Antibody based reagents that specifically recognize toxic oligomeric forms of tau
Inventors
Sierks, Michael • Tian, Huilai
Assignees
Oligomerix Inc • Arizona State University Downtown Phoenix campus
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Publication Number
US-9650436-B2
Publication Date
2017-05-16
Expiration Date
Abstract
The invention relates to antibodies, antibody fragments and binding agents that specifically recognize oligomeric tau but do not bind to monomelic tau, fibrillar tau or non-disease associated forms of tau.
Core Innovation
The document describes antibody-based binding reagents, including antibody fragments such as scFv and nanobodies, that selectively recognize toxic oligomeric tau. The binding is directed to oligomeric tau while not recognizing monomeric tau or fibrillar/non-disease associated tau forms, and the reagents are defined using amino acid sequence identity and specific SEQ ID NO sequences.
The background rationale states that oligomeric tau is implicated in Alzheimer’s disease and tauopathies and is associated with neurotoxicity. The document contrasts toxic oligomeric tau with non-disease associated tau forms and with monomeric and fibrillar tau to support the need for oligomer-specific binding reagents, and presents the described binding reagents as tools to detect disease-relevant tau conformations and potentially to inhibit toxicity and/or aggregation.
The document outlines a selection approach for isolating oligomer-specific clones, including phage-display biopanning with negative selections against BSA and monomeric tau and sometimes a control brain, to enrich for clones that bind toxic oligomeric tau. It reports example scFv sequences, including F9T/SEQ ID NO:1 and other sequences such as D11C and H2A, and describes specificity for trimeric tau rather than monomeric tau.
Claims Coverage
The provided independent claims define binding molecules by sequence identity to a specific reference sequence and by membership in a specified set of SEQ ID NO amino acid sequences. Across the set, the coverage includes at least two independent claim groupings, with additional dependent refinements related to tau-conformation binding specificity.
Binding molecule with sequence identity to SEQ ID NO:1
A binding molecule comprising at least 80% sequence identity to amino acid sequence SEQ ID NO:1.
Binding molecule comprising one of specified SEQ ID NO sequences
A binding molecule comprising amino acid sequence SEQ ID NO:1, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, or SEQ ID NO:19.
Taken together, the independent claims cover binding molecules defined by high sequence identity to SEQ ID NO:1 or by inclusion of one of a specified set of SEQ ID NO sequences. The dependent claim summaries further indicate sequence narrowing to SEQ ID NO:1/9/11 and exclusion of binding to monomeric tau, fibrillar tau, and non-disease associated tau forms.
Stated Advantages
Selectively recognizes toxic oligomeric tau while not binding monomeric tau, fibrillar tau, or non-disease associated tau forms.
Provides oligomer-specific binding that is described as functionally relevant to neurotoxicity and disease state, including correlation with disease state/Braak stage.
Enables diagnostic use in CSF and brain samples and supports potential therapeutic use to inhibit toxicity and/or aggregation.
Documented Applications
Diagnostic use to detect disease-relevant tau binding in cerebrospinal fluid and brain samples, with relevance to disease state/Braak stage.
Therapeutic use to inhibit toxicity and/or aggregation.
Imaging use, described as possible imaging agents based on binding reagents.
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