Methods and compositions for the treatment of pancreatitis

Abstract

Methods and compositions for the treatment of acute pancreatitis in a mammal. Particular compositions comprise a binding element, a translocation element, and a therapeutic element able to prevent accumulation of digestive enzymes within the pancreas.

1 . A composition for the treatment of acute pancreatitis in a mammal comprising: 
 a. a first element comprising a binding element comprising a variable region of an antibody which will specifically bind a histamine receptor under physiological conditions;    b. a second element comprising a translocation element, said translocation element comprising a portion of a Clostridial toxin heavy chain having a translocation activity able to facilitate the transfer of a polypeptide across a vesicular membrane; and    c. a third element comprising a therapeutic element, said therapeutic element comprising a portion of a Clostridial toxin light chain retaining a SNARE-protein sequence-specific endopeptidase activity that, when present in the cytoplasm of a pancreatic cell, said Clostridial toxin light chain portion endopeptidase activity inhibits enzymatic secretion by said pancreatic cell    
     
     
         2 . The composition of  claim 1 , wherein said therapeutic element will cleave a SNARE protein and cleavage of said SNARE protein inhibits said secretion.  
     
     
         3 . The composition of  claim 2 , wherein said SNARE protein is selected from the group consisting of syntaxin, SNAP-25 and VAMP.  
     
     
         4 . The method of  claim 1 , wherein said composition further comprises a spacer moiety separating said binding element from said translocation element.  
     
     
         5 . The method of  claim 1 , wherein said composition further comprises a spacer moiety separating said binding element from said translocation element.  
     
     
         6 . The method of  claim 1 , wherein said composition further comprises a spacer moiety separating said binding element from said translocation element.  
     
     
         7 . A method for the treatment of a patient suffering from acute pancreatitis comprising: administering to said patient a pharmaceutically effective amount of a composition comprising a fusion protein comprising 
 a) a first element comprising a binding element comprising a variable region of an antibody which will specifically bind a histamine receptor under physiological conditions;    b) a second element comprising a translocation element, said translocation element comprising a portion of a Clostridial toxin heavy chain having a translocation activity able to facilitate the transfer of a polypeptide across a vesicular membrane; and    c) a third element comprising a therapeutic element, said therapeutic element comprising a portion of a Clostridial toxin light chain retaining a SNARE-protein sequence-specific endopeptidase activity that, when present in the cytoplasm of a pancreatic cell, said Clostridial toxin light chain portion endopeptidase activity inhibits enzymatic secretion by said pancreatic cell;    wherein said pharmaceutically effective amount of said composition is an amount of said composition sufficient to reduce or eliminate the autodigestion of pancreas tissue in acute pancreatitis; and    wherein enzymatic secretion inhibition by said composition reduces or eliminates the autodigestion of pancreas tissue in acute pancreatitis.    
     
     
         8 . The method of  claim 7 , wherein said Clostridial toxin light chain portion endopeptidase activity cleaves a SNARE protein selected from the group consisting of syntaxin, SNAP-25, and VAMP.  
     
     
         9 . The method of  claim 7 , wherein said composition is formulated in an infusion solution, and is administered to said patient intravenously.