COMBINATION THERAPIES BASED ON CTLA4 AND IL-17B INHIBITORS

Abstract

The present invention concerns the combination of CTLA4 and IL-17B inhibitors, especially for the treatment of patients and diseases resistant to anti-CTLA4 therapies.

Claims

1. A composition comprising a CTLA4 inhibitor and an IL-17B inhibitor.

2. (canceled)

3. A method for treating a cancer or an infectious disease in a subject, comprising administering to the subject the composition according to claim 1.

4. A method of treating a cancer or an infectious disease in a subject, comprising administering to the subject a composition comprising an IL-17B inhibitor, wherein the subject has been treated with a CTLA4 inhibitor.

5. The method according to claim 4 wherein administering the composition comprising the IL-17B inhibitor increases the sensitivity of the subject to the CTLA4 inhibitor.

6. The method according to claim 4 wherein the subject is resistant to the treatment with the CTLA4 inhibitor.

7. The method according to claim 3, wherein the infectious disease is selected in the group consisting of severe sepsis, septic shock, viral infections, fungal infections, mosquito-borne infectious diseases, and bacterial infections.

8. The method according to claim 7 wherein the infectious disease is selected in the group consisting of human immunodeficiency virus, simian immunodeficiency virus, hepatitis, HBV, and malaria.

9. The method according to claim 3 wherein the cancer is resistant to CTLA4 inhibitors.

10. The method according to claim 3 wherein the cancer is selected from the group consisting of melanoma; Renal Cell Carcinoma; ColoRectal Cancer; Small Cell Lung Cancer; Non-Small Cell Lung Cancer; esophageal cancer; breast cancer; Hepatocellular Carcinoma; thyroid cancer; pancreatic cancer; ovarian cancer; Myelodysplastic Syndrome; Acute Myeloid Leukemia; Diffuse Large B-Cell Lymphoma; glioblastoma; sarcoma; Soft tissue Sarcoma; nasopharyngeal carcinoma; mesothelioma; head and neck cancer; prostate cancer and gastrointestinal cancer.

11. The composition according to claim 1 wherein the CTLA4 inhibitor is an inhibitor of CTLA4 or of B7-1 or of B7-2.

12. The composition according to claim 11, wherein the CTLA4 inhibitor is ipilimumab or tremelimumab.

13. The composition according to claim 1, wherein the IL-17B inhibitor is an antibody directed against IL-17B or an antibody directed against a receptor of IL-17B (IL-17RB).

14. The composition according to claim 1 wherein the CTLA4 inhibitor or IL-17B inhibitor is an inhibitor of CTLA4 or IL-17B expression.

15. The composition according to claim 11, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

16. The composition according to claim 14, wherein the CTLA4 inhibitor or IL-17B inhibitor is a siRNA or an antisense oligonucleotide.

17. The method according to claim 7, wherein the viral infection is due to human immunodeficiency virus, simian immunodeficiency virus, hepatitis virus, cytomegalovirus or Epstein-Barr virus.

18. The method according to claim 8, wherein the infectious disease is HBV.

19. The method according to claim 7, wherein the fungal infection is mucormycosis.

20. The method according to claim 7, wherein the mosquito-borne infectious disease is malaria.

21. The method according to claim 7, wherein the bacterial infection is tuberculosis.

Description

FIGURES

[0122] FIG. 1. In vivo study of an anti-CTLA4 therapy in IL-17B WT vs KO mice in the B16F10 melanoma model

[0123] Tumor growth (A) and percent survival (Kaplan Meier survival curve; B) in WT and IL-17B KO mice treated with anti-CTLA4 antibody (α-CTLA4)

*** p<0.001

[0124] FIG. 2. In vivo study of anti-CTLA4 and anti-IL-17B therapies in the B16F10 melanoma murine model

Tumor growth (A and B) and percent survival (Kaplan Meier survival curve; C) in mice treated with anti-IL-17B antibody (α-IL-17B) or corresponding control antibody (IC), possibly in combination with anti-CTLA4 antibody (α-CTLA4) or corresponding control antibody (IC2)
*, p<0.05
**, p<0.01
****, p<0.0001

[0125] FIG. 3. In vivo study of an anti-CTLA4 therapy in IL-17B WT vs KO mice in the MC38 colon cancer model

Tumor growth (A and B) and percent survival (Kaplan Meier survival curve; C) in WT and IL-17B KO mice treated with anti-CTLA4 antibody (α-CTLA4) or corresponding control antibody (IC)
** p<0.01
*** p<0.001

EXAMPLES

Example 1/Efficacy of an Anti-CTLA4 Immunotherapy in the B16F10 Melanoma Model in the Presence (WT Mice) or Absence (IL-17B KO Mice) of IL-17B

1-1 Materials and Methods

[0126] 7-8-week-old C57BL6 WT mice and 7-8-week-old C57BL6 IL-17B KO mice were subcutaneously grafted with 5.10.sup.4 B16F10 cells, 10 WT and 9 KO animals per group. Tumor growth was monitored using a caliper. At day 6, mice were treated with anti-CTLA4 antibody (i.p. injections, 200 μg/mouse, BioXCell, 9H10) and then twice a week at day 9, 13, 17, 20 and 24. Animals were sacrificed when tumors reached 1500 mm.sup.3 or in case of ulceration.

1-2 Results and Conclusion

[0127] FIG. 1 shows the results obtained in terms of tumor growth (A) and percent survival (B).
The B16F10 melanoma model is markedly resistant to anti-CTLA4 therapy, which had no effect in WT animals. In sharp contrast, the response to anti-CTLA4 mAb in the IL-17B KO background was significantly improved with significantly improved mouse survival (p<0.001), including 1 complete response (11%).
In this difficult-to-treat and markedly resistant B16F10 melanoma model, the treatment with anti-CTLA4 antibody was improved in the IL-17B KO background, whereas anti-CTLA4 mAb alone had no effect.

Example 2/Efficacy of Anti-CTLA4 and Anti-IL-17B Immunotherapies in the B16F10 Melanoma Model

[0128] In order to confirm the results obtained in example 1 wherein the absence of IL-17B was obtained by the use of an IL-17B KO mouse, the experiment was repeated in WT mice treated with an anti-IL-17B antibody (FIG. 2).

2-1 Materials and Methods

[0129] 8-week-old C57BL6 mice were subcutaneously grafted with 5.10.sup.4 B16F10 cells, 10 animals per group. Tumor growth was monitored using a caliper. At day 5, mice were treated with anti-IL-17B antibody (i.t. injections, 200 μg/mouse) or control monoclonal mouse IgG1 antibody (i.t. injections, 200 μg/mouse, RD-Biotech clone B-D38), then four times during the first week and three times a week thereafter. At day 6, mice were treated with anti-CTLA4 antibody (i.p. injections, 200 μg/mouse, BioXCell, 9H10) or control polyclonal syrian hamster antibody (i.p. injections, 200 μg/mouse, BioXCell, BP0087) and then twice a week at day 9, 12, 16, 19 and 23. Animals were sacrificed when tumors reached 1500 mm.sup.3 or in case of ulceration.

2-2. Results and Conclusion

[0130] As shown previously, the B16F10 melanoma model is markedly resistant to anti-CTLA4 therapy, which had no effect. Treatment with an anti-IL-17B antibody alone did induce some responses, including 1 complete responder and long-term survivor. Strikingly and in line with the data obtained using the IL-17B KO mice, the combination of anti-IL-17B antibody and anti-CTLA4 antibody induced complete tumor eradication in all animals (10/10) that remained cleared from their tumor and long-term survivors.
In this difficult-to-treat and markedly resistant B16F10 melanoma model, the treatment with anti-IL-17B antibody combined with anti-CTLA4 antibody was able to induce complete tumor regressions in all animals, whereas anti-CTLA4 mAb was unable to induce responses in this model.

Example 3/Efficacy of an Anti-CTLA4 Immunotherapy in the MC38 Colon Cancer Model in the Presence (WT Mice) or Absence (IL-17B KO Mice) of IL-17B

[0131] In order to confirm the results obtained in example 1 in a melanoma model, the experiment was repeated in a colon cancer model.

3-1. Materials and Methods

[0132] 10-week-old C57BL6 WT mice and 9-11-week-old C57BL6 IL-17B KO were subcutaneously grafted with 5.10.sup.5 MC38 cells, 10 WT and 8 or 9 KO animals per group. Tumor growth was monitored using a caliper. At day 6, mice were treated with anti-CTLA4 antibody (i.p. injections, 200 μg/mouse, BioXCell, 9H10) or control polyclonal syrian hamster antibody (i.p. injections, 200 μg/mouse, BioXCell, BP0087), and then twice a week at day 9, 12, 15, 19, 23, 27, 30. Animals were sacrificed when tumors reached 1500 mm.sup.3 or in case of ulceration.

3-2. Results and Conclusion

[0133] As previously observed, the data shown on FIG. 3 reveal that the effect of the anti-CTLA4 antibody is improved in the KO background.
Anti-CTLA4 therapy was able to induce some transient responses in the WT mice, yet no complete responses were obtained and none of the animals survived. In the IL-17B KO background, the treatment with the anti-CTLA4 mAb was improved with 1 mouse out of 9 (11%) that achieved a complete response, remained tumor cleared and survived on the long term.
This example validates that the CTLA4 and IL-17B inhibitory approach according to the invention can be applied to other types of cancer or even to other diseases.