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 pharmaceutical composition comprising:
 (A) (1) a peptide that comprises an immunogenic Tau peptide, wherein said immunogenic Tau peptide is selected from the group of peptides consisting of SEQ ID NOs:1-20; or
 (2) an antibody, or a molecule comprising an epitope-binding portion thereof, that is capable of specifically binding to a misfolded and/or aggregate form of Tau protein with greater selectivity than to normal Tau protein;
 wherein said antibody and said epitope-binding portion thereof comprise the amino acid sequence of an epitope-binding portion of an antibody: 
 (a) that is capable of binding to an epitope of said misfolded and/or aggregate form phosphorylated Tau that is present on said peptide (AX 1); and 
 (b) that is capable of immunospecifically binding to phosphorylated Tau with greater selectivity than to non-phosphorylated Tau; and 
 
   (B) a pharmaceutically acceptable carrier or diluent.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein said pharmaceutical composition comprises said peptide (A)(1). 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein said pharmaceutical composition comprises said antibody that is capable of specifically binding to a misfolded and/or aggregate form of Tau protein with greater selectivity than to normal Tau protein, or said molecule comprising an epitope-binding portion thereof. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein said antibody (2)(a)/(b) was produced by immunization with a polypeptide fragment of Tau selected from the group consisting of SEQ ID NOs:1-20. 
     
     
         5 . The pharmaceutical composition of  claim 3 , wherein said antibody that is capable of specifically binding to a misfolded and/or aggregate form of Tau protein with greater selectivity than to normal Tau protein is a monoclonal antibody. 
     
     
         6 . The pharmaceutical composition of  claim 3 , wherein said antibody that is capable of specifically binding to a misfolded and/or aggregate form of Tau protein with greater selectivity than to normal Tau protein is a recombinantly-produced antibody. 
     
     
         7 . The pharmaceutical composition of  claim 3 , wherein said composition contains an amount of said antibody that is capable of specifically binding to a misfolded and/or aggregate form of Tau protein with greater selectivity than to normal Tau protein, or said epitope-binding portion thereof, effective:
 (A) to promote the clearance of Tau aggregates from the brain of a recipient subject; or   (B) for the treatment of Alzheimer's disease or other tauopathy of a recipient subject.   
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein said recipient subject exhibits a symptom of Alzheimer's disease or said other tauopathy. 
     
     
         9 . The pharmaceutical composition of  claim 3 , wherein said composition additionally comprises a second antibody or binding portion thereof. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein said second antibody or binding portion thereof binds to one or more additional epitopes of said misfolded and/or aggregate form of Tau protein. 
     
     
         11 . The pharmaceutical composition of  claim 9 , wherein said second antibody or binding portion thereof binds to one or more epitopes of amyloid-beta (Aβ). 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein said composition contains an amount of said second antibody or binding portion thereof effective for the treatment of an amyloidogenic disease of a recipient subject. 
     
     
         13 . The pharmaceutical composition of  claim 9 , wherein said second antibody or binding portion thereof binds to one or more epitopes of α-synuclein. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein said composition contains an amount of said second antibody or binding portion thereof effective for the treatment of a neurodegenerative disease of a recipient subject. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein said neurodegenerative disease is Parkinson's Disease. 
     
     
         16 . The pharmaceutical composition of  claim 3 , wherein said molecule that comprises said epitope-binding portion of said antibody that is capable of specifically binding to a misfolded and/or aggregate form of Tau protein with greater selectivity than to normal Tau protein is a Fab fragment. 
     
     
         17 . The pharmaceutical composition of  claim 3 , wherein said molecule that comprises said epitope-binding portion of said antibody that is capable of specifically binding to a misfolded and/or aggregate form of Tau protein with greater selectivity than to normal Tau protein is a bispecific Fab fragment portion, one arm of which has said specificity for binding to said Tau epitope, and a second arm of which has specificity for binding to an Fc receptor.