Antibody-based formulations

Claims

1. A lyophilized pharmaceutical formulation for treating a disease or disorder involving CD38 expression, obtained by lyophilizing a liquid formulation comprising an antibody to CD38 at a concentration of 55 to 75 mg / ml, polysorbate 20 at a concentration of 0.1% w / w to 0.2% w / w, a histidine buffer at a pH of 6.0 to 6.5 and a concentration of 5 mM to 15 mM, and sucrose at a concentration of 150 to 350 mM, wherein said antibody to CD38 comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:

8.

2. A lyophilized pharmaceutical composition according to claim 1, wherein said histidine buffer has a pH of 6.

0.

3. A lyophilized pharmaceutical composition according to claim 1 or 2, wherein said antibody to CD38 is present at a concentration of 65 mg / ml.

4. A lyophilized pharmaceutical composition according to any one of claims 1 to 3, wherein polysorbate 20 is present at a concentration of 0.1% w / w.

5. A lyophilized pharmaceutical composition according to any one of claims 1-4, wherein the sucrose is at a concentration of 260 mM.

6. A lyophilized pharmaceutical composition according to any one of claims 1-5, wherein the histidine buffer is at a concentration of 10 mM.

7. A method for producing a liquid formulation based on an antibody to CD38, which comprises providing a lyophilized pharmaceutical formulation according to any one of claims 1-6 and reconstituting said lyophilized formulation by adding water.

8. A reconstituted pharmaceutical composition based on an antibody to CD38 for the treatment of a disease or disorder in which the expression of CD38 is involved, comprising water and a lyophilized composition according to claim 1.

9. The reconstituted pharmaceutical composition of claim 8, wherein polysorbate 20 is present at a concentration of 0.1% w / w.

10. The reconstituted pharmaceutical composition according to claim 8 or 9, wherein the histidine buffer is at a concentration of 10 mM.

11. The reconstituted pharmaceutical composition according to any one of claims 8-10, wherein sucrose is present at a concentration of 260 mM.

12. The reconstituted pharmaceutical composition according to any one of claims 8-11, wherein said antibody to CD38 is present at a concentration of 65 mg / ml.

13. The use of a lyophilized pharmaceutical composition according to any one of claims 1 to 6 or a reconstituted pharmaceutical composition according to any one of claims 8 to 12 in the treatment of a disease or disorder in which CD38 expression is involved.

14. The use according to claim 13, wherein said disease or disorder is cancer.

15. The use according to claim 14, wherein said cancer is a hematological malignancy selected from leukemia, lymphoma and myeloma, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and multiple myeloma (MM), or a solid cancer selected from sarcoma and carcinoma, such as breast cancer, ovarian cancer, gastrointestinal cancer, lung cancer, pancreatic cancer, prostate cancer, melanoma tumors, colorectal cancer, head and neck cancer, bladder cancer, esophageal cancer, liver cancer, thyroid cancer and kidney cancer.

16. The use according to claim 13, wherein said disease or disorder is an inflammatory disorder.

17. The use according to claim 16, wherein said inflammatory disorder is selected from inflammatory bowel disease, rheumatoid arthritis, psoriasis, amyloidosis, systemic lupus erythematosus (SLE), atopic dermatitis, Wegener's granulomatosis, psoriatic arthritis.

18. A method for reducing the formation of aggregates of an anti-CD38 antibody in a composition containing 55 to 75 mg / ml of an anti-CD38 antibody, comprising combining: a) an antibody to CD38, which comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8; b) non-ionic surfactant; c) sucrose; and d) histidine buffer.

19. The method of claim 18, wherein said non-ionic surfactant is polysorbate 20.

20. The method of claim 18, wherein said non-ionic surfactant is from 0.05 to 0.2% w / w polysorbate 20.

21. The method of claim 18, wherein said non-ionic surfactant is 0.1% w / w polysorbate 20.

22. The method of claim 18, wherein the composition has a pH of about 6.

23. The method of claim 18, wherein the composition comprises from 150 mM to 350 mM sucrose.

24. The method of claim 18, wherein the composition comprises about 260 mM sucrose.

25. The method of claim 18, wherein the composition comprises from 5 mM to 15 mM of a histidine buffer.

26. The method according to claim 18, wherein the composition has a pH from 5.5 to 6.

5.

27. The method of claim 18, wherein the CD38 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8, said non-ionic surfactant is 0.05 - 0.2% w / w polysorbate 20 and comprises 150 mM to 350 mM sucrose.

28. The method of claim 18, wherein the composition exhibits long-term storage stability as characterized by size-specific high performance liquid chromatography (SE-HPLC) analysis after 4 weeks of storage at 25°C and 60% relative humidity by a monomer content greater than 90%.

29. The method of claim 18, wherein the composition exhibits long-term storage stability, which is characterized by size-specific high performance liquid chromatography (SE-HPLC) analysis after 4 weeks of storage at 40°C and 70% relative humidity by a monomer content of greater than 90%.

30. A method for producing a storage-stable product based on an antibody to CD38, comprising filling a syringe or vial with a composition containing from 55 to 75 mg / ml of an antibody to CD38, wherein the antibody to CD38 comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8, wherein the antibody to CD38 is stabilized using a non-ionic surfactant, sucrose and a histidine buffer, thereby forming a filled syringe or vial containing a stable composition of the antibody to CD38.

31. The method of claim 30, wherein said non-ionic surfactant is polysorbate 20.

32. The method of claim 30, wherein said non-ionic surfactant is from 0.05 to 0.2% w / w polysorbate 20.

33. The method of claim 30, wherein said nonionic surfactant is 0.1% w / w polysorbate 20.

34. The method according to claim 30, wherein the composition comprises from 150 mM to 350 mM sucrose.

35. The method of claim 30, wherein the composition comprises about 260 mM sucrose.

36. The method according to claim 30, wherein the composition comprises from 5 mM to 15 mM of a histidine buffer.

37. The method according to claim 30, wherein the composition has a pH from 5.5 to 6.

5.

38. The method of claim 30, wherein said non-ionic surfactant is 0.05-0.2% w / w polysorbate 20 and contains 150-350 mM sucrose.

39. The method of claim 30, wherein the composition exhibits long-term storage stability, which is characterized by size-specific high performance liquid chromatography (SE-HPLC) analysis after 4 weeks of storage at 25°C and 60% relative humidity by a monomer content of greater than 90%.

40. The method of claim 30, wherein the composition exhibits long-term storage stability, which is characterized by size-specific high-performance liquid chromatography (SE-HPLC) analysis after 4 weeks of storage at 40°C and 70% relative humidity by a monomer content of greater than 90%.

41. The method of claim 30, further comprising injecting the composition in the filled syringe into the subject.