Immunotherapy for Clearing Pathological Tau Conformers

Abstract

The present invention relates to methods of treating and preventing Alzheimer's Disease or other tauopathies in a subject by administering a tau protein, its immunogenic epitopes, or antibodies recognizing the tau protein or its immunogenic epitopes under conditions effective to treat or prevent Alzheimer's Disease of other tauopathies. Also disclosed are methods of promoting clearance of from the brain of the subject and of slowing progression of tangle-related behavioral phenotype in a subject.

1 . A desired antibody, or binding portion thereof, capable of binding to pathological Tau protein, wherein:
 said antibody and said binding portion thereof comprise three Light Chain CDRs and three Heavy Chain CDRs, and are capable of binding an epitope of pathological Tau protein possessing phosphorylated serine residues at positions 396 and 404 thereof, said epitope being formed by residues 379-408 of said pathological Tau protein; and   said binding is sufficiently specific for pathological Tau protein, relative to normal Tau protein, that under conditions sufficient to detect minimal binding of said antibody to pathological Tau protein, binding to normal Tau protein is not observed;   wherein said antibody is produced by a process that comprises:   (A) immunizing a murine or human subject with an immunogen that comprises a Tau peptide portion, wherein the amino acid sequence of said Tau peptide portion of said immunogen consists of the amino acid sequence of SEQ ID NO:2, and   (B) permitting said immunized subject to produce said desired antibody capable of binding said epitope of pathological Tau protein, wherein said desired antibody is characterized by its ability to recognize Tau aggregates in the brains of homozygous transgenic (Tg) P301L mice.   
     
     
         2 . The antibody, or binding portion thereof, of  claim 1 , wherein said process further comprises:
 (C) producing a monoclonal, chimeric, human or humanized antibody derivative of said desired antibody (B), or binding portion thereof, that is characterized by its ability to recognize Tau aggregates in the brains of homozygous transgenic (T 2 ) P301L mice.   
     
     
         3 . A pharmaceutical composition for the treatment of Alzheimer's disease or other tauopathy in a recipient human subject, wherein said composition comprises a therapeutically effective amount of the antibody, or binding portion thereof, of  claim 1 , and a pharmaceutically acceptable diluent, excipient, adjuvant or carrier; wherein said therapeutically effective amount is sufficient to at least partially arrest a symptom or characteristic of said Alzheimer's disease or other tauopathy in said recipient subject. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein said symptom that is at least partially arrested is Tau pathology-related cognitive impairment. 
     
     
         5 . The pharmaceutical composition of  claim 3 , wherein said characteristic that is at least partially arrested is the formation of Tau aggregates. 
     
     
         6 . The pharmaceutical composition of  claim 3 , wherein said subject is a recipient human subject that suffers from Alzheimer's disease. 
     
     
         7 . The pharmaceutical composition of  claim 3 , wherein said recipient human subject suffers from one or more tauopathy selected from the group consisting of frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, a diffuse neurofibrillary tangle with calcification, and Down syndrome. 
     
     
         8 . (canceled) 
     
     
         9 . A pharmaceutical composition for the treatment of Alzheimer's disease or other tauopathy in a recipient human subject, wherein said composition comprises a therapeutically effective amount of the antibody, or binding portion thereof, of  claim 2 , and a pharmaceutically acceptable diluent, excipient, adjuvant or carrier; wherein said therapeutically effective amount is sufficient to at least partially arrest a symptom or characteristic of said Alzheimer's disease or other tauopathy in said recipient subject. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein said symptom that is at least partially arrested is Tau pathology-related cognitive impairment. 
     
     
         11 . The pharmaceutical composition of  claim 9 , wherein said characteristic that is at least partially arrested is the formation of Tau aggregates. 
     
     
         12 . The pharmaceutical composition of  claim 9 , wherein said subject is a human subject that suffers from Alzheimer's disease. 
     
     
         13 . The pharmaceutical composition of  claim 9 , wherein said recipient human subject suffers from one or more tauopathy selected from the group consisting of frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, a diffuse neurofibrillary tangle with calcification, and Down syndrome. 
     
     
         14 . (canceled) 
     
     
         15 . A method of treating Alzheimer's disease or other tauopathy in a recipient human subject in need thereof, wherein said method comprises administering the pharmaceutical composition of  claim 3  to a recipient human subject in a dosage regimen sufficient to at least partially arrest a symptom or characteristic of said Alzheimer's disease or other tauopathy in said recipient subject. 
     
     
         16 . The method of  claim 15 , wherein said symptom that is at least partially arrested is Tau pathology-related cognitive impairment. 
     
     
         17 . The method of  claim 15 , wherein said characteristic that is at least partially arrested is the formation of Tau aggregates. 
     
     
         18 . The method of  claim 15 , wherein said recipient human subject suffers from Alzheimer's disease. 
     
     
         19 . The method of  claim 15 , wherein said recipient human subject suffers from one or more tauopathy selected from the group consisting of frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, a diffuse neurofibrillary tangle with calcification, and Down syndrome. 
     
     
         20 . (canceled) 
     
     
         21 . A method of treating Alzheimer's disease or other tauopathy in a recipient human subject in need thereof, wherein said method comprises administering the pharmaceutical composition of  claim 9  to a recipient human subject in a dosage regimen sufficient to at least partially arrest a symptom or characteristic of said Alzheimer's disease or other tauopathy in said recipient subject. 
     
     
         22 . The method of  claim 21 , wherein said symptom that is at least partially arrested is Tau pathology-related cognitive impairment. 
     
     
         23 . The method of  claim 21 , wherein said characteristic that is at least partially arrested is the formation of Tau aggregates. 
     
     
         24 . The method of  claim 21 , wherein said recipient human subject suffers from Alzheimer's disease. 
     
     
         25 . The method of  claim 21 , wherein said recipient human subject suffers from one or more tauopathy selected from the group consisting of frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, a diffuse neurofibrillary tangle with calcification, and Down syndrome. 
     
     
         26 . (canceled)