Methods of improving transplant survival using il-2 receptor gamma chain antibodies

HK40137852APending Publication Date: 2026-09-18REGENERON PHARMACEUTICALS INC
View PDF 0 Cites 0 Cited by

Patent Information

Application Number
HK62026126684
Authority / Receiving Office
HK · HK
Patent Type
Applications
Current Assignee / Owner
Priority Date
2023-07-28
Filing Date
2026-07-27
Publication Date
2026-09-18
Estimated Expiration
2044-03-31

Smart Images

  • Figure 00000000_0000_ABST
    Figure 00000000_0000_ABST
Patent Text Reader

Abstract

The present disclosure provides methods for improving transplant survival or delaying the onset of transplant rejection by administering to a subject an IL-2Rγ antibody or a combination therapy comprising an IL2Rγ antibody and one or more additional therapeutic agents, such a CD28 signaling inhibitor such as a CTLA4-lg fusion protein.
Need to check novelty before this filing date? Find Prior Art

Description

This disclosure provides methods for improving transplant survival or delaying transplant rejection by administering an IL-2Rγ antibody, or a combination therapy comprising an IL-2Rγ antibody and one or more additional therapeutic agents (such as CD28 signaling inhibitors like CTLA4-Ig fusion protein), to subjects. Abstract

Claims

What is claimed is:

1. A method of improving organ or tissue transplant survival, the method comprising: administering to a subject at least one dose of an antibody that specifically binds to interleukin 2 receptor gamma chain (I L-2 Ry), or an antigen-binding fragment thereof, prior to an organ or tissue transplant in the subject; and administering to the subject one or more doses of a CD28 signaling inhibitor.

2. The method of claim 1, wherein the IL-2Ry antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:2, the HCDR2 comprises the amino acid sequence of SEQ ID NO:3, the HCDR3 comprises the amino acid sequence of SEQ ID NO:4, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence AAS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

3. The method of claim 1 or 2, wherein the IL-2Ry antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:5.

4. The method of any one of claims 1 to 3, wherein the IL-2Ry antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NQ:10.

5. The method of any one of claims 1 to 4, wherein the method comprises administering to the subject two or more doses of the IL-2Ry antibody or antigen-binding fragment thereof prior to the organ or tissue transplant.

6. The method of any one of claims 1 to 4, wherein the method comprises administering to the subject one or more doses of the IL-2Ry antibody or antigen-binding fragment thereof prior to the organ or tissue transplant and one or more doses of the IL-2Ry antibody or antigenbinding fragment thereof after the organ or tissue transplant.

7. The method of any one of claims 1 to 6, wherein the IL-2Ry antibody or antigen-binding fragment thereof is administered to the subject once a week, two times a week, or three times a week.

8. The method of any one of claims 1 to 7, wherein the CD28 signaling inhibitor is a fusion protein comprising an extracellular portion of cytotoxic T lymphocyte-associated protein 4 (CTLA4) and an Fc region of immunoglobulin I gG 1 (Ig).

9. The method of claim 8, wherein the CTLA4-lg fusion protein is abatacept or belatacept.

10. The method of any one of claims 1 to 9, wherein the CD28 signaling inhibitor is administered to the subject starting on the day of the organ or tissue transplant.

11. The method of any one of claims 1 to 9, wherein at least one dose of the CD28 signaling inhibitor is administered to the subject prior to the organ or tissue transplant.

12. The method of any one of claims 1 to 11, wherein the CD28 signaling inhibitor is administered to the subject three times a week, two times a week, once a week, or once every two weeks.

13. The method of any one of claims 1 to 12, wherein the method further comprises administering to the subject a CD40L inhibitor.

14. The method of claim 13, wherein the CD40L inhibitor is a CD40L antibody or an antigenbinding fragment thereof, or a fusion protein that specifically binds to CD40L.

15. The method of claim 13 or 14, wherein the CD40L inhibitor is dapirolizumab pegol, dazodalibep, frexalimab, letolizumab, ruplizumab, tegoprubart, or MR-1.

16. The method of any one of claims 13 to 15, wherein the CD40L inhibitor is administered to the subject once a week, two times a week, or three times a week.

17. The method of any one of claims 1 to 16, wherein:(a) the CD28 signaling inhibitor is abatacept and the CD40L inhibitor is dapirolizumab pegol, dazodalibep, frexalimab, letolizumab, ruplizumab, tegoprubart, or MR-1 ; or(b) the CD28 signaling inhibitor is belatacept and the CD40L inhibitor is dapirolizumab pegol, dazodalibep, frexalimab, letolizumab, ruplizumab, tegoprubart, or MR-1 ; or(c) the CD28 signaling inhibitor is abatacept and the CD40L inhibitor is MR-1 ; or(d) the CD28 signaling inhibitor is belatacept and the CD40L inhibitor is MR-1.

18. The method of any one of claims 1 to 17, wherein one or more of the IL-2Ry antibody or antigen-binding fragment thereof, the CD28 signaling inhibitor, and the CD40L inhibitor are administered to the subject starting at least two days prior to the organ or tissue transplant.

19. The method of any one of claims 1 to 18, wherein one or more of the IL-2Ry antibody or antigen-binding fragment thereof, the CD28 signaling inhibitor, and the CD40L inhibitor are administered to the subject until the onset of transplant rejection.

20. A method for delaying the onset of transplant rejection in a subject, the method comprising: administering to a subject at least one dose of an antibody that specifically binds to IL- 2Ry, or an antigen-binding fragment thereof, prior to an organ or tissue transplant in the subject; and administering to the subject one or more doses of a CD28 signaling inhibitor.

21. The method of claim 20, wherein the IL-2Ry antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:2, the HCDR2 comprises the amino acid sequence of SEQ ID NO:3, the HCDR3 comprises the amino acid sequence of SEQ ID NO:4, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence AAS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

22. The method of claim 20 or 21, wherein the IL-2Ry antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO:1 and an LCVR comprising the amino acid sequence of SEQ ID NO:5.

23. The method of any one of claims 20 to 22, wherein the IL-2Ry antibody or antigenbinding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NQ:10.

24. The method of any one of claims 20 to 23, wherein the method comprises administering to the subject two or more doses of the IL-2Ry antibody or antigen-binding fragment thereof prior to the organ or tissue transplant.

25. The method of any one of claims 20 to 23, wherein the method comprises administering to the subject one or more doses of the IL-2Ry antibody or antigen-binding fragment thereofprior to the organ or tissue transplant and one or more doses of the IL-2Ry antibody or antigenbinding fragment thereof after the organ or tissue transplant.

26. The method of any one of claims 20 to 25, wherein the IL-2Ry antibody or antigenbinding fragment thereof is administered to the subject once a week, two times a week, or three times a week.

27. The method of any one of claims 20 to 26, wherein the CD28 signaling inhibitor is a CTLA4-lg fusion protein.

28. The method of claim 27, wherein the CTLA4-lg fusion protein is abatacept or belatacept.

29. The method of any one of claims 20 to 28, wherein the CD28 signaling inhibitor is administered to the subject starting on the day of the organ or tissue transplant.

30. The method of any one of claims 20 to 28, wherein at least one dose of the CD28 signaling inhibitor is administered to the subject prior to the organ or tissue transplant31. The method of any one of claims 20 to 30, wherein the CD28 signaling inhibitor is administered to the subject once a week or two times a week.

32. The method of any one of claims 20 to 31 , wherein the method further comprises administering to the subject a CD40L inhibitor.

33. The method of claim 32, wherein the CD40L inhibitor is a CD40L antibody or an antigenbinding fragment thereof, or a fusion protein that specifically binds to CD40L.

34. The method of claim 32 or 33, wherein the CD40L inhibitor is dapirolizumab pegol, dazodalibep, frexalimab, letolizumab, ruplizumab, tegoprubart, or MR-1.

35. The method of any one of claims 32 to 45, wherein the CD40L inhibitor is administered to the subject once a week, two times a week, or three times a week.

36. The method of any one of claims 20 to 35, wherein:(a) the CD28 signaling inhibitor is abatacept and the CD40L inhibitor is dapirolizumab pegol, dazodalibep, frexalimab, letolizumab, ruplizumab, tegoprubart, or MR-1 ; or(b) the CD28 signaling inhibitor is belatacept and the CD40L inhibitor is dapirolizumab pegol, dazodalibep, frexalimab, letolizumab, ruplizumab, tegoprubart, or MR-1 ; or(c) the CD28 signaling inhibitor is abatacept and the CD40L inhibitor is MR-1 ; or(d) the CD28 signaling inhibitor is belatacept and the CD40L inhibitor is MR-1.

37. The method of any one of claims 20 to 36, wherein one or more of the IL-2Ry antibody or antigen-binding fragment thereof, the CD28 signaling inhibitor, and the CD40L inhibitor are administered to the subject starting at least two days prior to the organ or tissue transplant.

38. The method of any one of claims 20 to 37, wherein one or more of the IL-2Ry antibody or antigen-binding fragment thereof, the CD28 signaling inhibitor, and the CD40L inhibitor are administered to the subject until the onset of transplant rejection.

39. A method of improving organ or tissue transplant survival or delaying the onset of transplant rejection, the method comprising: administering to a subject at least one dose of an antibody that specifically binds to IL- 2Ry, or an antigen-binding fragment thereof, prior to an organ or tissue transplant in the subject; wherein the subject is taking or has been prescribed a CD28 signaling inhibitor.

40. The method of claim 39, wherein the CD28 signaling inhibitor is a CTLA4-lg fusion protein.

41. The method of claim 40, wherein the CTLA4-lg fusion protein is abatacept or belatacept.

42. The method of any one of claims 39 to 41 , wherein the subject is taking the CD28 signaling inhibitor at least one day before the organ or tissue transplant.

43. The method of any one of claims 39 to 41 , wherein the subject is taking the CD28 signaling inhibitor starting on the day of the organ or tissue transplant.

44. The method of any one of claims 39 to 43, wherein the IL-2Ry antibody or antigenbinding fragment thereof comprises three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:2, the HCDR2 comprises the amino acid sequence of SEQ ID NO:3, the HCDR3 comprises the amino acid sequence of SEQ ID NO:4, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence AAS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

45. The method of any one of claims 39 to 44, wherein the IL-2Ry antibody or antigenbinding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO:1 and an LCVR comprising the amino acid sequence of SEQ ID NO:5.

46. The method of any one of claims 39 to 45, wherein the IL-2Ry antibody or antigenbinding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NQ:10.

47. The method of any one of claims 39 to 46, wherein the method comprises administering to the subject: two or more doses of the IL-2Ry antibody or antigen-binding fragment thereof prior to the organ or tissue transplant; or one or more doses of the IL-2Ry antibody or antigen-binding fragment thereof prior to the organ or tissue transplant and one or more doses of the IL-2Ry antibody or antigen-binding fragment thereof after the organ or tissue transplant.

48. The method of any one of claims 39 to 47, wherein the IL-2Ry antibody or antigenbinding fragment thereof is administered to the subject once a week, two times a week, or three times a week.

49. A combination for use in improving organ or tissue transplant survival or for use in delaying the onset of transplant rejection in a subject, the combination comprising: an antibody that specifically binds to IL-2Ry or an antigen-binding fragment thereof; and a CD28 signaling inhibitor.

50. The combination of claim 49, wherein the IL-2Ry antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:2, the HCDR2 comprises the amino acid sequence of SEQ ID NO:3, the HCDR3 comprises the amino acid sequence of SEQ ID NO:4, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence AAS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

51. The combination of claim 50, wherein the IL-2Ry antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO:1 and an LCVR comprising the amino acid sequence of SEQ ID NO:5.

52. The combination of any one of claims 49 to 51 , wherein the IL-2Ry antibody or antigenbinding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

53. The combination of any one of claims 49 to 52, wherein the CD28 signaling inhibitor is a CTLA4-lg fusion protein.

54. The combination of claim 53, wherein the CTLA4-lg fusion protein is abatacept or belatacept.

55. The combination of any one of claims 49 to 54, further comprising a CD40L inhibitor, wherein the CD40L inhibitor is a CD40L antibody or an antigen-binding fragment thereof, or a fusion protein that specifically binds to CD40L.

56. The combination of claim 55, wherein the CD40L inhibitor is dapirolizumab pegol, dazodalibep, frexalimab, letolizumab, ruplizumab, tegoprubart, or MR-1.

57. The method of any one of claims 1 to 48 or the combination of any one of claims 49 to 56, wherein the organ or tissue transplant is a bone transplant, corneal transplant, heart transplant, heart valve transplant, kidney transplant, ligament transplant, liver transplant, lung transplant, pancreas transplant, skin transplant, tendon transplant, trachea transplant, or vascular tissue transplant.

58. A method of improving organ or tissue transplant survival or delaying the onset of transplant rejection in a subject, the method comprising: administering to a subject at least one dose of an antibody that specifically binds to interleukin 2 receptor gamma chain (I L-2Ry), or an antigen-binding fragment thereof, prior to an organ or tissue transplant in the subject; administering to the subject one or more doses of an antiproliferative agent.

59. The method of claim 58, wherein the IL-2Ry antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:2, the HCDR2 comprises the amino acid sequence of SEQ ID NO:3, the HCDR3 comprises the amino acid sequence of SEQ ID NO:4, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence AAS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

60. The method of claim 58 or 59, wherein the IL-2Ry antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:5.

61. The method of any one of claims 58 to 60, wherein the IL-2Ry antibody or antigenbinding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

62. The method of any one of claims 58 to 61 , wherein the method comprises administering to the subject two or more doses of the IL-2Ry antibody or antigen-binding fragment thereof prior to the organ or tissue transplant.

63. The method of any one of claims 58 to 61 , wherein the method comprises administering to the subject one or more doses of the IL-2Ry antibody or antigen-binding fragment thereof prior to the organ or tissue transplant and one or more doses of the IL-2Ry antibody or antigenbinding fragment thereof after the organ or tissue transplant.

64. The method of any one of claims 58 to 63, wherein the IL-2Ry antibody or antigenbinding fragment thereof is administered to the subject once a week, two times a week, or three times a week.

65. The method of any one of claims 58 to 64, wherein the antiproliferative agent is mycophenolate mofetil (MMF).

66. The method of any one of claims 58 to 65, wherein the antiproliferative agent is administered to the subject starting on the day of the organ or tissue transplant.

67. The method of any one of claims 58 to 65, wherein at least one dose of the antiproliferative agent is administered to the subject prior to the organ or tissue transplant.

68. The method of any one of claims 58 to 67, wherein the antiproliferative agent is administered to the subject daily.

69. The method of any one of claims 58 to 68, wherein one or both of the IL-2Ry antibody or antigen-binding fragment thereof and the antiproliferative agent are administered to the subject until the onset of transplant rejection.

70. A method of improving organ or tissue transplant survival or delaying the onset of transplant rejection, the method comprising: administering to a subject at least one dose of an antibody that specifically binds to IL- 2Ry, or an antigen-binding fragment thereof, prior to an organ or tissue transplant in the subject; wherein the subject is taking or has been prescribed an antiproliferative agent.

71. The method of claim 70, wherein the antiproliferative agent is MMF.

72. The method of claim 70 or 71 , wherein the subject is taking the antiproliferative agent at least one day before the organ or tissue transplant.

73. The method of any one of claims 70 to 72, wherein the subject is taking the antiproliferative agent starting on the day of the organ or tissue transplant.

74. The method of any one of claims 70 to 73, wherein the IL-2Ry antibody or antigenbinding fragment thereof comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:2, the HCDR2 comprises the amino acid sequence of SEQ ID NO:3, the HCDR3 comprises the amino acid sequence of SEQ ID NO:4, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence AAS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

75. The method of any one of claims 70 to 74, wherein the IL-2Ry antibody or antigenbinding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO:1 and an LCVR comprising the amino acid sequence of SEQ ID NO:5.

76. The method of any one of claims 70 to 75, wherein the IL-2Ry antibody or antigenbinding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NQ:10.

77. The method of any one of claims 70 to 76, wherein the method comprises administering to the subject: two or more doses of the IL-2Ry antibody or antigen-binding fragment thereof prior to the organ or tissue transplant; or one or more doses of the IL-2Ry antibody or antigen-binding fragment thereof prior to the organ or tissue transplant and one or more doses of the IL-2Ry antibody or antigen-binding fragment thereof after the organ or tissue transplant.

78. The method of any one of claims 70 to 77, wherein the IL-2Ry antibody or antigenbinding fragment thereof is administered to the subject once a week, two times a week, or three times a week.

79. A combination for use in improving organ or tissue transplant survival or for use in delaying the onset of transplant rejection in a subject, the combination comprising: an antibody that specifically binds to IL-2Ry or an antigen-binding fragment thereof; and an antiproliferative agent.

80. The combination of claim 79, wherein the IL-2Ry antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:2, the HCDR2 comprises the amino acid sequence of SEQ ID NO:3, the HCDR3 comprises the amino acid sequence of SEQ ID NO:4, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence AAS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

81. The combination of claim 80, wherein the IL-2Ry antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO:1 and an LCVR comprising the amino acid sequence of SEQ ID NO:5.

82. The combination of any one of claims 79 to 81 , wherein the IL-2Ry antibody or antigenbinding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NQ:10.

83. The combination of any one of claims 79 to 82, wherein the antiproliferative agent is MMF.