HUMAN ANTI-TAU ANTIBODIES
Provided are human tau-specific antibodies as well as fragments, derivatives and variants thereof as well as methods related thereto. Assays, kits, and solid supports related to antibodies specific for tau are also disclosed. The antibody, immunoglobulin chain(s), as well as binding fragments, derivatives and variants thereof can be used in pharmaceutical and diagnostic compositions for tau targeted immunotherapy and diagnosis, respectively.
1 . A human monoclonal anti-tau antibody, or a tau binding fragment thereof.
2 . The antibody of claim 1 which
(i) is capable of binding recombinant human tau;
(ii) is capable of binding pathologically modified tau;
(iii) binds to pathologically aggregated tau at the pre-tangle stage, in neurofibrillary tangles (NFT), neuropil threads and/or dystrophic neurites in the brain
(iv) does not substantially bind to physiological forms of tau in the brain;
(v) specifically binds any one of tau isoforms B to F or fetal tau represented by SEQ ID NOs: 1 to 6;
(vi) specifically binds a tau C-terminus;
(vii) specifically binds a tau N-terminus
(viii) specifically binds a tau epitope located in the microtubule binding domain which is masked in physiological microtubule-associated tau;
(ix) specifically binds pathologically aggregated tau at the pre-tangle stage, in neurofibrillary tangles (NFT), neuropil threads and/or dystrophic neurites in the brain;
(x) specifically binds a tau epitope which comprises the amino acid sequence of SEQ ID NO: 7;
(xi) specifically binds a tau epitope which comprises the amino acid sequence of SEQ ID NO: 41;
(xii) specifically binds a tau epitope which comprises the amino acid sequences of SEQ ID NO: 7 and 41; or
(xiii) specifically binds a tau epitope which comprises the amino acid sequence of SEQ ID NO: 42.
3 . The antibody or tau binding fragment thereof of claim 1 or 2 comprising
(a) a heavy chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 23, 29 and 35, a heavy chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:24, 30 and 36, and a heavy chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 25, 31 and 37;
(b) a light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32 and 38, a light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:27, 33 and 39, and a light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 40;
(c) a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 9, 13, 17 and 93; or
(d) a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO:11, 15 and 19.
4 . The antibody or tau binding fragment thereof of any one of claims 1 to 3 which is a chimeric murine-human or a murinized antibody.
5 . An antibody or antigen-binding fragment thereof which competes with the antibody of any one of claims 1 to 4 for specific binding to tau.
6 . The antibody or tau binding fragment thereof of any one of claims 1 to 5 , which is selected from the group consisting of a single chain Fv fragment (scFv), an F(ab′) fragment, an F(ab) fragment, and an F(ab′) 2 fragment.
7 . A polynucleotide encoding the antibody or tau binding fragment thereof of any one of claims 1 to 6 .
8 . A vector comprising the polynucleotide of claim 7 .
9 . A host cell comprising the polynucleotide of claim 7 or the vector of claim 8 .
10 . A method for preparing an anti-tau antibody or tau binding fragment thereof, comprising
(a) culturing the cell of claim 9 ; and
(b) isolating said antibody or tau binding fragment thereof from the culture.
11 . An anti-tau antibody or tau binding fragment thereof encoded by the polynucleotide of claim 7 or obtainable by the method of claim 10 .
12 . The antibody or tau binding fragment thereof of any one of claim 1 to 6 or 11 , which is
(a) detectably labeled wherein the detectable label is selected from the group consisting of an enzyme, a radioisotope, a fluorophore and a heavy metal; or
(b) which is attached to a drug.
13 . A composition comprising the antibody or tau binding fragment thereof of any one of claim 1 to 6 , 11 or 12 , the polynucleotide of claim 7 , the vector of claim 8 or the host cell of claim 9 , wherein the composition is
(i) a pharmaceutical composition further comprising a pharmaceutically acceptable carrier; or
(ii) a diagnostic composition further comprising one or more reagents conventionally used in immuno or nucleic acid based diagnostic methods.
14 . The composition of claim 13 further comprising an additional agent useful for treating a neurodegenerative tauopathy.
15 . The anti-tau antibody or tau binding fragment thereof of any one of claim 1 to 6 , 11 or 12 , the polynucleotide of claim 7 , the vector of claim 8 or the host cell of claim 9 for use in
(i) prophylactic or therapeutic treatment of a neurodegenerative tauopathy in a subject, or
(ii) monitoring the progression of a neurodegenerative tauopathy in a subject, or the response to a treatment of a neurodegenerative tauopathy in a subject
wherein the neurodegenerative tauopathy is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis/parkinsonism-dementia complex, argyrophilic grain dementia, British type amyloid angiopathy, cerebral amyloid angiopathy, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, Gerstmann-Sträussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, Tangle only dementia, multi-infarct dementia and ischemic stroke.
16 . A method of diagnosing or monitoring the progression of a neurodegenerative tauopathy in a subject, the method comprising
(a) assessing the level of pathologically modified or aggregated tau in a sample from the subject to be diagnosed with at least one antibody of any one of claim 1 to 6 , 11 or 12 ; and
(b) comparing the level of modified or aggregated tau to a reference standard that indicates the level of the pathologically modified or aggregated tau in one or more control subjects,
wherein a difference or similarity between the level of pathologically modified or aggregated tau and the reference standard indicates that the subject has a neurodegenerative tauopathy, wherein the neurodegenerative tauopathy is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis/parkinsonism—dementia complex, argyrophilic grain dementia, British type amyloid angiopathy, cerebral amyloid angiopathy, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, Gerstmann-Sträussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, Tangle only dementia, multi-infarct dementia and ischemic stroke.
17 . The antibody or tau binding fragment thereof of any one of claim 1 to 6 , 11 or 12 for use in in vivo detection of or targeting a therapeutic or diagnostic agent to tau in the human or animal body, wherein said in vivo detection comprises positron emission tomography (PET), single photon emission tomography (SPECT), near infrared (NIR) optical imaging or magnetic resonance imaging (MRI).
18 . A peptide having an epitope of tau specifically recognized by the antibody of any one of claim 1 to 6 , 11 or 12 , wherein the peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 9, 41, 42 and combinations thereof.
19 . A method for diagnosing a neurodegenerative tauopathy in a subject, comprising detecting the presence of an antibody that binds to the peptide of claim 18 in a biological sample of said subject.
20 . A kit useful in the diagnosis of a neurodegenerative tauopathy, said kit comprising the antibody or tau binding fragment thereof of any one of claim 1 to 6 , 11 or 12 , the polynucleotide of claim 7 , the vector of claim 8 or the host cell of claim 9 or the peptide of claim 18 , with reagents or instructions for use.