Antibody based reagents that specifically recognize toxic oligomeric forms of tau
Inventors
Moe, James G. • Davidowitz, Eliot J.
Assignees
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Publication Number
US-10465001-B2
Publication Date
2019-11-05
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 invention provides an antibody or antibody fragment that specifically recognizes oligomeric tau while not binding monomeric tau, fibrillar tau, or non-disease associated forms of tau. The antibody fragment comprises one of several specified amino acid sequences, and the described binding selectivity differentiates toxic tau oligomers from other tau species that are not associated with disease.
The described problem being solved is the need for agents that recognize toxic oligomeric tau species linked to neurotoxicity and early-stage neurodegeneration, while avoiding binding to monomeric tau, fibrillar tau, and non-disease-associated tau forms. The rationale presented is that oligomeric tau correlates with neurotoxicity and early-stage neurodegeneration in Alzheimer’s disease, frontotemporal dementia, other tauopathies, and neurodegeneration following traumatic brain injury.
The invention further describes sequence-defined antibody fragments generated using a modified AFM-guided phage-display biopanning workflow. The workflow includes negative panning against generic protein and against monomeric tau, while positive selection is performed against specific oligomeric tau forms such as trimeric tau 4N1R. The described outcomes include antibody fragments and nanobodies that bind oligomeric tau aggregates in Alzheimer’s disease mouse brain tissue and show time-dependent appearance prior to neurofibrillary tangles.
In addition to binding and discrimination, the invention states functional relevance for oligomeric tau recognition and downstream use. The described agents are used for inhibiting tau aggregation and for detecting and discriminating disease-context samples by contacting physiological samples such as brain tissue, serum, cerebrospinal fluid, blood, urine, or saliva and determining binding indicative of tau oligomers. The document also describes labeling and imaging for in vivo or ex vivo detection and correlating detection with disease stage and plaque frequency.
Claims Coverage
Independent claim clm-00001 covers a sequence-defined antibody or antibody fragment with binding specificity for oligomeric tau and non-binding for monomeric tau, fibrillar tau, and non-disease associated tau forms; it specifies that the fragment contains one of seven amino acid sequences. Dependent coverage in the provided claim list further includes structural, sequence-subset, selection/workflow-definition, aggregation-inhibition comparison, and physiological detection with disease-context indications.
Oligomeric tau-specific antibody fragment with specified SEQ IDs
An antibody or antibody fragment that specifically recognizes oligomeric tau but does not bind monomeric tau, fibrillar tau or non-disease associated forms of tau, wherein the antibody fragment comprises 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.
Antibody fragment lacking a constant domain region
The antibody fragment specifies that it lacks the antibody constant domain region.
Restricted SEQ ID subset
The antibody fragment comprises an amino acid sequence corresponding to SEQ ID NO:1, SEQ ID NO:9, or SEQ ID NO:11.
AFM-monitored negative panning with phage selection
An isolated antibody (or antibody fragment) is defined as an scFv fragment obtained by a negative panning process using AFM binding monitoring against a generic protein and monomeric tau, followed by incubation with tau oligomers and elution of bound phage.
Reduced rate of tau aggregate formation
Contacting with an antibody or antibody fragment reduces the formation rate of tau aggregates compared to the rate without the antibody or antibody fragment.
Detection in physiological samples indicating early-stage disease context
A method for detecting tau in a physiological sample by contacting the sample with an antibody (or antibody fragment) and determining whether binding indicates tau oligomers, which are used as indicators of early-stage AD, frontotemporal dementia, other tauopathies, or neurodegeneration after traumatic brain injury.
The provided claim set centers on an antibody or antibody fragment that is sequence-defined and specifically recognizes oligomeric tau while avoiding binding to monomeric, fibrillar, and non-disease-associated tau. Dependent subject matter in the provided list further limits the fragment by constant-domain absence, narrows SEQ ID options, specifies an AFM-monitored negative panning selection workflow, and adds functional limitations for reduced tau aggregate formation and disease-context detection in physiological samples.
Stated Advantages
Specifically recognizes oligomeric tau while not binding monomeric tau, fibrillar tau, or non-disease-associated forms of tau.
Indicates early-stage Alzheimer’s disease, frontotemporal dementia, other tauopathies, or neurodegeneration after traumatic brain injury through binding to tau oligomers.
Reduces the formation rate of tau aggregates.
Documented Applications
Detecting tau in physiological samples by contacting the sample with an antibody (or antibody fragment) and determining whether binding indicates tau oligomers, used as indicators of early-stage AD, frontotemporal dementia, other tauopathies, or neurodegeneration after traumatic brain injury.
Inhibiting tau aggregation using the antibody or antibody fragment, including effects related to tau aggregate formation rate.
Detection in physiological samples including brain tissue, serum, cerebrospinal fluid (CSF), blood, urine, and saliva, including described use with labeling and imaging for in vivo or ex vivo detection.
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