Combination therapy involving antibodies against claudin 18.2 for treatment of pancreatic adenocarcinoma

Patent metadata

Field	Value
Publication number	US-9770487-B2
Application number	US-201414769046-A
Country	US
Kind code	B2
Filing date	Feb 18, 2014
Priority date	Feb 20, 2013
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

The present invention provides a combination therapy for effectively treating and/or preventing diseases associated with cells expressing CLDN18.2, including cancer diseases such as pancreatic cancer and metastases thereof.

First claim

The invention claimed is:

1. A method of treating pancreatic adenocarcinoma or ductal pancreatic adenocarcinoma in a patient comprising administering to the patient (i) an antibody having the ability of binding to claudin 18 splice variant 2 (CLDN18.2), wherein the antibody comprises a heavy chain variable region (VH) having a CDR1 of positions 45-52 of SEQ ID NO: 17, a CDR2 of positions 70-77 of SEQ ID NO: 17, and a CDR3 of positions 116-126 of SEQ ID NO: 17, and a light chain variable region (VL) having a CDR1 of positions 47-58 of SEQ ID NO: 24, a CDR2 of positions 76-78 of SEQ ID NO: 24, and a CDR3 of positions 115-123 of SEQ ID NO: 24 and wherein the antibody mediates killing of cells expressing CLDN18.2 and (ii) gemcitabine or a prodrug thereof, wherein the pancreatic adenocarcinoma or ductal pancreatic adenocarcinoma is characterized by cells expressing CLDN18.2, and wherein gemcitabine or a prodrug thereof is administered to the patient prior to the antibody having the ability of binding to CLDN18.2.

2. The method of claim 1 , wherein the method comprises administering a combination of gemcitabine and oxaliplatin, a combination of gemcitabine and cisplatin, or a combination of gemcitabine and carboplatin.

3. A method of treating pancreatic adenocarcinoma or ductal pancreatic adenocarcinoma in a patient comprising administering to the patient (i) an antibody having the ability of binding to claudin 18 splice variant 2 (CLDN18.2), wherein the antibody comprises a heavy chain variable region (VH) having a CDR1 of positions 45-52 of SEQ ID NO: 17, a CDR2 of positions 70-77 of SEQ ID NO: 17, and a CDR3 of positions 116-126 of SEQ ID NO: 17, and a light chain variable region (VL) having a CDR1 of positions 47-58 of SEQ ID NO: 24, a CDR2 of positions 76-78 of SEQ ID NO: 24, and a CDR3 of positions 115-123 of SEQ ID NO: 24 and wherein the antibody mediates killing of cells expressing CLDN18.2 and (ii) gemcitabine, wherein the pancreatic adenocarcinoma or ductal pancreatic adenocarcinoma is characterized by cells expressing CLDN18.2, and wherein gemcitabine is administered to the patient prior to the antibody having the ability of binding to CLDN18.2.

4. The method of claim 1 , wherein the antibody having the ability of binding to CLDN18.2 binds to the first extracellular loop of CLDN18.2.

5. The method of claim 1 , wherein the antibody having the ability of binding to CLDN18.2 mediates cell killing by one or more of complement dependent cytotoxicity (CDC) mediated lysis, antibody dependent cellular cytotoxicity (ADCC) mediated lysis, induction of apoptosis and inhibition of proliferation.

6. The method of claim 1 , wherein the antibody having the ability of binding to CLDN18.2 is an antibody selected from the group consisting of (i) an antibody produced by and/or obtainable from a clone deposited under the accession no. DSM ACC2810, (ii) an antibody which is a chimerized or humanized form of the antibody under (i), (iii) an antibody having the specificity of the antibody under (i) and (iv) an antibody comprising the antigen binding portion or antigen binding site, in particular the variable region, of the antibody under (i) and preferably having the specificity of the antibody under (i).

7. The method of claim 3 , wherein the antibody having the ability of binding to CLDN18.2 binds to the first extracellular loop of CLDN18.2.

8. The method of claim 3 , wherein the antibody having the ability of binding to CLDN18.2 mediates cell killing by one or more of complement dependent cytotoxicity (CDC) mediated lysis, antibody dependent cellular cytotoxicity (ADCC) mediated lysis, induction of apoptosis and inhibition of proliferation.

9. The method of claim 3 , wherein the antibody having the ability of binding to CLDN18.2 is an antibody selected from the group consisting of (i) an antibody produced by and/or obtainable from a clone deposited under the accession no. DSM ACC2810, (ii) an antibody which is a chimerized or humanized form of the antibody under (i), (iii) an antibody having the specificity of the antibody under (i) and (iv) an antibody comprising the antigen binding portion or antigen binding site, in particular the variable region, of the antibody under (i) and preferably having the specificity of the antibody under (i).

10. The method of claim 1 , wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 32.

11. The method of claim 1 , wherein the VL comprises an amino acid sequence represented by SEQ ID NO: 39.

12. The method of claim 1 , wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 32 and the VL comprises an amino acid sequence represented by SEQ ID NO: 39.

13. The method of claim 1 , wherein the antibody comprises a heavy chain having an amino acid sequence represented by SEQ ID NO: 17 and a light chain having an amino acid sequence represented by SEQ ID NO: 24.

14. The method of claim 3 , wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 32.

15. The method of claim 3 , wherein the VL comprises an amino acid sequence represented by SEQ ID NO: 39.

16. The method of claim 3 , wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 32 and the VL comprises an amino acid sequence represented by SEQ ID NO: 39.

17. The method of claim 3 , wherein the antibody comprises a heavy chain having an amino acid sequence represented by SEQ ID NO: 17 and a light chain having an amino acid sequence represented by SEQ ID NO: 24.

18. The method of claim 1 , wherein development or growth of a metastasis is inhibited.

19. The method of claim 3 , wherein development or growth of a metastasis is inhibited.

20. A method for treating pancreatic adenocarcinoma or ductal pancreatic adenocarcinoma in a patient comprising (i) increasing susceptibility of a pancreatic cancer cell to killing by an anti-CLDN18.2 antibody by administering to the patient gemcitabine or a prodrug thereof and (ii) administering to the patient an antibody having the ability of binding to claudin 18 splice variant 2 (CLDN18.2), wherein the antibody comprises a heavy chain variable region (VH) having a CDR1 of positions 45-52 of SEQ ID NO: 17, a CDR2 of positions 70-77 of SEQ ID NO: 17, and a CDR3 of positions 116-126 of SEQ ID NO: 17, and a light chain variable region (VL) having a CDR1 of positions 47-58 of SEQ ID NO: 24, a CDR2 of positions 76-78 of SEQ ID NO: 24, and a CDR3 of positions 115-123 of SEQ ID NO: 24, wherein the antibody mediates killing of cells expressing CLDN18.2, and wherein gemcitabine or a prodrug thereof is administered to the patient prior to the antibody having the ability of binding to CLDN18.2.

21. The method of claim 20 , wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 32.

22. The method of claim 20 , wherein the VL comprises an amino acid sequence represented by SEQ ID NO: 39.

23. The method of claim 20 , wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 32 and the VL comprises an amino acid sequence represented by SEQ ID NO: 39.

24. The method of claim 20 , wherein the antibody comprises a heavy chain having an amino acid sequence represented by SEQ ID NO: 17 and a light chain having an amino acid sequence represented by SEQ ID NO: 24.

25. The method of claim 1 , wherein gemcitabine or a prodrug thereof is administered to the patient at least 48 hours prior to the antibody having the ability of binding to CLDN18.2.

Assignees

• Ganymed Pharmaceuticals Ag
• Tron-Translationale Onkologie An Der Universitätsmedizin Der Johannes Gutenberg-Universität Mainzgem
• Tron—Translationale Onkologie An Der Univ Der Johannes Gutenberg-Universitat Mainz Ggmbh

Inventors

• Sahin Ugur
• Tureci Ozlem
• Mitnacht-Kraus Rita
• Woll Stefan
• Jacobs Stefan
• Heinz Cornelia

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P43/00

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

• A61P1/18

  for pancreatic disorders, e.g. pancreatic enzymes · CPC title

• A61K31/7052

  having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides · CPC title