Antibody-based molecules specific for the truncated ASP421 epitope of Tau and their uses in the diagnosis and treatment of tauopathy
The present invention relates to antibody-based molecules (including single domain antibody fragment, scFv molecules, antibodies, antibody fragments, diabodies, and the epitope-binding domains thereof) that are capable of immunospecifically and selectively binding to the truncated Asp421 epitope of Tau. Such antibody-based molecules are useful to detect pathological Tau protein conformer if present in a biological sample, especially in conjunction with the diagnosis and/or treatment of Alzheimer's disease or other tauopathy, and thus provide a diagnostic for Alzheimer's disease and other Tau pathologies. The antibody-based molecules of the present invention have particular utility as diagnostic markers for, Alzheimer's disease and related tauopathies and as pharmaceutical compositions for the treatment of such conditions.
1. An antibody-based molecule that is capable of immunospecifically binding to the Truncated Asp421 Epitope of Tau, wherein said epitope is present on a peptide having the sequence of Tau 407-421 (SEQ ID NO:7): HLSNVSSTGSIDMVD,
wherein:
(A) said aspartate residue of SEQ ID NO:7 is the C-terminal Tau residue of said polypeptide;
(B) relative to said immunospecific binding, said antibody-based molecule exhibits substantially diminished binding to a polypeptide that contains additional Tau sequence residues C-terminal to said aspartate residue of SEQ ID NO:7; and
(C) said antibody-based molecule comprises:
(i) a Variable Light Chain CDR1, CDR2, CDR3 having the amino acid sequence of SEQ ID NOs:37, 38 and 39, respectively; and
(ii) a Variable Heavy Chain CDR1, CDR2, CDR3 respectively having the amino acid sequence of SEQ ID NOs:41, 42 and 43, respectively.
2. The antibody-based molecule of claim 1 , wherein upon peripheral injection into a recipient, said molecule is capable of co-localizing with a Tau aggregate.
3. A pharmaceutical composition for the treatment of Alzheimer's disease or another tauopathy of a subject in need thereof, wherein said pharmaceutical composition comprises an effective amount of the antibody-based molecule of claim 1 , and one or more carriers, diluents and/or stabilizers.
4. The pharmaceutical composition of claim 3 , wherein said tauopathy is selected from the group consisting of frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, progressive subcortical gliosis, tangle only dementia, diffuse neurofibrillary tangles with calcification, argyrophilic grain dementia, amyotrophic lateral sclerosis parkinsonism-dementia complex, dementia pugilistica, Down syndrome, Gerstmann-Straussler-Scheinker disease, Hallerworden-Spatz disease, inclusion body myositis, Creutzfeld-Jakob disease, multiple system atropy, Niemann-Pick disease type C, prion protein cerebral amyloid angiopathy, subacute sclerosing panencephalitis, myotonic dystrophy, non-guanamian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, acute traumatic brain injury and chronic traumatic encephalopathy.
5. The antibody-based molecule of claim 1 , wherein said molecule is an antibody, a diabody, an scFv, or comprises an epitope-binding fragment of an antibody, diabody or scFv.
6. The antibody-based molecule of claim 5 , wherein said molecule is an antibody.
7. The antibody-based molecule of claim 5 , wherein said molecule is a humanized antibody or comprises an epitope-binding fragment of a humanized antibody.
8. The antibody-based molecule of claim 5 , wherein said molecule is an scFv.
9. The antibody-based molecule of any of claim 1 , which is detectably labeled.
10. The antibody-based molecule of claim 9 , wherein said detectable label is a fluorescent label, a chemoluminescent label, a paramagnetic label, a radioisotopic label or an enzyme label.
11. A kit for detecting or measuring the presence or amount of said truncated Tau protein in the brain of a subject, or for diagnosing Alzheimer's disease or another tauopathy in a subject, wherein said kit comprises the antibody-based molecule of claim 9 .
12. A method for detecting or measuring the presence or amount of truncated Tau protein in the brain, cerebrospinal fluid, blood, serum or plasma of a recipient subject, wherein said method comprises contacting said brain, cerebrospinal fluid, blood, serum or plasma of said subject with the antibody-based molecule of claim 9 and detecting or measuring binding between said truncated Tau protein and said antibody-based molecule.
13. The method of claim 12 , wherein said detection or measurement is for diagnosing Alzheimer's disease or another tauopathy of a subject.
14. The method of claim 13 , wherein said tauopathy is selected from the group consisting of frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, progressive subcortical gliosis, tangle only dementia, diffuse neurofibrillary tangles with calcification, argyrophilic grain dementia, amyotrophic lateral sclerosis parkinsonism-dementia complex, dementia pugilistica, Down syndrome, Gerstmann-Straussler-Scheinker disease, Hallerworden-Spatz disease, inclusion body myositis, Creutzfeld-Jakob disease, multiple system atropy, Niemann-Pick disease type C, prion protein cerebral amyloid angiopathy, subacute sclerosing panencephalitis, myotonic dystrophy, non-guanamian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, acute traumatic brain injury and chronic traumatic encephalopathy.
15. The method of claim 12 , wherein said detection or measurement comprises in vivo or ex vivo imaging of said antibody-based molecule bound to said truncated Tau protein.
16. The method of claim 15 , wherein said detection or measurement is for the treatment of Alzheimer's disease or another tauopathy of said subject.
17. The method of claim 16 , wherein said tauopathy is selected from the group consisting of frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, progressive subcortical gliosis, tangle only dementia, diffuse neurofibrillary tangles with calcification, argyrophilic grain dementia, amyotrophic lateral sclerosis parkinsonism-dementia complex, dementia pugilistica, Down syndrome, Gerstmann-Straussler-Scheinker disease, Hallerworden-Spatz disease, inclusion body myositis, Creutzfeld-Jakob disease, multiple system atropy, Niemann-Pick disease type C, prion protein cerebral amyloid angiopathy, subacute sclerosing panencephalitis, myotonic dystrophy, non-guanamian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, acute traumatic brain injury and chronic traumatic encephalopathy.