Chimeric T cell receotors

• US 20040043401A1
• Filed: 05/28/2003
• Published: 03/04/2004
• Est. Priority Date: 05/28/2002
• Status: Active Grant

• Current Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Original Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Maher, John, Brentjens, Renier, Sadelain, Michel
• Granted Patent: US 7,446,190 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/70521 CD28, CD152
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/3069 Reproductive system, e.g. ovaria, uterus, testes, prostate
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

Chimeric T cell receptors (TCR) are provided that combine, in a single chimeric species, the intracellular domain of CD3 ζ-chain, a signaling region from a costimulatory protein such as CD28, and a binding element that specifically interacts with a selected target. When expressed, for example in T-lymphocytes from the individual to be treated for a condition associated with the selected target, a T cell immune response is stimulated in the individual to the target cells. The chimeric TCR'"'"'s are able to provide both the activation and the co-stimulation signals from a single molecule to more effectively direct T-lymphocyte cytotoxicity against the selected target and T-lymphocyte proliferation.

Claims

1. A nucleic acid polymer encoding a chimeric T cell receptor, said chimeric T cell receptor comprising a zeta chain portion comprising the intracellular domain of human CD3 ζ

chain, a costimulatory signaling region and a binding element that specifically interacts with a selected target.

2. The nucleic acid polymer of claim 1, wherein the binding element is a member of an immunological binding pair.

3. The nucleic acid polymer of claim 2, wherein the binding element is an antibody.

4. The nucleic acid polymer of claim 3, wherein the antibody is a single chain antibody.

5. The nucleic acid polymer of claim 4, wherein the single chain antibody binds to prostate specific membrane antigen.

6. The nucleic acid polymer of claim 4, wherein the single chain antibody binds to CD19.

7. The nucleic acid polymer of claim 4, wherein the encoded T cell receptor comprises binding element-costimulatory signaling region-zeta chain portion in that order.

8. The nucleic acid polymer of claim 1, wherein the costimulatory signaling region comprises the intracellular domain of CD28.

9. The nucleic acid polymer of claim 8, wherein the costimulatory signaling region consists of the sequence of Seq. ID No. 7.

10. The nucleic acid polymer of claim 9, wherein the binding element is a member of an immunological binding pair.

11. The nucleic acid polymer of claim 10, wherein the binding element is an antibody.

12. The nucleic acid polymer of claim 11, wherein the antibody is a single chain anti body.

13. The nucleic acid polymer of claim 12, wherein the single chain antibody binds to prostate specific membrane antigen.

14. The nucleic acid polymer of claim 12, wherein the single chain antibody binds to CD19.

15. The nucleic acid polymer of claim 12, wherein the encoded T cell receptor comprises binding element-costimulatory signaling region-zeta chain portion in that order.

16. The nucleic acid polymer of claim 1, wherein the zeta chain portion comprises the sequence of Seq. ID. No. 3.

17. The nucleic acid polymer of claim 16, wherein the binding element is a member of an immunological binding pair.

18. The nucleic acid polymer of claim 17, wherein the binding element is an antibody.

19. The nucleic acid polymer of claim 18, wherein the antibody is a single chain anti body.

20. The nucleic acid polymer of claim 19, wherein the single chain antibody binds to prostate specific membrane antigen.

21. The nucleic acid polymer of claim 19, wherein the single chain antibody binds to CD19.

22. The nucleic acid polymer of claim 19, wherein the encoded T cell receptor comprises binding element-costimulatory signaling region-zeta chain portion in that order.

23. The nucleic acid polymer of claim 22, wherein the costimulatory signaling region comprises the intracellular domain of CD28.

24. The nucleic acid polymer of claim 23, wherein the costimulatory signaling region consists of the sequence of Seq. ID No. 7.

25. The nucleic acid polymer of claim 1, wherein the encoded T cell receptor comprises binding element-CD28 signaling region-zeta chain portion in that order.

26. A chimeric T cell receptor, said chimeric T cell receptor comprising a zeta chain portion comprising the intracellular domain of human CD3 ζ

chain, a costimulatory signaling region and a binding element that specifically interacts with a selected target.

27. The receptor of claim 26, wherein the binding element is a member of an immunological binding pair.

28. The receptor of claim 27, wherein the binding element is an antibody.

29. The receptor of claim 28, wherein the antibody is a single chain antibody.

30. The receptor of claim 29, wherein the single chain antibody binds to prostate specific membrane antigen.

31. The receptor of claim 29, wherein the single chain antibody binds to CD19.

32. The receptor of claim 29, wherein the T cell receptor comprises binding element-costimulatory signaling region-zeta chain portion in that order.

33. The receptor of claim 26, wherein the costimulatory signaling region comprises the intracellular domain of CD28.

34. The receptor of claim 33, wherein the costimulatory signaling region consists of the sequence of Seq. ID No. 7.

35. The receptor of claim 34, wherein the binding element is a member of an immunological binding pair.

36. The receptor of claim 35, wherein the binding element is an antibody.

37. The receptor of claim 36, wherein the antibody is a single chain antibody.

38. The receptor of claim 37, wherein the single chain antibody binds to prostate specific membrane antigen.

39. The receptor of claim 37, wherein the single chain antibody binds to CD19.

40. The receptor of claim 37, wherein the T cell receptor comprises binding element-costimulatory signaling region-zeta chain portion in that order.

41. The receptor of claim 26, wherein the zeta chain portion comprises a sequence encoded by the sequence of Seq. ID. No. 3.

42. The receptor of claim 41, wherein the binding element is a member of an immunological binding pair.

43. The receptor of claim 42, wherein the binding element is an antibody.

44. The receptor of claim 43, wherein the antibody is a single chain antibody.

45. The receptor of claim 44, wherein the single chain antibody binds to prostate specific membrane antigen.

46. The receptor of claim 45, wherein the single chain antibody binds to CD19.

47. The receptor of claim 45, wherein the T cell receptor comprises binding element-costimulatory signaling region-zeta chain portion in that order.

48. The receptor of claim 47, wherein the costimulatory signaling region comprises the intracellular domain of CD28.

49. The receptor of claim 48, wherein the costimulatory signaling region consists of a sequence encoded by the sequence of Seq. ID No. 7.

50. The receptor of claim 26, wherein the T cell receptor comprises binding element-CD28 signaling region-zeta chain portion in that order.

51. A method for stimulating a T cell mediated immune response to a target cell population in a subject individual comprising the step of administering to the subject individual a chimeric T cell receptor comprising a zeta chain portion comprising the intracellular domain of human CD3 ζ

chain, a costimulatory signaling region and a binding element that specifically interacts with a selected target such that the chimeric T cell receptor is expressed in T lymphocytes of the subject individual, wherein the binding element is selected to specifically recognize the target cell population.

52. The method of claim 51, wherein the binding element is a member of an immunological binding pair.

53. The method of claim 52, wherein the binding element is an antibody.

54. The method of claim 53, wherein the antibody is a single chain antibody.

55. The method of claim 54, wherein the single chain antibody binds to prostate specific membrane antigen.

56. The method of claim 54, wherein the single chain antibody binds to CD19.

57. The method of claim 53, wherein the T cell receptor comprises binding element-costimulatory signaling region-zeta chain portion in that order.

58. The method of claim 51, wherein the costimulatory signaling region comprises the intracellular domain of CD28.

59. The method of claim 58, wherein the costimulatory signaling region consists of a sequence encoded by the sequence of Seq. ID No. 7.

60. The method of claim 59, wherein the binding element is a member of an immunological binding pair.

61. The method of claim 60, wherein the binding element is an antibody.

62. The method of claim 61, wherein the antibody is a single chain antibody.

63. The method of claim 62, wherein the single chain antibody binds to prostate specific membrane antigen.

64. The method of claim 62, wherein the single chain antibody binds to CD19.

65. The method of claim 62, wherein the T cell receptor comprises binding element-costimulatory signaling region-zeta chain portion in that order.

66. The method of claim 51, wherein the zeta chain portion comprises a sequence encoded by the sequence of Seq. ID. No. 3.

67. The method of claim 66, wherein the binding element is a member of an immunological binding pair.

68. The method of claim 67, wherein the binding element is an antibody.

69. The method of claim 68, wherein the antibody is a single chain antibody.

70. The method of claim 69, wherein the single chain antibody binds to prostate specific membrane antigen.

71. The method of claim 69, wherein the single chain antibody binds to CD19.

72. The method of claim 69, wherein the T cell receptor comprises binding element-costimulatory signaling region-zeta chain portion in that order.

73. The method of claim 72, wherein the costimulatory signaling region comprises the intracellular domain of CD28.

74. The method of claim 73, wherein the costimulatory signaling region consists of a sequence encoded by the sequence of Seq. ID No. 7.

75. The method of claim 51, wherein the T cell receptor comprises binding element-CD28 signaling region-zeta chain portion in that order.