Antibodies recognizing α-synuclein

• US 10,081,674 B2
• Filed: 02/10/2017
• Issued: 09/25/2018
• Est. Priority Date: 10/08/2012
• Status: Expired due to Fees

• Current Assignee: Prothena Biosciences Limited
• Original Assignee: Prothena Biosciences Limited
• Inventors: Barbour, Robin, Games Thiel, Kate Dora, Nijjar, Tarlochan S.
• Primary Examiner(s): Weidner, Adam M
• Assistant Examiner(s): Fontainhas, Aurora M
• Application Number:
  US15/429,962
• Publication Number:
  US 20170152310A1
• Time in Patent Office: 592 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 method of treating, reducing risk, lessening severity or delaying onset of a Lewy body disease in a patient having or at risk of a Lewy body disease comprising administering to the patient an effective regime of an antibody comprising three light chain CDRs and three heavy chain CDRs of monoclonal antibody 5C1, wherein 5C1 is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:

9 and light chain variable region having an amino acid sequence comprising SEQ ID NO;

24 and thereby treating, reducing risk, lessening severity or delaying onset of the disease.

2. The method of claim 1, wherein the disease is Parkinson'"'"'s disease.

3. The method of claim 1, wherein the disease is multiple system atrophy (MSA) or Dementia with Lewy Bodies (DLB).

4. The method of claim 1, wherein the method inhibits decline of cognitive function in the patient.

5. The method of claim 1, wherein the method reduces neuritic and/or axonal alpha synuclein aggregates.

6. The method of claim 1, wherein the method reduces neuritic dystrophy in the patient.

7. The method of claim 1, wherein the method preserves synaptic and/or dendritic densities.

8. The method of claim 1, where in the antibody comprises three heavy chain CDRs of SEQ ID NO:

9 as defined by Kabat and three light chain CDRs of SEQ ID NO;

24 as defined by Kabat.

9. The method of claim 1, wherein the antibody has a human IgG1 Isotype.

10. The method of claim 1, wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:

17 and a mature light chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO;

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

11. The method of claim 1, wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region.

12. The method of claim 11, 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.

13. The method of claim 11, wherein the mature heavy chain variable region has an amino acid sequence comprising SEQ ID NO:

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

31.

14. 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 comprising three light chain CDRs and three heavy chain CDRs of monoclonal antibody 5C1, wherein 5C1 is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:

9 and light chain variable region having an amino acid sequence comprising SEQ ID NO;

24 and thereby inhibiting synuclein aggregation or reducing Lewy bodies or synuclein aggregates.

15. The method of claim 14, wherein the disease is Parkinson'"'"'s disease.

16. The method of claim 14, wherein the disease is multiple system atrophy (MSA) or Dementia with Lewy Bodies (DLB).

17. The method of claim 14, wherein the method inhibits decline of cognitive function in the patient.

18. The method of claim 14, wherein the method reduces neuritic and/or axonal alpha synuclein aggregates.

19. The method of claim 14, wherein the method reduces neuritic dystrophy in the patient.

20. The method of claim 14, wherein the method preserves synaptic and/or dendritic densities.

21. The method of claim 14, wherein the antibody comprises three heavy chain CDRs of SEQ ID NO:

9 as defined by Kabat and three light chain CDRs of SEQ ID NO;

24 as defined by Kabat.

22. The method of claim 14, wherein the antibody has a human IgG1 isotype.

23. The method of claim 14, wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:

17 and a mature light chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO;

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

24. The method of claim 14, wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region.

25. The method of claim 24, 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.

26. The method of claim 24, wherein the mature heavy chain variable region has an amino acid sequence comprising SEQ ID NO:

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

31.