Antibodies directed to the receptor tyrosine kinase c-Met

Patent metadata

Field	Value
Publication number	US-9169329-B2
Application number	US-201113701151-A
Country	US
Kind code	B2
Filing date	Jun 1, 2011
Priority date	Jun 1, 2010
Publication date	Oct 27, 2015
Grant date	Oct 27, 2015

Abstract

The present invention relates to antibodies that specifically bind to unprocessed c-Met present on the surface of tumor cells. These antibodies are useful in the diagnosis and treatment of cancer or as agents for delivering moieties to cancer cells. The antibodies of the present invention may also be used in therapy in combination with chemotherapeutics or anti-cancer agents.

First claim

The invention claimed is:

1. An isolated antibody or antigen-binding fragment thereof that specifically binds to c-Met on a tumor cell wherein the antibody or fragment comprises an immunoglobulin heavy chain variable region amino acid sequence comprising the complementarity determining region (CDR) sequences SEQ ID NO:23, SEQ ID NO:24 and SEQ ID NO:25 and an immunoglobulin light chain variable region amino acid sequence comprising the complementarity determining region (CDR) sequences SEQ ID NO:26, SEQ ID NO:27 and SEQ ID NO:28.

2. The isolated antibody or antigen-binding fragment thereof according to claim 1 which comprises an immunoglobulin heavy chain comprising a variable region amino acid sequence which is at least 90% identical to SEQ ID NO:29, wherein the antibody specifically binds c-Met.

3. The isolated antibody or antigen-binding fragment thereof according to claim 1 which comprises an immunoglobulin light chain comprising a variable region amino acid sequence which is at least 90% identical to SEQ ID NO:30, wherein the antibody specifically binds c-Met.

4. The isolated antibody or antigen-binding fragment thereof according to claim 1 , comprising an immunoglobulin heavy chain comprising a variable region amino acid sequence set forth in SEQ ID NO:29 and an immunoglobulin light chain comprising a variable region amino acid sequence set forth in SEQ ID NO:30.

5. The antigen-binding fragment according to claim 1 , which is an scFv.

6. The antibody or antigen-binding fragment thereof according to claim 1 that specifically binds to c-Met on a tumor cell and induces downregulation of the receptor in the absence of c-Met receptor activation, wherein the epitope comprises the amino acid sequence DVLPEFRDSY (SEQ ID NO:4) and wherein the antibody is not a Met4 antibody produced by the hybridoma cell line deposited with the ATCC under Accession No. PTA-7680.

7. The antibody according to claim 1 , comprising an immunoglobulin heavy chain comprising a variable region amino acid sequence set forth in SEQ ID NO:29 and an immunoglobulin light chain comprising a variable region amino acid sequence set forth in SEQ ID NO:30.

8. The antibody according to claim 1 having a binding affinity (K D ) for c-Met of about 3 nM.

9. A method of inhibiting cellular proliferation of a tumor cell expressing c-Met in a subject, comprising administering to the subject an antibody or antigen binding fragment thereof according to claim 1 .

10. The method according to claim 9 , wherein the antigen-binding fragment is an scFv.

11. The antibody or antigen-binding fragment thereof according to claim 1 conjugated to an agent.

12. The antibody or antigen-binding fragment thereof according to claim 11 , conjugated to an agent selected from a detectable or functional label, or therapeutic agent selected from a cytotoxin or anti-neoplastic agent.

13. An isolated nucleic acid sequence encoding an antibody or antigen-binding fragment according to claim 1 .

14. The nucleic acid sequence according to claim 13 , wherein the sequence comprises the heavy chain variable region sequence of SEQ ID NO:39 and the light chain variable region sequence of SEQ ID NO:40.

15. A vector comprising an isolated nucleic acid sequence according to claim 14 .

16. A host cell comprising the vector according to claim 15 .

17. A pharmaceutical composition comprising an antibody or antigen-binding fragment according to any one of claims 1 to 4 or an antibody conjugate according to claim 11 together with a pharmaceutically acceptable carrier or excipient.

18. The pharmaceutical composition according to claim 17 further comprising an anti-cancer agent or therapeutic, an inhibitor of angiogenesis, or an immune modulator.

19. A method of treating undesirable tumor cell proliferation in a subject wherein the tumor cell expresses c-Met which comprises administering to said subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 4 or a conjugate according to claim 11 .

20. A method for detecting cells expressing c-Met in a subject, the method comprising contacting the subject, or a sample obtained therefrom, with an antibody or antigen-binding fragment according to any one of claims 1 to 4 or a conjugate according to claim 11 and analysing the subject or sample for binding between human c-Met and the antibody or conjugate, wherein binding detects cells expressing c-Met.

Assignees

• Johns Terrance Grant
• Gherardi Ermanno
• Scott Andrew Mark
• Ludwig Inst Cancer Res
• Univ Monash

Inventors

• Johns Terrance Grant
• Gherardi Ermanno
• Scott Andrew Mark

Classifications

• G01N33/74

  involving hormones {or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors} · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K16/2803 Primary

  against the immunoglobulin superfamily · CPC title

• C07K14/705

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• A61P35/02

  specific for leukemia · CPC title