OBTAINING ANTIBODY-DRUG CONJUGATE AND ITS LYOPHILIZATION

RU2023102041A3Pending Publication Date: 2026-06-29DAIICHI SANKYO CO LTD

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Patent Information

Authority / Receiving Office: RU · RU
Patent Type: Applications
Current Assignee / Owner: DAIICHI SANKYO CO LTD
Filing Date: 2018-08-22
Publication Date: 2026-06-29

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Claims

1. A pharmaceutical composition comprising: (i) an antibody-drug conjugate, (ii) histidine buffer, (iii) sucrose or trehalose and (iv) surfactant, wherein the antibody-drug conjugate is an antibody-drug conjugate in which the drug-linker moiety is represented by the following formula: [Formula 1] , where A represents the binding position of the antibody, conjugated to the antibody via a thioester linkage.

2. The pharmaceutical composition according to claim 1, wherein the surfactant is polysorbate 80 or polysorbate 20.

3. A pharmaceutical composition according to claim 1 or 2, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 3-80 mmol histidine buffer, (iii) 24-320 mg sucrose or trehalose and (iv) 0.05-1.6 mg polysorbate 80 or polysorbate 20.

4. A pharmaceutical composition according to any one of paragraphs 1-3, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 10-40 mmol histidine buffer, (iii) 90 mg sucrose or 100 mg trehalose hydrate and (iv) 0.2-0.4 mg polysorbate 80 or polysorbate 20.

5. A pharmaceutical composition according to any one of paragraphs 1-4, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 10 or 25 mmol histidine buffer, (iii) 90 mg sucrose and (iv) 0.2 or 0.3 mg polysorbate 80 or polysorbate 20.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the pH of the composition when the antibody-drug conjugate is dissolved in water at a concentration of 20 mg / ml is 4.0-7.

0.

7. The pharmaceutical composition of any one of claims 1-6, wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, or an anti-GPR20 antibody.

8. The pharmaceutical composition of claim 7, wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.

9. The pharmaceutical composition of claim 8, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence comprising amino acid residues 1-449 of SEQ ID NO: 1 and a light chain comprising an amino acid sequence comprising amino acid residues 1-214 of SEQ ID NO: 2, or an antibody comprising a heavy chain comprising an amino acid sequence represented by SEQ ID NO: 1 and a light chain comprising an amino acid sequence represented by SEQ ID NO:

2.

10. The pharmaceutical composition of claim 8 or 9, wherein the average number of conjugated drug-linker units per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

11. A pharmaceutical composition according to any one of paragraphs 8-10, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 25 mmol histidine buffer, (iii) 90 mg sucrose and (iv) 0.3 mg polysorbate 80, where the pH of the composition when the antibody-drug conjugate is dissolved in water at a concentration of 20 mg / mL is 5.

5.

12. A pharmaceutical composition according to any one of paragraphs 8-10, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 0.89 mg L-histidine and 4.04 mg L-histidine hydrochloride hydrate, (iii) 90 mg sucrose and (iv) 0.3 mg polysorbate 80.

13. A pharmaceutical composition according to any one of paragraphs 8-10, comprising: (i) 100 mg of antibody-drug conjugate, (ii) 4.45 mg L-histidine and 20.2 mg L-histidine hydrochloride hydrate, (iii) 450 mg sucrose and (iv) 1.5 mg polysorbate 80.

14. The pharmaceutical composition of claim 7, wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.

15. The pharmaceutical composition of claim 14, wherein the anti-HER3 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 3 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 4, or a variant of the antibody in which the lysine residue at the carboxy terminus of the heavy chain is deleted.

16. The pharmaceutical composition of claim 14 or 15, wherein the average number of conjugated drug-linker units per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

17. A pharmaceutical composition according to any one of paragraphs 14-16, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 25 mmol histidine buffer, (iii) 90 mg sucrose and (iv) 0.3 mg polysorbate 20, where the pH of the composition when the antibody-drug conjugate is dissolved in water at a concentration of 20 mg / mL is 5.

4.

18. A pharmaceutical composition according to any one of paragraphs 14-16, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 0.81 mg L-histidine and 4.14 mg L-histidine hydrochloride hydrate, (iii) 90 mg sucrose and (iv) 0.3 mg polysorbate 20.

19. A pharmaceutical composition according to any one of paragraphs 14-16, comprising: (i) 100 mg of antibody-drug conjugate, (ii) 4.06 mg L-histidine and 20.7 mg L-histidine hydrochloride hydrate, (iii) 450 mg sucrose and (iv) 1.5 mg polysorbate 20.

20. The pharmaceutical composition of claim 7, wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.

21. The pharmaceutical composition of claim 20, wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20-470 of SEQ ID NO: 5, and a light chain consisting of an amino acid sequence consisting of amino acid residues 21-234 of SEQ ID NO: 6, or an antibody variant in which the lysine residue at the carboxy terminus of the heavy chain is deleted.

22. The pharmaceutical composition of claim 20 or 21, wherein the average number of conjugated drug-linker units per antibody molecule in the antibody-drug conjugate is in the range of 3 to 5.

23. A pharmaceutical composition according to any one of paragraphs 20-22, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 10 mmol histidine buffer, (iii) 90 mg sucrose and (iv) 0.2 or 0.3 mg polysorbate 80, where the pH of the composition when the antibody-drug conjugate is dissolved in water at a concentration of 20 mg / mL is 6.

0.

24. A pharmaceutical composition according to any one of paragraphs 20-22, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 0.78 mg L-histidine and 1.05 mg L-histidine hydrochloride hydrate, (iii) 90 mg sucrose and (iv) 0.2 or 0.3 mg polysorbate 80.

25. A pharmaceutical composition according to any one of paragraphs 20-22, comprising: (i) 100 mg of antibody-drug conjugate, (ii) 3.88 mg L-histidine and 5.26 mg L-histidine hydrochloride hydrate, (iii) 450 mg sucrose and (iv) 1.0 or 1.5 mg polysorbate 80.

26. The pharmaceutical composition of claim 7, wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.

27. The pharmaceutical composition of claim 26, wherein the anti-B7-H3 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20-471 of SEQ ID NO: 7 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21-233 of SEQ ID NO: 8, or a variant of the antibody in which the lysine residue at the carboxy terminus of the heavy chain is deleted.

28. The pharmaceutical composition of claim 26 or 27, wherein the average number of conjugated drug-linker units per antibody molecule in the antibody-drug conjugate is in the range of 3 to 5.

29. A pharmaceutical composition according to any one of paragraphs 26-28, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 10 mmol histidine buffer, (iii) 90 mg sucrose and (iv) 0.2 or 0.3 mg polysorbate 20, where the pH of the composition when the antibody-drug conjugate is dissolved in water at a concentration of 20 mg / mL is 5.

9.

30. A pharmaceutical composition according to any one of paragraphs 26-28, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 0.65 mg L-histidine and 1.22 mg L-histidine hydrochloride hydrate, (iii) 90 mg sucrose and (iv) 0.2 or 0.3 mg polysorbate 20.

31. A pharmaceutical composition according to any one of paragraphs 26-28, comprising: (i) 100 mg of antibody-drug conjugate, (ii) 3.23 mg L-histidine and 6.12 mg L-histidine hydrochloride hydrate, (iii) 450 mg sucrose and (iv) 1.0 or 1.5 mg polysorbate 20.

32. The pharmaceutical composition of claim 7, wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody.

33. The pharmaceutical composition of claim 32, wherein the anti-GPR20 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 20-472 of SEQ ID NO: 9 and a light chain consisting of an amino acid sequence consisting of amino acid residues 21-234 of SEQ ID NO: 10, or a variant of the antibody in which the lysine residue at the carboxy terminus of the heavy chain is deleted.

34. The pharmaceutical composition of claim 32 or 33, wherein the average number of conjugated drug-linker units per antibody molecule in the antibody-drug conjugate is in the range of 7 to 8.

35. A pharmaceutical composition according to any one of paragraphs 32-34, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 10 mmol histidine buffer, (iii) 90 mg sucrose and (iv) 0.3 mg polysorbate 80, where the pH of the composition when the antibody-drug conjugate is dissolved in water at a concentration of 20 mg / mL is 5.

4.

36. A pharmaceutical composition according to any one of paragraphs 32-34, comprising: (i) per 20 mg antibody-drug conjugate, (ii) 0.32 mg L-histidine and 1.66 mg L-histidine hydrochloride hydrate, (iii) 90 mg sucrose and (iv) 0.3 mg polysorbate 80.

37. A pharmaceutical composition according to any one of paragraphs 32-34, comprising: (i) 100 mg of antibody-drug conjugate, (ii) 1.62 mg L-histidine and 8.29 mg L-histidine hydrochloride hydrate, (iii) 450 mg sucrose and (iv) 1.5 mg polysorbate 80.

38. A pharmaceutical composition according to any one of claims 1-37, wherein the composition is in the form of an injection composition.

39. The pharmaceutical composition of claim 38, wherein the composition is in the form of an aqueous composition for injection.

40. The pharmaceutical composition according to claim 39, wherein the concentration of the antibody-drug conjugate is 20 mg / ml.

41. The pharmaceutical composition according to claim 39 or 40, wherein the composition is frozen.

42. The pharmaceutical composition of claim 38, wherein the composition is in the form of a lyophilized composition for injection.

43. The pharmaceutical composition according to claim 42, wherein the composition is stored in a dark bottle.

44. A pharmaceutical composition according to any one of claims 1-43, wherein the composition is intended for the treatment of cancer.

45. A method for producing a pharmaceutical composition according to claim 42, comprising the steps of: (1) obtaining an aqueous solution containing predetermined amounts (i) an antibody-drug conjugate, (ii) histidine buffer, (iii) sucrose or trehalose and (iv) surfactant, (2) if necessary, adjust the pH of the aqueous solution to a predetermined value, and then (3) lyophilization of an aqueous solution.

46. The production method according to claim 45, wherein the step of lyophilizing the aqueous solution includes an annealing process at a shelf temperature that is close to the eutectic point of the aqueous solution, where proximity to the eutectic point means the range from a temperature that is 1.5°C below the eutectic point to a temperature that is 1.5°C above the eutectic point.

47. The production method according to paragraph 46, characterized in that the time of the primary drying process is reduced compared to when annealing is carried out at a shelf temperature that is 5°C below the eutectic point.

48. The production method according to paragraph 46 or 47, characterized in that a lyophilized cake is obtained that has less shrinkage compared to that obtained when annealing is carried out at a shelf temperature that is 5°C below the eutectic point.

49. The method of production according to claim 45, wherein the step of lyophilizing the aqueous solution includes a method of carrying out annealing at a shelf temperature of -4 to -1°C.

50. The production method according to claim 49, wherein the stage of lyophilization of the aqueous solution also includes a primary drying process at a shelf temperature of -5 to 5°C under vacuum conditions of 5 to 15 Pa.

51. The production method according to claim 50, wherein the stage of lyophilization of the aqueous solution also includes a secondary drying process at a shelf temperature of 40 to 50°C under vacuum conditions of 5 to 15 Pa.