IP Library › Granted Patent US 8,859,501
Granted Patent B2
US 8,859,501 · App. 13/957,239 · Granted Oct 14, 2014

Protofibril-binding antibodies and their use in thereapeutic and diagnostic methods for parkinson's disease, dementia with lewy bodies and other alpha-synucleinopathies

Inventors: Eva Nordström (Rönninge, SE); Alex Kasrayan (Stockholm, SE); Monica Ekberg (Stockholm, SE); Valentina Screpanti Sundquist (Spånga, SE); Lars Lannfelt (Stockholm, SE); Mats Holmquist (Sollentuna, SE)
Assignee: BioArctic Neuroscience AB
C07K16/18C07K2317/33G01N2800/2814G01N2800/2821G01N2800/302C07K2317/34G01N2800/30G01N33/6896G01N2800/2835G01N2800/387
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Quick Facts
Patent No.
US 8,859,501
App. No.
13/957,239
Granted
Oct 14, 2014
Kind
B2
Abstract

Antibodies and fragments thereof have high affinity for human α-synuclein protofibrils and low binding of α-synuclein monomers, wherein the antibodies or fragments have specified Complementarity Determining Region (CDR) sequences. Compositions comprise such an antibody or fragment and methods of detecting α-synuclein protofibrils use such an antibody or fragment. In further embodiments, methods of preventing, delaying onset of or treating a neurodegenerative disorder with α-synuclein pathology comprise administering such an antibody or fragment, and such an antibody or fragment is used in the manufacture of a pharmaceutical composition for treatment of a neurodegenerative disorder with α-synuclein pathology. Such an antibody or fragment is used in the diagnosis or monitoring of the development of a neurodegenerative disorder with α-synuclein pathology, and in methods for reducing or inhibiting α-synuclein aggregation by administration of such an antibody or fragment.

Claims (76)

1. A method of decreasing the amount of α-synuclein protofibrils in a subject, comprising administering to the individual an antibody or fragment thereof having high affinity for human α-synuclein protofibrils and low affinity for α-synuclein monomers and having a combination of three variable heavy (VH) CDR sequences and three variable light (VL) CDR sequences selected from the following combinations:

SEQ ID NOS: 22, 28, 35, 41, 47 and 50,

SEQ ID NOS: 23, 29, 36, 42, 47 and 50,

SEQ ID NOS: 24, 30, 37, 43, 48 and 51,

SEQ ID NOS: 25, 31, 38, 44, 47 and 52,

SEQ ID NOS: 26, 32, 39, 45, 47 and 53,

SEQ ID NOS: 23, 33, 37, 43, 48 and 54, and

SEQ ID NOS: 27, 34, 40, 46, 49 and 55.

2. The method of claim 1 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 22, 28, 35, 41, 47 and 50.

3. The method of claim 1 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 29, 36, 42, 47 and 50.

4. The method of claim 1 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 24, 30, 37, 43, 48 and 51.

5. The method of claim 1 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 25, 31, 38, 44, 47 and 52.

6. The method of claim 1 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 26, 32, 39, 45, 47 and 53.

7. The method of claim 1 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 33, 37, 43, 48 and 54.

8. The method of claim 1 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 27, 34, 40, 46, 49 and 55.

9. A method of treating a neurodegenerative disorder with α-synuclein pathology in an individual, or delaying onset of a neurodegenerative disorder with α-synuclein pathology in an individual at risk of developing the disorder, wherein the disorder with α-synuclein pathology is characterized by deposition of Lewy bodies and Lewy neurites, comprising administering to the individual an antibody or fragment thereof having high affinity for human α-synuclein protofibrils and low affinity for α-synuclein monomers and having a combination of three variable heavy (VH) CDR sequences and three variable light (VL) CDR sequences selected from the following combinations:

SEQ ID NOS: 22, 28, 35, 41, 47 and 50,

SEQ ID NOS: 23, 29, 36, 42, 47 and 50,

SEQ ID NOS: 24, 30, 37, 43, 48 and 51,

SEQ ID NOS: 25, 31, 38, 44, 47 and 52,

SEQ ID NOS: 26, 32, 39, 45, 47 and 53,

SEQ ID NOS: 23, 33, 37, 43, 48 and 54, and

SEQ ID NOS: 27, 34, 40, 46, 49 and 55.

10. The method of claim 9 , for delaying onset of the neurodegenerative disorder with α-synuclein pathology in an individual at risk of developing the disorder.

11. The method of claim 10 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 22, 28, 35, 41, 47 and 50.

12. The method of claim 10 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 29, 36, 42, 47 and 50.

13. The method of claim 10 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 24, 30, 37, 43, 48 and 51.

14. The method of claim 10 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 25, 31, 38, 44, 47 and 52.

15. The method of claim 10 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 26, 32, 39, 45, 47 and 53.

16. The method of claim 10 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 33, 37, 43, 48 and 54.

17. The method of claim 10 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 27, 34, 40, 46, 49 and 55.

18. The method of claim 9 , for treating the neurodegenerative disorder with α-synuclein pathology in an individual.

19. The method of claim 18 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 22, 28, 35, 41, 47 and 50.

20. The method of claim 18 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 29, 36, 42, 47 and 50.

21. The method of claim 18 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS:24, 30, 37, 43, 48 and 51.

22. The method of claim 18 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 25, 31, 38, 44, 47 and 52.

23. The method of claim 18 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 26, 32, 39, 45, 47 and 53.

24. The method of claim 18 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 33, 37, 43, 48 and 54.

25. The method of claim 18 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 27, 34, 40, 46, 49 and 55.

26. A method of treating a neurodegenerative disorder with α-synuclein pathology in an individual, or a delaying onset of a neurodegenerative disorder with α-synuclein pathology in an individual at risk of developing the disorder, wherein the disorder with α-synuclein pathology is selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), the Lewy body variant of Alzheimer's disease, and multiple system atrophy (MSA), comprising administering to the individual an antibody or fragment thereof having high affinity for human α-synuclein protofibrils and low affinity for α-synuclein monomers and having a combination of three variable heavy (VH) CDR sequences and three variable light (VL) CDR sequences selected from the following combinations:

SEQ ID NOS: 22, 28, 35, 41, 47 and 50,

SEQ ID NOS: 23, 29, 36, 42, 47 and 50,

SEQ ID NOS: 24, 30, 37, 43, 48 and 51,

SEQ ID NOS: 25, 31, 38, 44, 47 and 52,

SEQ ID NOS: 26, 32, 39, 45, 47 and 53,

SEQ ID NOS: 23, 33, 37, 43, 48 and 54, and

SEQ ID NOS: 27, 34, 40, 46, 49 and 55.

27. The method of claim 26 , wherein the neurodegenerative disorder is dementia with Lewy bodies (DLB) or the Lewy body variant of Alzheimer's disease.

28. The method of claim 26 , wherein the neurodegenerative disorder is the Lewy body variant of Alzheimer's disease.

29. The method of claim 26 , wherein the neurodegenerative disorder is dementia with Lewy bodies (DLB).

30. The method of claim 26 , wherein the neurodegenerative disorder is Parkinson's disease (PD).

31. The method of claim 30 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 22, 28, 35, 41, 47 and 50.

32. The method of claim 30 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 29, 36, 42, 47 and 50.

33. The method of claim 30 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 24, 30, 37, 43, 48 and 51.

34. The method of claim 30 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 25, 31, 38, 44, 47 and 52.

35. The method of claim 30 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 26, 32, 39, 45, 47 and 53.

36. The method of claim 30 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 33, 37, 43, 48 and 54.

37. The method of claim 30 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 27, 34, 40, 46, 49 and 55.

38. The method of claim 26 , wherein the antibody or fragment has low affinity for β-synuclein monomers.

39. The method of claim 26 , wherein the antibody or fragment has low affinity for α-synuclein fibrils.

40. The method of claim 26 , for delaying onset of the neurodegenerative disorder with α-synuclein pathology in an individual at risk for developing the disorder.

41. The method of claim 40 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 22, 28, 35, 41, 47 and 50.

42. The method of claim 40 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 29, 36, 42, 47 and 50.

43. The method of claim 40 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 24, 30, 37, 43, 48 and 51.

44. The method of claim 40 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 25, 31, 38, 44, 47 and 52.

45. The method of claim 40 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 26, 32, 39, 45, 47 and 53.

46. The method of claim 40 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 33, 37, 43, 48 and 54.

47. The method of claim 40 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 27, 34, 40, 46, 49 and 55.

48. The method of claim 26 , for treating the neurodegenerative disorder with α-synuclein pathology in an individual.

49. The method of claim 48 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 22, 28, 35, 41, 47 and 50.

50. The method of claim 48 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 29, 36, 42, 47 and 50.

51. The method of claim 48 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 24, 30, 37, 43, 48 and 51.

52. The method of claim 48 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 25, 31, 38, 44, 47 and 52.

53. The method of claim 48 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 26, 32, 39, 45, 47 and 53.

54. The method of claim 48 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 33, 37, 43, 48 and 54.

55. The method of claim 48 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 27, 34, 40, 46, 49 and 55.

Continuity (4)
Continuation 13578710
Provisional Application 61406260 · Oct 25, 2010
Provisional Application 61308638 · Feb 26, 2010
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