Alpha-synuclein antibodies and uses thereof
The invention describes antibodies having a high affinity for aggregated forms of α-synuclein and a low affinity for monomeric forms of α-synuclein. The antibodies are useful in the diagnosis of neurodegenerative diseases.
1. An antibody or fragment thereof having high binding affinity for α-synuclein oligomers, high binding affinity to α-synuclein fibrils, and low binding affinity for α-synuclein monomers
wherein the antibody or fragment thereof comprises a VH chain wherein the CDR1 region has the amino acid sequence of SEQ ID NO:16, SEQ ID NO:28, or SEQ ID NO:40; wherein the CDR2 region has the amino acid sequence of SEQ ID NO:17, SEQ ID NO:29, or SEQ ID NO:41; and wherein the CDR3 region has the amino acid sequence of SEQ ID NO:18, SEQ ID NO:30, or SEQ ID NO:42;
and/or wherein the antibody or fragment thereof comprises a VL chain wherein the CDR1 region has the amino acid sequence SEQ ID NO:22, SEQ ID NO:34, or SEQ ID NO:46; wherein the CDR2 has the amino acid sequence of SEQ ID NO:23, SEQ ID NO:35, or SEQ ID NO:47; and wherein the CDR3 region has the amino acid sequence of SEQ ID NO:24, SEQ ID NO:36, or SEQ ID NO:48.
2. The antibody or fragment thereof according to claim 1 comprising an immunoglobin heavy chain variable region (VH), wherein the wherein the VH comprises the amino acid sequence as shown in SEQ ID NO:2, SEQ ID NO: 6 or SEQ ID NO: 10.
3. The antibody or fragment thereof according to claim 1 comprising an immunoglobin light chain variable region (VL), wherein the wherein the VL comprises the amino acid sequence as shown in SEQ ID NO:4, SEQ ID NO: 8 or SEQ ID NO: 12.
4. The antibody or fragment thereof according to claim 1 comprising an immunoglobin heavy chain variable region (VH) and an immunoglobin light chain variable region (VL), wherein the VH and VL comprise, respectively, the amino acid sequence as shown in SEQ ID NO:2 and SEQ ID NO:4, SEQ ID NO:6 and SEQ ID NO: 8, or SEQ ID NO:10 and SEQ ID NO: 12.
5. The antibody or fragment thereof according to claim 1 comprising:
a VH chain wherein the CDR1 region has the amino acid sequence of SEQ ID NO:16, SEQ ID NO:28, or SEQ ID NO: 40; wherein the CDR2 region has the amino acid sequence of SEQ ID NO:17, SEQ ID NO:29, or SEQ ID NO: 41; and wherein the CDR3 region has the amino acid sequence of SEQ ID NO:18, SEQ ID NO:30, or SEQ ID NO: 42; and
a VL chain wherein the CDR1 region has the amino acid sequence SEQ ID NO:22, SEQ ID NO:34, or SEQ ID NO: 46; wherein the CDR2 has the amino acid sequence of SEQ ID NO:23, SEQ ID NO:35, or SEQ ID NO: 47; and wherein the CDR3 region has the amino acid sequence of SEQ ID NO:24, SEQ ID NO:36, or SEQ ID NO: 48.
6. An antibody or fragment thereof according to claim 1 wherein the antibody or fragment thereof has a dissociation constant, Kd, of less than 10 −7 M for human α-synuclein oligomers and fibrils.
7. An antibody or fragment thereof according to claim 1 wherein the antibody or fragment thereof has a dissociation constant, Kd, of more than 10 −5 M for monomeric α-synuclein.
8. An antibody or fragment thereof according to claim 1 wherein the antibody has a higher affinity for α-synuclein fibrils than for oligomeric forms of α-synuclein.
9. An antibody or fragment thereof according to claim 1 wherein the antibody or fragment thereof binds to an epitope comprising a C-terminal region of α-synuclein.
10. An antibody or fragment thereof according to claim 1 wherein the antibody or fragment thereof is a conformational antibody.
11. An antibody or fragment thereof according to claim 1 wherein the antibody or fragment thereof do not recognise a linear epitope of α-synuclein.
12. An antibody or fragment thereof according to claim 1 wherein the antibody is a monoclonal antibody.
13. An antibody or fragment thereof according to claim 1 for use as a medicament.
14. A pharmaceutical composition comprising an antibody or fragment thereof according to claim 1 and a pharmaceutically acceptable diluent or carrier.
15. An antibody or fragment thereof according to claim 1 for use as an imaging agent.
16. An antibody or fragment thereof according to claim 1 wherein the antibody is bound to a detectable label.
17. An antibody or fragment thereof according to claim 16 wherein the detectable label is selected from a fluorescent label, a radioactive label or a contrast agent.
18. A test kit for use in a method of determining whether or not an individual has a neurodegenerative disease comprising an antibody or fragment thereof according to claim 1 .
19. A method for treating a neurodegenerative disorder with α-synuclein pathology in an individual comprising administrating an antibody or fragment thereof according to claim 1 to the individual.
20. A method according to claim 19 , wherein the neurodegenerative disorder is Parkinson's disease, dementia with Lewy Bodies, Alzheimer's disease, multiple system atrophy, psychosis, schizophrenia or Creutzfeldt-Jakob disease.
21. A method of detecting α-synuclein fibrils and aggregates comprising the steps of
adding the antibody or fragment thereof according to claim 1 to a biological sample, and
detecting the presence of a complex formed between α-synuclein fibrils and/or aggregates and the antibody or fragment.
22. A method for imaging α-synuclein aggregates comprising
administering the antibody or fragment thereof according to claim 1 to an individual, and
detecting the antibody.
23. The method according to claim 22 wherein the antibody comprises a detectable label.
24. A method for diagnosing a neurodegenerative disease associated with α-synuclein comprising:
adding the antibody or fragment thereof according to claim 1 to a biological sample from a subject, and
detecting the presence or absence of a complex formed between α-synuclein aggregates and the antibody or fragment.