Antibody that recognises the T14 peptide of AChE
Inventors
GREENFIELD, SUSAN ADELE • GARCIA-RATES, Sara • MORRILL, Paul
Assignees
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Publication Number
US-10954306-B2
Publication Date
2021-03-23
Expiration Date
Abstract
The invention relates to antibodies, and in particular, to antibodies used in the diagnosis and treatment of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. The invention extends to methods of diagnosis and therapy of neurodegenerative disorders, and to assays and screens for isolating novel therapeutic compounds for treating such diseases.
Core Innovation
The disclosure concerns antibody(s) or an antigen-binding fragment that specifically binds to an exposed C-terminal lysine (K) residue of SEQ ID No:3 (T14). The antibody specifically binds to SEQ ID No:6, which corresponds to an exposed C-terminal epitope containing the VHWK motif, and is described as not binding SEQ ID No:2 (T30), SEQ ID No:4 (T15), and/or SEQ ID No:8 (beta-amyloid).
The disclosed use links the antibody-based detection of antigen comprising SEQ ID No:3 (T14) to diagnosis and therapy of neurodegenerative disorders, primarily Alzheimer’s disease. The disclosure asserts detectability of T14 in patient CSF and serum, and it describes validation results that include increased T14 in AD CSF compared to controls while Aβ is unchanged, ELISA/Western blot specificity, and immunohistochemistry showing T14 in vulnerable neurons.
The disclosure further outlines additional uses including biomarker kits, therapeutic use that can be optionally provided as an antibody-drug conjugate (ADC) with cytotoxic moieties, and drug discovery/screening assays for agents that inhibit T14 synthesis/activity. The overall concept is to use the binding selectivity of the deposited polyclonal antibody to detect T14 and to support diagnostic decisions and compound evaluation based on increased or decreased T14 presence, concentration, or activity.
Claims Coverage
The partial content provides four independent claims (clm-00001, clm-00002, clm-00003, clm-00006). Across these independent claims, the coverage centers on a deposited polyclonal antibody that specifically binds SEQ ID No:3 (T14) via the exposed C-terminal lysine and the SEQ ID No:6 (VHWK) epitope, combined with conditional diagnosis/treatment steps or compound-utility evaluation based on increased or decreased T14 detection, presence, concentration, or activity versus one or more controls.
Alzheimer’s diagnosis and treatment using a selective deposited polyclonal antibody
A method for diagnosing and treating a subject suffering from Alzheimer’s disease (or a pre-disposition thereto) that obtains a sample, contacts the sample with the polyclonal antibody deposited at American Type Culture Collection Patent Deposit Number PTA-126567 (or an antigen-binding fragment), detects the presence of an antigen comprising SEQ ID No:3, diagnoses when increased presence of antigen is detected compared to one or more control samples, and administering an effective amount of a treatment for Alzheimer’s disease to the diagnosed subject.
Selective binding constraints for T14 detection
In the diagnosis and treatment method, the polyclonal antibody or antigen-binding fragment specifically binds to the exposed C-terminal lysine (K) residue of SEQ ID No:3, specifically binds to SEQ ID No:6, and does not bind to SEQ ID No:2, SEQ ID No:4 and/or SEQ ID No:8.
Putative therapeutic compound evaluation by measuring absence or change in T14
A method for evaluating a putative therapeutic compound for use in the treatment or amelioration of Alzheimer’s disease that contacts a sample comprising the putative therapeutic compound with the polyclonal antibody deposited at PTA-126567 (or an antigen-binding fragment), measures the presence and/or amount of T14 by detecting binding of T14 to the antibody, and determines usefulness if no T14 is detected or if a decrease in T14 concentration or activity is detected versus controls; and determines lack of usefulness if T14 is detected or if an increase in T14 concentration or activity is detected versus controls.
Diagnosis and treatment based on detecting SEQ ID No:3 and comparing antibody binding to controls
A method for diagnosing and treating a subject suffering from, or a pre-disposition thereto, Alzheimer’s disease that obtains a sample, detects the presence of SEQ ID No:3 using the polyclonal antibody deposited at PTA-126567, diagnoses when increased presence of the antibody binding to SEQ ID No:3 is detected compared to one or more controls, and administering an effective amount of a treatment for Alzheimer’s disease to the diagnosed subject.
Overall, the independent claims require a deposited polyclonal antibody that selectively detects SEQ ID No:3 (T14) through an exposed C-terminal lysine/VHWK-related epitope, and they use detection outcomes—specifically increased presence or increased antibody binding versus controls for diagnosis, and absence or decreased T14 (or opposite trends) for evaluating therapeutic compound usefulness—to drive Alzheimer’s diagnosis/treatment selection or compound utility determination.
Stated Advantages
Detectability of T14 in patient CSF and serum is asserted.
In AD CSF, increased T14 is described compared to controls while Aβ is unchanged.
ELISA/Western blot specificity is described for the antibody.
Immunohistochemistry is described as showing T14 in vulnerable neurons.
Documented Applications
Diagnosis and therapy of Alzheimer's disease (including subjects with pre-disposition thereto) using detection of T14 (SEQ ID No:3) with the deposited polyclonal antibody.
Evaluating a putative therapeutic compound for treatment or amelioration of Alzheimer’s disease by measuring T14 presence/amount and determining usefulness based on absence or decrease versus controls, and lack of usefulness based on detection or increase versus controls.
Biomarker kits for detecting T14 are described.
Therapeutic use is described, including optionally providing the antibody as an antibody-drug conjugate (ADC) with cytotoxic moieties.
Drug discovery/screening assays are described for agents that inhibit T14 synthesis/activity.
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