Antibody based reagents that specifically recognize toxic oligomeric forms of tau

Abstract

The invention relates to antibodies, antibody fragments and binding agents that specifically recognize oligomeric tau but do not bind to monomeric tau, fibrillar tau or non-disease associated forms of tau.

1 - 20 . (canceled) 
     
     
         21 . A binding molecule comprising at least one complementarity domain region (CDR) having an amino acid sequence TSGMH, FILHDGSDKYYADSVYG, SQRELLGAEYLQN, TGTSSDVGGYKYVS, DVSNRPS, and/or SSYTSSSTLV of SEQ ID NO:1, or SYAMS, AISGSGGSTYYADSVKG, GGDYGSGDY, QGDSLRSYYAS, GKNIRPS, and/or HSRDSSGTHLRV of SEQ ID NO:11. 
     
     
         22 . The binding molecule of  claim 21 , wherein the binding molecule comprises at least one complementarity domain region (CDR) having an amino acid sequence TSGMH, FILHDGSDKYYADSVYG, SQRELLGAEYLQN, TGTSSDVGGYKYVS, DVSNRPS, and SSYTSSSTLV of SEQ ID NO:1. 
     
     
         23 . The binding molecule of  claim 22 , wherein the binding molecule comprises six CDRs having amino acid sequences TSGMH, FILHDGSDKYYADSVYG, SQRELLGAEYLQN, TGTSSDVGGYKYVS, DVSNRPS, and SSYTSSSTLV of SEQ ID NO:1. 
     
     
         24 . The binding molecule of  claim 21 , wherein the binding molecule comprises at least one complementarity domain region (CDR) having an amino acid sequence SYAMS, AISGSGGSTYYADSVKG, GGDYGSGDY, QGDSLRSYYAS, GKNIRPS, and/or HSRDSSGTHLRV of SEQ ID NO:11. 
     
     
         25 . The binding molecule of  claim 24 , wherein the binding molecule comprises six CDRs having amino acid sequences SYAMS, AISGSGGSTYYADSVKG, GGDYGSGDY, QGDSLRSYYAS, GKNIRPS, and/or HSRDSSGTHLRV of SEQ ID NO:11. 
     
     
         26 . The binding molecule of  claim 21 , wherein the binding molecule binds to oligomeric tau and does not bind monomeric tau, fibrillar tau or non-disease associated forms of tau. 
     
     
         27 . A method of inhibiting the aggregation of tau, the method comprising contacting a composition that comprises tau oligomers with the binding molecule of  claim 21 . 
     
     
         28 . The method of  claim 27 , wherein said aggregation of tau is in a cell. 
     
     
         29 . The method of  claim 27 , wherein said contacting with the binding molecule decreases a rate of formation of tau aggregates as compared to said rate in the absence of the composition or the binding molecule. 
     
     
         30 . The method of  claim 27 , wherein the tau oligomers are dimeric or trimeric tau. 
     
     
         31 . The method of  claim 30 , wherein the tau oligomers are soluble. 
     
     
         32 . The method of  claim 27 , wherein the binding molecule binds to oligomeric tau and does not bind monomeric tau, fibrillary tau or non-disease associated forms of tau. 
     
     
         33 . A method of detecting the presence of tau in a physiological sample, the method comprising
 contacting a physiological sample with the binding molecule of  claim 21 ; and   determining the binding of the binding molecule with said physiological sample wherein binding of the binding molecule to said physiological sample is indicative of the presence of tau oligomers in said physiological sample, wherein said presence of said tau oligomers is indicative of early stage Alzheimer's disease (AD), frontotemporal dementia, other tauopathies, or neurodegeneration following traumatic brain injury.   
     
     
         34 . The method of  claim 33 , wherein the physiological sample is brain tissue, serum, cerebrospinal fluid (CSF), blood, urine or saliva. 
     
     
         35 . A method of inhibiting the aggregation of tau in a physiological sample, the method comprising contacting a composition that comprises tau oligomers with the binding molecule of  claim 21 . 
     
     
         36 . The method of  claim 35 , wherein said aggregation of tau is in a cell. 
     
     
         37 . The method of  claim 35 , wherein said contacting with the binding molecule decreases a rate of formation of tau aggregates as compared to said rate in the absence of the composition or the binding molecule. 
     
     
         38 . The method of  claim 35 , wherein the tau oligomers are dimeric or trimeric tau. 
     
     
         39 . The method of  claim 38 , wherein the tau oligomers are soluble. 
     
     
         40 . The method of  claim 35 , wherein the binding molecule binds to oligomeric tau and does not bind monomeric tau, fibrillary tau or non-disease associated forms of tau. 
     
     
         41 . A method of preventing or inhibiting the accumulation of tau in the brain of a mammal, the method comprising administering to said mammal a composition comprising the binding molecule of  claim 21 . 
     
     
         42 . The method of  claim 41 , wherein the binding molecule binds to oligomeric tau and does not bind monomeric tau, fibrillary tau or non-disease associated forms of tau.