Protofibril-binding antibodies and their use in therapeutic and diagnostic methods for parkinson's disease, dementia with lewy bodies and other α-synucleinopathies
In an in vivo method for detecting α-synuclein protofibrils in human tissue, an antibody or fragment thereof is administered to a human. The antibody or fragment is labelled with a detectable label. A complex formed between the antibody or fragment and α-synuclein protofibrils in the human tissue is detected. The antibody or fragment has high affinity for human α-synuclein protofibrils and low affinity for α-synuclein monomers and has a combination of three specified variable heavy (VH) CDR sequences and three specified variable light (VL) CDR sequences.
1. An in vivo method for detecting α-synuclein protofibrils in human tissue, comprising administering an antibody or fragment thereof to a human, wherein the antibody or fragment thereof is labelled with a detectable label, and detecting a complex formed between the antibody or fragment thereof and α-synuclein protofibrils in the human tissue, wherein the antibody or fragment thereof has high affinity for human α-synuclein protofibrils and low affinity for α-synuclein monomers and has 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 method of claim 1 , wherein the human has or is at risk of developing a neurodegenerative disorder with α-synuclein pathology characterized by deposition of Lewy bodies and Lewy neurites.
3. The method of claim 2 , wherein the amount of detected complex is quantified for diagnosis of the neurodegenerative disorder.
4. The method of claim 2 , wherein the human has the neurodegenerative disorder and the amount of detected complex is quantified, and wherein, subsequent to the detection step, the human is administered a treatment for the neurodegenerative disorder, and thereafter, the method further comprises administering an additional quantity of the labelled antibody or fragment thereof to the human, detecting a complex formed between the antibody or fragment thereof and α-synuclein protofibrils in the human tissue, and quantifying the amount of detected complex to monitor effect of the treatment.
5. The method of claim 1 , wherein the human has or is at risk of developing a neurodegenerative disorder with α-synuclein pathology selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), the Lewy body variant of Alzheimer's disease, and multiple system atrophy (MSA).
6. The method of claim 5 , wherein the amount of detected complex is quantified for diagnosis of the neurodegenerative disorder.
7. The method of claim 5 , wherein the human has the neurodegenerative disorder and the amount of detected complex is quantified, and wherein, subsequent to the detection step, the human is administered a treatment for the neurodegenerative disorder, and thereafter, the method further comprises administering an additional quantity of the labelled antibody or fragment thereof to the human, detecting a complex formed between the antibody or fragment thereof and α-synuclein protofibrils in the human tissue, and quantifying the amount of detected complex to monitor effect of the treatment.
8. The method of claim 5 , wherein the human has or is at risk of developing Parkinson's disease.
9. The method of claim 8 , wherein the amount of detected complex is quantified for diagnosis of Parkinson's disease.
10. The method of claim 5 , wherein the human has Parkinson's disease and the amount of detected complex is quantified, and wherein, subsequent to the detection step, the human is administered a treatment for Parkinson's disease, and thereafter, the method further comprises administering an additional quantity of the labelled antibody or fragment thereof to the human, detecting a complex formed between the antibody or fragment thereof and α-synuclein protofibrils in the human tissue, and quantifying the amount of detected complex to monitor effect of the treatment.
11. The method of claim 5 , wherein the human has or is at risk of developing dementia with Lewy bodies (DLB) or the Lewy body variant of Alzheimer's disease.
12. The method of claim 11 , wherein the amount of detected complex is quantified for diagnosis of dementia with Lewy bodies (DLB) or the Lewy body variant of Alzheimer's disease.
13. The method of claim 11 , wherein the human has dementia with Lewy bodies (DLB) or the Lewy body variant of Alzheimer's disease and the amount of detected complex is quantified, and wherein, subsequent to the detection step, the human is administered a treatment for dementia with Lewy bodies (DLB) or the Lewy body variant of Alzheimer's disease, respectively, and thereafter, the method further comprises administering an additional quantity of the labelled antibody or fragment thereof to the human, detecting a complex formed between the antibody or fragment thereof and α-synuclein protofibrils in the human tissue, and quantifying the amount of detected complex to monitor effect of the treatment.
14. The method of claim 1 , wherein the antibody or fragment is labelled with a radioactive ligand.
15. The method of claim 1 , wherein the antibody is monoclonal.
16. The method of claim 15 , wherein the monoclonal antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 22, 28, 35, 41, 47 and 50.
17. The method of claim 15 , wherein the monoclonal antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 23, 29, 36, 42, 47 and 50.
18. The method of claim 15 , wherein the monoclonal antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 24, 30, 37, 43, 48 and 51.
19. The method of claim 15 , wherein the monoclonal antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 25, 31, 38, 44, 47 and 52.
20. The method of claim 15 , wherein the monoclonal antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 26, 32, 39, 45, 47 and 53.
21. The method of claim 15 , wherein the monoclonal antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 23, 33, 37, 43, 48 and 54.
22. The method of claim 15 , wherein the monoclonal antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 27, 34, 40, 46, 49 and 55.
23. The method of claim 1 , wherein the antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 22, 28, 35, 41, 47 and 50.
24. The method of claim 1 , wherein the antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 23, 29, 36, 42, 47 and 50.
25. The method of claim 1 , wherein the antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 24, 30, 37, 43, 48 and 51.
26. The method of claim 1 , wherein the antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 25, 31, 38, 44, 47 and 52.
27. The method of claim 1 , wherein the antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 26, 32, 39, 45, 47 and 53.
28. The method of claim 1 , wherein the antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 23, 33, 37, 43, 48 and 54.
29. The method of claim 1 , wherein the antibody or fragment thereof has a CDR sequence combination of SEQ ID NOS: 27, 34, 40, 46, 49 and 55.