Bacteriophage gene 3 protein compositions and use as amyloid binding agents
Inventors
Krishnan, Rajaraman • Fisher, Richard
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9493515-B2
Publication Date
2016-11-15
Expiration Date
Abstract
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.
Core Innovation
The invention provides a fusion protein for binding misfolded and/or aggregated amyloid protein. The fusion protein comprises an amyloid-binding polypeptide derived from filamentous bacteriophage gene 3 protein (g3p) and an immunoglobulin IgG constant region. The amyloid-binding polypeptide comprises a wild type g3p, an amyloid-binding fragment of wild type g3p, or a mutant of the wild type g3p or its fragment that retains the ability to bind to amyloid.
The invention identifies amyloid-binding fragments and domain features of g3p as directly involved in amyloid binding and disaggregation. It emphasizes fragments that include the N1 domain and N2 domain, including an N1-N2 fragment, and it highlights an N2 hinge region. The mechanism is described in terms of hinge-unfolding thermodynamics, characterized by melting temperature (T_M), and native protein conformation modulating binding and disaggregation.
In addition to therapeutic compositions, the invention includes compositions with detectable labels. A detectable label is joined to a fusion protein capable of binding misfolded and/or aggregated amyloid protein, where the fusion protein includes an immunoglobulin IgG constant region and an amyloid-binding polypeptide derived from g3p. The document describes fusion constructs such as rs-g3p(N1N2) and rs-g3p(N1N2)-Ig Fc fusions.
Claims Coverage
The partial content includes three independent claims, covering IgG fusion pharmaceutical compositions with g3p-derived amyloid-binding polypeptides, the same fusion concept in a unit dosage form, and a detectable-label composition for binding misfolded and/or aggregated amyloid protein using an IgG constant region and an N2-domain-containing g3p polypeptide or fragment.
IgG fusion with g3p amyloid-binding polypeptide for treatment
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 wild type g3p; an amyloid-binding fragment of wild type g3p; or a mutant of (a) or (b) that retains the ability to bind to amyloid.
Unit dosage form IgG fusion with g3p amyloid-binding polypeptide
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 wild type g3p, an amyloid-binding fragment of wild type g3p, or a mutant of (a) or (b) that retains the ability to bind to amyloid; wherein the pharmaceutical composition is in unit dosage form.
Detectable label joined to IgG fusion containing N2-domain g3p amyloid binder
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 wild type g3p that comprises a full-length N2 domain; an amyloid-binding fragment of wild type g3p that comprises a full-length N2 domain; a mutant g3p that comprises a full-length N2 domain or corresponding mutant thereof that retains the ability to bind to amyloid; or 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.
Across the independent claims, coverage centers on IgG constant region fusion proteins containing g3p-derived amyloid-binding polypeptides, whether wild type, fragments, or mutants retaining amyloid binding, for treating misfolded and/or aggregated amyloid-associated diseases, with additional embodiments in unit dosage form and in labeled binding compositions emphasizing full-length N2-domain-containing g3p polypeptides or fragments.
Stated Advantages
Treats a disease or disorder associated with misfolded and/or aggregated amyloid protein.
Documented Applications
Reducing amyloid plaques in a Tg2576 Alzheimer’s mouse model.
Binding misfolded and/or aggregated amyloid protein using compositions that include detectable labels joined to IgG fusion proteins.
Interested in licensing this patent?