Antibodies to α-synuclein and uses thereof

Patent metadata

Field	Value
Publication number	US-10160800-B2
Application number	US-201715611416-A
Country	US
Kind code	B2
Filing date	Jun 1, 2017
Priority date	Jun 2, 2016
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

The invention provides antibodies that specifically bind human α-synuclein with a high affinity and reduces α-synuclein spreading in vivo, recombinant polypeptides comprising said antibodies or antigen-binding fragment thereof and methods for generating such polypeptides, as well as compositions and methods for generating α-synuclein antibodies, and methods of using α-synuclein antibodies for the treatment of diseases of the central nervous system, in particular alpha-synucleinopathies.

First claim

The invention claimed is:

1. An antibody, or antigen-binding fragment thereof that binds to human α-synuciein, wherein the antibody or antigen-binding fragment thereof comprises:
a) three heavy chain CDRs having sequences:
(i) H-CDR1 of SEQ ID NO: 5,
(ii) H-CDR2 of SEQ ID NO: 15; and
(iii) H-CDR3 of SEQ ID NO: 16, and

b) three light chain CDRs having sequences:
(i) L-CDR1 of SEQ ID NO: 20,
(ii) L-CDR2 of SEQ ID NO: 10; and
(iii) L-CDR3 of SEQ ID NO: 21.

2. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to human α-synuclein with a K D of less than 500 pM.

3. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof reduces cell to cell transfer of α-synuclein in vivo.

4. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds human α-synuclein but not human β-synuclein or human γ-synuclein.

5. The antibody or antigen-binding fragment thereof of claim 2 , wherein the antibody or antigen-binding fragment thereof binds to human, rat and cynomolgus α-synuclein.

6. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 14.

7. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 14.

8. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 14.

9. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable light chain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ. ID NO: 19.

10. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable light chain comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19.

11. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable light chain comprising the amino acid sequence of SEQ ID NO: 19.

12. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 12.

13. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 12.

14. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 17.

15. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence of SEQ ID NO: 17.

16. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 14, and wherein the antibody or antigen-binding fragment thereof further comprises a variable light chain comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19.

17. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding, fragment thereof comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 14, and wherein the antibody or antigen-binding fragment thereof further comprises a variable light chain comprising the amino acid sequence of SEQ ID NO: 19.

18. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 12 and, wherein the antibody or antigen-binding fragment thereof further comprises a light chain comprising the amino acid sequence of SEQ ID NO: 17.

19. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is an antibody.

20. The antibody of claim 1 , wherein the antibody comprises a L234F/L235E/P331S triple mutation in the Fc region.

21. A pharmaceutical composition comprising an antibody, or antigen-binding fragment thereof, according to claim 1 , and a pharmaceutically acceptable excipient.

22. An isolated nucleic acid molecule encoding the antibody, or antigen-binding, fragment thereof, according to claim 1 .

23. The isolated nucleic acid molecule of claim 22 , wherein the nucleic acid molecule comprises a nucleotide sequence that is at least 90% identical to the nucleotide sequence of SEQ ID NO: 13.

24. The isolated nucleic acid molecule of claim 22 , wherein the nucleic acid molecule comprises a nucleotide sequence that is at least 90% identical to the nucleotide sequence of SEQ ID NO: 18.

25. A host cell comprising a vector comprising the nucleic acid molecule of claim 22 .

26. A method of treating an α-synucleinopathy disease of the central nervous system (CNS) in a patient, the method comprising administering to the patient an antibody, or antigen-binding fragment thereof, according to claim 1 .

27. The method according to claim 26 , wherein the disease is Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA).

Assignees

• Medimmune Ltd

Inventors

• Schofield Darren
• Perkinton Michael
• Irving Lorraine
• Thom George

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title