Combination therapy involving antibodies against Claudin 18.2 for treatment of 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 gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, and cancer of the gallbladder and metastases thereof.
1. A method of treating a cancer disease characterized by cells expressing claudin 18 splice variant 2, comprising administering to a patient an antibody having the ability of binding to claudin 18 splice variant 2 (CLDN18.2) in combination with an agent stabilizing or increasing expression of CLDN18.2, wherein the agent stabilizing or increasing expression of CLDN18.2 comprises (i) capecitabine and oxaliplatin; (ii) folinic acid, 5-fluorouracil or a prodrug thereof, and oxaliplatin; or (iii) epirubicin, oxaliplatin, and 5-fluorouracil or a prodrug thereof,
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.
2. The method of claim 1 , wherein the antibody has a heavy chain variable region comprising an amino acid sequence represented by SEQ ID NO: 32.
3. The method of claim 1 , wherein the antibody has a light chain variable region comprising an amino acid sequence represented by SEQ ID NO: 39.
4. The method of claim 1 , wherein the antibody has a heavy chain variable region comprising an amino acid sequence represented by SEQ ID NO: 32 and a light chain variable region comprising an amino acid sequence represented by SEQ ID NO: 39.
5. The method of claim 4 , wherein the agent stabilizing or increasing expression of CLDN18.2 comprises capecitabine and oxaliplatin.
6. The method of claim 5 , wherein the antibody is a chimeric antibody comprising a human kappa light chain constant region and a human IgG1 heavy chain constant region.
7. The method of claim 6 , wherein the human kappa light chain constant region is allotype Km(3) and/or the human IgG1 heavy chain constant region is allotype G1m(3).
8. The method of claim 6 , wherein the human kappa light chain constant region comprises an amino acid sequence represented by SEQ ID NO: 12 and the human IgG1 heavy chain constant region comprises an amino acid sequence represented by SEQ ID NO: 13.
9. The method of claim 5 , wherein the cancer disease is selected from the group consisting of gastric cancer and cancer of the eso-gastric junction.
10. The method of claim 4 , wherein the cancer disease is selected from the group consisting of cancer of the esophagus, gastric cancer, cancer of the eso-gastric junction, and gastroesophageal cancer.
11. The method of claim 10 , wherein the agent stabilizing or increasing expression of CLDN18.2 comprises folinic acid, 5-fluorouracil, and oxaliplatin.
12. The method of claim 11 , 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) and/or the human IgG1 heavy chain constant region is allotype G1m(3).
14. The method of claim 12 , wherein the human kappa light chain constant region comprises an amino acid sequence represented by SEQ ID NO: 12 and the human IgG1 heavy chain constant region comprises an amino acid sequence represented by SEQ ID NO: 13.
15. The method of claim 10 , wherein the agent stabilizing or increasing expression of CLDN18.2 comprises epirubicin, oxaliplatin and 5-fluorouracil.
16. The method of claim 15 , wherein the antibody is a chimeric antibody comprising a human kappa light chain constant region and a human IgG1 heavy chain constant region.
17. The method of claim 16 , wherein the human kappa light chain constant region is allotype Km(3) and/or the human IgG1 heavy chain constant region is allotype G1m(3).
18. The method of claim 16 , wherein the human kappa light chain constant region comprises an amino acid sequence represented by SEQ ID NO: 12 and the human IgG1 heavy chain constant region comprises an amino acid sequence represented by SEQ ID NO: 13.