A pharmaceutical composition of an immunocytokine comprising a heterodimeric protein complex based on IL-15 / IL-15Rα

Claims

1. A pharmaceutical composition comprising: a. larnefpendekin alpha; b. buffer; c. stabilizer; d. Surfactants; e. water.

2. The pharmaceutical composition according to claim 1, wherein larnefpendecine alpha is in a concentration of 0.01 mg / ml to 10.0 mg / ml.

3. The pharmaceutical composition according to claim 2, wherein larnefpendecine alfa is in a concentration of from 0.01 mg / ml to 6.0 mg / ml, or from 0.05 mg / ml to 6.0 mg / ml, or from 0.05 mg / ml to 5.0 mg / ml, or from 0.1 mg / ml to 4.0 mg / ml, or from 0.2 mg / ml to 3.0 mg / ml, or from 0.2 mg / ml to 2.0 mg / ml, or from 0.3 mg / ml to 1.5 mg / ml, or from 0.3 mg / ml to 1.0 mg / ml, or from 0.4 mg / ml to 0.6 mg / ml, or from 0.45 mg / ml to 0.55 mg / ml, or from 4.0 mg / ml to 6.0 mg / ml, or from 6.0 mg / ml to 8.0 mg / ml, or from 8.0 mg / ml to 10.0 mg / ml.

4. The pharmaceutical composition according to claim 3, wherein larnefpendecine alfa is at a concentration of 0.01 mg / ml, or 0.05 mg / ml, or 0.1 mg / ml, or 0.2 mg / ml, or 0.3 mg / ml, or 0.4 mg / ml, or 0.5 mg / ml, or 0.6 mg / ml, or 0.7 mg / ml, or 0.8 mg / ml, or 0.9 mg / ml, or 1.0 mg / ml, or 1.1 mg / ml, or 1.2 mg / ml, or 1.3 mg / ml, or 1.4 mg / ml, or 1.5 mg / ml, or 1.6 mg / ml, or 1.7 mg / ml, or 1.8 mg / ml, or 1.9 mg / ml, or 2.0 mg / ml, or 2.5 mg / ml, or 3.0 mg / ml, or 3.5 mg / ml, or 4.0 mg / ml, or 4.5 mg / ml, or 4.6 mg / ml, or 4.7 mg / ml, or 4.8 mg / ml, or 4.9 mg / ml, or 5.0 mg / ml, or 5.5 mg / ml, or 6.0 mg / ml, or 6.5 mg / ml, or 7.0 mg / ml, or 7.5 mg / ml, or 8.0 mg / ml, or 8.5 mg / ml, or 9.0 mg / ml, or 9.5 mg / ml, or 10.0 mg / ml.

5. The pharmaceutical composition according to claim 1, wherein the buffer is a phosphate buffer.

6. The pharmaceutical composition according to claim 5, wherein the phosphate buffer consists of disodium hydrogen phosphate dihydrate and sodium dihydrogen phosphate dihydrate.

7. The pharmaceutical composition according to claim 6, wherein disodium hydrogen phosphate dihydrate is in a concentration of 0.1 mg / ml to 8.0 mg / ml.

8. The pharmaceutical composition according to claim 7, wherein disodium hydrogen phosphate dihydrate is in a concentration of from 0.1 mg / ml to 4.0 mg / ml, or from 0.1 mg / ml to 3.0 mg / ml, or from 0.1 mg / ml to 2.0 mg / ml, or from 0.1 mg / ml to 1.5 mg / ml, or from 0.3 mg / ml to 1.2 mg / ml, or from 0.4 mg / ml to 1.1 mg / ml, or from 0.5 mg / ml to 1.0 mg / ml, or from 0.6 mg / ml to 0.9 mg / ml, or from 0.7 mg / ml to 0.8 mg / ml, or from 0.1 mg / ml to 0.2 mg / ml, or from 0.2 mg / ml to 1.0 mg / ml, or from 1.0 mg / ml to 2.0 mg / ml, or from 2.0 mg / ml to 3.0 mg / ml, or from 3.0 mg / ml to 4.0 mg / ml, or from 4.0 mg / ml to 5.0 mg / ml, or from 5.0 mg / ml to 6.0 mg / ml, or from 6.0 mg / ml to 7.0 mg / ml, or from 7.0 mg / ml to 8.0 mg / ml.

9. The pharmaceutical composition according to claim 8, wherein disodium hydrogen phosphate dihydrate is at a concentration of 0.1 mg / ml, or 0.185 mg / ml, or 0.2 mg / ml, or 0.3 mg / ml, or 0.4 mg / ml, or 0.5 mg / ml, or 0.6 mg / ml, or 0.7 mg / ml, or 0.74 mg / ml, or 0.741 mg / ml, or 0.742 mg / ml, or 0.743 mg / ml, or 0.744 mg / ml, or 0.745 mg / ml, or 0.8 mg / ml, or 0.9 mg / ml, or 1.0 mg / ml, or 1.1 mg / ml, or 1.2 mg / ml, or 1.296 mg / ml, or 1.3 mg / ml, or 1.4 mg / ml, or 1.5 mg / ml, or 2.0 mg / ml, or 2.5 mg / ml, or 2.542 mg / ml, or 3.0 mg / ml, or 3.5 mg / ml, or 4.0 mg / ml, or 4.5 mg / ml, or 5.0 mg / ml, or 5.5 mg / ml, or 6.0 mg / ml, or 6.5 mg / ml, or 7.0 mg / ml, or 7.5 mg / ml, or 7.837 mg / ml, or 8.0 mg / ml.

10. The pharmaceutical composition according to claim 6, wherein sodium dihydrogen phosphate dihydrate is in a concentration of 0.05 mg / ml to 4.5 mg / ml.

11. The pharmaceutical composition according to claim 10, wherein sodium dihydrogen phosphate dihydrate is in a concentration of from 0.05 mg / ml to 3.5 mg / ml, or from 0.05 mg / ml to 2.0 mg / ml, or from 0.05 mg / ml to 1.0 mg / ml, or from 0.05 mg / ml to 0.8 mg / ml, or from 0.1 mg / ml to 0.4 mg / ml, or from 0.1 mg / ml to 0.2 mg / ml, or from 0.5 mg / ml to 1.0 mg / ml, or from 1.0 mg / ml to 2.0 mg / ml, or from 2.0 mg / ml to 3.0 mg / ml, or from 3.0 mg / ml to 4.0 mg / ml, or from 4.0 mg / ml to 4.5 mg / ml.

12. The pharmaceutical composition according to claim 11, wherein sodium dihydrogen phosphate dihydrate is at a concentration of 0.05 mg / ml, or 0.1 mg / ml, or 0.114 mg / ml, or 0.12 mg / ml, or 0.125 mg / ml, or 0.126 mg / ml, or 0.127 mg / ml, or 0.128 mg / ml, or 0.129 mg / ml, or 0.13 mg / ml, or 0.2 mg / ml, or 0.3 mg / ml, or 0.4 mg / ml, or 0.5 mg / ml, or 0.595 mg / ml, or 0.6 mg / ml, or 0.7 mg / ml, or 0.796 mg / ml, or 0.8 mg / ml, or 0.9 mg / ml, or 1.0 mg / ml, or 1.1 mg / ml, or 1.2 mg / ml, or 1.3 mg / ml, or 1.4 mg / ml, or 1.451 mg / ml, or 1.5 mg / ml, or 2.0 mg / ml, or 3.0 mg / ml, or 3.5 mg / ml, or 4.0 mg / ml, or 4.162 mg / ml, or 4.5 mg / ml.

13. The pharmaceutical composition according to claim 5, wherein the phosphate buffer is in a concentration of 1 mM to 35 mM.

14. The pharmaceutical composition according to claim 13, wherein the phosphate buffer is at a concentration of 1 mM to 25 mM, or 1 mM to 20 mM, or 1 mM to 15 mM, or 1 mM to 10 mM, or 2 mM to 8 mM, or 3 mM to 7 mM, or 4 mM to 6 mM, or 4.5 mM to 5.5 mM, or 10 mM to 20 mM, or 20 mM to 35 mM.

15. The pharmaceutical composition according to claim 14, wherein the phosphate buffer at a concentration of 1 mM, or 2 mM, or 3 mM, or 4 mM, or 5 mM, or 6 mM, or 7 mM, or 8 mM, or 9 mM, or 10 mM, or 11 mM, or 12 mM, or 13 mM, or 14 mM, or 15 mM, or 16 mM, or 17 mM, or 18 mM, or 19 mM, or 20 mM, or 21 mM, or 22 mM, or 23 mM, or 24 mM, or 25 mM, or 26 mM, or 27 mM, or 28 mM, or 29 mM, or 30 mM, or 31 mM, or 32 mM, or 33 mM, or 34 mM, or 35 mM.

16. The pharmaceutical composition according to claim 1, wherein the stabilizer is an amino acid and / or a polyol.

17. The pharmaceutical composition according to claim 16, wherein the stabilizer is methionine or sorbitol, or a combination thereof.

18. The pharmaceutical composition according to claim 17, wherein the methionine is L-Methionine.

19. The pharmaceutical composition according to claim 17, wherein the sorbitol is D(-)-sorbitol.

20. The pharmaceutical composition according to claim 18, wherein L-Methionine is in a concentration of 1.0 mg / ml to 3.5 mg / ml.

21. The pharmaceutical composition according to claim 20, wherein L-Methionine is in a concentration of 1.0 mg / ml to 3.0 mg / ml, or 1.5 mg / ml to 3.0 mg / ml, or 2.0 mg / ml to 2.5 mg / ml, or 1.0 mg / ml to 2.0 mg / ml, or 2.5 mg / ml to 3.5 mg / ml.

22. The pharmaceutical composition according to claim 21, wherein L-methionine is at a concentration of 1.0 mg / ml, or 1.5 mg / ml, or 1.57 mg / ml, or 2.0 mg / ml, or 2.1 mg / ml, or 2.2 mg / ml, or 2.21 mg / ml, or 2.22 mg / ml, or 2.23 mg / ml, or 2.24 mg / ml, or 2.25 mg / ml, or 2.26 mg / ml, or 2.27 mg / ml, or 2.28 mg / ml, or 2.29 mg / ml, or 2.3 mg / ml, or 2.4 mg / ml, or 2.5 mg / ml, or 2.91 mg / ml, or 3.0 mg / ml, or 3.5 mg / ml.

23. The pharmaceutical composition according to claim 19, wherein D(-)-sorbitol is in a concentration of 20 mg / ml to 80 mg / ml.

24. The pharmaceutical composition according to claim 23, wherein D(-)-sorbitol is in a concentration of 30 mg / ml to 70 mg / ml, or 40 mg / ml to 60 mg / ml, or 45 mg / ml to 55 mg / ml, or 48 mg / ml to 52 mg / ml, or 30 mg / ml to 45 mg / ml, or 55 mg / ml to 70 mg / ml, or 70 mg / ml to 80 mg / ml.

25. The pharmaceutical composition according to claim 24, wherein D(-)-sorbitol is at a concentration of 20 mg / ml, or 25 mg / ml, or 30 mg / ml, or 35 mg / ml, or 40 mg / ml, or 45 mg / ml, or 46 mg / ml, or 47 mg / ml, or 48 mg / ml, or 49 mg / ml, or 50 mg / ml, or 51 mg / ml, or 52 mg / ml, or 53 mg / ml, or 54 mg / ml, or 55 mg / ml, or 60 mg / ml, or 65 mg / ml, or 70 mg / ml, or 75 mg / ml, or 80 mg / ml.

26. The pharmaceutical composition according to claim 1, wherein the surfactant can be a non-ionic or ionic surfactant.

27. The pharmaceutical composition according to claim 26, wherein the non-ionic surfactant may be poloxamer 188, or polysorbate 20, or polysorbate 80.

28. The pharmaceutical composition according to claim 27, wherein poloxamer 188 is in a concentration of 0.1 mg / ml to 3.0 mg / ml.

29. The pharmaceutical composition according to claim 28, wherein poloxamer 188 is in a concentration of 0.1 mg / ml to 2.0 mg / ml, or 0.5 mg / ml to 1.5 mg / ml, or 0.8 mg / ml to 1.2 mg / ml, or 2.0 mg / ml to 3.0 mg / ml.

30. The pharmaceutical composition according to claim 29, wherein poloxamer 188 is at a concentration of 0.1 mg / ml, or 0.5 mg / ml, or 0.6 mg / ml, or 0.7 mg / ml, or 0.8 mg / ml, or 0.9 mg / ml, or 0.95 mg / ml, or 1.0 mg / ml, or 1.05 mg / ml, or 1.1 mg / ml, or 1.2 mg / ml, or 1.3 mg / ml, or 1.4 mg / ml, or 1.5 mg / ml, or 2.0 mg / ml, or 2.5 mg / ml, or 3.0 mg / ml.

31. The pharmaceutical composition according to claim 1, wherein the pH is from 4.5 to 8.

5.

32. The pharmaceutical composition according to claim 31, wherein the pH is from 5.0 to 8.5, or from 5.5 to 8.5, or from 6.0 to 8.0, or from 7.0 to 8.0, or from 4.5 to 6.0, or from 8.0 to 8.

5.

33. The pharmaceutical composition according to claim 32, where the pH is 4.5, or 5.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5 , or 8.0, or 8.

5.

34. The pharmaceutical composition according to claim 1, which is larnefpendekin alpha 0.01–10.0 mg / ml disodium hydrophosphate dihydrate 0.1–8.0 mg / ml sodium dihydrophosphate dihydrate 0.05–4.5 mg / ml D(-)-Sorbitol 20–80 mg / mL Surfactant 0.1–3.0 mg / ml L-Methionine 1.0–3.5 mg / mL 35. The pharmaceutical composition according to claim 34, which is larnefpendekin alpha 0.01–10.0 mg / ml disodium hydrophosphate dihydrate 0.1–8.0 mg / ml sodium dihydrophosphate dihydrate 0.05–4.5 mg / mL D(-)-Sorbitol 20–80 mg / mL poloxamer 188 0.1–3.0 mg / ml L-Methionine 1.0–3.5 mg / mL 36. The pharmaceutical composition according to claim 35, which is larnefpendekin alpha 0.05–5.0 mg / ml disodium hydrophosphate dihydrate 0.1–4.0 mg / mL sodium dihydrophosphate dihydrate 0.05–3.0 mg / ml D(-)-Sorbitol 30–70 mg / mL poloxamer 188 0.1–2.5 mg / ml L-Methionine 1.0–3.0 mg / mL 37. The pharmaceutical composition according to claim 36, which is larnefpendekin alpha 0.1–3.0 mg / mL disodium hydrophosphate dihydrate 0.2–2.0 mg / ml sodium dihydrophosphate dihydrate 0.05–2.0 mg / ml D(-)-Sorbitol 35–65 mg / mL poloxamer 188 0.1–2.0 mg / ml L-Methionine 1.5–2.5 mg / ml 38. The pharmaceutical composition according to claim 37, which is larnefpendekin alpha 0.1–1.0 mg / mL disodium hydrophosphate dihydrate 0.3–1.0 mg / mL sodium dihydrophosphate dihydrate 0.05–1.0 mg / ml D(-)-Sorbitol 40–60 mg / ml poloxamer 188 0.5–1.5 mg / mL L-Methionine 1.8–2.5 mg / ml 39. The pharmaceutical composition according to claim 38, which is larnefpendekin alpha 0.4–0.6 mg / mL disodium hydrophosphate dihydrate 0.7–0.8 mg / ml sodium dihydrophosphate dihydrate 0.09–0.15 mg / ml D(-)-Sorbitol 45–55 mg / ml poloxamer 188 0.9–1.1 mg / mL L-Methionine 2.0–2.4 mg / mL 40. The pharmaceutical composition according to claim 39, which is larnefpendekin alpha 0.5 mg mL disodium hydrophosphate dihydrate 0.743 mg mL sodium dihydrophosphate dihydrate 0.129 mg mL D(-)-Sorbitol 50 mg / ml poloxamer 188 1 mg / mL L-Methionine 2.24 mg mL 41. The pharmaceutical composition according to claim 40, which is larnefpendekin alpha 0.5 mg mL disodium hydrophosphate dihydrate 0.743 mg mL sodium dihydrophosphate dihydrate 0.129 mg mL D(-)-Sorbitol 50 mg / mL poloxamer 188 1 mg / mL L-Methionine 2.24 mg mL water 1 mL 42. The pharmaceutical composition according to claim 41, which is larnefpendekin alpha 0.5 mg mL disodium hydrophosphate dihydrate 0.743 mg mL sodium dihydrophosphate dihydrate 0.129 mg mL D(-)-Sorbitol 50 mg / ml poloxamer 188 1 mg / mL L-Methionine 2.24 mg mL per 1 ml or larnefpendekin alpha 0.5 mg mL disodium hydrophosphate dihydrate 0.743 mg sodium dihydrophosphate dihydrate 0.129 mg D(-)-Sorbitol 50 mg poloxamer 188 1 mg L-Methionine 2.24 mg per 1 ml 43. The pharmaceutical composition according to item 1 contains per 1 ml of solution: larnefpendecine alpha 0.5 mg / ml, disodium hydrogen phosphate dihydrate 0.743 mg, sodium dihydrogen phosphate dihydrate 0.129 mg, D(-)-Sorbitol 50 mg, poloxamer 188 1.0 mg, L-Methionine 2.24 mg, water for injection up to 1 ml.

44. A pharmaceutical composition according to paragraphs 1-43, intended for parenteral administration.

45. A pharmaceutical composition according to paragraphs 1-43, intended for intravenous, intramuscular, subcutaneous or intravesical administration.

46. ​​The pharmaceutical composition according to claims 1-43 for stimulating the activation and / or proliferation of IL-15Rbeta / gamma-positive cells.

47. A method of treating a disease or disorder with a pharmaceutical composition according to claims 1-43.

48. The method of claim 47, wherein the disease or disorder is an oncological or autoimmune disease.

49. Method according to paragraph48, where the cancer is bladder cancer, prostate cancer, kidney cancer, HNSCC (head and neck squamous cell carcinoma), melanoma, carcinoma, Merkel cell carcinoma, hepatocellular carcinoma, esophageal cancer, cervical cancer, ovarian cancer, breast cancer, TNBC (triple-negative breast cancer), glioblastoma, NSCLC (non-small cell lung cancer), small cell lung cancer, CRC (colorectal cancer), MSI CRC (microsatellite instability-high colorectal cancer), colorectal cancer, leukemia, acute leukemia, myeloid leukemia, T- and B-cell acute lymphoblastic leukemia, lymphoma, Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, follicular lymphoma, marginalized B-cell lymphoma zones, diffuse large B-cell lymphoma, multiple myeloma, sarcoma, acute myeloid leukemia, high-risk myelodysplastic syndrome, pancreatic cancer, cancer of unknown origin.

50. Use of a pharmaceutical composition according to paragraphs 1-43 for the treatment of a disease or disorder.

51. The use according to claim 50, wherein the disease or disorder is an oncological or autoimmune disease.

52. Application under paragraph51, where the cancer is bladder cancer, prostate cancer, renal cancer, HNSCC (head and neck squamous cell carcinoma), melanoma, carcinoma, Merkel cell carcinoma, hepatocellular carcinoma, esophageal cancer, cervical cancer, ovarian cancer, breast cancer, TNBC (triple-negative breast cancer), glioblastoma, NSCLC (non-small cell lung cancer), small cell lung cancer, CRC (colorectal cancer), MSI CRC (microsatellite instability-high colorectal cancer), colorectal cancer, leukemia, acute leukemia, myeloid leukemia, T- and B-cell acute lymphoblastic leukemia, lymphoma, Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, follicular lymphoma, marginalized B-cell lymphoma zones, diffuse large B-cell lymphoma, multiple myeloma, sarcoma, acute myeloid leukemia, high-risk myelodysplastic syndrome, pancreatic cancer, cancer of unknown origin.