Humanized antibodies that recognize alpha-synuclein

Patent metadata

Field	Value
Publication number	US-9556259-B2
Application number	US-201414156441-A
Country	US
Kind code	B2
Filing date	Jan 15, 2014
Priority date	Oct 28, 2011
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The present application discloses humanized 9E4 antibodies. The antibodies bind to human alpha synuclein and can be used for immunotherapy of Lewy body disease.

First claim

What is claimed is:

1. A method of treating a patient having or at risk of a synucleinopathy, 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:11 and a humanized light chain comprising the three Kabat CDRs of SEQ ID NO:4, provided that position L36 (Kabat numbering) is occupied by F and/or position L83 (Kabat numbering) is occupied by L and/or position H73 (Kabat numbering) is occupied by D, and/or position H93 (Kabat numbering) is occupied by S; wherein a patient at risk of a synucleinopathy has a risk factor conferring a statistically significant risk of developing the synucleinopathy compared with subjects lacking the risk factor.

2. The method of claim 1 , wherein the patient has REM sleep behavior disorder (RBD).

3. A method of detecting Lewy bodies in a patient having or at risk of a Lewy body disease, comprising administering to the patient an effective amount of an antibody that binds alpha synuclein, the antibody comprising a humanized heavy chain comprising the three Kabat CDRs of SEQ ID NO:11 and a humanized light chain comprising the three Kabat CDRs of SEQ ID NO:4, provided that position L36 (Kabat numbering) is occupied by F and/or position L83 (Kabat numbering) is occupied by L and/or position H73 (Kabat numbering) is occupied by D, and/or position H93 (Kabat numbering) is occupied by S; wherein a patient at risk of a synucleinopathy has a risk factor conferring a statistically significant risk of developing the synucleinopathy compared with subjects lacking the risk factor; and detecting bound antibody in the patient.

4. A method of reducing Lewy body formation in a patient having or at risk of a Lewy body disease, comprising administering to the patient an effective amount of an antibody that binds alpha synuclein, the antibody comprising a humanized heavy chain comprising the three Kabat CDRs of SEQ ID NO:11 and a humanized light chain comprising the three Kabat CDRs of SEQ ID NO:4, provided that position L36 (Kabat numbering) is occupied by F and/or position L83 (Kabat numbering) is occupied by L and/or position H73 (Kabat numbering) is occupied by D, and/or position H93 (Kabat numbering) is occupied by S; wherein a patient at risk of a synucleinopathy has a risk factor conferring a statistically significant risk of developing the synucleinopathy compared with subjects lacking the risk factor.

5. A method of inhibiting synuclein aggregation or reducing Lewy bodies or synuclein aggregates in a patient having or at risk of a Lewy body disease, comprising administering to the patient an effective amount of an antibody that binds alpha synuclein, the antibody comprising a humanized heavy chain comprising the three Kabat CDRs of SEQ ID NO:11 and a humanized light chain comprising the three Kabat CDRs of SEQ ID NO:4, provided that position L36 (Kabat numbering) is occupied by F and/or position L83 (Kabat numbering) is occupied by L and/or position H73 (Kabat numbering) is occupied by D, and/or position H93 (Kabat numbering) is occupied by S; wherein a patient at risk of a synucleinopathy has a risk factor conferring a statistically significant risk of developing the synucleinopathy compared with subjects lacking the risk factor.

6. The method of any of claims 1 - 3 , and 4 - 5 , wherein the synucleinopathy or Lewy body disease is Parkinson's disease.

7. The method of claim 1 , wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence designated SEQ ID NO:10 and a mature light chain variable region having an amino acid sequence designated SEQ ID NO:5.

8. The method of claim 1 , wherein position L36 (Kabat numbering) is occupied by F and position L83 (Kabat numbering) is occupied by L.

9. The method of claim 1 , wherein position L36 (Kabat numbering) is occupied by F.

10. The method of claim 1 , wherein position L83 (Kabat numbering) is occupied by L.

11. The method of claim 1 , wherein position H73 (Kabat numbering) is occupied by D.

12. The method of claim 1 , wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence of SEQ ID NO:11 and a mature light chain variable region having an amino acid sequence of SEQ ID NO:4.

13. The method of claim 1 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:10.

14. The method of claim 1 , wherein the mature light chain variable region has an amino acid sequence designated SEQ ID NO: 5.

15. The method of claim 1 , wherein position H73 (Kabat numbering) is occupied by D and position H93 (Kabat numbering) is occupied by A.

16. The method of claim 1 , wherein the mature light chain variable region has an amino acid sequence of SEQ ID NO:3, 4, or 5, and the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:8, 9, or 10.

17. The method of claim 16 , wherein the antibody further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:32.

18. The method of claim 16 , wherein the antibody further comprises a light chain constant region having the amino acid sequence of SEQ ID NO:13.

19. The method of claim 1 , wherein the antibody further comprises a heavy chain constant region of human IgG1 isotype.

20. The method of claim 1 , wherein the antibody is a Fab fragment.

21. The method of claim 3 , wherein position L36 (Kabat numbering) is occupied by F and position L83 (Kabat numbering) is occupied by L.

22. The method of claim 3 , wherein position L36 (Kabat numbering) is occupied by F.

23. The method of claim 3 , wherein position L83 (Kabat numbering) is occupied by L.

24. The method of claim 3 , wherein position H73 (Kabat numbering) is occupied by D.

25. The method of claim 3 , wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence of SEQ ID NO:11 and a mature light chain variable region having an amino acid sequence of SEQ ID NO:4.

26. The method of claim 3 , wherein the mature heavy chain variable region has an amino acid sequence designated SEQ ID NO:10 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO: 5.

27. The method of claim 3 , wherein position H73 (Kabat numbering) is occupied by D and position H93 (Kabat numbering) is occupied by A.

28. The method of claim 3 , wherein the mature light chain variable region has an amino acid sequence of SEQ ID NO:3, 4, or 5, and the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:8, 9, or 10.

29. The method of claim 28 , wherein the antibody further comprises a heavy chain constant region having the amino acid sequence of SEQ ID NO:32.

30. The method of claim 28 , wherein the antibody further comprises a light chain constant region having the amino acid sequence of SEQ ID NO:13.

31. The method of claim 3 , wherein the antibody further comprises a heavy chain constant region of human IgG1 isotype.

32. The method of claim 3 , wherein the antibody is a Fab fragment.

33. The method of claim 4 , wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence designated SEQ ID NO:10 and a mature light chain variable region having an amino

Assignees

• Neotope Biosciences Ltd
• Prothena Biosciences Ltd

Inventors

• Saldanha José William
• Nijjar Tarlochan S

Classifications

• A61K39/00 Primary

  Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53) · CPC title

• G01N33/6896

  Neurological disorders, e.g. Alzheimer's disease · CPC title

• C07K2317/567

  Framework region [FR] · CPC title

• C07K16/18 Primary

  against material from animals or humans · CPC title

• G01N2800/2835

  Movement disorders, e.g. Parkinson, Huntington, Tourette · CPC title