α4β7 integrin antibody composition and method of use

Abstract

Variant α4β7 integrin antibodies and methods of use are provided herein. In one aspect, the disclosure provides a multi-dose regimen for use in the treatment of a disease in a subject requiring treatment of the disease, comprising: (a) a first liquid injectable formulation containing a total dose of at least 500 mg of α4β7-binding antibody; and (b) a second liquid injectable formulation containing a total dose of at least 120 mg of α4β7-binding antibody, wherein the α4β7-binding antibody comprises (i) a heavy chain consisting of the amino acid sequence of SEQ ID NO: 1 and (ii) a light chain consisting of the amino acid sequence of SEQ ID NO: 3.

Claims

1. A multi-dose regimen for use in the treatment of a disease in a subject requiring treatment for the disease, (a) A first liquid formulation for injection containing at least 500 mg of α4β7-binding antibody in a total dose, (b) A second liquid formulation for injection containing at least 120 mg of the α4β7-binding antibody in a total dose Includes, The α4β7-binding antibody described above, (i) A heavy chain consisting of the amino acid sequence according to Sequence ID No. 1 and (ii) Light chain consisting of amino acid sequence according to Sequence ID No. 3 and A multi-dose regimen consisting of several components.

2. The multiple-dose regimen according to claim 1, wherein the first liquid injectable formulation contains the α4β7-binding antibody in a total dose of about 500 mg to about 1200 mg, and the second liquid injectable formulation contains the α4β7-binding antibody in a total dose of about 120 mg to about 450 mg.

3. A multiple-dose regimen according to claim 1 or claim 2, wherein the first liquid injectable formulation contains a total dose of approximately 600 mg of the α4β7-binding antibody, and the second liquid injectable formulation contains a total dose of approximately 300 mg of the α4β7-binding antibody.

4. The multiple-dose regimen according to any one of claims 1 to 3, wherein the first injectable liquid formulation is for intravenous administration.

5. The multiple-dose regimen according to any one of claims 1 to 3, wherein the first injectable liquid formulation is for subcutaneous administration.

6. The multi-dose regimen according to claim 5, wherein the first injectable liquid formulation is suitable for administration as a single injection or multiple injections.

7. The multiple-dose regimen according to any one of claims 1 to 6, wherein the second liquid injectable preparation is for subcutaneous administration.

8. The multi-dose regimen according to claim 7, wherein the second injectable liquid formulation is suitable for administration as a single injection or multiple injections.

9. The multiple-dose regimen according to any one of claims 1 to 8, wherein the disease is inflammatory bowel disease.

10. The multiple-dose regimen according to claim 9, wherein the inflammatory bowel disease is Crohn's disease.

11. The multiple-dose regimen according to claim 9, wherein the inflammatory bowel disease is ulcerative colitis.

12. A drug regimen for use in the treatment of a disease in a subject requiring treatment for the disease, (a) A first formulation comprising at least about 500 mg of α4β7-binding antibody for administration to the subject, (b) A second formulation comprising at least about 120 mg of the α4β7-binding antibody in a total dose, wherein the second formulation is to be administered subcutaneously to the subject after the first formulation, and thereafter as a maintenance dose subcutaneously at least 8 weeks after administration of the second formulation. Includes, The α4β7-binding antibody described above, (i) A heavy chain consisting of the amino acid sequence according to Sequence ID No. 1 and (ii) Light chain consisting of amino acid sequence according to Sequence ID No. 3 and A medication regimen consisting of the following.

13. The drug regimen according to claim 12, wherein the first formulation is for subcutaneous administration.

14. The drug regimen according to claim 12, wherein the first formulation is for intravenous administration.

15. The drug regimen according to any one of claims 12 to 14, wherein the first formulation comprises the α4β7-binding antibody in a total dose ranging from about 500 mg to about 1200 mg.

16. The drug regimen according to any one of claims 12 to 14, wherein the first formulation comprises a total dose of approximately 600 mg of the α4β7-binding antibody.

17. The drug regimen according to any one of claims 12 to 16, wherein the second formulation comprises the α4β7-binding antibody in a total dose ranging from about 120 mg to about 450 mg.

18. The drug regimen according to any one of claims 12 to 16, wherein the second formulation comprises a total dose of approximately 300 mg of the α4β7-binding antibody.

19. The drug regimen according to any one of claims 12 to 18, wherein the second formulation is administered at least two weeks after the first formulation, and thereafter, at least eight weeks after the administration of the second formulation, it is administered as a maintenance dose.

20. The drug regimen according to any one of claims 12 to 20, wherein the first formulation is suitable for administration as a single injection or multiple injections.

21. The drug regimen according to any one of claims 12 to 20, wherein the second formulation is suitable for administration as a single injection or multiple injections.

22. The drug regimen according to any one of claims 12 to 21, wherein the first formulation and the second formulation do not contain citrate.

23. The drug regimen according to any one of claims 12 to 22, wherein the disease is inflammatory bowel disease.

24. The drug regimen according to claim 23, wherein the inflammatory bowel disease is Crohn's disease.

25. The drug regimen according to claim 23, wherein the inflammatory bowel disease is ulcerative colitis.

26. a) A heavy chain consisting of the amino acid sequence according to Sequence ID No. 1 and b) A light chain consisting of the amino acid sequence according to Sequence ID No. 3 and An injectable dosage form of an α4β7-binding antibody comprising: The average serum half-life of the α4β7-binding antibody in cynomolgus monkeys exceeds approximately 10 days. Injectable dosage form.

27. The injectable dosage form according to claim 26, wherein the mean serum half-life in cynomolgus monkeys is about 17 days or longer.

28. The injectable dosage form according to claim 26 or claim 27, wherein the injectable dosage form is an injectable liquid preparation.

29. The injectable dosage form according to claim 28, wherein the α4β7-binding antibody is present at a concentration of at least 180 mg / mL.

30. The injectable dosage form according to claim 28, wherein the liquid injectable preparation does not contain citrate.

31. A method for treating a disease in a patient who requires treatment for the disease, (a) administering an effective induction dose of an α4β7-binding antibody, and (b) one or more effective maintenance doses of the α4β7-binding antibody to a subject in need thereof, wherein the one or more maintenance doses are administered subcutaneously at intervals of at least eight weeks. Includes, The α4β7-binding antibody described above, (a) A heavy chain consisting of the amino acid sequence according to Sequence ID No. 1 and (b) Light chain consisting of the amino acid sequence according to Sequence ID No. 3 and A method consisting of the following.

32. The method according to claim 31, wherein the disease is inflammatory bowel disease.

33. The method according to claim 32, wherein the inflammatory bowel disease is Crohn's disease.

34. The method according to claim 33, wherein the inflammatory bowel disease is ulcerative colitis.

35. The method according to any one of claims 31 to 34, wherein the effective amount induction dose of the α4β7-binding antibody is at least 600 mg, and each of the one or more effective amounts maintenance doses of the α4β7-binding antibody is at least 300 mg.

36. The method according to claim 35, wherein the effective amount induction dose of the α4β7-binding antibody is about 600 mg, and each of the one or more effective amounts maintenance doses of the α4β7-binding antibody is about 300 mg.

37. The method according to any one of claims 31 to 36, wherein the effective amount of the α4β7-binding antibody is administered subcutaneously in the induction dose.

38. The method according to any one of claims 31 to 36, wherein the effective amount of the α4β7-binding antibody is administered intravenously in the induction dose.

39. The method according to any one of claims 31 to 36, wherein one or more maintenance doses are administered subcutaneously at intervals of approximately 12 weeks.

40. The method according to any one of claims 31 to 36, wherein one or more maintenance doses are administered subcutaneously at intervals of approximately 26 weeks.

41. The method according to any one of claims 31 to 40, wherein the induction dose comprises the α4β7-binding antibody in an amount approximately twice or greater than the dose of each of the one or more maintenance doses.

42. Regarding α4β7-binding antibodies, six weeks after administration of the α4β7-binding antibody to the subject, the C2 level was 35 μg / mL or higher. ｔｒｏｕｇｈ A method for achieving this in the subject requiring it, comprising the step of administering at least about 600 mg of the α4β7-binding antibody to the subject requiring it, wherein the α4β7-binding antibody is (a) A heavy chain consisting of the amino acid sequence according to Sequence ID No. 1 and (b) Light chain consisting of the amino acid sequence according to Sequence ID No. 3 and A method consisting of the following.

43. The method according to claim 42, wherein approximately 600 mg to approximately 1200 mg of the α4β7-binding antibody is administered intravenously.

44. The method according to claim 42, wherein approximately 600 mg to approximately 1200 mg of the α4β7-binding antibody is administered subcutaneously.

45. The method according to claim 43, wherein approximately 600 mg of the α4β7-binding antibody is administered intravenously.

46. The method according to claim 44, wherein approximately 600 mg of the α4β7-binding antibody is administered subcutaneously.

47. The method further includes administering at least about 300 mg of the α4β7-binding antibody to the subject requiring it, thereby achieving a steady state C of at least 6 μg / mL. ｔｒｏｕｇｈ The method according to any one of claims 42 to 46, which brings about the following.

48. Serum C at least 60 μg / mL ａｖｇＷ０－Ｗ１２ The method according to claim 47, which brings about the following.

49. By administering at least about 600 mg of the α4β7-binding antibody, at least 30 μg / mL of serum C is obtained. ａｖｇＷ３０－Ｗ４０ The method according to claim 47, which brings about the following.

50. The method according to any one of claims 42 to 49, further comprising the step of administering at least about 300 mg of the α4β7-binding antibody to a subject requiring such administration, wherein the administration results in an average serum concentration of the α4β7-binding antibody exceeding 35 μg / mL for 10 weeks following the administration of at least about 300 mg of the α4β7-binding antibody.

51. The method according to any one of claims 42 to 49, further comprising the step of subcutaneously administering at least about 300 mg of the α4β7-binding antibody to the subject requiring it, four weeks after administering the most recent dose of the α4β7-binding antibody.

52. The method according to any one of claims 42 to 49, further comprising the step of subcutaneously administering to the subject at least about 600 mg of the α4β7-binding antibody as a maintenance dose every 26 weeks, after administering the most recent dose of the α4β7-binding antibody.

53. (a) A heavy chain consisting of the amino acid sequence according to Sequence ID No. 1 and (b) Light chain consisting of the amino acid sequence according to Sequence ID No. 3 and An α4β7-binding antibody consisting of [the specified components].

54. Isolated nucleic acids encoding the heavy and / or light chain of an α4β7-binding antibody according to claim 53.

55. The isolated nucleic acid according to claim 54, which encodes sequence number 1.

56. The isolated nucleic acid according to claim 54, which encodes sequence number 3.

57. Recombinant host cells comprising an isolated nucleic acid according to any one of claims 54 to 56 or an expression vector comprising an isolated nucleic acid according to any one of claims 54 to 56.

58. The multiple-dose regimen according to claim 1, the drug regimen according to claim 11, the injectable dosage form according to claim 26, or the method according to claim 31, wherein the disease is an inflammatory disease of the gastrointestinal tract.

59. A multiple-dose regimen according to any one of claims 1 to 11, a drug administration regimen according to any one of claims 12 to 25, the method according to any one of claims 31 to 41, the method according to any one of claims 42 to 52, or the antibody according to claim 53, wherein the average serum half-life of the α4β7-binding antibody in cynomolgus monkeys is more than approximately 10 days.

60. A multiple-dose regimen according to any one of claims 1 to 11, a drug administration regimen according to any one of claims 12 to 25, the method according to any one of claims 31 to 41, the method according to any one of claims 42 to 52, or the antibody according to claim 53, wherein the mean serum half-life in cynomolgus monkeys is about 17 days or longer.

61. The α4β7-binding antibody described above has the following characteristics: (a) The melting temperature TmOnset is higher than approximately 55°C. (b) The melting temperature TmOnset is higher than 56.2°C. (c) The proportion of GOF is between approximately 55.1% and approximately 60.4%. (d) The proportion of G1F is between approximately 16.6% and approximately 18.8%. (e) The proportion of Man5 is between approximately 7.3% and approximately 8.8%. (f) Not induce the T cell activation markers CD25 or CD69. (g) Not causing the release of one or more cytokines, including IL-6, IL-8, IL-1β, IFNγ, IL-4, IL-17, IL-2, IL-23p70, and TNF. (h) It does not induce complement-dependent cell-mediated cytotoxicity (CDC) in primary human PBMCs and in human β-lymphoid cells expressing α4β7. (i) It does not induce antibody-dependent cell-mediated cytotoxicity (ADCC) in human NK cells, and (j) Without affecting the inhibitory activity of regulatory T cells expressing α4β7 integrin, wherein the inhibitory activity is measured by the presence of elevated CD71, CD25, Ki67, granzyme B, or OX40. A multi-dose regimen according to any one of claims 1 to 11, a drug administration regimen according to any one of claims 12 to 25, an injectable dosage form according to any one of claims 26 to 30, the method according to any one of claims 31 to 41, the method according to any one of claims 42 to 52, or the antibody according to claim 53.

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