Human Anti-Tau Antibodies

Abstract

Provided are novel 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.

What is claimed is: 
     
         1 . A human monoclonal anti-tau antibody, or a tau binding fragment thereof 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.   
     
     
         2 . The antibody or tau binding fragment thereof of  claim 1  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. 
 
     
     
         3 . The antibody or tau binding fragment thereof of  claim 2  which is a chimeric murine-human or a murinized antibody. 
     
     
         4 . An antibody or antigen-binding fragment thereof which competes with the antibody of  claim 2  for specific binding to tau. 
     
     
         5 . The antibody or tau binding fragment thereof of  claim 2 , 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. 
     
     
         6 . A polynucleotide encoding the antibody or tau binding fragment thereof of  claim 2 . 
     
     
         7 . A vector comprising the polynucleotide of  claim 6 . 
     
     
         8 . A host cell comprising the vector of  claim 7 . 
     
     
         9 . A method for preparing an anti-tau antibody or tau binding fragment thereof, comprising
 (a) culturing the cell of  claim 8 ; and   (b) isolating said antibody or tau binding fragment thereof from the culture.   
     
     
         10 . An anti-tau antibody or tau binding fragment thereof obtainable by the method of  claim 9 . 
     
     
         11 . The anti-tau antibody or tau binding fragment thereof of  claim 2 , 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.   
     
     
         12 . A composition comprising the anti-tau antibody or tau binding fragment thereof of  claim 2 , 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.   
     
     
         13 . The composition of  claim 12  further comprising an additional agent useful for treating a neurodegenerative tauopathy. 
     
     
         14 . 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 the antibody or tau binding fragment thereof of  claim 2 ; 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-Straüssler-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.   
     
     
         15 . A method for in vivo detection of or targeting a therapeutic or diagnostic agent to tau in the human or animal body, comprising administering a composition comprising the antibody or tau binding fragment thereof of  claim 2  attached to a therapeutic or diagnostic agent, 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). 
     
     
         16 . A peptide having an epitope of tau specifically recognized by the antibody of  claim 2 , wherein the peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 9, 41, 42 and combinations thereof. 
     
     
         17 . A method for diagnosing a neurodegenerative tauopathy in a subject, comprising detecting the presence of an antibody that binds to the peptide of  claim 16  in a biological sample of said subject. 
     
     
         18 . A kit useful in the diagnosis of a neurodegenerative tauopathy, said kit comprising the antibody or tau binding fragment thereof of  claim 2 , with reagents or instructions for use.