NZ781933B2

NZ781933B2 - Combination of pd-1 inhibitors and lag-3 inhibitors for enhanced efficacy in treating cancer

Info

Publication number: NZ781933B2
Application number: NZ781933A
Authority: NZ
Inventors: Glenn Kroog; Tasha N Sims
Original assignee: Regeneron Pharmaceuticals Inc
Filing date: 2020-05-12
Publication date: 2025-10-29

Abstract

The present disclosure provides methods for treating or inhibiting the growth of cancer comprising selecting a patient with cancer and administering a therapeutically effective amount of a LAG-3 inhibitor in combination with a therapeutically effective amount of a PD-1 inhibitor (e.g., an anti-PD-1 antibody or antigen-binding fragment thereof). In certain embodiments, the administration of the PD-1 inhibitor enhances the efficacy of a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody or antigen-binding fragment thereof) in inhibiting the growth of cancer.

Claims

We claim:

1. Use of at least one dose of each of: (a) an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 8; wherein at least one dose of the anti-PD-1 antibody comprises 350 mg or 700 mg; and (b) an antibody or antigen-binding fragment thereof that specifically binds lymphocyte activation gene-3 (LAG-3) comprising three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) of an HCVR and three light chain CDRs (LCDR1, LCDR2 and LCDR3) of an LCVR, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 18; wherein at least one dose of the anti-LAG3 antibody comprises 1600 mg; in the manufacture of one or more medicaments for use in treating cancer or inhibiting the growth of a tumor in a patient in need thereof, wherein the anti-LAG-3 antibody is to be administered concurrently with the anti-PD-1 antibody.

2. The use of claim 1, wherein one dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 700 mg.

3. The use of claim 1, wherein one dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 350 mg.

4. The use of claim 1, wherein the use comprises: two or more doses of the anti-LAG-3 antibody or antigen-binding fragment thereof in combination with two or more doses of the anti-PD-1 antibody or antigen-binding fragment thereof.

5. The use of claim 4, wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 350 mg.

6. The use of claim 4, wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 700 mg.

7. The use of any one of claims 4 to 6, wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is to be administered 0.5 weeks to 12 weeks after the immediately preceding dose.

8. The use of any one of claims 4 to 7, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is to be administered 0.5 weeks to 12 weeks after the immediately preceding dose.

9. The use of any one of claims 4 to 8, wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is to be administered once in three weeks or once in six weeks.

10. The use of any one of claims 4 to 9, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is to be administered once in three weeks or once in six weeks.

11. The use of any one of claims 1 to 10, wherein the antibodies are formulated for intravenous, subcutaneous, or intraperitoneal use.

12. The use of any one of claims 1 to 11, wherein the cancer is selected from the group consisting of astrocytoma, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, cervical cancer, clear cell renal cell carcinoma, colorectal cancer, microsatellite-intermediate colorectal cancer, cutaneous squamous cell carcinoma, diffuse large B-cell lymphoma, endometrial cancer, esophageal cancer, fibrosarcoma, gastric cancer, glioblastoma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatic cell carcinoma, leukemia, liver cancer, leiomyosarcoma, lung cancer, lymphoma, melanoma, mesothelioma, myeloma, nasopharyngeal cancer, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, primary and/or recurrent cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, squamous cell cancer, synovial sarcoma, thyroid cancer, triple negative breast cancer, uterine cancer, and Wilms’ tumor.

13. The use of any one of claims 1 to 12, wherein the patient has received prior anti- cancer therapy comprising one or more of a PD-1 inhibitor, a PD-L1 inhibitor, surgery, radiation therapy or chemotherapy.

14. The use of any one of claims 1 to 13, wherein the patient is resistant or inadequately responsive to, or relapsed after prior therapy.

15. The use of any one of claims 1 to 12, wherein the patient has not received prior anti- cancer therapy.

16. The use of claim 13, wherein the prior anti-cancer therapy comprises a PD-1 inhibitor or a PD-L1 inhibitor.

17. The use of any one of claims 1 to 16, wherein the use produces a therapeutic effect selected from the group consisting of delay in tumor growth, reduction in tumor cell number, tumor regression, increase in survival, partial response, and complete response.

18. The use of claim 17, wherein tumor growth is delayed by at least 10 days as compared to an untreated patient.

19. The use of claim 17, wherein the tumor growth is inhibited by at least 50% as compared to an untreated patient.

20. The use of claim 17, wherein the tumor growth is inhibited by at least 20% as compared to a patient treated with either antibody as monotherapy.

21. The use of any one of claims 1 to 20, further comprising the use of a third therapeutic agent or therapy, wherein the third therapeutic agent or therapy is selected from the group consisting of radiation, a chemotherapeutic agent, a cancer vaccine, a PD-L1 inhibitor, a CTLA-4 inhibitor, a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, a CD28 agonist, a CD38 inhibitor, an indoleamine-2,3-dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin-2 (Ang2) inhibitor, a transforming growth factor beta (TGFß) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an antibody to a tumor-specific antigen, Bacillus Calmette-Guerin vaccine, granulocyte-macrophage colony-stimulating factor, an oncolytic virus, a cytotoxin, an interleukin 6 receptor (IL-6R) inhibitor, an interleukin 4 receptor (IL-4R) inhibitor, an IL-10 inhibitor, IL-2, IL-7, IL-21, IL-12, IL-15, an antibody- drug conjugate, a GITR agonist, a 4-1BB agonist, CD20xCD3 bispecific antibody, MUC16xCD3 bispecific antibody, and an anti-inflammatory drug.

22. The use of claim 1, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises an HCVR amino acid sequence as set forth in SEQ ID NO: 1 and an LCVR amino acid sequence as set forth in SEQ ID NO: 2.

23. The use of any one of claims 1 to 22, wherein the anti-PD-1 antibody or antigen- binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO:

24. The use of claim 1, wherein the anti-LAG3 antibody or antigen-binding fragment thereof comprises an HCVR amino acid sequence as set forth in SEQ ID NO: 11 and an LCVR amino acid sequence as set forth in SEQ ID NO: 12.

25. The use of any one of claims 1 to 24, wherein the anti-LAG-3 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20.

26. The use of any one of claims 1 to 25, wherein the inhibition is more efficacious than the use of either antibody as a monotherapy.

27. The use of claim 1, wherein (a) comprises 350 mg or 700 mg anti-PD-1 antibody or antigen-binding fragment thereof and (b) comprises 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof, wherein: (1) the patient has a tumor and has received prior treatment comprising a PD-1 inhibitor or PD-L1 inhibitor; and (2) (a) and (b) are to be administered once every 3 weeks, or once every 6 weeks.

28. The use of claim 27, wherein the patient further has one or more of the following criteria: (i) ineligible for platinum based therapy, or tumor progression or recurrence within 6 months of last dose of platinum therapy; (ii) confirmed diagnosis of malignancy; (iii) demonstrated progression of a tumor for which there is no available therapy likely to convey clinical benefit; (iv) disease progression/recurrence after one platinum-containing regimen; (v) anti-PD-1/PD-L1 experienced stage IIIB, IIIC, or IV NSCLC with no more than 2 prior therapies for metastatic disease; (vi) anti-PD-1/PD-L1 experienced advanced or metastatic ccRCC with a clear cell component who had received no more than 2 previous regimens of anti-angiogenic therapy; (vii) anti-PD-1/PD-L1 experienced advanced or metastatic non-uveal melanoma who have received no more than 2 previous regimens for metastatic disease; (viii) anti-PD-1/PD-L1 experienced relapsed/refractory DLBCL who have either progressed after or are not candidates for autologous stem cell transplant; (ix) anti-PD-1/PD-L1 experienced recurrent and/or metastatic HNSCC (irrespective of HPV status) with no curative options; (x) anti-PD-1/PD-L1 experienced locally advanced or metastatic CSCC not appropriate for surgery; or (xi) the patient has =1% LAG-3 expression in tumor tissue, wherein the tumor tissue comprises tumor cells and tumor-infiltrating immune cells.

29. The use of claim 1, wherein (a) comprises 350 mg or 700 mg anti-PD-1 antibody or antigen-binding fragment thereof; and (b) comprises 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof, wherein: (1) the patient has a tumor and has not received prior treatment with a PD-1 inhibitor or PD-L1 inhibitor; and (2) (a) and (b) are to be administered once every 3 weeks, or once every 6 weeks.

30. The use of claim 29, wherein the patient further has one or more of the following criteria: (i) ineligible for platinum based therapy, or who have had tumor progression or recurrence within 6 months of last dose of platinum therapy; (ii) confirmed diagnosis of malignancy; (iii) demonstrated progression of a tumor for which there is no available therapy likely to convey clinical benefit; (iv) anti-PD-1/PD-L1 naïve stage IIIB, IIIC, or IV NSCLC either without prior therapy for metastatic disease; (v) disease progression/recurrence after one platinum-containing regimen; (vi) anti-PD-1/PD-L1 naïve advanced or metastatic ccRCC with a clear cell component who had received no more than 2 previous regimens of anti-angiogenic therapy; (vii) anti-PD-1/PD-L1 naïve metastatic TNBC (estrogen, progesterone, and human epidermal growth factor receptor 2 negative) who have received 5 or fewer prior lines of therapy; (viii) anti-PD-1/PD-L1 naïve advanced or metastatic non-uveal melanoma who have received no more than 2 previous regimens for metastatic disease; (ix) anti-PD-1/PD-L1 naïve relapsed/refractory DLBCL who have either progressed after or are not candidates for autologous stem cell transplant; (x) anti-PD-1/PD-L1 naïve recurrent and/or metastatic HNSCC (irrespective of HPV status) with no curative options; (xi) anti-PD-1/PD-L1 naive locally advanced or metastatic CSCC not appropriate for surgery; or (xii) the patient has =1% LAG-3 expression in tumor tissue, wherein the tumor tissue comprises tumor cells and tumor-infiltrating immune cells.

31. The use of claim 1, wherein (a) comprises 350 mg or 700 mg anti-PD-1 antibody or antigen-binding fragment thereof , and (b) comprises 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof , wherein: (1) the patient has a tumor; and (2) (a) is to be administered as a monotherapy for about one month to about twelve months; then (a) in combination with (b) are to be administered once every 3 weeks, or once every 6 weeks.

32. The use of claim 1, wherein (a) comprises 350 mg or 700 mg anti-PD-1 antibody or antigen-binding fragment thereof; and (b) comprises 1600 mg anti-LAG3 antibody or antigen-binding fragment thereof, wherein: (1) (a) and (b) are to be administered in an initial loading dose; and (2) in one or more secondary doses, wherein the one or more secondary doses occur one to four weeks after the immediately preceding dose.

33. The use of claim 32, further comprising: (3) one or more tertiary doses, wherein the one or more tertiary doses occur three to twelve weeks after the immediately preceding dose.

34. The use of claim 32, wherein the one or more secondary doses occur three weeks after the immediately preceding dose.

35. The use of claim 33, wherein the one or more tertiary doses occur three weeks or six weeks after the immediately preceding dose.

36. The use of claim 32, wherein the initial loading dose comprises (a) 350 mg or 700 mg anti-PD-1 antibody or antigen-binding fragment thereof and (b) 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof.

37. The use of claim 32, wherein the one or more secondary doses comprise: (a) 350 mg anti-PD-1 antibody or antigen-binding fragment thereof and (b) 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof.

38. The use of claim 33, wherein the one or more tertiary doses comprise: (a) 350 mg anti-PD-1 antibody or antigen-binding fragment thereof and (b) 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof.

39. The use of claim 32, wherein the one or more secondary doses comprise: (a) 700 mg anti-PD-1 antibody or antigen-binding fragment thereof and (b) 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof.

40. The use of claim 33, wherein the one or more tertiary doses comprise: (a) 700 mg anti-PD-1 antibody or antigen-binding fragment thereof and (b) 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof.

41. The use of claim 32, wherein the cancer is selected from the group consisting of astrocytoma, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, clear cell renal cell carcinoma, colorectal cancer, microsatellite-intermediate colorectal cancer, cutaneous squamous cell carcinoma, diffuse large B-cell lymphoma, endometrial cancer, esophageal cancer, fibrosarcoma, gastric cancer, glioblastoma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatic cell carcinoma, leukemia, liver cancer, leiomyosarcoma, lung cancer, lymphoma, melanoma, mesothelioma, myeloma, nasopharyngeal cancer, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, primary and/or recurrent cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, squamous cell cancer, synovial sarcoma, thyroid cancer, triple negative breast cancer, uterine cancer, and Wilms’ tumor.

42. The use of any one of claims 32 to 41, wherein: the anti-PD-1 antibody or antigen-binding fragment thereof comprises the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: