Methods and compositions to treat and detect misfolded-SOD1 mediated diseases
Inventors
Assignees
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Publication Number
US-7977314-B2
Publication Date
2011-07-12
Expiration Date
Abstract
The invention provides a method for treating a medical condition, disease, or disorder mediated by a misfolded form of superoxide dismutase (SOD) in a subject in need of treatment. The method optionally comprises administering to the subject a composition comprising a pharmaceutically acceptable vehicle and an agent selected from (1) an exogenous antibody or fragment thereof that binds selectively to the misfolded form of SOD, and/or (2) an immunogen that elicits production of an endogenous antibody that binds selectively to the misfolded form of SOD, and/or (3) a nucleic acid sequence encoding (1) or (2). In certain embodiments, the invention provides methods of treating diseases such as Alzheimer's Disease, Parkinson's Disease or amyotrophic lateral sclerosis using amyotrophic disease-specific epitopes, and compositions including these epitopes. The invention also provides antibodies that bind to monomeric or misfolded SOD1, and not on the molecular surface of native homodimeric SOD1. In addition, the invention includes methods of diagnosing Alzheimer's Disease, Parkinson's Disease or amyotrophic lateral sclerosis in a subject. Also, the invention provides methods of identifying substances for the treatment or prevention of Alzheimer's Disease, Parkinson's Disease or amyotrophic lateral sclerosis and kits using the binding proteins of the invention.
Core Innovation
The invention relates to immunotherapeutic targeting and detection of disease-specific epitopes exposed selectively on misfolded or non-native human superoxide dismutase 1 (SOD1) species. The disease-specific epitopes are described as being exposed on misfolded, non-native, or aggregated SOD1 but not on native SOD1 homodimer.
Exemplary disease-specific epitopes include SEQ ID NO:1 through SEQ ID NO:7, an oxidized analog DSE1a (SEQ ID NO:8 with cysteic acid), and other specified SEQ ID NO targets. The document describes isolated peptides and immunogens, nucleic acids encoding these disease-specific epitope peptides, and immunization with the isolated peptides or nucleic acids encoding them to elicit endogenous antibodies.
The document further provides exogenous antibodies or binding fragments that recognize these disease-specific epitopes and are stated to treat SOD1-mediated neurodegenerative diseases and familial ALS mediated by a misfolded form of human SOD1. It also describes detection, diagnosis, immunoassay, kit, and drug-screening concepts based on measuring antibody-antigen complex and selective binding to misfolded SOD1, including optional disaggregation to expose masked epitopes.
Claims Coverage
Independent claims are directed to a method for treating familial ALS mediated by misfolded human SOD1 using an exogenous antibody or binding fragment that selectively binds defined SOD1 epitopes. The claim set presents 6 inventive features, with dependent claims further refining epitope size, oxidized amino acids, antibody class, a specific hybridoma source, and expanded SEQ ID NO binding scope.
Selective exogenous antibody binding to defined SOD1 disease-specific epitope sequences
Administering a pharmaceutically acceptable vehicle and an exogenous antibody or binding fragment that binds selectively to all or part of SEQ ID NO:74 or SEQ ID NO:2, wherein administering treats familial ALS mediated by a misfolded form of human SOD1.
Epitope span of at least 5 contiguous amino acids in the selective bound region
Using an exogenous antibody that binds to at least 5 contiguous amino acids of SEQ ID NO:74 or SEQ ID NO:2.
Oxidized amino acids included within the bound epitope region
Using an exogenous antibody where the bound sequence includes one or more oxidized amino acids in the region bound within SEQ ID NO:74 or SEQ ID NO:2.
Permitted antibody types including monoclonal, polyclonal, chimeric, or humanized
Employing an exogenous antibody that is monoclonal, polyclonal, chimeric, or humanized.
Specific hybridoma-deposited antibody source
Using an exogenous SOD1 antibody produced by the hybridoma 3H1 and deposited with the International Depository Authority of Canada on Feb. 22, 2007.
Expanded binding target scope to SEQ ID NOs:46-56
The exogenous antibody binds all or part of any one of SEQ ID NOs:46-56.
Overall, the claim set centers on treating familial ALS mediated by misfolded SOD1 via selective exogenous antibody or binding fragment binding to defined SEQ ID NO targets, further constrained by epitope size, inclusion of oxidized amino acids, permissible antibody class, a specific hybridoma-derived antibody deposit, and additional binding targets to SEQ ID NOs:46-56.
Stated Advantages
Treats familial ALS mediated by a misfolded form of human SOD1.
Allows selective binding to misfolded or non-native SOD1 disease-specific epitopes while not binding native SOD1 homodimer.
Enables detection and diagnosis using antibody-antigen complex measurement.
Enables drug screening based on binding to misfolded SOD1.
Documented Applications
Treatment of familial ALS mediated by a misfolded form of human SOD1 using exogenous antibodies or binding fragments that selectively bind defined DSE sequences.
Detection and diagnosis via measurement of antibody-antigen complexes.
Drug screening using binding to misfolded SOD1.
Detecting and monitoring misfolded SOD1-related neurodegenerative diseases using antibodies and interpreting binding against ALS, AD, PD, Lewy body, and no-disease controls.
Immunoassay-based detection of antibody-bound misfolded SOD1 conformations using sample types including cerebrospinal fluid, plasma or serum, whole blood, blood cells, spinal cord tissue, and brain cells or tissue.
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