Bacteriophage gene 3 protein compositions and use as amyloid binding agents
The invention relates to agents and to pharmaceutical compositions for reducing the formation of amyloid and/or for promoting the disaggregation of amyloid proteins. The compositions may also be used to detect amyloid.
1. A method of treating a subject for a disease or disorder associated with misfolded and/or aggregated amyloid beta, tau, α-synuclein, and/or prion protein, comprising administering to the subject an amyloid-binding polypeptide, wherein the polypeptide comprises at least one of:
(a) a wild-type M13 g3p (SEQ ID NO:1),
(b) an amyloid-binding fragment of wild-type M13 g3p, or
(c) a mutant of (a) or (b) that is at least 95% identical to SEQ ID NO:1 or an amyloid-binding fragment of SEQ ID NO:1;
and wherein the subject is not administered a filamentous bacteriophage.
2. The method of claim 1 , wherein the amyloid-binding polypeptide comprises the N2 domain of wild-type g3p or a corresponding fragment of a mutant g3p.
3. The method of claim 1 , wherein the wild-type g3p or amyloid-binding fragment of wild-type g3p is identical to SEQ ID NO:1 or an amyloid-binding fragment of SEQ ID NO:1.
4. The method of claim 1 , wherein the amyloid-binding polypeptide is at least 95% identical to SEQ ID NO:1 or an amyloid-binding fragment of SEQ ID NO:1.
5. The method of claim 1 , wherein the amyloid-binding polypeptide is at least 98% identical to the SEQ ID NO:1 or an amyloid-binding fragment of SEQ ID NO:1.
6. The method of claim 1 , wherein the amyloid-binding polypeptide is at least 95% identical to the N1-N2 domains of SEQ ID NO:1.
7. The method of claim 1 , wherein the amyloid-binding polypeptide comprises the N1-N2 domains of wild-type g3p or a corresponding fragment of a mutant g3p.
8. The method of claim 1 , wherein the amyloid-binding polypeptide comprises wild-type or mutant full-length g3p.
9. The method of claim 1 , wherein the amyloid-binding polypeptide comprises an N1-N2 fragment of g3p, wherein the hinge region of N2 is mutated to result in a polypeptide with reduced hinge melting temperature and higher affinity for amyloid as compared to a corresponding wild type M13 phage polypeptide.
10. The method of claim 1 , wherein the disease or disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, prion diseases, and tauopathies.
11. The method of claim 10 , wherein the prion disease is bovine spongiform encephalitis.
12. The method of claim 10 , wherein the disease or condition is Alzheimer's disease.
13. The method of claim 12 , wherein the Alzheimer's disease is selected from early onset Alzheimer's disease, late onset Alzheimer's disease and presymptomatic Alzheimer's disease.
14. The method of claim 1 , wherein the subject is positive for the biomarker florbetapir when that biomarker is used as an imaging agent in positron emission tomography.
15. The method of claim 1 , wherein the amyloid-binding polypeptide is capable of reducing amyloid, inhibiting amyloid formation, inhibiting amyloid aggregation, or removing toxic oligomer, or preventing toxic oligomer formation.
16. A method of treating a subject for a disease or disorder associated with misfolded and/or aggregated amyloid beta, tau, α-synuclein, and/or prion protein, comprising administering to the subject a fusion protein, wherein the fusion protein comprises an amyloid-binding polypeptide and an immunoglobulin constant region, wherein the amyloid-binding polypeptide comprises at least one of:
(a) a wild-type M13 g3p (SEQ ID NO: 1),
(b) an amyloid-binding fragment of wild-type M13 g3p, or
(c) a mutant of (a) or (b) that is at least 95% identical to SEQ ID NO: 1 or an amyloid-binding fragment of SEQ ID NO: 1.
17. The method of claim 16 , wherein the immunoglobulin constant region is an immunoglobulin Fc fragment.
18. The method of claim 17 , wherein the immunoglobulin Fc fragment is an Fc fragment of IgG or IgM.
19. The method of claim 18 , wherein the IgG is IgG1.
20. The method of claim 16 , wherein the amyloid-binding polypeptide is at least 95% identical to the N1-N2 domains of SEQ ID NO:1.
21. The method of claim 16 , wherein the amyloid-binding polypeptide comprises the N1-N2 domains of wild-type g3p or a corresponding fragment of a mutant g3p.
22. The method of claim 16 , wherein the disease or disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, prion diseases, and tauopathies.
23. The method of claim 22 , wherein the prion disease is bovine spongiform encephalitis.
24. The method of claim 22 , wherein the disease or condition is Alzheimer's disease.
25. The method of claim 24 , wherein the Alzheimer's disease is selected from early onset Alzheimer's disease, late onset Alzheimer's disease and presymptomatic Alzheimer's disease.
26. The method of claim 16 , wherein the subject is positive for the biomarker florbetapir when that biomarker is used as an imaging agent in positron emission tomography.
27. The method of claim 16 , wherein the amyloid-binding polypeptide is capable of reducing amyloid, inhibiting amyloid formation, inhibiting amyloid aggregation, or removing toxic oligomer, or preventing toxic oligomer formation.