Human anti-alpha-synuclein antibodies
Provided are human alpha-synuclein-specific autoantibodies as well as fragments, derivatives and variants thereof as well as methods related thereto. Assays, kits, and solid supports related to antibodies specific for α-synuclein are also disclosed. The antibody, immunoglobulin chain(s), as well as binding fragments, derivatives and variants thereof can be used in pharmaceutical and diagnostic compositions for α-synuclein targeted immunotherapy and diagnosis, respectively.
1. A human monoclonal anti-α-synuclein antibody, or an α-synuclein binding fragment thereof comprising:
a VH CDR1 comprising residues 31-35 of SEQ ID NO:9, a VH CDR2 comprising residues 50-68 of SEQ ID NO:9, a VH CDR3 comprising residues 101-102 of SEQ ID NO:9, a VL CDR1 comprising residues 23-33 of SEQ ID NO:12, a VL CDR2 comprising residues 49-55 of SEQ ID NO:12, and a VL CDR3 comprising residues 88-98 of SEQ ID NO:12.
2. A human monoclonal anti-α-synuclein antibody, or an α-synuclein binding fragment thereof comprising:
a VH CDR1 comprising residues 31-35 of SEQ ID NO:3, a VH CDR2 comprising residues 50-66 of SEQ ID NO:3, a VH CDR3 comprising residues 99-110 of SEQ ID NO:3, a VL CDR1 comprising residues 23-33 of SEQ ID NO:6, a VL CDR2 comprising residues 49-55 of SEQ ID NO:6, and a VL CDR3 comprising residues 88-98 of SEQ ID NO:6.
3. A human monoclonal anti-α-synuclein antibody, or an α-synuclein binding fragment thereof comprising:
a VH CDR1 comprising residues 31-35 of SEQ ID NO:15, a VH CDR2 comprising residues 50-66 of SEQ ID NO:15, a VH CDR3 comprising residues 99-112 of SEQ ID NO:15, a VL CDR1 comprising residues 24-34 of SEQ ID NO:18, a VL CDR2 comprising residues 50-56 of SEQ ID NO:18, and a VL CDR3 comprising residues 89-96 of SEQ ID NO:18.
4. A human monoclonal anti-α-synuclein antibody, or an α-synuclein binding fragment thereof comprising:
a VH CDR1 comprising residues 31-35 of SEQ ID NO:15, a VH CDR2 comprising residues 50-66 of SEQ ID NO:15, a VH CDR3 comprising residues 99-112 of SEQ ID NO:15, a VL CDR1 comprising residues 24-34 of SEQ ID NO:21, a VL CDR2 comprising residues 50-56 of SEQ ID NO:21, and a VL CDR3 comprising residues 89-97 of SEQ ID NO:21.
5. A human monoclonal anti-α-synuclein antibody, or an α-synuclein binding fragment thereof comprising:
a) a VH region comprising the amino acid sequence of SEQ ID NO:10 and
b) a VL region comprising the amino acid sequence of SEQ ID NO:13.
6. A human monoclonal anti-α-synuclein antibody, or an α-synuclein binding fragment thereof comprising:
a) a VH region comprising the amino acid sequence of SEQ ID NO:4 and
b) a VL region comprising the amino acid sequence of SEQ ID NO:7.
7. A human monoclonal anti-α-synuclein antibody, or an α-synuclein binding fragment thereof comprising:
a) a VH region comprising the amino acid sequence of SEQ ID NO:16 and
b) a VL region comprising the amino acid sequence of SEQ ID NO:19.
8. A human monoclonal anti-α-synuclein antibody, or an α-synuclein binding fragment thereof comprising:
a) a VH region comprising the amino acid sequence of SEQ ID NO:16 and
b) a VL region comprising the amino acid sequence of SEQ ID NO:22.
9. The antibody or α-synuclein binding fragment thereof of claims 1 - 8 , which is
(i) detectably labeled, wherein the detectable label is selected from the group consisting of an enzyme, a radioisotope, a fluorophore and a heavy metal; or
(ii) attached to a drug.
10. The antibody or α-synuclein binding fragment thereof of any one of claims 1 - 8 comprising a human IgG1 heavy chain constant region.
11. The antibody or α-synuclein binding fragment thereof of claim 10 comprising a human lambda light chain constant region.
12. The antibody or α-synuclein binding fragment thereof of any one of claims 1 - 8 comprising a human lambda light chain constant region.
13. A composition comprising the antibody or α-synuclein binding fragment thereof of any one of claims 1 - 8 wherein the composition is
(i) a pharmaceutical composition further comprising a pharmaceutically acceptable carrier; or
(ii) a diagnostic composition further comprising one or more immuno or nucleic acid based diagnostic reagents.
14. A kit for the diagnosis of a synucleinopathic disease, said kit comprising the antibody or α-synuclein binding fragment thereof of any one of claims 1 - 8 with reagents and/or instructions for use.
15. The kit of claim 14 , wherein the synucleinopathic disease is Parkinson's disease.
16. A polynucleotide encoding the antibody or α-synuclein binding fragment thereof of any one of claims 1 - 8 .
17. A vector comprising the polynucleotide of claim 16 .
18. A host cell comprising a the vector of claim 17 .
19. A method for preparing an anti-α-synuclein antibody or fragment thereof, said method comprising
(a) culturing the cell of claim 18 ; and
(b) isolating said antibody or fragment hereof from the culture.
20. A method of treating synucleinopathic disease in a subject, comprising administering a therapeutically effective dose of the antibody or α-synuclein binding fragment thereof of any one of claims 1 - 8 .
21. The method of claim 20 , wherein the synucleinopathic disease is Parkinson's disease.
22. The method of claim 21 , wherein the human monoclonal anti-α-synuclein antibody, or an α-synuclein binding fragment thereof, comprises:
a VH CDR1 comprising residues 31-35 of SEQ ID NO:9, a VH CDR2 comprising residues 50-68 of SEQ ID NO:9, a VH CDR3 comprising residues 101-102 of SEQ ID NO:9, a VL CDR1 comprising residues 23-33 of SEQ ID NO:12, a VL CDR2 comprising residues 49-55 of SEQ ID NO:12, and a VL CDR3 comprising residues 88-98 of SEQ ID NO:12.
23. The method of claim 21 , wherein the human monoclonal anti-α-synuclein antibody, or an α-synuclein binding fragment thereof, comprises:
a) a VH region comprising the amino acid sequence of SEQ ID NO:10 and
b) a VL region comprising the amino acid sequence of SEQ ID NO:13.
24. A method of diagnosing a synucleinopathic disease in a subject, the method comprising:
(a) assessing a level of α-synuclein in a sample from the subject to be diagnosed with the antibody or α-synuclein binding fragment thereof of any one of claims 1 - 8 ; and
(b) comparing the level of the α-synuclein to a control,
wherein a difference or similarity between the level of the α-synuclein and the indicates that the subject has a synucleinopathic disease.
25. The method of claim 24 , wherein the synucleinopathic disease is Parkinson's disease.
26. A method for in vivo detection of or targeting a therapeutic and/or diagnostic agent to α-synuclein in the human or animal body, comprising administering a composition comprising the antibody or α-synuclein binding fragment thereof of any one of claims 1 - 8 attached to a therapeutic or diagnostic agent, wherein α-synuclein is detected by positron emission tomography (PET), single photon emission tomography (SPECT), near infrared (NIR) optical imaging, magnetic resonance imaging (MRI), or a combination thereof.