bispecific antibody inhibits the growth of U118-MG tumors. Example 21: Synthesis of maytansinoid Matans¡n-3-N-methyl-L-alan¡na-N-Me-beta-alan¡na-carbam¡l-(p-amino)benz¡l-c¡trul¡navalina-adipoyl-succinate was synthesized (Compound 1 in Figure 20) from Compound 2 (Figure 19) as described below. Maitansin-3-N-methyl-L-alanine-Fmoc-N-Me-beta-alanine (Compound 3, Figure 19). Des-acetyl-maytansine (compound 2, Figure 19, 0.433 g, 0.666 mmol), Fmoc-N-Me-beta-Ala (0.434 g, 1.33 mmol) and HATU (0.757 g, 1.99 mmol) were weighed into a dry flask. , dissolved in anhydrous DMF (9 mL) and treated with 4-methylmorpholine (0.300 mL, 2.73 mmol). The flask was sealed with a rubber stopper, purged with argon, and the reaction stirred at room temperature. After 3 days, the mixture was evaporated to an oil, dissolved in acetonitrile and water, and purified by flash chromatography on a 275 g C18 silica column (30-90% acetonitrile in water for 20 min, acetic acid to 0.05% in both phases). Lyophilization of the product fractions gave the title compound as a white solid. The crude was purified on a 80 g silica gel column (5:5:1 EtOAc-EtOAc:DCM:MeOH over 17 min). The pure fractions were combined, evaporated and dried in vacuo overnight to give the title compound as a white solid (0.424 g, 66%). MS (ESI, pos.): Calcd for C51H61CIN4O12, 956.4; found 956.9 (Μ + H), 979.0 (M + Na), 939.0 (MH2O + H). N-tert-butoxycarbonyl-N-methyl-beta-alanine succinate ester (compound 4, Figure 19). The title compound was prepared from commercial Boc-N-Me-beta-Ala-OH by a method well known in the art (cf.- Widdison et al., J. Med. Chem., 2006, 49(14) , 4401).1H NMR (300 MHz, CDCh): δ 3.62 (mb, 2H), 2.88 (m, 9H), 1.47 (s, 9H). Maytansin-3-N-methyl-L-alanine-Boc-N-Me-beta-alanine (Compound 5, Figure 19). Method A: The product from the previous step (Compound 4, Figure 19, 0.453 g, 1.51 mmol) and des-acetylmaytansine (Compound 2, Figure 19, 0.304 g, 0.468 mmol) were dissolved in 3:1 acetonitrile:water (8 mL ), were treated with 1 M aqueous NaHCOs (0.5 mL) and stirred at room temperature for 18 hours. When the reaction was complete as determined by TLC, it was then stirred with brine for 10 min and extracted three times with ethyl acetate (EtOAc). The combined organic layers were then dried over Na2SO4, filtered and the filtrate concentrated and dried in vacuo to a gold syrup which was purified by flash column chromatography on a 20 g silica gel cartridge (0-10% MeOH in EtOAc for 15 min) to give the title compound as a white solid (0.084 g, 43%). MS (ESI, pos.): Calculated for C41 H59CIN40i2, 834.4; found 835.2 (Μ + H), 857.2 (M + Na), 817.4 (MH2O + H). Method B: Boc-N-Me-beta-Ala-OH (0.294 g, 1.45 mmol) was dissolved in anhydrous DMF (5 mL), treated with pentafluorophenyl diphenylphosphinate (FDPP, 0.555 g, 1.44 mmol), and the reaction was stirred at room temperature for 30 min. The mixture was then transferred to a larger flask containing a mixture of des-acetyl-maytansine (Compound 2, Figure 19, 0.462 g, 0.711 mmol) and diisopropylethylamine (DIEA, 0.250 mL, 1.44 mmol) in anhydrous DMF (7 mL), the flask was sealed with a rubber stopper, purged with argon, and the reaction stirred again at room temperature. After 24 hours, the reaction was concentrated in vacuo to an oil, dissolved in ethyl acetate (EtOAc, 2 mL) and purified on a 40 g silica gel cartridge (5:5 EtOAc-EtOAc / DCM / MeOH: 1 for 15 min), giving the title compound as a pale yellow solid (0.468 g, 79%). MS (ESI, pos.): Calcd for C41H59CIN4O12, 834.4; found 857.2 (M + Na), 817.2 (MH2O + H). Maitansin-3-N-methyl-L-alanine-N-Me-beta-alanine (Compound 6, Figure 19). Method A: Maytansine-N-Me-L-Ala-Boc-N-Me-beta-Ala (Compound 5, Figure 19, 0.464 g, 0.555 mmol) in a 3:1:1 mixture of acetonitrile / water / trifluoroacetic acid (7 mL), the flask was sealed with a rubber stopper, purged with argon, and the reaction stirred at room temperature for 24 hours, then stoppered and stored at -20 °C for 3 days. The crude reaction mixture was warmed to room temperature for 2 hours, briefly concentrated in vacuo, purified on a 100 g C18 RediSep Gold column (20-80% acetonitrile in water for 25 min, 0.1% TFA in both solvents), and the combined pure fractions were partially evaporated at room temperature, frozen in a dry ice bath, and lyophilized to give the title compound as a pale yellow solid (0.295 g, 63%). MS (ESI, pos.): Calcd for C35H51CIN4O10, 734.3; found 735.7 (Μ + H), 1471.3 (2M + H). Method B: Maytansine-N-Me-L-Ala-Fmoc-beta-Ala (Compound 3, Figure 19, 0.422 g, 0.441 mmol) in 5% piperidine in DMF (6.00 mL, 3.04 mmol), reaction flask it was sealed with a rubber stopper, purged with argon and the mixture was stirred at room temperature. After 3 hours, the reaction was complete by LCMS, whereupon it was concentrated in vacuo, sealed, and stored at -20SC overnight. The crude product was warmed to room temperature, treated with acetonitrile and 10% aqueous solution. acetic acid (3 mL each) and purified by flash chromatography on a 275 g C18 silica column (10-90% acetonitrile in water for 20 min, 0.05% acetic acid in both solvents). Lyophilization of the product fractions gave the title compound as a white solid. The solid was triturated three times with dry diethyl ether, filtered, the solids washed from the frit with DCM and the filtrate evaporated and dried, in vacuo to give the title compound as a white solid (0.311 g, 89%). . MS (ESI, pos.): Calcd for C36H51CIN4O10, 734.3; found 735.0 (Μ + H). Matansin-3-N-methyl-L-alanine-N-Me-beta-alanin-carbamyl-(p-amino)benzyl-citrulline-valineFmoc (Compound 7, Figure 20). Step 1: The product from the previous step (Compound 6, Figure 19, 0.310 g, 0.390 mmol), 1-hydroxy7-azabenzotriazole (HOAT, 0.164 g, 1.20 mmol), sodium bicarbonate (0.138 g, 1.64 mmol), and Fmoc benzyl-(p-nitrophenyl)-valinecitrulline-(p-amino)carbonate (0.595 g, 0.776 mmol, was prepared by a method known in the art, cf.-Gangwar et al., US Patent 7,714,016 B2 ) were dissolved in anhydrous DMF (10 mL), the reaction flask was sealed with a rubber stopper, purged with argon, and the mixture was stirred at room temperature. After 24 hours, the reaction was partially evaporated in vacuo to ca. 2-3 mL, treated with 10% aqueous acetic acid and water (ca. 1 mL each), dissolved in acetonitrile (ca. 6 mL), and purified by chromatography. flash on a 275 g C18 silica column (30-90% acetonitrile in water for 20 min, 0.05% acetic acid in both solvents). Partial evaporation, freezing and lyophilization gave the title compound as a white solid (0.362 g, 68%). MS (ESI, pos.): Calculated for C70H88CIN9O17, 1361.6; found 1362.1 (Μ + H), 1384.1 (M + Na), 1344.1 (MH2O + H). Step 2: The product from the previous step (0.360 g, 0.264 mmol) was dissolved in 5% piperidine in M A / Ε / ΖυΖΊ / UOO4OO DMF (7 mL), the reaction flask was sealed with a rubber stopper, purged with argon, and the mixture was stirred at room temperature. After 3 hours, the reaction was evaporated in vacuo, the residue was treated with 10% aqueous acetic acid (2 mL), dissolved in acetonitrile (4 mL), and purified by flash chromatography on a 275 C18 silica column. g (10-70% acetonitrile in water for 20 min, 0.05% acetic acid in both solvents). Pure fractions were combined, stored at -208C overnight, partially evaporated in vacuo at 25 - 30SC, frozen on dry ice and lyophilized for 6 days to give the title compound as a pale yellow solid (0.303 g, 95 %). MS (ESI, pos.): Calcd for C15H78CIN9O15, 1139.5; found 1140.1 (Μ + H), 1162.0 (M + Na). Maytans¡n-3-N-methyl-L-alanine-N-Me-beta-alanine-carbamyl-(p-amino)benzyl-citrul¡navalin-adipic acid (Compound 8, Figure 20). The product from the previous step (Compound 7, Figure 20, 0.205 g, 0.171 mmol), adipic acid (0.258 g, 1.77 mmol), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 0.215 g, 0.869 mmol) were dissolved in dry DCM (10 mL) and anhydrous methanol (5 mL), the reaction flask sealed with a rubber stopper, purged with argon, and the mixture stirred at room temperature. After 21 hours, the reaction was evaporated in vacuo, the residue dissolved in a few mL of acetonitrile / water, and purified by flash chromatography on a 150 g C18 silica column (20-80% acetonitrile in water for 17 min). , 0.05% acetic acid in both solvents). Partial evaporation, freezing and lyophilization of the pure fractions for 18 hours gave the title compound as a white solid (0.140 g, 65%). MS (ESI, pos.): Calculated for CsiHssCINgOis, 1267.6; found 1268.9 (M + H), 1290.9 (M + Na). Maitansin-3-N-methyl-L-alanine-N-Me-beta-alanine-carbamyl-(p-amino)benzyl-citrulline-valineadipoyl-succinate (Compound 1, Figure 20). The product of the previous step (Compound 8, Figure 20, 0.061 g, 0.048 mmol), N-hydroxysuccinimide (0.063 g, 0.55 mmol) and N-(3-dimethylaminopropyl)N'-ethylcarbodiimide hydrochloride (EDC -HCl, 0.071 g, 0.37 mmol) were dissolved in dry DCM (7 mL), the reaction flask sealed with a rubber stopper, purged with argon, and the mixture stirred at room temperature. After 5 days, the reaction was evaporated in vacuo, the residue dissolved in a few mL of acetonitrile / water, and purified by flash chromatography on a 100 g C18 silica column (30-90% acetonitrile in water for 15 min, 0.05% acetic acid in both solvents). Partial evaporation, freezing and lyophilization of the cleaner product fractions for 18 hours gave the title compound as a white solid (0.044 g, 67%). MS (ESI, pos.): Calculated for C65H89CIN10O20,1364.6; found 1365.7 (Μ + H), 1387.7 (M + Na), 1347.7 (MH2O + H).1H-NMR (500 MHz; CDCE): δ 7.56 (d, J = 8.3 Hz, 2 H), 7.20 (d, J = 8.7Hz, 1H), 6.80 (s, 1H), 6.71 (m, 1H), 6.62 (d, J = 10.0Hz, 1H), 6.39 (dd, J = 15.1, 11.3Hz, 1 H), 5.68 (dd, J = 15.3, 9.1 Hz, 1 H), 5.38-5.32 (m, 1 H), 5.03 (t, J = 15.1 Hz, 1 H), 4.88 (d, J = 12.3 Hz, 1H), 4.73 (d, J = 11.3 Hz, 1H), 4.61 (dd, J= 9.1,3.6 Hz, 1H), 4.26 (d, J= 7.0 Hz, 1H), 4.17 (t, J = 7.1 Hz, 1H), 3.95 (s, 3H), 3.61 (d, J= 11.7 Hz, 1H), 3.57 (d, J= 12.4 Hz, 1H), 3.46 (d, J= 9.1 Hz , 2H), 3.33 (s, 3H), 3.27 (t, J= 6.9 Hz, 1H), 3.17-3.07 (m, 5H), 2.97 (dd, J= 16.6, 9.9 Hz, 1H) , 2.88 (d, J = 11.7 Hz, 3H), 2.84 (s, 4H), 2.77 (s, 2H), 2.66 (s, 2H), 2.62 (t, J= 4.8 Hz, 2H) , 2.56 (d, J= 13.1 Hz, 1 H), 2.32 (t, J= 6.6 Hz, 2 H), 2.15 (d, J = 14.0 Hz, 1 H), 2.10 (q, J = 6.8 Hz, 1 H), 1.92 (s, 4 H), 1.75 (m, 5 H), 1.61 (s, 3 H), 1.52 (s, 3 H), 1.27 (d, J = 6.3 Hz, 3 H), 1.22 ( dt, J = 12.7, 6.3 Hz, 6H), 0.95 (t, J = 5.9 Hz, 7 H), 0.78 (s, 3 H). ΜΛ / I / UOO4OO DM1 was synthesized as a single diastereomer based on the procedures described in WO 2015 / 031396 (eg, Example 2, paragraph

[00106] ), incorporated herein by reference in its entirety. Example 22. Conjugation of antibodies and characterization of conjugates antibody conjugation Antibodies (H4H14639D, H4H13312P, H4H14635D, and isotype control; 10-20 mg / mL) were conjugated in 50 mM HEPES, 150 mM NaCI, pH 8.0 and 10-15% (v / v) DMA with an excess of 5 -6 times of SMCC-DM1 diastereoisomer prepared as described in Example 21 (Maitansinoid A) or maytansin3-N-methyl-L-alanine-N-Me-beta-alanine-carbamyl-(p-amino)benzyl-citrulline- valine-adipoyl-succinate (Compound 1, Figure 20) (Maitansinoid B) for 2 hours at room temperature. Conjugates were purified by size exclusion chromatography or extensive ultrafiltration and filter sterilized. Protein concentrations were determined by UV spectral analysis. Size exclusion HPLC established that all conjugates used were >90% monomeric, and RP-HPLC established that there was <1% unconjugated linker payload. All conjugated antibodies were analyzed by UV for linker payload values ​​according to Hamblett et al. (American Association for Cancer Research. 2004 Oct 15; 10(20): 7063-70) and / or by difference in mass, native vs. conjugated. The ratios of payload to antibodies are indicated in Table 24. Table 24: Percent Yield and Payload to Antibody Ratio for Each of the Antibody-Drug Conjugates Antibody Production (%) DAR (MS) DAR (UV) H4H14639D-maytansinoid A 60 3.8 3.7 H4H14639D-maytansinoid B 50 2.4 2.4 H4H13312P-maytansinoid A 60 4.1 4.1 H4H13312P-maytansinoid B 50 2.3 2.5 Isotype Control REGN1945-maytansinoid B 70 2.3 2.5 Isotype Control REGN1945-maytansinoid A 80 3.7 3.7 Characterization of conjugates by liquid chromatography-mass spectrometry To determine the loading of linker payloads on the antibody, the conjugates were deglycosylated and analyzed by LC-MS. For the assay, 50 pg of the conjugate was diluted with milli-Q water to a final concentration of 1 mg / mL. Ten pL of PNGase F solution [PNGase F solution was prepared by adding 150 pL of PNGase F stock (New England Biolabs, Cat # P0704L) and 850 pL of milli-Q water and mixed well] was added to the conjugate solution. diluted and then incubated at 37°C overnight. Injections of 5 pL of each sample were made in LC-MS (Waters Synat G2-SI) and eluted with 0.1 mL / minute of a 20-40% gradient mobile phase for 25 minutes (Mobile Phase A: 0.1% v / v FA in H2O; Mobile Phase B: 0.1% v / v FA in acetonitrile). LC separation was achieved on a Waters Acquity BEH C4 column (1.0 X 50 mM, 1.7 pM) at 80SC. Mass spectrometry spectra were deconvoluted using Masslynx software and the drug to antibody ratio (DAR) was calculated using the following equations: 1. Relative percentage (%) of drug (Dn) by peak distribution intensity (Pl): Dn % = ΡΙη / Σ(ΡΙ0+ΡΙ1+ΡΙ2.......+Pli)x100 (n = 0, 1,2,3,...,i) 2. Average DAR calculation: DAR=Z(1xD1 %+2xD2 %+3xD3 %+......+¡xD¡%) Example 23. Binding Affinities Derived from Surface Plasmon Resonance and Kinetic Constants of Conjugated Human Anti-MET Monoclonal Antibodies (monospecific and bispecific) Equilibrium dissociation constants (Kd values) were determined for MET binding to anti-MET antibodies conjugated to MCC-DM1 diastereomer (maytansinoid A) or maytansin-3-N-methyl-Lalan¡ne-N-Me-beta. -alanine-carbamyl(p-am¡no)benz¡lo-citrullina-va¡na-ad¡po¡l-succinate (Compound 1, Figure 20) (maytansinoid B) by using an assay of real-time surface plasmon resonance biosensor on a Biacore 2000 instrument. The Biacore sensor surface was derivatized by amine coupling with a mouse monoclonal anti-human Fe antibody (GE Healthcare, #BR-100839) to capture anti-MET ADC antibodies and parental unmodified antibodies expressed with human constant regions. All Biacore binding studies were performed in HEPES-buffered saline (HBS)-EP running buffer (0.01 M HEPES pH 7.4, 0.15 M NaCl, 3 mM EDTA 0.05% v / v P20 surfactant). Human MET was prepared in-house by expressing a C-terminal myc-mychexahistidine tag (hMET-mmh). Different concentrations (3-fold dilutions) of hMET-mmh (ranging from 30 nM to 1.1 nM) prepared in HBS-EP running buffer were injected onto the captured surface of antibody or anti-MET ADC at a flow rate of 40 pL / min. . The association of hMETmmh with each of the captured ADCs and monoclonal antibodies was monitored for 4 minutes. Subsequently, hMET-mmh dissociation was monitored for 6 min in HBSEP running buffer. The anti-human Fc surface was regenerated by a brief injection of 20 mM H3PO4. All binding kinetics experiments were performed at 25 °C. Kinetic association (ka) and dissociation (ka) rate constants were determined by fitting real-time sensorgrams to a 1:1 binding model using Scrubber 2.0c curve-fitting software. All sensorgrams were double referenced by subtracting the signal of the buffer injection sensorgram from the corresponding analyte sensorgram, thus eliminating artifacts caused by antibody dissociation from the capture surface. The ΜΛ / t / ZUZ I / UOÓ4OÓ 100 binding dissociation equilibrium constants (Kd) and dissociative half-life (1½) were calculated from the kinetic rate constants as: Ko(M) = ^yr / 2(min)=^ Binding kinetic parameters for maytansinoid A or maytansinoid B conjugated anti-Met monospecific and bispecific antibodies are shown below in Table 25, with some experiments performed in duplicate. Table 25: Biacore binding affinities of mono- and bispecific conjugated monoclonal anti-MET antibodies at 25 °C Captured mAb antibody (RU) Antigen bound (RU) ka (1 / Ms) kd (1 / s) Kd (M) t1 / 2 (min) H4H13312P2 148.1±1.2 12.3 2.59E+05 5.35E-03 2.07E- 08 2.2 H4H13312P2 142.7±0.3 12.1 1.87E+05 4.85E-03 2.59E-08 2.4 H4H13312P2- Maytansinoid A 232.6±0.5 11.9 1.82E+05 7.18E-03 3.94E-0 8 1.6 H4H13312P2- Maytansinoid B 263.0±2.6 10.9 1.80 E+05 6.32E-03 3.51 E-08 1.8 H4H14639D 283.6±4.4 82.8 5.90E+05 1.56E-03 2.64E-09 7.4 H4H14639D- Maitansinoid A 207.7±0.8 55.8 4.95E+05 1.81E-03 3.65E-09 6.4 H4H14639D- Maytansinoid B 227.5±0.4 55.4 4.83E+05 1.87E-03 3.86E-09 6.2 H4H14639D- Maytansinoid A 284.0±1.1 62.8 4.70E+05 1.76E-03 3.74 E-09 6.6 H4H14639D- Maytansinoid B 268.7±0.7 72.8 4.91 E+05 1.45E-03 2.95E-09 8.0 Example 24: In Vitro Potencies of Anti-MET Antibody Drug Conjugates (ADC) To determine the relative cell killing potency of the anti-MET antibody drug conjugates (ADC) described herein, cell killing assays were performed on multiple cell lines expressing varying levels of endogenous MET. Cell lines EBC-1 (Riken Cell Bank; #RBRC-RCB1965), MKN-45 (JCRB; #JCRB0254), NCI-H1993 (ATCC; #CRL5909), and J.RT3 (ATCC; #TIB-153) were maintained. in RPMI + 10% FBS + 1X penicillin / streptomycin / L-glutamine (P / S / G), SNU-5 (ATCC; # CRL-5973) were maintained in Iscove + 10% FBS + 1X P / S / G, Hs746t (ATCC; #HTB-135) and HEK293 (ATCC; #003041) were maintained in DME + 10% FBS + 1X P / S / G, MDA101 MB-231 (ATCC; # ΗΤΒ-26) were maintained in Liebowitz's L-15 + 10% FBS + 1X P / S / G + 1X non-essential amino acids (NEAAs) without CO2, U87MG (ATCC; # HTB- 14) were maintained in MEM Earle's Salts + 15% FBS + 1X P / S / G + 1X NEAA, T47D (ATCC; #HTB-133) were maintained in RPM1 1640 + 10% FBS + 1X P / S / G + 10 mM HEPES + 1 mM sodium pyruvate + 10 pg / mL bovine insulin and A549 (ATCC; #CCL-185) were maintained in Kaighn's F-12 nutrient mix (HAM's F-12K) + FBS at 10% + 1X P / S / G. Initially, the relative binding of anti-MET antibodies was assessed with unconjugated H4H14635D, H4H14639D and H4H13312P2 antibodies across the panel of cell lines by flow cytometry. Briefly, 1x106 cells were incubated with 10 pg / mL of H4H14635D, H4H14639D, H4H13312P2 or an isotype control antibody (REGN1945) for 30 min on ice in PBS + 2% FBS (FACS buffer). After a FACS buffer wash, cells were incubated with 10 pg / mL Alexa647-conjugated anti-human secondary antibody (Jackson ImmunoResearch, #109-606-170) for 30 min on ice. After additional washing with FACS buffer, samples were fixed with Cytofix (BD Biosciences, #554655), filtered with FACS buffer, and processed on an IQue flow cytometer (Intelicyte). Mean fluorescence intensity (MFI) data were determined using the FlowJo software (FlowJo LLC). FACS binding is expressed as times MFI binding above isotype control levels and the results are summarized in Table 26. The relative binding of the three anti-Met antibodies was comparable in each cell line and varied from 447-fold to 7-fold above isotype controls. No detectable binding of any of the 3 anti-MET antibodies tested was observed in T47D, HEK293 or J.RT3 cells. To measure the in vitro cytotoxicity of the anti-MET ADCs, nuclear counts were assessed after a 3- or 6-day treatment with the ADCs. Briefly, cells were seeded in collagen-coated 96-well plates (Greiner, VWR; #82050-812) at 750-3000 cells / well in complete growth medium and grown overnight at 37°C, in 5% CO2. %. For cell viability curves, serially diluted ADCs, unconjugated antibodies, or free payloads were added to cells at final concentrations ranging from 100 nM to 0.01 nM (depending on toxin concentration) and incubated for 3 or 6 days. at 37 °C in 5% CO2. Cells were subsequently treated with Hoechst 33342 nuclear stain at 3 pg / mL (Invitrogen, #H3570) while fixing with 4% formaldehyde. Images were acquired on ImageXpress micro XL (Molecular Devices, Sunnyvale, CA) and nuclear counts were determined using MetaXpress image analysis software (Molecular Devices, Sunnyvale, CA). Nuclear background counts from cells treated with 40 nM digitonin were subtracted from all wells and viability was expressed as a percentage of untreated controls. ICsose values ​​were determined from a four-parameter logistic equation on a 10-point response curve (GraphPad Prism). The untreated condition for each dose-response curve is also included in the analysis and is represented as the lowest dose. The IC50 values ​​and the percentage of cell death are shown in Tables 27 and 28. As summarized in Table 27, the anti-MET antibody drug conjugate H4H14639Dmaytansinoid A specifically reduced cell viability in the EBC-1, SNU-5, MKNΜΛΖ t / ZUZ IZUO0400 cell backgrounds. 102 45, NCI-H1993, and Met-amplified Hs746t with IC50 values ​​ranging from 0.35 nM to 0.96 nM. The percentage of dead cells (maximum % kill) ranged from 73% to 100%. H4H14639DMaitansinoid A also specifically killed 84% of A549 cells with IC50 values ​​of 13.91 nM. The ICsode H4H14639D-Maitansinoid A values ​​were higher than 37 nM in cell lines with low expression (MDA-MB-231 and U87MG) and without expression (T47D, HEK293 and J.RT3). The similarly conjugated isotype control antibody killed all cell lines with IC50 values ​​greater than 35 nM. The methyl disulfide version of DM1 (MeS-DM1) killed all lines tested with IC50 values ​​ranging from 0.07 nM to 2.86 nM. In a separate experiment, three anti-Met antibodies (H4H14639D, H4H14635D, and H4H13312P2) were conjugated to maytansinoid, maytansinoid A, or maytansinoid B payloads, and in vitro cytotoxicity was assessed in EBC-1, Hs746t, A549, and T47D cells. after 6 days of treatment. As summarized in Table 28, all anti-Met antibody-drug conjugates potently and specifically reduced cell viability in Met-positive cells, with IC50 values ​​as low as 10 pM in EBC-1 cells, 0.82 nM in Hs746t cells. and 3.5 nM in A549 cells. The percentage of dead cells was greater than 95% in EBC-1 cells, greater than 86% in Hs746t cells, and greater than 72% in A549 cells. T47D (Met-negative) cells were not specifically killed by anti-Met ADCs. Isotype control antibodies similarly conjugated reduced cell viability in all cell lines tested with IC50 values ​​greater than 5 nM in EBC-1 cells, greater than 33 nM in Hs746t cells, and greater than 90 nM in A549 cells and T47D. Unconjugated H4H14639D reduced cell viability in EBC-1, Hs746t, and A549 cells, but to a lesser extent than conjugated antibodies. Unconjugated H4H14635D and H4H13312P2 had little or no impact on viability in any of the cell lines tested. The methyl disulfide version of DM1 (MeS-DM1) killed all lines tested with IC50 values ​​ranging from 0.12 nM to 1.39 nM. In contrast, M24 (the released payload of maytansinoid B) killed cells with IC50 >100 nM. Table 26: FACS binding of unconjugated MET antibodies to tumor cell lines. ΜΛ / t / ZUZ I / UOÓ4OÓ EBC-1 cell line FACS binding (MFI fold above isotype control) Unstained 0.7 Secondary only 0.6 REGN1945 (Isotype Control) 1 H4H14635D 263 H4H14639D 252 H4H13312P2 147 SNU-5 1 1.2 1 477 454 235 MKN- 45 1 0.8 1 183 156 94 NCI-H1993* 1 2 ND ND 188 188 Hs746t 0.8 1.1 1 39 34 27 MDA-MB231 3 5.6 1 11 12 7 U87MG 1.6 1.7 1 18 18 10 103 T47D 1 0.9 1 1.3 1 1.4 A549 0.7 0.5 1 12 10 7 HEK293 0.2 0.2 1 1.8 1.8 1.2 J.RT3 0.8 1 1 1.6 1.4 1.1 * Expressed as times above without staining for NCI-H1993. MA / t / ZUZ I / UOÓ4OÓ Table 27: ICso and maximum % kill of anti-MET ADCs in 3-day in vitro cytotoxicity assay. Antibody-drug conjugate EBC-1 SNU-5 MKN-45 NCI-H1993 IC50 (nM) Maximum % death IC50 (nM) Maximum % death IC50 (nM) Maximum % death IC50 (nM) Maximum % death DM1 (MeS- DM1) 2.22 90 1.22 99 2.73 85 2.86 81 H4H14639D 0.82 37 0.30 40 ND 0 ND 0 H4H14639D- Maytansinoid A 0.96 89 0.40 100 0.35 86 0.41 94 REGN1 945- Maitansinoid A 35.06 65 >100 14 >100 39 49.42 68 Antibody-drug conjugate Hs746t MDA-MB-231 U87MG IC50 (nM) Maximum % death IC50 (nM) Maximum % death IC50 (nM) Maximum % death DM1 (free drug) 1.46 81 1.53 89 0.61 89 H4H14639D 0.42 7 > 100 6 >100 6 H4H14639D- Maytansinoid A 0.56 73 >100 48 100 58 REGN1945- Maytansinoid A 33.22 44 >100 42 94.71 58 Antibody-drug conjugate T47D A549 HEK293 J.RT3 ICso (nM) Maximum % death ICso (nM) Maximum % death ICso (nM) Maximum % death ICso (nM) Maximum % death DM1 (free drug) 1.33 91 2.56 97 0.15 95 0.07 100 H4H14639D >100 0 >100 37 ND 0 >100 5 H4H14639D- Maytansinoid A >100 6 13.91 84 40.90 65 37.82 59 REGN1945- Maytansinoid A >100 1 >100 63 >100 44 39.79 70 104 Table 28: IC50 and maximum % kill of anti-MET ADC in 6-day in vitro cytotoxicity assay. Antibody-drug conjugate EBC-1 Hs746t T47D A549 ICso (nM) Maximum % death IC50 (nM) Maximum % death IC50 (nM) Maximum % death IC50 (nM) Maximum % death DM1 (MeS-DM1) 0.12 62 1.39 88 0.24 96 0.49 90 M24 (payload released from maytansinoid B) >100 32 >100 10 >100 0 >100 10 H4H14639D 0.37 66 0.44 35 >100 0 0.17 29 H4H14639D- Maitansine ide A 0.27 97 0.82 87 >100 3 6.01 86 H4H14639D- Maitansinoid B 0.01 96 0.86 90 >100 0 3.54 80 H4H13312P2 >100 30 >100 0 >100 0 >100 7 H4H13312P2- Maitansinoid A 0.39 95 1.59 87 >100 6 18.30 89 H4H13312P2- Maytansinoid B 0.07 95 0.89 90 >100 3 27.10 85 H4H14635D >100 11 >100 7 >100 7 >100 0 H4H14635D- Maytansinoid A 0.76 96 1.76 86 >100 92 6.78 91 H4H14635D- Maytansinoid B 0.26 96 2.32 89 >100 2 21.40 72 REGN1945 >100 0 >100 0 >100 0 >100 1 REGN1945- Maytansinoid A 28.08 93 33.06 76 >100 14 93.40 49 REGN1945- Maytansinoid B 5.01 97 >100 0 >100 1 >100 15 Example 25: In vivo efficacy against gastric cancer cells 3 million Hs746T gastric cancer cells were implanted subcutaneously in the flank of CB-17 SCID mice. Once tumor volumes reached approximately 150 mm3, mice were randomized into groups of 6 and treated with control antibodies REGN1945-maltansinoid B or REGN1945-maytansinoid A at 10 mg / kg or with H4H14639D-maytansinoid A or H4H14639Dmaytansinoid B at 3 or 10 mg / kg. All antibodies were administered three times with a frequency of once a week. Tumor growth was monitored for 37 days after implantation. 105 The effect of H4H14639D-maytansinoid A or H4H14639D-maytansinoid B on the growth of human tumor xenografts in immunosuppressed mice was evaluated, and the results are shown in Table 29. Tumors treated with the control antibodies, REGN1945-maytansinoid B or REGN1945-maytansinoid A, grew to reach protocol size limits in 20 days. Tumors treated with H4H14639D-maytansinoid A at 3 mg / kg grew to protocol size limits in 27 days. Growth of tumors treated with H4H14639D-maytansinoid B at 3 mg / kg was inhibited for the duration of the experiment. Treatment of tumors with H4H14639D-maytansinoid A or H4H14639D-maytansinoid B at 10 mg / kg induced regression of tumor size from the start of treatment. Table 29: Tumor Growth in SCID Mice Treated with Anti-Met-C Antibody Conjugates Antibody (mg / kg) Tumor growth (mm3) since the start of treatment (mean ± SD) REGN1945-Maitansinoid A 10 mg / kg 1244 ±199 REGN1945-Maitansinoid B 10 mg / kg 1345 ±121 H4H14639D-Maitansinoid A 3 mg / kg 832 ± 15 H4H14639D-Maitans¡no¡de A 10 mg / kg -148 ± 0.17 H4H14639D-Maitansino¡de B 3 mg / kg 19 ± 147 H4H14639D -Maitansinolde B 10 mg / kg -137 ±0 Example 26: In vivo efficacy against lung cancer cells 5 million EBC1 lung cancer cells were implanted subcutaneously in the flank of CB-17 SCID mice. Once tumor volumes reached approximately 170 mm3, mice were randomized into groups of 6 and treated with the control antibody REGN1945maytansinoid B at 15 mg / kg or H4H14639D-maytansinoid B at 2.5, 5, 10, or 15 mg / kg. The antibodies were administered twice with a frequency of once a week. Tumor growth was monitored for 73 days after implantation. The effect of H4H14639D on the growth of human tumor xenografts in immunocompromised mice was evaluated. Tumors treated with the control antibody, REGN1945-maytansinoid B, grew to protocol size limits in 24 days (IACUC protocols require the sacrifice of animals harboring tumors greater than 2 cm in diameter, approximately 1500 mm3 ). Treatment of tumors with H4H14639D-maytansinoid B at 2.5, 5, 10, or 15 mg / kg induced regression of tumor size from the start of treatment. The results are shown in Table 30. 106 Table 30: Tumor growth in SCID mice treated with anti-Met-C antibody conjugates Antibody (mg / kg) Tumor growth (mm3) since the start of treatment (mean ± SD) REGN1945-Maitansinoid B 15 mg / kg 1106 ± 165 H4H14639D-Maitansinoid B 2.5 mg / kg -142 ±24 H4H14639D-Maitansinoid B 5 mg / kg -163 ±0 H4H14639D-maytansinoid B 10 mg / kg -173 ±0 H4H14639D-maytansinoid B 15 mg / kg -179 ±0 ΜΛ / t / ZUZ I / UOÓ4OÓ Example 27: In Vivo Efficacy Against Patient-Derived NSCLC Tumors Tumors derived from NSCLC patients CTG-0165 expressing Met were implanted subcutaneously into the flank of nu / nu nude mice. Once tumor volumes reached approximately 150 mm3, mice were randomized into groups of 6 and treated with control antibodies REGN1945-maytansinoid B or REGN1945-maytansinoid A at 10 mg / kg or with H4H14639Dmaytansinoid A or H4H14639D-ma. Tansinoid B at 3 or 10 mg / kg. All antibodies were administered three times with a frequency of once a week. Tumor growth was monitored for 61 days after implantation. The effect of H4H14639D-maytansinoid A or H4H14639D-maytansinoid B on the growth of human tumor xenografts in immunosuppressed mice was evaluated. Tumors treated with control antibodies REGN1945-maytansinoid A or REGN1945-maytansinoid B grew to protocol size limits in 27 days. The growth of tumors treated with H4H14639D-maytansinoid A or H4H14639D-maytansinoid B was inhibited at 3 mg / kg for 27 days. Treatment of tumors with H4H14639D-maytansinoid A or H4H14639D-maytansinoid B at 10 mg / kg induced regression of tumor size from the start of treatment. The data is provided in Table 31. Table 31: Tumor Growth in Nude Mice Treated with Anti-Met-C Antibody Conjugates Antibody (mg / kg) Tumor growth (mm3) since the start of treatment (mean + SD) REGN1945-maytansinoid A 10 mg / kg 967± 136 REGN1945-maytansinoid B 10 mg / kg 1537 ±373 H4H14639D-maytansinoid A 3 mg / kg 154 ±227 H4H14639D-maytansinoid A 10 mg / kg -141 ±2.3 H4H14639D-maytansinoid B 3 mg / kg 517 ±362 H4H14639D-maytansinoid B 10 mg / kg -145±2 107 Example 28: Hydrogen / Deuterium (H / D) exchange-based epitope mapping Mapping of anti-Met antibodies H4H13312P2, H4H13306P2 and H4H14639D that bind to human MET Experiments were carried out to determine the specific regions of the ectodomain of the human hepatocyte growth factor receptor (SEQ ID NO: 155: human Met isoform 1 (Uniprot ID: P08581) expressed with a myc-myc-hexahistidine tag. (.mmh,), hereinafter referred to as hMet) with which the anti-Met antibodies H4H13312P2, H4H13306P2 and H4H14639D interact. H4H13312P2 and H4H13306P2 are bivalent monospecific anti-Met antibodies; H4H14639D is a bispecific antibody comprising two heavy chains that bind to different epitopes on Met, each from H4H13312P2 and H4H13306P2, respectively, and a universal light chain. (See example 5). Hydrogen / deuterium exchange (H / D) epitope mapping with mass spectrometry (HDX-MS) was used to determine the binding epitopes of the aforementioned antibodies. A general description of the HDX method is set out in, for example, Ehring (1999) Analytical Biochemistry 267(2):252-259; and Engen and Smith (2001) Anal. Chem. 73:256A-265A. experimental procedure To map the binding epitope(s) of anti-Met antibodies H4H13312P2, H4H13306P2, and H4H14639D on hMET via HDX, individual antibodies were covalently attached to separate NHS-activated Sepharose 4 fast flow beads (GE Healthcare, Pittsburgh , PA). Both antigen and complex methods were used, as described below, to confirm the binding epitopes of the anti-Met antibodies. In the 'on antigen' experimental condition, hMET was deuterated for 5.0 min or 10.0 min in PBS buffer prepared with D2O. Deuterated antigen was bound to either H4H13312P2 or H4H13306P2 antibody beads through a brief incubation, and then eluted from the beads with ice-cold low pH quenching buffer. The eluted sample was manually loaded onto a Waters H / DX-MS system consisting of integrated online peptide digestion, capture, 9.0 min liquid chromatography (LC) separation, and Synapt G2-YES MS data acquisition. In the 'in complex' experimental condition, hMET was first bound to H4H13312P2 or H4H13306P2 beads and then deuterated for 5.0 min or 10.0 min via incubation in PBS buffer prepared with D2O. Deuterated hMET was eluted and analyzed by Waters H / DX-MS system as mentioned above. For identification of hMET peptic peptides, LC-MSE data from the undeuterated sample was processed and searched against human MET using Waters ProteinLynx Global Server (PLGS) software. Identified peptides were imported into DynamX 3.0 software and filtered based on the following two criteria: 1) minimum products per amino acid are 0.3; 2) The replication file threshold is 3.0. Subsequently, DynamX 3.0 software automatically calculated the deuterium uptake difference of each identified peptide between antigen and complex at 5 min and 10 min deuterium time points. The individual isotopic peak of each peptide collected by the DynamX software for the centroid value calculation was also examined manually to ensure the accuracy of the deuterium absorption calculation. M A / E / ZUZ I / UOO4OO 108 In general, delta values ​​for deuteration above 0.2 were used as the cutoff to determine a specific binding epitope. Results Using on-line pepsin digestion through the Waters Enzymate™ BEH pepsin column (2.1 x 30 mm, 5 pm) in conjunction with 9.0 minute LC-MSE data acquisition, a total of 162 human MET peptic peptides with traceable deuterium uptake for 'in antigen' and 'in complex' experiments when H4H13312P2 antibody beads were used. These peptides represent a sequence coverage of 55.7%. Among all these peptides, only five were found to have significantly reduced deuteration uptake upon binding to H4H13312P2 (in complex) compared to antigen deuteration alone (in antigen). The centroid values ​​of these five peptides in both experimental conditions are illustrated in Table 32. The region corresponding to residues 192-204 covered by these five peptides was defined as the binding epitope for the H4H13312P2 antibody based on data from HDX. Table 32: hMET peptic peptides with reduced deuterium uptake on binding to H4H13312P2 ΜΛ / t / ZUZ I / UO0400 hMET residues Deuteration 5 min Deuteration 10 min In Centroid MH+ complex In Centroid MH+ antigen Δ In Centroid MH+ complex In Centroid MH+ antigen Δ 192-202 1351.25 1351.83 -0.58 1351.39 1352.27 -0.88 192-203 1482.34 1482.94 -0.60 1482.50 1483.40 -0.90 192-204 1629.84 1630.71 -0.87 1630.01 1631.10 -1.09 193-202 1252.07 1252.79 -0.72 1252.25 1253.08 -0.83 193-203 1383.22 1383. 79 -0.57 1383.40 1384.17 -0.77 For the HDX experiment carried out using H4H13306P2 antibody beads, a total of 98 hMET peptic peptides with traceable deuterium uptake were reproducibly identified during 'on antigen' and 'in complex' experiments. These 98 peptides represent a sequence coverage of 52.1%. Among all these peptides, twelve were observed to have significantly reduced deuteration uptake upon binding to H4H13306P2 (in complex) compared to deuteration of the antigen alone (in antigen). The centroid values ​​of these twelve peptides in both experimental conditions were illustrated in Table 33. The regions corresponding to SOSSIS residues and residues 421-455 covered by these peptides were defined as the binding epitope for antibody H4H13306P2 based on the HDX data. Table 33: hMET peptic peptides with reduced deuterium uptake upon binding to H4H13306P2 hMET residues Deuteration 5 min Deuteration 10 min In MH+ Centroid complex In MH+ Centroid antigen Δ In MH+ Centroid complex In MH+ Centroid antigen Δ 305-312 818.20 818.83 -0.63 818.31 819.13 -0.82 305-315 1161.50 1162 .58 -1.08 1161.80 1162.95 -1.15 109 306-313 818.48 818.97 -0.49 818.71 819.28 -0.57 421-431 1206.24 1206.75 -0.51 1206.28 1206.95 -0.67 421-435 1581.28 1581.84 -0 .56 1581.41 1582.09 -0.68 421-438 1941.58 1942.15 -0.57 1941.71 1942.39 -0.68 422-438 1794.58 1795.04 - 0.46 1794.72 1795.34 -0.62 439-447 963.90 964.83 -0.93 963.97 965.24 -1.27 439-455 1846.58 1847.79 -1.21 1847.24 1847.85 -0.61 439-456 1960.24 1961.32 -1.08 1960.83 1961.42 -0.59 441-455 1586.30 1587.71 -1.41 1587.33 1587.79 -0.46 442 -455 1487.50 1488.50 -1.00 1487.92 1488.54 -0.62 The same methodology described above was used to determine the binding epitopes for the bispecific anti-Met antibody H4H14639D. The binding epitopes of H4H14639D in hMET, determined by this methodology, correspond to the epitopes determined for the parental antibodies. Anti-Met H4H13312P2 antibody binding epitope: AA 192-204: VRRLKETKDGFMF (SEQ ID NO: 156) of SEQ ID NO: 155. Anti-Met H4H13306P2 antibody binding epitope: AA 305-315: LARQIGASLND (SEQ ID NO: 157) of SEQ ID NO: 155 and AA 421-455: FIKGDLTIANLGTSEGRFMQVVVSRSGPSTPHVNF (SEQ ID NO: 158) of SEQ ID NO: 155. Example 29: Inhibition of Cell Proliferation and Cell Viability by MET x MET Bispecific Antibody ADC in Uveal Melanoma Cell Lines The bispecific c-Met antibody H4H14639D conjugated to one of the two maytansinoid payloads and designated H4H14639D-maytans¡no¡de A and H4H14639D-maytansinoid B was tested in uveal melanoma cell lines to determine effects on cell proliferation and growth. Cell viability in relation to c-Met expression in cell lines. In a first experiment, uveal melanoma cells expressing c-Met, OMM1.3, Mel202, Mel270, and MP65 were seeded overnight in 96-well plates at 1,000 cells per well in RPMI with 10% FBS and were They were incubated at 37 °C with 5% CO2. Cells were treated for seven days with increasing doses of REGN1945, REGN1945-maytansinoid A, REGN1945-maytansinoid B, H4H14639D, H4H14639D-MAYTANSINOID A, and H4H14639D-maytansinoid B from 0.01 nM to 100 nM. After 7 days, relative cell viability was determined by measuring the reduction of WST-8 in the colorimetric assay, Dojindo Cell Counting Kit 8, using the Emax Plus Microplate Reader (Molecular Devices). In a second experiment, uveal melanoma cells expressing c-Met, OMM1.3, as well as c-Met-negative OCM3 cells, were seeded overnight in 96-well plates at 1,000 cells per well in RPMI with 10% FBS and incubated at 37 °C with COaalS%. Cells were treated with increasing doses of REGN1945, REGN1945-maytansinoid B, H4H14639D, and H4H14639D-maytansinoid B from 0.3125 nM to 10 nM. After 7 days, relative cell viability was determined by measuring the reduction of WST-8 in the colorimetric assay, Dojindo Cell Counting Kit 8, using the Emax Plus Microplate Reader (Molecular Devices). Tables 34-38 and Figures 21A to 21D and 22A to 22B show that the bispecific c-Met antibody 110 conjugated to a maytansinoid payload, H4H14639D-maytansin¡de B, reduces the viability of uveal melanoma cells expressing c-Met protein relative to control treatments. H4H14639D-maytansinoid B had no effect on the viability of the c-Met negative cell line. Figures 21A to 21D, on a logarithmic scale, depict the impact on cell viability at lower ADC concentrations. Data for H4H14639D-Maitansinoid A is also shown in Figures 21A to 21D. The unconjugated antibody H4H14639D did not significantly reduce the viability of c-Met-expressing uveal melanoma cells, indicating that these cells do not depend on Met signaling for survival. Figure 33 shows data from a third experiment in which thirteen cell lines were treated with increasing doses of REGN1945, REGN1945-maytansinoid B, H4H14639D and H4H14639D-maytansinoid B for 3 days. H4H14639D-maytansinoid B decreases the viability of MET-expressing uveal melanoma cell lines in a dose-dependent manner with an IC50 of less than 1 nM. Table 34: % viability of Mel270 cells after treatment with H4H14639Dmaytansinoid B M A / Ε / ΖυΖΊ / UOÓ4OÓ Mel270 % cell viability (n = 3) REGN1945 1 nM 100.13±3.46 REGN1945 10 nM 98.20±4.38 REGN1945-Maitansinoid B 1 nM 84.35±10.79 REGN1945-Maitansinoid B 10 nM 92.26±4.8 6 H4H14639D 1nM 92.77±4.49 H4H14639D 10 nM 89.61 ±5.06 H4H14639D-Maitansinoid B 1 nM 11.96±0.51 H4H14639D-Maitansinoid B 10 nM 3.59±0.33 Table 35: % viability of Mel202 cells after treatment with H4H14639Dmaytansinoid B Mel202 % cell viability (n = 3) REGN1945 1 nM 98.80±99.46 REGN1945 10 nM 90.74±9.03 REGN1945-Maitansinoid B 1 nM 96.86±5.29 REGN1945-Maitansinoid B 10 nM 95.90±8.12 H 4H14639D 1nM 91.36±10.57 H4H14639D 10nM 87.74± 5.43 H4H14639D-Maitansinoid B 1 nM 25.82±0.36 H4H14639D-Maitansinoid B 10 nM 5.80±0.21 111 Table 36: % viability of OMM1.3 cells after treatment with H4H14639Dmaytansinoid B 0MM1.3 % cell viability (n = 3) REGN1945 1nM 86.86+4.46 REGN1945 10 nM 81.89±5.13 REGN1945-Maitansinoid B 1 nM 87.37±12.49 REGN1945-Maltansinoid B 10 nM 93.66±11.1 7 H4H14639D 1nM 106.30±4.76 H4H14639D 10nM 109.87±20.36 H4H14639D-Maitansinoid B 1 nM 12.60+0.60 H4H14639D-Maitansinoid B 10 nM 3.66±0.65 Table 37: % viability of MP65 cells after treatment with H4H14639Dmaytansinoid B MP65 % cell viability (n = 3) REGN1945 1 nM 101.40±33.52 REGN1945 10 nM 99.58±11.88 REGN1945-Maitansinoid B 1 nM 81.21 ±27.03 REGN1945-Maitansinoid B 10 nM 135.27±5 4.14 H4H14639D 1nM 101.10±28.58 H4H14639D 10nM 92.87 ±40.98 H4H14639D-Maitansinoid B 1 nM 48.43±14.45 H4H14639D-Maitansinoid B 10 nM 40.00±7.10 Table 38: % viability of OCM3 cells after treatment with H4H14639Dmaytansinoid B OCM3 % cell viability (n = 3) REGN1945 1.25 nM 104.25±6.73 REGN1945 10 nM 89.64+7.83 REGN1945-Maitansinoid B 1.25 nM 88.16+15.49 REGN1945-Maitansinoid B 10 nM 87.5 6±15.08 H4H14639D 1.25nM 89.65±9.52 H4H14639D 10nM 95.02±7.51 H4H14639D-Maitansinoid B 1.25 nM 94.36+4.61 H4H14639D-Maitansinoid B 10 nM 86.93+3.95 112 Example 30: MET x MET bispecific antibody ADC induces apoptosis in uveal melanoma cells Uveal melanoma cells expressing c-Met, OMM1.3 and Mel202, as well as the c-Met-negative cell line, OCM3, were plated overnight in 60 mm3 plates at 800,000 cells per plate in RPMI with FBS at 10% and incubated at 37 °C with 5% COz. Cells were treated with REGN1945 (isotype control antibody) at 1.25, 2.5 nM or 10 nM, REGN1945-maytansinoid A, H4H14639D or H4H14639D-maytansinoid B for 48 hours. Cells were then harvested with trypsin, washed with PBS, fixed with 4% paraformaldehyde for 30 min at room temperature, and stained with DAPI overnight at 4 °C. Cells were plated on a microscope slide and sealed with Cytoseal 40. Apoptotic cells were quantified under a microscope with ultraviolet light to excite DAPI fluorescence. The c-Met bispecific antibody conjugated to a maytansinoid payload, H4H14639Dmaytansinoid B, significantly induced apoptosis of uveal melanoma cells expressing c-Met protein in a dose-dependent manner (see Tables 39 and 40) in relation to the control treatments and c-Met negative cell line (see Table 41). See also Figures 23 and 24. In another experiment, up to 40% apoptosis was induced in cell lines expressing c-Met, OMM1.3 and Mel202, but not OCM3 when treated with 10 nM METxMET-ADC for 48 hours. (data not revealed). By conjugating a c-Met-specific antibody to a cytotoxic compound, uveal melanoma cells can be selectively directed to apoptosis. Table 39: Apoptosis induced by H4H14639D-maytansinoid B in OMM1.3 cells OMM1.3 % apoptosis (n = 1) Untreated 1 REGN1945 1.25 nM 1.67 REGN1945 2.5 nM 1.67 REGN1945-Maitansinoid B 1.25 nM 0.67 REGN1945-Maitansinoid B 2.5 nM 0.33 H4H14639D 1.25 nM 0.67 H4H14639D 2.5 nM 0.67 H4H14639D-Maitansinoid B 1.25 nM 15.00 H4H14639D-Maitansinoid B 2.5 nM 28.33 Table 40: Apoptosis induced by H4H14639D-maytansinoid B in Mel202 cells Mel202 % apoptosis (n = 1) Untreated 0.00 REGN 1945 1.25 nM 0.00 REGN1945 2.5 nM 0.67 REGN1945-Maitansinoid B 1.25 nM 0.33 113 REGN1945-Maitansinoid B 2.5 nM 0.67 H4H14639D 1.25 nM 0.00 H4H14639D2.5 nM 0.33 H4H14639D-Maitansinoid B 1.25 nM 18.33 H4H14639D-Maitansinoid B 2.5 n 22.33 M A / E / ZUZI / UOO4OO Table 41: Apoptosis induced by H4H14639D-maytansinoid B in OCM3 cells OCM3 % apoptosis (n = 1) Untreated 0.67 REGN1945 1.25 nM 1.00 REGN1945 2.5 nM 0.33 REGN1945-Maitansinoid B 1.25 nM 0.67 REGN1945-Maitansinoid B 2.5 nM 0.67 H4H14639 D 1.25 nM 2.00 H4H14639D2.5 nM 1.67 H4H14639D-Maitansinoid B 1.25 nM 1.33 H4H14639D-Maitansinoid B 2.5 nM 2.67 Example 31: MET x MET Bispecific Antibody ADC Alters Cell Cycle in Uveal Melanoma Cells Uveal melanoma cells expressing c-Met, OMM1.3 and Mel202, as well as the c-Met-negative cell line, OCM3, were plated overnight in 60 mm3 plates at 800,000 cells per plate in RPMI with 10% FBS. % and incubated at 37 °C with 5% CO2. Cells were untreated or treated with 10 nM H4H14639D-maytans¡no¡de B for 1, 3, 6, 24, and 48 hours. Cells were then harvested with trypsin, washed with PBS, fixed with cold 70% ethanol overnight at -20°C, incubated in Millipore anti-MPM2 antibody for 2 hours, washed with PBS, incubated in Invitrogen Alexa Fluor conjugated anti-mouse IgG. 488 (Invitrogen) and washed again with PBS. Cells were then stained with 500 pg / mL propidium iodide and incubated overnight at 4SC. The cells were then passed through a cell filter before passage through the BD Bioscience LSR II flow cytometer. Data was analyzed using FCS Express 6 by De Novo software. The bispecific c-Met antibody conjugated to a maytansinoid payload, H4H14639Dmaytansinoid B, significantly induced mitotic arrest in OMM1.3 and Mel202 cells (Figures 25 and 26, respectively) after 6-24 hours of treatment, but did not induce mitotic arrest. in OCM3 cells (Figure 27). There was an increase in the SubG1 population in cells expressing c-Met treated with H4H14639D-maytansino¡de B between 24-48 hours, indicating the induction of apoptosis, but no increase in the SubG1 population was observed in c-Met cells. Negative met. See Tables 42-44. Cell cycle analysis confirmed that the introduction of the maytansinoid payload induced mitotic arrest and, consequently, 114 apoptosis occurred only in the c-Met-expressing cell lines, OMM1.3 and Mel202, and not in the c-Met-negative cell line OCM3. Table 42: OMM1.3 cell cycle distribution after 24 hours of treatment with ΜΛ / t / ZUZ I / UOÓ4OÓ H4H14639D-maytansinoid B Not treated % cells (n = 1) H4H14639d-maitansinoid b % cells (n = 1) subg1 1 h 0.11 1 h 0.03 2h 0.15 2 h 0.08 6h 0.09 6 h 0.20 24 h 0.12 24 h 6.68 48 h 0.21 48 h 14.80 G1 G1 1 h 59.21 1 h 56.80 2h 55.82 2 h 53.79 6h 57.12 6 h 49.82 24 h 57.45 24 h 29.97 48 h 56.14 48 h 31.05 S S 1 h 16.59 1 h 17 .51 2h 17.29 2h 17.76 6h 15.71 6h 16.51 24 h 4:49 p.m. 24 h 1:16 p.m. h 22.76 48 h 35.60 M M 1 h 1.44 1 h 0.95 2h 1.55 2h 2.41 6h 1.82 6h 7.26 24h 1.67 24h 25.12 48h 1.33 48h 11.06 115 Table 43: Cell cycle distribution of Mel202 after 24 hours of treatment with H4H14639D-maytansinoid B Untreated % of cells (n = 1) H4H14639D- Maytansinoid B % of cells (n = 1) SubG1 SubG1 1 h 0.37 1 h 0.45 2 h 0.25 2 h 0.61 6 h 0.41 6 h 0.57 24 h 0.63 24 h 25.82 48 h 1.42 48 h 62.93 G1 G1 1 h 25.98 1 h 24.85 2 h 23.45 2 h 23.30 6 h 26.27 6 h 21.06 24 h 24.47 24 h 19.81 48 h 26.81 48 h 6.34 S S 1 h 10.2 7 1 hour 9.27 2 hours 9.45 2 hours 10.03 6 h 7.76 6 h 10.03 24 h 9.68 24 h 25.38 48 h 4.20 48 h 9.29 G2 / M G2ZM 1 h 50.56 1 h 52.45 2 h 50.94 2 h 52.36 6 h 54.72 6 h 59.96 24 h 57. 40 24 hours 23.87 48 hours 60.32 48 hours 13.02 M M 1 h 0.32 1 h 0.09 2 h 0.53 2 h 1.06 6 h 1.00 6 h 6.79 24 h 0.73 24 h 2.95 48 h 0.17 48 h 0.02 ΜΛΖ t / ZUZ I ZUO0403 116 Table 44: Cell cycle distribution of OCM3 after 24 hours of treatment with H4H14639D-maytansinoid B Untreated % of cells (n = 1) H4H14639D- Maytansinoid B % of cells (n = 1) SubG1 SubG1 1 h 0.62 1 h 0.47 2 h 0.64 2 h 0.51 6 h 0.82 6 h 0.97 24 h 0.91 24 h 1.01 48 h 0.85 48 h 2.02 G1 G1 1 h 62.65 1 h 62.71 2 h 67.37 2 h 66.79 6 h 69.06 6 h 70.32 24 h 68.31 24 h 64.57 48 h 72.85 48 h 68.62 S S 1 h 15.5 3 1 a.m. 4:01 p.m. 2 a.m. 1:92 p.m. 2 a.m. 2:30 p.m. 6 13.66 6 13.41 24 14.55 24 16.28 48 12.52 48 13.14 G2 / M G2 / M 1 19.47 1 18.64 2 16.44 2 16.51 6 15.17 6 13.92 24 14.83 24 hours 16.64 48 hours 12.22 48 h 14.35 M M 1 h 1.59 1 h 1.34 2 h 1.69 2 h 2.03 6 h 1.53 6 h 1.72 24 h 1.30 24 h 2.99 48 h 0.81 48 h 1.74 Example 32: Expression of c-Met in uveal melanoma cell lines Western blot analyzes were performed to assess differences in levels of ΜΛ / t / ZUZ I / UOÓ4OÓ 117 c-Met protein expression in several uveal melanoma cell lines, as well as a gastric carcinoma cell line and a lung carcinoma cell line. Cell lines with variable levels of c-Met expression include SNU-5, a gastric carcinoma cell line, A549, a lung carcinoma cell line, as well as uveal melanoma cell lines, Mel290, 92.1, OMM1. 3, OMM1, Mel285, Mel202, Mel270, OCM1A, OCM3, MP41, MP65, MP46 and UM004, were seeded in 60 mm3 plates at 1,000,000 cells per plate in RPMI with 10% FBS and incubated at 37 °C with 5% CO2 for 24 hours. Cells were then harvested with trypsin, washed with PBS and used with RIPA buffer. Protein uses were run on 4-12% Novex 20-well midi gels (Invitrogen) and then transferred to a PVDF membrane. The membrane was then blocked in 5% skimmed milk powder, incubated in primary antibodies against c-Met (Cell Signaling) and tubulin (Cell Signaling) overnight on a shaker at 4 °C, washed with TBST, incubated in appropriate secondary antibodies (GE Healthcare) conjugated to HRP and washed with TBST. ECL HRP substrate was added to the membrane and the fluorescence image was taken using a Fujifilm XA-2 camera. Results Uveal melanoma cell lines are commonly identified by mutations in G proteins such as GNAQ or GNA11, but they also exhibit differential expression of c-Met. As shown in Figure 28, each of the uveal melanoma cell lines expresses the c-Met receptor at some level, except for the OCM1A and OCM3 cell lines, which turn out to be BRAF'600E mutant cells. SNU-5 is a positive control gastric carcinoma cell line known to express c-Met highly, while A549 is a lung carcinoma cell line also expressing c-Met. Example 33: MET x MET Bispecific Antibody ADC Induces PARP Cleavage and Histone H3 Phosphorylation Western blot analyzes were performed to assess c-Met protein levels, PARP cleavage, and histone H3 phosphorylation in various uveal melanoma cell lines after H4H14639D-maytansinoid B treatment. Uveal melanoma cells expressing c-Met, OMM1.3 and Mel202, as well as the c-Met-negative cell line, OCM3, were plated overnight in 60 mm3 plates at 800,000 cells per plate in RPMI with FBS at 10% and incubated at 37 °C with 5% CO2. Cells were either untreated or treated with increasing doses of REGN1945-maytansinoid B, H4H14639D and H4H14639D-maytansinoid B from 0.5 to 10 nM for 24 hours. Cells were then harvested with trypsin, washed with PBS and used with RIPA buffer. Protein uses were run on 4-12% Novex 20-well midi gels (Invitrogen) and then transferred to a PVDF membrane. The membrane was then blocked in 5% skimmed milk powder, incubated in primary antibodies against PARP (Cell Signaling), phosphorylated histone H3 (Cell Signaling), and tubulin (Cell Signaling) overnight on a shaker at 4 °C. , washed with TBST, incubated in the appropriate HRP-conjugated secondary antibodies (GE Healthcare) and washed with TBST. ECL HRP substrate was added to the membrane and fluorescence image was taken using the ΜΛ / I 7UOO4OO 118 using a Fujifilm XA-2 camera. In another experiment, uveal melanoma cells expressing c-Met, OMM1.3, as well as a c-Met-negative cell line, OCM3, were plated overnight in 60 mm3 plates at 800,000 cells per plate in RPMI with 10% FBS and incubated at 37 °C with 5% CO salt. However, in this experiment, cells were either untreated or treated with 10 nM REGN1945-maytansinoid B, H4H14639D, and H4H14639D-maytansinoid B for the longer time periods of 24, 48, and 72 hours. Cells were then harvested with trypsin, washed with PBS and used with RIPA buffer. Protein lysates were run on 4-12% Novex 20-well midi gels (Invitrogen) and then transferred to a PVDF membrane. The membrane was then blocked in 5% skimmed milk powder, incubated in primary antibodies against c-Met (Cell Signaling), PARP (Cell Signaling), phosphorylated histone-H3 (Cell Signaling) and tubulin (Cell Signaling) for overnight on a shaker at 4 °C, washed with TBST, incubated in the appropriate secondary antibodies (GE Healthcare) conjugated to HRP and washed with TBST. ECL HRP substrate was added to the membrane and the fluorescence image was taken using a Fujifilm XA-2 camera. Results Figure 29 is an image of a Western blot showing that H4H14639Dmaytansinoid B induces PARP (a marker of apoptosis) cleavage in OMM1.3 cells and Mel202 cells after 24 hours of treatment. Neither REGN1945-maytansinoid B nor H4H14639D induced PARP cleavage. Unlike c-Met-positive cell lines, OCM3 cells did not show PARP cleavage after treatment with H4H14639D-maltansinoid B. Figure 29 also shows a significant increase in histone H3 phosphorylation in OMM1.3 cells and Mel202 treated with H4H14639Dmaytansinoid B compared to REGN1945-maytansinoid B and H4H14639D, but not in OCM3 cells. Histone H3 phosphorylation is induced during mitosis and is evidence of maytansinoid-induced mitotic arrest in the cell. In Figure 29, histone H3 phosphorylation is observed only in cells expressing c-Met (OMM1.3 and Mel202) and not in OCM3 and is evidence that the maytansinoid is transported into the cell by the antibody. c-Met. These data further demonstrate the specificity and effectiveness of the c-Met ADC. Figure 30 is an image of a Western blot showing a time-dependent induction of PARP cleavage in OMM1.3 cells treated with H4H14639D-maltansinno¡de B but not in OMM1.3 cells treated with REGN1945-maitansino¡de. B or with H4H14639D. PARP protein was not affected by H4H14639D-maytansinoid B treatment in OCM3 cells. Furthermore, total Met protein expression is decreased when treated with H4H14639D and H4H14639D-M114 compared to untreated and REGN1945-M114, indicating receptor internalization after antibody or ADC treatment. Finally, there was a significant increase in histone H3 phosphorylation in OMM1.3 cells treated with H4H14639D-maytansinoid B (compared to treatment with REGN1945-maytansinoid B or H4H14639D), but again, this increase was not observed. observed in OCM3 cells. In conclusion, an illustrative bispecific anti-c-Met antibody, the H4H14639D antibody, targets M A / E / ZUZ I / UOO4OO 119 specifically to c-Met in cells that express this receptor. By conjugating this antibody to a maytansinoid (H4H14639D-Maitansinoid B), apoptosis can be specifically and potently induced in uveal melanoma cell lines expressing c-Met. Example 34: MET x MET Bispecific Antibody ADC Inhibits Invasion of c-Met Expressing Uveal Melanoma Cells Uveal melanoma cells expressing c-Met, OMM1.3, were seeded overnight on matrigel inserts placed in a 24-well plate at 120,000 cells per insert in RPMI with 0.1% FBS with the following treatments: control without treat, R1945 at 125, 250, and 500 pM, R1945-maltansinoid B, H4H14639D, and H4H14639D-maltansinoid B. RPMI with 10% FBS and 50 ng / mL human HGF as chemotactic were plated into the well. After approximately 24 hours, the insert side of the matrigel was cleaned of non-migrated cells. Migrated cells were fixed in methanol for 2 min and stained with 1% toludine for 2 min and then washed twice with ddFW. The dried matrigels were then placed on microscope slides and sealed with Cytoseal 60. Images were taken using the Nikon TE-2000-U microscope. Results The c-Met H4H14639D-maytansinoid B bispecific antibody significantly inhibited the invasion of OMM1.3 uveal melanoma cells expressing c-Met protein relative to control treatments (R1945 and R1945-maytansinoid B) beginning at 250 pm. There was also a significant inhibition of cell invasion in cells treated with H4H14639D starting at 250 pM. Cell viability, however, is not affected by the payload of conjugated maytansinoid in H4H14639D-maytansinoid B at this dose. See Figure 32. The present description is not limited in its scope by the specific embodiments described in the present description. In fact, various modifications of the invention in addition to those described in the present description will be apparent to those skilled in the art from the above description and accompanying figures. Said modifications are intended to be included within the scope of the appended claims.

Claims

1. A method for treating uveal melanoma, reducing the growth of a uveal melanoma tumor and / or inducing regression of a uveal melanoma in a subject, the method comprising administering to a subject in need an antibody-drug conjugate (ADC) comprising a bispecific antigen-binding molecule and a cytotoxin, wherein the bispecific antigen-binding molecule comprises: a first antigen-binding domain (D1); and a second antigen-binding domain (D2); wherein D1 binds specifically to a first human MET epitope; and wherein D2 binds specifically to a second human MET epitope.

2. The method according to claim 1, wherein uveal melanoma expresses MET.

3. The method according to claim 1, wherein D1 comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 58 and three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

138.

4. The method according to claim 1, wherein D2 comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 82 and three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

138.

5. The method according to claim 1, wherein the bispecific antigen-binding molecule comprises the CDRs within the D1-HCVR amino acid sequence of SEQ ID NO: 58 and the CDRs within the D2-HCVR amino acid sequence of SEQ ID NO:

82.

6. The method according to claim 1, wherein the first epitope of human MET comprises amino acids 192-204 of SEQ ID NO:

155.

7. The method according to claim 1, wherein the second epitope of human MET comprises amino acids 305-315 and 421-455 of SEQ ID NO:

155.

8. The method according to claim 1, wherein the first epitope of human MET comprises amino acids 192-204 of SEQ ID NO: 155; and wherein the second epitope of human MET comprises amino acids 305-315 and 421-455 of SEQ ID NO:

155.

9. The method according to claim 1, wherein the cytotoxin is selected from the group consisting of biotoxins, chemotherapeutic agents, and radioisotopes.

10. The method according to claim 1, wherein the cytotoxin is selected from the group consisting of maitansinoids, auristatins, tomaimicins, duocarmycins, 225Ac, 227Th and derivatives thereof.

11. The method according to claim 1, wherein the cytotoxin is conjugated to the bispecific antigen-binding molecule via a linker and wherein the cytotoxin is: ML / t / ZUZ I / UOO4OO >_____ where the is the linker binding.

12. The method according to claim 11, wherein the linker is: a OO wherein the linkage indicated by 5 represents the linkage to the bispecific antigen-binding molecule and the linkage indicated by 5 represents the linkage to the cytotoxin.

13. The method according to claim 1, wherein the cytotoxin is conjugated to the bispecific antigen-binding molecule via a linker and wherein the cytotoxin is: >_____ where is the linker. 122 14. The method according to claim 13, wherein the linker is o.,nh2 wherein the linkage indicated by 2 represents the linkage to the bispecific antigen-binding molecule and the linkage indicated by 2 represents the linkage to the cytotoxin.

15. A method for inhibiting proliferation, inhibiting invasion, inducing apoptosis and / or decreasing the viability of a uveal melanoma cell, the method comprising contacting the cell with an antibody-drug conjugate (ADC) comprising a bispecific antigen-binding molecule and a cytotoxin, wherein the bispecific antigen-binding molecule comprises: a first antigen-binding domain (D1); and a second antigen-binding domain (D2); wherein D1 binds specifically to a first human MET epitope; and wherein D2 binds specifically to a second human MET epitope.

16. The method according to claim 15, wherein D1 comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 58 and three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

138.

17. The method according to claim 15, wherein D2 comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 82 and three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

138.

18. The method according to claim 15, wherein the cytotoxin is conjugated to the bispecific antigen-binding molecule via a linker v, wherein the cytotoxin is: 123 >_____ where the is the linker binding.

19. The method according to claim 18, wherein the linker is: MA / E / ZυZΊ / UO 0400 wherein the linkage indicated by 2 represents the linkage to the bispecific antigen-binding molecule and the linkage indicated by 2 represents the linkage to the cytotoxin.

20. The method according to claim 15, wherein the cytotoxin is conjugated to the bispecific antigen-binding molecule via a linker and wherein the cytotoxin is: >_____ wherein $ is the linker binding.

21. The method according to claim 20, wherein the linker is where the linkage indicated by A represents the linkage to the bispecific antigen-binding molecule and the linkage indicated by 2 represents the linkage to the cytotoxin.

22. A method for inducing mitotic arrest of a uveal melanoma cell, the method comprising contacting the cell in vivo with an antibody-drug conjugate (ADC) comprising a bispecific antigen-binding molecule and a cytotoxin, wherein the bispecific antigen-binding molecule comprises: a first antigen-binding domain (D1); and a second antigen-binding domain (D2); 124 wherein D1 binds specifically to a first human MET epitope; and wherein D2 binds specifically to a second human MET epitope.

23. The method according to claim 22, wherein D1 comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 58 and three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

138.

24. The method according to claim 22, wherein D2 comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 82 and three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

138.

25. The method according to claim 22, wherein the cytotoxin is conjugated to the bispecific antigen-binding molecule through a linker and wherein the cytotoxin is: wherein the is the binding to a linker.

26. The method according to claim 25, wherein the linker is: OR wherein the linkage indicated by 2 represents the linkage to the bispecific antigen-binding molecule and the linkage indicated by 2 represents the linkage to the cytotoxin.

27. The method according to claim 22, wherein the cytotoxin is conjugated to the bispecific antigen-binding molecule via a linker and wherein the cytotoxin is: 125 MA / t / ZUZ I / UOÓ4OÓ >_____ where the is the linker binding.

28. The method according to claim 27, wherein the linker is where the linkage indicated by 5 represents the linkage to the bispecific antigen-binding molecule and the linkage indicated by 5 represents the linkage to the cytotoxin.

29. A method for treating eye cancer or inhibiting metastasis in a subject suffering from a tumor expressing c-Met, the method comprising administering to the subject a bispecific antigen-binding molecule comprising: a first antigen-binding domain (D1); and a second antigen-binding domain (D2); wherein D1 binds specifically to a first human MET epitope; and wherein D2 binds specifically to a second human MET epitope.

30. The method according to claim 29, wherein the eye cancer is selected from the group consisting of uveal melanoma, orbital lymphoma, retinoblastoma, and medulloepithelioma.

31. The method according to claim 29, further comprising administering to the subject a second therapeutic agent against cancer.

32. The method according to claim 29, wherein D1 and D2 do not compete with each other for joining human MET.

33. The method according to claim 29, wherein D1 comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical thereto and three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical thereto.

34. The method according to claim 29, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 60; HCDR2 comprises the amino acid sequence of SEQ ID NO: 62; HCDR3 comprises the amino acid sequence of SEQ ID NO: 64; LCDR1 comprises the amino acid sequence of SEQ ID NO: 140; LCDR2 comprises the amino acid sequence of SEQ ID NO: 142; and LCDR3 comprises the amino acid sequence of SEQ ID NO:

144.

35. The method according to claim 34, wherein the bispecific antigen-binding molecule comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical thereto; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical thereto.

36. The method according to claim 35, wherein the bispecific antigen-binding molecule comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 58; and an LCVR comprising the amino acid sequence of SEQ ID NO:

138.

37. The method according to claim 36, wherein D2 comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical thereto and three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical thereto.

38. The method according to claim 37, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 84; HCDR2 comprises the amino acid sequence of SEQ ID NO: 86; HCDR3 comprises the amino acid sequence of SEQ ID NO: 88; LCDR1 comprises the amino acid sequence of SEQ ID NO: 140; LCDR2 comprises the amino acid sequence of SEQ ID NO: 142; and LCDR3 comprises the amino acid sequence of SEQ ID NO:

144.

39. The method according to claim 38, wherein the bispecific antigen-binding molecule comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical thereto; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical thereto.

40. The method according to claim 39, wherein the bispecific antigen-binding molecule comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 82; and an LCVR comprising the amino acid sequence of SEQ ID NO:

138.

41. The method according to claim 29, wherein the bispecific antigen-binding molecule is conjugated with a cytotoxin to form an antibody-drug conjugate (ADC) and wherein the cytotoxin is a maitansinoid.