Antitumor combination containing anti-CEACAM5 antibody-drug conjugate, anti-PD1 / PD-L1 antibody, and anti-CTLA4 antibody.

Abstract

This disclosure relates to a combination of (i) an antibody-drug conjugate (ADC) containing an anti-CEACAM5 antibody, (ii) an anti-PD-1 antibody or an anti-PD-L1 antibody, and (ii) an anti-CTLA4 antibody for use in the treatment of cancer.

Claims

1. A combination of (i) an antibody-drug conjugate (ADC) containing an anti-CEACAM5 antibody and (ii) an anti-CTLA4 antibody for use in the treatment of cancer.

2. The combination for use according to claim 1, wherein the anti-CEACAM5 antibody comprises CDR-H1 having the amino acid sequence of SEQ ID NO: 1, CDR-H2 having the amino acid sequence of SEQ ID NO: 2, CDR-H3 having the amino acid sequence of SEQ ID NO: 3, CDR-L1 having the amino acid sequence of SEQ ID NO: 4, CDR-L2 having the amino acid sequence NTR, and CDR-L3 having the amino acid sequence of SEQ ID NO:

5.

3. The combination for use according to claim 1 or 2, wherein the antibody-drug conjugate comprises at least one chemotherapeutic agent.

4. The combination for use according to claim 3, wherein the chemotherapeutic agent is a metansinoid selected from N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-meitansine (DM1), N2'-deacetyl-N2'-(4-methyl-4-mercapto-1-oxopentyl)-meitansine (DM4), and combinations thereof.

5. The combination for use according to claim 3 or 4, wherein the anti-CEACAM5 antibody is covalently bonded to the at least one chemotherapeutic agent via an inclementable linker, the linker being selected from N-succinimidylpyridyl dithiobutyrate (SPDB), 4-(pyridine-2-yldisulfanyl)-2-sulfobutyrate (sulfo-SPDB), and succinimidyl (N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

6. The combination for use according to any one of claims 1 to 5, wherein the antibody-drug conjugate is tusamitamab / ravtansine.

7. The antibody-drug conjugate is administered at a dose of 80 mg / m ２ to 210 mg / m ２ ; or at a dose of 80 mg / m ２ to 170 mg / m ２ ; or at a dose of 80 mg / m ２ to 150 mg / m ２ ; or at a dose of 80 mg / m ２ to 120 mg / m ２ ; or at a dose of 80 mg / m ２ to 100 mg / m ２ for use according to any one of claims 1 to 6.

8. The combination for use according to any one of claims 1 to 7, wherein the anti-CTLA4 antibody is ipilimumab, tremelimumab, quavonlimab, or zarifremab.

9. The combination for use according to any one of claims 1 to 8, wherein the anti-CTLA4 antibody is administered in a dose of 1 mg / kg to 10 mg / kg, or in a dose of 3 mg / kg to 10 mg / kg.

10. The combination for use according to any one of claims 1 to 9, wherein (i) the antibody-drug conjugate and (ii) the anti-CTLA4 antibody are administered on the first day of the first cycle of treatment and on the first day of at least one additional cycle of treatment.

11. The combination for use according to any one of claims 1 to 10, wherein (i) the antibody-drug conjugate and (ii) the anti-CTLA4 antibody are administered once every three weeks or once every two weeks.

12. (iii) A combination for use according to any one of claims 1 to 11, further comprising an anti-PD-1 antibody or an anti-PD-L1 antibody.

13. The combination for use according to claim 12, wherein the anti-PD-1 antibody is selected from the group consisting of pembrolizumab, nivolumab, semiprimab, cintilimab, dostallimab, and tislerizumab.

14. The combination for use according to claim 12 or 13, wherein the anti-PD-1 antibody or the anti-PD-L1 antibody is administered in a dose of 150 mg to 400 mg, or in a dose of 150 mg to 300 mg.

15. The combination for use according to any one of claims 1 to 14, wherein the cancer is a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥ 2+ in 1% or more and less than 50% of cancer cells, or a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥ 2+ in 50% or more of cancer cells.

16. A combination for use according to any one of claims 1 to 15, wherein the cancer is selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, gastroesophageal junction adenocarcinoma (GEJ), esophageal cancer, lung cancer, cervical cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer, prostate cancer, neuroendocrine cancer, and skin cancer.

17. A kit of parts comprising: (i) a pharmaceutical composition comprising an antibody-drug conjugate according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient; (ii) a pharmaceutical composition comprising an anti-CTLA4 antibody and a pharmaceutically acceptable excipient; and optionally, (iii) a pharmaceutical composition comprising an anti-PD-1 antibody or an anti-PD-L1 antibody and a pharmaceutically acceptable excipient.

18. A kit of parts according to claim 17, for use in the treatment of cancer.

19. (i) For the manufacture of kits of parts for cancer treatment The use of an antibody-drug conjugate according to any one of claims 1 to 7, in combination with (ii) an anti-CTLA4 antibody and optionally (iii) an anti-PD-1 antibody or an anti-PD-L1 antibody.

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