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 pharmaceutical composition comprising a fusion protein that comprises an amyloid-binding polypeptide and an immunoglobulin IgG constant region,
wherein the amyloid binding polypeptide is present in an amount sufficient to treat a disease or disorder associated with misfolded and/or aggregated amyloid protein and a pharmaceutically acceptable carrier, and
wherein the polypeptide comprises at least one of:
(a) a wild type g3p;
(b) an amyloid-binding fragment of wild type g3p; or
(c) a mutant of (a) or (b) that retains the ability to bind to amyloid.
2. A pharmaceutical composition comprising a fusion protein that comprises an immunoglobulin IgG constant region and an amyloid-binding polypeptide in an amount sufficient to treat a disease or disorder associated with misfolded and/or aggregated amyloid protein and a pharmaceutically acceptable carrier;
wherein the polypeptide comprises at least one of:
(a) a wild type g3p,
(b) an amyloid-binding fragment of wild type g3p, or
(c) a mutant of (a) or (b) that retains the ability to bind to amyloid;
wherein the pharmaceutical composition is in unit dosage form.
3. The pharmaceutical composition according to claim 1 , wherein the immunoglobulin constant region is an immunoglobulin Fc fragment.
4. The pharmaceutical composition according to claim 3 , wherein the immunoglobulin Fc fragment is an Fc fragment of IgG1.
5. The pharmaceutical composition according to claim 1 or 2 , wherein the amyloid-binding polypeptide comprises an amyloid-binding fragment of the N2 domain of wild type g3p or a corresponding fragment of a mutant g3p.
6. The pharmaceutical composition according to claim 1 or 2 , wherein the amyloid-binding polypeptide comprises an N1-N2 fragment of wild type g3p or a corresponding fragment of a mutant g3p.
7. The pharmaceutical composition according to claim 1 or 2 , wherein the amyloid-binding polypeptide comprises wild type or mutant full-length g3p.
8. The pharmaceutical composition according to claim 1 or 2 , 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.
9. The pharmaceutical composition according to claim 1 or 2 , wherein the amyloid-binding polypeptide is at least 85% identical to SEQ ID NO:1 or an amyloid-binding fragment of SEQ ID NO:1.
10. The pharmaceutical composition according to claim 1 or 2 , wherein the amyloid-binding polypeptide is at least 90% identical to SEQ ID NO:1 or an amyloid-binding fragment of SEQ ID NO:1.
11. The pharmaceutical composition according to claim 1 or 2 , 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.
12. The pharmaceutical composition according to claim 1 or 2 , wherein the amyloid-binding polypeptide is at least 98% identical to SEQ ID NO:1 or an amyloid-binding fragment of SEQ ID NO:1.
13. The pharmaceutical composition according to claim 1 or 2 , wherein the amyloid-binding polypeptide is at least 95% identical to the N1-N2 fragment of SEQ ID NO:1.
14. The pharmaceutical composition according to claim 1 or 2 , 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.
15. A composition comprising a detectable label joined to a fusion protein that is capable of binding to misfolded and/or aggregated amyloid protein, and comprises an immunoglobulin IgG constant region and at least one amyloid-binding polypeptide selected from:
(a) a wild type g3p that comprises a full-length N2 domain,
(b) an amyloid-binding fragment of wild type g3p that comprises a full-length N2 domain,
(c) a mutant g3p that comprises a full-length N2 domain or corresponding mutant thereof that retains the ability to bind to amyloid, or
(d) a mutant amyloid-binding fragment of g3p that comprises a full-length N2 domain or corresponding mutant thereof that retains the ability to bind to amyloid.