ANTI-MET ANTIBODIES, BISPECIFIC ANTIGEN BINDING MOLECULES THAT BIND MET, AND METHODS OF USE THEREOF
Provided herein are antibodies and bispecific antigen-binding molecules that bind MET and methods of use thereof. The bispecific antigen-binding molecules comprise a first and a second antigen-binding domain, wherein the first and second antigen-binding domains bind to two different (preferably non-overlapping) epitopes of the extracellular domain of human MET. The bispecific antigen-binding molecules are capable of blocking the interaction between human MET and its ligand HGF. The bispecific antigen-binding molecules can exhibit minimal or no MET agonist activity, e.g., as compared to monovalent antigen-binding molecules that comprise only one of the antigen-binding domains of the bispecific molecule, which tend to exert unwanted MET agonist activity. Also included are antibody-drug conjugates (ADCs) comprising the antibodies or bispecific antigen-binding molecules provided herein linked to a cytotoxic agent, radionuclide, or other moiety, as well as methods of treating cancer in a subject by administering to the subject a bispecific antigen-binding molecule or an ADC thereof.
1 . A nucleic acid molecule comprising a polynucleotide sequence that encodes an amino acid sequence comprising a heavy chain variable region (HCVR) of an isolated antibody or antigen-binding fragment thereof that binds to human MET, wherein the antibody or antigen-binding fragment thereof comprises:
three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within the HCVR, wherein the HCVR amino acid sequence comprises SEQ ID NO: 58.
2 . The nucleic acid molecule of claim 1 , comprising:
a polynucleotide sequence that encodes the HCVR comprising: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 64.
3 . The nucleic acid molecule of claim 1 , comprising a nucleotide sequence as set forth in SEQ ID NO: 57, or a substantially identical sequence having at least 95% homology thereto.
4 . An expression vector comprising the nucleic acid molecule of claim 1 .
5 . An isolated host cell comprising the expression vector of claim 4 .
6 . A nucleic acid molecule comprising a polynucleotide sequence that encodes an amino acid sequence comprising an HCVR of an isolated antibody or antigen-binding fragment thereof that binds to human MET, wherein the antibody or antigen-binding fragment thereof comprises:
three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the HCVR, wherein the HCVR amino acid sequence comprises SEQ ID NO: 82.
7 . The nucleic acid molecule of claim 6 , comprising:
a polynucleotide sequence that encodes the HCVR comprising: an HCDR1 comprising the amino acid sequence of SEQ ID NO: 84, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 86, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 88.
8 . The nucleic acid molecule of claim 6 , comprising a nucleotide sequence as set forth in SEQ ID NO: 81, or a substantially identical sequence having at least 95% homology thereto.
9 . An expression vector comprising the nucleic acid molecule of claim 6 .
10 . An isolated host cell comprising the expression vector of claim 9 .
11 . A nucleic acid molecule comprising a polynucleotide sequence that encodes an amino acid sequence comprising a light chain variable region (LCVR) of an isolated antibody or antigen-binding fragment thereof that binds to human MET, wherein the antibody or antigen-binding fragment thereof comprises:
three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the LCVR sequence, wherein the LCVR amino acid sequence comprises SEQ ID NO: 138.
12 . The nucleic acid molecule of claim 11 , comprising:
a polynucleotide sequence that encodes the LCVR comprising: an LCDR1 comprising the amino acid sequence of SEQ ID NO: 140, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 142, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 144.
13 . The nucleic acid molecule of claim 11 , comprising a nucleotide sequence as set forth in SEQ ID NO: 137, or a substantially identical sequence having at least 95% homology thereto.
14 . An expression vector comprising the nucleic acid molecule of claim 11 .
15 . An isolated host cell comprising the expression vector of claim 14 .
16 . The nucleic acid molecule of claim 1 , further comprising a polynucleotide sequence that encodes an LCVR, wherein the LCVR comprises three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the LCVR sequence, and wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 138.
17 . The nucleic acid molecule of claim 16 , comprising:
a polynucleotide sequence that encodes the HCVR and the LCVR comprising:
an HCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 62, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 64; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 140, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 142, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 144.
18 . An expression vector comprising the nucleic acid molecule of claim 16 .
19 . An isolated host cell comprising the expression vector of claim 18 .
20 . The nucleic acid molecule of claim 6 , further comprising a polynucleotide sequence that encodes an LCVR, wherein the LCVR comprises three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the LCVR sequence, and wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 138.
21 . The nucleic acid molecule of claim 20 , comprising:
a polynucleotide sequence that encodes the HCVR and the LCVR comprising:
an HCDR1 comprising the amino acid sequence of SEQ ID NO: 84, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 86, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 88; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 140, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 142, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 144.
22 . An expression vector comprising the nucleic acid molecule of claim 20 .
23 . An isolated host cell comprising the expression vector of claim 22 .
24 . A set of expression vectors comprising:
(a) a first expression vector comprising the expression vector of claim 4 ;
(b) a second expression vector encoding an amino acid sequence comprising the sequence of SEQ ID NO: 82; and/or
(c) a third expression vector encoding the amino acid sequence comprising the sequence of SEQ ID NO: 138.
25 . An isolated host cell comprising the set of expression vectors of claim 24 .
26 . A method of producing a bispecific antibody or antigen-binding molecule that specifically binds human MET, the method comprising growing the host cell of claim 25 under conditions permitting production of the antibody or antigen-binding molecule thereof, and optionally recovering the antibody or antigen-binding molecule so produced.