Protofibril-binding antibodies and their use in therapeutic and diagnostic methods for Parkinson's disease, dementia with lewy bodies and other α-synucleinopathies
Antibodies and fragments thereof have high affinity for human α-synuclein protofibrils and low binding of α-synuclein monomers, wherein the antibodies or fragments have specified Complementarity Determining Region (CDR) sequences. Compositions comprise such an antibody or fragment and methods of detecting α-synuclein protofibrils use such an antibody or fragment. In further embodiments, methods of preventing, delaying onset of or treating a neurodegenerative disorder with α-synuclein pathology comprise administering such an antibody or fragment, and such an antibody or fragment is used in the manufacture of a pharmaceutical composition for treatment of a neurodegenerative disorder with α-synuclein pathology. Such an antibody or fragment is used in the diagnosis or monitoring of the development of a neurodegenerative disorder with α-synuclein pathology, and in methods for reducing or inhibiting α-synuclein aggregation by administration of such an antibody or fragment.
1. An isolated antibody or fragment thereof having high affinity for human α-synuclein protofibrils and low binding of α-synuclein monomers and having a combination of three variable heavy (VH) CDR sequences and three variable light (VL) CDR sequences selected from the following combinations:
SEQ ID NOS: 22, 28, 35, 41, 47 and 50,
SEQ ID NOS: 23, 29, 36, 42, 47 and 50,
SEQ ID NOS: 24, 30, 37, 43, 48 and 51,
SEQ ID NOS: 25, 31, 38, 44, 47 and 52,
SEQ ID NOS: 26, 32, 39, 45, 47 and 53,
SEQ ID NOS: 23, 33, 37, 43, 48 and 54, and
SEQ ID NOS: 27, 34, 40, 46, 49 and 55.
2. The antibody or fragment according to claim 1 , having a CDR sequence combination of SEQ ID NOS: 22, 28, 35, 41, 47 and 50.
3. The antibody or fragment according to claim 1 , having a CDR sequence combination of SEQ ID NOS: 23, 29, 36, 42, 47 and 50.
4. The antibody or fragment according to claim 1 , having a CDR sequence combination of SEQ ID NOS: 24, 30, 37, 43, 48 and 51.
5. The antibody or fragment according to claim 1 , having a CDR sequence combination of SEQ ID NOS: 25, 31, 38, 44, 47 and 52.
6. The antibody or fragment according to claim 1 , having a CDR sequence combination of SEQ ID NOS: 26, 32, 39, 45, 47 and 53.
7. The antibody or fragment according to claim 1 , having a CDR sequence combination of SEQ ID NOS: 23, 33, 37, 43, 48 and 54.
8. The antibody or fragment according to claim 1 , having a CDR sequence combination of SEQ ID NOS: 27, 34, 40, 46, 49 and 55.
9. A pharmaceutical composition comprising an antibody or fragment according to claim 1 , and a pharmaceutically acceptable carrier.
10. The composition according to claim 9 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 22, 28, 35, 41, 47 and 50.
11. The composition according to claim 9 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 29, 36, 42, 47 and 50.
12. The composition according to claim 9 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 24, 30, 37, 43, 48 and 51.
13. The composition according to claim 9 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 25, 31, 38, 44, 47 and 52.
14. The composition according to claim 9 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 26, 32, 39, 45, 47 and 53.
15. The composition according to claim 9 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 33, 37, 43, 48 and 54.
16. The composition according to claim 9 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 27, 34, 40, 46, 49 and 55.
17. A method of detecting α-synuclein protofibrils, comprising the steps of
adding the antibody or fragment according to claim 1 to a biological sample comprising or suspected of comprising α-synuclein protofibrils, and
detecting the presence of a complex formed between α-synuclein protofibril and said antibody or fragment.
18. The method according to claim 17 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 22, 28, 35, 41, 47 and 50.
19. The method according to claim 17 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 29, 36, 42, 47 and 50.
20. The method according to claim 17 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 24, 30, 37, 43, 48 and 51.
21. The method according to claim 17 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 25, 31, 38, 44, 47 and 52.
22. The method according to claim 17 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 26, 32, 39, 45, 47 and 53.
23. The method according to claim 17 wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 23, 33, 37, 43, 48 and 54.
24. The method according to claim 17 , wherein the antibody or fragment has a CDR sequence combination of SEQ ID NOS: 27, 34, 40, 46, 49 and 55.
25. Method for reducing the amount of α-synuclein oligomers in a subject in need thereof by administration of an antibody or fragment according to claim 1 to the subject.