Clinical methods for use of a PD-L1-binding molecule comprising a Shiga toxin effector
The present disclosure relates to PD-L1-binding molecules comprising a Shiga toxin effector region, a PD-L1-binding region, and a T cell epitope, and pharmaceutical compositions thereof. The PD-L1 binding molecules and pharmaceutical compositions thereof have uses for selectively killing specific cells (e.g., PD-L1 positive tumor cells and/or immune cells), for selectively delivering cargos to specific cells (e.g., PD-L1 positive tumor cells or immune cells), and as therapeutics for treating or slowing the progression of cancer (e.g., non-small cell lung cancer or squamous cell carcinoma of the head and neck). The present disclosure also relates to clinical methods for use of the disclosed PD-L1 binding molecules for treating a subject in need thereof.
1. A method for treating or slowing the progression of a solid tumor, the method comprising administering to a subject in need thereof an effective amount of a PD-L1 binding molecule, wherein the PD-L1 binding molecule comprises a polypeptide having the sequence of SEQ ID NO: 1;
wherein the PD-L1 binding molecule is administered at a dose of about 50 μg/kg, about 63 μg/kg, about 75 μg/kg, about 80 μg/kg, or about 85 μg/kg 1 μg/kg to about 200 μg/kg of the subject's body weight.
2. The method of claim 1 , wherein the solid tumor expresses PD-L1.
3. The method of claim 1 , wherein the PD-L1 binding molecule is administered weekly during a first 28-day cycle, wherein the PD-L1 binding molecule is administered on days 1, 8, 15, and 22 of the first 28-day cycle.
4. The method of claim 1 , wherein the PD-L1 binding molecule is administered two times during a first 28-day cycle, wherein the PD-L1 binding molecule is administered on days 1 and 15 of the first 28-day cycle.
5. The method of claim 1 , wherein the PD-L1 binding molecule is administered three times during a first 28-day cycle, wherein the PD-L1 binding molecule is administered on days 1, 8, and 15 of the first 28-day cycle.
6. The method of claim 3 , further comprising administering the PD-L1 binding molecule weekly during a second 28-day cycle following the first 28-day cycle, wherein the PD-L1 binding molecule is administered on days 1, 8, 15, and 22 of the second 28-day cycle.
7. The method of claim 3 , wherein the PD-L1 binding molecule is administered two times during a second 28-day cycle following the first 28-day cycle, wherein the PD-L1 binding molecule is administered on days 1 and 15 of the second 28-day cycle.
8. The method of claim 3 , wherein the PD-L1 binding molecule is administered three times during a second 28-day cycle, wherein the PD-L1 binding molecule is administered on days 1, 8, and 15 of the second 28-day cycle.
9. The method of claim 6 , wherein the PD-L1 binding molecule is administered at a dose of about 50 μg/kg, about 63 μg/kg, about 75 μg/kg, about 80 μg/kg, or about 85 μg/kg, about 90 μg/kg, about 95 μg/kg, about 100 μg/kg, about 125 #g/kg, or about 150 μg/kg of the subject's body weight during the second 28-day cycle.
10. The method of claim 6 , further comprising administering the PD-L1 binding molecule weekly during a third 28-day cycle following the first and second 28-day cycles, wherein the PD-L1 binding molecule is administered on days 1, 8, 15, and 22 of the third 28-day cycle.
11. The method of claim 6 , wherein the PD-L1 binding molecule is administered two times during a third 28-day cycle following the first and second 28-day cycles, wherein the PD-L1 binding molecule is administered on days 1 and 15 of the third 28-day cycle.
12. The method of claim 6 , wherein the PD-L1 binding molecule is administered three times during a third 28-day cycle following the first and second 28-day cycles, wherein the PD-L1 binding molecule is administered on days 1, 8, and 15 of the third 28-day cycle.
13. The method of claim 10 , wherein the PD-L1 binding molecule is administered at a dose of about 50 μg/kg, about 63 μg/kg, about 75 μg/kg, about 80 μg/kg, or about 85 μg/kg of the subject's body weight during the third 28-day cycle.
14. The method of claim 10 , further comprising administering the PD-L1 binding molecule for at least one additional 28-day cycle.
15. The method of claim 14 , wherein the PD-L1 binding molecule is administered at a dose of about 50 μg/kg, about 63 μg/kg, about 75 μg/kg, about 80 μg/kg, or about 85 μg/kg of the subject's body weight during the at least one additional 28-day cycle.
16. The method of claim 3 , wherein the dose of the PD-L1 binding molecule administered to the subject over one or more cycles is about 5 mg to about 100 mg.
17. The method of claim 3 , wherein the PD-L1 binding molecule is administered by intravenous infusion.
18. The method of claim 17 , wherein the intravenous infusion is over about 5 minutes to about 120 minutes.
19. The method of claim 18 , wherein the intravenous infusion is over about 30 minutes.
20. The method of claim 1 , wherein the solid tumor is squamous cell carcinoma of the head and neck.
21. The method of claim 1 , wherein the solid tumor is non-small cell lung cancer.
22. The method of claim 1 , wherein the solid tumor is unresectable, locally advanced, or metastatic.
23. The method of claim 1 , wherein the cancer is relapsed or refractory to treatment with at least one additional anti-cancer therapy.
24. The method of claim 23 , wherein the cancer is relapsed or refractory to treatment with at least one of ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, tremelimumab or cemiplimab.
25. The method of claim 23 , wherein the cancer is relapsed or refractory to a platinum-based therapy.
26. A method for treating or slowing the progression of non-small cell lung cancer, the method comprising administering to a subject in need thereof an effective amount of a PD-L1 binding molecule, wherein the PD-L1 binding molecule comprises a polypeptide having the sequence of SEQ ID NO: 1;
wherein the PD-L1 binding molecule is administered at a dose in the range of about 50 μg/kg, about 63 μg/kg, about 75 μg/kg, about 80 μg/kg, or about 85 μg/kg of the subject's body weight.
27. The method of claim 26 , wherein the non-small cell lung cancer expresses PD-L1.
28. A method for treating or slowing the progression of squamous cell carcinoma of the head and neck, the method comprising administering to a subject in need thereof an effective amount of a PD-L1 binding molecule, wherein the PD-L1 binding molecule comprises a polypeptide having the sequence of SEQ ID NO: 1;
wherein the PD-L1 binding molecule is administered at a dose in the range of about 50 μg/kg, about 63 μg/kg, about 75 μg/kg, about 80 μg/kg, or about 85 μg/kg of the subject's body weight.
29. The method of claim 28 , wherein the squamous cell carcinoma of the head and neck expresses PD-L1.
30. A method for treating or slowing the progression of a solid tumor that expresses PD-L1, the method comprising administering to a subject in need thereof an effective amount of a PD-L1 binding molecule, wherein the PD-L1 binding molecule comprises a polypeptide having the sequence of SEQ ID NO: 1;
wherein the PD-L1 binding molecule is administered at a dose in the range of about 50 μg/kg, about 63 μg/kg, about 75 μg/kg, about 80 μg/kg, or about 85 μg/kg of the subject's body weight.
31. A method of treating or slowing the progression of a solid tumor that expresses PD-L1, the method comprising screening the subject for an HLA: A*02 haplotype and treating the subject that is positive for the HLA: A*02 haplotype with a PD-L1 binding molecule comprising a polypeptide having the sequence of SEQ ID NO: 1;
wherein the PD-L1 binding molecule is administered at a dose in the range of about 50 μg/kg, about 63 μg/kg, about 75 μg/kg, about 80 μg/kg, or about 85 μg/kg of the subject's body weight.
32. A method of treating or slowing the progression of a solid tumor, wherein the method comprises administering to a subject in need thereof an effective amount of a PD-L1 binding molecule, wherein the PD-L1 binding molecule comprises a polypeptide having the sequence of SEQ ID NO: 1;
wherein the PD-L1 binding molecule is administered at a dose in the range of about 50 μg/kg, about 63 μg/kg, about 75 μg/kg, about 80 μg/kg, or about 85 μg/kg of the subject's body weight; and/or
wherein prior to administration of the PD-L1 binding molecule, PD-L1 expression is detected on cells isolated or derived from the solid tumor; and/or
wherein prior to administration of the PD-L1 binding molecule, the subject is screened for an HLA: A*02 haplotype.
33. A method of treating or slowing the progression of a solid tumor, wherein the method comprises administering to a subject in need thereof an effective amount of a PD-L1 binding molecule, wherein the PD-L1 binding molecule comprises a polypeptide having the sequence of SEQ ID NO: 1;
wherein the PD-L1 binding molecule is administered at a dose in the range of about 50 μg/kg, about 63 μg/kg, about 75 μg/kg, about 80 μg/kg, or about 85 μg/kg of the subject's body weight; and
wherein prior to administration of the PD-L1 binding molecule, PD-L1 expression is detected on cells isolated or derived from the solid tumor.
34. The method of claim 33 , wherein prior to administration of the PD-L1 binding molecule, the subject is screened for an HLA: A*02 haplotype or the subject is screened for cytomegalovirus (CMV).
35. A method of treating or slowing the progression of a solid tumor, wherein the method comprises administering to a subject in need thereof an effective amount of a PD-L1 binding molecule, wherein the PD-L1 binding molecule comprises a polypeptide having the sequence of SEQ ID NO: 1;
wherein the PD-L1 binding molecule is administered at a dose in the range of about 50 μg/kg, about 63 μg/kg, about 75 μg/kg, about 80 μg/kg, or about 85 μg/kg 1 μg/kg to about 200 #g/kg of the subject's body weight; and
wherein prior to administration of the PD-L1 binding molecule, the subject is screened for CMV.
36. The method of claim 35 , wherein prior to administration of the PD-L1 binding molecule, the subject is screened for an HLA: A*02 haplotype or PD-L1 expression is detected on cells isolated or derived from the solid tumor.
37. The method of claim 1 , wherein the PD-L1 binding molecule is administered at a dose of about 63 μg/kg of the subject's body weight.
38. The method of claim 1 , A method for treating or slowing the progression of a solid tumor, the method comprising administering to a subject in need thereof an effective amount of a PD-L1 binding molecule, wherein the PD-L1 binding molecule comprises a polypeptide having the sequence of SEQ ID NO: 1;
wherein the PD-L1 binding molecule is administered at a dose of about 83 μg/kg of the subject's body weight.
39. The method of claim 26 , wherein the PD-L1 binding molecule is administered at a dose of about 63 μg/kg of the subject's body weight.
40. The method of claim 28 , wherein the PD-L1 binding molecule is administered at a dose of about 63 μg/kg of the subject's body weight.
41. The method of claim 3 , wherein the dose of the PD-L1 binding molecule administered to the subject over the first 28-day cycle is about 1 mg.