WO2021058735A1 - Cancer treatment with anti-met antibody compositions - Google Patents

Abstract

Provided herein are methods for treating a cancer patient with a composition comprising two anti-MET antibodies or antigen-binding fragments thereof. These methods are useful for treating cancers such as non-small cell lung cancer.

Description

CANCER TREATMENT WITH ANTI-MET ANTIBODY COMPOSITIONS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from United States Provisional Patent Application 62/906,559, filed September 26, 2019, whose disclosure is incorporated by reference herein in its entirety.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The electronic copy of the Sequence Listing, created on August 31 , 2020, is named 022675_W0060_SL.txt and is 31,740 bytes in size.

BACKGROUND OF THE INVENTION

[0003] MET (also known as c-MET) is a receptor tyrosine kinase comprising a 50 kDa a-subunit and a 145 kDa b-subunit. The only known ligand for MET is hepatocyte growth factor (HGF), which is also known as scatter factor. Binding of HGF to MET leads to receptor dimerization and autophosphorylation of b-subunit residues Y1349 and Y1356, activating downstream signaling pathways that include the phosphoinositol 3-kinase (PI3K)-protein kinase B (Akt) pathway, the signal transducer and activator of transcription factor (STAT) pathway, the mitogen- activated protein kinase (MAPK) pathway, and the nuclear factor kappa-light-chain- enhancer of activated B cells (NFKB) pathway. This ultimately leads to increased mitogenesis, cell proliferation, cell survival, and cell motility. Elevated MET activation is frequently observed in epithelial tumors and correlates with poor prognosis in many malignancies, including gastric and lung cancer.

[0004] Dysregulation of MET or HGF activity may occur, e.g., through overexpression, gene amplification, mutation (e.g., exon 14 deletion), or alternative splicing of MET, through increased production of HGF, and/or through HGF ligand- induced autocrine/paracrine loop signaling. Such dysregulation plays a role in many cancers by facilitating cancer invasiveness, angiogenesis, metastasis, and tumor growth, thus leading to a more aggressive cancer phenotype and a poorer prognosis.

[0005] Elevated MET activation may result from MET amplification. In accordance with the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidelines for testing of HER2 amplification, MET amplification may be defined as positive with a MET/CEP7 ratio (CEP7 being the centromeric region of chromosome 7) of > 2.2 (occasionally 2.0), equivocal with a ratio between 1 .8 and 2.2, and negative with a ratio of < 1 .8. There are currently no approved therapeutics for targeted treatment of MET-amplified solid tumor malignancies. [0006] The levels of MET receptor on the cell surface are a balance between the amount of MET synthesized and the amount degraded. Degradation of wild-type MET is triggered by binding of the ubiquitin ligase Cbl to the intracellular region of MET encoded by exon 14 of the MET gene. Mutations in the regions surrounding MET exon 14 introduce failure in the splicing of the MET transcript, resulting in skipping of exon 14. The resulting truncated MET receptor (MET^Ex14del) cannot bind to Cbl, leading to decreased MET degradation and increased accumulation of receptor on the cell surface.

[0007] MET is also known to interact with signaling pathways involving other receptors, such as EGFR, TGF-b, and FIER3, and may play a role in resistance to treatments targeting those receptors. For example, elevated MET is observed in tumors escaping EGFR-targeting treatments. MET inhibitors, such as anti-MET antibodies, thus may be effective in combination with other receptor inhibitors in overcoming resistant phenotypes.

[0008] In view of the critical role of MET in cancer progression, there is a need for effective cancer treatment methods targeting MET.

SUMMARY OF THE INVENTION

[0009] The present disclosure relates to methods for treating a cancer patient using an antibody composition comprising a first anti-MET antibody or an antigen binding portion thereof and a second anti-MET antibody or an antigen-binding portion thereof. In particular aspects, the antibody composition is Sym015.

[0010] In some aspects, the present disclosure provides a method for treating a MET-expressing cancer in a patient, the method comprising administering to the patient a composition comprising: a) a first anti-MET antibody that comprises heavy chain CDR1 -3 amino acid sequences of SEQ ID NOs: 5-7, respectively, and light chain CDR1-3 amino acid sequences of SEQ ID NOs: 8-10, respectively; and b) a second anti-MET antibody that comprises heavy chain CDR1-3 amino acid sequences of SEQ ID NOs: 15-17, respectively, and light chain CDR1-3 amino acid sequences of SEQ ID NOs: 18-20, respectively, wherein the composition is administered one or more times at a dose of 6-24 mg/kg. [0011] In some aspects, the first anti-MET antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 4; and the second anti-MET antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14.

[0012] In some aspects, the first anti-MET antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO: 2; and the second anti-MET antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0013] In some aspects, the composition comprises the first and second anti-MET antibodies at a molar or weight ratio of 1:1, 1:2, 1:3, 2:1, or 3:1, e.g., 1:1.

[0014] In some aspects, the composition is administered at a dose of 6, 12, 18, or 24 mg/kg. In some aspects, the composition is administered at a dose of 6-12, 6-18, 12-18, 12-24, or 18-24 mg/kg. The composition may be administered, e.g., every two weeks.

[0015] In some aspects, the composition is administered at one of the doses described herein as a loading dose and at another of the doses described herein as a maintenance dose. For example, the composition may be administered at an 18 mg/kg loading dose followed (after an interval of two weeks) by a 12 mg/kg maintenance dose every two weeks.

[0016] In some aspects, the composition is formulated for intravenous administration.

[0017] In some aspects, the cancer treated by a method described herein is non small cell lung cancer (NSCLC). In certain aspects, the cancer is wild-type for KRAS. In certain aspects, the cancer is MET-amplified and/or has a deletion of MET exon 14 (MET^Ex14Del).

[0018] In some aspects, the patient treated by a method described herein has been treated previously for the cancer with another therapeutic agent. In certain aspects, the previous treatment comprised a MET-targeting agent (e.g., an anti-MET antibody or a MET tyrosine kinase inhibitor) and/or an EGFR-targeting agent (e.g., an anti-EGFR antibody or an EGFR tyrosine kinase inhibitor).

[0019] In some aspects, the patient is relapsed or refractory to treatment of the cancer.

[0020] In some aspects, treatment with an antibody composition described herein results in one or more of the following: a) tumor regression; b) delay of tumor progression; c) inhibition of cancer progression; d) inhibition of cancer metastasis; e) prevention of cancer recurrence or residual disease; and f) prolonged survival.

[0021] In some aspects, the present disclosure provides an anti-MET antibody composition for use in treating a MET-expressing cancer in a patient in a method described herein. The cancer may be, e.g., NSCLC.

[0022] In some aspects, the present disclosure provides the use of an anti-MET antibody composition for the manufacture of a medicament for treating a MET- expressing cancer in a patient in a method described herein. The cancer may be, e.g, NSCLC.

[0023] In some aspects of the method of treatment as described herein, the anti- MET antibody composition for use as described herein, or the use of an anti-MET antibody composition for the manufacture of a medicament as described herein, the patient is human.

BRIEF DESCRIPTION OF THE DRAWINGS [0024] FIG. 1 is a graph showing the median serum concentration over a period of five weeks following intravenous infusion of Sym015 at 6, 12, 18, or 24 mg/kg every two weeks (“Q2W”), or at a loading dose of 18 mg/kg followed by a maintenance dose of 12 mg/kg Q2W (“RP2D dose”). [0025] FIG. 2 is a waterfall plot of the best change in tumor size in Cohort 1 of Example 2 after treatment with Sym015 at a loading dose of 18 mg/kg followed by a maintenance dose of 12 mg/kg Q2W. “X” signifies patients still receiving treatment at the time of data collection.

[0026] FIG. 3 is a waterfall plot of the best change in tumor size in a non-small cell lung cancer (NSCLC) subgroup of Cohort 1 of Example 2 after treatment with Sym015 at a loading dose of 18 mg/kg followed by a maintenance dose of 12 mg/kg Q2W. “X” signifies patients still receiving treatment at the time of data collection. Patients with prior MET TKI treatment are indicated, as well as patients with ongoing Sym015 treatment.

DETAILED DESCRIPTION OF THE INVENTION [0027] The present disclosure provides cancer treatment regimens using an antibody composition comprising a first anti-MET antibody or an antigen-binding portion thereof and a second anti-MET antibody or an antigen-binding portion thereof (e.g., Sym015). Sym015 is a mixture of humanized lgG1 anti-MET antibodies 9006 and 9338 in a 1:1 ratio (PCT Patent Publication WO 2016/042412, incorporated herein by reference in its entirety), selected for synergistic cancer cell growth inhibition. Sym015 blocks ligand binding to MET, thus inhibiting MET phosphorylation and signaling, without agonist activity. Further, Sym015 mediates MET internalization and degradation, and triggers secondary effector functions (ADCC and CDC). In preclinical studies, Sym015 activity has been shown in tumors resistant to other anti-MET antibody therapy, including in cancer models with MET amplification and MET exon 14 skipping alterations (Poulsen et al. , Clin Cancer Res. (2017) 23(19):5923-35).

[0028] Cancers treated by the treatment regimens described herein may include, e.g., non-small cell lung cancer, gastric cancer, hepatocellular carcinoma, esophageal cancer, colorectal cancer, kidney papillary cell cancer, glioblastoma, adrenocortical carcinoma, renal cell carcinoma, prostate cancer, and other cancers that express or overexpress MET or rely on MET pathway activation. Compared to currently available treatments for such cancers, including antibody treatments, it is contemplated that the composition of the present disclosure will provide a superior clinical response. [0029] Unless otherwise stated, as used herein, “MET” refers to human MET (c- MET). A human MET polypeptide sequence is available under NCBI Accession No. NM_000245.4, shown here as SEQ ID NO: 21.

[0030] The term “antibody” (Ab) or “immunoglobulin” (Ig), as used herein, refers to a tetramer comprising two heavy (H) chains (about 50-70 kDa) and two light (L) chains (about 25 kDa) inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable domain (VH) and a heavy chain constant region (CH). Each light chain is composed of a light chain variable domain (VL) and a light chain constant region (CL). The VH and VL domains can be subdivided further 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 (H-CDR herein designates a CDR from the heavy chain; and L-CDR herein designates a CDR from the light chain) and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The assignment of amino acid numbers in the heavy or light chain may be in accordance with IMGT^® definitions (Lefranc et al. , Dev Comp Immunol 27(1):55-77 (2003)); or the definitions of Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD (1987 and 1991)); Chothia & Lesk, J. Mol. Biol. 196:901-917 (1987); Chothia et al., Nature 342:878-883 (1989); MacCallum et al., J. Mol. Biol. 262:732-745 (1996); or Honegger and Pliickthun, J. Mol. Biol. 309(3):657-70 (2001). [0031] The term “recombinant antibody” refers to an antibody that is expressed from a cell or cell line comprising the nucleotide sequence(s) that encode the antibody, wherein said nucleotide sequence(s) are not naturally associated with the cell.

[0032] The term “humanized” refers to the fact that where an antibody is wholly or partially of non-human origin, for example a murine antibody obtained from immunization of mice with an antigen of interest or a chimeric antibody based on such a murine antibody, it is possible to replace certain amino acids, in particular in the framework regions and constant domains of the heavy and light chains, in order to avoid or minimize an immune response in humans. The specificity of an antibody’s interaction with a target antigen resides primarily in the amino acid residues located in the six CDRs of the heavy and light chain. The amino acid sequences within CDRs are therefore much more variable between individual antibodies than sequences outside of CDRs. Because CDR sequences are responsible for most antibody-antigen interactions, it is possible to express recombinant antibodies that mimic the properties of a specific naturally occurring antibody, or more generally any specific antibody with a given amino acid sequence, e.g., by constructing expression vectors that express CDR sequences from the specific antibody grafted into framework sequences from a different antibody. As a result, it is possible to “humanize” a non-human antibody and still substantially maintain the binding specificity and affinity of the original antibody. Although it is not possible to precisely predict the immunogenicity and thereby the human anti antibody response of a particular antibody, non-human antibodies tend to be more immunogenic than human antibodies. Chimeric antibodies, where the foreign (usually rodent) constant regions have been replaced with sequences of human origin, have been shown to be generally less immunogenic than antibodies of fully foreign origin, and the trend in therapeutic antibodies is towards humanized or fully human antibodies. Chimeric antibodies or other antibodies of non-human origin thus can be humanized to reduce the risk of a human anti-antibody response.

[0033] The term “isolated protein”, “isolated polypeptide” or “isolated antibody” refers to a protein, polypeptide or antibody that by virtue of its origin or source of derivation (1 ) is not associated with naturally associated components that accompany it in its native state, (2) is free of other proteins from the same species, (3) is expressed by a cell from a different species, and/or (4) does not occur in nature. Thus, a polypeptide that is chemically synthesized or synthesized in a cellular system different from the cell from which it naturally originates will be “isolated” from its naturally associated components. A protein may also be rendered substantially free of naturally associated components by isolation, using protein purification techniques well known in the art.

[0034] The term “affinity” refers to a measure of the attraction between an antigen and an antibody. The intrinsic attractiveness of the antibody for the antigen is typically expressed as the binding affinity equilibrium constant (KD) of a particular antibody-antigen interaction. An antibody is said to specifically bind to an antigen when the KD is < 1 mM, preferably < 100 nM. A KD binding affinity constant can be measured, e.g., by surface plasmon resonance (BIAcore™) or Bio-Layer Interferometry, for example using the IBIS MX96 SPR system from IBIS Technologies or the Octet™ system from ForteBio. [0035] The term “epitope” as used herein refers to a portion (determinant) of an antigen that specifically binds to an antibody or a related molecule such as a bi specific binding molecule. Epitopic determinants generally consist of chemically active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains and generally have specific three-dimensional structural characteristics, as well as specific charge characteristics. An epitope may be “linear” or “conformational.” In a linear epitope, all of the points of interaction between a protein (e.g., an antigen) and an interacting molecule (such as an antibody) occur linearly along the primary amino acid sequence of the protein. In a conformational epitope, the points of interaction occur across amino acid residues on the protein that are separated from one another in the primary amino acid sequence. Once a desired epitope on an antigen is determined, it is possible to generate antibodies to that epitope using techniques well known in the art. For example, an antibody to a linear epitope may be generated, e.g., by immunizing an animal with a peptide having the amino acid residues of the linear epitope. An antibody to a conformational epitope may be generated, e.g., by immunizing an animal with a mini-domain containing the relevant amino acid residues of the conformational epitope. An antibody to a particular epitope can also be generated, e.g., by immunizing an animal with the target molecule of interest (e.g., MET) or a relevant portion thereof, then screening for binding to the epitope.

[0036] One can determine whether an antibody binds to the same epitope as or competes for binding with an anti-MET antibody of the present disclosure by using methods known in the art, including, without limitation, competition assays, epitope binning, and alanine scanning. In one aspect, one allows the anti-MET antibody of the present disclosure to bind to MET under saturating conditions, and then measures the ability of the test antibody to bind to MET. If the test antibody is able to bind to MET at the same time as the reference anti-MET antibody, then the test antibody binds to a different epitope than the reference anti-MET antibody.

However, if the test antibody is not able to bind to MET at the same time, then the test antibody binds to the same epitope, an overlapping epitope, or an epitope that is in close proximity to the epitope bound by the anti-MET antibody of the present disclosure. This experiment can be performed using, e.g., ELISA, RIA, BIACORE™, SPR, Bio-Layer Interferometry or flow cytometry. To test whether an anti- MET antibody cross-corn petes with another anti-MET antibody, one may use the competition method described above in two directions, i.e. , determining if the known antibody blocks the test antibody and vice versa. Such cross-competition experiments may be performed, e.g., using an IBIS MX96 SPR instrument or the Octet™ system.

[0037] The term “antigen-binding portion” of an antibody (or simply “antibody portion”), as used herein, refers to one or more portions or fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., human MET, or a portion thereof). It has been shown that certain fragments of a full-length antibody can perform the antigen-binding function of the antibody. Examples of binding fragments encompassed within the term “antigen-binding portion” include (i) a Fab fragment: a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment: a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment, which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) capable of specifically binding to an antigen. Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH domains pair to form monovalent molecules (known as single chain Fv (scFv)). Also within the present disclosure are antigen-binding molecules comprising a VH and/or a VL. In the case of a VH, the molecule may also comprise one or more of a CH1 , hinge, CH2, or CH3 region. Such single chain antibodies are also intended to be encompassed within the term “antigen-binding portion” of an antibody. Other forms of single chain antibodies, such as diabodies, are also encompassed. Diabodies are bivalent, bi-specific antibodies in which VH and VL domains are expressed on a single polypeptide chain but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites.

[0038] Antibody portions, such as Fab and F(ab')2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion of whole antibodies. Moreover, antibodies, antibody portions and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, e.g., as described herein.

[0039] The class (isotype) and subclass of anti-MET antibodies may be determined by any method known in the art. In general, the class and subclass of an antibody may be determined using antibodies that are specific for a particular class and subclass of antibody. Such antibodies are available commercially. The class and subclass can be determined by ELISA, Western Blot as well as other techniques. Alternatively, the class and subclass may be determined by sequencing all or a portion of the constant regions of the heavy and/or light chains of the antibodies, comparing their amino acid sequences to the known amino acid sequences of various classes and subclasses of immunoglobulins, and determining the class and subclass of the antibodies.

[0040] Unless otherwise indicated, all antibody amino acid residue numbers referred to in this disclosure are those under the IMGT® numbering scheme.

I. Anti- MET Antibody Compositions

[0041] The treatment regimens described herein use an antibody composition comprising a first anti-MET antibody or an antigen-binding portion thereof and a second anti-MET antibody or an antigen-binding portion thereof.

[0042] In some aspects, the first anti-MET antibody or antigen-binding portion competes or cross-corn petes for binding to MET with, or binds to the same epitope of MET as, an antibody comprising a heavy chain (HC) with the amino acid sequence of SEQ ID NO: 1 and a light chain (LC) with the amino acid sequence of SEQ ID NO: 2.

[0043] In some aspects, the first anti-MET antibody or antigen-binding portion has a heavy chain CDR3 (H-CDR3) amino acid sequence of SEQ ID NO: 7.

[0044] In some aspects, the first anti-MET antibody or antigen-binding portion has heavy chain CDR1-3 (H-CDR1-3) comprising the amino acid sequences of SEQ ID NOs: 5-7 respectively.

[0045] In some aspects, the first anti-MET antibody or antigen-binding portion has a heavy chain variable domain (VH) amino acid sequence that is at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:

3. [0046] In some aspects, the first anti-MET antibody or antigen-binding portion has a VH comprising the amino acid sequence of SEQ ID NO: 3.

[0047] In some aspects, the first anti-MET antibody has an HC amino acid sequence that is at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1.

[0048] In some aspects, the first anti-MET antibody comprises an HC amino acid sequence of SEQ ID NO: 1.

[0049] In some aspects, the first anti-MET antibody or antigen-binding portion has a light chain CDR3 (L-CDR3) amino acid sequence of SEQ ID NO: 10.

[0050] In some aspects, the first anti-MET antibody or antigen-binding portion has light chain CDR1-3 (L-CDR1-3) comprising the amino acid sequences of SEQ ID NOs: 8-10, respectively.

[0051] In some aspects, the first anti-MET antibody or antigen-binding portion has a light chain variable domain (VL) amino acid sequence that is at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:

4.

[0052] In some aspects, the first anti-MET antibody or antigen-binding portion has a VL comprising the amino acid sequence of SEQ ID NO: 4.

[0053] In some aspects, the first anti-MET antibody has an LC amino acid sequence that is at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2.

[0054] In some aspects, the first anti-MET antibody comprises an LC amino acid sequence of SEQ ID NO: 2.

[0055] In certain aspects, the first anti-MET antibody comprises any one of the above-described heavy chains and any one of the above-described light chains. [0056] In some aspects, the first anti-MET antibody or antigen-binding portion of the present disclosure comprises H-CDR1-3 amino acid sequences of SEQ ID NOs: 5-7, respectively, and L-CDR1-3 amino acid sequences of SEQ ID NOs: 8-10, respectively.

[0057] In some aspects, the first anti-MET antibody or antigen-binding portion of the present disclosure comprises a VH that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 3 and a VL that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4. [0058] In some aspects, the first anti-MET antibody or antigen-binding portion of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 3 and a VL comprising the amino acid sequence of SEQ ID NO: 4.

[0059] In some aspects, the first anti-MET antibody or antigen-binding portion of the present disclosure comprises an HC that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1 and an LC that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2.

[0060] In some aspects, the first anti-MET antibody of the present disclosure comprises an HC comprising the amino acid sequence of SEQ ID NO: 1 and an LC comprising the amino acid sequence of SEQ ID NO: 2.

[0061] In some aspects, the second anti-MET antibody or antigen-binding portion competes or cross-corn petes for binding to MET with, or binds to the same epitope of MET as, an antibody comprising an HC with the amino acid sequence of SEQ ID NO: 11 and an LC with the amino acid sequence of SEQ ID NO: 12.

[0062] In some aspects, the second anti-MET antibody or antigen-binding portion has an H-CDR3 amino acid sequence of SEQ ID NO: 17.

[0063] In some aspects, the second anti-MET antibody or antigen-binding portion has H-CDR1-3 comprising the amino acid sequences of SEQ ID NOs: 15-17 respectively.

[0064] In some aspects, the second anti-MET antibody or antigen-binding portion has a VH amino acid sequence that is at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 13.

[0065] In some aspects, the second anti-MET antibody or antigen-binding portion has a VH comprising the amino acid sequence of SEQ ID NO: 13.

[0066] In some aspects, the second anti-MET antibody has an HC amino acid sequence that is at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 11.

[0067] In some aspects, the second anti-MET antibody comprises an HC amino acid sequence of SEQ ID NO: 11.

[0068] In some aspects, the second anti-MET antibody or antigen-binding portion has an L-CDR3 amino acid sequence of SEQ ID NO: 20. [0069] In some aspects, the second anti-MET antibody or antigen-binding portion has L-CDR1-3 comprising the amino acid sequences of SEQ ID NOs: 18-20, respectively.

[0070] In some aspects, the second anti-MET antibody or antigen-binding portion has a VL amino acid sequence that is at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 14.

[0071] In some aspects, the second anti-MET antibody or antigen-binding portion has a VL comprising the amino acid sequence of SEQ ID NO: 14.

[0072] In some aspects, the second anti-MET antibody has an LC amino acid sequence that is at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 12.

[0073] In some aspects, the second anti-MET antibody comprises an LC amino acid sequence of SEQ ID NO: 12.

[0074] In certain aspects, the second anti-MET antibody comprises any one of the above-described heavy chains and any one of the above-described light chains. [0075] In some aspects, the second anti-MET antibody or antigen-binding portion of the present disclosure comprises H-CDR1-3 amino acid sequences of SEQ ID NOs: 15-17, respectively, and L-CDR1-3 amino acid sequences of SEQ ID NOs: 18- 20, respectively.

[0076] In some aspects, the second anti-MET antibody or antigen-binding portion of the present disclosure comprises a VH that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 13 and a VL that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%,

95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 14.

[0077] In some aspects, the second anti-MET antibody or antigen-binding portion of the present disclosure comprises a VH comprising the amino acid sequence of SEQ ID NO: 13 and a VL comprising the amino acid sequence of SEQ ID NO: 14. [0078] In some aspects, the second anti-MET antibody or antigen-binding portion of the present disclosure comprises an HC that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 11 and an LC that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 12. [0079] In some aspects, the second anti-MET antibody of the present disclosure comprises an HC comprising the amino acid sequence of SEQ ID NO: 11 and an LC comprising the amino acid sequence of SEQ ID NO: 12.

[0080] In certain aspects, an antibody composition used in a treatment regimen described herein comprises any of the above-described first anti-MET antibodies or antigen-binding portions thereof and any of the above-described second anti-MET antibodies or antigen-binding portions thereof.

[0081] In some aspects, an antibody composition used in a treatment regimen described herein comprises:

- a first anti-MET antibody or antigen-binding portion thereof that competes or cross- competes for binding to MET with, or binds to the same epitope of MET as, an antibody comprising an HC with the amino acid sequence of SEQ ID NO: 1 and an LC with the amino acid sequence of SEQ ID NO: 2; and

- a second anti-MET antibody or antigen-binding portion thereof that competes or cross-corn petes for binding to MET with, or binds to the same epitope of MET as, an antibody comprising an HC with the amino acid sequence of SEQ ID NO: 11 and an LC with the amino acid sequence of SEQ ID NO: 12.

[0082] In some embodiments, the first MET antibody may bind SEMA-a blade 3, and the second MET antibody may bind SEMA-a blade 2. Combined targeting of these domains produces surprising synergistic inhibitory effects on the MET signaling pathway.

[0083] In some aspects, an antibody composition used in a treatment regimen described herein comprises:

- a first anti-MET antibody or antigen-binding portion thereof that comprises H- CDR1-3 amino acid sequences of SEQ ID NOs: 5-7, respectively, and L-CDR1-3 amino acid sequences of SEQ ID NOs: 8-10, respectively; and

- a second anti-MET antibody or antigen-binding portion thereof that comprises H- CDR1-3 amino acid sequences of SEQ ID NOs: 15-17, respectively, and L-CDR1-3 amino acid sequences of SEQ ID NOs: 18-20, respectively.

[0084] In some aspects, an antibody composition used in a treatment regimen described herein comprises:

- a first anti-MET antibody or antigen-binding portion thereof that comprises a VH that is at least 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 3 and a VL that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4; and

- a second anti-MET antibody or antigen-binding portion thereof that comprises a VH that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 13 and a VL that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 14.

[0085] In some aspects, an antibody composition used in a treatment regimen described herein comprises:

- a first anti-MET antibody or antigen-binding portion thereof that comprises a VH comprising the amino acid sequence of SEQ ID NO: 3 and a VL comprising the amino acid sequence of SEQ ID NO: 4; and

- a second anti-MET antibody or antigen-binding portion thereof that comprises a VH comprising the amino acid sequence of SEQ ID NO: 3 and a VL comprising the amino acid sequence of SEQ ID NO: 4.

[0086] In some aspects, an antibody composition used in a treatment regimen described herein comprises:

- a first anti-MET antibody or antigen-binding portion thereof that comprises an HC that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1 and an LC that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2; and

- a second anti-MET antibody or antigen-binding portion thereof that comprises an HC that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 11 and an LC that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 12.

[0087] In some aspects, an antibody composition used in a treatment regimen described herein comprises:

- a first anti-MET antibody that comprises an HC comprising the amino acid sequence of SEQ ID NO: 1 and an LC comprising the amino acid sequence of SEQ ID NO: 2; and - a second anti-MET antibody that comprises an HC comprising the amino acid sequence of SEQ ID NO: 11 and an LC comprising the amino acid sequence of SEQ ID NO: 12.

[0088] In some aspects, an antibody composition used in a treatment regimen described herein is Sym015.

[0089] In some aspects, the antibodies described herein do not have the C- terminal lysine in the heavy chain. The C-terminal lysine may be removed during manufacture or by recombinant technology (i.e. , the coding sequence of the heavy chain does not include a codon for the C-terminal terminal lysine). Thus, contemplated within the present disclosure also are antibodies comprising the heavy chain amino acid sequence of SEQ ID NO: 1 or 11 without the C-terminal lysine. [0090] The class of an anti-MET antibody described herein (e.g., one or both of the anti-MET antibodies in a composition described herein) may be changed or switched with another class or subclass. In one aspect of the present disclosure, a nucleic acid molecule encoding VL or VH is isolated using methods well known in the art such that it does not include nucleic acid sequences encoding CL or CH, respectively. The nucleic acid molecules encoding VL or VH then are operatively linked to a nucleic acid sequence encoding a CL or CH, respectively, from a different class of immunoglobulin molecule. This may be achieved using a vector or nucleic acid molecule that comprises a CL or CH chain, as described above. For example, an anti-MET antibody that was originally IgM may be class switched to IgG. Further, the class switching may be used to convert one IgG subclass to another, e.g., from IgGi to lgG2. A k light chain constant region can be changed, e.g., to a l light chain constant region. A preferred method for producing an antibody of the present disclosure with a desired Ig isotype comprises the steps of isolating a nucleic acid molecule encoding the heavy chain of an anti-MET antibody and a nucleic acid molecule encoding the light chain of an anti-MET antibody, obtaining the variable domain of the heavy chain, ligating the variable domain of the heavy chain with the constant region of a heavy chain of the desired isotype, expressing the light chain and the ligated heavy chain in a cell, and collecting the anti-MET antibody with the desired isotype.

[0091] An anti-MET antibody described herein (e.g., one or both of the anti-MET antibodies in a composition described herein) can be an IgG, an IgM, an IgE, an IgA, or an IgD molecule, but is typically of the IgG isotype, e.g., of IgG subclass IgGi, lgG2a or lgG2b, lgG3 or lgG4. In one aspect, one or both antibodies are of the isotype subclass IgGi.

[0092] In one aspect, the anti-MET antibody (e.g., one or both of the anti-MET antibodies in a composition described herein) may comprise at least one mutation in the Fc region. A number of different Fc mutations are known, where these mutations provide altered effector function. For example, in many cases it will be desirable to reduce or eliminate effector function, e.g., where ligand/receptor interactions are undesired or in the case of antibody-drug conjugates.

[0093] In one aspect, the anti-MET antibody comprises at least one mutation in the Fc region that reduces effector function, e.g., mutations at one or more of positions 228, 233, 234 and 235, where amino acid positions are numbered according to the IMGT^® numbering scheme.

[0094] In one aspect, one or both of the amino acid residues at positions 234 and 235 may be mutated, for example from Leu to Ala (L234A/L235A). These mutations reduce effector function of the Fc region of IgGi antibodies. The amino acid positions are numbered according to the IMGT^® numbering scheme.

[0095] In some aspects, where the antibody is of the lgG4 subclass, it may comprise the mutation S228P, where the amino acid position is numbered according to the IMGT^® numbering scheme. This mutation is known to reduce undesired Fab arm exchange.

[0096] In some embodiments, at least one, at least two, or all of the anti-MET antibodies in a composition described herein have at least one property, or any combination of properties, selected from the group consisting of:

• does not bind to mouse or chicken MET;

• binds to an epitope of human MET comprising residues that are present on the SEMA domain;

• induces internalization and/or degradation of MET;

• binds to human MET with a K_D of 1 x 10⁹ M or less;

• inhibits growth in vitro of at least one cell line selected from SNU5, EBC1 , MKN45, Katoll, OE33, and Okajima;

• inhibits MET phosphorylation;

• inhibits MET downstream signaling; • inhibits primary endothelial cell proliferation in the presence or absence of HGF; and

• inhibits tumor growth in vivo.

[0097] In some embodiments, any of the anti-MET antibody compositions described herein has at least one property, or any combination of properties, selected from the group consisting of:

• induces internalization and/or degradation of MET;

• inhibits growth in vitro of at least one cell line selected from SNU5, EBC1 , MKN45, Katoll, OE33, and Okajima;

• inhibits MET phosphorylation;

• inhibits MET downstream signaling;

• inhibits primary endothelial cell proliferation in the presence or absence of HGF;

• induces antibody-dependent cellular toxicity (ADCC);

• induces complement-dependent cytotoxicity (CDC); and

• inhibits tumor growth in vivo.

Bi-specific Binding Molecules

[0098] In a further aspect, the present disclosure provides regimens for treating cancer using a bi-specific binding molecule having the binding specificities (e.g., comprising the antigen-binding portions, such as the six CDRs or the VH and VL) of two anti-MET antibodies described herein, e.g., antibodies 9006 and 9338 of Sym015. Such bi-specific binding molecules are known in the art. In some embodiments, the bi-specific binding molecule may comprise a first antigen-binding domain comprising the H-CDR1-3 amino acid sequences of SEQ ID NOs: 5-7 and the L-CDR1-3 amino acid sequences of SEQ ID NOs: 8-10, and a second antigen binding domain comprising the H-CDR1-3 amino acid sequences of SEQ ID NOs: 15-77 and the L-CDR1-3 amino acid sequences of SEQ ID NOs: 18-20. In some embodiments, the bi-specific binding molecule may comprise a first antigen-binding domain comprising a VH amino acid sequence of SEQ ID NO: 3 and a VL amino acid sequence of SEQ ID NO: 4, and a second antigen-binding domain comprising a VH amino acid sequence of SEQ ID NO: 13 and a VL amino acid sequence of SEQ ID NO: 14. [0099] It is contemplated that a bi-specific binding molecule described herein may be used in place of an anti-MET antibody composition in a treatment regimen described herein.

II. Treatment Regimens

[0100] In some embodiments, an anti-MET antibody composition described herein (e.g., Sym015) is administered to a patient at a dose of 1-100 mg/kg, e.g., 1-5, 1-10, 5-10, 10-15, 10-20, 15-20, 20-30, 20-25, 1-20, 1-30, 1-40, 1-50, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, or 90-100 mg/kg. In certain embodiments, the composition may be administered at a dose of 6-24 mg/kg. In certain embodiments, the composition may be administered at a dose of 1 , 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 40, 50, 60, 70, 75, 80, 90, or 100 mg/kg, or any combination thereof for multiple doses. In certain embodiments, the composition is initially administered at a first dose (“loading dose”) and then at a second, different dose (“maintenance dose”); any combination of the above doses are contemplated for loading and maintenance doses. The loading dose may be given one or more times, and may be a higher or lower dose than the maintenance dose and/or given more or less frequently (if given more than once) than the maintenance dose. In particular embodiments, the loading dose may be higher than the maintenance dose. For example, the patient may be given one loading dose of 18 mg/kg, then subsequent maintenance doses of 10-15 mg/kg (e.g., 12 mg/kg).

[0101] The term “dose,” as used herein, refers to an amount of a therapeutic agent (such as an antibody composition described herein) administered to a patient at a single session over a period of time deemed appropriate by a physician or other medical professional (e.g., IV infusion over about 0.5 - 4 hours).

[0102] In some embodiments, the anti-MET antibody composition is administered in repeated cycles of 1 , 2, 3, 4, 5, 6, 7, or 8 weeks. A cycle refers to a treatment regimen that is given for a period of time and that can be repeated. In certain embodiments, the composition is administered in two-week cycles. In certain embodiments, the composition is administered on one, two, three, four, five, six, or seven days of the cycle. In particular embodiments, the composition is administered on the first day only of each cycle (e.g., administered once every two weeks). In some embodiments, where there is a loading dose, the loading dose may be administered on the first day of the first cycle and the maintenance doses may begin on the first day of the second cycle. In particular embodiments, the composition is administered at a loading dose of 18 mg/kg, followed by maintenance doses of 12 mg/kg every two weeks.

[0103] The composition may be administered via parenteral administration. As used herein, “parenteral administration” of a composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the composition through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internal organ. Parenteral administration thus includes, but is not limited to, administration of a composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal, intravenous, intraarterial, intrathecal, intraurethral, intracranial, intratumoral, and intrasynovial injection or infusions; and kidney dialytic infusion techniques. Regional perfusion is also contemplated.

[0104] In certain embodiments, the composition is administered by intravenous (IV) infusion. The IV infusion may take place over, e.g., 30, 45, 60, 75, 90, 105, or 120 or more minutes. In particular embodiments, the infusion time is 60 minutes. Infusion times may be extended as necessary to accommodate individual patients’ tolerance of treatment. Where the composition is administered in more than one dose, in some embodiments, the infusion time for the first dose (e.g., a loading dose) is longer than the infusion time for subsequent doses (e.g., maintenance doses). For example, a composition described herein may be administered intravenously over 1.5 hours for a loading dose (e.g., 18 mg/kg) and administered intravenously over 1 hour for a maintenance dose (e.g., 12 mg/kg).

[0105] In some embodiments, the composition is administered as a monotherapy.

In other embodiments, the composition may be administered in combination with one or more other therapeutic agents, for example, other anti-MET antibodies or MET inhibitors (e.g., tyrosine kinase inhibitors), or anti-EGFR antibodies or EGFR inhibitors (e.g., tyrosine kinase inhibitors). In certain embodiments, the composition may be administered in combination with onartuzumab (OA-5D5, OAM4558g, MetMAb), ficlatuzumab (AV-299), rilotumumab (AMG102), TAK-701 , ARGX-111 , emibetuzumab (LY2875358/LA480), ABT-700 (H224G11), 36C4, LY3164530, savolitinib, capmatinib, tivantinib, cabozantinib, foretinib, golvatinib, crizotinib, erlotinib, gefitinib, osimertinib, rociletinib, tepotinib, or any combination thereof. In some embodiments, the composition may be administered in combination with chemotherapy (e.g., cisplatin).

[0106] It is understood that the treatment regimens described herein may be methods of treatment as described herein, an antibody composition as described herein for use in a treatment regimen described herein, or use of an antibody composition as described herein for the manufacture of a medicament for a treatment regimen described herein.

III. Premedication

[0107] In some embodiments, a patient treated by the present regimen is premedicated to reduce the risk of infusion-related reactions (IRRs). In certain embodiments, the premedication may be administered prior to each dose of Sym015. The premedication may comprise, e.g., a glucocorticoid, an antihistamine (e.g., an H1 or H2 antagonist), acetaminophen, or any combination thereof. In some embodiments, the premedication comprises a glucocorticoid and/or an antihistamine, in combination with an H2 antagonist and/or acetaminophen. In particular embodiments, the patient is premedicated as follows:

Glucocorticoid therapy equivalent to 80-100 mg IV methylprednisolone, approximately 0.5 to 2 hours prior to the start of Sym015 infusion; and/or

Antihistamine (H1 antagonist) equivalent to 25-50 mg IV diphenhydramine, approximately 0.5 hours prior to the start of Sym015 infusion; and optionally including:

Antihistamine (H2) antagonist such as 50 mg IV ranitidine or 30 mg famotidine, approximately 0.5 hours prior to the start of Sym015 infusion; and/or Acetaminophen such as 1000 mg IV or PO (orally), approximately 0.5 hours prior to the start of Sym015 infusion.

IV. Patient Selection

[0108] The treatment regimens of the present disclosure may be used to treat a patient with cancer, e.g., NSCLC. In some embodiments, a treatment regimen of the present disclosure includes the step of selecting a patient with a cancer described herein. In certain embodiments, the patient is a mammal, e.g., a human.

[0109] “Treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a biological disorder and/or at least one of its attendant symptoms. As used herein, to “alleviate” a disease, disorder or condition means reducing the severity and/or occurrence frequency of the symptoms of the disease, disorder, or condition. Further, references herein to “treatment” include references to curative, palliative and prophylactic treatment. Treatment of cancer encompasses inhibiting cancer growth (including causing partial or complete cancer regression), inhibiting cancer progression or metastasis, preventing cancer recurrence or residual disease, and/or prolonging the patient’s survival.

[0110] In some embodiments, the patient to be treated with a treatment regimen of the present disclosure has a cancer that is wild-type for KRAS.

[0111] In some embodiments, the patient to be treated with a treatment regimen of the present disclosure has a cancer that displays a MET amplification (increased copies of the MET gene) and/or a MET gene exon 14 skipping alteration (MET^Ex14del). Cancer cells used for the determination may be obtained through tumor biopsy or through collection of circulating tumor cells. Additionally or alternatively, the determination may be made through analysis of circulating tumor DNA (ctDNA). MET amplification and MET^Ex14del can be assessed in a tumor biopsy using any method known in the art, e.g., FISH, CISH, SISH, NGS, quantitative polymerase chain reaction (qPCR), etc., or in blood or other body fluids (i.e., urine) by analysis of circulating tumor DNA (by methods including but not limited to Guardant360^® analysis), circulating tumor cells, exosomes etc.

[0112] In some embodiments, MET amplification is assayed in a tumor biopsy (e.g., performed since the last documented disease progression) from the patient and is defined as:

- gene:copy number (G:CN) > or > 2.0, 2.2, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 15.0, or 20.0 (e.g., 3.0) scored in 20, 30, 40, 50, 60, 70, or 80 (e.g., 50) tumor nuclei by FISH, CISH, SISH, or any similar assay; and/or

- copy number > 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 (e.g., 5) as determined by next-generation sequencing (NGS) or quantitative PCR (qPCR). In some embodiments, MET amplification is determined by analyzing ctDNA from the patient (e.g., by results of 2+ or 3+ or a plasma copy number higher than 2.1 in Guardant360^® analysis). In certain embodiments, the amplification may be focal. [0113] In some embodiments, the presence of a MET exon 14 skipping alteration is assayed by analyzing a tumor biopsy (e.g., performed since the last documented disease progression, and using a method including but not limited to an NGS or PCR-based method) from the patient and/or is assessed via analysis (including but not limited to Guardant360^® analysis) of ctDNA, circulating tumor cells or exosomes obtained from a patient. In certain embodiments, MET^Ex14del is assessed via liquid biopsy (e.g., blood).

[0114] In some embodiments, the patient has a MET-expressing cancer, e.g., a solid malignancy, which may originate in a tissue selected from the group consisting of skin, lung, intestine, colon, ovary, brain, prostate, kidney, soft tissues, head and neck, liver, bone, bladder, breast, stomach, uterus, cervix, and pancreas. In other embodiments, the patient has a hematological malignancy. The patient may have, for example, a cancer selected from melanoma (e.g., advanced or metastatic melanoma), skin basal cell cancer, glioblastoma, glioma, gliosarcoma, astrocytoma, meningioma, neuroblastoma, adrenocortical cancer, head and neck squamous cell cancer, oral cancer, salivary gland cancer, nasopharyngeal cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, and squamous cell lung cancer), esophageal cancer, gastroesophageal junction cancer, gastric cancer, gastrointestinal cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma, biliary tract cancer, colon cancer, colorectal carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, upper urinary tract cancer, urothelial cancer, renal cell carcinoma, kidney cancer, genitourinary cancer, cervical cancer, prostate cancer, fibrosarcoma, liposarcoma, rhabdomyosarcoma, osteosarcoma, histiocytoma, pancreatic cancer, endometrial cancer, cancer of the appendix, advanced Merkel cell cancer, multiple myeloma, sarcomas, choriocarcinoma, erythroleukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, mast cell leukemia, small lymphocytic lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, monocytic lymphoma, HTLV-associated T cell leukemia/lymphoma, mesothelioma, and solid tumors. The cancer may be, e.g., at an early, intermediate, late, locally advanced, or metastatic stage, and may be relapsed or refractory to other therapeutics or there may be no standard therapy available. In certain embodiments, the patient has lung, gastric, colorectal, hepatocellular, or renal cancer or cholangiocarcinoma. In particular embodiments, the patient has non-small cell lung cancer (also known as non-small cell lung carcinoma; NSCLC).

[0115] In some embodiments, the patient is relapsed or refractory to treatment with a MET-targeting and/or EGFR-targeting agent, e.g., one or more agents selected from onartuzumab (OA-5D5, OAM4558g, MetMAb), ficlatuzumab (AV-299), rilotumumab (AMG102), TAK-701, ARGX-11, emibetuzumab (LY2875358/LA480), ABT-700 (H224G11), 36C4, LY3164530, savolitinib, capmatinib, tivantinib, cabozantinib, foretinib, golvatinib, crizotinib, erlotinib, gefitinib, osimertinib, rociletinib, or any combination thereof. In some embodiments, the patient is relapsed or refractory to a chemotherapeutic agent, e.g., a systemic or cytotoxic chemotherapeutic agent.

[0116] In some embodiments, the patient:

- is an adult (i.e. , at least 18 years of age);

- has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 ;

- has a life expectancy of greater than three months;

- has locally advanced or metastatic cancer (e.g., NSCLC) that is refractory to standard therapy or for which no standard therapy is available; or

- any combination of the above, such as all of the above.

In certain embodiments, the patient additionally:

I.

- has MET amplification (e.g., as defined by MET gene copy number to control probe ratio (G:CN) > 2.2 scored in 50 tumor nucleic by FISH, CISH, SISH, or a similar assay, or copy number > 5 by NGS or qPCR);

- is KRAS WT for the cancer;

- has received no prior therapy with MET-targeting agents, or has received prior therapy with a MET-targeting TKI; or

- any combination of the above, such as all of the above; or

II.

- has NSCLC; - has MET amplification (e.g., as defined by G:CN > 3.0 scored in 50 tumor nucleic by FISH, CISH, SISH, or a similar assay, or copy number > 5 by NGS or qPCR)

- may have received prior therapy with MET-targeting and/or EGFR-targeting agents (e.g., antibodies or tyrosine kinase inhibitors); or

- any combination of the above, such as all of the above; or

III.

- has NSCLC;

- has a MET exon 14 skipping alteration (MET^Ex14Del);

- may have received prior therapy with MET-targeting and/or EGFR-targeting agents (e.g., antibodies or tyrosine kinase inhibitors); or

- any combination of the above, such as all of the above.

[0117] In some embodiments, the patient:

- has not been treated for the primary malignancy with any antineoplastic agent without delayed toxicity within four weeks or five plasma half-lives, whichever is shortest, prior to treatment (except within six weeks for nitrosoureas and mitomycin C);

- has not had immunosuppressive or systemic hormonal therapy (>10 mg daily prednisone equivalent) within two weeks prior to treatment;

- has not been treated with hematopoietic growth factors within two weeks prior to treatment;

- does not have an active second malignancy or history of another malignancy within three years prior to treatment;

- does not have a central nervous system (CNS) malignancy (e.g., a primary CNS malignancy and/or a known CNS or leptomeningeal metastases not controlled by prior surgery or radiotherapy, or symptoms suggesting CNS involvement for which treatment is required);

- does not show inadequate recovery from toxicity due to a prior antineoplastic therapy;

- has not had a major surgical procedure within four weeks prior to treatment, or inadequate recovery from any prior surgical procedure;

- does not have non-healing wounds on any part of the body;

- does not have active thrombosis, or a history of deep vein thrombosis or pulmonary embolism within one month prior to treatment unless adequately treated or stable;

- does not have uncontrolled bleeding or a known bleeding diathesis; - does not have a significant cardiovascular condition, such as, e.g.: a) congestive heart failure currently requiring therapy; b) Class III or IV cardiovascular disease according to the New York Heart Association’s (NYHA) functional criteria c) need for antiarrhythmic medical therapy for a ventricular arrhythmia; d) severe conduction disturbance (e.g., 3rd degree heart block)’ e) unstable angina pectoris (last episode at least 6 months prior to treatment); f) uncontrolled hypertension; and g) myocardial infarction within 6 months prior to treatment;

- does not have abnormal hematologic, renal, or hepatic function, as demonstrated by, e.g.: a) absolute neutrophil count (ANC) < 1.5 x 10⁹/L (1500/mm³); b) hemoglobin < 9 g/dL; c) platelet count < 75 x 10⁹/L (75,000/mm³); d) serum creatinine > 1.5 x upper limit of normal (ULN); e) aspartate aminotransferase (AST) > 3.5 x ULN or AST > 5 x ULN in case of known liver metastases; f) alanine aminotransferase (ALT) > 3.5 x ULN or ALT > 5 x ULN in case of known liver metastases; g) total bilirubin > 1.5 x ULN; h) prothrombin time as assessed by International Normalized Ratio (INR) > 1.5 x ULN; and/or i) partial thromboplastin time (PTT) > 1.5 x ULN (unless on a stable dose of anticoagulant therapy for a prior thrombotic event);

- does not have any of the following within two weeks:

- serious or uncontrolled infection;

- infection requiring parenteral antibiotics; and

- unexplained fever of > 38°C;

- does not have any known or suspected hypersensitivity to any excipient of the Sym015 pharmaceutical composition;

- does not have any other life-threatening illness, significant organ dysfunction, or clinically significant lab abnormality; or

- any combination of the above, e.g., all of the above. In certain embodiments, the patient additionally:

I.

- may not have had any prior therapy with MET-inhibiting agents, except optionally a MET-targeting TKI;

- has not had prior therapy with an antibody to hepatocyte growth factor (HGF); or

- both of the above; or

II.

- does not demonstrate MET polysomy in the absence of MET amplification;

- has not had radiotherapy against target lesions within four weeks prior to treatment unless there is documented progression of the lesion following the radiotherapy; or

- both of the above.

[0118] In certain embodiments, the patient has a locally advanced or metastatic solid tumor (e.g., an NSCLC tumor) that is refractory to standard therapy, and may have:

- MET amplification (FISH/CISH/SISH > 2.2 or NGS/qPCR copy number > 5), wild- type for KRAS, and optionally prior therapy with MET-targeting agents;

- MET amplification (FISH/CISH/SISH G:CN > 3.0 or NGS/qPCR > 5), and optionally prior therapy with MET- or EGFR-targeting agents; and/or

- MET^Ex14Del, and optionally prior therapy with MET- or EGFR-targeting agents.

In some embodiments, the tumor is KRAS WT.

V. Treatment Outcomes

[0119] In some embodiments, an anti-MET antibody composition treatment regimen described herein leads to partial or complete tumor regression (e.g., tumor reduction of at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%). In some embodiments, treatment delays tumor progression, e.g., by inhibiting tumor growth. In some embodiments, treatment inhibits tumor progression (e.g., tumor growth) or metastasis. In some embodiments, treatment prevents cancer recurrence or residual disease. In some embodiments, treatment prolongs survival.

[0120] In some embodiments, a treatment regimen of the present disclosure (e.g., to treat NSCLC) results in a complete response (CR), partial response (PR), or stable disease (SD), and does not result in progressive disease (PD), as defined by RECIST v1.1 (Eisenhauer et al., EurJ Cancer 45:228-47 (2009)). [0121] In some embodiments, a treatment regimen of the present disclosure does not result in detectable levels of circulating antibodies reactive for antibody 9006 and/or 9338 in the patient’s serum.

VI. Articles of Manufacture and Kits

[0122] The present disclosure also provides articles of manufacture, e.g., kits, comprising one or more containers (e.g., single-use or multi-use containers) containing a pharmaceutical composition of an anti-MET antibody composition described herein at a dose described herein, optionally an additional biologically active molecule (e.g., another therapeutic agent, such as one described herein), and instructions for use according to a treatment regimen described herein. The composition and optional additional biologically active molecule can be packaged separately in suitable packing such as a vial or ampule made from non-reactive glass or plastic. In certain embodiments, the vial or ampule holds a concentrated stock (e.g., 2x, 5x, 10x or more) of the composition and optionally the biologically active molecule. In certain embodiments, the articles of manufacture such as kits include a medical device for administering the composition and/or biologically active molecule (e.g., a syringe and a needle); and/or an appropriate diluent (e.g., sterile water and normal saline). The present disclosure also includes methods for manufacturing said articles.

[0123] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. In case of conflict, the present specification, including definitions, will control.

[0124] Generally, nomenclature used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, analytical chemistry, synthetic organic chemistry, medicinal and pharmaceutical chemistry, and protein and nucleic acid chemistry and hybridization described herein are those well- known and commonly used in the art. Enzymatic reactions and purification techniques are performed according to manufacturer’s specifications, as commonly accomplished in the art or as described herein.

[0125] Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Throughout this specification and aspects, the words “have” and “comprise,” or variations such as “has,” “having,” “comprises,” or “comprising,” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0126] All publications and other references mentioned herein are incorporated by reference in their entirety. Although a number of documents are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

[0127] In order that the present disclosure may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the present disclosure in any manner.

EXAMPLES

Example 1. Dose-Escalation Study for Sym015

[0128] A dose-escalation study was performed to evaluate the safety, tolerability, and pharmacokinetics of Sym015 across a range of dose levels when administered on a Q2W schedule to subjects with KRAS WT advanced solid tumor malignancies refractory to available therapy.

[0129] Twelve patients were treated in the dose escalation study as shown in Table 1.

Table 1. Dose Escalation Study Parameters

[0130] Sym015 was well tolerated across all four dose levels. Five patients experienced adverse events (AEs); however, all treatment-related AEs were Grade 1 or 2, using the following general definitions of Grades 1 to 5: Grade 1 : Mild Grade 2: Moderate Grade 3: Severe

Grade 4: Life-threatening or disabling Grade 5: Death caused by the event.

Example 2. Antitumor Activity Study for Sym015

[0131] This example describes a study for evaluating the antitumor activity of Sym015 when administered to subjects at an 18 mg/kg loading dose administered IV over 1.5 hours followed by a 12 mg/kg maintenance dose administered IV over 1 hour on Days 1 and 15 of each 28-day cycle (+ 2 days) in the following cohorts:

1. Patients with MET-amplified, KRAS WT solid tumors (with a subset that has received prior MET tyrosine kinase inhibitor (TKI) treatment);

2. Patients with MET-amplified advanced NSCLC (with or without prior treatment with a MET- and/or EGFR-targeting agent); and

3. Patients with MET^Ex14Del advanced NSCLC (with or without MET amplification, and with or without prior treatment with a MET- and/or EGFR-targeting agent).

Secondary objectives of the study are to assess safety and tolerability, PK profile, immunogenicity, and potential pharmacodynamic markers of action of the dosage regimen.

Inclusion Criteria

[0132] Each patient must meet at least the following criteria to be included in this study:

1. Male or female at least 18 years of age at the time of informed consent;

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 ;

3. Life expectancy of greater than three months as assessed during screening;

4. Documented solid tumor malignancy: histologically or cytologically confirmed NSCLC; locally advanced or metastatic; refractory to standard therapy or no standard therapy available; measurable according to RECIST v1.1 ; and assessed within four weeks of cycle 1 day 1 (C1/D1) by CT or MRI. [0133] For Cohort 1 , additional inclusion criteria include:

1 . Confirmed MET amplification as defined by G:CN > 2.2 scored in 50 tumor nuclei by FISH, CISH, SISH, or a similar assay, or copy number > 5 by NGS or qPCR;

2. Tumor documented to be KRAS WT by local assessment (e.g., via Guardant 360 analysis) according to institutional standards; and

3. No prior therapy with MET-targeting agents, except for a subset of patients entered into Cohort 1 after having received prior therapy with a MET-targeting TKI.

[0134] For Cohort 2, additional inclusion criteria include:

1 . Documented NSCLC meeting disease criteria as defined above;

2. Documented MET amplification as defined by either a) or b) below: a) Local assessment in a recent tumor biopsy (with no intervening antineoplastic therapy), with G:CN > 3.0 scored in 50 tumor nuclei by FISH, CISH, SISH, or a similar assay, or copy number >5 by NGS or qPCR. Subsequent central confirmation is required, but the patient may be enrolled and treated based on local assessment before central confirmation results have been obtained. b) Central confirmation in a newly performed pre-dosing tumor biopsy (G:CN > 3.0 scored in 50 tumor nuclei by FISH). If central confirmation is not possible due to assay failure/technical error, enrollment may be allowed based on Guardant360 MET amplification results of 2+ or 3+ on a case per case basis;

3. May have received prior therapy with MET-targeting and/or EGFR-targeting agents (e.g., antibodies or TKIs); and

4. Willingness to undergo a pre-dosing biopsy (mandatory unless a recent tumor biopsy as defined above is available), and potentially a biopsy at the end of Cycle 2 (EOC2) (optional), from a primary or metastatic tumor site considered safely accessible for biopsy.

[0135] For Cohort 3, additional inclusion criteria include:

1 . Documented NSCLC meeting disease criteria as defined above;

2. Documented MET^Ex14Del (tumors need not be MET-amplified). MET^Ex14Del may be documented according to local institutional standards. Assessment in ctDNA by Guardant360 technology or equivalent is allowed. Tissue from a recent (performed since the last documented disease progression, with no intervening antineoplastic therapy) or newly performed pre-dosing tumor biopsy must be submitted for central assessment;

3. May have received prior therapy with MET-targeting and/or EGFR-targeting agents (e.g., antibodies or TKIs); and

4. Willingness to undergo a pre-dosing biopsy (mandatory unless a recent tumor biopsy as defined above is available), and potentially a biopsy at the end of Cycle 2 (EOC2) (optional), from a primary or metastatic tumor site considered safely accessible for biopsy.

Exclusion Criteria

[0136] Patients who meet any of the following criteria will be excluded from the study:

1. Treatment for the primary malignancy with any antineoplastic agent without delayed toxicity within four weeks or five plasma half-lives, whichever is shortest, prior to C1/D1 (except within six weeks for nitrosoureas and mitomycin C);

2. Immunosuppressive or systemic hormonal therapy (>10 mg daily prednisone equivalent) within two weeks prior to C1/D1 ;

3. Use of hematopoietic growth factors within two weeks prior to C1/D1 ;

4. An active second malignancy or history of another malignancy within three years (with the exception of treated, non-melanoma skin cancers; treated carcinoma in situ of the breast or cervix; controlled, superficial carcinoma of the urinary bladder; and T1a or b carcinoma of the prostate treated according to local standard of care, with prostate-specific antigen (PSA) within normal limits for the institution);

5. Central nervous system malignancy including primary CNS malignancies and/or known, untreated CNS or leptomeningeal metastases, or spinal cord compression; patients with any of these not controlled by prior surgery or radiotherapy; or symptoms suggesting CNS involvement for which treatment is required (treated CNS metastases are allowed if asymptomatic, not requiring therapy, and stable);

6. Inadequate recovery from an acute toxicity due to a prior antineoplastic therapy (with the exception of Grade 2 alopecia and/or peripheral neuropathy, patients must have recovered (go Grade < 1 ) from acute toxicity by C1/D1 );

7. Major surgical procedure within four weeks prior to C1/D1 , or inadequate recovery from any prior surgical procedure;

8. Non-healing wounds on any part of the body;

9. Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within one month prior to C1/D1, unless adequately treated or stable;

10. Active uncontrolled bleeding or a known bleeding diathesis;

11. Significant cardiovascular disease or condition, including: a) Congestive heart failure currently requiring therapy; b) Class III or IV cardiovascular disease according to the New York Heart Association’s (NYHA) functional criteria c) Need for antiarrhythmic medical therapy for a ventricular arrhythmia; d) Severe conduction disturbance (e.g., 3rd degree heart block)’ e) Unstable angina pectoris (last episode at least 6 months prior to C1/D1); f) Uncontrolled hypertension; and g) Myocardial infarction within 6 months prior to C1/D1 ;

12. Abnormal hematologic, renal, or hepatic function as defined by the following criteria: a) Absolute neutrophil count (ANC) < 1.5 x 10⁹/L (1500/mm³); b) Hemoglobin < 9 g/dL; c) Platelet count < 75 x 10⁹/L (75,000/mm³); d) Serum creatinine > 1.5 x upper limit of normal (ULN) for the institution; e) Aspartate aminotransferase (AST) > 3.5 x ULN for the institution or AST > 5 x ULN for the institution in case of known liver metastases; f) Alanine aminotransferase (ALT) > 3.5 x ULN for the institution or ALT > 5 x ULN for the institution in case of known liver metastases; g) Total bilirubin > 1.5 x ULN for the institution; h) Prothrombin time as assessed by International Normalized Ratio (INR) > 1.5 x ULN for the institution; and/or i) Partial thromboplastin time (PTT) > 1.5 x ULN for the institution (unless on a stable dose of anticoagulant therapy for a prior thrombotic event);

13. Any of the following within two weeks prior to C1/D1 : Any serious or uncontrolled infection;

Any infection requiring parenteral antibiotics; and Unexplained fever of > 38°C;

14. Known or suspected hypersensitivity to any of the excipients of the Sym015 pharmaceutical composition; and

15. Any other life-threatening illness, significant organ system dysfunction, or clinically significant laboratory abnormality, which would either compromise the patient’s safety or interfere with the evaluation of the safety of the trial drug.

[0137] For Cohort 1, additional exclusion criteria include:

Prior therapy with MET-inhibiting agents, except for a subset of patients entered into Cohort 1 after having received prior therapy with a MET-targeting TKI; and

Prior therapy with an antibody to hepatocyte growth factor (HGF).

[0138] For Cohorts 1 and 2, additional exclusion criteria include:

Tumor status demonstrating MET polysomy in the absence of MET amplification; and

Radiotherapy against target lesions within four weeks prior to C1/D1 , unless there is documented progression of the lesion following the radiotherapy.

Results I. Safety

[0139] Safety data has been collected for 45 patients. Of these, 20 have non small cell lung cancer (NSCLC), 12 have gastric cancer, 4 have colorectal cancer, 2 have bile duct cancer, 1 has breast cancer, and 6 have other solid tumors. All patients have received at least one dose of the study treatment.

[0140] Of the 20 NSCLC patients, 10 were previously treated with a MET targeted therapy, and 3 were previously treated with an EGFR TKI. 8 patients displayed MET amplification, and 12 displayed the MET^Ex14Del alteration.

[0141] The most common treatment-related adverse events overall patients (n=45) in part II of the study were peripheral edema in 11 patients (24.4%), fatigue and nausea in 10 patients (22.2%) each, constipation and decreased appetite in 9 patients (20.0%) each, cough in 8 patients (17.8%), and abdominal pain, anemia, and pyrexia in 7 patients (15.6%) each. There were no deaths or discontinuations reported due to treatment related adverse events.

II. Pharmacokinetics

[0142] Serum concentration results over time for 22 patients dosed with Sym015 are shown for the first two infusions in FIG. 1. The corresponding pharmacokinetic (PK) parameters for the first infusion (Cycle 1 , Day1 ) are shown in Table 2.

Table 2. Mean Non-Compartmental PK Parameters Following Sym015 First Dose

\v2. terminal elimination half-life CL: clearance V_z: volume of distribution

[0143] The pharmacokinetics of Sym015 were slightly non-linear with a dose- dependent half-life of 7-12 days. No anti-drug antibody (ADA) to treatment was identified and the ADA formation was low.

III. Antitumor Response [0144] Preliminary data from this study (Table 3, FIG. 2) demonstrates Sym015 antitumor activity in multiple solid tumor malignancies. Further, Sym015 monotherapy shows antitumor activity (ORR 25.0%) in the subgroup of NSCLC patients with MET amplification or MET^Ex14Del (FIG. 3). The median OS for NSCLC MET^Exi4Dei patients previously treated with an anti-MET TKI or antibody was 9.1 months. Median OS was not reached in overall NSCLC population and in other subgroups.

Table 3. Summary of Best Overall Response, Objective Response Rate and Disease Control Rate

Cl: confidence interval, CR: complete response, DCR: disease control rate, n: number of patients, ORR: overall response rate, PD: progressive disease, PR: partial response, SD: stable disease. SD 4M: stable disease at four months, SD 6M: stable disease at six months. CR, PD, PR, and SD are as defined according to RECIST v1 .1 . [0145] In summary, when administered at an 18 mg/kg loading dose followed by

12 mg/kg maintenance doses Q2W, Sym015 antibody therapy is safe and well tolerated. Further, this Sym015 dosing regimen shows antitumor efficacy for various cancers, and particularly for NSCLC with MET amplification and/or MET^Ex14Del. Response rates in MET amplification and MET^Ex14Del NSCLC patients who had not been treated previously with MET TKI were similar to response rates for MET TKIs. Further, Sym015 treatment reduced (9/12 evaluable patients) or stabilized (2/12 evaluable patients) MET amplification or MET^Ex14Del ctDNA load. Remarkably, Sym015 shows clinical activity in patients previously treated with an anti-MET therapy. For all cohorts in this study, it is expected that treatment with Sym015 will have beneficial antitumor activity.

Example 3. Case Study for Sym015 Treatment of NSCLC Patient [0146] This example describes the treatment of a 48 year-old male patient with MET-amplified (6.77 copies by NGS) NSCLC who had not been treated previously with tyrosine kinase inhibitors. A tumor biopsy from the patient showed a FISH MET/CEP7 of 3.05.

[0147] The patient was treated with Sym015 at an 18 mg/kg loading dose followed by 12 mg/kg maintenance doses Q2W over 96 weeks (22 months). Partial response was noted after the 4 cycles of treatment and tumor reduction of 53% was observed in the patient after 6 cycle of treatment with Sym015 treatment. Example 4. Case Study for Sym015 Treatment of Adenocarcinoma Patient [0148] This example describes the treatment of a 75 year-old female patient with poorly differentiated adenocarcinoma wild-type for EGFR. A fresh tumor biopsy from the patient showed MET amplification of 5-6 copies and MET^Ex14WT as determined by local NGS. The patient had previously been heavily treated with agents including the EGFR inhibitor erlotinib.

[0149] The patient was treated with Sym015 at an 18 mg/kg loading dose followed by 12 mg/kg maintenance doses Q2W over 30 weeks (and ongoing). The treatment has resulted in a partial response so far, with tumor reduction of 44%. Example 5. Case Study for Sym015 Treatment of Adenocarcinoma Patient [0150] This example describes the treatment of a 65 year-old female patient with adenocarcinoma who had not been treated previously with MET tyrosine kinase inhibitors. MET^Ex14Del status was centrally confirmed in fresh tumor.

[0151] The patient was treated with Sym015 at an 18 mg/kg loading dose followed by 12 mg/kg maintenance doses Q2W over 34 weeks. The treatment resulted in a tumor reduction of 39%.

Example 6. Case Study for Sym015 Treatment of Adenocarcinoma Patient [0152] This example describes the treatment of a 78 year-old male patient with adenocarcinoma. MET^Ex14Del status was confirmed through local testing (1.5 year old tumor), as well as in ctDNA with four other MET kinase domain mutations. The patient had previously been treated with the MET tyrosine kinase inhibitor crizotinib. [0153] The patient was treated with Sym015 at an 18 mg/kg loading dose followed by 12 mg/kg maintenance doses Q2W over 16 weeks. The treatment resulted in a tumor reduction of 20%.

Table 4. List of Sequences

Claims

CLAIMS What is claimed is:

1. A method for treating a MET-expressing cancer in a human patient, the method comprising administering to the patient a composition comprising: a) a first anti-MET antibody that comprises heavy chain CDR1 -3 amino acid sequences of SEQ ID NOs: 5-7, respectively, and light chain CDR1-3 amino acid sequences of SEQ ID NOs: 8-10, respectively; and b) a second anti-MET antibody that comprises heavy chain CDR1-3 amino acid sequences of SEQ ID NOs: 15-17, respectively, and light chain CDR1-3 amino acid sequences of SEQ ID NOs: 18-20, respectively, wherein the composition is administered one or more times at a dose of 6-24 mg/kg each time.

2. The method of claim 1 , wherein: a) the first anti-MET antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 4; and b) the second anti-MET antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14.

3. The method of claim 1 , wherein: a) the first anti-MET antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO: 2; and b) the second anti-MET antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain comprising the amino acid sequence of SEQ ID NO: 12.

4. The method of any one of claims 1-3, wherein the composition comprises the first and second anti-MET antibodies at a molar or weight ratio of 1 : 1.

5. The method of any one of claims 1 -4, wherein the composition is administered at a dose of 6, 12, 18, or 24 mg/kg.

6. The method of any one of claims 1 -5, wherein the composition is administered every two weeks.

7. The method of any one of claims 1-4, wherein the composition is administered at an 18 mg/kg loading dose followed by a 12 mg/kg maintenance dose every two weeks.

8. The method of any one of claims 1 -7, wherein the composition is formulated for intravenous administration.

9. The method of any one of claims 1 -8, wherein the cancer is non-small cell lung cancer (NSCLC).

10. The method of any one of claims 1 -9, wherein the cancer is wild-type for KRAS.

11. The method of any one of claims 1 -9, wherein the cancer is MET-amplified and/or has a deletion of MET exon 14 (MET^Ex14Del).

12. The method of any one of claims 1-11, wherein the patient has been treated previously for the cancer with another therapeutic agent.

13. The method of claim 12, wherein the previous treatment comprised a MET- targeting agent and/or an EGFR-targeting agent.

14. The method of claim 13, wherein the MET-targeting agent is an anti-MET antibody or a MET tyrosine kinase inhibitor.

15. The method of any one of claims 1-14, wherein the patient is relapsed or refractory to treatment of the cancer.

16. The method of any one of claims 1 -15, wherein treatment with the composition results in one or more of the following: a) tumor regression; b) delay of tumor progression; c) inhibition of cancer progression; d) inhibition of cancer metastasis; e) prevention of cancer recurrence or residual disease; and f) prolonged survival.

17. An anti-MET antibody composition for use in treating a MET-expressing cancer in a patient in a method of any one of claims 1-16.

18. The anti-MET antibody composition for use of claim 17, wherein the cancer is non-small cell lung cancer (NSCLC).

19. Use of an anti-MET antibody composition for the manufacture of a medicament for treating a MET-expressing cancer in a patient in a method of any one of claims 1 -16.

20. The use of claim 19, wherein the cancer is non-small cell lung cancer (NSCLC)