Antibodies to alpha-synuclein and uses thereof

Patent metadata

Field	Value
Publication number	US-11560424-B2
Application number	US-202017111159-A
Country	US
Kind code	B2
Filing date	Dec 3, 2020
Priority date	Jun 2, 2016
Publication date	Jan 24, 2023
Grant date	Jan 24, 2023

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 human α-synuclein, wherein the antibody or antigen-binding fragment thereof comprises:
a) three heavy chain CDRs having sequences:
(i) H-CDR1 of SEQ ID NO: 25,
(ii) H-CDR2 of SEQ ID NO: 26, and
(iii) H-CDR3 of SEQ ID NO: 27, and
b) three light chain CDRs having sequences:
(i) L-CDR1 of SEQ ID NO: 31,
(ii) L-CDR2 of SEQ ID NO: 32 and
(iii) L-CDR3 of SEQ ID NO: 33.

2. The antibody or antigen-binding fragment thereof, according to claim 1 , wherein the antibody or antigen-binding fragment thereof is an IgA, IgD, IgE, IgM, IgG1, IgG2, IgG3 or IgG4 antibody or antigen-binding fragment thereof.

3. The antibody or antigen-binding fragment thereof, according to claim 1 , wherein the antibody or antigen-binding fragment thereof is an IgG1 antibody or antigen-binding fragment thereof that comprises a L234F/L235E/P331S triple mutation in the Fc region.

4. The antibody or antigen-binding fragment thereof, according to claim 1 , wherein the antibody or antigen-binding fragment thereof competes with antibody aslo0452 ngl-3 for binding to human α-synuclein.

5. The antibody or antigen-binding fragment thereof, according to claim 1 , wherein the antibody or antigen-binding fragment thereof binds to the same epitope on human α-synuclein as antibody aslo0452 ngl-3.

6. The antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody or antigen-binding fragment thereof is fused with a transporter molecule for delivery across the blood-brain barrier (BBB).

7. The antibody or antigen-binding fragment thereof according to claim 6 , wherein the transporter molecule is
a) an immunoglobulin-derived polypeptide comprising BBBt0626gl or a blood-brain barrier-penetrable fragment thereof, or
b) BBBt0626 or a blood-brain barrier-penetrable fragment thereof, or
c) or BBBt0632gl or a blood-brain barrier-penetrable fragment thereof.

8. The antibody or antigen-binding fragment thereof according to claim 7 , wherein the transporter molecule is a single chain fragment (scFv) comprising:
(i) the heavy chain variable region (VH) of BBBt0626gl of SEQ ID NO: 39 and the light chain variable region (VL) of BBBt0626gl of SEQ ID NO: 43, or
(ii) the heavy chain variable region (VH) of BBBt0626 of SEQ ID NO: 47 and the light chain variable region (VL) of BBBt0626 of SEQ ID NO: 43,
or

(iii) the heavy chain variable region (VH) of BBBt0632gl of SEQ ID NO: 48 and the light chain variable region (VL) of BBBt0632gl of SEQ ID NO: 52.

9. 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.

10. 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.

11. 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.

12. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to human, rat and cynomolgus α-synuclein.

13. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to native endogenous human α-synuclein.

14. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to aggregates of human α-synuclein.

15. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds pathological forms of α-synuclein.

16. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof reduces α-synuclein levels in the brain interstitial fluid and/or in the cerebrospinal fluid.

17. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 24.

18. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24.

19. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising the amino acid sequence of SEQ ID NO: 24.

20. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable light chain region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 30.

21. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable light chain region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 30.

22. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable light chain region comprising the amino acid sequence of SEQ ID NO: 30.

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

24. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a L234F/L235E/P331S triple mutation in the Fc region.

25. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24 and a variable light chain region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 30.

26. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a variable heavy chain region comprising the amino acid sequence of SEQ ID NO: 24 and a variable light chain region comprising the amino acid sequence of SEQ ID NO: 30.

27. 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: 22 and a light chain comprising the amino acid sequence of SEQ ID NO: 28.

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

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

30. The isolated nucleic acid molecule of claim 29 , wherein the nucleic acid molecule comprises a nucleotide sequence that is at least 90% identical to the nucleotide sequence of SEQ ID NO: 23.

31. The isolated nucleic acid

Assignees

• Medimmune Ltd

Inventors

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

Classifications

• G01N33/577

  involving monoclonal antibodies {binding reaction mechanisms characterised by the use of monoclonal antibodies (G01N33/5302 - G01N33/576 take precedence)} · CPC title

• C07K2317/524

  CH2 domain · CPC title

• G01N33/537

  with separation of immune complex from unbound antigen or antibody · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• A61K2039/505

  comprising antibodies · CPC title