Suppression of immune response via inhibition of cathepsin S

Abstract

Methods and products for suppressing a class II MHC-restricted immune response in a mammal, or in mammalian cells, are described. The methods depend upon inhibiting invariant chain proteolysis by cathepsin S from class II MHC/invariant chain complexes, thereby reducing the competency of class II MHC molecules for binding antigenic peptides, reducing presentation of antigenic peptides by class II MHC molecules, and suppressing immune responses. The methods may be employed in the treatment of autoimmune diseases, allergic responses, and organ or tissue graft rejection. Pharmaceutical and therapeutic compositions which are peptide based inhibitors of cathepsin S are also described.

1 . A method for suppressing a class II NMC-restricted immune response in a mammal, comprising 
 administering to said mammal an effective amount of an agent which inhibits cathepsin S, said amount of said agent inhibiting proteolysis of invariant chain by cathepsin S and thereby inhibiting formation of class II/antigenic peptide complexes from class II MHC/invariant chain complexes in said mammal.    
     
     
         2 . A method as in  claim 1  wherein 
 said mammal is at risk of, or afflicted with, an autoimmune disease; and    said agent is administered in an amount effective to suppress an autoimmune response.    
     
     
         3 . A method as in  claim 2  wherein 
 said autoimmune disease is selected from the group consisting of juvenile-onset diabetes (insulin dependent), multiple sclerosis, pemphigus vulgaris, Grave's disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis and Hashimoto's thyroiditis.    
     
     
         4 . A method as in  claim 1  wherein 
 said mammal is at risk of, or afflicted with, an allergic response; and    said agent is administered in an amount effective to suppress an allergic response.    
     
     
         5 . A method as in  claim 4  wherein said allergic response is an asthmatic response.  
     
     
         6 . A method as in  claim 1  wherein 
 said mammal has undergone, or is about to undergo, an organ or tissue graft; and    said agent is administered in an amount effective to suppress an allogeneic immune response.    
     
     
         7 . A method for inhibiting invariant chain proteolysis from class II MHC/invariant chain complexes in a mammalian cell, comprising: 
 administering to said cell an agent which inhibits cathepsin S.    
     
     
         8 . A method for reducing the competency of class II MHC molecules for binding antigenic peptides in a mammalian cell, comprising: 
 administering to said cell an agent which inhibits cathepsin S, said agent inhibiting invariant chain proteolysis from class II MHC/invariant chain complexes to reduce the competency of class II MHC molecules for binding antigenic peptides in said cell.    
     
     
         9 . A method for reducing presentation of antigenic peptide by class II MHC molecules in a mammalian cell, comprising: 
 administering to said cell an agent which inhibits cathepsin S. said agent inhibiting invariant chain proteolysis from class II MC/invariant chain complexes to reduce presentation of antigenic peptide by class II NHC molecules in said mammal.    
     
     
         10 . A method as in any one of claims  7 - 9  wherein 
 said mammalian cell is disposed in a mammal in vivo.    
     
     
         11 . A method as in any one of claims  7 - 9  wherein 
 said mammalian cell is disposed in vitro.    
     
     
         12 . A method as in any one of claims  1 - 9  wherein 
 said agent is a cysteine protease inhibitor.    
     
     
         13 . A method as in any one of claims  1 - 9  wherein 
 said agent is a selective inhibitor of cathepsin S relative to a cysteine protease selected from the group consisting of cathepsins K, L, H, O2 and B.    
     
     
         14 . A method as in any one of claims  1 - 9  wherein 
 said agent is a specific inhibitor of cathepsin S.    
     
     
         15 . A method as in any one of claims  1 - 9  wherein said agent is a peptide-based inhibitor of cathepsin S.  
     
     
         16 . A method as in  claim 15  wherein said peptide-based inhibitor of cathepsin S is based upon a peptide sequence which comprises 2-20 consecutive residues of a preferred invariant chain cleavage site of cathepsin S.  
     
     
         17 . A method as in  claim 15  wherein 
 said peptide sequence is selected from the group consisting of Asn-Leu, Glu-Asn-Leu, Arg-Met, Leu-Arg-Met, Leu-Leu-Leu, and Leu-Hph.    
     
     
         18 . A method as in  claim 15  wherein 
 Said peptide-based inhibitor is morpholinurea-leucine-homophenylaianine vinylsulfone phenyl (LHVS).    
     
     
         19 . A method as in  claim 15  or  16  wherein said peptide-based inhibitor is a peptide-based vinylsulfone or a modified peptide-based vinylsulfone.  
     
     
         20 . A method as in  claim 15  or  16  wherein said peptide-based inhibitor is selected from the group consisting of peptidyl aldehydes, nitriles, α-ketocarbonyls, halomethyl ketones, diazomethyl ketones, (acyloxy)-methyl ketones, vinyl sulfones, ketomethylsulfonium salts, epoxides, and N-peptidyl-O-acyl-hydroxylamines.  
     
     
         21 . The method as in  claim 15  or  16  wherein said agent is selected from the group consisting of Asn-Leu-vinylsulfone, Arg-Met-vinylsulfone, Leu-Arg-Met-vinylsulfone, Glu-Asn-Leu-vinylsulfone, and Leu-Leu-Leu-vinylsulfone.  
     
     
         22 . The method of  claim 15  or  16  wherein said agent is selected from the group consisting of N-(carboxybenzyl) -Asn-Leu-vinylsulfone, N-(carboxybenzyl)-Arg-Met-vinylsulfone, N-(carboxybenzyl)-Leu-Arg-Met-vinylsulfone, N-(carboxybenzyl)-Glu-Asn-Leu-vinylsulfone, and N-(carboxybenzyl)-Leu-Leu-Leu-vinylsulfone.  
     
     
         23 . The method of  claim 15  or  16  wherein said agent is selected from the group consisting of N-(nitrophenylacetyl)-Asn-Leu-vinylsulfone, N-(nitrophenylacetyl)-Arg-Met-vinylsulfone, N-(nitrophenylacetyl)-Leu-Arg-Met-vinylsulfone, N-(nitrophenylacetyl)-Glu-Asn-Leu-vinylsulfone, and N-(nitrophenylacetyl)-Leu-Leu-Leu-vinylsulfone.  
     
     
         24 . An inhibitor of cathepsin S comprising 
 a peptide-based inhibitor of cathepsin S,    wherein said peptide-based inhibitor of cathepsin S is based upon a peptide sequence which comprises at least about 2-20 consecutive residues from a preferred invariant chain cleavage site of cathepsin S.    
     
     
         25 . An inhibitor as in  claim 24  wherein 
 said peptide sequence is selected from the group consisting of Asn-Leu, Glu-Asn-Leu, Arg-Met, Leu-Arg-Met, Leu-Leu-Leu, and Leu-Hph.    
     
     
         26 . An inhibitor as in  claim 24  wherein said peptide-based inhibitor is a peptide-based vinylsulfone or a modified peptide-based vinylsulfone.  
     
     
         27 . An inhibitor as in  claim 24  wherein said peptide-based inhibitor is selected from the group consisting of peptidyl aidehydes, nitrites, α-ketocarbonyls, halo methyl ketones, diazomethyl ketones, (acyloxy)-methyl ketones, vinyl sulfones, ketomethylsulfonium salts, epoxides, and N-peptidyl-O-acyl-hydroxylamines.  
     
     
         28 . An inhibitor as in  claim 24  wherein said inhibitor is selected from the group consisting of Asn-Leu-vinylsulfone, Arg-Met-vinylsulfone, Leu-Arg-Met-vinylsulfone, Glu-Asn-Leu-vinylsulfone, and Leu-Leu-Leu-vinylsulfone.  
     
     
         29 . An inhibitor as in  claim 24  wherein said inhibitor is selected from the group consisting of N-(carboxybenzyl)-Asn-Leu-vinylsulfone, N-(carboxybenzyl)-Arg-Met-vinylsulfone, N-(carboxybenzyl)-Leu-Arg-Met-vinylsulfone, N-(carboxybenzyl)-Glu-Asn-Leu-vinylsulfone, and N-(carboxybenzyl)-Leu-Leu-Leu-vinylsulfone.  
     
     
         30 . An inhibitor as in  claim 24  wherein said inhibitor is selected from the group consisting of N-(nitrophenylacetyl)-Asn-Leu-vinylsulfone, N-(nitrophenylacetyl)-Arg-Met-vinylsulfone, N-(nitrophenylacetyl)-Leu-Arg-Met-vinylsulfone, N-(nitrophenylacetyl)-Glu-Asn-Leu-vinylsulfone, and N-(nitrophenylacetyl)-Leu-Leu-Leu-vinylsulfone.  
     
     
         31 . An inhibitor as in any one of claims  24 - 30  wherein said inhibitor is formulated as a pharmaceutical or therapeutic preparation suitable for administration to mammalian cells in vivo or in vitro.  
     
     
         32 . The use of an inhibitor as in any one of claims  24 - 31  in the manufacture of a medicament for use according to the methods of any one of claims  1 - 11 .