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 bispecific antigen-binding molecule comprising:
a first antigen-binding domain (D1) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 58 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138; and
a second antigen-binding domain (D2) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 82 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138;
wherein D1 specifically binds a first epitope of human MET; and
wherein D2 specifically binds a second epitope of human MET.
2. The bispecific antigen-binding molecule of claim 1 , wherein the bispecific antigen-binding molecule is conjugated to a cytotoxin.
3. The bispecific antigen-binding molecule of claim 2 , wherein the cytotoxin is selected from the group consisting of biotoxins, chemotherapeutic agents, and radioisotopes.
4. The bispecific antigen-binding molecule of claim 2 , wherein the cytotoxin is selected from the group consisting of maytansinoids, auristatins, duocarmycins, 225 Ac, 227 Th, and any derivatives thereof. and any derivatives thereof.
5. The bispecific antigen-binding molecule of claim 1 , wherein the bispecific antigen-binding molecule is conjugated to a cytotoxic agent through a linker.
6. The bispecific antigen-binding molecule of claim 5 , wherein the cytotoxic agent is a maytansinoid.
7. The bispecific antigen-binding molecule of claim 6 , wherein the maytansinoid is:
wherein the
is the bond to the linker.
8. The bispecific antigen-binding molecule of claim 7 , wherein the linker is:
wherein the bond noted with
represents the bond to the bispecific antigen-binding molecule and the bond noted with
represents the bond to the maytansinoid.
9. The bispecific antigen-binding molecule of claim 6 , wherein the maytansinoid is
wherein the
is the bond to the linker.
10. The bispecific antigen-binding molecule of claim 9 , wherein the linker is:
wherein the bond noted with
represents the bond to the bispecific antigen-binding molecule and the bond noted with
represents the bond to the maytansinoid.
11. A pharmaceutical composition comprising the bispecific antigen-binding molecule of claim 1 , and a pharmaceutically acceptable carrier.
12. A method of treating a cancer in a subject suffering from a tumor harboring a MET genetic alteration and/or a tumor whose growth is driven by autocrine HGF signaling, the method comprising administering to the subject the bispecific antigen-binding molecule of claim 1 .
13. A method of treating a cancer, reducing tumor growth, and/or causing tumor regression in a subject suffering from a MET positive tumor, the method comprising administering to a subject in need thereof the bispecific antigen-binding molecule of claim 2 .
14. A bispecific antigen-binding molecule comprising:
a first antigen-binding domain D1 comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:60; HCDR2 comprising the amino acid sequence of SEQ ID NO:62; HCDR3 comprising the amino acid sequence of SEQ ID NO:64; LCDR1 comprising the amino acid sequence of SEQ ID NO:140; LCDR2 comprising the amino acid sequence of SEQ ID NO:142; and LCDR3 comprising the amino acid sequence of SEQ ID NO:144; wherein D1 specifically binds a first epitope of human MET; and
a second antigen-binding domain D2 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; wherein D2 specifically binds a second epitope of human MET.
15. The bispecific antigen-binding molecule of claim 14 , wherein D1 comprises: an HCVR comprising the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical thereto; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical thereto.
16. The bispecific antigen-binding molecule of claim 15 , wherein D1 comprises: an HCVR comprising the amino acid sequence of SEQ ID NO: 58; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138.
17. The bispecific antigen-binding molecule of claim 14 , wherein D2 comprises: an HCVR comprising the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical thereto; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical thereto.
18. The bispecific antigen-binding molecule of claim 17 , wherein D2 comprises: an HCVR comprising the amino acid sequence of SEQ ID NO: 82; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138.
19. The bispecific antigen-binding molecule of claim 14 , wherein the bispecific antigen-binding molecule is conjugated to a maytansinoid through a linker, and wherein the maytansinoid is
wherein the
is the bond to the linker.
20. The bispecific antigen-binding molecule of claim 19 , wherein the linker is:
wherein the bond noted with
represents the bond to the bispecific antigen-binding molecule and the bond noted with
represents the bond to the maytansinoid.
21. The bispecific antigen-binding molecule of claim 20 , wherein:
D1 comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 58 and an LCVR comprising the amino acid sequence of SEQ ID NO: 138; and
D2 comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 82; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138.
22. A method for preparing an antibody-drug conjugate comprising contacting:
(a) an anti-MET antibody comprising the three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 58 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138; or
(b) a MET×MET bispecific antigen-binding protein comprising:
a first antigen binding domain D1 comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 58 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138, wherein D1 specifically binds a first epitope of human MET and
a second antigen binding domain D2 comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 82 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138 wherein D2 specifically binds a second epitope of human MET,
with a compound having the following formula A 1 :
and aqueous diluent.
23. An antibody-drug conjugate prepared by the process of:
(i) contacting a compound of formula (a):
with a compound of formula (b):
in the presence of silica gel and diluent to synthesize an intermediate; and
(ii) contacting:
(a) an anti-MET antibody comprising the three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:58 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:138; or
(b) a MET×MET bispecific antigen-binding protein comprising:
a first antigen binding domain D 1 comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 58 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138, wherein D1 specifically binds a first epitope of human MET, and
a second antigen binding domain D2 comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 82 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 138 wherein D2 specifically binds a second epitope of human MET, with the intermediate and aqueous diluent.
24. A bispecific antigen-binding molecule comprising:
a first antigen binding domain D 1 comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO:20; HCDR2 comprising the amino acid sequence of SEQ ID NO:22; HCDR3 comprising the amino acid sequence of SEQ ID NO:24; LCDR1 comprising the amino acid sequence of SEQ ID NO:140; LCDR2 comprising the amino acid sequence of SEQ ID NO:142; and LCDR3 comprising the amino acid sequence of SEQ ID NO:144; wherein D1 specifically binds a first epitope of human MET; and
a second antigen binding domain D2 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; wherein D2 specifically binds a second epitope of human MET.
25. The bispecific antigen-binding molecule of claim 24 , wherein:
D1 comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 18 and an LCVR comprising the amino acid sequence of SEQ ID NO: 138; and
D2 comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 82; and an LCVR comprising the amino acid sequence of SEQ ID NO: 138.
26. A bispecific antigen-binding molecule comprising:
a first antigen-binding domain (D1) wherein D1 specifically binds a first epitope of human MET; and
a second antigen-binding domain (D2) wherein D2 specifically binds a second epitope of human MET; and
wherein D1 comprises the CDRs within the D1-HCVR amino acid sequence of SEQ ID NO: 18 and the CDRs within the D1-LCVR amino acid sequence of SEQ ID NO: 138, and D2 comprises the CDRs within the D2-HCVR amino acid sequence of SEQ ID NO: 82 and the D2-LCVR amino acid sequence of SEQ ID NO: 138.