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.

1 .- 42 . (canceled) 
     
     
         43 . A polynucleotide linked to a heterologous nucleic acid, wherein the polynucleotide is selected from the group consisting of:
 (a) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:79, 80, and 81, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:46 binds to tau;   (b) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:82, 83, and 84, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau;   (c) a polynucleotide encoding (i) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:79, 80, and 81, respectively; and (ii) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:82, 83, and 84, respectively, wherein the VH when paired with the VL binds to tau;   (d) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:46 binds to tau;   (e) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:221 binds to tau;   (f) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:222 binds to tau;   (g) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:46, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau;   (h) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:221, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau;   (i) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:222, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau;   (j) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45 and an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:46;   (k) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45 and an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:221;   (l) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:45 and an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:222;   (m) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:91, 92, and 93, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:46 binds to tau;   (n) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:94, 95, and 96, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau; and   (o) a polynucleotide encoding (i) an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:91, 92, and 93, respectively; and (ii) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs: 94, 95, and 96, respectively, wherein the VH when paired with the VL binds to tau.   
     
     
         44 . The polynucleotide of  claim 43 , wherein the heterologous nucleic acid is a regulatory element. 
     
     
         45 . The polynucleotide of  claim 43 , wherein the heterologous nucleic acid is a secretory signal peptide. 
     
     
         46 . A host cell comprising the polynucleotide of  claim 43 . 
     
     
         47 . A cDNA comprising a polynucleotide encoding a polypeptide comprising any one of:
 (a) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:79, 80, and 81, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:46 binds to tau; or   (b) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:82, 83, and 84, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau.   
     
     
         48 . The cDNA of  claim 47 , wherein the polypeptide comprises:
 an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in any one of SEQ ID NO: 44 or 45; or   an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in any one of SEQ ID NO:46, 221, or 222.   
     
     
         49 . An expression vector comprising a heterologous promoter operably linked to a polynucleotide encoding a polypeptide comprising:
 (a) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:79, 80, and 81, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:46 binds to tau; or   (b) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:82, 83, and 84, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:45 binds to tau.   
     
     
         50 . The expression vector of  claim 49 , wherein the polypeptide comprises:
 an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in any one of SEQ ID NO: 44 or 45; or   an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in any one of SEQ ID NO:46, 221, or 222.   
     
     
         51 . The expression vector of  claim 49 , wherein the expression vector is a plasmid, phage, or virus. 
     
     
         52 . A host cell comprising the expression vector of  claim 49 . 
     
     
         53 . A method for preparing an anti-human tau antibody or human tau-binding fragment thereof, the method comprising:
 culturing the host cell of  claim 52  in a cell culture; and   isolating the anti-human tau antibody or human tau-binding fragment thereof from the cell culture.   
     
     
         54 . The method of  claim 53 , further comprising formulating the anti-human tau antibody or human tau-binding fragment thereof into a sterile pharmaceutical composition suitable for administration to a human subject. 
     
     
         55 . A method of treating (i) a neurodegenerative tauopathy in a human subject in need thereof; or (ii) abnormal accumulation or deposition of tau in the central nervous system in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an anti-tau antibody or tau-binding fragment thereof, wherein the anti-tau antibody or tau-binding fragment thereof comprises:
 a VH comprising VH complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO: 44 or 45; and   a VL comprising VL complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO:46, 221, or 222.   
     
     
         56 . The method of  claim 55 , wherein:
 the VH comprises an amino acid sequence set forth in any one of SEQ ID NO: 44 or 45; and   the VL comprises an amino acid sequence set forth in any one of SEQ ID NO:46, 221, or 222.   
     
     
         57 . The method of  claim 55 , wherein the antibody or antigen-binding fragment thereof comprises a human IgG1 heavy chain constant region and a human lambda light chain constant region. 
     
     
         58 . The method of  claim 55 , 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. 
     
     
         59 . A method for in vivo detection of tau deposition in the brain, the method comprising: administering to a human subject an antibody or antigen-binding fragment thereof that specifically binds to tau, wherein the antibody or antigen-binding fragment thereof comprises: a VH comprising VH complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO: 44 or 45; and a VL comprising VL complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO:46, 221, or 222, wherein the antibody or antigen-binding fragment thereof is attached to a detectable label; and
 detecting the detectable label in the brain of the human subject, to thereby detect tau deposition in the brain of the human subject.   
     
     
         60 . An antibody or antigen-binding fragment thereof that binds to human tau and comprises:
 a VH comprising VH complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO: 44 or 45; and a VL comprising VL complementarity determining regions 1, 2, and 3 of the amino acid sequences set forth in any one of SEQ ID NO:46, 221, or 222,   wherein the antibody or antigen-binding fragment thereof comprises polyethylene glycol or a detectable label selected from the group consisting of an enzyme, a radioisotope, a fluorescent compound, a chemiluminescent compound, a bioluminescent compound, and a heavy metal.