Anti-tau antibodies and methods of use

Abstract

The invention provides anti-Tau antibodies and methods of using the same.

1 . (canceled) 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . An isolated antibody that binds to human Tau, wherein the antibody comprises:
 a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 342; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 343; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 344; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 608; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 609; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 610; or   b) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 605; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 606; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 607; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 345; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 346; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 347.   
     
     
         5 . The isolated antibody of  claim 4 , wherein the antibody binds to monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau. 
     
     
         6 . The isolated antibody of  claim 4 , wherein the antibody binds an epitope within amino acids 2 to 24 of mature human Tau. 
     
     
         7 . The isolated antibody of  claim 4 , which is a monoclonal antibody. 
     
     
         8 . The isolated antibody of  claim 4 , which is a human, humanized, or chimeric antibody. 
     
     
         9 . The antibody of  claim 4 , which is an antibody fragment that binds human Tau. 
     
     
         10 . The antibody of  claim 4 , wherein the human Tau comprises the sequence of SEQ ID NO: 2. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The isolated antibody of  claim 4 , wherein the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 340; and a light chain variable region comprising a sequence selected from SEQ ID NOs: 608, 609, and 610. 
     
     
         15 . The isolated antibody of  claim 4 , wherein the antibody comprises a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 605, 606, and 607; and a light chain variable region comprising the sequence of SEQ ID NO: 341. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . The isolated antibody of  claim 4 , wherein the antibody is an IgG 1  or an IgG 4  antibody. 
     
     
         23 . The isolated antibody of  claim 22 , wherein the antibody is an IgG 4  antibody. 
     
     
         24 . The isolated antibody of  claim 23 , wherein the antibody comprises M252Y, S254T, and T256E mutations. 
     
     
         25 . The isolated antibody of  claim 24 , wherein the antibody comprises an S228P mutation. 
     
     
         26 . (canceled) 
     
     
         27 . The isolated antibody of  claim 4 , wherein the antibody binds monomeric Tau with a K D  of less than 5 nM. 
     
     
         28 . The isolated antibody of  claim 4 , wherein the antibody binds to human monomeric Tau with a K D  of less than 1 nM. 
     
     
         29 . The isolated antibody of  claim 27 , wherein K D  is determined by surface plasmon resonance. 
     
     
         30 . The isolated antibody of  claim 4 , which binds cynomolgus monkey Tau. 
     
     
         31 . An isolated nucleic acid that encodes the antibody of  claim 4 . 
     
     
         32 . A host cell comprising the nucleic acid of  claim 31 . 
     
     
         33 . A method of producing an antibody comprising culturing the host cell of  claim 32  under conditions suitable for producing the antibody. 
     
     
         34 . An immunoconjugate comprising the isolated antibody of  claim 4  and a second therapeutic agent. 
     
     
         35 . A labeled antibody comprising the antibody of  claim 4  and a detectable label. 
     
     
         36 . A pharmaceutical composition comprising the isolated antibody of  claim 4  and a pharmaceutically acceptable carrier. 
     
     
         37 . A method of treating a Tau protein associated disease comprising administering to an individual with a Tau protein related disease the antibody of  claim 4 . 
     
     
         38 . The method of  claim 37 , wherein the Tau protein associated disease is a tauopathy. 
     
     
         39 . The method of  claim 38 , wherein the tauopathy is a neurodegenerative tauopathy. 
     
     
         40 . The method of  claim 37 , wherein the tauopathy is selected from Alzheimer's Disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jacob disease, Dementia pugilistica, Down Syndrome, Gerstmann-Straussler-Scheinker disease, inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, Non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal sdegeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, Pallido-ponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, Subacute sclerosing panencephalitis, Tangle only dementia, Postencephalitic Parkinsonism, and Myotonic dystrophy. 
     
     
         41 . The method of  claim 38 , wherein the tauopathy is Alzheimer's disease or progressive supranuclear palsy. 
     
     
         42 . A method of retaining or increasing cognitive memory capacity or slowing memory loss in an individual, comprising administering the antibody of  claim 4 . 
     
     
         43 . A method of reducing the level of Tau protein, non-phosphorylated Tau protein, phosphorylated Tau protein, or hyperphosphorylated Tau protein in an individual with a tauopathy, comprising administering the antibody of  claim 4 . 
     
     
         44 . The method of  claim 37 , wherein the method comprises administering at least one additional therapy. 
     
     
         45 . The method of  claim 44 , wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, BACE1 inhibitors, cholinesterase inhibitors (ChEIs), NMDA receptor antagonists, and nutritional supplements. 
     
     
         46 .- 62 . (canceled) 
     
     
         63 . A method of detecting neurofibrillary tangles, neuropil threads, or dystrophic neuritis comprising contacting a sample with the antibody of  claim 4 . 
     
     
         64 . The method of  claim 63 , wherein the sample is a brain sample, a cerebrospinal fluid sample, or a blood sample. 
     
     
         65 . The method of  claim 45 , wherein the ChEI is tacrine, rivastigmine, donepezil, or galantamine; and wherein the NMDA receptor antagonist is memantine. 
     
     
         66 . The method of  claim 45 , wherein the anti-amyloid beta antibody is crenezumab.