Immunological control of beta-amyloid levels in vivo

Abstract

An antibody and vectorized antibody, capable of crossing the blood brain barrier, which catalyze hydrolysis of β-amyloid at a predetermined amide linkage are described. The antibody preferentially binds a transition state analog which mimics the transition state adopted by β-amyloid during hydrolysis. Also described are methods for sequestering free β-amyloid in an animal's bloodstream or for reducing β-amyloid or for disaggregating or preventing the formation of amyloid plaques in an animal's brain by administering β-amyloid specific antibodies or by immunization with endogenous β-amyloid epitopes. Methods which utilize or generate antibodies which catalyze the hydrolysis of β-amyloid for reducing levels of circulating β-amyloid in an animal; which generate antibodies that catalyze hydrolysis of a polypeptide by immunization with an epitope having a statine analog which mimics the polypeptide's hydrolysis transition state; and which utilize reduced peptide bond analogs to mimic the polypeptide's hydrolysis transition state are also provided.

1 . A method for inhibiting the formation of,8-amyloid plaques in the brain of a human, the method comprising: 
 a) providing a β-amyloid epitope; and    b) administering the epitope of step a) to the human under conditions appropriate for the stimulation of an immune response directed toward the epitope, the immune response being characterized by the generation of circulating antibodies which bind specifically to the epitope present on endogenous, β-amyloid in the human.    
     
     
         2 . The method of  claim 1  wherein the epitope of step a) is administered in an adjuvant formulation.  
     
     
         3 . The method of  claim 2  wherein the adjuvant formulation comprises oil emulsion.  
     
     
         4 . The method of  claim 1  wherein the binding of circulating antibodies to endogenous β-amyloid detectably alters the equilibrium distribution of free β-amyloid in circulation versus free β-amyloid in the brain of the human.  
     
     
         5 . The method of  claim 1  wherein the epitope of β-amyloid is linked to an immunogenic carrier moiety.  
     
     
         6 . The method of  claim 5  wherein the immunogenic carrier moiety is Keyhole Limpet Hemocyanin (KLH).  
     
     
         7 . The method of  claim 1  wherein the epitope is provided as β-amyloid peptide Aβ 1-43 .  
     
     
         8 . The method of  claim 1  wherein the epitope is provided as β-amyloid peptide Aβ 1-40 .  
     
     
         9 . The method of  claim 1  wherein the epitope is provided as a peptide fragment of β-amyloid, the peptide fragment being derived from the N-terminal region of the β-amyloid peptide Aβ 1-43 .  
     
     
         10 . The method of  claim 1  wherein the epitope is provided as a peptide fragment of β-amyloid, the peptide fragment being derived from the central region of the β-amyloid peptide Aβ 1-43 .  
     
     
         11 . The method of  claim 1  wherein the epitope is provided as a peptide fragment of β-amyloid, the peptide fragment being derived from the C-terminal region of β-amyloid peptide.  
     
     
         12 . A method for inhibiting the formation of β-amyloid aggregates and plaques in the brain of a human, the method comprising: 
 a) providing a plurality of peptide fragments derived from β-amyloid peptide Aβ 1-43 , each peptide fragment comprising one or more β-amyloid epitopes; and    b) administering the plurality of peptide fragments of step a) to the human under conditions appropriate for the stimulation of an immune response directed toward the β-amyloid epitopes, the immune response being characterized by the generation of circulating antibodies which bind specifically to one or more epitopes present on endogenous, β-amyloid in the human.    
     
     
         13 . The method of  claim 12  wherein at least one epitope is provided as a peptide fragment of β-amyloid, the peptide fragment being derived from the N-terminal region of the β-amyloid peptide Aβ 1-43 .  
     
     
         14 . The method of  claim 12  wherein at least one epitope is provided as a peptide fragment of β-amyloid, the peptide fragment being derived from the central region of the β-amyloid peptide Aβ 1-43 .  
     
     
         15 . The method of  claim 12  wherein at least one epitope is provided as a peptide fragment of β-amyloid, the peptide fragment being derived from the C-terminal region of β-amyloid peptide.