Combination drug including TLR7 agonist

Patent metadata

Field	Value
Publication number	US-12226480-B2
Application number	US-201816772846-A
Country	US
Kind code	B2
Filing date	Dec 20, 2018
Priority date	Dec 21, 2017
Publication date	Feb 18, 2025
Grant date	Feb 18, 2025

Abstract

The present invention provides an agent for inducing effector memory T cell or an agent for inducing MHC class I for treating or preventing a cancer, comprising a TLR7 agonist which is used with an immune checkpoint inhibitor. And, the present invention also provides a medicament for treating or preventing a cancer, comprising a TLR7 agonist which is used with an immune checkpoint inhibitor.

First claim

The invention claimed is:

1. A method for inducing an effector memory T cell response or inducing an MHC class I response in a human patient in need thereof, comprising
administering to the human patient a therapeutically effective amount of a TLR7 agonist in combination with a therapeutically effective amount of an immune checkpoint inhibitor,
wherein the TLR7 agonist is N-{4-[(2-amino-4-{[(3S)-1-hydroxyhexan-3-yl]amino}-6-methylpyrimidin-5-yl)methyl]-3-methoxybenzyl}-N-(2,2,2-trifluoroethyl)glycine, N-{4-[(2-amino-4-{[(3S)-1-hydroxyhexan-3-yl]amino}-6-methylpyrimidin-5-yl)methyl]-3-methoxybenzyl}-N-(2,2-difluoroethyl)glycine, or a pharmaceutically acceptable salt thereof, and
the immune checkpoint inhibitor is an anti-PD-1 antibody, or an anti-CTLA-4 antibody, and
wherein the TLR7 agonist is administered prior or posterior to the immune checkpoint inhibitor, and
wherein the human patient has a cancer and is refractory to the immune checkpoint inhibitor.

2. The method according to claim 1 , wherein the cancer is selected from the group consisting of non-small-cell lung cancer, small cell lung cancer, pancreatic cancer, malignant melanoma, renal cell carcinoma, gastric cancer, colon cancer, rectal cancer, small intestinal cancer, breast cancer, germ cell cancer, bladder cancer, prostate cancer, endometrial cancer, cervical cancer, ovarian cancer, liver cancer, Merkel cell carcinoma, bone cancer, head and neck cancer, cutaneous malignant melanoma, intraorbital malignant melanoma, anal cancer, testicular cancer, esophageal cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urothelial cancer, penile cancer, glioblastoma multiforme, brain tumor, chronic leukemia, acute leukemia, malignant lymphoma, myelodysplastic syndrome, and multiple myeloma.

3. The method according to claim 2 , wherein the cancer is acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma.

4. The method according to claim 1 , wherein the human patient has relapsed with the cancer.

5. The method according to claim 1 , which effects a long-term anticancer immunity.

6. The method according to claim 1 , wherein the TLR7 agonist is N-{4-[(2-amino-4-{[(3S)-1-hydroxyhexan-3-yl]amino}-6-methylpyrimidin-5-yl)methyl]-3-methoxybenzyl}-N-(2,2,2-trifluoroethyl)glycine, or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1 , wherein the immune checkpoint inhibitor is pembrolizumab.

8. The method according to claim 1 , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

9. The method according to claim 1 , wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

10. The method according to claim 1 , wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, tislelizumab, dostarlimab, spartalizumab, camrelizumab, sintilimab, BI-754091, ABBV-181, CC-90006, AGEN-2034w, LZM-009, Sym-021, HLX-10, or BCD-100,
the anti-CTLA-4 antibody is ipilimumab, tremelimumab, BMS-986218, MK-1308, or BMS-986249.

11. The method according to claim 1 , wherein the TLR7 agonist and the immune checkpoint inhibitor are simultaneously administered.

12. The method according to claim 1 , wherein the TLR7 agonist and the immune checkpoint inhibitor are separately administered.

13. The method according to claim 1 , wherein the TLR7 agonist is administered prior to the immune checkpoint inhibitor.

14. The method according to claim 1 , wherein the TLR7 agonist is administered posterior to the immune checkpoint inhibitor.

15. The method according to claim 1 , wherein the method induces an effector memory T cell response in the human patient in need thereof.

16. The method according to claim 1 , wherein the method induces an MHC class I response in the human patient in need thereof.

17. A method for treating a cancer in a human patient in need thereof, comprising
administering to the human patient a therapeutically effective amount of a TLR7 agonist selected from N-{4-[(2-amino-4-{[(3S)-1-hydroxyhexan-3-yl]amino}-6-methylpyrimidin-5-yl)methyl]-3-methoxybenzyl}-N-(2,2,2-trifluoroethyl)glycine, N-{4-[(2-amino-4-{[(3S)-1-hydroxyhexan-3-yl]amino}-6-methylpyrimidin-5-yl)methyl]-3-methoxybenzyl}-N-(2,2-difluoroethyl)glycine, or a pharmaceutically acceptable salt thereof,
in combination with a therapeutically effective amount of an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-CTLA-4 antibody, and
wherein the human patient is refractory to the immune checkpoint inhibitor.

18. The method according to claim 17 , wherein the TLR7 agonist is N-{4-[(2-amino-4-{[(3S)-1-hydroxyhexan-3-yl]amino}-6-methylpyrimidin-5-yl)methyl]-3-methoxybenzyl}-N-(2,2,2-trifluoroethyl)glycine, or a pharmaceutically acceptable salt thereof.

19. The method according to claim 17 , wherein the immune checkpoint inhibitor is pembrolizumab.

20. The method according to claim 17 , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

21. The method according to claim 17 , wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

22. The method according to claim 17 , wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, tislelizumab, dostarlimab, spartalizumab, camrelizumab, sintilimab, BI-754091, ABBV-181, CC-90006, AGEN-2034w, LZM-009, Sym-021, HLX-10, or BCD-100,
the anti-CTLA-4 antibody is ipilimumab, tremelimumab, BMS-986218, MK-1308, or BMS-986249.

23. The method according to claim 17 , wherein the human patient suffers from relapse of the cancer.

24. The method according to claim 17 , wherein the method effects a long-term anticancer immunity.

25. A method for treating a cancer in a human patient in need thereof, which comprises administering to the human patient a therapeutically effective amount of N-{4-[(2-amino-4-{[(3S)-1-hydroxyhexan-3-yl]amino}-6-methylpyrimidin-5-yl)methyl]-3-methoxybenzyl}-N-(2,2,2-trifluoroethyl)glycine, N-{4-[(2-amino-4-{[(3S)-1-hydroxyhexan-3-yl]amino}-6-methylpyrimidin-5-yl)methyl]-3-methoxybenzyl}-N-(2,2-difluoroethyl)glycine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-CTLA-4 antibody, and
wherein the human patient is refractory to the immune checkpoint inhibitor.

26. The method according to claim 1 , wherein the cancer is chosen from head and neck cancer, renal cell carcinoma, Hodgkin's lymphoma, non-small-cell lung cancer, and gastric cancer.

27. The method of according to claim 17 , wherein the cancer is chosen from non-small-cell lung cancer; small cell lung cancer; pancreatic cancer; malignant melanoma; renal cell carcinoma; gastric cancer; colon cancer; rectal cancer; small intestinal cancer; breast cancer; germ cell cancer; bladder cancer; prostate cancer; endometrial cancer; cervical cancer; ovarian cancer; liver cancer; Merkel cell carcinoma; bone cancer; head and neck cancer; cutaneous or intraorbital malignant melanoma; anal cancer; testicular cancer; esophageal cancer; endocrine system cancer; thyroid cancer; parathyroid cancer; adrenal cancer; soft tissue sarcoma; urothelial cancer; penile cancer; glioblastoma multiforme; brain tumor; chronic or acute leukemia; malignant lymphoma; myelo

Assignees

• Sumitomo Pharma Co Ltd

Inventors

• Ota Yosuke
• Otsubo Takeshi

Classifications

• A61K31/522

  having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir · CPC title

• A61K31/505 Primary

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title