Combination therapy of a pd-1 antagonist and lag3 antagonist and lenvatinib or a pharmaceutically acceptable salt thereof for treating patients with cancer

Patent metadata

Field	Value
Publication number	US-2024010729-A1
Application number	US-202118245222-A
Country	US
Kind code	A1
Filing date	Sep 14, 2021
Priority date	Sep 15, 2020
Publication date	Jan 11, 2024
Grant date	—

Abstract

The present disclosure describes combination therapies comprising an antagonist of Programmed Death 1 receptor (PD-1), a Lymphocyte-Activation Gene 3 (LAG3) antagonist, and lenvatinib or a pharmaceutically acceptable salt thereof and the use of the combination therapies for the treatment cancer.

First claim

1 . A method for treating cancer in an individual comprising administering to an individual a PD-1 antagonist, a LAG3 antagonist, and lenvatinib or a pharmaceutically acceptable salt thereof.

2 . The method of claim 1 , wherein the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof.

3 . The method of claim 1 , wherein the individual is a human and the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof, that specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1.

4 . The method of claim 3 , w % herein the PD-1 antagonist also blocks binding of human PD-L2 to human PD-1.

5 . The method of claim 4 , wherein the PD-1 antagonist is an antibody, or antigen binding fragment thereof, that comprises: (a) a light chain variable region comprising light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 1, 2 and 3, respectively and (b) a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 6, 7 and 8, respectively.

6 . The method of claim 4 , wherein the PD-1 antagonist is an anti-PD-1 antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:9 and the light chain comprises a light chain variable region comprising SEQ ID NO: 4.

7 . The method of claim 4 , wherein the PD-1 antagonist is an anti-PD-1 antibody that comprises two heavy chains and two light chains, and wherein the heavy chain comprises SEQ ID NO:10 and the light chain comprises SEQ ID NO:5.

8 . The method of claim 4 , wherein the PD-1 antagonist is pembrolizumab.

9 . The method of claim 4 , wherein the PD-1 antagonist is a pembrolizumab variant.

10 . The method of claim 4 , wherein the PD-1 antagonist is nivolumab.

11 . The method of any one of claims 1 to 10 , wherein the LAG3 antagonist is a monoclonal antibody, or an antigen binding fragment thereof that blocks binding of LAG3 to MHC Class 11 molecules.

12 . The method of any one of claims 1 to 10 , wherein the LAG3 antagonist is an antibody, or antigen binding fragment thereof, that comprises: (a) a light chain variable region comprising light chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 26, 27 and 28 and (b) a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 of SEQ ID NOs: 29, 30 and 31.

13 . The method of any one of claims 1 to 10 , wherein the LAG3 antagonist is an anti-LAG3 monoclonal antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:25 and the light chain comprises a light chain variable region comprising SEQ ID NO: 24.

14 . The method of any one of claims 1 to 10 , wherein the LAG3 antagonist is an anti-LAG3 antibody that comprises two heavy chains and two light chains, and wherein the heavy chain comprises SEQ ID NO:23 and the light chain comprises SEQ ID NO:22.

15 . The method of any one of claims 1 to 10 , wherein the LAG3 antagonist is an Ab6 variant.

16 . The method of any one of claims 1 to 10 , wherein the LAG3 antagonist is an Ab6 antibody.

17 . The method of claim 1 , wherein the PD-1 antagonist is a humanized anti-PD-1 antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising heavy chain CDRs of SEQ ID NOs: 6, 7 and 8 and the light chain comprises a light chain variable region comprising light chain CDRs of SEQ ID NOs: 1, 2 and 3; and the LAG3 antagonist is a humanized anti-LAG3 antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising heavy chain CDRs of SEQ ID NOs: 29, 30 and 31 and the light chain comprises a light chain variable region comprising light chain CDRs of SEQ ID NOs: 26, 27 and 28.

18 . The method of claim 1 , wherein the PD-1 antagonist is an anti-PD-1 antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:9 and the light chain comprises a light chain variable region comprising SEQ ID NO: 4; and the LAG3 antagonist is an anti-LAG3 antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:25 and the light chain comprises a light chain variable region comprising SEQ ID NO: 24.

19 . The method of claim 1 , wherein the PD-1 antagonist is an anti-PD-1 antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises SEQ ID NO:10 and the light chain comprises SEQ ID NO: 5; and the LAG3 antagonist is an anti-LAG3 antibody that comprises a heavy chain and a light chain, and wherein the heavy chain comprises SEQ ID NO:23 and the light chain comprises SEQ ID NO: 22.

20 . The method of any one of claims 1 to 19 , wherein the PD-1 antagonist and LAG3 antagonist are co-formulated.

21 . The method of any one of claims 1 to 19 , wherein the PD-1 antagonist and the LAG3 antagonist are co-administered.

22 . The method of any one of claims 1 to 21 , wherein lenvatinib mesylate is administered.

23 . The method of claim 1 , comprising administering via intravenous infusion to the individual a composition comprising 200 mg of pembrolizumab and 800 mg of anti-LAG3 antibody Ab6 every three weeks, and orally administering 8-20 mg of lenvatinib or a pharmaceutically acceptable salt thereof.

24 . The method of claim 1 , comprising co-administering 200 mg pembrolizumab and 800 mg Ab6 on Day 1 every three weeks for intravenous infusion, and 8-20 mg of lenvatinib or a pharmaceutically acceptable salt thereof orally daily.

25 . The method of claim 1 , comprising administering 400 mg pembrolizumab on Day 1 every six weeks and 800 mg Ab6 on Day 1 every three weeks for intravenous infusion, and orally administering daily 8-20 mg of lenvatinib or a pharmaceutically acceptable salt thereof.

26 . The method of any one of claims 1 to 25 , wherein the individual has not been previously treated with anti-PD-1 or anti-PD-L1 therapy.

27 . The method of any one of claims 1 to 25 , wherein the individual progressed with previous treatment with anti-PD-1 or anti-PD-L1 therapy.

28 . The method of any one of claims 1 to 25 , wherein the individual progressed with previous treatment with PD-1 or PD-L1 checkpoint inhibitor in combination or in sequence with a VEGF receptor tyrosine kinase inhibitor.

29 . The method of any one of claims 1 to 28 , wherein the cancer is colorectal cancer.

30 . The method of any one of claims 1 to 26 , wherein the cancer is non-microsatellite instability-high (non-MSI-H) or proficient mismatch repair (pMMR) colorectal cancer.

31 . The method of any one of claims 1 to 28 , wherein the cancer is renal cell carcinoma.

32 . The method of any one of claims 1 to 28 , wherein the cancer is clear cell renal cell carcinoma.

Assignees

• Healy Jane Anne
• Jha Sujata Shrawankumar
• Marinello Patricia
• Perini Rodolfo Fleury
• Willemann Rogerio Jaqueline
• Merck Sharp & Dohme Llc

Inventors

• Healy Jane Anne
• Jha Sujata Shrawankuma
• Marinello Patricia
• Perini Rodolfo Fleury
• Willemann Rogerio Jaqueline

Classifications

• C07K16/2818 Primary

  against CD28 or CD152 · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• C07K16/2833

  against MHC-molecules, e.g. HLA-molecules · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K2039/507

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