Bacteriophage gene 3 protein compositions and use as amyloid binding agents
AssigneeNeuroPhage Pharmaceuticals, Inc.
InventorsRajaraman KRISHNAN, Richard Fisher
Life of this patent
Estimating the term…
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.
Claims29
1-59. (canceled)
A method of treating a subject for a disease or disorder associated with misfolded and/or aggregated amyloid protein, comprising administering to the subject a polypeptide, wherein the polypeptide comprises an amyloid-binding domain selected from 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;
- and wherein the subject is not administered a filamentous bacteriophage.
A method of treating a subject for a disease or disorder associated with misfolded and/or aggregated amyloid protein, comprising administering to the subject a fusion protein, wherein the fusion protein comprises an amyloid-binding domain and at least one additional protein or protein domain with which the amyloid-binding domain is not normally associated, wherein the amyloid-binding domain 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.
The method of claim 2, wherein the at least one additional protein or protein domain comprises an immunoglobulin constant region.
The method of claim 3, wherein the immunoglobulin constant region is an immunoglobulin Fc fragment.
The method of claim 4, wherein the immunoglobulin Fe fragment is an Fe fragment of IgG or IgM.
The method of claim 5, wherein the IgG is IgG1.
The method of claim 1, wherein the amyloid-binding portion comprises an amyloid-binding fragment of the N2 domain of wild-type g3p or a corresponding fragment of a mutant g3p.
The method of claim 1, wherein the wild-type g3p or amyloid-binding fragment of wild-type g3p is identical to the amino acid sequence of the corresponding portion of SEQ ID NO:1.
The method of claim 1, wherein the polypeptide is at least 85% identical to the amino acid sequence of the corresponding portion of SEQ ID NO:1.
The method of claim 1, wherein the polypeptide is at least 90% identical to the amino acid sequence of the corresponding portion of SEQ ID NO:1.
The method of claim 1, wherein the polypeptide is at least 95% identical to the amino acid sequence of the corresponding portion of SEQ ID NO:1.
The method of claim 1, wherein the polypeptide is at least 98% identical to the amino acid sequence of the corresponding portion of SEQ ID NO:1.
The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to the N1-N2 fragment of SEQ ID NO:1.
The method of claim 2, wherein the amyloid-binding polypeptide comprises an amino acid sequence that is at least 95% identical to the N1-N2 fragment of SEQ ID NO:1.
The method of claim 1, wherein the amyloid-binding polypeptide comprises an N1-N2 fragment of wild-type g3p or a corresponding fragment of a mutant g3p.
The method of claim 2, wherein the amyloid-binding polypeptide comprises an N1-N2 fragment of wild-type g3p or a corresponding fragment of a mutant g3p.
The method of claim 1, wherein the amyloid-binding polypeptide comprises wild-type or mutant full-length g3p.
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.
The method of claim 1, wherein the disease or disorder is selected from the group consisting of Alzheimer's disease, early onset Alzheimer's disease, late onset Alzheimer's disease, presymptomatic Alzheimer's disease, Parkinson's disease, SAA amyloidosis, cystatin C, hereditary Icelandic syndrome, senility, multiple myeloma;
- prion diseases, kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussier-Scheinker disease (GSS), fatal familial insomnia (FFI), scrapie, bovine spongiform encephalitis (BSE), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA1, SCA3, SCA6, or SCA7), Huntington disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, hereditary cerebral amyloid angiopathy, familial amyloidosis, frontotemporal lobe dementia, frontotemporal lobar degeneration (FTLD), peripheral amyloidosis, British/Danish dementia, and familial encephalopathy.
The method of claim 2, wherein the disease or disorder is selected from the group consisting of Alzheimer's disease, early onset Alzheimer's disease, late onset Alzheimer's disease, presymptomatic Alzheimer's disease, Parkinson's disease, SAA amyloidosis, cystatin C, hereditary Icelandic syndrome, senility, multiple myeloma;
- prion diseases, kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI), scrapie, bovine spongiform encephalitis (BSE), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA1, SCA3, SCA6, or SCA7), Huntington disease, dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, hereditary cerebral amyloid angiopathy, familial amyloidosis, frontotemporal lobe dementia, frontotemporal lobar degeneration (FTLD), peripheral amyloidosis, British/Danish dementia, and familial encephalopathy.
The method of claim 19, wherein the disease or condition is selected from the group consisting of Parkinson's disease, Alzheimer's disease, and Huntington's disease.
The method of claim 20, wherein the disease or condition is selected from the group consisting of Parkinson's disease, Alzheimer's disease, and Huntington's disease.
The method of claim 21, wherein the disease or condition is Alzheimer's disease.
The method of claim 22, wherein the disease or condition is Alzheimer's disease.
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.
The method of claim 2, wherein the subject is positive for the biomarker florbetapir when that biomarker is used as an imaging agent in positron emission tomography.
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 formation, or preventing toxic oligomer formation.
The method of claim 2, wherein the amyloid-binding polypeptide is capable of reducing amyloid, inhibiting amyloid formation, inhibiting amyloid aggregation, or removing toxic oligomer formation, or preventing toxic oligomer formation.
Dependencies are inferred from the claim text.