Combination of pd-1 inhibitors and lag-3 inhibitors for enhanced efficacy in treating melanoma
Combining LAG-3 and PD-1 inhibitors addresses the limitations of single-agent immunotherapy for melanoma by enhancing tumor growth inhibition through a synergistic immune response.
Patent Information
- Application Number
- HK62026124241
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-03-13
- Filing Date
- 2026-06-02
- Publication Date
- 2026-07-31
AI Technical Summary
Current treatments for melanoma are inadequate in effectively inhibiting tumor growth, particularly when using single-agent immunotherapy with PD-1 or LAG-3 inhibitors.
Combining a LAG-3 inhibitor with a PD-1 inhibitor, such as anti-PD-1 antibodies or their antigen-binding fragments, to enhance the therapeutic efficacy in treating melanoma.
The combination therapy significantly enhances the inhibition of melanoma growth by synergistically leveraging the immune response, providing a more effective treatment approach.
Smart Images
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Abstract
Description
Abstract This disclosure provides a method for treating or inhibiting melanoma growth, comprising selecting a patient with melanoma and administering a combination of a LAG-3 inhibitor and a PD-1 inhibitor (e.g., an anti-PD-1 antibody or its antigen-binding fragment). In some embodiments, the administration of the PD-1 inhibitor enhances the efficacy of the LAG-3 inhibitor (e.g., an anti-LAG-3 antibody or its antigen-binding fragment) in inhibiting melanoma growth.
Claims
We claim:1 . A method of treating melanoma or inhibiting the growth of a melanoma comprising administering to a subject in need thereof a therapeutically effective amount each of (a) an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1 ); and (b) an antibody or antigen-binding fragment thereof that specifically binds lymphocyte activation gene-3 (LAG-3), wherein the melanoma is unresectable locally advanced melanoma, unresectable metastatic melanoma, or completely resected high-risk melanoma.
2. The method of claim 1 , wherein one dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 50 to 1500 mg.
3. The method of claim 1 or 2, wherein one dose of the anti-PD-1 antibody or antigenbinding fragment thereof comprises 350mg.
4. The method of any one of claims 1 to 3, wherein one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises between 50 to 8000 mg.
5. The method of any one of claims 1 to 4, wherein one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg.
6. The method of any one of claims 1 to 4, wherein one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 1600 mg.
7. The method of any one of claims 1 to 6, wherein the anti-LAG-3 antibody or antigenbinding fragment thereof is administered prior to, concurrent with or after the anti-PD-1 antibody or antigen-binding fragment thereof.
8. The method of claim 7, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof is administered prior to the anti-PD-1 antibody or antigen-binding fragment thereof.
9. The method of claim 7, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof is administered the same day as the anti-PD-1 antibody or antigen-binding fragment thereof.
10. The method of any one of claims 1 to 9, wherein two or more doses of the anti-LAG- 3 antibody or antigen-binding fragment thereof are administered in combination with two or more doses of the anti-PD-1 antibody or antigen-binding fragment thereof.11 . The method of claim 10, wherein each dose of the anti-PD-1 antibody or antigenbinding fragment thereof comprises 350 mg.
12. The method of claim 10 or 11 , wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises between 50 and 8000 mg.
13. The method of any one of claims 10 to 12, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 1600 mg.
14. The method of any one of claims 10 to 12, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg.
15. The method of claim 10, wherein each dose of the anti-PD-1 antibody or antigenbinding fragment thereof comprises 200 mg, 250 mg or 350 mg and each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg, 800 mg, 1000 mg, 1400 mg, or 1600 mg.
16. The method of any one of claims 10 to 15, wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately preceding dose.
17. The method of any one of claims 10 to 16, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately preceding dose.
18. The method of any one of claims 10 to 17, wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in six weeks.
19. The method of any one of claims 10 to 18, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once in six weeks.
20. The method of any one of claims 10 to 17, wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in three weeks.21 . The method of any one of claims 10 to 18 or 20, wherein each dose of the anti-LAG- 3 antibody or antigen-binding fragment thereof is administered once in three weeks.
22. The method of any one of claims 1 to 21 , wherein the antibodies are administered intravenously, subcutaneously, or intraperitoneally.
23. The method of any one of claims 1 to 22, wherein the melanoma is unresectable locally advanced melanoma.
24. The method of any one of claims 1 to 22, wherein the melanoma is unresectable metastatic melanoma.
25. The method of claim 23 or 24, wherein the patient is further selected as having one or more of the following criteria:(i) at least 12 years of age on the date of providing informed consent;(ii) either stage IIC, III, or stage IV per AJCC 8th edition (Amin, 2017) and have histologically confirmed melanoma that is completely surgically resected;(iii) patients with stage II IA disease must have at least 1 lymph node micrometastasis measuring >1 mm in greatest diameter;(iv) Stage IIC melanoma confirmed by a pathologically negative Sentinel lymph node biopsy (SLNB) specimen and no evidence of regional or distant metastasis;(v) complete surgical resection performed within 12 weeks prior to treatment, and treatment may occur only after satisfactory wound healing from the surgery;(vi) disease-free status as documented by a complete physical examination and imaging studies prior to treatment;(vii) patient shows >1% LAG3 in the tumor tissue as determined by IHC or iPET ; and(viii) patients must not have received systemic anti-cancer therapy or radiation therapy for melanoma in the previous 5 years.
26. The method of any one of claims 1 to 22, wherein the melanoma is completely resected high-risk melanoma.
27. The method of claim 26, wherein the patient is further selected as having one or more of the following criteria:(1) >12 years of age;(2) Stage lie, III or IV (all M-stages) and histologically confirmed melanoma, completely resected < 12 weeks prior to treatment;(3) no prior systemic anti-cancer therapy or radiation therapy for melanoma in the previous 5 years;(4) shows >1% LAG3 in the tumor tissue as determined by IHC or iPET;(5) no evidence of metastatic disease; and(6) an Eastern Cooperative Oncology Group performance status (PS) of 0 or 1 (for adult pts), Karnofsky PS >70 (pts >16 years) or Lansky PS >70 (pts <16 years).
28. The method of any one of claims 1 to 27, wherein the treatment produces a therapeutic effect selected from the group consisting of delay in melanoma growth, reduction in melanoma cell number, melanoma regression, increase in survival, partial response, and complete response.
29. The method of claim 28, wherein melanoma growth is delayed by at least 10 days as compared to an untreated subject.
30. The method of claim 28, wherein the melanoma growth is inhibited by at least 50% as compared to an untreated subject.31 . The method of claim 28, wherein the melanoma growth is inhibited by at least 20% as compared to a subject administered with either antibody as monotherapy.
32. The method of any one of claims 1 to 31 further comprising administering to the subject an additional therapeutic agent or therapy, wherein the additional therapeutic agent or therapy is selected from the group consisting of radiation, surgery, achemotherapeutic 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 (TGF|3) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an antibody to a tumor-specific antigen, Bacillus Calmette-Guerin vaccine, granulocytemacrophage 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 4-1 BB agonist, CD20xCD3 bispecific antibody, MUC16xCD3 bispecific antibody, and an antiinflammatory drug.
33. The method of any one of claims 1 to 32, wherein the anti-PD-1 antibody or antigenbinding fragment thereof comprises the 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 HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.
34. The method of claim 33, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 1 and the LCVR comprises the amino acid sequence of SEQ ID NO: 2.
35. The method of any one of claims 1 to 34, wherein the anti-PD-1 antibody 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: 10.
36. The method of any one of claims 1 to 35, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the heavy chain CDRs (HCDR1 , HCDR2 and HCDR3) of a HCVR and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) of a LCVR, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; LCDR1 comprises the amino acid sequence of SEQID NO: 16; LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 18.
37. The method of claim 36, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 11 and the LCVR comprises the amino acid sequence of SEQ ID NO: 12.
38. The method of any one of claims 1 to 37, 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.
39. The method of any one of claims 1 to 38, wherein the inhibition is more efficacious than administration of either antibody as a monotherapy.
40. A method of treating melanoma or inhibiting the growth of melanoma comprising:(1) selecting a patient with melanoma, wherein the patient has unresectable locally advanced melanoma, unresectable metastatic melanoma, or completely resected high-risk melanoma; and(2) administering to the patient (a) 350 mg anti-PD-1 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2; and (b) 400 mg or 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 11 / 12.41 . The method of claim 40, wherein the administering of step (2) occurs once every 3 weeks.
42. The method of claim 40, wherein the administering of step (2) occurs once every 6 weeks.
43. The method of claim 40, wherein the patient is further selected as having one or more of the following criteria:(1) >12 years of age;(2) Stage lie, III or IV (all M-stages) and histologically confirmed melanoma, completely resected < 12 weeks prior to treatment;(3) no prior systemic anti-cancer therapy or radiation therapy for melanoma in the previous 5 years;(4) no evidence of metastatic disease; and(5) an Eastern Cooperative Oncology Group performance status (PS) of 0 or 1 (for adult pts), Karnofsky PS >70 (pts >16 years) or Lansky PS >70 (pts <16 years).
44. A method of treating melanoma or inhibiting the growth of melanoma comprising:(1) selecting a patient with an unresectable locally advanced melanoma, unresectable metastatic melanoma, or completely resected high-risk melanoma, wherein the selected patient has not received prior systemic treatment for advanced disease; and(2) administering to the patient (a) 350 mg anti-PD-1 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2; and (b) 400 mg or 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 11 / 12.
45. The method of claim 44, wherein the administering of step (2) occurs once every 3 weeks.
46. The method of claim 44, wherein the administering of step (2) once every 6 weeks.
47. The method of claim 44, wherein the patient is further selected as having one or more of the following criteria:(1) >12 years of age;(2) Stage lie, III or IV (all M-stages) and histologically confirmed melanoma, completely resected < 12 weeks prior to treatment;(3) no prior systemic anti-cancer therapy or radiation therapy for melanoma in the previous 5 years;(4) no evidence of metastatic disease on staging investigations; and(5) an Eastern Cooperative Oncology Group performance status (PS) of 0 or 1 (for adult pts), Karnofsky PS >70 (pts >16 years) or Lansky PS >70 (pts <16 years).
48. A method of treating melanoma or inhibiting the growth of melanoma comprising:(1) selecting a patient with a melanoma; and(2) administering to the patient (a) 400 mg or 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pairof SEQ ID NOs: 11 / 12 in combination with (a), (b) 350 mg anti-PD-1 antibody or antigenbinding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2.
49. The method of claim 48, wherein the step of administering occurs once every 3 weeks.
50. The method of claim 48, wherein the step of administering occurs once every 6 weeks.51 . A method of treating melanoma or inhibiting the growth of melanoma comprising:(a) selecting a patient with melanoma wherein the patient has completed surgery to treat the melanoma; and(b) administering to the patient:(1) an initial loading dose comprising an anti-PD-1 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2; and an anti-LAG-3 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 11 / 12; and(2) one or more secondary doses, wherein the one or more secondary doses occur one to four weeks after the immediately preceding dose.
52. The method of claim 51 , wherein the patient shows > 1% of more LAG3 in the melanoma tissue.
53. The method of claim 51 , wherein the patient is diagnosed with Stage IV melanoma.
54. The method of claim 51 , wherein the patient is further selected as having one or more of the following criteria:(1) >12 years of age;(2) Stage lie, III or IV (all M-stages) and histologically confirmed melanoma, completely resected < 12 weeks prior to treatment;(3) no prior systemic anti-cancer therapy or radiation therapy for melanoma in the previous 5 years;(4) shows >1% LAG3 in the tumor tissue as determined by IHC or iPET;(5) no evidence of metastatic disease; and(6) an Eastern Cooperative Oncology Group performance status (PS) of 0 or 1 (for adult pts), Karnofsky PS >70 (pts >16 years) or Lansky PS >70 (pts <16 years).
55. The method of claim 51 , further comprising administering to a patient in need thereof:(3) one or more tertiary doses, wherein the one or more tertiary doses occur three to twelve weeks after the immediately preceding dose.
56. The method of claim 51 , wherein the one or more secondary doses occur three weeks after the immediately preceding dose.
54. The method of claim 55, wherein the one or more tertiary doses occur three weeks or six weeks after the immediately preceding dose.
58. The method of claim 51 , wherein the initial loading dose comprises (a) 500 mg to 1500 mg anti-PD-1 antibody or antigen-binding fragment thereof and (b) 50 mg to 8000 mg anti-LAG-3 antibody or antigen-binding fragment thereof.
59. The method of claim 51 , wherein the one or more secondary doses comprise: (a) 350 mg anti-PD-1 antibody or antigen-binding fragment thereof and (b) 400 mg, 800 mg, 1000 mg, 1400 mg, 1600mg or 2000 mg anti-LAG-3 antibody or antigen-binding fragment thereof.
60. The method of claim 55, wherein the one or more tertiary doses comprise: (a) 350 mg anti-PD-1 antibody or antigen-binding fragment thereof and (b) 400 mg, 800 mg, 1000 mg, 1400 mg, 1600mg or 2000 mg anti-LAG-3 antibody or antigen-binding fragment thereof.