Antibodies recognizing α-synuclein

• US 10,669,331 B2
• Filed: 04/16/2019
• Issued: 06/02/2020
• Est. Priority Date: 10/08/2012
• Status: Active Grant

• Current Assignee: Prothena Biosciences Limited
• Original Assignee: Prothena Biosciences Limited
• Inventors: Barbour, Robin, Games Thiel, Kate Dora, Nijjar, Tarlochan S.
• Primary Examiner(s): Fontainhas, Aurora M
• Application Number:
  US16/385,968
• Publication Number:
  US 20190315843A1
• Time in Patent Office: 413 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/6056 Antibodies
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/28 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 Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/14 Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

The invention provides monoclonal antibody 5C1 and related antibodies. The 5C1 antibody binds to an epitope within residues 118-126 of α-synuclein. The antibodies of the invention are useful, for example, for treating and/or diagnosing disorders associated with α-synuclein, particularly accumulation of α-synuclein deposits. Such disorders include Lewy body diseases, such as Parkinson'"'"'s disease, Diffuse Lewy Body Disease (DLBD), Lewy body variant of Alzheimer'"'"'s disease (LBV), Combined Alzheimer'"'"'s and Parkinson disease, pure autonomic failure and multiple system atrophy (MSA).

Claims

1. A nucleic acid encoding the heavy and light chains of an antibody comprising a mature heavy chain variable region comprising three CDRs of SEQ ID NO:

17 and having an amino acid sequence at least 90% identical to SEQ ID NO;

17 and a mature light chain variable region comprising three CDRs of SEQ ID NO;

31 and having an amino acid sequence at least 90% identical to SEQ ID NO;

31, wherein the antibody specifically binds to human alpha synuclein.

2. The nucleic acid of claim 1, wherein the antibody comprises three Kabat CDRs of SEQ ID NOS:

10-12, respectively and three Kabat CDRs of SEQ ID NOS;

25-27, respectively.

3. The nucleic acid of claim 1, wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence at least 95% identical to SEQ ID NO:

17 and a mature light chain variable region at least 95% identical to SEQ ID NO;

31.

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

17 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO;

31.

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

18 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO;

31.

6. The nucleic acid of claim 2, provided positions H11, H27, H30, H48, and H73 of the mature heavy chain variable region are occupied by L, Y, T, I, and K, respectively, and positions L12 and L14 of the mature light chain variable region are occupied by S.

7. The nucleic acid of claim 2, provided at least one of the positions H67, H69, and H94 of the mature heavy chain variable region is occupied by A, L, and S, respectively.

8. The nucleic acid of claim 7, provided positions H67, H69, and H94 of the mature heavy chain variable region are occupied by A, L, and S, respectively.

9. The nucleic acid of claim 8, provided positions L2, L49, and L87 of the mature light chain variable region are occupied by V, N, and F, respectively.

10. The nucleic acid of claim 1 encoding the mature heavy chain variable region fused to a heavy chain constant region and the mature light chain variable region is-fused to a light chain constant region.

11. The nucleic acid of claim 10, wherein the heavy chain constant region is a mutant form of a natural human heavy chain constant region which has reduced binding to an Fey receptor relative to the natural human heavy chain constant region.

12. The nucleic acid of claim 10, wherein the heavy chain constant region is an IgG1 isotype.

13. The nucleic acid of claim 10, wherein the mature heavy chain variable region is fused to a heavy chain constant region having the sequence of SEQ ID NO:

38 and/or the mature light chain variable region is fused to a light chain constant region having the sequence of SEQ ID NO;

40.

14. The nucleic acid of claim 1 having a sequence comprising any of SEQ ID NOS:

19-23 and any of SEQ ID NOS. 33-37.

15. A recombinant expression vector comprising a nucleic acid according to claim 1.

16. A host cell transformed with the recombinant expression vector according to claim 15.

17. The vector of claim 15, wherein the antibody is an Fv fragment.

18. The vector of claim 15, wherein the antibody is a Fab fragment.

19. The vector of claim 15, comprising one or more regulatory sequences selected from a promoter, enhancer, ribosome binding site, and transcription termination signal.

20. The vector of claim 15, wherein the nucleic acid further encodes signal peptides fused to the mature heavy and light chain variable regions.

21. The vector of claim 15, wherein the nucleic acid is codon-optimized for expression in a host cell.

22. A mammalian host cell comprising a first and second vector comprising nucleic acids encoding a mature heavy chain variable region and a mature light chain variable region, respectively, each operably linked to one or more regulatory sequences to effect expression an antibody comprising a mature heavy chain variable region comprising three CDRs of SEQ ID NO:

17 and having an amino acid sequence at least 90% identical to SEQ ID NO;

17 and a mature light chain variable region comprising three CDRs of SEQ ID NO;

31 and having an amino acid sequence at least 90% identical to SEQ ID NO;

31, wherein the antibody specifically binds to human alpha synuclein.