Monoclonal antibodies against claudin-18 for treatment of cancer

Patent metadata

Field	Value
Publication number	US-9499609-B2
Application number	US-201113306545-A
Country	US
Kind code	B2
Filing date	Nov 29, 2011
Priority date	Nov 24, 2005
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

The present invention provides antibodies useful as therapeutics for treating and/or preventing diseases associated with cells expressing CLD1 8, including tumor-related diseases such as gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, and cancer of the gallbladder.

First claim

The invention claimed is:

1. An antibody having the ability of binding to CLD18 and mediating killing of cells expressing CLD18, wherein the antibody binds to CLD18A2 but not to CLD18A1 and wherein the antibody binds to an epitope within loopD3 consisting of SEQ ID NO: 29 of CLD18A2, and said killing of cells is mediated by inducing CDC mediated lysis and/or ADCC mediated lysis.

2. The antibody of claim 1 wherein said killing of cells is induced by binding of said antibody to CLD18A2 expressed by said cells.

3. The antibody of claim 1 wherein said cells expressing CLD18A2 are cancer cells.

4. The antibody of claim 3 wherein the cancer cells are selected from the group consisting of tumorigenic gastric, esophageal, pancreatic and lung cancer cells.

5. The antibody of claim 1 wherein said ADCC mediated lysis takes place in the presence of effector cells selected from the group consisting of monocytes, mononuclear cells, NK cells and PMNs.

6. The antibody of claim 1 which is a monoclonal, chimeric or humanized antibody, or an antigen-binding fragment of an antibody.

7. The antibody of claim 1 selected from the group consisting of an IgG1, an IgG2, preferably IgG2a and IgG2b, an IgG3, an IgG4, and an IgM antibody.

8. The antibody of claim 1 wherein CLD18A2 has the amino acid sequence according to SEQ ID NO:2.

9. The antibody of claim 1 wherein CLD18A1 has the amino acid sequence according to SEQ ID NO:8.

10. The antibody of claim 1 which is specific for cancer cells, preferably stomach cancer cells.

11. The antibody of claim 1 wherein said CLD18A2 is expressed on the surface of said cells.

12. The antibody of claim 1 which is obtainable by a method comprising the step of immunizing an animal with a protein or peptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 18, 20, and 31, or an immunogenic fragment thereof, or a nucleic acid or host cell expressing said protein or peptide, or immunogenic fragment thereof.

13. A hybridoma capable of producing the antibody of claim 1 .

14. A conjugate comprising an antibody of claim 1 coupled to a therapeutic agent.

15. The conjugate of claim 14 wherein the therapeutic agent is a toxin, a radioisotope, a drug or a cytotoxic agent.

16. A pharmaceutical composition comprising an antibody of claim 1 , and a pharmaceutically acceptable carrier.

17. An antibody having the ability of binding to CLD18 and mediating killing of cells expressing CLD18, wherein the antibody binds to CLD18A2 but not to CLD18A1 and wherein the antibody binds to the amino acid sequence of SEQ ID NO: 29, and said killing of cells is mediated by inducing CDC mediated lysis and/or ADCC mediated lysis.

18. An antibody having the ability of binding to CLD18 and mediating killing of cells expressing CLD18, wherein the antibody binds to CLD18A2 but not to CLD18A1 and wherein the antibody binds to a peptide consisting of the amino acid sequence of SEQ ID NO: 29, and said killing of cells is mediated by inducing CDC mediated lysis and/or ADCC mediated lysis.

19. A method of killing a cancer cell expressing CLD18A2, comprising contacting the cell with an effective amount of an antibody of claim 1 .

20. A method of treating cancer involving cells expressing CLD18A2, comprising administering to a subject an antibody of claim 1 .

21. The method of claim 20 wherein the cancer is selected from the group consisting of gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, and cancer of the gallbladder.

Assignees

• Sahin Ugur
• Türeci Özlem
• Usener Dirk
• Fritz Stefan
• Uherek Christoph
• Brandenburg Gunda
• Geppert Harald-Gerhard
• Schröder Anja Kristina
• Thiel Phillippe
• Ganymed Pharmaceuticals Ag
• Johannes Gutenberg-Universitat Mainz

Inventors

• Sahin Ugur
• Türeci Özlem
• Usener Dirk
• Fritz Stefan
• Uherek Christoph
• Brandenburg Gunda
• Geppert Harald-Gerhard
• Schröder Anja Kristina
• Thiel Phillippe

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6823

  Double chain ricin · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title