Methods for treating cancer, or von-hippel lindau disease using a combination of a tigit antagonist, a pd-1 antagonist, and a hif-2-alpha inhibitor

Patent metadata

Field	Value
Publication number	US-2025333509-A1
Application number	US-202318869398-A
Country	US
Kind code	A1
Filing date	May 26, 2023
Priority date	Jun 2, 2022
Publication date	Oct 30, 2025
Grant date	—

Abstract

Provided herein are methods of treating cancer, or von-Hippel Lindau disease, which comprise administering to a human patient in need thereof: (a) a TIGIT antagonist; (b) a PD-1 antagonist; and an HIF-2α inhibitor. Also provided are kits containing such agents and uses of therapeutic combinations of such agents for the treatment of cancer, or von-Hippel Lindau disease.

First claim

1 . A method of treating cancer, comprising administering to a human patient in need thereof a therapeutic combination comprising an effective amount of:
(a) a TIGIT antagonist; (b) a PD-1 antagonist; and (c) belzutifan.

2 . The method of claim 1 , wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer (CRC), esophageal cancer, gastrointestinal cancer, hepatocellular carcinoma (HCC), melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, and renal cell carcinoma (RCC).

3 . The method of claim 2 , wherein the cancer is RCC, optionally wherein the RCC is advanced RCC, optionally wherein the RCC is advanced RCC with clear cell component (ccRCC).

4 - 5 . (canceled)

6 . The method of claim 3 , wherein the human patient has not received prior systemic treatment for advanced disease and/or the RCC is metastatic RCC.

7 . (canceled)

8 . A kit comprising:
(a) a TIGIT antagonist; (b) a PD-1 antagonist; and (c) belzutifan.

9 - 16 . (canceled)

17 . The method of claim 1 , wherein the PD-1 antagonist and the TIGIT antagonist are co-formulated, the PD-1 antagonist and the TIGIT antagonist are in a fixed dose combination, or the PD-1 antagonist and the TIGIT antagonist are formulated separately.

18 - 19 . (canceled)

20 . The method of claim 1 ,
(i) wherein the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or antigen binding fragment thereof, optionally wherein the anti-human PD-1 monoclonal antibody is a humanized antibody or the anti-human PD-1 monoclonal antibody is a human antibody; and/or (ii) wherein the TIGIT antagonist is an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof, optionally wherein the anti-human TIGIT monoclonal antibody is a humanized antibody, or the anti-human TIGIT monoclonal antibody is a human antibody.

21 - 25 . (canceled)

26 . The method of claim 20 , wherein the anti-human PD-1 monoclonal antibody is pembrolizumab.

27 - 28 . (canceled)

29 . The method of claim 23 , wherein:
(i) the anti-human TIGIT monoclonal antibody or antigen binding fragment thereof comprises three light chain CDRs comprising CDRL1 having the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 having the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 having the amino acid sequence as set forth in SEQ ID NO: 113 and three heavy chain CDRs comprising CDRH1 having the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 having the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 having the amino acid sequence as set forth in SEQ ID NO: 110; (ii) the anti-human TIGIT monoclonal antibody or antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 152; or (iii) the anti-human TIGIT monoclonal antibody or antigen binding fragment thereof comprises a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and a heavy chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295.

30 - 31 . (canceled)

32 . The method of claim 1 , wherein:
(a) the PD-1 antagonist is pembrolizumab; and (b) the TIGIT antagonist comprises three light chain CDRs comprising CDRL1 having the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 having the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 having the amino acid sequence as set forth in SEQ ID NO: 113 and three heavy chain CDRs comprising CDRH1 having the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 having the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 having the amino acid sequence as set forth in SEQ ID NO: 110.

33 - 34 . (canceled)

35 . The method of claim 32 , wherein the TIGIT antagonist comprises a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 148 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 152, or the TIGIT antagonist comprises a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 294 and a heavy chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 295.

36 . (canceled)

37 . The method of claim 32 , wherein the human patient is administered about 200 mg, about 240 mg, or about 2 mg/kg pembrolizumab, and wherein pembrolizumab is administered once every three weeks.

38 - 41 . (canceled)

42 . The method of claim 32 , wherein the human patient is administered about 50, about 75, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, or about 300 mg of the TIGIT antagonist, and wherein the TIGIT antagonist is administered once every three weeks.

43 - 44 . (canceled)

45 . The method of claim 1 , wherein the human patient is administered about 40 mg, about 80 mg, or about 120 mg belzutifan, and wherein belzutifan is administered once a day.

46 . (canceled)

47 . A method of treating RCC, comprising administering to a human patient in need thereof a therapeutic combination comprising:
(a) about 200 mg pembrolizumab; (b) about 200 mg of an anti-TIGIT antibody or antigen binding fragment thereof comprising three light chain CDRs: CDRL1 having the amino acid sequence as set forth in SEQ ID NO: 111, CDRL2 having the amino acid sequence as set forth in SEQ ID NO: 112, and CDRL3 having the amino acid sequence as set forth in SEQ ID NO: 113, and three heavy chain CDRs: CDRH1 having the amino acid sequence as set forth in SEQ ID NO: 108, CDRH2 having the amino acid sequence as set forth in SEQ ID NO: 154, and CDRH3 having the amino acid sequence as set forth in SEQ ID NO: 110; and (c) about 120 mg belzutifan.

48 . The method of claim 47 , wherein (a) and (b) are administered once every three weeks and (c) is administered once a day.

49 . The method of claim 47 ,
(i) wherein (a) and (b) are administered on the same day, and wherein (a) and (b) are administered sequentially or concurrently; (ii) wherein (a) and (b) are co-formulated; or (iii) wherein (a) and (b) are in a fixed dose combination.

50 - 51 . (canceled)

52 . The method of claim 47 , wherein the RCC is advanced RCC, optionally wherein the RCC is advanced RCC with clear cell component (ccRCC).

53 . (canceled)

54 . The method of claim 52 , wherein the human patient has not received prior systemic treatment for advanced disease.

55 . A method of treating von-Hippel Lindau disease, comprising administering to a human patient in need thereof a therapeutic combination comprising an effective amount of:
(a) a TIGIT antagonist; (b) a PD-1 antagonist; and (c) belzutifan.

56 - 91 . (canceled)

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Burgents Joseph E
• Perini Rodolfo Fleury
• Keenan Tanya

Classifications

• A61K2039/545

  characterised by the dose, timing or administration schedule · CPC title

• A61K2039/507

  Comprising a combination of two or more separate antibodies · CPC title

• A61K31/277

  having a ring, e.g. verapamil · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title