IP Library › Granted Patent US 9,217,030
Granted Patent B2
US 9,217,030 · App. 14/340,355 · Granted Dec 22, 2015

Humanized antibodies that recognize alpha-synuclein

Inventors: Jose Saldanha (Enfield, GB); Tarlochan S. Nijjar (Orinda, CA)
Assignee: PROTHENA BIOSCIENCES LIMITED
C07K16/18A61K2039/505C07K2317/24C07K2317/56C07K2317/565C07K2317/567C07K2317/71C07K2317/76
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Quick Facts
Patent No.
US 9,217,030
App. No.
14/340,355
Granted
Dec 22, 2015
Kind
B2
Abstract

The present application discloses humanized 1H7 antibodies. The antibodies bind to human alpha synuclein and can be used for treatment and diagnosis of Lewy body disease.

Claims (82)

1. A method of treating a patient having or at risk of a Lewy body disease, comprising administering to the patient an effective regime of an antibody that binds alpha synuclein, the antibody comprising a mature heavy chain variable region at least 95% identical to SEQ ID NO:44 and a mature light chain variable region at least 95% identical to SEQ ID NO:45.

2. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence at least 98% identical to SEQ ID NO:44 and the mature light chain variable region has an amino acid sequence at least 95% identical to SEQ ID NO:45.

3. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence at least 99% identical to SEQ ID NO:44 and the mature light chain variable region has an amino acid sequence at least 95% identical to SEQ ID NO:45.

4. The method of claim of claim 1 , wherein the mature heavy chain variable region has the amino acid sequence of SEQ ID NO:44 and the mature light chain variable region has an amino acid sequence at least 95% identical to SEQ ID NO:45.

5. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence at least 95% identical to SEQ ID NO:44 and the mature light chain variable region has an amino acid sequence at least 98% identical to SEQ ID NO:45.

6. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence at least 95% identical to SEQ ID NO:44 and the mature light chain variable region has an amino acid sequence at least 99% identical to SEQ ID NO:45.

7. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence at least 95% identical to SEQ ID NO:44 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:45.

8. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence at least 98% identical to SEQ ID NO:44 and the mature light chain variable region has an amino acid sequence at least 98% identical to SEQ ID NO:45.

9. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence at least 99% identical to SEQ ID NO:44 and the mature light chain variable region has an amino acid sequence at least 99% identical to SEQ ID NO:45.

10. The method of claim of claim 1 , provided that position L46 (Kabat numbering) is occupied by F.

11. The method of claim of claim 1 , provided that position L49 (Kabat numbering) is occupied by C.

12. The method of claim of claim 1 , provided that position L83 (Kabat numbering) is occupied by A.

13. The method of claim of claim 1 , provided that position H11 (Kabat numbering) is occupied by L.

14. The method of claim of claim 1 , provided that position H28 (Kabat numbering) is occupied by S.

15. The method of claim of claim 1 , provided that position H38 (Kabat numbering) is occupied by K.

16. The method of claim of claim 1 , provided that position H48 (Kabat numbering) is occupied by I.

17. The method of claim of claim 1 , provided that position H67 (Kabat numbering) is occupied by A.

18. The method of claim of claim 1 , provided that position H69 (Kabat numbering) is occupied by L.

19. The method of claim of claim 1 , provided that position H71 (Kabat numbering) is occupied by A.

20. The method of claim of claim 1 , provided that position H91 (Kabat numbering) is occupied by F.

21. The method of claim of claim 1 , provided that position H97 (Kabat numbering) is occupied by S.

22. The method of claim 1 , wherein the amino acid sequence of the mature heavy chain variable region is SEQ ID NO:44 and the amino acid sequence of the mature light chain variable region is SEQ ID NO:45 except provided that position L46 (Kabat numbering) can be occupied by L or F and/or position L49 (Kabat numbering) can be occupied by Y or C and/or position L83 (Kabat numbering) can be occupied by F or A, and/or position H11 (Kabat numbering) can be occupied by V or L, and/or position H28 (Kabat numbering) can be occupied by T or S, and/or position H38 (Kabat numbering) can be occupied by R or K, and/or position H48 (Kabat numbering) can be occupied by M or I, and/or position H67 (Kabat numbering) can be occupied by V or A, and/or position H69 (Kabat numbering) can be occupied by M or L, and/or position H71 (Kabat numbering) can be occupied by T or A, and/or position H91 (Kabat numbering) can be occupied by Y or F, and/or H97 (Kabat numbering) can be occupied by C or S.

23. The method of claim 22 , wherein position H71 (Kabat numbering) is occupied by A.

24. The method of claim 22 , wherein position H67 (Kabat numbering) is occupied by A, position H71 (Kabat numbering) is occupied by A.

25. The method of claim 22 , wherein position L46 (Kabat numbering) is occupied by F.

26. The method of claim 23 , wherein position L46 (Kabat numbering) is occupied by F, position L49 (Kabat numbering) is occupied by C.

27. The method of claim 22 , wherein position L46 (Kabat numbering) is occupied by F, position L49 (Kabat numbering) is occupied by Y.

28. The method of claim 22 , wherein position H67 (Kabat numbering) is occupied by A, position H71 (Kabat numbering) is occupied by A, L46 (Kabat numbering) is occupied by F, and position L49 (Kabat numbering) is occupied by C.

29. The method of any one of claims 22 - 28 , wherein position H11 (Kabat numbering) is occupied by L and position H38 (Kabat numbering) is occupied by K.

30. The method of any one of claims 22 - 28 , wherein position H11 (Kabat numbering) is occupied by V and position H38 (Kabat numbering) is occupied by R.

31. The method of claim 30 , wherein position H28 (Kabat numbering) is occupied by S, position H48 (Kabat numbering) is occupied by I, position H69 (Kabat numbering) is occupied by L, and position H91 (Kabat numbering) is occupied by F.

32. The method of claim 29 , wherein position H28 (Kabat numbering) is occupied by T, position H48 (Kabat numbering) is occupied by M, position H69 (Kabat numbering) is occupied by M, and position H91 (Kabat numbering) is occupied by Y.

33. The method of claim 22 , wherein position L83 (Kabat numbering) is occupied by A.

34. The method of claim 22 , wherein position L83 (Kabat numbering) is occupied by F.

35. The method of claim 34 , wherein position H97 (Kabat numbering) is occupied by S.

36. The method of claim 34 , wherein position H97 (Kabat numbering) is occupied by C.

37. The method of claim 22 , wherein position L46 (Kabat numbering) is occupied by F, position L49 (Kabat numbering) is occupied by C and position L83 (Kabat numbering) is occupied by A.

38. The method of claim 22 , wherein position L46 (Kabat numbering) is occupied by F, position L49 (Kabat numbering) is occupied by Y and position L83 (Kabat numbering) is occupied by A.

39. The method of claim 22 , wherein position L46 (Kabat numbering) is occupied by F, position L49 (Kabat numbering) is occupied by C and position L83 (Kabat numbering) is occupied by F.

40. The method of claim 22 , wherein position L46 (Kabat numbering) is occupied by F, position L49 (Kabat numbering) is occupied by Y and position L83 (Kabat numbering) is occupied by F.

41. The method of claim 22 , wherein position H11 (Kabat numbering) is occupied by L, position H28 (Kabat numbering) is occupied by S, position H38 (Kabat numbering) is occupied by K, position H48 (Kabat numbering) is occupied by I, position H67 (Kabat numbering) is occupied by A, position H69 (Kabat numbering) is occupied by L, position H71 (Kabat numbering) is occupied by A, position H91 (Kabat numbering) is occupied by F and position H97 (Kabat numbering) is occupied by C.

42. The method of claim 22 , wherein position H11 (Kabat numbering) is occupied by V, position H28 (Kabat numbering) is occupied by S, position H38 (Kabat numbering) is occupied by R, position H48 (Kabat numbering) is occupied by I, position H67 (Kabat numbering) is occupied by A, position H69 (Kabat numbering) is occupied by L, position H71 (Kabat numbering) is occupied by A, position H91 (Kabat numbering) is occupied by F and position H97 (Kabat numbering) is occupied by C.

43. The method of claim 22 , wherein position H11 (Kabat numbering) is occupied by V, position H28 (Kabat numbering) is occupied by T, position H38 (Kabat numbering) is occupied by R, position H48 (Kabat numbering) is occupied by M, position H67 (Kabat numbering) is occupied by A, position H69 (Kabat numbering) is occupied by M, position H71 (Kabat numbering) is occupied by A, position H91 (Kabat numbering) is occupied by Y and position H97 (Kabat numbering) is occupied by C.

44. The method of claim 22 , wherein position H11 (Kabat numbering) is occupied by V, position H28 (Kabat numbering) is occupied by S, position H38 (Kabat numbering) is occupied by R, position H48 (Kabat numbering) is occupied by I, position H67 (Kabat numbering) is occupied by A, position H69 (Kabat numbering) is occupied by L, position H71 (Kabat numbering) is occupied by A, position H91 (Kabat numbering) is occupied by F and position H97 (Kabat numbering) is occupied by S.

45. The method of claim 22 , wherein position H11 (Kabat numbering) is occupied by V, position H28 (Kabat numbering) is occupied by T, position H38 (Kabat numbering) is occupied by R, position H48 (Kabat numbering) is occupied by M, position H67 (Kabat numbering) is occupied by A, position H69 (Kabat numbering) is occupied by M, position H71 (Kabat numbering) is occupied by A, position H91 (Kabat numbering) is occupied by Y and position H97 (Kabat numbering) is occupied by S.

46. A method of treating a patient having or at risk of a Lewy body disease, comprising administering to the patient an effective regime of an antibody that binds alpha synuclein, the antibody comprising a humanized heavy chain comprising the three Kabat CDRs of SEQ ID NO:44 and a humanized light chain comprising the three CDRs of SEQ ID NO:45 provided that position L46 (Kabat numbering) is occupied by F and/or position L49 (Kabat numbering) is occupied by C and/or position L83 (Kabat numbering) is occupied by F, and/or position H11 (Kabat numbering) is occupied by V, and/or position H28 (Kabat numbering) is occupied by T, and/or position H38 (Kabat numbering) is occupied by R, and/or position H48 (Kabat numbering) is occupied by M, and/or position H67 (Kabat numbering) is occupied by A, and/or position H69 (Kabat numbering) is occupied by M, and/or position H71 (Kabat numbering) is occupied by A, and/or position H91 (Kabat numbering) is occupied by Y.

47. The method of claim 46 , wherein position L46 (Kabat numbering) is occupied by F, and position L49 (Kabat numbering) is occupied by C.

48. The method of claim 46 , wherein position H67 (Kabat numbering) is occupied by A, and position H71 (Kabat numbering) is occupied by A.

49. The method of claim 46 , wherein position L46 (Kabat numbering) is occupied by F, position H67 (Kabat numbering) is occupied by A, position H71 (Kabat numbering) is occupied by A, and position L49 (Kabat numbering) is occupied by C.

50. The method of any on of claims 46 - 49 , wherein position H11 (Kabat numbering) is occupied by V and position H38 (Kabat numbering) is occupied by R.

51. The method of any one of claims 46 - 49 , wherein position H28 (Kabat numbering) is occupied by T, position H48 (Kabat numbering) is occupied by M, position H69 (Kabat numbering) is occupied by M, and position H91 (Kabat numbering) is occupied by Y.

52. The method of any one of claims 46 - 49 , wherein position L49 (Kabat numbering) is occupied by C and position L83 (Kabat numbering) is occupied by F.

53. The method of any one of claims 46 - 49 , wherein position H28 (Kabat numbering) is occupied by T, position H48 (Kabat numbering) is occupied by M, position H69 (Kabat numbering) is occupied by M, position H91 (Kabat numbering) is occupied by Y, position L49 (Kabat numbering) is occupied by C, and position L83 (Kabat numbering) is occupied by F.

54. The method of any one of claims 46 - 49 , wherein position H97 (Kabat numbering) is occupied by C.

55. The method of claim 46 , wherein position L46 (Kabat numbering) is occupied by F, position L49 (Kabat numbering) is occupied by C, position L83 (Kabat numbering) is occupied by F, position H11 (Kabat numbering) is occupied by V, H28 (Kabat numbering) is occupied by T, position H38 (Kabat numbering) is occupied by R, position H48 (Kabat numbering) is occupied by M, position H67 (Kabat numbering) is occupied by A, position H69 (Kabat numbering) is occupied by M, position H71 (Kabat numbering) is occupied by A, position H91 (Kabat numbering) is occupied by Y.

56. A method of treating a patient having or at risk of a Lewy body disease, comprising administering to the patient an effective regime of an antibody that binds alpha synuclein, the antibody comprising a mature heavy chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:23 and a mature light chain variable region at least 90% identical to SEQ ID NO:37.

57. The method of claim 56 comprising a mature heavy chain variable region comprising the three Kabat CDRs of SEQ ID NO:23 and a mature light chain variable region comprising the three Kabat CDRs of SEQ ID NO:37, provided that position H67 (Kabat numbering) is occupied by A, H71 (Kabat numbering) is occupied by A, position L46 (Kabat numbering) is occupied by F, and position L49 (Kabat numbering) is occupied by C.

58. The method of claim 56 or 57 , further provided position L83 (Kabat numbering) is occupied by F.

59. The method of claim 58 , further provided position H97 (Kabat numbering) is occupied by C.

60. The method of claim 59 , wherein the mature heavy chain has at least 95% sequence identity to SEQ ID NO:23 and the mature light chain has at least 95% sequence identity to SEQ ID NO:37.

61. The method of claim 56 , provided any differences in CDRs of the mature heavy chain variable region and mature light variable region from SEQ ID NOs. 23 and 37 respectively reside in positions H60-H65.

62. The method of claim 61 , wherein position L83 (Kabat numbering) is occupied by F or A, position H11 (Kabat numbering) is occupied by V, H28 (Kabat numbering) is occupied by T, position H38 (Kabat numbering) is occupied by R, position H48 (Kabat numbering) is occupied by M, position H67 (Kabat numbering) is occupied by A, position H69 (Kabat numbering) is occupied by M, position H71 (Kabat numbering) is occupied by A, position H91 (Kabat numbering) is occupied by Y.

63. The method of claim 62 , further provided position L83 (Kabat numbering) is occupied by F.

64. The method of claim 62 , further provided position H97 (Kabat numbering) is occupied by C.

65. The method of claim 64 , provided that any difference in the variable region framework of the mature heavy chain variable region and SEQ ID NO:23 are one or more of position H11 (Kabat numbering) occupied by V, H28 (Kabat numbering) occupied by T, position H38 (Kabat numbering) occupied by R, position H48 (Kabat numbering) occupied by M, position H69 (Kabat numbering) occupied by M, and position H91 (Kabat numbering) occupied by Y.

66. The method of claim 64 , provided that any difference in the variable region framework of the mature light chain variable region and SEQ ID NO:37 is position L83 (Kabat numbering) occupied by F or A.

67. The method of claim 56 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:23 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:37.

68. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:44 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:45, 33, 35, 37, or 39.

69. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:19 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO: 45, 33, 35, 37, or 39.

70. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:21 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:45, 33, 35, 37, or 39.

71. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:23 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO: 45, 33, 35, 37, or 39.

72. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:25 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO: 45, 33, 35, 37, or 39.

73. The method of claim of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:27 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO: 45, 33, 35, 37, or 39.

74. The method of any one of claim 1 , 22 , 46 , or 56 , wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain constant region is fused to a light chain constant region.

75. The method of claim 74 , wherein the heavy chain constant region has the amino acid sequence designated SEQ ID NO:52 provided the C-terminal lysine residue may be omitted.

76. The method of claim 74 , wherein the light chain constant region has the amino acid sequence designated SEQ ID NO:49.

77. The method of claim 67 , wherein the mature heavy chain variable region is fused to a heavy chain constant region having the amino acid sequence designated SEQ ID NO:52 provided the C-terminal lysine residue may be omitted and the mature light chain constant region is fused to a light chain constant region having the amino acid sequence designated SEQ ID NO:49.

78. The method of claim 77 , wherein the mature light chain comprises SEQ ID NO:53 and the mature heavy chain comprises SEQ ID NO:56.

79. The method of any one of claim 1 , 22 , 46 , or 56 , wherein the heavy chain constant region is a mutant form of natural human constant region which has reduced binding to an Fcγ receptor relative to the natural human constant region.

80. The method of any one of claim 1 , 22 , 46 , or 56 , wherein the heavy chain constant region is of human IgG1 isotype.

81. The method of claim 33 , wherein position H97 (Kabat numbering) is occupied by S.

82. The method of claim 33 , wherein position H97 (Kabat numbering) is occupied by C.

Assignments (2)
CHANGE OF ADDRESS Recorded Oct 26, 2016
From: PROTHENA BIOSCIENCES LIMITED
To: PROTHENA BIOSCIENCES LIMITED
Reel/Frame 040676/0780 →
CHANGE OF NAME Recorded Oct 15, 2015
From: NEOTOPE BIOSCIENCES LIMITED
To: PROTHENA BIOSCIENCES LIMITED
Reel/Frame 036801/0619 →
Continuity (4)
Continuation 13750983 · Jan 25, 2013
Provisional Application 61591835 · Jan 27, 2012
Provisional Application 61711207 · Oct 8, 2012
Related Publication 20150056187A1 · Feb 26, 2015