Anti-MET antibodies, bispecific antigen binding molecules that bind MET, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11142578-B2
Application number	US-201715814095-A
Country	US
Kind code	B2
Filing date	Nov 15, 2017
Priority date	Nov 16, 2016
Publication date	Oct 12, 2021
Grant date	Oct 12, 2021

Abstract

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.

First claim

What is claimed is:

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

Assignees

• Regeneron Pharma

Inventors

• Babb Robert
• Chen Gang
• Daly Christopher
• Dasilva John
• Macdonald Douglas
• Nittoli Thomas

Classifications

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/75

  Agonist effect on antigen · CPC title

• A61K47/68037

  the drug being a camptothecin [CPT] or derivatives · CPC title

• C07K5/06052 Primary

  Val-amino acid · CPC title

• A61K47/68033

  the drug being a maytansine · CPC title