US20180057595A1 - Anti-MET Antibodies and Methods of Use Thereof - Google Patents

Anti-MET Antibodies and Methods of Use Thereof Download PDF

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US20180057595A1
US20180057595A1 US15/558,306 US201615558306A US2018057595A1 US 20180057595 A1 US20180057595 A1 US 20180057595A1 US 201615558306 A US201615558306 A US 201615558306A US 2018057595 A1 US2018057595 A1 US 2018057595A1
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amino acid
antibody
seq
antigen
binding fragment
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Yan Yang
Sreekala Mandiyan
Brett Robinson
Lida Kimmel
Yaron Hadari
Timothy David Jones
Francis Joseph Carr
Robert George Edward Holgate
Richard Weldon
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Celldex Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell

Definitions

  • the hepatocyte growth factor (HGF) receptor MET (also known as HGFR, c-MET) is a single-pass receptor tyrosine kinase encoded by the MET gene.
  • the MET tyrosine kinase is a heterodimer comprising an extracellular ⁇ -subunit linked by a disulfide bond to a transmembrane ⁇ -subunit with an intracellular protein tyrosine kinase domain (see, e.g., Giordano, et al., Nature, 1989, 339:155-156).
  • the extracellular region of MET is organized into three functional regions.
  • the Sema domain also found in the semaphorins and plexins, covers a conserved sequence of about 500 amino acids. It is necessary for ligand binding and receptor dimerization.
  • the PSI domain (for domain found in plexin, semaphorin and integrins) covers approximately the next 50 residues from the N-terminus.
  • IPT for immunoglobulin-like fold shared by plexins and transcriptional factors domains connect the PSI domain to the transmembrane helix.
  • the MET intracellular segment harbors five key serine/tyrosine residues (Ser975, Tyr1234, Tyr1235, Tyr1349 and Tyr1356) that either regulate its enzymatic activity or form docking sites for adaptors and signal transducers (see, e.g., Trusolino and Comoglio, Nat. Rev. Cancer, 2002, 2:289-300; Kong-Beltran, et al., Cancer Cell, 2004, 6:75-84; Trusolino et al., Nat. Rev. Mol. Cell Biol., 2010, 11:834-848).
  • MET kinase The human MET gene encoding the MET kinase has been cloned as described by Cooper et al., Nature, 1984, 311:29-33.
  • MET kinase Upon binding of the ligand HGF, MET kinase is activated by receptor dimerization and trans-phosphorylation of the catalytic tyrosine residues Tyr1234 and Tyr1235. Subsequent phosphorylation of Tyr1349 and Tyr1356 in the C-terminal tail provides docking sites for the recruitment of signal transduction adaptors and transducers.
  • MET can also be activated by semaphorins in an HGF-independent manner when oligomerized with plexins, leading to stimulation of MET downstream effectors.
  • MET function is required for various events in embryonic morphogenesis. Loss-of-function studies indicate that MET signaling supports the growth and survival of hepatocytes and placental trophoblast cells, and the proper wiring of the nervous system. Moreover, MET signaling plays an important role in wound healing and the regeneration of the liver and the kidney (see, e.g., Trusolino et al., Nat. Rev. Mol. Cell Biol., 2010, 11:834-848).
  • Aberrant MET activation due to overexpression, mutations, or autocrine ligand production, has been implicated in connection with a number of cancers. Studies indicate that aberrant MET signaling is important not only for tumor growth but also for tumor metastasis.
  • antibodies e.g., monoclonal antibodies
  • antigen-binding fragments thereof which specifically bind to the extracellular domain (ECD) of MET such as human MET.
  • ECD extracellular domain
  • such anti-MET antibodies which specifically bind to an ECD of human MET (e.g., Sema/PSI domain of human MET-ECD), inhibit phosphorylation of MET and inhibit tumor cell proliferation or tumor growth better as an IgG 2 isotype as compared to as an IgG 1 isotype.
  • polynucleotides and vectors comprising sequences encoding such antibodies, cells (e.g., host cells) comprising such polynucleotides or vectors, and compositions, reagents and kits comprising such antibodies.
  • methods for modulating MET activity e.g., inhibiting MET activity, or MET expression levels, diagnostic methods and uses, and therapeutic methods and uses of such anti-MET antibodies.
  • methods for modulating ligand-dependent MET activity are methods for modulating MET-amplified (e.g., ligand-independent) MET activity.
  • a monoclonal antibody or antigen-binding fragment thereof that binds to the Sema/PSI domain of human MET, wherein the antibody or antigen-binding fragment thereof:
  • the antibody or antigen-binding fragment thereof comprises:
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 1, 2, and 3, respectively
  • the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 4, 5, and 6, respectively.
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 7, 8, and 9, respectively
  • the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 10, 11, and 12, respectively.
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 13, 14, and 15, respectively
  • the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 16, 17, and 18, respectively.
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 25, 26, and 27, respectively
  • the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 28, 17, and 29, respectively.
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 72, 14, and 15, respectively
  • the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 16, 73, and 18, respectively.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of MGWSCIILFLVATATGVHSQIVLTQSPAIMSX 136 SPGEKVTMTCSASSSVX 137 YMFWYQ QKX 138 GSSPRLLIYDTX 139 X 140 LASGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQW SX 141 IYPYTFGGGTKLEIK (SEQ ID NO: 273), wherein X 136 is any amino acid, for example, T or A, X 137 is any amino acid, for example, N or S, X 138 is any amino acid, for example, A or P, X 139 is any amino acid, for example, F or S, X 140 is any amino acid, for example, N or D, and X 141 is any amino acid, for example, I or N.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of QIVLTQSPAIMSX 43 SPGEKVTMTCSASSSVX 44 YMFWYQQKX 45 GSSPRLLIYDTX 46 X 47 LA SGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQWSX 48 IYPYTFGGGTKLEIK (SEQ ID NO: 48), wherein X 43 is any amino acid, for example, T or A, X 44 is any amino acid, for example, N or S, X 45 is any amino acid, for example, A or P, X 46 is any amino acid, for example, F or S, X 47 is any amino acid, for example, N or D, and X 48 is any amino acid, for example, I or N.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of QX 57 QLQQSGAELMKPGASVKISCKATGYX 58 FSX 59 YWIEWVKQRPGHGLEWIGEILPGS DX 60 X 61 KYX 62 EKFKGKATFTADTSSNTAYMQLSX 63 LTSEDSAVYYCARPSTX 64 PPDCW GQGTTLTVSA (SEQ ID NO:50), wherein X 57 is any amino acid, for example, V or A, X 58 is any amino acid, for example, I or T, X 59 is any amino acid, for example, N or S, X 60 is any amino acid, for example, Y or F, X 61 is any amino acid, for example, T or I, X 62 is any amino acid, for example, N or S, X 63 is any amino acid, for example, S or N, and X 64 is any amino acid, for example, I
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:58.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of DIQMTQSPX 26 SLSASX 27 GX 28 X 29 TIX 30 CLASADIHSNLAWYQQKPGX 31 X 32 PX33LLIYGN NLNDGVPSRFSGX 34 GX 35 GTX 36 X 37 X 38 LX 39 IX 40 SLQX 41 EDVX 42 IYFCQQSYDSPPTFGQGT KLEIK (SEQ ID NO:47), wherein X 26 is any amino acid, for example, S or G, X 27 is any amino acid, for example, V or L, X 28 is any amino acid, for example, D or E, X 29 is any amino acid, for example, R or T, X 30 is any amino acid, for example, T or E, X 31 is any amino acid, for example, K or N, X 32 is any amino acid, for example, A or S, X 33 is any amino acid, for example, K or Q,
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of EVQLVESGGGLVQPGX 49 SLKLSCAASGFTFSDSYMAWVRQAPX 50 KGLEWVASISSDG GGTYYRDSVKGRFX 51 ISRDNAKX 52 SLYLQMDSLRX 53 EDTATYYCTTEGIYTTDYYPYC FNYWGX 54 GX 55 MVTVSX 56 (SEQ ID NO:49), wherein X 49 is any amino acid, for example, G or R, X 50 is any amino acid, for example, G or T, X 51 is any amino acid, for example, T or S, X 52 is any amino acid, for example, S or N, X 53 is any amino acid, for example, T or S, X 54 is any amino acid, for example, Q or H, X 55 is any amino acid, for example, V or T, and X 56 is any amino acid, for example, S or A.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:59.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:52.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:53.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:54.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:55.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:56.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:61.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof specifically binds to human MET and monkey MET, but not mouse MET or dog MET. In certain embodiments, the antibody or antigen-binding fragment thereof specifically binds to the SEMA domain of human MET and monkey MET, but not the SEMA domain of mouse MET or dog MET.
  • the inhibition of MET activity occurs in SNU-5 cells, A549 cells, and/or Hop92 cells.
  • the IC50 for the inhibition of MET activity in SNU-5 cells is between about 100 pM to about 500 pM, about 25 pM to about 200 pM, or about 40 pM to about 160 pM, about 50 pM to about 125 pM, or about 5 pM to about 100 pM.
  • the maximal percent inhibition of MET activity in SNU-5 cells that is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • the IgG 2 isotype has a maximal percent inhibition of MET activity in SNU-5 cells that is between 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold more than the maximal percent inhibition of MET activity of the IgG 1 isotype.
  • the IC 50 for the inhibition of MET activity in A549 cells is between about 40 pM to about 250 pM, 100 pM to about 500 pM, about 25 pM to about 200 pM, or about 40 pM to about 160 pM, about 50 pM to about 125 pM, or about 5 pM to about 100 pM.
  • the IC50 for the inhibition of MET activity in Hop92 cells is between about 100 pM to about 500 pM, about 25 pM to about 200 pM, or about 40 pM to about 160 pM, about 50 pM to about 125 pM, or about 5 pM to about 100 pM.
  • the IC50 for the inhibition of MET activity in Hop92 cells is between 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold less than a humanized anti-MET antibody that does not bind the SEMA domain, e.g., a human SEMA domain, or a bivalent, IgG 4 anti-MET antibody that binds to the SEMA domain, e.g., a human SEMA domain.
  • the phosphorylation of MET is determined at MET amino acid residues Tyr1234 and/or Tyr1235.
  • the induction of MET degradation occurs in SNU-5 cells, A549 cells, U87MG cells, H596 cells, Hop92 cells, or in tumor cells.
  • the induction of MET degradation occurs in cells expressing MET comprising one or more mutations, e.g., deletions, in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene.
  • the induction of MET degradation occurs in cells with amplified MET.
  • the maximal percent induction of MET degradation in SNU-5 cells is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • the IgG 2 isotype maximal percent induction of MET degradation in the SNU-5 cells is between 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold more than the IgG 1 isotype maximal percent induction of MET degradation.
  • the inhibition of tumor cell proliferation occurs in SNU-5 tumor cells, EBC-1 tumor cells, U87MG tumor cells, A549 tumor cells, and/or H596 tumor cells.
  • the inhibition of tumor cell proliferation occurs in cells expressing MET comprising one or more mutations, e.g., deletions, in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene.
  • the inhibition of tumor cell proliferation occurs in cells with amplified MET.
  • the maximal percent inhibition for the inhibition of the SNU-5 tumor cell proliferation is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • the IgG 2 isotype maximal percent inhibition for the inhibition of the SNU-5 tumor cell proliferation is between 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold higher than the IgG 1 maximal percent inhibition.
  • the maximal percent inhibition for the inhibition of the EBC-1 tumor cell proliferation is at least about 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • the IgG 2 isotype maximal percent inhibition for the inhibition of the EBC-1 tumor cell proliferation is between 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold higher than the IgG 1 maximal percent inhibition.
  • the IC50 for the inhibition of tumor cell proliferation in the U87MG tumor cells is between about 100 nM to about 500 nM, about 25 nM to about 200 nM, or about 40 nM to about 160 nM, about 50 nM to about 125 nM, or about 5 nM to about 100 nM. In certain embodiments, the IC50 for the inhibition of tumor cell proliferation in the A549 tumor cells is between about 100 nM to about 500 nM, about 25 nM to about 200 nM, or about 40 nM to about 160 nM, about 50 nM to about 125 nM, or about 5 nM to about 100 nM.
  • the IC50 for the inhibition of tumor cell proliferation in the H596 tumor cells is between about 100 nM to about 500 nM, about 25 nM to about 200 nM, or about 40 nM to about 160 nM, about 50 nM to about 125 nM, or about 5 nM to about 100 nM.
  • the tumor growth is a U87 xenograft tumor model, a SNU15 xenograft tumor model, or a U87MG orthotopic tumor model.
  • the antibody or antigen binding fragment thereof inhibits the interaction between MET and hepatocyte growth factor (HGF) on cells.
  • the cells are A549 cells.
  • the IC50 for the inhibition of the interaction between MET and HGF on the A549 cells is between about 0.01 nM to 10,000 nM, 0.01 nM to 1,000 nM, 0.1 nM to 500 nM, 0.1 nM to 100 nM, or 0.1 nM to 50 nM.
  • the antibody or antigen-binding fragment thereof induces ubiquitination of MET in cells.
  • the cells are A549 cells.
  • the antibody or antigen-binding fragment thereof inhibits MET signaling in cells.
  • the cells are A549 cells.
  • the MET signaling is HGF-dependent.
  • the MET signaling is HGF-independent.
  • the inhibition of MET signaling is identified as inhibition of AKT and/or MET phosphorylation.
  • the antibody or antigen-binding fragment thereof inhibits HGF-induced endothelial to mesenchymal transition (EMT).
  • EMT HGF-induced endothelial to mesenchymal transition
  • the inhibition of HGF-induced EMT is determined by DU145 cell scatter.
  • the IC50 for the DU145 cell scatter is about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 1 nM, 0.75 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM, 0.005 nM, or 0.001 nM.
  • the DU145 cell scatter is percent inhibition is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%.
  • the IgG 2 isotype of the antibody alters MET dimer configuration as compared to the IgG 1 isotype of the antibody.
  • a monoclonal antibody or antigen-binding fragment thereof that binds to the Sema/PSI domain of MET, wherein the antibody or antigen-binding fragment thereof comprises:
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 1, 2, and 3, respectively
  • the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 265, 5, and 6, respectively.
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 7, 8, and 9, respectively
  • the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 266, 11, and 12, respectively.
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 13, 14, and 15, respectively
  • the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 16, 17, and 18, respectively.
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 19, 20, and 21, respectively
  • the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 267, 23, and 24, respectively.
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 25, 26, and 27, respectively
  • the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 28, 73, and 29, respectively.
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 72, 14, and 15, respectively
  • the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 16, 73, and 18, respectively.
  • the VL CDR1, VL CDR2, and VL CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 30, 31, and 32, respectively, and the VH CDR1, VH CDR2, and VH CDR3 of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOS: 33, 34, and 35, respectively.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of DIQMTQSPX 26 SLSASX 27 GX 28 X 29 TIX 30 CLASADIHSNLAWYQQKPGX 31 X 32 PX 33 LLIYGN NLNDGVPSRFSGX 34 GX 35 GTX 36 X 37 X 38 LX 39 IX 40 SLQX 41 EDVX 42 IYFCQQSYDSPPTFGQGT KLEIK (SEQ ID NO:47), wherein X 26 is any amino acid, for example, S or G, X 27 is any amino acid, for example, V or L, X 28 is any amino acid, for example, D or E, X 29 is any amino acid, for example, R or T, X 30 is any amino acid, for example, T or E, X 31 is any amino acid, for example, K or N, X 32 is any amino acid, for example, A or S, X 33 is any amino acid, for example, K or Q,
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of EVQLVESGGGLVQPGX 49 SLKLSCAASGFTFSDSYMAWVRQAPX 50 KGLEWVASISSDG GGTYYRDSVKGRFX 51 ISRDNAKX 52 SLYLQMDSLRX 53 EDTATYYCTTEGIYTTDYYPYC FNYWGX 54 GX 55 MVTVSX 56 (SEQ ID NO:49), wherein X 49 is any amino acid, for example, G or R, X 50 is any amino acid, for example, G or T, X 51 is any amino acid, for example, T or S, X 52 is any amino acid, for example, S or N, X 53 is any amino acid, for example, T or S, X 54 is any amino acid, for example, Q or H, X 55 is any amino acid, for example, V or T, and X 56 is any amino acid, for example, S or A.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:59.
  • antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:52.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:53.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:54.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:55.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:56.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:61.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:68.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:63.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:64.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:65.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:70.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of MGWSCIILFLVATATGVHSQIVLTQSPAIMSX 136 SPGEKVTMTCSASSSVX 137 YMFWYQ QKX 138 GSSPRLLIYDTX 139 X 140 LASGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQW SX 141 IYPYTFGGGTKLEIK (SEQ ID NO: 273), wherein X 136 is any amino acid, for example, T or A, X 137 is any amino acid, for example, N or S, X 138 is any amino acid, for example, A or P, X 139 is any amino acid, for example, F or S, X 140 is any amino acid, for example, N or D, and X 141 is any amino acid, for example, I or N.
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of QIVLTQSPAIMSX 43 SPGEKVTMTCSASSSVX 44 YMFWYQQKX 45 GSSPRLLIYDTX 46 X 47 LA SGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQWSX 48 IYPYTFGGGTKLEIK (SEQ ID NO: 48), wherein X 43 is any amino acid, for example, T or A, X 44 is any amino acid, for example, N or S, X 45 is any amino acid, for example, A or P, X 46 is any amino acid, for example, F or S, X 47 is any amino acid, for example, N or D, and X 48 is any amino acid, for example, I or N.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of QX 57 QLQQSGAELMKPGASVKISCKATGYX 58 FSX 59 YWIEWVKQRPGHGLEWIGEILPGS DX 60 X 61 KYX 62 EKFKGKATFTADTSSNTAYMQLSX 63 LTSEDSAVYYCARPSTX 64 PPDCW GQGTTLTVSA (SEQ ID NO:50), wherein X 57 is any amino acid, for example, V or A, X 58 is any amino acid, for example, I or T, X 59 is any amino acid, for example, N or S, X 60 is any amino acid, for example, Y or F, X 61 is any amino acid, for example, T or I, X 62 is any amino acid, for example, N or S, X 63 is any amino acid, for example, S or N, and X 64 is any amino acid, for example, I
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:57.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:66.
  • the antibody or antigen-binding fragment thereof comprises:
  • the antibody or antigen-binding fragment thereof comprises a VL comprising the amino acid sequence of SEQ ID NO:58.
  • the antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO:67.
  • the antibody or antigen-binding fragment thereof comprises:
  • an isolated antibody or antigen-binding fragment thereof that binds to the Sema domain of MET wherein the antibody or antigen-binding fragment thereof comprises:
  • an isolated antibody or antigen-binding fragment thereof that binds to the Sema domain of MET wherein the antibody or antigen-binding fragment thereof comprises:
  • an antibody or antigen-binding fragment thereof provided herein inhibits metastasis.
  • an antibody or antigen-binding fragment thereof provided herein comprises a human IgG 2 Fc region.
  • an antibody or antigen-binding fragment thereof provided herein is a chimeric antibody or a humanized antibody.
  • the humanized antibody is a deimmunized antibody or a composite human antibody.
  • n antibody or antigen-binding fragment thereof provided herein is a bispecific antibody or antigen-binding fragment thereof.
  • an antibody or antigen-binding fragment thereof provided herein is fused to a heterologous polypeptide.
  • an antibody or antigen-binding fragment thereof provided herein is conjugated to an agent.
  • the agent is suitable for imaging and therapy.
  • the agent is a radioisotope, quantum dots, or other nano-particles.
  • the agent is a toxin.
  • the toxin is abrin, ricin A, pseudomonas exotoxin, cholera toxin, or diphtheria toxin.
  • compositions comprising a therapeutically effective amount of an antibody or antigen-binding fragment provided herein.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • polynucleotide comprising nucleotide sequences encoding a VH chain region, a VL chain region, or both a VL chain region and a VH chain region, of an antibody provided herein.
  • polynucleotide comprising nucleotide sequences encoding a heavy chain, a light chain, or both heavy chain and a light chain of an antibody provided herein.
  • the polynucleotide is operably linked to a promoter.
  • Also provided herein is a population of polynucleotides comprising (i) a first polynucleotide comprising nucleotide sequences encoding a VH or a heavy chain of an antibody provided herein, and (ii) a second polypeptide comprising nucleotide sequences encoding a VL or a light chain of an antibody provided herein.
  • the first polynucleotide is operably linked to a first promoter
  • the second polynucleotide is operably linked to a second promoter.
  • Also provided herein is a vector comprising a polynucleotide provided herein.
  • Also provided herein is a population of vectors comprising (i) a first vector comprising nucleotide sequences encoding a VH or a heavy chain of an antibody provided herein, and (ii) a second vector comprising nucleotide sequences encoding a VL or a light chain of an antibody provided herein.
  • Also provided herein is a population of vectors comprising (i) a first vector comprising nucleotide sequences encoding a VH or a heavy chain of an antibody provided herein, and (ii) a second vector comprising nucleotide sequences encoding a VL or a light chain of an antibody provided herein.
  • Also provided herein is a cell comprising a polynucleotide provided herein.
  • Also provided herein is a cell comprising a population of polynucleotides provided herein.
  • Also provided herein is a cell comprising a vector provided herein.
  • Also provided herein is an isolated cell producing an antibody or antigen-binding fragment provided herein.
  • Also provided herein is a population of cells comprising (i) a first host cell comprising a polynucleotide comprising nucleotide sequences encoding a VH or a heavy chain of an antibody provided herein, and (ii) a second host cell comprising a polynucleotide comprising nucleotide sequences encoding a VL or a light chain of an antibody provided herein.
  • Also provided herein is a population of cells comprising (i) a first host cell comprising a polynucleotide comprising nucleotide sequences encoding a VH or a heavy chain of an antibody provided herein operably linked to a first promoter, and (ii) a second host cell comprising a polynucleotide comprising nucleotide sequences encoding a VL or a light chain of an antibody provided herein.
  • kits comprising an antibody or antigen-binding fragment provided herein.
  • the cancer is colorectal, gastric, lung, melanoma, uveal melanoma, non-small cell lung, stomach, esophagus, brain, liver, kidney, head and neck, thyroid, ovary, prostate, pancreas, breast, colon, oral, muscular, bone, glioma, or lymphoid cancer.
  • the cancer comprises cancer cells expressing MET.
  • the cancer comprises cancer cells expressing EGFR.
  • the cancer comprises cancer cells expressing MET comprising one or more mutations, e.g., deletions, in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene.
  • the one or more mutations in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene confers reduced HGF-induced receptor degradation.
  • the one or more mutations in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene mutates or removes the Tyr1003 site.
  • the cancer comprises cancer cells expressing with amplified MET.
  • the cancer is non-small cell lung cancer (e.g., lung adenocarcinoma).
  • the cancer is a brain glioma.
  • the cancer is a gastric cancer.
  • the cancer is colorectal, gastric, lung, melanoma, uveal melanoma, non-small cell lung, stomach, esophagus, brain, liver, kidney, head and neck, thyroid, ovary, prostate, pancreas, breast, colon, oral, muscular, bone, glioma, or lymphoid cancer.
  • the cancer comprises cancer cells expressing MET.
  • the cancer comprises cancer cells expressing EGFR.
  • the cancer comprises cancer cells expressing MET comprising one or more mutations, e.g., deletions, in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene.
  • the one or more mutations in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene confers reduced HGF-induced receptor degradation.
  • the one or more mutations in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene mutates or removes the Tyr1003 site.
  • the cancer comprises cancer cells expressing with amplified MET.
  • the cancer is non-small cell lung cancer (e.g., lung adenocarcinoma).
  • the cancer is a brain glioma.
  • the cancer is a gastric cancer.
  • Also provided herein is a method of managing, preventing, protecting against, or treating metastasis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment provided herein.
  • Also provided herein is a method of managing, preventing, protecting against, or treating metastasis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a composition provided herein.
  • the subject treated according to a method provided herein expresses a MET comprising one or more deletions in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene.
  • the one or more mutations in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene confers reduced HGF-induced receptor degradation.
  • the one or more mutations in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene mutate or remove the Tyr1003 site.
  • the subject treated according to a method provided herein expresses a MET protein comprising an isoleucine amino acid substitution at MET amino acid residue Thr1010. In certain embodiments, the subject treated according to a method provided herein has cancer, or is being treated for cancer with an anti-cancer therapeutic.
  • the cancer comprises cancer cells expressing MET. In certain embodiments, the cancer comprises cancer cells expressing EGFR.
  • a method provided herein further comprises administering to the patient another agent.
  • the agent is a chemotherapeutic agent.
  • Also provided herein is a method of making an antibody or an antigen-binding fragment thereof which specifically binds to the Sema domain of human MET, comprising culturing a cell provided herein to express the antibody or antigen-binding fragment.
  • Also provided herein is a method of making an antibody or an antigen-binding fragment thereof which specifically binds to the Sema domain of human MET, comprising expressing a polynucleotide provided herein.
  • FIG. 1 depicts an exemplary amino acid sequence of human MET ECD, wherein amino acid residues 1-24 comprise the signal sequence
  • FIG. 2 depicts a western blot of lysates from cells incubated with a control vector (1), HGF (2), or HGF in the presence of Ab237 (3), crizotinib (4), or a control chimeric IgG 1 anti-KLH antibody (5).
  • the western blot was probed with antibodies for detecting phosphorylated MET (“pMet”), phosphorylated Akt (“pAkt”), tubulin, phosphorylated MAPK (“pMAPK”), MET, Akt, and MAPK.
  • pMet phosphorylated MET
  • pAkt phosphorylated Akt
  • pMAPK phosphorylated MAPK
  • FIG. 3A depicts the degradation of MET in U87MG cells upon incubation with Ab235, Ab236, Ab237, Ab238, Ab239, or with a control chimeric IgG 1 anti-KLH antibody as determined by western blot analysis.
  • FIG. 3B depicts the degradation of MET in U87MG cells upon incubation with Ab235, Ab236, Ab237, Ab238, Ab239, or with a control chimeric IgG 1 anti-KLH antibody as determined by ELISA.
  • FIG. 3A depicts the degradation of MET in U87MG cells upon incubation with Ab235, Ab236, Ab237, Ab238, Ab239, or with a control chimeric IgG 1 anti-KLH antibody as determined by ELISA.
  • FIG. 3C depicts the degradation of MET in A549 cells upon incubation with Ab235, Ab236, Ab237, Ab238, Ab239, or with a control chimeric IgG 1 anti-KLH antibody as determined by western blot analysis.
  • FIG. 3D depicts the degradation of MET in A549 cells upon incubation with Ab235, Ab236, Ab237, Ab238, Ab239, or with a control chimeric IgG 1 anti-KLH antibody as determined by ELISA.
  • FIG. 3E depicts the degradation of MET in H596 cells upon incubation with Ab237C, anti-MET-1, anti-MET-2, or with a control chimeric IgG 1 anti-KLH antibody as determined by ELISA.
  • FIG. 3F depicts the degradation of MET in Hop92 cells upon incubation with Ab235, Ab236, Ab237, Ab238, Ab239, or with a control chimeric IgG1 anti-KLH antibody as determined by
  • FIG. 4A depicts immunohistochemistry of MET levels in tumor samples of a U87MG subcutaneous tumor model at day 4 post two intraperitoneal injections with PBS.
  • FIG. 4B depicts immunohistochemistry of MET levels in tumor samples of a U87MG subcutaneous tumor model at day 4 post two intraperitoneal injections with a control chimeric IgG 1 anti-KLH antibody.
  • FIG. 4C depicts immunohistochemistry of MET levels in tumor samples of a U87MG subcutaneous tumor model at day 4 post two intraperitoneal injections with Ab240.
  • FIG. 4D depicts immunohistochemistry of control Ig levels in tumor samples of a U87MG subcutaneous tumor model at day 4 post two intraperitoneal injections with a control chimeric IgG 1 anti-KLH antibody.
  • FIG. 5 depicts the ubiquitination of MET in A549 cells upon incubation with a control chimeric IgG 1 anti-KLH antibody, Ab237C-IgG 2a , or Ab237C as determined by immunoblot for ubiquitin on protein lysates immunoprecipitated with an anti-MET antibody.
  • FIG. 6A depicts proliferation of U87MG cells in the absence of HGF, upon treatment with Ab235 (triangles, point up), Ab236 (squares), Ab237 (triangles, point down), Ab238 (diamonds), Ab239 (vertical lines), or control (x).
  • FIG. 6B depicts bioluminescence signals observed in mice of U87MG orthotopic tumor models in vivo upon treatment with a control chimeric IgG 1 anti-KLH antibody, crizotinib, Ab235C, or Ab236C at the indicated days (e.g., days 28, 31, 35, 42 and 49) post tumor implant.
  • FIG. 6C depicts a graphical representation of the bioluminescence signals in FIG. 6B for mice treated with a control chimeric IgG 1 anti-KLH antibody (circles), crizotinib (triangles), Ab235C (squares), or Ab236C (diamonds).
  • FIG. 7A depicts the tumor volume at various days post tumor implant in a U87MG subcutaneous tumor model upon treatment with control (“vehicle”, dashed line, closed circles), control chimeric IgG 1 anti-KLH antibody (solid line, squares), Ab235C (solid line, open triangles), Ab236C (dashed line, solid circles), Ab237C (solid line, solid diamonds), Ab239C (solid line, open diamonds), or crizotinib (dashed line, squares) (50 mg/kg).
  • control dashed line, closed circles
  • control chimeric IgG 1 anti-KLH antibody solid line, squares
  • Ab235C solid line, open triangles
  • Ab236C dashed line, open triangles
  • Ab237C solid line, solid diamonds
  • Ab239C solid line, open diamonds
  • crizotinib dashetinib
  • FIG. 7B depicts the tumor volume at various days post tumor implant in a U87MG subcutaneous tumor model upon treatment with control (“vehicle”, circles and indicated with arrow), 30 mg/kg of control chimeric IgG 1 anti-KLH antibody (squares and indicated with arrow), 30 mg/kg of Ab237C (triangles, point up), 10 mg/kg of Ab237C (triangles, point down), 3 mg/kg of Ab237C (diamonds), 1 mg/kg of Ab237C (circles and indicated with arrow), or 50 mg/kg of crizotinib (squares and indicated with arrow).
  • the dashed line represents the endpoint.
  • FIG. 8A depicts the percent of MET phosphorylation (relative to control) in SNU-5 cells treated with control chimeric IgG 1 anti-KLH antibody (“control”, triangles, point up) or with Ab237C comprising a human IgG 1 constant region (“Ab237C-IgG 1 ”, circles), Ab237C comprising a human IgG 2 constant region (“Ab237C-IgG 2 ”, diamonds), or Ab237C comprising a human IgG 4 constant region (“Ab237C-IgG 4 ”, squares).
  • control chimeric IgG 1 anti-KLH antibody (“control”, triangles, point up) or with Ab237C comprising a human IgG 1 constant region (“Ab237C-IgG 1 ”, circles), Ab237C comprising a human IgG 2 constant region (“Ab237C-IgG 2 ”, diamonds), or Ab237C comprising a human IgG 4 constant region (“Ab237C-Ig
  • FIG. 8B depicts the % relative MET expression level (relative to no treatment) in SNU-5 cells treated with control chimeric IgG 1 anti-KLH antibody (“control”, triangles, point up) or with Ab237C comprising a human IgG 1 human constant region (“Ab237C-IgG1”, circles), Ab237C-IgG 2 (diamonds), or Ab237C-IgG 4 (squares).
  • FIG. 8C depicts the impact of treatment with control chimeric IgG 1 anti-KLH antibody (triangles) or with Ab237C (open circles), Ab237C-IgG 2 (diamonds), or Ab237C-IgG 4 (squares) on SNU-5 cell proliferation.
  • FIG. 8C depicts the impact of treatment with control chimeric IgG 1 anti-KLH antibody (triangles) or with Ab237C (open circles), Ab237C-IgG 2 (diamonds), or Ab237
  • FIG. 8D depicts the impact of treatment with Ab237C (circles), Ab237C-IgG 2 (diamonds), Ab237C-IgG 4 (squares), or a monovalent form of Ab237 (triangles) on EBC-1 cell proliferation.
  • FIG. 8E depicts the percent of MET phosphorylation (relative to control) in A549 cells treated with Ab237C comprising a human IgG 2 constant region (“Ab237C-IgG 2 ”, circles), or a humanized version of Ab237 comprising a human IgG 2 constant region (“hum-Ab237C-IgG 2 ”, squares).
  • FIG. 8E depicts the percent of MET phosphorylation (relative to control) in A549 cells treated with Ab237C comprising a human IgG 2 constant region (“Ab237C-IgG 2 ”, circles), or a humanized version of Ab237 comprising a human IgG 2 constant region (“hum-Ab2
  • FIG. 8F depicts the percent of MET phosphorylation (relative to control) in SNU-5 cells treated with Ab237C comprising a human IgG 2 constant region (“Ab237C-IgG 2 ”, circles), or a humanized version of Ab237 comprising a human IgG 2 constant region (“hum-Ab237C-IgG 2 ”, squares).
  • FIG. 8G depicts the percent of cell proliferation (relative to control) in SNU-5 cells treated with Ab237C comprising a human IgG 2 constant region (“Ab237C-IgG 2 ”, circles), or a humanized version of Ab237 comprising a human IgG 2 constant region (“hum-Ab237C-IgG 2 ”, squares).
  • FIG. 9A depicts the percent of MET phosphorylation (relative to control) in SNU-5 cells treated with control chimeric IgG 1 anti-KLH antibody (squares), Ab237C-IgG 2 (filled circles), Ab238C (which comprises an IgG 1 framework; triangles, point up), Ab238C comprising a human IgG 2 framework (“Ab238C-IgG 2 ”; triangles, point down), Ab239C (which comprises an IgG 1 framework; diamonds), or Ab239C comprising a human IgG 2 framework (“Ab239C-IgG 2 ”; open circles).
  • FIG. 9A depicts the percent of MET phosphorylation (relative to control) in SNU-5 cells treated with control chimeric IgG 1 anti-KLH antibody (squares), Ab237C-IgG 2 (filled circles), Ab238C (which comprises an IgG 1 framework; triangles, point up), Ab238C comprising a human Ig
  • FIG. 9B depicts the % relative MET expression level (relative to no treatment)in SNU-5 cells treated with control chimeric IgG 1 anti-KLH antibody (diamonds), Ab237C-IgG 2 (diamonds), Ab238C (circles), Ab238C-IgG 2 (triangles, point up), Ab239C (diamonds), or Ab239C-IgG 2 (open circles).
  • FIG. 9B depicts the % relative MET expression level (relative to no treatment)in SNU-5 cells treated with control chimeric IgG 1 anti-KLH antibody (diamonds), Ab237C-IgG 2 (diamonds), Ab238C (circles), Ab238C-IgG 2 (triangles, point up), Ab239C (diamonds), or Ab239C-IgG 2 (open circles).
  • FIG. 9C depicts the percent of MET phosphorylation (relative to control) in SNU-5 cells treated with Ab235C (which comprises an IgG 1 framework; circles), Ab235C comprising a human IgG 2 framework (“Ab235C-IgG 2 ”; squares), Ab236C (which comprises an IgG 1 framework; diamonds), or Ab236C comprising a human IgG 2 framework (“Ab236C-IgG 2 ”; triangles).
  • Ab235C which comprises an IgG 1 framework
  • Ab235C-IgG 2 Ab235C-IgG 2
  • Ab236C-IgG 2 which comprises an IgG 1 framework
  • FIGD depicts the % relative MET expression level in SNU-5 cells treated with Ab236C (which comprises an IgG 1 framework; circles), Ab236C comprising a human IgG 2 framework (“Ab236C-IgG 2 ”; squares), Ab235C (which comprises an IgG 1 framework; diamonds), or Ab235C comprising a human IgG 2 framework (“Ab235C-IgG 2 ”; triangles).
  • FIG. 10A depicts the effect of treatment with PBS (filled circles), control chimeric IgG 1 anti-KLH antibody (filled squares), Ab237C (open squares), Ab237C-IgG 2 (open circles), Ab237C-IgG 4 (triangle, point up), or a monovalent anti-MET antibody (triangle, point down) on tumor volume at the indicated days post tumor implant in a U87 xenograft mouse model.
  • FIG. 10A depicts the effect of treatment with PBS (filled circles), control chimeric IgG 1 anti-KLH antibody (filled squares), Ab237C (open squares), Ab237C-IgG 2 (open circles), Ab237C-IgG 4 (triangle, point up), or a monovalent anti-MET antibody (triangle, point down) on tumor volume at the indicated days post tumor implant in a U87 xenograft mouse model.
  • FIG. 10A depicts the effect of treatment with PBS (filled circles), control chimeric I
  • 10A depicts the effect of treatment with PBS (filled circles), control chimeric IgG 1 anti-KLH antibody (filled squares), Ab237C (open squares), Ab237C-IgG 2 (open circles), Ab237C-IgG 4 (triangle, point up), or a monovalent anti-MET antibody (triangle, point down) on tumor volume at the indicated days post tumor implant in a SNU-5 xenograft mouse model.
  • FIG. 11A depicts the effect of treatment with PBS (black circles), control chimeric IgG 1 anti-KLH antibody (black squares), Ab316 (triangles, point up), Ab317 (triangles, point down), Ab318 (diamonds), or Ab237C-IgG 2 (grey circles, and indicated with arrow) on tumor volume at the indicated days post tumor implant in a SNU5 xenograft mouse model at the indicated antibody doses.
  • FIG. 11A depicts the effect of treatment with PBS (black circles), control chimeric IgG 1 anti-KLH antibody (black squares), Ab316 (triangles, point up), Ab317 (triangles, point down), Ab318 (diamonds), or Ab237C-IgG 2 (grey circles, and indicated with arrow) on tumor volume at the indicated days post tumor implant in a SNU5 xenograft mouse model at the indicated antibody doses.
  • FIG. 11B depicts the effect of treatment with PBS (black circles), control chimeric IgG 1 anti-KLH antibody (squares), or hum-Ab237C-IgG 2 (triangles) on tumor volume at the indicated days post tumor implant in a SNU5 xenograft mouse model at the indicated antibody doses.
  • FIG. 11B depicts the effect of treatment with PBS (black circles), control chimeric IgG 1 anti-KLH antibody (squares), or hum-Ab237C-IgG 2 (triangles) on tumor volume at the indicated days post tumor implant in a SNU5 xenograft mouse model at the indicated antibody doses.
  • 11C depicts the effect of treatment with PBS (grey circles), control chimeric IgG 1 anti-KLH antibody (squares), Ab316 (triangles, point up), Ab317 (triangles, point down), Ab318 (diamonds), or Ab237C-IgG 2 (circles, and indicated with arrow) on tumor volume at the indicated days post tumor implant in a U87 xenograft mouse model at the indicated antibody doses.
  • 11D depicts the effect of treatment with PBS (grey circles), control chimeric IgG 1 anti-KLH antibody (squares), Ab316 (triangles, point up), Ab317 (triangles, point down), Ab318 (diamonds), or hum-Ab237C-IgG 2 (circles, and indicated with arrow) on tumor volume at the indicated days post tumor implant in a U87 xenograft mouse model at the indicated antibody doses.
  • FIG. 12A depicts that the anti-MET antibodies demonstrated no effect on MET shedding.
  • A549 cells were treated with PMA, HGF or anti-MET antibodies for 24 hrs. Cell culture medium was collected at the end of incubation and sMET-ECD levels were measured by ELISA using capture and detection antibodies against MET-ECD.
  • FIG. 12B depicts that the anti-MET antibodies induced MET ubiquitination.
  • A549 cells were treated with 1 nM of HGF or 1 nM of anti-MET antibodies for 15 min.
  • Cell lysates were immunoprecipitated with anti-ubiquitin antibody conjugated agarose (Santa Cruz) and immunoblotted with anti-MET antibody (Cell Signaling Technology). Total cell lysates from the same samples were immunoblotted with anti-MET antibody to show total MET protein level.
  • FIG. 13A depicts that the anti-MET antibodies induce MET degradation in cells with exon 14 deletion mutation.
  • H596 cells with MET an exon 14 mutation were incubated with 1 nM of HGF or 1 nM of antibody for 24 hrs. MET protein levels were detected by ELISA.
  • FIG. 13B depicts that the anti-MET antibodies inhibit proliferation of cells with exon 14 deletion mutation.
  • H596 cells were serum-starved and treated with indicated antibody for 5 days in the presence of HGF followed by measurement of cell proliferation by CellTiter-Glo.
  • FIG. 14 depicts that the anti-MET antibody induced MET degradation was partially inhibited by crizotinib.
  • A549 cells were either pre-incubated with 1 ⁇ M of crizotinib for 1 hr or without. Cells were then treated with 1 nM of HGF or 1 nM of antibody for 24 hrs after which MET protein level was quantified by ELISA.
  • antibodies e.g., monoclonal antibodies
  • antigen-binding fragments thereof that specifically bind to a MET polypeptide (e.g., an ECD of human MET) and modulate MET activity (e.g., MET signaling) and/or MET expression.
  • the antibodies provided herein display potent inhibition of tumor growth in pre-clinical models where MET has been implicated in tumor growth.
  • antibodies that modulate ligand-dependent MET activity In certain aspects, provided herein are antibodies that modulate MET-amplified (e.g., ligand-independent) MET activity.
  • such antibodies which specifically bind to an ECD of human MET (e.g., Sema/PSI domain, for example, a Sema domain or one or more amino acid residues thereof, such as one or more of amino acid residues Q328, R331, S336, L337, and N338 of human MET-ECD), inhibits MET activity (e.g., inhibits phosphorylation of MET, induces MET degradation, and/or inhibits tumor cell proliferation or tumor growth) better as an IgG 2 isotype as compared to as an IgG 1 isotype.
  • an ECD of human MET e.g., Sema/PSI domain, for example, a Sema domain or one or more amino acid residues thereof, such as one or more of amino acid residues Q328, R331, S336, L337, and N338 of human MET-ECD
  • inhibits MET activity e.g., inhibits phosphorylation of MET, induces MET degradation, and/or inhibit
  • isolated nucleic acids such as complementary DNA (cDNA), encoding such antibodies, and antigen-binding fragments thereof.
  • vectors e.g., expression vectors
  • cells e.g., host cells
  • methods of making such antibodies and cells e.g., host cells.
  • methods and uses for modulating MET expression or MET activity e.g., inhibiting MET expression or MET activity
  • treating or managing certain conditions or disorders described herein such as treating or managing cancer.
  • Related compositions e.g., pharmaceutical compositions
  • kits, and diagnostic methods are also provided.
  • c-Met or “MET” or “MET receptor” or “MET polypeptide” refer to the MET receptor tyrosine kinase protein as described in Park et al., 1987, Proc. Natl. Sci., 84:6379-6383, and Trusolino et al., 2010, Nat. Rev. Mol. Cell Biol., 11:834-848).
  • GenBankTM accession numbers NM_001127500.1 and NM_000245.2 provide an exemplary human MET nucleic acid sequence.
  • GenBankTM accession numbers NP_001120972.1 and NP_000236.2 provide exemplary human MET amino acid sequences.
  • Native MET comprises an extracellular domain, which comprises an alpha chain and a beta chain, and an intracellular domain, which comprises a portion of the beta chain.
  • the extracellular MET domain comprises a Sema domain, a PSI domain, and four IPT domains (see, e.g., Trusolino et al., 2010, Nat. Rev. Mol. Cell Biol., 11:834-848).
  • An exemplary amino acid sequence of an ECD of human MET is provided in FIG. 1 .
  • antibodies e.g., monoclonal antibodies, such as chimeric or humanized, for example, composite human, antibodies
  • an extracellular domain (ECD) of human MET e.g., Sema/PSI domain, for example, a Sema domain, of human MET
  • ECD extracellular domain
  • antibodies that bind to a Sema/PSI domain of human MET e.g., antibodies that bind to a Sema/PSI domain of human MET.
  • antibodies that bind to a Sema domain of human MET e.g., monoclonal antibodies, such as chimeric or humanized, for example, composite human, antibodies
  • antibodies that bind to one or more of amino acid residues Q328, R331, S336, L337, and N338 of human MET.
  • said antibodies modulate ligand-dependent MET activity.
  • said antibodies modulate MET-amplified (e.g., ligand-independent) MET activity.
  • an anti-MET antibody described herein, or an antigen-binding fragment thereof inhibits MET activity (e.g., ligand-dependent MET activity and/or MET-amplified (e.g., ligand-independent) MET activity) in a cell, for example, as determined by inhibition of phosphorylation of MET, cell proliferation, and/or cell scatter.
  • an anti-MET antibody described herein or an antigen-binding fragment thereof inhibits MET ligand (e.g., hepatocyte growth factor (HGF)) binding to MET receptor.
  • MET ligand e.g., hepatocyte growth factor (HGF)
  • an anti-MET antibody described herein or an antigen-binding fragment thereof induces MET receptor degradation.
  • an anti-MET antibody described herein or an antigen-binding fragment thereof induces HGF-induced receptor degradation of a MET receptor comprising one or more mutations, e.g., deletions, in exon 14 (encoding, e.g., Leu964-Asp1010) of the human MET gene.
  • an anti-MET antibody described herein or an antigen-binding fragment thereof blocks MET ligand (e.g., hepatocyte growth factor (HGF)) binding to MET receptor and induces MET receptor degradation.
  • a anti-MET antibody described herein or an antigen-binding fragment thereof inhibits MET ligand (e.g., hepatocyte growth factor (HGF)) binding to MET receptor and induces MET receptor degradation better as an IgG 2 isotype as compared to as an IgG 1 isotype.
  • an anti-MET antibody described herein or an antigen-binding fragment thereof inhibits tumor cell proliferation or tumor growth.
  • an anti-MET antibody described herein or an antigen-binding fragment thereof inhibits tumor cell proliferation or tumor growth better as an IgG 2 isotype as compared to as an IgG 1 isotype.
  • antibodies provided herein which specifically bind to an ECD of human MET (e.g., Sema/PSI domain, for example, a Sema domain, of human MET-ECD), inhibit MET activity (e.g., inhibit phosphorylation of MET, induce MET degradation, or inhibit tumor cell proliferation or tumor growth) better as an IgG 2 isotype (e.g., human IgG 2 isotype) as compared to as an IgG 1 isotype (e.g., human IgG 1 isotype) in cells (e.g., EBC-1 cells and SNU-5 cells) having ligand-independent MET activity, for example, in cells having MET amplification or MET mutant, e.g., constitutively active MET mutant.
  • ECD of human MET e
  • an anti-MET antibody described herein or an antigen-binding fragment thereof specifically binds to human MET and monkey MET, but not mouse MET or dog MET.
  • the antibody or antigen-binding fragment thereof specifically binds to the SEMA domain of human MET and monkey MET, but not the SEMA domain of mouse MET or dog MET.
  • provided herein are antibodies that bind to one or more of amino acid residues Q328, R331, S336, L337, and N338 of human MET.
  • antibodies or antigen-binding fragments described herein can comprise sequences that do not naturally exist within the antibody germline repertoire of an animal or mammal (e.g., human) in vivo.
  • the terms “about” or “approximately” mean within plus or minus 10% of a given value or range. In instances where an integer is required, the terms mean within plus or minus 10% of a given value or range, rounded either up or down to the nearest integer.
  • antibody and “immunoglobulin” and “Ig” are terms of art and can be used interchangeably herein and refer to a molecule with an antigen binding site that specifically binds an antigen.
  • Antibodies can include, for example, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, such as composite human antibodies or deimmunized antibodies, murine antibodies (e.g., mouse or rat antibodies), chimeric antibodies, synthetic antibodies, and tetrameric antibodies comprising two heavy chain and two light chain molecules.
  • antibodies can include, but are not limited to an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain-antibody heavy chain pair, intrabodies, heteroconjugate antibodies, single domain antibodies, and monovalent antibodies.
  • antibodies can include antigen-binding fragments or epitope binding fragments such as, but not limited to, single chain antibodies or single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), camelized antibodies, affybodies, Fab fragments, F(ab′) fragments, F(ab′) 2 fragments, and disulfide-linked Fvs (sdFv).
  • scFv single chain antibodies or single-chain Fvs
  • sdFv single-chain Fvs
  • antibodies described herein refer to polyclonal antibody populations.
  • Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY), any class, (e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 or IgA 2 ), or any subclass (e.g., IgG 2a or IgG 2b ) of immunoglobulin molecule.
  • antibodies described herein are IgG antibodies, or a class (e.g., human IgG 1 , IgG 2 , or IgG 4 ) or subclass thereof.
  • antibodies described herein are IgG 2 antibodies (e.g., human IgG 2 ) or a subclass thereof (e.g., human IgG 2a or human IgG 2b , or a mixture thereof).
  • antibodies described herein e.g., Ab235, Ab236, Ab237, Ab238, Ab239, and Ab241-Ab255
  • IgG 1 antibodies e.g., human IgG 1
  • subclass thereof e.g., human IgG 1
  • IgG 1 antibodies described herein comprise one or more amino acid substitutions and/or deletions in the constant region such that the antibody functions more like an IgG 2 (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof).
  • an “antigen” is a moiety or molecule that contains an epitope to which an antibody can specifically bind. As such, an antigen is also specifically bound by an antibody.
  • the antigen to which an antibody described herein binds is human MET, or a fragment thereof, for example, an extracellular domain of human MET.
  • the antigen to which an antibody described herein binds is the SEMA/PSI domain of human MET.
  • the SEMA/PSI domain of human MET refers to a polypeptide comprising the SEMA and PSI domains.
  • An exemplary SEMA/PSI domain corresponds to amino acids 25 to 562 of a human MET sequence provided in FIG. 1A .
  • an “epitope” is a term in the art and refers to a localized region of an antigen to which an antibody can specifically bind.
  • An epitope can be a linear epitope or a conformational, non-linear, or discontinuous, epitope.
  • an epitope can be contiguous amino acids of the polypeptide (a “linear” epitope) or an epitope can comprise amino acids from two or more non-contiguous regions of the polypeptide (a “conformational,” “non-linear” or “discontinuous” epitope).
  • a linear epitope may or may not be dependent on secondary, tertiary, or quaternary structure.
  • an anti-MET antibody described herein binds to a group of amino acids regardless of whether they are folded in a natural three dimensional protein structure.
  • an anti-MET antibody described herein does not recognize the individual amino acid residues making up the epitope, and require a particular conformation (e.g., bend, twist, turn or fold) in order to recognize and bind the epitope.
  • the terms “immunospecifically binds,” “immunospecifically recognizes,” “specifically binds,” and “specifically recognizes” are analogous terms in the context of antibodies and refer to molecules that bind to an antigen/epitope as such binding is understood by one skilled in the art.
  • a molecule that specifically binds to an antigen may bind to other peptides or polypeptides, generally with lower affinity as determined by, e.g., immunoassays, surface plasmon resonance assays, for example, BiacoreTM, KinExA platform (Sapidyne Instruments, Boise, Id.), or other assays known in the art.
  • molecules that specifically bind to an antigen bind to the antigen with a K a that is at least 2 logs, 2.5 logs, 3 logs, 4 logs or greater than the K a when the molecules bind to another antigen.
  • molecules that specifically bind to an antigen do not cross react with other proteins.
  • molecules that specifically bind to an antigen do not cross react with other non-MET proteins.
  • the term “monoclonal antibody” is a well known term of art that refers to an antibody obtained from a population of homogenous or substantially homogeneous antibodies.
  • the term “monoclonal” is not limited to any particular method for making the antibody.
  • a population of monoclonal antibodies can be generated by cells, a population of cells, or a cell line.
  • a “monoclonal antibody,” as used herein, is an antibody produced by a single cell or cell line wherein the antibody immunospecifically binds to a MET epitope (e.g., an epitope of the extracellular domain of human MET) as determined, e.g., by ELISA or other antigen-binding or competitive binding assay known in the art or in the Examples provided herein.
  • a monoclonal antibody can be a chimeric antibody or a humanized antibody.
  • a monoclonal antibody can be a composite human antibody.
  • a monoclonal antibody can be a deimmunized antibody.
  • a monoclonal antibody is a monovalent antibody or multivalent (e.g., bivalent) antibody.
  • a monoclonal antibody is a monospecific or multispecific antibody (e.g., bispecific antibody).
  • polyclonal antibodies refers to an antibody population that includes a variety of different antibodies that immunospecifically bind to the same and/or to different epitopes within an antigen or antigens.
  • variable region refers to a portion of an antibody, generally, a portion of an antibody light or heavy chain, typically about the amino-terminal 110 to 120 amino acids in a mature heavy chain and about the amino-terminal 90 to 100 amino acids in a mature light chain.
  • Variable regions comprise complementarity determining regions (CDRs) flanked by framework regions (FRs).
  • CDRs complementarity determining regions
  • FRs framework regions
  • the spatial orientation of CDRs and FRs are as follows, in an N-terminal to C-terminal direction: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • variable region is a human variable region.
  • variable region comprises murine (e.g., mouse or rat) CDRs and human framework regions (FRs).
  • variable region is a primate (e.g., human or non-human primate) variable region.
  • variable region comprises murine (e.g., mouse or rat) CDRs and primate (e.g., human or non-human primate) framework regions (FRs).
  • murine e.g., mouse or rat
  • primate e.g., human or non-human primate
  • framework regions FRs.
  • a variable region described herein is obtained from assembling two or more fragments of human sequences into a composite human sequence.
  • the CDRs of an antibody can be determined according to (i) the Kabat numbering system (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391 and, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242); or (ii) the Chothia numbering scheme, which will be referred to herein as the “Chothia CDRs” (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol., 196:901-917; Al-Lazikani et al., 1997, J. Mol.
  • CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35, which optionally can include one or two additional amino acids, following 35 (referred to in the Kabat numbering scheme as 35A and 35B) (CDR1), amino acid positions 50 to 65 (CDR2), and amino acid positions 95 to 102 (CDR3).
  • CDR1 amino acid positions 31 to 35
  • CDR2 amino acid positions 50 to 65
  • CDR3 amino acid positions 95 to 102
  • CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3).
  • the actual linear amino acid sequence of the antibody variable domain can contain fewer or additional amino acids due to a shortening or lengthening of a FR and/or CDR and, as such, an amino acid's Kabat number is not necessarily the same as its linear amino acid number.
  • Antibodies provided herein can be of any type (e.g., IgG, IgE, IgM, IgD, IgA or IgY), any class, (e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 or IgA 2 ), or any subclass (e.g., IgG 2a or IgG 2b , or a mixture thereof) of immunoglobulin molecule.
  • antibodies described herein are IgG antibodies (e.g., human IgG), or a class (e.g., human IgG 1 or IgG 4 ) or subclass thereof.
  • an antibody provided herein comprises IgG 2 constant region, e.g., human IgG 2 constant region, for example, an IgG 2a or IgG 2b antibody.
  • IgG 2a and IgG 2b e.g., human IgG 2a and human IgG 2b , respectively
  • an antibody provided herein comprises a mixture of an IgG 2a and an IgG 2b (e.g., human IgG 2a and human IgG 2b , respectively) constant region.
  • an anti-MET antibody provided herein or an antigen-binding fragment thereof comprises CDRs of a VL region and CDRs of a VH region of any one of antibodies Ab235-Ab255 described herein, and specifically binds MET.
  • an anti-MET antibody provided herein, or an antigen-binding fragment thereof comprises a VL region and a VH region of any one of antibodies Ab235-Ab255 described herein.
  • an antibody described herein comprises a VL domain as described herein, wherein the VL domain does not comprise a signal sequence. In certain embodiments, an antibody described herein comprises a VH domain as described herein, wherein the VH domain does not comprise a signal sequence. In certain embodiments, an antibody described herein comprises a VL domain and a VH domain, wherein the VL domain does not comprise a signal sequence, and wherein the VH domain does not comprise a signal sequence. In certain embodiments, an antibody described herein comprises a VL domain, wherein the VL domain comprises a signal sequence. In certain embodiments, an antibody described herein comprises a VH domain, wherein the VH domain comprises a signal sequence. In certain embodiments, an antibody described herein comprises a VL domain and a VH domain, wherein the VL domain comprises a signal sequence, and wherein the VH domain comprises a signal sequence.
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 57 and a VH region comprising SEQ ID NO: 66 (e.g., antibody Ab235).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 58 and a VH region comprising SEQ ID NO: 67 (e.g., antibody Ab236).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 59 and a VH region comprising SEQ ID NO: 68 (e.g., antibody Ab237).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 60 and a VH region comprising SEQ ID NO: 69 (e.g., antibody Ab238).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 61 and a VH region comprising SEQ ID NO: 70 (e.g., antibody Ab239).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 62 and a VH region comprising SEQ ID NO: 71 (e.g., antibody Ab240).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 52 and a VH region comprising SEQ ID NO: 63 (e.g., antibody Ab241).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 53 and a VH region comprising SEQ ID NO: 63 (e.g., antibody Ab242).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 54 and a VH region comprising SEQ ID NO: 63 (e.g., antibody Ab243).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 55 and a VH region comprising SEQ ID NO: 63 (e.g., antibody Ab244).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 56 and a VH region comprising SEQ ID NO: 63 (e.g., antibody Ab246).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 52 and a VH region comprising SEQ ID NO: 64 (e.g., antibody Ab246).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 53 and a VH region comprising SEQ ID NO: 64 (e.g., antibody Ab247).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 54 and a VH region comprising SEQ ID NO: 64 (e.g., antibody Ab248).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 55 and a VH region comprising SEQ ID NO: 64 (e.g., antibody Ab249).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 56 and a VH region comprising SEQ ID NO: 64 (e.g., antibody Ab250).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 52 and a VH region comprising SEQ ID NO: 65 (e.g., antibody Ab251).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 53 and a VH region comprising SEQ ID NO: 65 (e.g., antibody Ab252).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 54 and a VH region comprising SEQ ID NO: 65 (e.g., antibody Ab253).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 55 and a VH region comprising SEQ ID NO: 65 (e.g., antibody Ab254).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 56 and a VH region comprising SEQ ID NO: 65 (e.g., antibody Ab255).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 57 (e.g., the VL region of antibody Ab235).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 58 (e.g., the VL region of antibody Ab236).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 59 (e.g., the VL region of antibody Ab237).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 60 (e.g., the VL region of antibody Ab238).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 61 (e.g., the VL region of antibody Ab239).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 62 (e.g., the VL region of antibody Ab240).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 52 (e.g., the VL region of antibody Ab241).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 53 (e.g., the VL region of antibody Ab242).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 54 (e.g., the VL region of antibody Ab243).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 55 (e.g., the VL region of antibody Ab244).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 56 (e.g., the VL region of antibody Ab245).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 52 (e.g., the VL region of antibody Ab246).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 53 (e.g., the VL region of antibody Ab247).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 54 (e.g., the VL region of antibody Ab248).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 55 (e.g., the VL region of antibody Ab249).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 56 (e.g., the VL region of antibody Ab250).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 52 (e.g., the VL region of antibody Ab251).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 53 (e.g., the VL region of antibody Ab252).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 54 (e.g., the VL region of antibody Ab253).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 55 (e.g., the VL region of antibody Ab254).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL region comprising SEQ ID NO: 56 (e.g., the VL region of antibody Ab255).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 66 (e.g., the VH region of antibody Ab235).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 67 (e.g., the VH region of antibody Ab236).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 68 (e.g., the VH region of antibody Ab237).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 69 (e.g., the VH region of antibody Ab238).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 70 (e.g., the VH region of antibody Ab239).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 71 (e.g., the VH region of antibody Ab240).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 63 (e.g., the VH region of antibody Ab241).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises VH region comprising SEQ ID NO: 63 (e.g., the VH region of antibody Ab242).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 63 (e.g., the VH region of antibody Ab243).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 63 (e.g., the VH region of antibody Ab244).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 63 (e.g., the VH region of antibody Ab245).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 64 (e.g., the VH region of antibody Ab246).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 64 (e.g., the VH region of antibody Ab247).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 64 (e.g., the VH region of antibody Ab248).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 64 (e.g., the VH region of antibody Ab249).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 64 (e.g., the VH region of antibody Ab250).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 65 (e.g., the VH region of antibody Ab251).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 65 (e.g., the VH region of antibody Ab252).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 65 (e.g., the VH region of antibody Ab253).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 65 (e.g., the VH region of antibody Ab254).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH region comprising SEQ ID NO: 65 (e.g., the VH region of antibody Ab255).
  • an anti-MET antibody or an antigen-binding fragment thereof which specifically binds to an ECD of human MET and comprises VL CDRs (e.g., Kabat CDRs, Chothia CDRs, or IMGT CDRs) of a VL comprising the amino acid sequence as set forth in Table 9 and VH CDRs (e.g., Kabat CDRs, Chothia CDRs, or IMGT CDRs) of a VH comprising the amino acid sequence as set forth in Table 10.
  • VL CDRs e.g., Kabat CDRs, Chothia CDRs, or IMGT CDRs
  • VH CDRs e.g., Kabat CDRs, Chothia CDRs, or IMGT CDRs
  • an antibody or an antigen-binding fragment thereof which specifically binds to an ECD of human MET and comprises VL and VH CDRs of any of the anti-MET antibodies provided herein, for example as set forth in Tables 1 and 2.
  • VL FR Amino Acid Sequences (Kabat) VL FR1 VL FR2 VL FR3 VL FR4 Antibody (SEQ ID NO:) (SEQ ID NO;) (SEQ ID NO:) (SEQ ID NO:) (SEQ ID NO:) Ab235 QIVLTQSPAIMSTSP WYQQKAGSSPRLLI GVPVRFSGSGSGTSYS FGGGTKLEIKR GEKVTMTC (SEQ ID Y (SEQ ID NO: 111) LTISRMEAEDAATYYC (SEQ ID NO: 128) NO: 103) (SEQ ID NO: 122) Ab236 QIVLTQSPAIMSASP WYQQKPGSSPRLLI GVPVRFSGSGSGTSYS FGGGTKLEIKR GEKVTMTC (SEQ ID Y (SEQ ID NO: 112) LTISRMEAEDAATYYC (SEQ ID NO: 128) NO: 104) (SEQ ID NO: 122) Ab237 DIQMTQSPG
  • VH FR Amino Acid Sequences (Kabat) VH FR1 VH FR2 VH FR3 VH FR4 Antibody (SEQ ID NO:) (SEQ ID NO:) (SEQ ID NO:) (SEQ ID NO:) (SEQ ID NO:) Ab235 QVQLQQSGAELMKP WVKQRPGHGLEW KATFTADTSSNTAYMQL WGQGTTLTVS GASVKISCKATGYTF IG (SEQ ID NO: 82) SSLTSEDSAVYYCAR A (SEQ ID S (SEQ ID NO: 75) (SEQ ID NO: 268) NO: 97) Ab236 QAQLQQSGAELMKP WVKQRPGHGLEW KATFTADTSSNTAYMQL WGQGTTLTVS GASVKISCKATGYIF IG (SEQ ID NO: 82) SNLTSEDSAVYYCAR A (SEQ ID S (SEQ ID NO: 76) (S
  • an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to an ECD of MET comprises a light chain variable region (VL) comprising:
  • a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a side chain with a similar charge.
  • Families of amino acid residues having side chains with similar charges have been defined in the art. These families include amino acids with charged side chains (e.g., lysine, arginine, histidine, aspartic acid, glutamic acid), acidic side chains (e.g., aspartic acid, glutamic acid), basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan
  • an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to an ECD of MET comprises a light chain variable region (VL) comprising:
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab235, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab235 as set forth in Table 1 (SEQ ID NOS: 1, 2, and 3, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab236, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab236 as set forth in Table 1 (SEQ ID NOS: 7, 8, and 9, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab237, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab237 as set forth in Table 1 (SEQ ID NOS: 13, 14, and 15, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab238, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab238 as set forth in Table 1 (SEQ ID NOS: 19, 20, and 21, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab239, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab239 as set forth in Table 1 (SEQ ID NOS: 25, 26, and 27, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab240, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab240 as set forth in Table 1 (SEQ ID NOS: 30, 31, and 32, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of any one of Ab241-Ab255, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab241 as set forth in Table 1 (SEQ ID NOS: 72, 14, and 15, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to an ECD of MET comprises a heavy chain variable region (VH) comprising:
  • an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to an ECD of MET comprises a heavy chain variable region (VH) comprising:
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab235, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab235 as set forth in Table 2 (SEQ ID NOS: 265, 5, and 6, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab235, for example, the VH CDR1, VH CDR2, and VH CDR3 of as set forth in SEQ ID NOS: 4, 5, and 6, respectively.
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab236, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab236 as set forth in Table 2 (SEQ ID NOS: 266, 11, and 12, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab236, for example, the VH CDR1, VH CDR2, and VH CDR3 as set forth in SEQ ID NOS: 10, 11, and 12, respectively.
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab237, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab237 as set forth in Table 2 (SEQ ID NOS: 16, 17, and 18, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab238, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab238 as set forth in Table 2 (SEQ ID NOS: 267, 23, and 24, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab238, for example, the VH CDR1, VH CDR2, and VH CDR3 as set forth in SEQ ID NOS: 22, 23, and 24, respectively.
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab239, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab239 as set forth in Table 2 (SEQ ID NOS: 28, 73, and 29, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab240, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab240 as set forth in Table 2 (SEQ ID NOS: 33, 34, and 35, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of any one of Ab241-Ab255, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab241 as set forth in Table 2 (SEQ ID NOS: 16, 73, and 18, respectively).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises (i) the VH CDR1, VH CDR2, and VH CDR3 of Ab235, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab235 as set forth in Table 2 (SEQ ID NOS: 265, 5, and 6, respectively); and (ii) the VL CDR1, VL CDR2, and VL CDR3 of Ab235, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab235 as set forth in Table 1 (SEQ ID NOS: 1, 2, and 3, respectively).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises (i) the VH CDR1, VH CDR2, and VH CDR3 as set forth in SEQ ID NOS: 4, 5, and 6, respectively; and (ii) the VL CDR1, VL CDR2, and VL CDR3 of Ab235, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab235 as set forth in Table 1 (SEQ ID NOS: 1, 2, and 3, respectively).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises (i) the VH CDR1, VH CDR2, and VH CDR3 of Ab236, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab236 as set forth in Table 2 (SEQ ID NOS: 266, 11, and 12, respectively); and (ii) the VL CDR1, VL CDR2, and VL CDR3 of Ab236, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab236 as set forth in Table 1 (SEQ ID NOS: 7, 8, and 9, respectively).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises (i) the VH CDR1, VH CDR2, and VH CDR3 as set forth in SEQ ID NOS: 10, 11, and 12, respectively; and (ii) the VL CDR1, VL CDR2, and VL CDR3 of Ab236, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab236 as set forth in Table 1 (SEQ ID NOS: 7, 8, and 9, respectively).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises (i) the VH CDR1, VH CDR2, and VH CDR3 of Ab237, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab237 as set forth in Table 2 (SEQ ID NOS: 16, 17, and 18, respectively); and (ii) the VL CDR1, VL CDR2, and VL CDR3 of Ab237, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab237 as set forth in Table 1 (SEQ ID NOS: 13, 14, and 15, respectively).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises (i) the VH CDR1, VH CDR2, and VH CDR3 of Ab238, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab238 as set forth in Table 2 (SEQ ID NOS: 267, 23, and 24, respectively); and (ii) the VL CDR1, VL CDR2, and VL CDR3 of Ab238, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab238 as set forth in Table 1 (SEQ ID NOS: 19, 20, and 21, respectively).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises (i) the VH CDR1, VH CDR2, and VH CDR3 as set forth in SEQ ID NOS: 22, 23, and 24, respectively; and (ii) the VL CDR1, VL CDR2, and VL CDR3 of Ab238, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab238 as set forth in Table 1 (SEQ ID NOS: 19, 20, and 21, respectively).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises (i) the VH CDR1, VH CDR2, and VH CDR3 of Ab239, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab239 as set forth in Table 2 (SEQ ID NOS: 28, 29, and 30, respectively); and (ii) the VL CDR1, VL CDR2, and VL CDR3 of Ab239, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab239 as set forth in Table 1 (SEQ ID NOS: 25, 26, and 27, respectively).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises (i) the VH CDR1, VH CDR2, and VH CDR3 of Ab240, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab240 as set forth in Table 2 (SEQ ID NOS: 33, 34, and 35, respectively); and (ii) the VL CDR1, VL CDR2, and VL CDR3 of Ab240, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab240 as set forth in Table 1 (SEQ ID NOS: 30, 31, and 32, respectively).
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises (i) the VH CDR1, VH CDR2, and VH CDR3 of any of Ab241-Ab255, for example, the VH CDR1, VH CDR2, and VH CDR3 of any of Ab241-Ab255 as set forth in Table 2 (SEQ ID NOS: 16, 73, and 18, respectively); and (ii) the VL CDR1, VL CDR2, and VL CDR3 of any of Ab241-Ab255, for example, the VL CDR1, VL CDR2, and VL CDR3 of any of Ab241-Ab255 as set forth in Table 1 (SEQ ID NOS: 72, 14, and 15, respectively).
  • an antibody described herein or an antigen-binding fragment thereof comprising Kabat VL and VH CDRS (e.g., Kabat VL CDR 1, 2, and 3, and Kabat VH CDR 1, 2, and 3 for any of antibodies Ab235-Ab255 as described in Tables 1 and 2, respectively) further comprises framework regions surrounding the CDRs in the variable region (e.g., variable region in Tables 9 and 10) in the format, from the N-terminus to C-terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • an anti-MET antibody, or antigen-binding fragment thereof, described herein comprises CDRs of any of antibodies Ab235-Ab255, as determined by the IMGT (Immunogenetics) numbering system; see, e.g., Lefranc, M.-P., 1999, The Immunologist, 7:132-136 and Lefranc, M.-P. et al., 1999, Nucleic Acids Res., 27:209-212), both of which are incorporated herein by reference in their entirety.
  • IMGT Immunogenetics
  • CDRs within an antibody heavy chain molecule are typically present at amino acid positions 26 to 35 (CDR1), amino acid positions 51 to 57 (CDR2), and amino acid positions 93 to 102 (CDR3).
  • CDRs within an antibody light chain molecule are typically present at amino acid positions 27 to 32 (CDR1), amino acid positions 50 to 52 (CDR2), and amino acid positions 89 to 97 (CDR3).
  • an antibody or antigen-binding fragment thereof which specifically binds to an ECD of human MET and comprises VL and VH CDRs of any of Ab235-Ab255, for example as set forth in Tables 5 and 6.
  • VL CDR Amino Acid Sequences (IMGT) Antibody VL CDR1 (SEQ ID NO:) VL CDR2 (SEQ ID NO:) VL CDR3 (SEQ ID NO:) Ab235 SSVNY (SEQ ID NO: 163) DTF (SEQ ID NO: 164) QQWSIYPYT (SEQ ID NO: 165) Ab236 SSVSY (SEQ ID NO: 169) DTS (SEQ ID NO: 170) QQWSNYPYT (SEQ ID NO: 171) Ab237 ADIHSN (SEQ ID NO: 175) YGN (SEQ ID NO: 176) QQSYDSPPT (SEQ ID NO: 177) Ab238 EDIYSD (SEQ ID NO: 181) NAN (SEQ ID NO: 182) QQYNNYPPT (SEQ ID NO: 183) Ab239 SGDIGDRY (SEQ ID NO: 187) AAD (SEQ ID NO: 188) QSYDSNIDIV (SEQ ID NO:
  • VH CDR Amino Acid Sequences (IMGT) Antibody VH CDR1 (SEQ ID NO:) VH CDR2 (SEQ ID NO:) VH CDR3 (SEQ ID NO:) Ab235 GYTFSNYW (SEQ ID NO: 160) ILPGSDYT (SEQ ID NO: 161) ARPSTIPPDC (SEQ ID NO: 162) Ab236 GYIFSSYW (SEQ ID NO: 166) ILPGSDFI (SEQ ID NO: 167) ARPSTVPPDC (SEQ ID NO: 168) Ab237 GFTFSDSY (SEQ ID NO: 172) ISSDGGGT (SEQ ID NO: 173) TTEGIYTTDYYPYCFNY (SEQ ID NO: 174) Ab238 FSGFSLSTYGMG (SEQ ID IWWDDVN (SEQ ID NO: 179) ARIGTSHIVDA (SEQ ID NO: 178) NO: 180) Ab239 GFSFTDCYI (SEQ ID NO: 184) ISSDGGG
  • an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to an ECD of MET comprises a light chain variable region (VL) comprising:
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab235, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab235 as set forth in Table 5 (SEQ ID NOS: 163, 164, and 165, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab236, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab236 as set forth in Table 5 (SEQ ID NOS: : 169, 170, and 171, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab237, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab237 as set forth in Table 5 (SEQ ID NOS: 175, 176, and 177, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab238, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab238 as set forth in Table 5 (SEQ ID NOS: 178, 179, and 180, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab239, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab239 as set forth in Table 5 (SEQ ID NOS: 184, 185, and 186, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of any one of Ab241-Ab255, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab241 as set forth in Table 5 (SEQ ID NOS: 175, 176, and 177, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to an ECD of MET comprises a heavy chain variable region (VH) comprising:
  • an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to an ECD of MET comprises a heavy chain variable region (VH) comprising:
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab235, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab235 as set forth in Table 6 (SEQ ID NOS: 160, 161, and 162, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab236, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab236 as set forth in Table 6 (SEQ ID NOS: 166, 167, and 168, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab237, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab237 as set forth in Table 6 (SEQ ID NOS: 172, 173, and 174, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab238, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab238 as set forth in Table 6 (SEQ ID NOS: 178, 179, and 180, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab239, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab239 as set forth in Table 6 (SEQ ID NOS: 184, 185, and 186, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of any one of Ab241-Ab255, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab241 as set forth in Table 6 (SEQ ID NOS: 172, 173, and 174, respectively).
  • an antibody described herein or an antigen-binding fragment thereof comprising IMGT VL and VH CDRS e.g., IMGT VL CDR 1, 2, and 3, and IMGT VH CDR 1, 2, and 3 for any of antibodies Ab235-Ab255 as described in Tables 5 and 6, respectively
  • IMGT VL CDR 1, 2, and 3 further comprises framework regions surrounding the CDRs in the variable region (e.g., variable region in Tables 9 and 10) in the format, from the N-terminus to C-terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • the CDRs of an antibody described herein are Chothia CDRs (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol., 196:901-917; and U.S. Pat. No. 7,709,226).
  • the term “Chothia CDRs,” and like terms are recognized in the art and refer to antibody CDR sequences as determined according to the method of Chothia and Lesk, 1987, J. Mol. Biol., 196:901-917, which will be referred to herein as the “Chothia CDRs” (see also, e.g., U.S. Pat. No.
  • Chothia CDRs within an antibody light chain molecule are typically present at amino acid positions 26 to 33 (CDR1), amino acid positions 50 to 52 (CDR2), and amino acid positions 91 to 96 (CDR3).
  • the Chothia CDRs within an antibody heavy chain molecule are at amino acid positions 26 to 32 or 34 (CDR1), amino acid positions 52 to 56 (CDR2; in one embodiment, CDR2 is at positions 52A-56, wherein 52A follows position 52), and amino acid positions 95 to 102 (CDR3; in one embodiment, there is no amino acid at positions numbered 96-100); and the Chothia CDRs within an antibody light chain molecule are at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3).
  • These Chothia CDR positions may vary depending on the antibody, and may be determined according to methods known in the art.
  • antibodies that immunospecifically bind to a MET polypeptide that comprise one or more Chothia VL CDRs of a VL of any one of antibodies Ab235-Ab255 (see, Table 7 and/or one or more Chothia VH CDRs of a VH of any one of antibodies Ab235-Ab255 (see, Table 8).
  • antibodies described herein that immunospecifically bind to a MET polypeptide comprise one or more CDRs, in which the Chothia and Kabat CDRs have the same amino acid sequence.
  • provided herein are antibodies that immunospecifically bind to a MET polypeptide and which comprise combinations of Kabat CDRs and Chothia CDRs.
  • an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to an ECD of MET comprises a light chain variable region (VL) comprising:
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab235, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab235 as set forth in Table 7 (SEQ ID NOS: 133, 134, and 135, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab236, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab236 as set forth in Table 7 (SEQ ID NOS: :139, 140, and 141, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab237, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab237 as set forth in Table 7 (SEQ ID NOS: 145, 146, and 147, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab238, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab238 as set forth in Table 7 (SEQ ID NOS: 151, 152, and 153, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of Ab239, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab239 as set forth in Table 7 (SEQ ID NOS: 157, 158, and 159, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 of any one of Ab241-Ab255, for example, the VL CDR1, VL CDR2, and VL CDR3 of Ab241 as set forth in Table 7 (SEQ ID NOS: 145, 146, and 264, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1, VL CDR2, and VL CDR3 as set forth in SEQ ID NOS: 145, 146, and 147, respectively.
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1 and VL CDR2 as set forth in SEQ ID NOS: 145 and 146, respectively, and the VL CDR3 as set forth in SEQ ID NOS: 147 or 264.
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VL CDR1 and VL CDR2 as set forth in SEQ ID NOS: 145 and 146, respectively, and the VL CDR3 as set forth in PPTFGX 136 GT (SEQ ID NO: 272), wherein X 136 is any amino acid, for example, A or Q.
  • an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to an ECD of MET comprises a heavy chain variable region (VH) comprising:
  • an antibody described herein, or an antigen-binding fragment thereof, which specifically binds to an ECD of MET comprises a heavy chain variable region (VH) comprising:
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab235, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab235 as set forth in Table 8 (SEQ ID NOS: 130, 131, and 132, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab236, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab236 as set forth in Table 8 (SEQ ID NOS: 136, 137, and 138, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab237, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab237 as set forth in Table 8 (SEQ ID NOS: 142, 143, and 144, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab238, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab238 as set forth in Table 8 (SEQ ID NOS: 148, 149, and 150, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of Ab239, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab239 as set forth in Table 8 (SEQ ID NOS: 154, 155, and 156, respectively).
  • an antibody described herein, or an antigen-binding fragment thereof comprises the VH CDR1, VH CDR2, and VH CDR3 of any one of Ab241-Ab255, for example, the VH CDR1, VH CDR2, and VH CDR3 of Ab241 as set forth in Table 8 (SEQ ID NOS: 142, 143, and 144, respectively).
  • an antibody described herein or an antigen-binding fragment thereof comprising Chothia VL and VH CDRS e.g., Chothia VL CDR 1, 2, and 3, and Chothia VH CDR 1, 2, and 3 for any of antibodies Ab235-Ab255 as described in Tables 7 and 8, respectively
  • an anti-MET antibody described herein comprises a VL region comprising DIQMTQSPX 26 SLSASX 27 GX 28 X 29 TIX 30 CLASADIHSNLAWYQQKPGX 31 X 32 PX 33 LLIYGN NLNDGVPSRFSGX 34 GX 35 GTX 36 X 37 X 38 LX 39 IX 40 SLQX 41 EDVX 42 IYFCQQSYDSPPTFGQGT KLEIK (SEQ ID NO:47), wherein X 26 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., S or G, X 27 is any amino acid, for example, an amino acid with an nonpolar side chain, e.g., V or L, X 28 is any amino acid, for example, an amino acid with an charged side chain, for example, an acidic side chain, e.g., D or E, X 29 is any amino acid, for example, R or T, X 30 is any amino acid, for example,
  • any one of X 26 to X 42 is any amino acid.
  • X 26 is a conservative substitution of S or G
  • X 27 is a conservative substitution of V or L
  • X 28 is a conservative substitution of D or E
  • X 29 is a conservative substitution of R or T
  • X 30 is a conservative substitution of T or E
  • X 31 is a conservative substitution of K or N
  • X 32 is a conservative substitution of A or S
  • X 33 is a conservative substitution of K or Q
  • X 34 is a conservative substitution of F or S
  • X 35 is a conservative substitution of F or S
  • X 36 is a conservative substitution of D or Q
  • X 37 is a conservative substitution of F or Y
  • X 38 is a conservative substitution of T or S
  • X 39 is a conservative substitution of T or K
  • X 40 is a conservative substitution of S or N
  • X 41 is a conservative substitution of P or S
  • X 42 is a conservative substitution of A or S
  • an anti-MET antibody described herein comprises a VH region comprising EVQLVESGGGLVQPGX 49 SLKLSCAASGFTFSDSYMAWVRQAPX 50 KGLEWVASISSDG GGTYYRDSVKGRFX 51 ISRDNAKX 52 SLYLQMDSLRX 53 EDTATYYCTTEGIYTTDYYPYC FNYWGX 54 GX 55 MVTVSX 56 (SEQ ID NO:49, wherein X 49 is any amino acid, for example, G or R, X 50 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., G or T, X 51 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., T or S, X 52 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., S or N, X 53 is any amino acid, for example, an amino acid with
  • any one of X 49 to X 56 is any amino acid sequence.
  • X 49 is a conservative substitution of G or R
  • X 50 is a conservative substitution of G or T
  • X 51 is a conservative substitution of T or S
  • X 52 is a conservative substitution of S or N
  • X 53 is a conservative substitution of T or S
  • X 54 is a conservative substitution of Q or H
  • X 55 is a conservative substitution of V or T
  • X 56 is a conservative substitution of S or A.
  • an anti-MET antibody described herein comprises
  • an anti-MET antibody described herein comprises a VL region comprising DIQMTQSPSSLSASVGDRVTITCLASADIHSNLAWYQQKPGKAPX 68 LLIYYGNNLNDGV PSRFSGX 69 GX 70 GTDX 71 TLX 72 IX 73 SLQX 74 EDVAX 75 YFCQQSYDSPPTFGQGTKLEIK (SEQ ID NO: 238), wherein X 68 is any amino acid, for example, K or Q, X 69 is any amino acid, for example, S or F, X 70 is any amino acid, for example, S or F, X 71 is any amino acid, for example, an amino acid with an aromatic side chain, e.g., Y or F, X 72 is any amino acid, for example, T or K, X 73 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., S or N, X 74 is any amino amino acids, for example
  • any one of X 68 to X 75 is any amino acid.
  • X 43 is a conservative substitution of T or A
  • X 68 is a conservative substitution of K or Q
  • X 69 is a conservative substitution of S or F
  • X 70 is a conservative substitution of S or F
  • X 71 is a conservative substitution of Y or F
  • X 72 is a conservative substitution of T or K
  • X 73 is a conservative substitution of S or N
  • X 74 is a conservative substitution of P or S
  • X 75 is a conservative substitution of I or T.
  • an anti-MET antibody described herein comprises a VH region comprising EVQLVESGGGLVQPGGSLKLSCAASGFTFSDSYMAWVRQAPGKGLEWVASISSDGGG TYYRDSVKGRFTISRDNAKX 76 SLYLQMX 77 SLRTEDTATYYCTTEGIYTTDYYPYCFNY WGQGX 78 MV (SEQ ID NO: 239), wherein X 76 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., S or N, X 77 is any amino acid, for example, D or N, and X 78 is any amino acid, for example, T or V.
  • any one of X 76 to X 78 is any amino acid sequence.
  • X 76 is a conservative substitution of S or N
  • X 77 is a conservative substitution of D or N
  • X 78 is a conservative substitution of T or V.
  • an anti-MET antibody described herein comprises
  • an anti-MET antibody described herein comprises a VL region comprising MGWSCIILFLVATATGVHSQIVLTQSPAIMSX 136 SPGEKVTMTCSASSSVX 137 YMFWYQ QKX 138 GSSPRLLIYDTX 139 X 140 LASGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQW SX 141 IYPYTFGGGTKLEIK (SEQ ID NO: 273), wherein X 136 is any amino acid, for example, T or A, X 137 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., N or S, X 138 is any amino acid, for example, A or P, X 139 is any amino acid, for example, F or S, X 140 is any amino acid, for example, N or D, and X 141 is any amino acid, for example, I or N.
  • any one of X 136 to X 141 is any amino acid sequence.
  • X 136 is a conservative substitution of T or A
  • X 137 is a conservative substitution of N or S
  • X 138 is a conservative substitution of A or P
  • X 139 is a conservative substitution of F or S
  • X 140 is a conservative substitution of N or D
  • X 141 is a conservative substitution of I or N.
  • an anti-MET antibody described herein comprises a VL region comprising QIVLTQSPAIMSX 43 SPGEKVTMTCSASSSVX 44 YMFWYQQKX 45 GSSPRLLIYDTX 46 X 47 LA SGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQWSX 48 IYPYTFGGGTKLEIK (SEQ ID NO: 48), wherein X 43 is any amino acid, for example, T or A, X 44 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., N or S, X 45 is any amino acid, for example, A or P, X 46 is any amino acid, for example, F or S, X 47 is any amino acid, for example, N or D, and X 48 is any amino acid, for example, I or N.
  • any one of X 43 to X 48 is any amino acid sequence.
  • X 43 is a conservative substitution of T or A
  • X 44 is a conservative substitution of N or S
  • X 45 is a conservative substitution of A or P
  • X 46 is a conservative substitution of F or S
  • X 47 is a conservative substitution of N or D
  • X 48 is a conservative substitution of I or N.
  • an anti-MET antibody described herein comprises a VH region comprising QX 57 QLQQSGAELMKPGASVKISCKATGYX 58 FSX 59 YWIEWVKQRPGHGLEWIGEILPGS DX 60 X 61 KYX 62 EKFKGKATFTADTSSNTAYMQLSX 63 LTSEDSAVYYCARPSTX 64 PPDCW GQGTTLTVSA (SEQ ID NO:50), wherein X 57 is any amino acid, for example, an amino acid with an nonpolar side chain, e.g., V or A, X 58 is any amino acid, for example, I or T, X 59 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., N or S, X 60 is any amino acid, for example, an amino acid with an aromatic side chain, e.g., Y or F, X 61 is any amino acid, for example, T or I,
  • any one of X 57 to X 64 is any amino acid sequence.
  • X 57 is a conservative substitution of V or A
  • X 58 is a conservative substitution of I or T
  • X 59 is a conservative substitution of N or S
  • X 60 is a conservative substitution of Y or F
  • X 61 is a conservative substitution of T or I
  • X 62 is a conservative substitution of N or S
  • X 63 is a conservative substitution of S or N
  • X 64 is a conservative substitution of I or V.
  • an anti-MET antibody described herein comprises
  • an anti-MET antibody described herein comprises
  • an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VL as described in Table 9. In a specific embodiment, an anti-MET antibody described herein or an antigen-binding fragment thereof comprises a VH as described in Table 10.
  • an antibody described herein may be described by its VL region alone, or its VH region alone, or by its 3 VL CDRs alone, or its 3 VH CDRs alone. See, for example, Rader et al., 1998, Proc. Natl. Acad. Sci. USA, 95: 8910-8915, which is incorporated herein by reference in its entirety, describing the humanization of the mouse anti-av ⁇ 3 antibody by identifying a complementing light chain or heavy chain, respectively, from a human light chain or heavy chain library, resulting in humanized antibody variants having affinities as high or higher than the affinity of the original antibody.
  • the position of one or more CDRs along the VH (e.g., CDR1, CDR2, or CDR3) and/or VL (e.g., CDR1, CDR2, or CDR3) region of an antibody described herein may vary by one, two, three, four, five, or six amino acid positions so long as immunospecific binding to MET (e.g., human MET ECD, e.g., SEQ ID NO:190) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).
  • MET e.g., human MET ECD, e.g., SEQ ID NO:190
  • the position defining a CDR of any of antibody Ab235-Ab255 may vary by shifting the N-terminal and/or C-terminal boundary of the CDR by one, two, three, four, five, or six amino acids, relative to the CDR position in the VL or VH (see, e.g., Tables 9 or 10, respectively), so long as immunospecific binding to MET (e.g., human MET) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).
  • MET e.g., human MET
  • the length of one or more CDRs along the VH (e.g., CDR1, CDR2, or CDR3) and/or VL (e.g., CDR1, CDR2, or CDR3) region of an antibody described herein may vary (e.g., be shorter or longer) by one, two, three, four, five, or more amino acids, so long as immunospecific binding to MET (e.g., human MET ECD, e.g., SEQ ID NO:190) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).
  • MET e.g., human MET ECD, e.g., SEQ ID NO:190
  • a VH and/or VL CDR1, CDR2, and/or CDR3 described herein may be one, two, three, four, five or more amino acids shorter than one or more of the CDRs described by SEQ ID NO: 1-35, so long as immunospecific binding to MET (e.g., human MET ECD, e.g., SEQ ID NO:190) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).
  • MET e.g., human MET ECD, e.g., SEQ ID NO:190
  • VH and/or VL CDR1, CDR2, and/or CDR3 described herein may be one, two, three, four, five or more amino acids longer than one or more of the CDRs described by SEQ ID NOS: 1-35, so long as immunospecific binding to MET (e.g., human MET ECD, e.g., SEQ ID NO:190) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).
  • MET e.g., human MET ECD, e.g., SEQ ID NO:190
  • the amino terminus of a VH and/or VL CDR1, CDR2, and/or CDR3 described herein may be extended by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by SEQ ID NOS: 1-25, so long as immunospecific binding to MET (e.g., human MET ECD, e.g., SEQ ID NO:190) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).
  • MET e.g., human MET ECD, e.g., SEQ ID NO:190
  • the carboxy terminus of a VH and/or VL CDR1, CDR2, and/or CDR3 described herein may be extended by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by SEQ ID NOS: 1-35, so long as immunospecific binding to MET (e.g., human MET ECD, e.g., SEQ ID NO:190) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).
  • MET e.g., human MET ECD, e.g., SEQ ID NO:190
  • the amino terminus of a VH and/or VL CDR1, CDR2, and/or CDR3 described herein may be shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by SEQ ID NOS: 1-35, so long as immunospecific binding to MET (e.g., human MET, e.g., SEQ ID NO:190) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).
  • MET e.g., human MET, e.g., SEQ ID NO:190
  • the carboxy terminus of a VH and/or VL CDR1, CDR2, and/or CDR3 described herein may be shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by SEQ ID NOS: 1-35, so long as immunospecific binding to MET (e.g., human MET ECD, e.g., SEQ ID NO:190) is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%).
  • MET e.g., human MET ECD, e.g., SEQ ID NO:190
  • Section 6 describes an ELISA assay for measuring binding to an ECD of human MET. Briefly, ELISA plates are coated with 100 ⁇ L/well 1 ⁇ g/mL hu-MET-ECD in borate buffer at 4° C.
  • Section 6 describes FACS binding assays with A549 cells for ascertaining whether immunospecific binding of an anti-MET antibody to MET (e.g., human MET ECD, e.g., SEQ ID NO:190) is maintained.
  • MET e.g., human MET ECD, e.g., SEQ ID NO:190
  • an antibody comprising an antibody light chain and heavy chain, e.g., a separate light chain and heavy chain.
  • the light chain of an antibody described herein is a kappa ( ⁇ ) light chain.
  • the light chain of an antibody described herein is a lambda ( ⁇ ) light chain.
  • light chain is a mixed sequence, e.g., the variable portion of the light chain comprises kappa light chain sequences and the constant region of the light chain comprises lambda light chain sequences, or vice versa.
  • the light chain of an antibody described herein is a human kappa light chain or a human lambda light chain.
  • Non-limiting examples of human constant region sequences have been described in the art, e.g., see U.S. Pat. No. 5,693,780 and Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242.
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a light chain wherein the amino acid sequence of the VL chain region comprises any amino acid sequence described herein (e.g., SEQ ID NOS: 52-62), and wherein the constant region of the light chain comprises the amino acid sequence of a human kappa light chain constant region.
  • a MET polypeptide e.g., an ECD of MET, for example human MET
  • the constant region of the light chain comprises the amino acid sequence of a human kappa light chain constant region.
  • an antibody described herein which immunospecifically binds a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a light chain wherein the amino acid sequence of the VL chain region can comprise any amino acid sequence described herein (e.g., SEQ ID NOS:52-62), and wherein the constant region of the light chain comprises the amino acid sequence of a human lambda light chain constant region.
  • a MET polypeptide e.g., an ECD of MET, for example human MET
  • the amino acid sequence of the VL chain region can comprise any amino acid sequence described herein (e.g., SEQ ID NOS:52-62), and wherein the constant region of the light chain comprises the amino acid sequence of a human lambda light chain constant region.
  • the heavy chain of an antibody described herein can be an alpha ( ⁇ ), delta ( ⁇ ), epsilon ( ⁇ ), gamma ( ⁇ ) or mu ( ⁇ ) heavy chain.
  • the heavy chain of an antibody described can comprise a human alpha ( ⁇ ), delta ( ⁇ ), epsilon ( ⁇ ), gamma ( ⁇ ) or mu ( ⁇ ) heavy chain.
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a heavy chain wherein the amino acid sequence of the VH chain region can comprise any amino acid sequence described herein (e.g., any of SEQ ID NOs: 63-71), and wherein the constant region of the heavy chain comprises the amino acid sequence of a human gamma ( ⁇ ) heavy chain constant region.
  • a MET polypeptide e.g., an ECD of MET, for example human MET
  • the constant region of the heavy chain comprises the amino acid sequence of a human gamma ( ⁇ ) heavy chain constant region.
  • Non-limiting examples of human constant region sequences have been described in the art, e.g., see U.S. Pat. No. 5,693,780 and Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein, and wherein the constant regions comprise amino acid sequences of constant regions of an IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecule, or a human IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecule.
  • a MET polypeptide e.g., an ECD of MET, for example human MET
  • the constant regions comprise amino acid sequences of constant regions of an IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecule, or a human IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecule.
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein, and wherein the constant regions comprise amino acid sequences of constant regions of an IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecule, any class (e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 and IgA 2 ), or any subclass (e.g., IgG 2a and IgG 2b , or a mixture thereof) of immunoglobulin molecule.
  • a MET polypeptide e.g., an ECD of MET, for example human MET
  • the constant regions comprise amino acid sequences of constant regions of an IgG, IgE, IgM, IgD, IgA or Ig
  • the constant regions comprise the amino acid sequences of the constant regions of a human IgG, IgE, IgM, IgD, IgA or IgY immunoglobulin molecule, any class (e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 and IgA 2 ), or any subclass (e.g., IgG 2a and IgG 2b , or a mixture thereof) of immunoglobulin molecule.
  • any class e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 and IgA 2
  • any subclass e.g., IgG 2a and IgG 2b , or a mixture thereof
  • an antibody described herein, which immunospecifically binds to a MET polypeptide comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein, and wherein the constant regions comprise the amino acid sequences of the constant regions of an IgG 2 .
  • the IgG 2 is a human IgG 2 .
  • the IgG 2 (e.g., human IgG 2 ) is IgG 2a (e.g., human IgG 2a ).
  • the IgG 2 (e.g., human IgG 2 ) is IgG 2b (e.g., human IgG 2b ). In certain embodiments, the IgG 2 (e.g., human IgG 2 ) is a mixture of IgG 2a (e.g., human IgG 2a ) and IgG 2b (e.g., human IgG 2b ).
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein, and wherein the constant regions comprise the amino acid sequences of the constant regions of a human IgG 1 (e.g., isotype a, z, or f) or human IgG 4 .
  • an antibody described herein, which immunospecifically binds to a MET polypeptide comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein, and wherein the constant regions comprise the amino acid sequences of the constant region of a human IgG 1 (isotype f).
  • a MET polypeptide e.g., an ECD of MET, for example human MET
  • the constant regions comprise the amino acid sequences of the constant region of a human IgG 1 (isotype f).
  • human constant regions are described in the art, e.g., see Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242.
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein (e.g., VL and VH of Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255), and wherein the constant regions comprise the amino acid sequences of the constant regions of a human IgG 2 (e.g., IgG 2a or IgG 2b , or a mixture thereof).
  • a human IgG 2 e.g., IgG 2a or IgG 2b , or a mixture thereof.
  • an antibody described herein, which immunospecifically binds to a MET polypeptide comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein (e.g., VL and VH of Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255), and wherein the constant regions comprise the amino acid sequences of the constant region of a human IgG 2 (isotype IgG 2a ).
  • an antibody described herein, which immunospecifically binds to a MET polypeptide comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein (e.g.,. VL and VH of Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255), and wherein the constant regions comprise the amino acid sequences of the constant region of a human IgG 2 (isotype IgG 2b ).
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein, and wherein the constant regions comprise the amino acid sequence of the constant region of human IgG 2 isotype (e.g., human IgG 2 isotype where a mixture of IgG 2a and IgG 2b isotypes are present).
  • a MET polypeptide e.g., an ECD of MET, for example human MET
  • the constant regions comprise the amino acid sequence of the constant region of human IgG 2 isotype (e.g., human IgG 2 isotype where a mixture of IgG 2a and IgG 2b isotypes are present).
  • an antibody described herein, which immunospecifically binds to a MET polypeptide comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein (e.g.,. VL and VH of Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255), and wherein the constant regions comprise the amino acid sequences of the constant region of a human IgG 2 , for example, as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a light chain and a heavy chain, wherein (i) the light chain comprises a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of any one of Ab235-Ab255 (e.g., those listed in Tables 1, 5, and 7); (ii) the heavy chain comprises a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of any one of Ab235-Ab255 (e.g., those listed in Tables 2, 6, and 8); (iii) the light chain further comprises a constant light chain domain comprising the amino acid sequence of the constant domain of a human kappa light chain; and (iv) the heavy chain further comprises a constant heavy chain domain comprising the amino acid sequence of the constant domain of a human I
  • the human IgG 2 is human IgG 2a . In certain embodiments, the human IgG 2 is human IgG 2b . In certain embodiments, the IgG 2 (e.g., human IgG 2 ) comprises a mixture of IgG 2a (e.g., human IgG 2a ) and IgG 2b (e.g., human IgG 2b ).
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a light chain and a heavy chain, wherein (i) the light chain comprises a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 of Ab235 (e.g., the VL CDR1, VL CDR2 and VL CDR3 listed in any one of Tables 1, 5, and 7); (ii) the heavy chain comprises a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 of Ab235 (e.g., the VH CDR1, VH CDR2 and VH CDR3 listed in any one of Tables 2, 6, and 8); (iii) the light chain further comprises a human constant light chain domain; and (iv) the heavy chain further comprises a constant heavy chain domain comprising a constant domain of a human IgG 2 heavy chain.
  • the light chain comprises a
  • the human IgG 2 is human IgG 2a . In certain embodiments, the human IgG 2 is human IgG 2b . In certain embodiments, the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies. In certain embodiments, the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a light chain and a heavy chain, wherein (i) the light chain comprises a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 of Ab236 (e.g., the VL CDR1, VL CDR2 and VL CDR3 listed in any one of Tables 1, 5, and 7); (ii) the heavy chain comprises a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 of Ab236 (e.g., the VH CDR1, VH CDR2 and VH CDR3 listed in any one of Tables 2, 6, and 8); (iii) the light chain further comprises a human constant light chain domain; and (iv) the heavy chain further comprises a constant heavy chain domain comprising a constant domain of a human IgG 2 heavy chain.
  • the light chain comprises
  • the human IgG 2 is human IgG 2a . In certain embodiments, the human IgG 2 is human IgG 2b . In certain embodiments, the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies. In certain embodiments, the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a light chain and a heavy chain, wherein (i) the light chain comprises a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 of Ab237 (e.g., the VL CDR1, VL CDR2 and VL CDR3 listed in any one of Tables 1, 5, and 7); (ii) the heavy chain comprises a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 of Ab237 (e.g., the VH CDR1, VH CDR2 and VH CDR3 listed in any one of Tables 2, 6, and 8); (iii) the light chain further comprises a human constant light chain domain; and (iv) the heavy chain further comprises a constant heavy chain domain comprising a constant domain of a human IgG 2 heavy chain.
  • the light chain comprises
  • the human IgG 2 is human IgG 2a . In certain embodiments, the human IgG 2 is human IgG 2b . In certain embodiments, the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies. In certain embodiments, the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a light chain and a heavy chain, wherein (i) the light chain comprises a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 of Ab238 (e.g., the VL CDR1, VL CDR2 and VL CDR3 listed in any one of Tables 1, 5, and 7); (ii) the heavy chain comprises a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 of Ab238 (e.g., the VH CDR1, VH CDR2 and VH CDR3 listed in any one of Tables 2, 6, and 8); (iii) the light chain further comprises a human constant light chain domain; and (iv) the heavy chain further comprises a constant heavy chain domain comprising a constant domain of a human IgG 2 heavy chain.
  • the light chain comprises
  • the human IgG 2 is human IgG 2a . In certain embodiments, the human IgG 2 is human IgG 2b . In certain embodiments, the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies. In certain embodiments, the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a light chain and a heavy chain, wherein (i) the light chain comprises a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 of Ab239 (e.g., the VL CDR1, VL CDR2 and VL CDR3 listed in any one of Tables 1, 5, and 7); (ii) the heavy chain comprises a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 of Ab239 (e.g., the VH CDR1, VH CDR2 and VH CDR3 listed in any one of Tables 2, 6, and 8); (iii) the light chain further comprises a human constant light chain domain; and (iv) the heavy chain further comprises a constant heavy chain domain comprising a constant domain of a human IgG 2 heavy chain.
  • the light chain comprises
  • the human IgG 2 is human IgG 2a . In certain embodiments, the human IgG 2 is human IgG 2b . In certain embodiments, the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies. In certain embodiments, the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a light chain and a heavy chain, wherein (i) the light chain comprises a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 of Ab240 (e.g., the VL CDR1, VL CDR2 and VL CDR3 listed in any one of Tables 1, 5, and 7); (ii) the heavy chain comprises a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 of Ab240 (e.g., the VH CDR1, VH CDR2 and VH CDR3 listed in any one of Tables 2, 6, and 8); (iii) the light chain further comprises a human constant light chain domain; and (iv) the heavy chain further comprises a constant heavy chain domain comprising a constant domain of a human IgG 2 heavy chain.
  • the light chain comprises a
  • the human IgG 2 is human IgG 2a . In certain embodiments, the human IgG 2 is human IgG 2b . In certain embodiments, the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies. In certain embodiments, the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab235 (SEQ ID NOs: 57 and 66, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab236 (SEQ ID NOs: 58 and 67, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab237 (SEQ ID NOs: 59 and 68, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab238 (SEQ ID NOs: 60 and 69, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab239 (SEQ ID NOs: 61 and 70, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab240 (SEQ ID NOs: 62 and 71, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab241 (SEQ ID NOs: 52 and 63, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab242 (SEQ ID NOs: 53 and 63, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab243 (SEQ ID NOs: 54 and 63, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab244 (SEQ ID NOs: 55 and 63, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab245 (SEQ ID NOs: 56 and 63, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab246 (SEQ ID NOs: 52 and 64, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab247 (SEQ ID NOs: 53 and 64, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab248 (SEQ ID NOs: 54 and 64, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab249 (SEQ ID NOs: 55 and 64, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein, which immunospecifically binds to a MET polypeptide comprises a VL chain region and a VH chain region of Ab250 (SEQ ID NOs: 56 and 64, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein, which immunospecifically binds to a MET polypeptide comprises a VL chain region and a VH chain region of Ab251 (SEQ ID NOs: 52 and 65, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab252 (SEQ ID NOs: 53 and 65, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein, which immunospecifically binds to a MET polypeptide comprises a VL chain region and a VH chain region of Ab253 (SEQ ID NOs: 54 and 65, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein, which immunospecifically binds to a MET polypeptide comprises a VL chain region and a VH chain region of Ab254 (SEQ ID NOs: 55 and 65, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET) comprises a VL chain region and a VH chain region of Ab255 (SEQ ID NOs: 56 and 65, respectively); wherein the light chain further comprises a human constant light chain domain and the heavy chain further comprises a constant heavy chain domain comprising the constant domain of a human IgG 2 heavy chain.
  • the human IgG 2 is human IgG 2a .
  • the human IgG 2 is human IgG 2b .
  • the antibody is present as a mixture of the above human IgG 2a -containing antibodies and the above human IgG 2b -containing antibodies.
  • the human IgG 2 heavy chain comprises the amino acid sequence as set forth below:
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a light chain and a heavy chain, wherein (i) the light chain comprises a VL chain region comprising a VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of any one of Ab235-Ab255 (e.g., those listed in Tables 1, 5, and 7); (ii) the heavy chain comprises a VH chain region comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of any one of Ab235-Ab255 (e.g., those listed in Tables 2, 6, and 8); (iii) the light chain further comprises a constant light chain domain comprising the amino acid sequence of the constant domain of a human kappa light chain, for example, comprising the amino acid sequence TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW
  • the human IgG 2 is human IgG 2a . In certain embodiments, the human IgG 2 is human IgG 2b . In certain embodiments, the IgG 2 (e.g., human IgG 2 ) is a mixture of IgG 2a (e.g., human IgG 2a ) and IgG 2b (e.g., human IgG 2b ).
  • an antibody described herein which immunospecifically binds to a MET polypeptide (e.g., an ECD of MET, for example human MET), comprises a light chain and a heavy chain, wherein (i) the light chain comprises the amino acid seauence:
  • Framework regions described herein are determined based upon the boundaries of the CDR numbering system. In other words, if the CDRs are determined by, e.g., Kabat, IMGT, or Chothia, then the framework regions are the amino acid residues surrounding the CDRs in the variable region in the format, from the N-terminus to C-terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • FR1 is defined as the amino acid residues N-terminal to the CDR1 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system
  • FR2 is defined as the amino acid residues between CDR1 and CDR2 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system
  • FR3 is defined as the amino acid residues between CDR2 and CDR3 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system
  • FR4 is defined as the amino acid residues C-terminal to the CDR3 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for any one of antibodies Ab235-Ab255 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • VL FRs are in the following positions relative to VL CDRs in a VL sequence: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • VH FRs are in the following positions relative to VH CDRs in a VH sequence: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab235 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 103, and VL CDRs of Ab235.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 111, and VL CDRs of Ab235.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 122, and VL CDRs of Ab235.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 128, and VL CDRs of Ab235.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 103, the VL FR 2 having the amino acid sequence of SEQ ID NO: 111, the VL FR3 having the amino acid sequence of SEQ ID NO: 122, and the VL FR4 having the amino acid sequence of SEQ ID NO: 128, and VL CDRs of Ab235.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab236 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 104 and VL CDRs of Ab236.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 112 and VL CDRs of Ab236.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 122 and VL CDRs of Ab236.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 128 and VL CDRs of Ab236.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 104, the VL FR 2 having the amino acid sequence of SEQ ID NO: 112, the VL FR3 having the amino acid sequence of SEQ ID NO: 122, and the VL FR4 having the amino acid sequence of SEQ ID NO: 128 and VL CDRs of Ab236.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab237 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 105 and VL CDRs of Ab237.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 113 and VL CDRs of Ab237.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 123 and VL CDRs of Ab237.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab237.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 105, the VL FR 2 having the amino acid sequence of SEQ ID NO: 113, the VL FR3 having the amino acid sequence of SEQ ID NO: 123, and the VL FR4 having the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab237.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab238 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 106 and VL CDRs of Ab238.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 114 and VL CDRs of Ab238.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 124 and VL CDRs of Ab238.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 128 and VL CDRs of Ab238.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 106, the VL FR 2 having the amino acid sequence of SEQ ID NO: 114, the VL FR3 having the amino acid sequence of SEQ ID NO: 124, and the VL FR4 having the amino acid sequence of SEQ ID NO: 128 and VL CDRs of Ab238.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab239 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 107 and VL CDRs of Ab239.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 115 and VL CDRs of Ab239.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 125 and VL CDRs of Ab239.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 128 and VL CDRs of Ab239.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 107, the VL FR 2 having the amino acid sequence of SEQ ID NO: 115, the VL FR3 having the amino acid sequence of SEQ ID NO: 125, and the VL FR4 having the amino acid sequence of SEQ ID NO: 128 and VL CDRs of Ab239.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab240 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 103 and VL CDRs of Ab240.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 111 and VL CDRs of Ab240.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 122 and VL CDRs of Ab240.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 128 and VL CDRs of Ab240.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 103, the VL FR 2 having the amino acid sequence of SEQ ID NO: 111, the VL FR3 having the amino acid sequence of SEQ ID NO: 122, and the VL FR4 having the amino acid sequence of SEQ ID NO: 128 and VL CDRs of Ab240.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab241 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab241.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 109 and VL CDRs of Ab241.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 117 and VL CDRs of Ab241.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab241.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 109, the VL FR3 having the amino acid sequence of SEQ ID NO: 117, and the VL FR4 having the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab241.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab242 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab242.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab242.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 118 and VL CDRs of Ab242.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab242.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 103, the VL FR 2 having the amino acid sequence of SEQ ID NO: 111, the VL FR3 having the amino acid sequence of SEQ ID NO: 122, and the VL FR4 having the amino acid sequence of SEQ ID NO: 128 and VL CDRs of Ab242.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab243 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab243.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab243.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 119 and VL CDRs of Ab243.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab243.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 110, the VL FR3 having the amino acid sequence of SEQ ID NO: 119, and the VL FR4 having the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab243.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab244 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab244.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab244.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 120 and VL CDRs of Ab244.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab244.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 110, the VL FR3 having the amino acid sequence of SEQ ID NO: 120, and the VL FR4 having the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab244.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab245 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab245.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab245.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 121 and VL CDRs of Ab245.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab245.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 110, the VL FR3 having the amino acid sequence of SEQ ID NO: 121, and the VL FR4 having the amino acid sequence of SEQ ID NO: 1278 and VL CDRs of Ab245.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab246 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab246.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 109 and VL CDRs of Ab246.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 117 and VL CDRs of Ab246.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab246.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 109, the VL FR3 having the amino acid sequence of SEQ ID NO: 117, and the VL FR4 having the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab246.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab247 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab247.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab247.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 118 and VL CDRs of Ab247.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab247.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 103, the VL FR 2 having the amino acid sequence of SEQ ID NO: 111, the VL FR3 having the amino acid sequence of SEQ ID NO: 122, and the VL FR4 having the amino acid sequence of SEQ ID NO: 128 and VL CDRs of Ab247.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab248 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab248.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab248.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 119 and VL CDRs of Ab248.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab248.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 110, the VL FR3 having the amino acid sequence of SEQ ID NO: 119, and the VL FR4 having the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab248.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab249 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab249.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab249.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 120 and VL CDRs of Ab249.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab249.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 110, the VL FR3 having the amino acid sequence of SEQ ID NO: 120, and the VL FR4 having the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab249.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab2550 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab250.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab250.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 121 and VL CDRs of Ab250.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab250.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 110, the VL FR3 having the amino acid sequence of SEQ ID NO: 121, and the VL FR4 having the amino acid sequence of SEQ ID NO: 1278 and VL CDRs of Ab250.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab251 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab251.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 109 and VL CDRs of Ab251.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 117 and VL CDRs of Ab251.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab251.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 109, the VL FR3 having the amino acid sequence of SEQ ID NO: 117, and the VL FR4 having the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab251.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab252 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab252.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab252.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 118 and VL CDRs of Ab252.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab252.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 103, the VL FR 2 having the amino acid sequence of SEQ ID NO: 111, the VL FR3 having the amino acid sequence of SEQ ID NO: 122, and the VL FR4 having the amino acid sequence of SEQ ID NO: 128 and VL CDRs of Ab252.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab253 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab253.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab253.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 119 and VL CDRs of Ab253.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab253.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 110, the VL FR3 having the amino acid sequence of SEQ ID NO: 119, and the VL FR4 having the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab253.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab254 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab254.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab254.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 120 and VL CDRs of Ab254.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab254.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 110, the VL FR3 having the amino acid sequence of SEQ ID NO: 120, and the VL FR4 having the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab254.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence described herein for Ab255 (e.g., see Table 3), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 102 and VL CDRs of Ab255.
  • the VL FR2 has the amino acid sequence of SEQ ID NO: 110 and VL CDRs of Ab255.
  • the VL FR3 has the amino acid sequence of SEQ ID NO: 121 and VL CDRs of Ab255.
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 127 and VL CDRs of Ab255.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 102, the VL FR 2 having the amino acid sequence of SEQ ID NO: 110, the VL FR3 having the amino acid sequence of SEQ ID NO: 121, and the VL FR4 having the amino acid sequence of SEQ ID NO: 1278.
  • an antibody described herein comprises one or more VL framework regions (FRs) having the amino acid sequence of (a) SEQ ID NO:240; (b) WYQQKPGKAPX 79 LLIY (SEQ ID NO: 241), wherein X 79 is any amino acid, for example, K or Q; (c) GVPSRFSGX 80 GX 81 GTDX 82 TLX 83 IX 84 SLQX 85 EDVAX 86 YFC, wherein X 80 is any amino acid, for example, S or F, X 81 is any amino acid, for example, S or F, X 82 is any amino acid, for example, an amino acid with an aromatic side chain, e.g., Y or F, X 83 is any amino acid, for example, T or K, X 84 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., S or N, X 85 is any amino acid, for example, P or S
  • an antibody e.g., murine, rodent, chimeric or humanized antibody
  • a VL region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VL FR1 has the amino acid sequence of SEQ ID NO: 240 and VL CDRs of any one of Ab235-Ab255.
  • the VL FR2 has the amino acid sequence of WYQQKPGKAPX 79 LLIY (SEQ ID NO: 241), wherein X 79 is any amino acid, for example, K or Q and VL CDRs of any of Ab235-Ab255.
  • the VL FR3 has the amino acid sequence of GVPSRFSGX 80 GX 81 GTDX 82 TLX 83 IX 84 SLQX 85 EDVAX 86 YFC, wherein X 80 is any amino acid, for example, S or F, X 81 is any amino acid, for example, S or F, X 82 is any amino acid, for example, an amino acid with an aromatic side chain, e.g., Y or F, X 83 is any amino acid, for example, T or K, X 84 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., S or N, X 85 is any amino acid, for example, P or S, and X 86 is any amino acid, for example, an amino acid with a nonpolar side chain, e.g., I or T and VL CDRs of any of Ab235-Ab255.
  • X 80 is any amino acid, for example, S or F
  • X 81 is
  • the VL FR4 has the amino acid sequence of SEQ ID NO: 243 and VL CDRs of any of Ab235-Ab255.
  • the an antibody described herein comprises one or more of the VL FR1 having the amino acid sequence of SEQ ID NO: 240, the VL FR 2 having the amino acid sequence of WYQQKPGKAPX 79 LLIY (SEQ ID NO: 241), wherein X 79 is any amino acid, for example, K or Q, the VL FR3 having the amino acid sequence of GVPSRFSGX 80 GX 81 GTDX 82 TLX 83 IX 84 SLQX 85 EDVAX 86 YFC, wherein X 80 is any amino acid, for example, S or F, X 81 is any amino acid, for example, S or F, X 82 is any amino acid, for example, an amino acid with an aromatic side chain, e.g., Y or F, X 83 is any amino acid, for
  • any one of X 79 to X 86 is any amino acid sequence.
  • X 79 is a conservative substitution of K or Q
  • X 80 is a conservative substitution of S or F
  • X 81 is a conservative substitution of S or F
  • X 82 is a conservative substitution of Y or F
  • X 83 is a conservative substitution of T or K
  • X 84 is a conservative substitution of S or N
  • X 85 is a conservative substitution of P or S
  • X 86 is a conservative substitution of I or T.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab235 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 75 and VH CDRs of Ab235.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 82 and VH CDRs of Ab235.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 89 and VH CDRs of Ab235.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 268 and VH CDRs of Ab235.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 97 and VH CDRs of Ab235.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 75, the VH FR 2 having the amino acid sequence of SEQ ID NO: 82, the VH FR3 having the amino acid sequence of SEQ ID NO: 89, and the VH FR4 having the amino acid sequence of SEQ ID NO: 97.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 75, the VH FR 2 having the amino acid sequence of SEQ ID NO: 82, the VH FR3 having the amino acid sequence of SEQ ID NO: 268, and the VH FR4 having the amino acid sequence of SEQ ID NO: 97.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab236 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 76 and VH CDRs of Ab236.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 82 and VH CDRs of Ab236.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 90 and VH CDRs of Ab236.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 269 and VH CDRs of Ab236.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 97 and VH CDRs of Ab236.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 76, the VH FR 2 having the amino acid sequence of SEQ ID NO: 82, the VH FR3 having the amino acid sequence of SEQ ID NO: 90, and the VH FR4 having the amino acid sequence of SEQ ID NO: 97 and VH CDRs of Ab236.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 76, the VH FR 2 having the amino acid sequence of SEQ ID NO: 82, the VH FR3 having the amino acid sequence of SEQ ID NO: 269, and the VH FR4 having the amino acid sequence of SEQ ID NO: 97 and VH CDRs of Ab236.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab237 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 77 and VH CDRs of Ab237.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 83 and VH CDRs of Ab237.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 91 and VH CDRs of Ab237.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 270 and VH CDRs of Ab237.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 98 and VH CDRs of Ab237.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 77, the VH FR 2 having the amino acid sequence of SEQ ID NO: 83, the VH FR3 having the amino acid sequence of SEQ ID NO: 91, and the VH FR4 having the amino acid sequence of SEQ ID NO: 98 and VH CDRs of Ab237.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 77, the VH FR 2 having the amino acid sequence of SEQ ID NO: 83, the VH FR3 having the amino acid sequence of SEQ ID NO: 270, and the VH FR4 having the amino acid sequence of SEQ ID NO: 98 and VH CDRs of Ab237.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab238 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 78 and VH CDRs of Ab238.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 84 and VH CDRs of Ab238. In some embodiments, the VH FR2 has the amino acid sequence of SEQ ID NO: 271 and VH CDRs of Ab238. In some embodiments, the VH FR3 has the amino acid sequence of SEQ ID NO: 92 and VH CDRs of Ab238. In some embodiments, the VH FR4 has the amino acid sequence of SEQ ID NO: 99 and VH CDRs of Ab238.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 78, the VH FR 2 having the amino acid sequence of SEQ ID NO: 84, the VH FR3 having the amino acid sequence of SEQ ID NO: 92, and the VH FR4 having the amino acid sequence of SEQ ID NO: 99 and VH CDRs of Ab238.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 78, the VH FR 2 having the amino acid sequence of SEQ ID NO: 271, the VH FR3 having the amino acid sequence of SEQ ID NO: 92, and the VH FR4 having the amino acid sequence of SEQ ID NO: 99 and VH CDRs of Ab238.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab239 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 79 and VH CDRs of Ab239.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 83 and VH CDRs of Ab239.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 93 and VH CDRs of Ab239.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 100 and VH CDRs of Ab239.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 79, the VH FR 2 having the amino acid sequence of SEQ ID NO: 83, the VH FR3 having the amino acid sequence of SEQ ID NO: 93, and the VH FR4 having the amino acid sequence of SEQ ID NO: 100 and VH CDRs of Ab239.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab240 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 80 and VH CDRs of Ab240.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 84 and VH CDRs of Ab240.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 94 and VH CDRs of Ab240.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 101 and VH CDRs of Ab240.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 80, the VH FR 2 having the amino acid sequence of SEQ ID NO: 84, the VH FR3 having the amino acid sequence of SEQ ID NO: 94, and the VH FR4 having the amino acid sequence of SEQ ID NO: 101 and VH CDRs of Ab240.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab241 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab241.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab241.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 86 and VH CDRs of Ab241.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab241.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR 2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 86, and the VH FR4 having the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab241.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab242 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab242.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab242.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 86 and VH CDRs of Ab242.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab242.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR 2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 86, and the VH FR4 having the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab242.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab243 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab243.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab243.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 86 and VH CDRs of Ab243.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab243.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR 2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 86, and the VH FR4 having the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab243.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab244 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab244.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab244.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 86 and VH CDRs of Ab244.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab244.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR 2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 86, and the VH FR4 having the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab244.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab245 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab245.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab245.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 86 and VH CDRs of Ab245.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab245.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR 2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 86, and the VH FR4 having the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab245
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab246 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab246.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab246.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 87 and VH CDRs of Ab246.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab246.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR 2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 87, and the VH FR4 having the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab246.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab247 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab247.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab247.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 87 and VH CDRs of Ab247.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab247.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR 2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 87, and the VH FR4 having the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab247.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab248 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab248.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab248.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 87 and VH CDRs of Ab248.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab248.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR 2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 87, and the VH FR4 having the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab248.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab249 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab249.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab249.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 87 and VH CDRs of Ab249.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab249.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR 2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 87, and the VH FR4 having the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab249.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab250 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine (e.g., rodent), chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab250.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab250.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 87 and VH CDRs of Ab250.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab250.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR 2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 87, and the VH FR4 having the amino acid sequence of SEQ ID NO: 95 and VH CDRs of Ab250.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab251 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab251.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab251.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 88 and VH CDRs of Ab251.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 96 and VH CDRs of Ab251.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 88, and the VH FR4 having the amino acid sequence of SEQ ID NO: 96 and VH CDRs of Ab251.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab252 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab252.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab252.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 88 and VH CDRs of Ab252.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 96 and VH CDRs of Ab252.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 88, and the VH FR4 having the amino acid sequence of SEQ ID NO: 96 and VH CDRs of Ab252.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab253 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab253.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab253.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 88 and VH CDRs of Ab253.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 96 and VH CDRs of Ab253.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 88, and the VH FR4 having the amino acid sequence of SEQ ID NO: 96 and VH CDRs of Ab253.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab254 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab254.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab254.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 88 and VH CDRs of Ab254.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 96 and VH CDRs of Ab254.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR 2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 88, and the VH FR4 having the amino acid sequence of SEQ ID NO: 96 and VH CDRs of Ab254.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence described herein for Ab255 (e.g., see Table 4), wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • an antibody (e.g., murine, rodent, chimeric or humanized antibody) described herein comprises a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 74 and VH CDRs of Ab255.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 81 and VH CDRs of Ab255.
  • the VH FR3 has the amino acid sequence of SEQ ID NO: 88 and VH CDRs of Ab255.
  • the VH FR4 has the amino acid sequence of SEQ ID NO: 96 and VH CDRs of Ab255.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 74, the VH FR2 having the amino acid sequence of SEQ ID NO: 81, the VH FR3 having the amino acid sequence of SEQ ID NO: 88, and the VH FR4 having the amino acid sequence of SEQ ID NO: 96 and VH CDRs of Ab255.
  • an antibody described herein comprises one or more VH framework regions (FRs) having the amino acid sequence of (a) SEQ ID NO:244; (b) SEQ ID NO: 245; (c) RFTISRDNAKX 87 SLYLQMX 88 SLRTEDTATYYCTT (SEQ ID NO: 246), wherein X 87 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., S or N, and X 88 is any amino acid, for example, D or N; and (d) WGQGX 89 MV (SEQ ID NO: 247), wherein X 89 is any amino acid, for example, T or V, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190).
  • FRs VH framework regions having the amino acid sequence of (a) SEQ ID NO:244; (b) SEQ ID NO: 245; (c)
  • an antibody e.g., murine, rodent, chimeric or humanized antibody
  • a VH region comprising FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the VH FR1 has the amino acid sequence of SEQ ID NO: 244 and VH CDRs of any one of Ab235-Ab255.
  • the VH FR2 has the amino acid sequence of SEQ ID NO: 245 and VH CDRs of any of Ab235-Ab255.
  • the VH FR3 has the amino acid sequence of RFTISRDNAKX 87 SLYLQMX 88 SLRTEDTATYYCTT (SEQ ID NO: 246), wherein X 87 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., S or N, and X 88 is any amino acid, for example, D or N and VH CDRs of any of Ab235-Ab255.
  • the VH FR4 has the amino acid sequence of WGQGX 89 MV (SEQ ID NO: 247), wherein X 89 is any amino acid, for example, T or V and VH CDRs of any of Ab235-Ab255.
  • the an antibody described herein comprises one or more of the VH FR1 having the amino acid sequence of SEQ ID NO: 244, the VH FR 2 having the amino acid sequence of SEQ ID NO: 245, wherein X 79 is any amino acid, for example, K or Q, the VH FR3 having the amino acid sequence of RFTISRDNAKX 87 SLYLQMX 88 SLRTEDTATYYCTT (SEQ ID NO: 246), wherein X 87 is any amino acid, for example, an amino acid with an uncharged polar side chain, e.g., S or N, and X 88 is any amino acid, for example, D or N, and the VH FR4 having the amino acid sequence of WGQGX 89 MV (SEQ ID NO: 247), wherein X 89 is any amino acid, for example, T or V.
  • any one of X 87 to X 89 is any amino acid sequence.
  • X 87 is a conservative substitution of S or N
  • X 88 is a conservative substitution of D or N
  • X 89 is a conservative substitution of T or V.
  • an antibody described herein which immunospecifically binds to MET, e.g., human MET ECD (e.g., SEQ ID NO:190), comprises framework regions (e.g., framework regions of the VL domain and/or VH domain) that are human framework regions or derived from human framework regions.
  • framework regions e.g., framework regions of the VL domain and/or VH domain
  • Non-limiting examples of human framework regions are described in the art, e.g., see Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • an antibody described herein comprises framework regions (e.g., framework regions of the VL domain and/or VH domain) that are primate (e.g., non-human primate) framework regions or derived from primate (e.g., non-human primate) framework regions.
  • primate e.g., non-human primate
  • non-human primate e.g., non-human primate
  • CDRs from antigen-specific non-human antibodies are grafted onto homologous human or non-human primate acceptor frameworks.
  • the non-human primate acceptor frameworks are from Old World apes.
  • the Old World ape acceptor framework is from Pan troglodytes, Pan paniscus or Gorilla gorilla.
  • the non-human primate acceptor frameworks are from the chimpanzee Pan troglodytes.
  • the non-human primate acceptor frameworks are Old World monkey acceptor frameworks.
  • the Old World monkey acceptor frameworks are from the genus Macaca.
  • the non-human primate acceptor frameworks are is derived from the cynomolgus monkey Macaca cynomolgus.
  • Non-human primate framework sequences are described in U.S. Patent Application Publication No. US 2005/0208625.
  • a composite human antibody can be generated using, for example, Composite Human AntibodyTM technology (Antitope Ltd., Cambridge, United Kingdom).
  • composite human antibodies can be generated by fusing together segments of unrelated human antibody variable regions, which are subsequently evaluated for their avoidance of T cell epitope inclusion (see, e.g., Baker et al., 2010, Self Nonself., 1(4):314-322; and Bryson et al., 2010, BioDrugs, 24(1):1-8), for example, deimmunization (see, e.g., Jones et al., 2009, Methods Mol Biol., 525:405-23).
  • antibodies described herein are deimmunized antibodies.
  • Deimmunization is a technology for location and removal of T-cell epitopes through the combined use of immunological and molecular biology techniques (see, e.g., Jones et al., 2009, Methods Mol Biol., 525:405-23; and Perry et al., 2008, Drugs R D., 9(6):385-96).
  • mutations to remove T-cell epitopes can generally be introduced, for example in the constant region, VL and/or VH regions, without significantly reducing the binding affinity of an antibody.
  • mutations to remove T-cell epitopes are introduced in one or more VL CDRs and/or VH CDRs without significantly reducing the binding affinity of an antibody. In specific embodiments, mutations to remove T-cell epitopes are not introduced in VL CDRs and/or VH CDRs of an antibody. In certain embodiments, mutations to remove T-cell epitopes are introduced in one or more VL FRs and/or VH FRs without significantly reducing the binding affinity of an antibody.
  • an antibody described herein or an antigen-binding fragment thereof comprises amino acid sequences with certain percent identity relative to any one of Ab235-Ab255.
  • the determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • a preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. U.S.A. 87:2264 2268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. U.S.A. 90:5873 5877.
  • Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol. 215:403.
  • Gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389 3402.
  • PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.).
  • BLAST Gapped BLAST
  • PSI Blast programs the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov).
  • NBLAST National Center for Biotechnology Information
  • Another preferred, non limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11 17. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package.
  • ALIGN program version 2.0
  • the percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 57, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 57, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab235 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 57, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab235 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 66, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 66, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab235 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 66, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab235 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 57, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 66, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO: 1).
  • MET e.g., human MET ECD (SEQ ID NO: 1).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3and/or VH CDRs 1-3) of antibody Ab235 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • VL CDRs 1-3 and/or VH CDRs 1-3 identical to the CDRs (e.g., VL CDRs 1-3and/or VH CDRs 1-3) of antibody Ab235 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab236 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 58, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab236 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 67, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 67, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab236 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 67, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab236 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 67, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab236 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • antibody Ab236 e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8.
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 59, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 59, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab237 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 59, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab237 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 68 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 68, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab237 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 68, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab237 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 59, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 68, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab237 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • VL CDRs 1-3 and/or VH CDRs 1-3 identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab237 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 60, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 60, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab238 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 60, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab238 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 69 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 69, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab238 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 69, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab238 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 60, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 69, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab238 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • VL CDRs 1-3 and/or VH CDRs 1-3 identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab238 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 61, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 61, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab239 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 61, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab239 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 70 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 70, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab239 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 70, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab239 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 61, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 70, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab239 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • VL CDRs 1-3 and/or VH CDRs 1-3 identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab239 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 62, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 62, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab240 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 62, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab240 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 71 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 71, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab240 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 71, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab240 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 62, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 71, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab240 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • antibody Ab240 e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8.
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab241 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 52, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab241 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab241 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 63, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab241 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab241 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • antibody Ab241 e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8.
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 53, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 53, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab242 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 53, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab242 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab242 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 63, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab242 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 53, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab242 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • antibody Ab242 e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8.
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab243 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 54, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab243 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab243 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 63, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab243 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab243 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • antibody Ab243 e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8.
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab244 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 55, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab244 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab244 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 63, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab244 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3and/or VH CDRs 1-3) of antibody Ab244 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • VL CDRs 1-3 and/or VH CDRs 1-3 identical to the CDRs (e.g., VL CDRs 1-3and/or VH CDRs 1-3) of antibody Ab244 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab245 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 56, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab245 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab245 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 63, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab245 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 63, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (amino acid residues 25 to 934 of SEQ ID NO:190).
  • MET e.g., human MET ECD (amino acid residues 25 to 934 of SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab245 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • VL CDRs 1-3 and/or VH CDRs 1-3 identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab245 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab246 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 52, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab246 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab246 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 64, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab246 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab246 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • antibody Ab246 e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8.
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 53, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 53, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab247 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 53, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab247 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab247 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 64, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab247 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 53, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab247 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • VL CDRs 1-3 and/or VH CDRs 1-3 identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab247 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab248 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 54, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab248 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab248 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 64, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab248 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab248 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • antibody Ab248 e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8.
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab249 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 55, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab249 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab249 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 64, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab249 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab249 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • VL CDRs 1-3 and/or VH CDRs 1-3 identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab249 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab250 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 56, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab250 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab250 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 64, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab250 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 64, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab250 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • antibody Ab250 e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8.
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab251 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 52, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab251 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab251 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 65, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab251 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab251 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • antibody Ab251 e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8.
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 53, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 53, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab252 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 53, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab252 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab252 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 65, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab252 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 53, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab252 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • VH CDRs 1-3 identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab252 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab253 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 54, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab253 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab253 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 65, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab253 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab253 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • VH CDRs 1-3 identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab253 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab254 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 55, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab254 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab254 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 65, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab254 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 55, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab254 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • antibody Ab254 e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8.
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VL CDRs 1-3) that are identical to the CDRs (e.g., VL CDRs 1-3) of antibody Ab255 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • CDRs e.g., VL CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VL domain comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 56, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • the antibody comprises VL CDRs that are identical to the VL CDRs of antibody Ab255 (e.g., as set forth in Table 1, Table 5, or Table 7).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65 wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190), and wherein the antibody comprises CDRs (e.g., VH CDRs 1-3) that are identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab255 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • CDRs e.g., VH CDRs 1-3
  • an antibody described herein or an antigen-binding fragment thereof comprises a VH domain comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions of SEQ ID NO: 65, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody comprises CDRs (e.g., VH CDRs 1-3) identical to the CDRs (e.g., VH CDRs 1-3) of antibody Ab255 (e.g., as set forth in Table 2, Table 6, or Table 8).
  • an antibody described herein or an antigen-binding fragment thereof comprises (i) a VL domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, and (ii) a VH domain having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 65, respectively, wherein the antibody immunospecifically binds to MET, e.g., human MET ECD (SEQ ID NO:190).
  • MET e.g., human MET ECD (SEQ ID NO:190).
  • such an antibody or an antigen-binding fragment thereof comprises CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab255 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • CDRs e.g., VL CDRs 1-3 and/or VH CDRs 1-3
  • VH CDRs 1-3 identical to the CDRs (e.g., VL CDRs 1-3 and/or VH CDRs 1-3) of antibody Ab255 (e.g., as set forth in Tables 1 and 2, Tables 5 and 6, or Tables 7 and 8).
  • antibodies that bind the same or an overlapping epitope of MET e.g., an epitope located in an ECD of human MET, such as in a Sema domain or Sema/PSI domain
  • an antibody described herein e.g., antibody Ab235, Ab236, Ab237, Ab238, Ab239, Ab240, Ab241, Ab242, Ab243, Ab244, Ab245, Ab246, Ab247, Ab248, Ab249, Ab250, Ab251, Ab252, Ab253, Ab254, or Ab255
  • antibodies that compete e.g., in a dose dependent manner) for binding to MET (e.g., an ECD of human MET) with an antibody described herein (e.g., antibody Ab235, Ab236, Ab237, Ab238, Ab239, Ab240, Ab241, Ab242, Ab243, Ab244, Ab245, Ab246, Ab247, Ab248, Ab249, Ab250, Ab251, Ab252, Ab253, Ab254,
  • antibodies that bind the same or an overlapping epitope of MET e.g., an epitope located in an ECD of human MET, such as in a Sema domain or Sema/PSI domain
  • MET e.g., an epitope located in an ECD of human MET, such as in a Sema domain or Sema/PSI domain
  • Ab235, Ab236, Ab237, Ab239, Ab241, Ab242, Ab243, Ab244, Ab245, Ab246, Ab247, Ab248, Ab249, Ab250, Ab251, Ab252, Ab253, Ab254, or Ab255 and is capable of inhibiting (e.g., partially inhibiting) phosphorylation of MET and of inhibiting (e.g., partially inhibiting) tumor cell proliferation or tumor growth better as an IgG 2 isotype as compared to as an IgG 1 isotype.
  • Antibodies that bind to the same or overlapping epitopes of MET can be identified using routine techniques such as those utilized in the examples presented herein.
  • An immunoassay for example, used to demonstrate the ability of one antibody to block the binding of another antibody to a target antigen, i.e., a competitive binding assay.
  • Competition binding assays also can be used to determine whether two antibodies have similar binding specificity for an epitope.
  • Competitive binding can be determined in an assay in which the immunoglobulin under test inhibits specific binding of a reference antibody to a common antigen, such as MET.
  • RIA solid phase direct or indirect radioimmunoassay
  • EIA solid phase direct or indirect enzyme immunoassay
  • sandwich competition assay see Stahli et al., (1983) Methods in Enzymology 9:242
  • solid phase direct biotin-avidin EIA see Kirkland et al., (1986) J. Immunol. 137:3614
  • solid phase direct labeled assay solid phase direct labeled sandwich assay
  • solid phase direct label RIA using I-125 label see Morel et al., (1988) Mol. Immunol.
  • Such an assay involves the use of purified antigen (e.g., MET, such as an ECD of human MET) bound to a solid surface or cells bearing either of these, an unlabeled test immunoglobulin and a labeled reference immunoglobulin.
  • MET purified antigen
  • Competitive inhibition can be measured by determining the amount of label bound to the solid surface or cells in the presence of the test immunoglobulin. Usually the test immunoglobulin is present in excess.
  • a competition binding assay can be configured in a large number of different formats using either labeled antigen or labeled antibody.
  • the antigen is immobilized on a 96-well plate.
  • the ability of unlabeled antibodies to block the binding of labeled antibodies to the antigen is then measured using radioactive or enzyme labels.
  • competition binding assays can be used to determine whether binding of an antibody is competitively inhibited, e.g., in a dose dependent manner, by another antibody, thereby signaling that the antibodies bind essentially the same epitope, or overlapping epitopes, e.g., sterically overlapping epitopes.
  • Such competition binding assays can include, for example, competition ELISA assays, which can be configured in all number of different formats, using either labeled antigen or labeled antibody.
  • an antibody can be tested in competition binding assays with an antibody described herein, e.g., antibody Ab235, Ab236, Ab237, Ab238, Ab239, Ab240, Ab241, Ab242, Ab243, Ab244, Ab245, Ab246, Ab247, Ab248, Ab249, Ab250, Ab251, Ab252, Ab253, Ab254, or Ab255, or a chimeric or Fab antibody thereof, or an antibody comprising VH CDRs and VL CDRs of any of antibodies Ab235-Ab255.
  • an antibody described herein, e.g., antibody Ab235, Ab236, Ab237, Ab238, Ab239, Ab240, Ab241, Ab242, Ab243, Ab244, Ab245, Ab246, Ab247, Ab248, Ab249, Ab250, Ab251, Ab252, Ab253, Ab254, or Ab255, or a chimeric or Fab antibody thereof, or an antibody comprising VH CDRs and VL CDRs of any of antibodies Ab235-Ab255.
  • an antibody which competitively blocks (e.g., in a dose dependent manner) binding of antibodies comprising the amino acid sequences described herein for specific binding to a MET polypeptide (e.g., an ECD of MET, for example human MET), as determined using assays known to one of skill in the art or described herein (e.g., ELISA competitive assays).
  • a competitively blocking antibody inhibits one or more MET activities.
  • an antibody which competes (e.g., in a dose dependent manner) for specific binding to a MET polypeptide (e.g., an ECD of MET, for example human MET), with an antibody comprising the amino acid sequences described herein (e.g., VL and/or VH amino acid sequences of antibody Ab235, Ab236, Ab237, Ab238, Ab239, Ab240, Ab241, Ab242, Ab243, Ab244, Ab245, Ab246, Ab247, Ab248, Ab249, Ab250, Ab251, Ab252, Ab253, Ab254, or Ab255 (see, e.g., SEQ ID NOS: 52-71), as determined using assays known to one of skill in the art or described herein (e.g., ELISA competitive assays).
  • a MET polypeptide e.g., an ECD of MET, for example human MET
  • an antibody comprising the amino acid sequences described herein (e.g., VL and/or VH amino acid
  • an antibody which competes (e.g., in a dose dependent manner) for specific binding to a MET polypeptide (e.g., an ECD of MET, for example human MET), with any one of antibodies Ab235-Ab255.
  • a MET polypeptide e.g., an ECD of MET, for example human MET
  • an antibody which competes (e.g., in a dose dependent manner) for specific binding to a MET polypeptide (e.g., an ECD of MET, for example human MET), with an antibody comprising a VL chain region having the amino acid sequence of SEQ ID NO: 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62, and a VH chain region having the amino acid sequence of SEQ ID NO: 62, 63, 64, 65, 66, 67, 68, 69, 70, or 71.
  • a MET polypeptide e.g., an ECD of MET, for example human MET
  • an antibody comprising a VL chain region having the amino acid sequence of SEQ ID NO: 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62, and a VH chain region having the amino acid sequence of SEQ ID NO: 62, 63, 64, 65, 66,
  • antibodies that compete (e.g., in a dose dependent manner) for specific binding to an epitope of a MET polypeptide (e.g., an epitope of an ECD of human MET, such as of a Sema domain or Sema/PSI domain), with any one of antibody Ab235, Ab236, Ab237, Ab239, Ab241, Ab242, Ab243, Ab244, Ab245, Ab246, Ab247, Ab248, Ab249, Ab250, Ab251, Ab252, Ab253, Ab254, or Ab255, and (ii) that are capable of inhibiting (e.g., partially inhibiting) phosphorylation of MET and of inhibiting (e.g., partially inhibiting) tumor cell proliferation or tumor growth, better as an IgG 2 isotype as compared to as an IgG 1 isotype.
  • a MET polypeptide e.g., an epitope of an ECD of human MET, such as of a Sema domain or Sema/PSI domain
  • antibodies (i) that compete (e.g., in a dose dependent manner) for specific binding to an epitope of a MET polypeptide e.g., an epitope of an ECD of human MET, such as of a Sema domain or Sema/PSI domain
  • an epitope of a MET polypeptide e.g., an epitope of an ECD of human MET, such as of a Sema domain or Sema/PSI domain
  • an epitope of a MET polypeptide e.g., an epitope of an ECD of human MET, such as of a Sema domain or Sema/PSI domain
  • an epitope of a MET polypeptide e.g., an epitope of an ECD of human MET, such as of a Sema domain or Sema/PSI domain
  • an antibody described herein is one that is competitively blocked (e.g., in a dose dependent manner) by an antibody that specifically binds MET and comprises a VL chain region having the amino acid sequence of SEQ ID NO: 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62, and a VH chain region having the amino acid sequence of SEQ ID NO: 62, 63, 64, 65, 66, 67, 68, 69, 70, or 71, for specific binding to a MET polypeptide (e.g., an ECD of MET, for example human MET).
  • a MET polypeptide e.g., an ECD of MET, for example human MET
  • antibodies that competitively block (e.g., in a dose dependent manner) any one of antibody Ab235, Ab236, Ab237, Ab239, Ab241, Ab242, Ab243, Ab244, Ab245, Ab246, Ab247, Ab248, Ab249, Ab250, Ab251, Ab252, Ab253, Ab254, or Ab255, for specific binding to an epitope of a MET polypeptide (e.g., an epitope of an ECD of human MET, such as of a Sema domain or Sema/PSI domain), and (ii) that are capable of inhibiting (e.g., partially inhibiting) phosphorylation of MET and of inhibiting (e.g., partially inhibiting) tumor cell proliferation or tumor growth, better as an IgG 2 isotype as compared to as an IgG 1 isotype.
  • a MET polypeptide e.g., an epitope of an ECD of human MET, such as of a Sema domain or Sema/PSI
  • an antibody or an antigen-binding fragment thereof, which immunospecifically binds to the same epitope as that of an antibody (e.g., any one of antibodies Ab235-Ab255) comprising the amino acid sequences described herein (see, e.g., Tables 1-8) for specific binding to a MET polypeptide (e.g., an ECD of MET, for example human MET, such as of a Sema domain or Sema/PSI domain).
  • a MET polypeptide e.g., an ECD of MET, for example human MET, such as of a Sema domain or Sema/PSI domain.
  • Assays known to one of skill in the art or described herein e.g., ELISA assays
  • an antibody described herein, or an antigen-binding fragment thereof immunospecifically binds to the same epitope as that of an antibody that specifically binds MET (e.g., any one of antibodies Ab235-Ab255) and comprises a VL chain region having the amino acid sequence of SEQ ID NO: 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62, and a VH chain region having the amino acid sequence of SEQ ID NO: 62, 63, 64, 65, 66, 67, 68, 69, 70, or 71.
  • MET e.g., any one of antibodies Ab235-Ab255
  • antibodies that immunospecifically binds the same epitope of a MET polypeptide (e.g., an epitope of an ECD of human MET, such as of a Sema domain or Sema/PSI domain) as that of antibody Ab235, Ab236, Ab237, Ab239, Ab241, Ab242, Ab243, Ab244, Ab245, Ab246, Ab247, Ab248, Ab249, Ab250, Ab251, Ab252, Ab253, Ab254, or Ab255; and (ii) that are capable of inhibiting (e.g., partially inhibiting) phosphorylation of MET and of inhibiting (e.g., partially inhibiting) tumor cell proliferation or tumor growth, better as an IgG 2 isotype as compared to as an IgG 1 isotype.
  • a MET polypeptide e.g., an epitope of an ECD of human MET, such as of a Sema domain or Sema/PSI domain
  • antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema domain in an ECD of human MET) and that can modulate MET activity and/or expression (e.g., inhibit MET activity and/or expression.
  • said antibodies modulate ligand-dependent MET activity.
  • said antibodies modulate MET-amplified (e.g., ligand-independent) MET activity.
  • a MET antagonist is provided herein that is an antibody described herein that immunospecifically binds to an ECD of human MET, e.g., a Sema domain of an ECD of human MET, and that inhibits (e.g., partially inhibits) at least one MET activity (e.g., MET phosphorylation or MET signaling).
  • a MET antagonist provided herein is an antibody described herein that immunospecifically binds to an ECD of human MET, e.g., a Sema or PSI domain of an ECD of human MET, and that inhibits or decreases/reduces MET expression.
  • antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET) and that (a) inhibit MET activity in a cell as determined by inhibition of phosphorylation of MET; (b) induce MET degradation in a cell; and (c) inhibit tumor cell proliferation or tumor growth.
  • MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET) and that (a) inhibit phosphorylation of MET; (b) induce MET degradation in a cell; (c) inhibit tumor cell proliferation or tumor growth; and/or (d) inhibit ligand binding to MET.
  • MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET) and that (a) induce MET degradation in a cell (e.g., cell with MET amplification or MET mutation); and (b) inhibit ligand binding to MET (e.g., in cells expressing wild-type MET).
  • MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET) and that (a) have increased MET antagonistic activities as IgG 2 isotypes (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) as compared to the antibodies (e.g., Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255) as IgG 1 isotypes; and (b) inhibit ligand binding.
  • MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • IgG 2 isotypes e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof
  • the antibodies e.g., Ab235, Ab236, Ab237, Ab239
  • antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET) and that (a) have increased MET antagonistic activities as IgG 2 isotypes (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) as compared to the antibodies (e.g., Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255) as IgG 1 isotypes; and (b) induces receptor degradation.
  • MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • IgG 2 isotypes e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof
  • the antibodies e.g., Ab235, Ab236, Ab237, Ab239,
  • antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET) and that (a) inhibit phosphorylation of MET; (b) induce MET degradation in a cell; (c) inhibit tumor cell proliferation or tumor growth; and/or (d) inhibit ligand binding to MET, better as an IgG 2 (e.g., human IgG 2 ) isotype as compared to as an IgG 1 (e.g., human IgG 1 ) isotype.
  • MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • IgG 2 e.g., human IgG 2
  • IgG 1 e.g., human IgG 1
  • an anti-MET antibody provided herein exhibits better MET antagonistic activity (e.g., blocking MET phosphorylation, inducing MET degradation, or inhibiting tumor cell proliferation or tumor growth) as a human IgG 2 isotype than a human IgG 1 isotype in cells (e.g., EBC-1 cells and SNU-5 cells) having ligand-independent MET activity, for example, cells having MET amplification or a constitutively active MET mutant.
  • MET antagonistic activity e.g., blocking MET phosphorylation, inducing MET degradation, or inhibiting tumor cell proliferation or tumor growth
  • MET activity can relate to any activity of MET such as those known or described in the art.
  • Non-limiting examples of MET activity include: MET receptor dimerization, MET receptor heterodimerization with other receptors (e.g., EGFR, HER2, HER3, or RET), MET receptor phosphorylation (e.g., tyrosine phosphorylation (such as MET ligand-dependent phosphorylation) or autophosphorylation in the cytoplasmic domain), signaling downstream of the MET receptor (e.g., SHC, Grb2, Stat3, Src, Gab 1, PLC-g, p85, PI3K, Crk/CRKL, AKT, Ras, or MAPK/ERK signaling), cell proliferation such as MET ligand (e.g., HGF) induced enhancement of cell proliferation (e.g., cancer cell proliferation), or cell survival (e.g., cancer cells), MET ligand (e.g., HGF) induced anti-apoptosis
  • MET activity or MET function are used interchangeably herein.
  • MET activity is induced by MET ligand (e.g., HGF) binding to MET receptor.
  • MET ligand e.g., HGF
  • an increase in MET activity or signaling can occur, in the absence of MET ligand (e.g., HGF) binding MET receptor, due to high (or overexpression) expression of MET receptors.
  • High or overexpression of MET in a cell refers to an expression level which is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% more than the expression level of a reference cell known to have normal MET expression or MET activity or more than the average expression level of MET in a population of cells or samples known to have normal MET expression or MET activity.
  • Expression levels of MET can be assessed by methods described herein or known to one of skill in the art (e.g., Western blotting, ELISA, or immunohistochemistry).
  • antibodies that immunospecifically bind to MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • decrease MET expression In certain embodiments, provided herein are antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET) and induce ubiquitination of MET. In certain embodiments, provided herein are antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET) and induce MET degradation or turnover.
  • MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET) and block (e.g., partially block) MET ligand-dependent and MET-amplified (e.g., ligand-independent) MET signaling.
  • MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • block e.g., partially block
  • MET ligand-dependent and MET-amplified e.g., ligand-independent
  • ligand-independent MET activation is may involve association of MET with membrane-spanning proteins, such as, for example integrin activation, plexins, CD44, G protein coupled receptors and other receptor tyrosine kinases, such as, for example, EGFR and RET (see, e.g., Varkaris et al., 2013, Int. J. Cancer, 133(7):1536-1546).
  • membrane-spanning proteins such as, for example integrin activation, plexins, CD44, G protein coupled receptors and other receptor tyrosine kinases, such as, for example, EGFR and RET (see, e.g., Varkaris et al., 2013, Int. J. Cancer, 133(7):1536-1546).
  • anti-MET antibodies provided herein have increased MET antagonistic activities as IgG 2 isotypes (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) as compared to the antibodies (e.g., Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255) as IgG 1 isotypes.
  • the IgG 2 isotype may provide an enhanced alteration in distance or positioning of MET kinase dimer, allowing for enhanced antagonistic properties against MET activity (e.g., ligand-dependent and/or MET-amplified (e.g., ligand-independent) MET activity).
  • MET activity e.g., ligand-dependent and/or MET-amplified (e.g., ligand-independent) MET activity.
  • anti-MET antibodies provided herein do not have agonist activities.
  • anti-MET antibodies provided herein e.g., Ab235-Ab255
  • Identification of agonist activities is performed by assays known to one of ordinary skill in the art, such as, e.g., cell proliferation and cell scatter assays, ELISA or immunoblot assays to assess phosphorylation of MET or the activity of downstream MET signaling components, such as, for example, MAPK and/or AKT.
  • antibodies described herein specifically bind to an ECD of MET and block or inhibit (e.g., partially inhibit) binding of MET ligand (e.g., HGF) to MET by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% as assessed by methods described herein or known to one of skill in the art, e.g., ELISA assay, flow cytometry, or competition assay.
  • MET ligand e.g., HGF
  • inhibition by anti-MET antibodies described herein (e.g., monoclonal antibody) of MET ligand (e.g., HGF) binding to MET can be characterized by IC 50 values, which reflects the concentration of anti-MET antibodies achieving 50% inhibition of binding of MET ligand to MET.
  • an anti-MET antibody described herein inhibits binding of MET ligand to MET with an IC 50 of at most about 10,000 nM, 1,000 nM, 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.75 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, 0.05 nM, 0.01 nM, 0.005 nM, or 0.001
  • an anti-MET antibody described herein inhibits binding of MET ligand to MET with an IC 50 of at least about 10,000 nM, 1,000 nM, 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.75 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, 0.05 nM, 0.01 nM, 0.005 nM, or 0.001 nM, as assessed by methods described herein and/or known to one of skill in the art, (e.g., ELISA assay or flow cytometry).
  • an anti-MET antibody described herein inhibits binding of MET ligand to MET with an IC 50 in the range of about 0.01 nM to 10 nM, 0.1 nM to 20 nM, 0.1 nM to 10 nM, 0.1 nM to 5 nM, or 0.01 nM to 20 nM, as assessed by methods described herein and/or known to one of skill in the art, (e.g., ELISA assay or flow cytometry).
  • antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET) and that (a) have increased MET antagonistic activities as IgG 2 isotypes (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) as compared to the antibodies (e.g., Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255) as IgG 1 isotypes; and (b) inhibit ligand binding.
  • MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • IgG 2 isotypes e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof
  • the antibodies e.g., Ab235, Ab236, Ab237, Ab239
  • anti-MET antibodies provided herein have increased MET antagonistic activities as IgG 2 isotypes (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) as compared to the antibodies (e.g., Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255) as IgG 1 isotypes.
  • the IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) may provide an enhanced alteration in distance or positioning of MET kinase dimer, allowing for enhanced anti-MET activity.
  • an anti-MET antibody described herein inhibits binding of MET ligand (e.g., HGF) to MET with a lower IC 50 as an IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , and human IgG 2b , or a mixture thereof) than as an IgG 1 isotype, as assessed by methods described herein and/or known to one of skill in the art, (e.g., ELISA assay or flow cytometry).
  • MET ligand e.g., HGF
  • IgG 2 isotype e.g., human IgG 2 , human IgG 2a , and human IgG 2b , or a mixture thereof
  • the IC 50 of the IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , and human IgG 2b , or a mixture thereof) is between at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold less than the IC 50 of the IgG 1 isotype, as assessed by methods described herein and/or known to one of skill in the art, (e.g., ELISA assay or flow cytometry).
  • an anti-MET antibody described herein (e.g., any one of antibodies Ab235-Ab255 or an antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235-255) does not block or inhibit MET receptor dimerization.
  • an anti-MET antibody described herein only negligibly (e.g., less than about 2% or 3% or within a standard of error or deviation) inhibits or reduces MET receptor dimerization.
  • an anti-MET antibody described herein does not induce or enhance MET receptor dimer dissociation.
  • an anti-MET antibody described herein only negligibly (e.g., less than about 2% or 3% or within a standard of error or deviation) induces or enhances MET receptor dimer dissociation.
  • an anti-MET antibody described herein can specifically bind to a MET receptor dimer and not block or inhibit MET receptor dimerization.
  • an anti-MET antibody described herein can specifically bind to a MET receptor monomer and not block or inhibit MET receptor dimerization.
  • any such antibodies or antigen-binding fragments thereof inhibit ligand binding to MET.
  • an antibody described herein e.g., any one of antibodies Ab235-Ab255, or an antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235-Ab255
  • MET receptor dimerization is induced when MET ligand binds to MET.
  • antibodies described herein specifically bind to MET and block or inhibit (e.g., partially inhibit) dimerization of MET receptors by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein or known to one of skill in the art, e.g., immunoprecipitation assay, relative to dimerization of MET receptors in the presence of MET ligand stimulation without any antibody or with an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • an unrelated antibody e.g., an antibody that does not immunospecifically bind to MET.
  • antibodies described herein specifically bind to MET and partially inhibit dimerization of MET receptors by about 25% to 75%.
  • Blocking or inhibition (e.g., partial inhibition) of dimerization of MET receptors by antibodies described herein can be assessed in the presences of MET ligand stimulation.
  • cells expressing MET can be contacted with MET ligand (e.g., HGF) in the presence or absence of anti-MET antibodies described herein, and the level of MET receptor dimerization is determined.
  • MET ligand e.g., HGF
  • MET ligand-induced MET receptor dimerization in the absence of anti-MET antibody is at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold higher than MET receptor dimerization in the presence of anti-MET antibody provided herein as assessed by methods described herein or known to one of skill in the art (e.g., immunoprecipitation assays). Tyrosine phosphorylation of one or more residues in the cytoplasmic domain of MET can be an indicator of MET receptor dimerization.
  • anti-MET antibodies provided herein have increased MET antagonistic activities as IgG 2 isotypes (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) as compared to the antibodies (e.g., Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255) as IgG 1 isotypes.
  • the IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , and human IgG 2b , or a mixture thereof) may provide an enhanced alteration in distance or positioning of MET kinase dimer, allowing for enhanced anti-MET activity.
  • MET ligand (e.g., HGF)-induced MET receptor dimerization in the presence of an anti-MET antibody described herein e.g., any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255 or antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255
  • an anti-MET antibody described herein e.g., any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255 or antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255
  • an IgG 1 isotype is at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8
  • an anti-MET antibody described herein can inhibit (e.g., partially inhibit) MET activity by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% as assessed by methods described herein and/or known to one of skill in the art, relative to MET activity in the presence of MET ligand stimulation without any antibody or with an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • an unrelated antibody e.g., an antibody that does not immunospecifically bind to MET.
  • an anti-MET antibody described herein can inhibit (e.g., partially inhibit) MET activity by at least about 25% to about 65% as assessed by methods described herein and/or known to one of skill in the art, relative to MET activity in the presence of MET ligand stimulation without any antibody or with an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • Non-limiting examples of MET activity can include, MET receptor dimerization, MET receptor heterodimerization with other receptors (e.g., EGFR, HER2, HER3, or RET), MET receptor phosphorylation (e.g., tyrosine phosphorylation or autophosphorylation in the cytoplasmic domain), signaling downstream of the MET receptor (e.g., SHC, Grb2, Stat3, Src, Gab 1, PLC-g, p85, PI3K, Crk/CRKL, AKT, Ras, or MAPK/ERK signaling), MET ligand (e.g., HGF) induced enhancement of cell proliferation, or cell survival, and MET ligand (e.g., HGF) induced anti-apoptosis.
  • MET receptor dimerization e.g., EGFR, HER2, HER3, or RET
  • MET receptor phosphorylation e.g., tyrosine phosphorylation or autophosphorylation
  • anti-MET antibodies provided herein have increased MET antagonistic activities as IgG 2 isotypes (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) as compared to the antibodies (e.g., Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255) as IgG 1 isotypes.
  • the IgG 2 isotype may provide an enhanced alteration in distance or positioning of MET kinase dimer, allowing for enhanced inhibition of MET activity.
  • an anti-MET antibody described herein inhibits ligand-dependent MET activity.
  • an anti-MET antibody described herein inhibits MET-amplified (e.g., ligand-independent) MET activity.
  • an anti-MET antibody described herein inhibits ligand-dependent and MET-amplified (e.g., ligand-independent) MET activity.
  • an antibody described herein e.g., any one of antibodies Ab235-Ab255, or an antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235-Ab255
  • can block e.g., partially block
  • inhibit e.g., partially inhibit
  • phosphorylation of MET specifically tyrosine phosphorylation of one or more residues in the cytoplasmic domain of MET.
  • MET receptor dimerization and phosphorylation is induced when MET ligand (e.g. HGF) binds to MET.
  • MET receptor dimerization and/or phosphorylation can occur independently of MET ligand binding to MET receptor.
  • MET receptor dimerization and/or phosphorylation can occur due to gain-of-function mutations or overexpression of MET.
  • Non-limiting examples of tyrosine residues in the cytoplasmic domain of human MET include residues 1003, 1234, 1235, 1349, and 1356 (see, e.g., Organ and Tsao, 2011, Ther. Adv. Med. Oncol., 391 Suppl): S7-S19, e.g., at FIG. 1 ).
  • an anti-MET antibody described herein can inhibit receptor phosphorylation at tyrosine residue 1234 and/or 1235 of human MET.
  • antibodies described herein specifically bind to MET and block, inhibit, or reduce tyrosine phosphorylation in the cytoplasmic domain of MET by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% as assessed by methods described herein or known to one of skill in the art, e.g., ELISA assay as described in Section 6 or immunoblotting assay, relative to phosphorylation in the presence of MET ligand stimulation without any antibody or with an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • an unrelated antibody e.g., an antibody that does not immunospecifically bind to MET.
  • antibodies described herein specifically bind to MET and block or inhibit tyrosine phosphorylation in the cytoplasmic domain of MET by at least about 25%, optionally to about 65% or 75%, as assessed by methods described herein or known to one of skill in the art, e.g., ELISA assay as described in Section 6 or immunoblotting assay. In certain embodiments, antibodies described herein specifically bind to MET and block or inhibit tyrosine phosphorylation of the cytoplasmic domain of MET by at least about 25% to about 80% as assessed by methods described herein or known to one of skill in the art, e.g., ELISA assay as described in Section 6 or immunoblotting assay.
  • antibodies described herein specifically bind to MET and block or inhibit tyrosine phosphorylation of the cytoplasmic domain of MET by at least about 50% to about 80%, 90%, 95% or 100% as assessed by methods described herein or known to one of skill in the art, e.g., ELISA assay as described in Section 6 or immunoblotting assay.
  • antibodies described herein specifically bind to MET and block or inhibit tyrosine phosphorylation of the cytoplasmic domain of MET with an IC 50 of less than about 400 pM or less than about 300 pM as assessed by methods described herein (e.g., phosphorylation inhibition assay with SNU-5 cells, A549 cells, and Hop92 cells expressing wild-type MET as described in Section 6 below) or known to one of skill in the art.
  • antibodies described herein specifically bind to MET and block or inhibit tyrosine phosphorylation of the cytoplasmic domain of MET with an IC 50 of less than about 200 pM. In specific embodiments, antibodies described herein specifically bind to MET and block or inhibit tyrosine phosphorylation of the cytoplasmic domain of MET with an IC 50 of less than about 150 pM. In specific embodiments, antibodies described herein specifically bind to MET and block or inhibit tyrosine phosphorylation of the cytoplasmic domain of MET with an IC 50 of less than about 50 pM.
  • antibodies described herein specifically bind to MET and block or inhibit tyrosine phosphorylation of the cytoplasmic domain of MET with an IC 50 in the range of about 30pM to about 300 pM, 100 pM to about 500 pM, about 25 pM to about 200 pM, about 40 pM to about 160 pM, about 50 pM to about 125 pM, or about 5 pM to about 100 pM.
  • an IC 50 for inhibition of tyrosine phosphorylation can be determined by assaying lysates from cells, e.g., SNU-5 cells, A549 cells, and Hop92 cells, recombinantly expressing MET, in ELISA which detects tyrosine phosphorylation, for example, as described in Section 6 below.
  • cells e.g., SNU-5 cells, A549 cells, and Hop92 cells, recombinantly expressing MET
  • the cells are not sorted prior to use in the phosphorylation inhibition assays.
  • antibodies described herein specifically bind to MET and block or inhibit phosphorylation of one or more tyrosine residues in the cytoplasmic domain of MET by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% as assessed by methods described herein or known to one of skill in the art, e.g., immunoblotting assay, relative to phosphorylation in the presence of MET ligand stimulation without any antibody or with an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • an unrelated antibody e.g., an antibody that does not immunospecifically bind to MET.
  • blocking or inhibition (e.g., partial inhibition) of phosphorylation of one or more tyrosine residues of the cytoplasmic domain of MET by antibodies described herein can be assessed upon MET ligand stimulation.
  • cells expressing MET are contacted with MET ligand in the presence or absence of anti-MET antibodies described herein, and the level of phosphorylation of one or more tyrosine residues in the cytoplasmic domain of MET can be determined.
  • MET ligand induced phosphorylation of one or more tyrosine residues of the cytoplasmic domain of MET in the absence of anti-MET antibody is at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold higher than MET ligand induced phosphorylation of one or more tyrosine residues of the cytoplasmic domain of MET in the presence of anti-MET antibody, as assessed by methods described herein or known to one of skill in the art (e.g., immunoblotting assays), relative to phosphorylation in the presence of MET ligand stimulation without any antibody or with an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • an unrelated antibody
  • anti-MET antibodies provided herein have increased MET antagonistic activities as IgG 2 isotypes (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) as compared to the antibodies (e.g., Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255) as IgG 1 isotypes.
  • the IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) may provide an enhanced alteration in distance or positioning of MET kinase dimer, allowing for enhanced anti-MET activity.
  • an anti-MET antibody described herein inhibits tyrosine phosphorylation of the cytoplasmic domain of MET with a lower IC 50 as an IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , and human IgG 2b , or a mixture thereof) than as an IgG 1 isotype, as assessed by methods described herein and/or known to one of skill in the art, (e.g., ELISA assay or immunoblot).
  • IgG 2 isotype e.g., human IgG 2 , human IgG 2a , and human IgG 2b , or a mixture thereof
  • the IC 50 of the IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , and human IgG 2b , or a mixture thereof) is between at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold less than the IC 50 of the IgG 1 isotype, as assessed by methods described herein and/or known to one of skill in the art, (e.g., ELISA assay or immunoblot).
  • the IC 50 of the IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , and human IgG 2b , or a mixture thereof) is between at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold less than the IC 50 of the IgG 1 isotype, as assessed by methods described herein and/or known to one of skill in the art, (e.g., ELISA assay or immunoblot).
  • an anti-MET antibody described herein inhibits tyrosine phosphorylation of the cytoplasmic domain of MET with a lower IC 50 as compared to the IC 50 for the inhibition of tyrosine phosphorylation of the cytoplasmic domain of MET mediated by a humanized anti-MET antibody that does not bind the SEMA domain (“anti-MET-1”) or a bivalent, IgG 4 anti-MET antibody that binds to the SEMA domain (“anti-MET-2”).
  • the IC so of the anti-MET antibody described herein is about between at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold less than the IC 50 of the anti-MET-1 or anti-MET-2 antibody.
  • an anti-MET antibody described herein inhibits tyrosine phosphorylation of the cytoplasmic domain of MET (e.g., in a cell, such as, for example, a SNU-5 cell, an EBC-1 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell) as an IgG 2 with a maximal percent inhibition of at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • antibodies described herein specifically bind to MET and induce or enhance MET receptor degradation (e.g., in a cell, such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell) by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assays), relative to degradation in the absence of antibody or in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • a cell such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell
  • a cell such as,
  • antibodies described herein specifically bind to MET and induce or enhance MET receptor degradation by at least about 25% or 35%, optionally to about 75%, as assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assays), relative to degradation in the absence of antibody or in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • antibodies described herein specifically bind to MET and induce or enhance MET receptor degradation (e.g., in a cell, such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell) by at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold as assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assays), relative to degradation in the absence of antibody or in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • a cell such as, for example, SNU-5 cell, an A549 cell,
  • antibodies that immunospecifically bind to MET (e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET) and that (a) have increased MET antagonistic activities as IgG 2 isotypes (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) as compared to the antibodies (e.g., Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255) as IgG 1 isotypes; and (b) induces receptor degradation.
  • MET e.g., an ECD of human MET or a Sema/PSI domain in an ECD of human MET
  • IgG 2 isotypes e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof
  • the antibodies e.g., Ab235, Ab236, Ab237, Ab239,
  • anti-MET antibodies provided herein have increased MET antagonistic activities as IgG 2 isotypes (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) as compared to the antibodies (e.g., Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255) as IgG 1 isotypes.
  • the IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , and human IgG 2b , or a mixture thereof) may provide an enhanced alteration in distance or positioning of MET kinase dimer, allowing for enhanced anti-MET activity.
  • an anti-MET antibody described herein induces or enhances MET receptor degradation (e.g., in a cell, such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell) as an IgG 1 isotype is at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold less than MET
  • an anti-MET antibody described herein induces or enhances MET receptor degradation (e.g., in a cell, such as, for example, a SNU-5 cell, an EBC-1 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell) as an IgG 2 with a maximal percent induction/enhancement of at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • antibodies described herein specifically bind to MET and induce or enhance MET receptor ubiquitination (e.g., in a cell, such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell) by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein or known to one of skill in the art (e.g., immunoprecipitation and immunoblot assays), relative to ubiquitination in the absence of antibody or in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • a cell such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in
  • antibodies described herein specifically bind to MET and induce or enhance MET receptor ubiquitination by at least about 25% or 35%, optionally to about 75%, as assessed by methods described herein or known to one of skill in the art (e.g., immunoprecipitation and immunoblot assays), relative to ubiquitination in the absence of antibody or in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • antibodies described herein specifically bind to MET and induce or enhance MET receptor ubiquitination (e.g., in a cell, such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell) by at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold as assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assays), relative to ubiquitination in the absence of antibody or in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • a cell such as, for example, SNU-5 cell
  • an anti-MET antibody described herein induces or enhances MET receptor ubiquitination (e.g., in a cell, such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell) as an IgG 1 isotype is at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold
  • ubiquitination and/or degradation e.g., kinetics or rate of degradation
  • Techniques for quantitating or monitoring ubiquitination and/or degradation e.g., kinetics or rate of degradation
  • ubiquitination and/or degradation e.g., kinetics or rate of degradation
  • cell surface receptors e.g., cell surface receptors
  • fluorescent and radioactive techniques see, e.g., International Patent Application Publication No. WO 2008/153926 A2
  • pulse chase experiments or experiments using radiolabeled ligands such as 125 I-HGF can be carried out to quantitatively measure degradation of MET.
  • MET degradation can be analyzed by western blot or ELISA analysis, see, for example, Section 6.
  • antibodies described herein specifically bind to MET and induce or enhance MET receptor internalization (e.g., in a cell, such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell) by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assays), relative to internalization in the absence of antibody or in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • a cell such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell
  • a cell such
  • antibodies described herein specifically bind to MET and induce or enhance MET receptor internalization by at least about 25% or 35%, optionally to about 75%, as assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assays), relative to internalization in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • an unrelated antibody e.g., an antibody that does not immunospecifically bind to MET.
  • antibodies described herein specifically bind to MET and induce or enhance MET receptor internalization (e.g., in a cell, such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell) by at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold as assessed by methods described herein or known to one of skill in the art (e.g., pulse-chase assays), relative to internalization in the absence of antibody or in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • a cell such as, for example, SNU-5 cell, an A549 cell
  • an anti-MET antibody described herein induces or enhances MET receptor internalization (e.g., in a cell, such as, for example, SNU-5 cell, an A549 cell, a U87MG cell, a H596 cell, a Hop92 cell, or in a tumor cell) as human IgG 1 isotype is at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold less than
  • Techniques for quantitating or monitoring receptor internalization e.g., kinetics or rate of internalization of cell surface receptors are well known in the art and may involve, for example, a variety of fluorescent and radioactive techniques (see, e.g., International Patent Application Publication No. WO 2008/153926 A2).
  • pulse chase experiments or experiments using radiolabeled ligands such as 125 I-HGF can be carried out to quantitatively measure internalization of MET.
  • MET ligand e.g., HGF binding to its receptor MET stimulates several distinct signaling pathways, including for example members of phosphatidylinositol (PI) 3-kinases, and mitogen-activated protein kinase (MAPK) (see Trusolino et al., Nat. Rev. Mol. Cell Biol., 2010, 11:834-848).
  • PI phosphatidylinositol
  • MAPK mitogen-activated protein kinase
  • Phosphorylated tyrosines in the cytoplasmic domain of MET can provide for binding sites for, for example, PI3K and Grb2.
  • anti-MET antibodies described herein which act as inhibitors of MET activity can inhibit signaling of a member of the PI3K-Akt, STAT, NF ⁇ B or MAPK pathway kinases.
  • anti-MET antibodies described herein which act as inhibitors of MET activity can inhibit binding (or inhibit interaction) to the cytoplasmic domain of MET, and/or to one or more members of the PI3K-Akt, STAT, NF ⁇ B or MAPK pathway kinases.
  • anti-MET antibodies described herein which act as inhibitors of MET activity can inhibit activation by MET of one or more members of the PI3K-Akt, STAT, NF ⁇ B or MAPK pathway kinases.
  • anti-MET antibodies described herein which act as inhibitors of MET activity can inhibit phosphorylation (e.g., tyrosine phosphorylation in the cytoplasmic domain) of one or more members of the PI3K-Akt, STAT, NF ⁇ B or MAPK pathway kinases.
  • anti-MET antibodies described herein which act as inhibitors of MET activity can inhibit downstream signaling such as, for example, phosphorylation of MAPK, phosphorylation of P13K, or phosphorylation of AKT.
  • an anti-MET antibody described herein can inhibit or reduce phosphorylation of MAPK (e.g., MET ligand (e.g., HGF) induced phosphorylation of MAPK) by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein or known to one of skill in the art, e.g., Western blot or ELISA assay as described in Section 6 or immunoblotting assay, relative to phosphorylation in the presence of MET ligand stimulation without any antibody or with an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • MAPK e.g., MET ligand (e.g., HGF) induced phosphorylation of MAPK
  • MAPK e.g., MET ligand (e.g., HGF)
  • an anti-MET antibody described herein can inhibit or reduce phosphorylation of AKT (e.g., MET ligand (e.g., HGF) induced phosphorylation of AKT) by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein or known to one of skill in the art, e.g., Western blot or ELISA assay as described in Section 6 or immunoblotting assay, relative to phosphorylation in the presence of MET ligand stimulation without any antibody or with an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • AKT e.g., MET ligand (e.g., HGF) induced phosphorylation of AKT
  • an anti-MET antibody described herein can inhibit downstream signaling, such as, for example, signaling of a member of the PI3K-Akt, STAT, NF ⁇ B or MAPK pathway kinases, as an IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold,
  • downstream signaling such as, for example, signaling of a member of the PI3K-Akt, STAT, NF ⁇ B or MAPK pathway kinases, as an IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , human IgG 2b
  • an anti-MET antibody described herein which can act as an inhibitor of MET activity can act as an inhibitor of MET activity (e.g., any one of antibodies Ab235-Ab255, or an antigen-binding fragment thereof or an antibody comprising CDRs of any one of antibodies Ab235-Ab255) or activity can inhibit cellular proliferation of cells (e.g., cancer cells, such as, for example, SNU-5 cells, EBC-1 cells, U87MG cells, A549 cells, and H596 cells), for example, cells that express MET and that respond to MET signaling (e.g., cells that proliferate in response to MET ligand stimulation and MET signaling).
  • cancer cells e.g., cancer cells, such as, for example, SNU-5 cells, EBC-1 cells, U87MG cells, A549 cells, and H596 cells
  • cells that express MET and that respond to MET signaling e.g., cells that proliferate in response to MET ligand stimulation and MET signaling.
  • an anti-MET antibody described herein which can act as an inhibitor of MET activity can act as an inhibitor of MET activity (e.g., any one of antibodies Ab235-Ab255, or an antigen-binding fragment thereof or an antibody comprising CDRs of any one of antibodies Ab235-Ab255) or activity can inhibit cellular proliferation of cancer cells expressing MET, such as, for example, SNU-5 cells, EBC-1 cells, U87MG cells, A549 cells, and H596 cells), for example, cells that express MET and that respond to MET signaling (e.g., cells that proliferate in response to MET ligand stimulation and MET signaling).
  • Cell proliferation assays are described in the art and can be readily carried out by one of skill in the art.
  • cell proliferation can be assayed by measuring Bromodeoxyuridine (BrdU) incorporation (see, e.g., Hoshino et al., 1986, Int. J. Cancer 38, 369; Campana et al., 1988, J. Immunol. Meth. 107:79) or (3H) thymidine incorporation (see, e.g., Blechman et al., Cell, 1995, 80:103-113; Chen, J., 1996, Oncogene 13:1395-403; Jeoung, J., 1995, J. Biol. Chem.
  • RNA and mRNA and activity can be determined by any method well known in the art.
  • protein can be quantitated by known immunodiagnostic methods such as ELISA, Western blotting or immunoprecipitation using antibodies, including commercially available antibodies.
  • mRNA can be quantitated using methods that are well known and routine in the art, for example, using northern analysis, RNase protection, or polymerase chain reaction in connection with reverse transcription.
  • antibodies described herein specifically bind to MET and inhibit cell proliferation by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein or known to one of skill in the art (e.g., BrdU incorporation assay).
  • antibodies described herein specifically bind to MET and block or inhibit cellular proliferation of cells (e.g., cancer cells, such as, for example, SNU-5 cells, EBC-1 cells, U87MG cells, A549 cells, and H596 cells) with an IC 50 of less than about 400 pM or less than about 300 pM as assessed by methods described herein (e.g., as described in Section 6 below) or known to one of skill in the art.
  • cancer cells e.g., cancer cells, such as, for example, SNU-5 cells, EBC-1 cells, U87MG cells, A549 cells, and H596 cells
  • IC 50 of less than about 400 pM or less than about 300 pM as assessed by methods described herein (e.g., as described in Section 6 below) or known to one of skill in the art.
  • antibodies described herein specifically bind to MET and block or inhibit cellular proliferation of cells (e.g., cancer cells, such as, for example, SNU-5 cells, EBC-1 cells, U87MG cells, A549 cells, and H596 cells) with an IC 50 of less than about 300 nM. In specific embodiments, antibodies described herein specifically bind to MET and block or inhibit cellular proliferation with an IC 50 of less than about 150 nM. In specific embodiments, antibodies described herein specifically bind to MET and block or inhibit cellular proliferation with an IC 50 of less than about 50 nM.
  • cancer cells e.g., cancer cells, such as, for example, SNU-5 cells, EBC-1 cells, U87MG cells, A549 cells, and H596 cells
  • antibodies described herein specifically bind to MET and block or inhibit cellular proliferation with an IC 50 in the range of about 100 nM to about 500 nM, about 25 nM to about 200 nM, or about 40 nM to about 160 nM, about 50 nM to about 125 nM, or about 5 nM to about 100 nM. In certain embodiments, antibodies described herein specifically bind to MET and block or inhibit cellular proliferation of U87MG cells with an IC 50 in the range of about 1 nM to about 50 nM, about 5 nM to about 30 nM, or about 9 nM to about 25 nM.
  • antibodies described herein specifically bind to MET and block or inhibit cellular proliferation of U87MG cells with an IC 50 of less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, or less than about 5 nM. In certain embodiments, antibodies described herein specifically bind to MET and block or inhibit cellular proliferation of A549 cells with an IC 50 in the range of about 1 nM to about 30 nM, about 2.5 nM to about 20 nM, or about 4 nM to about 15 nM.
  • antibodies described herein specifically bind to MET and block or inhibit cellular proliferation of A549 cells with an IC 50 of less than about 20 nM, less than about 10 nM, less than about 7.5 nM, less than about 6 nM, less than about 5 nM, or less than about 4.5 nM. In certain embodiments, antibodies described herein specifically bind to MET and block or inhibit cellular proliferation of H596 cells with an IC 50 in the range of about 0.01 nM to about 2 nM, about 0.1 nM to about 1.5 nM, or about 0.2 nM to about 1 nM.
  • antibodies described herein specifically bind to MET and block or inhibit cellular proliferation of H596 cells with an IC 50 of less than about 1.5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.01 nM, less than about 0.05 nM, or less than about 0.01 nM.
  • anti-MET antibodies provided herein have increased MET antagonistic activities as IgG 2 isotypes (e.g., human IgG 2 , human IgG 2a , human IgG 2b , or a mixture thereof) as compared to the antibodies (e.g., Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255) as IgG 1 isotypes.
  • the IgG 2 isotype (e.g., human IgG 2 , human IgG 2a , and human IgG 2b , or a mixture thereof) may provide an enhanced alteration in distance or positioning of MET kinase dimer, allowing for enhanced anti-MET activity.
  • inhibition of cellular proliferation of cells e.g., cancer cells, such as, for example, SNU-5 cells, EBC-1 cells, U87MG cells, A549 cells, and H596 cells
  • cells that express MET and that respond to MET signaling e.g., cells that proliferate in response to MET ligand stimulation and MET signaling
  • an anti-MET antibody described herein e.g., any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255 or antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255
  • IgG 1 isotype is at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20
  • an anti-MET antibody described herein which can act as an inhibitor of MET activity can reduce or inhibit survival of cells (e.g., cancer cells, such as, for example, SNU-5 cells, EBC-1 cells, U87MG cells, A549 cells, and H596 cells), for example, cells that express MET and that respond to MET signaling (e.g., cells that proliferate in response to MET ligand stimulation and MET signaling).
  • cells e.g., cancer cells, such as, for example, SNU-5 cells, EBC-1 cells, U87MG cells, A549 cells, and H596 cells
  • cells that express MET and that respond to MET signaling e.g., cells that proliferate in response to MET ligand stimulation and MET signaling.
  • Cell survival assays are described in the art and can be readily carried out by one of skill in the art.
  • cell viability can be assessed by using trypan-blue staining or other cell death or viability markers known in the art.
  • the level of cellular ATP is measured to determined cell viability.
  • cell viability is measured in three-day and seven-day periods using an assay standard in the art, such as the CellTiter-Glo Assay Kit (Promega) which measures levels of intracellular ATP. A reduction in cellular ATP is indicative of a cytotoxic effect.
  • cell viability can be measured in the neutral red uptake assay.
  • visual observation for morphological changes can include enlargement, granularity, cells with ragged edges, a filmy appearance, rounding, detachment from the surface of the well, or other changes. These changes are given a designation of T (100% toxic), PVH (partially toxic-very heavy-80%), PH (partially toxic-heavy-60%), P (partially toxic-40%), Ps (partially toxic-slight-20%), or 0 (no toxicity-0%), conforming to the degree of cytotoxicity seen. A 50% cell inhibitory (cytotoxic) concentration (IC 50 ) is determined by regression analysis of these data.
  • antibodies described herein specifically bind to MET and inhibit (e.g., partially inhibit) cell survival by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein or known to one of skill in the art (e.g., trypan blue exclusion assay).
  • inhibition of cell survival in the presence of an anti-MET antibody described herein e.g., any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255 or antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255
  • an anti-MET antibody described herein e.g., any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255 or antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255
  • IgG 1 isotype is at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold
  • Cells and cell lines which are appropriate for use in the assays described herein relating to MET activity are readily available (e.g., ATCC) or can be readily identified using methods known in the art.
  • cells and/or cell lines that express MET endogenously or that possess MET signaling or activity are known to one of skill in the art.
  • cells or cell lines that are appropriate for use in the assays described herein can express MET, either endogenously or recombinantly.
  • cells or cell lines for use in cell proliferation assays can express MET, endogenously or recombinantly, and proliferate or increase proliferation in response to MET ligand (e.g., HGF) stimulation.
  • MET ligand e.g., HGF
  • Cells or cell lines for use in cell viability assays can express MET, endogenously or recombinantly, and exert changes in cell viability in response to MET ligand (e.g., HGF) stimulation.
  • Cells or cell lines for use in apoptosis assays can express MET, endogenously or recombinantly, and exert changes in apoptosis in response to MET ligand (e.g., HGF) stimulation.
  • Cells or cell lines for use in cell proliferation, cell viability, or other assays can express MET, endogenously or recombinantly, and exert changes in proliferation or activation of other cell types response to MET ligand (e.g., HGF) stimulation.
  • Non-limiting examples of cells that can be used in the methods and assays described herein include SNU-5 cells, EBC-1 cells, U87MG cells, A549 cells, Hop92 cells, and H596 cells.
  • Non-limiting examples of cells that can be used in the methods and assays described herein to assess ligand (e.g., HGF) independent MET signaling and activity include EBC-1 cells and SNU-5 cells.
  • cells that can be used in the methods and assays described herein to assess ligand-independent MET activity include MET amplified cells such as MET amplified tumor cells or cells expressing mutant MET, for example a constitutively active mutant MET.
  • Non-limiting examples of cells that can be used in the methods and assays described herein to assess ligand (e.g., HGF) dependent MET signaling and activity include A549 cells, U87MG cells, Hop92 cells, and H596 cells.
  • cells that can be used in the methods and assays described herein to assess ligand-dependent MET activity include cells expressing wild-type MET, for example tumor cells expressing wild-type MET, or cells (e.g., tumor cells) expressing normal levels of MET, e.g., cells that do not contain MET amplification.
  • cells that can be used in the methods and assays described herein include primary cells, transformed cells, stem cells, mast cells, primordial germ cells, oocytes, spermatocytes, embryonic stem cells, hematopoietic cells, erythroleukemia cells (e.g., F36P and TF-1 cell lines), colorectal cancer cell lines, such as SNU-C1, SW48, RKO, COLO 205, SW1417, LS411N, NCI-H508, HT-29, SK-CO-1, SW1116, SW948, T84, LS123, LoVo, and SW837, gastric cancer cell lines, such as HGC27, GCIY, MKN7, TMK1,ECC12, AGS, CLS-145, 23132/87, MKN-45, SK-GT-2, HGC-27, and KATO-III, lung cancer cell lines, such as H526, DMS153, DMS79, NCI-H2126, NCI-
  • cells that can be used in the methods and assays described herein include immune cells, such as macrophages, dendritic cells, and natural killer (NK) cells.
  • immune cells such as macrophages, dendritic cells, and natural killer (NK) cells.
  • NK cells natural killer cells.
  • cells that can be used in the methods and assay described herein include H1299 cells.
  • cells and cell lines that express MET can routinely be generated recombinantly.
  • Non-limiting examples of cells that can be engineered to express MET recombinantly include COS cells, HEK 293 cells, CHO cells, H1299 cells, fibroblasts (e.g., human fibroblasts) such as NIH3T3 cells, and MEFS.
  • cells for use in the methods described herein are H1299 cells expressing human MET ECD (e.g., SEQ ID NO:190).
  • an anti-MET antibody described herein which can act as an inhibitor of MET activity (e.g., any one of antibodies Ab235-Ab255, or an antigen-binding fragment thereof or an antibody comprising CDRs of any one of antibodies Ab235-Ab255), is capable of inhibiting or reducing metastasis, inhibiting tumor growth or inducing tumor regression in mouse model studies.
  • tumor cell lines can be introduced into nude mice, and the mice can be administered anti-MET antibodies described herein one or more times, and tumor progression of the injected tumor cells can be monitored over a period of weeks and/or months.
  • administration of anti-MET antibodies to the nude mice can occur prior to introduction of the tumor cell lines.
  • tumor cell line e.g., tumor cell line expressing MET
  • tumor cell lines for use in these xenograft mouse models include non-small cell lung carncinoma cell line H1299, megakaryoblastic leukemia cell lines such as MO7e; gastrointestinal stromal tumor cell lines such as ST-882, GIST430, GIST48, GIST48B and GIST882; human erythroleukemic cell lines such as HEL and TF-1; human promyelocytic leukemia cell line, HL60; neuroblastoma cell lines such as SK-N-SH, SK-SY5Y, H-EP1, SK-N-BE(2), SK-N-BE(ZkM17), SK-N-BE(2)C, LA-N-1, or LA-N-1-5s; and small cell lung carcinoma cell lines such as H526, DMS153, DMS79, ECC12, TMK
  • Additional cell lines include A549 cells, SNU-5 cells, EBC-1 cells, Hop92 cells, and H596 cells.
  • a tumor cell line for use in a xenograft mouse model is the GIST882, GIST430, GIST48, GIST48B, HEL, HL60, H526, DMS153, or DMS79 cell line.
  • suitable cell lines for use in xenograft tumor models can be generated by recombinantly expressing MET.
  • antibodies described herein e.g., any one of antibodies Ab235-Ab255, or an antigen-binding fragment thereof or an antibody comprising CDRs of any one of antibodies Ab235-Ab255
  • antibodies described herein specifically bind to MET and inhibit tumor growth or induce tumor regression in a mouse model by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% as assessed by methods described herein or known to one of skill in the art.
  • antibodies described herein e.g., any one of antibodies Ab235-Ab255 or an antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235-Ab255
  • antibodies described herein specifically bind to MET and inhibit tumor growth or induce tumor regression in a mouse model by at least about 25% or 35%, optionally to about 75%, as assessed by methods described herein or known to one of skill in the art.
  • antibodies described herein specifically bind to MET and inhibit tumor growth or induce tumor regression in a mouse model by at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold as assessed by methods described herein or known to one of skill in the art.
  • tumor growth or induce tumor regression in a mouse model in the presence of an anti-MET antibody described herein e.g., any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255 or antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255
  • an anti-MET antibody described herein e.g., any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255 or antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235, Ab236, Ab237, Ab239, and Ab241-Ab255
  • an IgG 1 isotype is at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold,
  • Determining tumor growth inhibition or tumor regression can be assessed, for example, by monitoring tumor size over a period of time, such as by physical measurement of palpable tumors, or other visual detection methods.
  • tumor cell lines can be generated to recombinantly express a visualization agent, such as green fluorescent protein (GFP) or luciferase, then in vivo visualization of GFP can be carried out by microscopy, and in vivo visualization of luciferase can be carried out by administering luciferase substrate to the xenograft mice and detecting luminescent due to the luciferase enzyme processing the luciferase substrate. The degree or level of detection of GFP or luciferase correlates to the size of the tumor in the xenograft mice.
  • a visualization agent such as green fluorescent protein (GFP) or luciferase
  • anti-MET antibodies described herein bind specifically to MET antigen and can increase survival of animals in tumor xenograft models.
  • antibodies described herein e.g., any one of antibodies Ab235-Ab255 or an antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235-Ab255
  • antibodies described herein specifically bind to MET and increase survival of mice in tumor xenograft models by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein or known to one of skill in the art.
  • antibodies described herein e.g., any one of antibodies Ab235-Ab255 or an antigen-binding fragment thereof, or an antibody comprising CDRs of any one of antibodies Ab235-Ab255
  • antibodies described herein specifically bind to MET and increase survival of mice in tumor xenograft models by at least about 25% or 35%, optionally to about 75%, as assessed by methods described herein or known to one of skill in the art.
  • antibodies described herein specifically bind to MET and increase survival of mice in tumor xenograft models by at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold as assessed by methods described herein or known to one of skill in the art.
  • survival of mice in tumor xenograft models in the presence of an anti-MET antibody described herein is at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold lower than survival of mice in tumor xenograft models in the presence of the anti-MET antibody, or antigen-binding fragment thereof, as an IgG 2 isotype (e.g., human IgG
  • antibodies described herein specifically bind to MET and inhibit endothelial-to-mesenchymal transition (EMT) (e.g., in a cell, such as, for example, DU145 cells) by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% as assessed by methods described herein or known to one of skill in the art (e.g., immunoprecipitation and immunoblot assays), relative to EMT inhibition in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • EMT endothelial-to-mesenchymal transition
  • antibodies described herein specifically bind to MET and inhibit EMT by at least about 25% or 35%, optionally to about 75%, as assessed by methods described herein or known to one of skill in the art (e.g., immunoprecipitation and immunoblot assays), relative to EMT inhibition in the absence of antibody or in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • antibodies described herein specifically bind to MET and inhibit EMT (e.g., in a cell, such as, for example, DU145 cells) by at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold as assessed by methods described herein or known to one of skill in the art (e.g., DU145 cell scatter assay), relative to EMT inhibition in the absence of antibody or in the presence of an unrelated antibody (e.g., an antibody that does not immunospecifically bind to MET).
  • EMT e.g., in a cell, such as, for example, DU145 cells
  • an anti-MET antibody described herein inhibits EMT with an IC 50 of at most about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 1 nM, 0.75 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM, 0.005 nM, or 0.001 nM, as assessed by methods described herein and/or known to one of skill in the art, (e.g., DU145 cell scatter assays).
  • an anti-MET antibody described herein inhibits EMT with an IC 50 of at least about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 1 nM, 0.75 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM, 0.005 nM, or 0.001 nM, as assessed by methods described herein and/or known to one of skill in the art, (e.g., DU145 cell scatter assays).
  • an anti-MET antibody described herein inhibits binding of MET ligand to MET with an IC 50 in the range of about 0.1 nM to 500 nM, 0.1 nM to 100 nM, or 0.1 nM to 50 nM, as assessed by methods described herein and/or known to one of skill in the art, (e.g., DU145 cell scatter assays).
  • an anti-MET antibody described herein inhibits EMT (e.g., in a cell, such as, for example, DU145 cells) as an IgG 1 isotype is at least about 1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold less than EMT inhibition in the presence of the anti-MET antibody, or antigen-binding fragment thereof, as an IgG 2 isotype (e.g., human Ig
  • antibodies e.g., monoclonal antibodies such as chimeric or humanized antibodies
  • an agent e.g., a diagnostic, detectable or therapeutic agent, for example, a polypeptide or small molecule.
  • the linked, e.g., conjugated or fused, antibodies can be useful, e.g., for monitoring or prognosing the onset, development, progression and/or severity of a condition or disease, for example, as part of a clinical testing procedure, such as determining the efficacy of a particular therapy, by, for example, imaging procedures.
  • the linked, e.g., conjugated or fused, antibodies can be useful, e.g., for treating or managing a condition or disorder described herein, or for treating or managing effects of a condition or disorder described herein.
  • Antibodies described herein can also be conjugated to a molecule (e.g., polyethylene glycol) which can affect one or more biological and/or molecular properties of the antibodies, for example, stability (e.g., in serum), half-life, solubility, and antigenicity.
  • a conjugate comprising an agent (e.g., therapeutic agent) linked to an antibody described herein (or an antigen-binding fragment thereof), which antibody immunospecifically binds to an ECD of human MET, for example, an antibody comprising CDRs of any one of antibodies Ab235-Ab255, for example as set forth in Tables 1, 2, and 5-8.
  • agent e.g., therapeutic agent
  • an antibody described herein or an antigen-binding fragment thereof
  • antibodies and antigen-binding fragments thereof can be linked to detectable molecules or substances including, but not limited to, various enzymes, prosthetic groups (such as, but not limited to, streptavidin/biotin and avidin/biotin), fluorescent molecules, bioluminescent molecules, radioactive molecules, such as radioisotopes, quantum dots, or other nanoparticles, and positron emitting metals using various positron emission tomographies, and non-radioactive paramagnetic metal ions.
  • prosthetic groups such as, but not limited to, streptavidin/biotin and avidin/biotin
  • fluorescent molecules such as, but not limited to, streptavidin/biotin and avidin/biotin
  • bioluminescent molecules such as, but not limited to, streptavidin/biotin and avidin/biotin
  • radioactive molecules such as radioisotopes, quantum dots, or other nanoparticles
  • positron emitting metals using various positron emission tomographies, and non-
  • antibodies, or antigen-binding fragments thereof can be linked to a therapeutic agent, such as a cytotoxin, e.g., a cytostatic or cytocidal agent, or a radioactive metal ion, e.g., alpha-emitters.
  • a cytotoxin or cytotoxic agent includes any agent that is detrimental to cells.
  • the antibody or antigen-binding fragment is conjugated or fused directly to an agent, e.g., a diagnostic or therapeutic agent.
  • the antibody or antigen-binding fragment, and agent are conjugated or fused via one or more linkers.
  • a linker is an enzyme-cleavable linker and/or a disulfide linker.
  • antibodies or antigen-binding fragments described herein can be fused to agents, such as peptides, to facilitate purification.
  • agents such as peptides
  • a peptide can be a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc.), among others, many of which are commercially available.
  • Other peptide tags useful for purification include, but are not limited to, the hemagglutinin (“HA”) tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., 1984, Cell 37:767), and the “FLAG” tag.
  • Antibodies and antigen-binding fragments described herein can also be attached to solid supports.
  • Such solid supports can include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.
  • Such attachment can be useful, for example, for immunoassays or purification of the target antigen.
  • an antibody described herein or an antigen-binding fragment thereof is an extracellular drug conjugate (ECD) comprising an antibody linked to a drug which acts outside of the cell, optionally by a linker (see, e.g., PCT International Patent Application Publication No. WO 2011/031870).
  • ECD extracellular drug conjugate
  • the drug sends a signal into the cell and internalization of the conjugate is not required.
  • Antibodies or an antigen-binding fragments described herein that immunospecifically bind to MET can be produced by any method known in the art, for example, by chemical synthesis or by recombinant expression techniques. Such methods can employ conventional techniques in molecular biology, microbiology, genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization, and related fields within the skill of the art. These techniques are described, for example, in the references cited herein and are fully explained in the literature. See, e.g., Maniatis et al.
  • Monoclonal antibodies can, for example, be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof.
  • monoclonal antibodies can be produced using hybridoma techniques including those known in the art and taught, for example, in Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T - Cell Hybridomas 563 681 (Elsevier, N.Y., 1981).
  • the term “monoclonal antibody” as used herein is not limited to antibodies produced through hybridoma technology.
  • monoclonal antibodies can be produced recombinantly from host cells engineered to express an antibody described herein (e.g., anti-MET antibody comprising the CDRs of any one of antibodies Ab235-Ab255) or a fragment thereof, for example, a light chain and/or heavy chain of such an antibody.
  • an antibody described herein e.g., anti-MET antibody comprising the CDRs of any one of antibodies Ab235-Ab255
  • a fragment thereof for example, a light chain and/or heavy chain of such an antibody.
  • the antibodies described herein or antigen-binding fragments thereof can also be generated using various phage display methods known in the art.
  • phage display methods functional antibody domains are displayed on the surface of phage particles which carry the polynucleotide sequences encoding them.
  • Examples of phage display methods that can be used to make the antibodies described herein include those disclosed in Brinkman et al., 1995, J. Immunol. Methods 182:41-50; Ames et al., 1995, J. Immunol. Methods 184:177-186; Kettleborough et al., 1994, Eur. J. Immunol.
  • Antibodies described herein can, for example, include chimeric antibodies.
  • a chimeric antibody is a molecule in which different portions of the antibody are derived from different immunoglobulin molecules.
  • a chimeric antibody can contain a variable region of a mouse or rat monoclonal antibody fused to a constant region of a human antibody.
  • Methods for producing chimeric antibodies are known in the art. See, e.g., Morrison, 1985, Science 229:1202; Oi et al., 1986, BioTechniques 4:214; Gillies et al., 1989, J. Immunol. Methods 125:191-202; and U.S. Pat. Nos. 5,807,715, 4,816,567, 4,816,397, and 6,331,415.
  • Antibodies or antigen-binding fragments produced using techniques such as those described herein can be isolated using standard, well known techniques.
  • antibodies or antigen-binding fragments can be suitably separated from, e.g., culture medium, ascites fluid, serum, cell lysate, synthesis reaction material or the like by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
  • an “isolated” or “purified” antibody is substantially free of cellular material or other proteins from the cell or tissue source from which the antibody is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized.
  • Antibodies described herein include antibody fragments which recognize specific MET antigens (e.g., ECD of MET) and can be generated by any technique known to those of skill in the art.
  • Fab and F(ab′) 2 fragments described herein can be produced by proteolytic cleavage of immunoglobulin molecules, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab′) 2 fragments).
  • a Fab fragment corresponds to one of the two identical arms of an antibody molecule and contains the complete light chain paired with the VH and CH1 domains of the heavy chain.
  • a F(ab′) 2 fragment contains the two antigen-binding arms of an antibody molecule linked by disulfide bonds in the hinge region.
  • antibody fragments described herein can routinely be produced via well known recombinant expression techniques. See, e.g., PCT publication No. WO 92/22324; Mullinax et al., 1992, BioTechniques 12(6):864-869; Sawai et al., 1995, AJRI 34:26-34; and Better et al., 1988, Science 240:1041-1043.
  • Antibodies described herein can, for example, include humanized antibodies, e.g., deimmunized or composite human antibodies.
  • a humanized antibody can comprise human constant region sequences.
  • a humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgG 1 , IgG 2 , IgG 3 and IgG 4 .
  • a humanized antibody can comprise kappa or lambda light chain constant sequences.
  • Humanized antibodies can be produced using a variety of techniques known in the art, including but not limited to, CDR-grafting (European Patent No. EP 239,400; International publication No. WO 91/09967; and U.S. Pat. Nos. 5,225,539, 5,530,101, and 5,585,089), veneering or resurfacing (European Patent Nos. EP 592,106 and EP 519,596; Padlan, 1991, Molecular Immunology 28(4/5):489-498; Studnicka et al., 1994, Protein Engineering 7(6):805-814; and Roguska et al., 1994, PNAS 91:969-973), chain shuffling (U.S. Pat. No.
  • a composite human antibody can be generated using, for example, Composite Human AntibodyTM technology (Antitope Ltd., Cambridge, United Kingdom).
  • variable region sequences are designed from fragments of multiple human antibody variable region sequences in a manner that avoids T cell epitopes, thereby minimizing the immunogenicity of the resulting antibody.
  • Such antibodies can comprise human constant region sequences, e.g., human light chain and/or heavy chain constant regions.
  • a deimmunized antibody is an antibody in which T-cell epitopes have been removed. Methods for making deimmunized antibodies have been described. See, e.g., Jones et al., Methods Mol Biol. 2009;525:405-23, xiv, and De Groot et al., Cell. Immunol. 244:148-153(2006)).
  • Deimmunized antibodies comprise T-cell epitope-depleted variable regions and human constant regions. Briefly, VH and VL of an antibody are cloned and T-cell epitopes are subsequently identified by testing overlapping peptides derived from the VH and VL of the antibody in a T cell proliferation assay.
  • T cell epitopes are identified via in silico methods to identify peptide binding to human MHC class II. Mutations are introduced in the VH and VL to abrogate binding to human MHC class II. Mutated VH and VL are then utilized to generate the deimmunized antibody.
  • Antibodies described herein can, for example, be multispecific, e.g., bispecific, antibodies.
  • Methods for making multispecific (e.g, bispecific antibodies) have been described, see, for example, U.S. Pat. Nos. 7,951,917, 7,183,076, 8,227,577, 5,837,242, 5,989,830, 5,869,620, 6,132,992, and 8,586,713.
  • Single domain antibodies for example, antibodies lacking the light chains, can be produced by methods well-known in the art. See Riechmann et al., 1999, J. Immunol. 231:25-38; Nuttall et al., 2000, Curr. Pharm. Biotechnol. 1(3):253-263; Muylderman, 2001, J. Biotechnol. 74(4):277302; U.S. Pat. No. 6,005,079; and International Publication Nos. WO 94/04678, WO 94/25591, and WO 01/44301.
  • Human antibodies can be produced using any method known in the art. For example, well known transgenic mice which are incapable of expressing functional endogenous murine immunoglobulins, but which can express human immunoglobulin genes, can be used. Alternatively, for example, phage display techniques, described above, can be utilized. Moreover, in some embodiments, human antibodies can, for example, be produced using mouse-human hybridomas.
  • human peripheral blood lymphocytes transformed with Epstein-Barr virus can be fused with mouse myeloma cells to produce mouse-human hybridomas secreting human monoclonal antibodies, and these mouse-human hybridomas can be screened to determine ones which secrete human monoclonal antibodies that immunospecifically bind to a target antigen (e.g., ECD of human MET).
  • ECD of human MET a target antigen
  • Such methods are known and are described in the art, see, e.g., Shinmoto et al., Cytotechnology, 2004, 46:19-23; Naganawa et al., Human Antibodies, 2005, 14:27-31.
  • polynucleotides comprising a nucleotide sequence encoding an antibody described herein or a fragment thereof (e.g., a variable light chain region and/or variable heavy chain region) that immunospecifically binds to a MET antigen
  • vectors e.g., vectors comprising such polynucleotides for recombinant expression in host cells (e.g., E. coli and mammalian cells).
  • host cells e.g., E. coli and mammalian cells.
  • cells e.g., host cells.
  • methods of making the antibodies and antigen-binding fragments described herein are also provided herein.
  • polynucleotides comprising a nucleotide sequence encoding the light chain or heavy chain of an antibody described herein.
  • polynucleotides comprising a nucleotide sequence encoding the light chain and heavy chain of an antibody described herein.
  • the polynucleotides can comprise nucleotide sequences encoding a light chain comprising the VL FRs and CDRs of antibodies described herein (see, e.g., Tables 1, 5, and 7, and Table 3, respectively).
  • the polynucleotides can comprise nucleotide sequences encoding a heavy chain comprising the VH FRs and CDRs of antibodies described herein (see, e.g., Tables 2, 6, and 8, and Table 4, respectively).
  • a polynucleotide described herein encodes a VL chain region comprising the amino acid sequence of SEQ ID NO: 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62.
  • a polynucleotide described herein encodes a VH chain region comprising the amino acid sequence of any one of SEQ ID NOs: 63, 64, 65, 66, 67, 68, 69, 70, or 71.
  • polynucleotides comprising a nucleotide sequence encoding an anti-MET antibody comprising three VL chain CDRs, e.g., containing VL CDR1, VL CDR2, and VL CDR3 of any one of antibodies Ab235-Ab255 (e.g., see Tables 1, 5, and 7).
  • polynucleotides comprising three VH chain CDRs, e.g., containing VH CDR1, VH CDR2, and VH CDR3 of any one of antibodies Ab235-Ab255 (e.g., see Tables 2, 6, and 8).
  • polynucleotides comprising a nucleotide sequence encoding an anti-MET antibody comprising three VH chain CDRs, e.g., containing VL CDR1, VL CDR2, and VL CDR3 of any one of antibodies Ab235-Ab255 (e.g., see Tables 1, 5, and 7) and three VH chain CDRs, e.g., containing VH CDR1, VH CDR2, and VH CDR3 of any one of antibodies Ab235-Ab255 (e.g., see Tables 2, 6, and 8).
  • polynucleotides comprising a nucleotide sequence encoding an anti-MET antibody comprising a VL chain region, e.g., containing FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, comprising an amino acid sequences described herein (e.g., see Tables 1, 5, and 7, or Table 3).
  • polynucleotides comprising a nucleotide sequence encoding an anti-MET antibody comprising a VH chain region, e.g., containing FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, comprising an amino acid sequence described herein (e.g., see Tables 2, 6, and 8, or Table 4).
  • a polynucleotide described herein comprises a nucleotide sequence encoding an antibody provided herein comprising a variable light (VL) chain region comprising an amino acid described herein (e.g., see Table 9), wherein the antibody immunospecifically binds to a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190.
  • VL variable light chain region comprising an amino acid described herein
  • a polynucleotide described herein comprises a nucleotide sequence encoding an antibody provided herein comprising a variable heavy (VH) chain region comprising an amino acid sequence described herein (e.g., see Table 10), wherein the antibody immunospecifically binds to a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190.
  • VH variable heavy chain region comprising an amino acid sequence described herein
  • a polynucleotide comprises a nucleotide sequence encoding an antibody described herein comprising a VL chain region comprising one or more VL FRs having the amino acid sequence described herein (e.g., see Table 3), wherein the antibody immunospecifically binds to a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190.
  • a MET polypeptide e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190.
  • a polynucleotide comprises a nucleotide sequence encoding an antibody described herein comprising a VH chain region comprising one or more VH FRs having the amino acid sequence described herein (e.g., see Table 4), wherein the antibody immunospecifically binds to a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190.
  • a MET polypeptide e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190.
  • a polynucleotide provided herein comprises a nucleotide sequence encoding an antibody described herein comprising: framework regions (e.g., framework regions of the VL domain and VH domain) that are human framework regions, wherein the antibody immunospecifically binds a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190.
  • framework regions e.g., framework regions of the VL domain and VH domain
  • the antibody immunospecifically binds a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190.
  • a polynucleotide provided herein comprises a nucleotide sequence as described in Table 11 or 16, encoding a VH or a VL, respectively, of an antibody described herein (e.g., Ab235-Ab255), which immunospecifically binds to a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190.
  • a polynucleotide provided herein is operably linked to a promoter for expression of such polynucleotide sequence in a host cell.
  • the promoter is derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter, the vaccinia virus 7.5K promoter).
  • the expression of nucleotide sequences encoding antibodies described herein is regulated by a constitutive promoter, inducible promoter or tissue specific promoter.
  • a polynucleotide comprising a nucleotide sequence encoding an antibody comprising a light chain and a heavy chain, e.g., a separate light chain and heavy chain.
  • a polynucleotide provided herein comprises a nucleotide sequence encoding a kappa light chain.
  • a polynucleotide provided herein comprises a nucleotide sequence encoding a lambda light chain.
  • a polynucleotide provided herein comprises a nucleotide sequence encoding an antibody described herein comprising a human kappa light chain or a human lambda light chain.
  • a polynucleotide provided herein comprises a nucleotide sequence encoding an antibody described herein, which immunospecifically binds to a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190, wherein the antibody comprises a light chain, and wherein the amino acid sequence of the VL chain region can comprise any amino acid sequence described herein (e.g., SEQ ID NO: 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62), and wherein the constant region of the light chain comprises the amino acid sequence of a human kappa light chain constant region.
  • a polynucleotide provided herein comprises a nucleotide sequence encoding an antibody described herein, which immunospecifically binds to a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190, and comprises a light chain, wherein the amino acid sequence of the VL chain region can comprises any amino acid sequence described herein (e.g., SEQ ID NO: 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or 62), and wherein the constant region of the light chain comprises the amino acid sequence of a human lambda light chain constant region.
  • human constant region sequences can be those described in U.S. Pat. No. 5,693,780.
  • a polynucleotide provided herein comprises a nucleotide sequence encoding an antibody described herein, which immunospecifically binds to a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190, wherein the antibody comprises a heavy chain, wherein the amino acid sequence of the VH chain region can comprise any amino acid sequence described herein (e.g., SEQ ID NO: 63, 64, 65, 66, 67, 68, 69, 70, or 71), and wherein the constant region of the heavy chain comprises the amino acid sequence of a human gamma ( ⁇ ) heavy chain constant region, for example, human gamma ( ⁇ ) 1 heavy chain constant region, human gamma ( ⁇ ) 2 heavy chain constant region, human gamma ( ⁇ ) 3 heavy chain constant region, or human gamma ( ⁇ ) 4 heavy chain constant region.
  • a polynucleotide provided herein comprises a nucleotide sequence encoding an antibody described herein, which immunospecifically binds to a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190, wherein the antibody comprises a heavy chain, wherein the amino acid sequence of the VH chain region can comprise any amino acid sequence described herein (e.g., SEQ ID NO: 63, 64, 65, 66, 67, 68, 69, 70, or 71), and wherein the constant region of the heavy chain comprises the amino acid sequence of a human gamma ( ⁇ ) 2 heavy chain constant region, for example, human gamma ( ⁇ ) 2a and/or 2b heavy chain constant region.
  • a MET polypeptide e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET),
  • a polynucleotide provided herein comprises a nucleotide sequence encoding an antibody described herein (or an antigen-binding fragment thereof), which immunospecifically binds a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190, wherein the antibody comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein, and wherein the constant regions comprise the amino acid sequences of the constant regions of a human IgG 1 (e.g., isotype a, z, or f) or human IgG 4 .
  • a human IgG 1 e.g., isotype a, z, or f
  • a polynucleotide provided herein comprises a nucleotide sequence encoding an antibody described herein (or an antigen-binding fragment thereof), which immunospecifically binds a MET polypeptide, e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190, wherein the antibody comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein, and wherein the constant regions comprise the amino acid sequences of the constant regions of a human IgG 2 (e.g., human IgG 2a or human IgG 2b ).
  • a MET polypeptide e.g., a human MET polypeptide, for example, an ECD of MET (e.g., human MET), for example SEQ ID NO:190
  • the antibody comprises a VL chain region and a VH chain region comprising any amino acid sequences described herein
  • the constant regions are of a human IgG 2 alpha isotype (e.g., human IgG 2a ). In a specific embodiment, the constant regions are of a human IgG 2 beta isotype (e.g., human IgG 2b ). In a specific embodiment, the constant regions are a mixture of human IgG 2a and human IgG 2b isotypes.
  • polynucleotides comprising a nucleotide sequence encoding an anti-MET antibody, or an antigen-binding fragment or domain thereof, designated herein, see, e.g., Tables 1-10, for example antibody Ab235-Ab255.
  • polynucleotides encoding an anti-MET antibody or a fragment thereof that are optimized, e.g., by codon/RNA optimization, replacement with heterologous signal sequences, and elimination of mRNA instability elements.
  • Methods to generate optimized nucleic acids encoding an anti-MET antibody or a fragment thereof (e.g., light chain, heavy chain, VH domain, or VL domain) for recombinant expression by introducing codon changes and/or eliminating inhibitory regions in the mRNA can be carried out by adapting the optimization methods described in, e.g., U.S. Pat. Nos. 5,965,726; 6,174,666; 6,291,664; 6,414,132; and 6,794,498, accordingly.
  • potential splice sites and instability elements within the RNA can be mutated without altering the amino acids encoded by the nucleic acid sequences to increase stability of the RNA for recombinant expression.
  • the alterations utilize the degeneracy of the genetic code, e.g., using an alternative codon for an identical amino acid.
  • Such methods can increase expression of an anti-MET antibody or fragment thereof by at least 1 fold, 2 fold, 3 fold, 4 fold, 5 fold, 10 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, or 100 fold or more relative to the expression of an anti-MET antibody encoded by polynucleotides that have not been optimized.
  • the polynucleotides described herein can be produced and the nucleotide sequences of the polynucleotides determined, by any method known in the art.
  • Nucleotide sequences encoding antibodies described herein, e.g., antibodies comprising sequences described in Tables 1-10, and, optionally, comprising constant region sequences, for example, human constant region sequences can be determined using methods well known in the art, e.g., nucleotide codons known to encode particular amino acids can be identified and assembled in such a way to generate a nucleic acid that encodes the antibody.
  • Such a polynucleotide encoding the antibody can be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier et al., 1994, BioTechniques 17:242), which, briefly, involves the synthesis of overlapping oligonucleotides containing portions of the sequence encoding the antibody, annealing and ligating of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR.
  • a polynucleotide encoding an antibody described herein can be generated from nucleic acid or nucleic acids using methods well known in the art (e.g., PCR and other molecular cloning methods).
  • cells e.g., host cells
  • cells expressing (e.g., recombinantly) antibodies described herein (or an antigen-binding fragment thereof) which specifically bind to an ECD of human MET and related polynucleotides and expression vectors.
  • vectors e.g., expression vectors
  • host cells comprising such vectors for recombinantly expressing anti-MET antibodies described herein (e.g., human or humanized antibody).
  • methods for producing an antibody described herein, comprising expressing such an antibody from a host cell.
  • Recombinant expression of an antibody described herein e.g., a full-length antibody, heavy and/or light chain of an antibody, or a single chain antibody described herein
  • an expression vector containing a polynucleotide that encodes the antibody Once a polynucleotide encoding an antibody molecule, heavy and/or light chain of an antibody, or a fragment thereof (e.g., heavy and/or light chain variable domains) described herein has been obtained, the vector for the production of the antibody molecule can be produced by recombinant DNA technology using techniques well-known in the art.
  • a polynucleotide containing an antibody or antibody fragment (e.g., light chain or heavy chain) encoding nucleotide sequence are described herein.
  • Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody or antibody fragment (e.g., light chain or heavy chain) coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination.
  • replicable vectors comprising a nucleotide sequence encoding an antibody molecule described herein, a heavy or light chain of an antibody, a heavy or light chain variable domain of an antibody or a fragment thereof, or a heavy or light chain CDR, operably linked to a promoter.
  • Such vectors can, for example, include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., International Publication Nos. WO 86/05807 and WO 89/01036; and U.S. Pat. No. 5,122,464) and variable domains of the antibody can be cloned into such a vector for expression of the entire heavy, the entire light chain, or both the entire heavy and light chains.
  • An expression vector can be transferred to a cell (e.g., host cell) by conventional techniques and the resulting cells can then be cultured by conventional techniques to produce an antibody described herein (e.g., an antibody comprising the CDRs of any one of antibodies Ab235-Ab255) or a fragment thereof.
  • a cell e.g., host cell
  • the resulting cells can then be cultured by conventional techniques to produce an antibody described herein (e.g., an antibody comprising the CDRs of any one of antibodies Ab235-Ab255) or a fragment thereof.
  • an antibody described herein e.g., an antibody comprising the CDRs of any one of antibodies Ab235-Ab255
  • a promoter for expression of such sequences in the host cell e.g., an antibody comprising the CDRs of any one of antibodies Ab235-Ab255
  • vectors encoding both the heavy and light chains can be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.
  • a host cell contains a vector comprising a polynucleotide encoding both the heavy chain and light chain of an antibody described herein (e.g., an antibody comprising the CDRs of any one of antibodies Ab235-Ab255), or a fragment thereof.
  • a host cell contains two different vectors, a first vector comprising a polynucleotide encoding a heavy chain or a heavy chain variable region of an antibody described herein (e.g., an antibody comprising the CDRs of any one of antibodies Ab235-Ab255), or a fragment thereof, and a second vector comprising a polynucleotide encoding a light chain or a light chain variable region of an antibody described herein (e.g., an antibody comprising the CDRs of any one of antibodies Ab235-Ab255), or a fragment thereof.
  • a first vector comprising a polynucleotide encoding a heavy chain or a heavy chain variable region of an antibody described herein (e.g., an antibody comprising the CDRs of any one of antibodies Ab235-Ab255), or a fragment thereof.
  • a second vector comprising a polynucleotide encoding a light chain or a light chain variable region of an antibody described herein (e.g.,
  • a first host cell comprises a first vector comprising a polynucleotide encoding a heavy chain or a heavy chain variable region of an antibody described herein (e.g., an antibody comprising the CDRs of any one of antibodies Ab235-Ab255), or a fragment thereof
  • a second host cell comprises a second vector comprising a polynucleotide encoding a light chain or a light chain variable region of an antibody described herein (e.g., an antibody comprising the CDRs of any one of antibodies Ab235-Ab255).
  • a heavy chain/heavy chain variable region expressed by a first cell associated with a light chain/light chain variable region of a second cell to form an anti-MET antibody described herein (e.g., antibody comprising the CDRs of any one of antibodies Ab235-Ab255) or an antigen-binding fragment thereof.
  • an anti-MET antibody described herein e.g., antibody comprising the CDRs of any one of antibodies Ab235-Ab255
  • a population of host cells comprising such first host cell and such second host cell.
  • a population of vectors comprising a first vector comprising a polynucleotide encoding a light chain/light chain variable region of an anti-MET antibody described herein (e.g., antibody comprising the CDRs of any one of antibodies Ab235-Ab255), and a second vector comprising a polynucleotide encoding a heavy chain/heavy chain variable region of an anti-MET antibody described herein (e.g., antibody comprising the CDRs of any one of antibodies Ab235-Ab255).
  • host-expression vector systems can be utilized to express antibody molecules described herein (e.g., an antibody comprising the CDRs of any one of antibodies Ab235-Ab255) (see, e.g., U.S. Pat. No. 5,807,715).
  • host-expression systems represent vehicles by which the coding sequences of interest can be produced and subsequently purified, but also represent cells which can, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule described herein in situ. These include but are not limited to microorganisms such as bacteria (e.g., E. coli and B.
  • subtilis transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast (e.g., Saccharomyces Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing antibody coding sequences; plant cell systems (e.g., green algae such as Chlamydomonas reinhardtii ) infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, MDCK, HEK 293, NSO, PER.C6, VERO, CRL7O3O, H
  • cells for expressing antibodies described herein are CHO cells, for example CHO cells from the CHO GS SystemTM (Lonza).
  • a mammalian expression vector is pOptiVECTM or pcDNA3.3.
  • bacterial cells such as Escherichia coli, or eukaryotic cells (e.g., mammalian cells), especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule.
  • mammalian cells such as Chinese hamster ovary (CHO) cells
  • CHO Chinese hamster ovary
  • a vector such as the major intermediate early gene promoter element from human cytomegalovirus
  • antibodies described herein are produced by CHO cells or NS0 cells.
  • the expression of nucleotide sequences encoding antibodies described herein which immunospecifically bind to an ECD of MET is regulated by a constitutive promoter, inducible promoter or tissue specific promoter.
  • a number of expression vectors can be advantageously selected depending upon the use intended for the antibody molecule being expressed.
  • vectors which direct the expression of high levels of fusion protein products that are readily purified can be desirable.
  • Such vectors include, but are not limited to, the E. coli expression vector pUR278 (Ruther et al., 1983, EMBO 12:1791), in which the antibody coding sequence can be ligated individually into the vector in frame with the lac Z coding region so that a fusion protein is produced; pIN vectors (Inouye & Inouye, 1985, Nucleic Acids Res.
  • pGEX vectors can also be used to express foreign polypeptides as fusion proteins with glutathione 5-transferase (GST).
  • GST glutathione 5-transferase
  • fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione agarose beads followed by elution in the presence of free glutathione.
  • the pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.
  • Autographa californica nuclear polyhedrosis virus (AcNPV), for example, can be used as a vector to express foreign genes.
  • the virus grows in Spodoptera frugiperda cells.
  • the antibody coding sequence can be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter).
  • a number of viral-based expression systems can be utilized.
  • the antibody coding sequence of interest can be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence.
  • This chimeric gene can then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing the antibody molecule in infected hosts (e.g., see Logan & Shenk, 1984, Proc. Natl.
  • Specific initiation signals can also be required for efficient translation of inserted antibody coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression can be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see, e.g., Bittner et al., 1987, Methods in Enzymol. 153:51-544).

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