Combination therapy involving antibodies against claudin 18.2 for treatment of pancreatic cancer
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.
1. A method of treating a pancreatic cancer or a precancerous pancreatic lesion characterized by pancreas cells expressing claudin 18 splice variant 2 (CLDN18.2), the method comprising the steps of:
increasing susceptibility of the pancreas cells to killing by an anti-CLDN18.2 antibody by administering to a patient gemcitabine or a prodrug thereof; and
administering to the patient an anti-CLDN18.2 antibody, 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 has the ability of binding to CLDN18.2 and mediates killing of cells expressing CLDN18.2;
wherein the patient has cancerous or precancerous pancreas tissue comprising cells expressing CLDN18.2.
2. The method of claim 1 , wherein the precancerous tissue is a pancreas intraepithelial neoplasia.
3. The method of claim 1 , wherein the pancreatic cancer is a ductal adenocarcinoma, a mucinous adenocarcinoma, a neuroendocrine carcinoma, an acinic cell carcinoma or a metastasis of any of the said carcinomas.
4. 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.
5. The method of claim 1 , wherein gemcitabine or a prodrug thereof is administered to the patient prior to the antibody having the anti-CLDN18.2 antibody.
6. The method of claim 1 , wherein the anti-CLDN18.2 antibody binds to the first extracellular loop of CLDN18.2.
7. The method of claim 1 , wherein the anti-CLDN18.2 antibody 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.
8. The method of claim 1 , wherein the anti-CLDN18.2 antibody 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).
9. The method of claim 1 , wherein the VH comprises an amino acid sequence represented by SEQ ID NO: 32.
10. The method of claim 1 , wherein the VL comprises an amino acid sequence represented by SEQ ID NO: 39.
11. 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.
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; and wherein the antibody is a chimeric antibody comprising a human kappa light chain constant region and a human IgG1 heavy chain constant region.
13. The method of claim 12 , wherein the human kappa light chain constant region is allotype Km(3).
14. The method of claim 12 , wherein the human IgG1 heavy chain constant region is allotype G1m(3).
15. The method of claim 12 , wherein the human kappa light chain constant region is allotype Km(3) and the human IgG1 heavy chain constant region is allotype G1m(3).
16. The method of claim 1 , wherein the anti-CLDN18.2 antibody comprises a heavy chain having an amino acid sequence represented by SEQ ID NO: 17 and a light chain having an amino acid represented by SEQ ID NO: 24.
17. The method of claim 1 , wherein development or growth of a metastasis is inhibited.
18. The method of claim 1 , wherein gemcitabine or a prodrug thereof is administered to the patient at least 48 hours prior to the anti-CLDN18.2 antibody.
19. A method of treating a pancreatic cancer or a precancerous pancreatic lesion characterized by pancreas cells expressing claudin 18 splice variant 2 (CLDN18.2), the method comprising the steps of:
increasing susceptibility of the pancreas cells to killing by an anti-CLDN18.2 antibody by administering to a patient gemcitabine or a prodrug thereof, wherein the administration of gemcitabine or a prodrug thereof provides an increase in the number of CLDN18.2 proteins on the surface of the pancreas cells; and
administering to the patient an anti-CLDN18.2 antibody, 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 has the ability of binding to CLDN18.2 and mediates killing of cells expressing CLDN18.2;
wherein the patient has cancerous or precancerous pancreas tissue comprising cells expressing CLDN18.2.
20. The method of claim 1 , wherein immunohistochemical or immunofluorescence analysis confirms that the patient has cancerous or precancerous pancreas tissue comprising cells expressing CLDN18.2.
21. The method of claim 19 , wherein the pancreatic cancer is pancreatic adenocarcinoma or ductal pancreatic adenocarcinoma.
22. The method of claim 19 , wherein the pancreatic cancer is metastatic pancreatic adenocarcinoma.
23. The method of claim 19 , further comprising administering a taxane.
24. The method of claim 23 , wherein the taxane is paclitaxel.
25. The method of claim 24 , wherein the paclitaxel is albumin-bound paclitaxel.
26. The method of claim 19 , wherein the anti-CLDN18.2 antibody is administered at a dose of 300 mg/m 2 to 1000 mg/m 2 .
27. The method of claim 19 , wherein the anti-CLDN18.2 antibody is administered repeatedly over a period of at least three months.
28. The method of claim 27 , wherein gemcitabine or a prodrug thereof is administered weekly during the period.
29. The method of claim 19 , 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.
30. The method of claim 19 , 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; and wherein the antibody is a chimeric antibody comprising a human kappa light chain constant region and a human IgG1 heavy chain constant region.
31. The method of claim 30 , wherein the human kappa light chain constant region is allotype Km(3).
32. The method of claim 30 , wherein the human IgG1 heavy chain constant region is allotype G1m(3).
33. The method of claim 30 , wherein the human kappa light chain constant region is allotype Km(3) and the human IgG1 heavy chain constant region is allotype G1m(3).
34. The method of claim 19 , wherein the anti-CLDN18.2 antibody comprises a heavy chain having an amino acid sequence represented by SEQ ID NO: 17 and a light chain having an amino acid represented by SEQ ID NO: 24.
35. The method of claim 1 , further comprising administering a taxane.
36. The method of claim 35 , wherein the taxane is paclitaxel.
37. The method of claim 36 , wherein the paclitaxel is albumin-bound paclitaxel.
38. The method of claim 1 , wherein the anti-CLDN18.2 antibody is administered at a dose of 300 mg/m 2 to 1000 mg/m 2 .
39. The method of claim 1 , wherein the anti-CLDN18.2 antibody is administered repeatedly over a period of at least three months.
40. The method of claim 39 , wherein gemcitabine or a prodrug thereof is administered weekly during the period.