Prevention and treatment of synucleinopathic and amyloidogenic disease

• US 8,092,801 B2
• Filed: 02/25/2008
• Issued: 01/10/2012
• Est. Priority Date: 02/23/2007
• Status: Active Grant

• Current Assignee: Prothena Biosciences Limited, Regents of the University of California (University of California)
• Original Assignee: Neotope Biosciences Limited (Prothena Corp. Plc)
• Inventors: Schenk, Dale B., Masliah, Eliezar, Buttini, Manuel J., Chilcote, Tamie J., Rockenstein, Edward, Games, Kate Dora
• Primary Examiner(s): Kolker, Daniel E
• Application Number:
  US12/037,081
• Publication Number:
  US 20100278814A1
• Time in Patent Office: 1,415 Days
• Field of Search: None
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/55566 Emulsions, e.g. Freund's adjuvant, MF59
• CPC Class Codes: A61K 2039/6056 Antibodies
• CPC Class Codes: A61K 39/0007 Nervous system antigens; Prions
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 16/28 against receptors, cell surface antigens or cell surface determinants
• 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 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2317/80 remaining in the (producing) cell, i.e. intracellular antibodies or intrabodies
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The invention provides improved agents and methods for treatment of diseases associated with synucleinopathic diseases, including Lewy bodies of alpha-synuclein in the brain of a patient. Such methods entail administering agents that induce a beneficial immunogenic response against the Lewy body. The methods are particularly useful for prophylactic and therapeutic treatment of Parkinson'"'"'s disease.

Claims

1. A method of treating, reducing the risk of, lessening the severity of, or delaying the outset of a disease characterized by Lewy bodies or alpha-synuclein aggregation in the brain, the method comprising administering to a patient having or at risk of the disease an effective regime of an antibody that specifically binds to an epitope within residues 118-126 of intact human alpha-synuclein, residues being numbered according to SEQ ID NO:

1.

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

3. The method of claim 1, wherein the antibody is a monoclonal antibody.

4. The method of claim 3, wherein the antibody is a chimeric antibody, a human antibody, or a humanized antibody.

5. The method of claim 4, wherein the antibody is monoclonal antibody 9E4 (ATCC accession number PTA-8221) or humanized or chimeric 9E4.

6. The method of claim 3, wherein the antibody is an antibody of human IgG1 isotype.

7. The method of claim 1 wherein the antibody competes with mouse monoclonal antibody 9E4 (ATCC accession number PTA-8221) for binding to human alpha-synuclein.

8. The method of claim 1, wherein the antibody is administered with a pharmaceutical carrier as a pharmaceutical composition.

9. The method of claim 8, wherein the antibody is administered at a dosage of 0.0001 to 100 mg antibody/kg body weight.

10. The method of claim 8, wherein the antibody is administered in multiple dosages over at least six months.

11. The method of claim 8, wherein the antibody is administered intraperitoneally, orally, subcutaneously, intracranially, intramuscularly, topically, intranasally or intravenously.

12. The method of claim 1, wherein the antibody is administered by a peripheral route.

13. The method of claim 1, wherein the antibody is administered at a dose of 1-10 mg/kg.

14. The method of claim 1, wherein the antibody is humanized 9E4 and comprises the CDRs of mouse monoclonal 9E4 (ATCC accession number PTA-8221) as defined by Kabat.

15. The method of claim 1, wherein the antibody is humanized 9E4 and comprises the CDRs of mouse 9E4 (ATCC accession number PTA-8221) as defined by Chothia.