Bacteriophage gene 3 protein compositions and use as amyloid binding agents
Inventors
Krishnan, Rajaraman • Fisher, Richard
Assignees
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Publication Number
US-9493516-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 patent describes amyloid-binding polypeptides derived from filamentous bacteriophage gene 3 protein (g3p), including wild-type M13 g3p (SEQ ID NO:1), amyloid-binding fragments of wild-type M13 g3p such as N1, N2, and N1-N2, and mutant or variant forms that are at least 95% identical to SEQ ID NO:1. These compositions directly bind amyloid fibers and are used as agents to bind amyloid aggregates associated with neurodegenerative and prion diseases.
The disclosure addresses diseases or disorders associated with misfolded and/or aggregated amyloid beta, tau, alpha-synuclein, and/or prion protein. It states that g3p binding to amyloid fibers, followed by hinge-domain unfolding, supports amyloid disaggregation, and that impairment of the interaction, including proteolytic removal of g3p, abrogates amyloid interactions.
The patent also describes fusion protein embodiments that include an immunoglobulin constant region and the amyloid-binding polypeptide. These embodiments are described as promoting binding, inhibiting amyloid formation and aggregation, disaggregating aggregates, and reducing toxic oligomers and toxic oligomer formation.
The disclosure further states diagnostic and subject-characterization use, including use of florbetapir as an imaging agent in positron emission tomography (PET) to assess whether a subject tests positive for an amyloid biomarker prior to or in connection with treatment.
Claims Coverage
The claims include two independent claims, each directed to treatment of a subject for a disease or disorder associated with misfolded and/or aggregated amyloid beta, tau, alpha-synuclein, and/or prion protein. The inventive coverage centers on administering amyloid-binding g3p-derived polypeptides or an immunoglobulin constant region fusion protein, with one claim also excluding administration of a filamentous bacteriophage.
Amyloid-binding g3p polypeptide for treating misfolded and/or aggregated amyloid proteins
A method of treating a subject by administering an amyloid-binding polypeptide comprising wild-type M13 g3p (SEQ ID NO:1), an amyloid-binding fragment of wild-type M13 g3p, or a mutant of either that is at least 95% identical to SEQ ID NO:1 or an amyloid-binding fragment of SEQ ID NO:1.
Excluding filamentous bacteriophage administration
The non-fusion method specifies that the subject is not administered a filamentous bacteriophage.
Amyloid-binding g3p fusion protein with immunoglobulin constant region
A method of treating a subject by administering a fusion protein comprising an amyloid-binding polypeptide and an immunoglobulin constant region, where the amyloid-binding polypeptide comprises wild-type M13 g3p (SEQ ID NO:1), an amyloid-binding fragment of wild-type M13 g3p, or a mutant of either that is at least 95% identical to SEQ ID NO:1 or an amyloid-binding fragment of SEQ ID NO:1.
Overall claim coverage is directed to treatment by administering g3p-derived amyloid-binding polypeptides, including wild-type M13 g3p, amyloid-binding fragments such as N1, N2, and N1-N2, or at least 95% identical mutants, and to an immunoglobulin constant region fusion protein containing such a polypeptide. The non-fusion independent claim additionally requires that a filamentous bacteriophage is not administered.
Stated Advantages
Reduces amyloid plaque in a Tg2576 mouse model with an N1-N2 Ig fusion.
Reduces PrPSc accumulation in cell culture.
Inhibits amyloid formation and aggregation and disaggregates amyloid aggregates.
Removes toxic oligomers and prevents toxic oligomer formation.
Documented Applications
Treatment for diseases or disorders associated with misfolded and/or aggregated amyloid beta, tau, alpha-synuclein, and/or prion protein, including prion diseases and neurodegenerative disease contexts.
Diagnostic subject characterization using florbetapir as an imaging agent in positron emission tomography (PET) to assess whether a subject tests positive for an amyloid biomarker.
Use of g3p-derived constructs and Ig/Fc fusions in cellular contexts to reduce pathological protein accumulation and amyloid/oligomer-related effects.
Use in a Tg2576 mouse model to report reduced amyloid plaque with an N1-N2-Ig fusion.
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