Synthethic peptides and pharmaceutical compositions comprising them for the treatment of systemic lupus erythematosus

Abstract

Synthetic peptides based on a complementarity-determining region (CDR) of the heavy or light chain of a pathogenic anti-DNA monoclonal antibody that induces a systemic lupus erythematosus (SLE)-like disease in mice, and analogs, and salts and chemical derivatives thereof; dual peptides comprising two such peptides or analogs covalently linked to one another either directly or through a short linking chain; peptide polymers comprising a plurality of sequences of said peptide or analog thereof; and peptide polymers attached to a macromolecular carrier, are disclosed, and pharmaceutical compositions comprising them for the treatment of SLE in humans.

1 . A synthetic peptide selected from the group consisting of: 
 (i) a peptide of at least 12 and at most 30 amino acid residues based on a complementarity-determining region (CDR) of the heavy or light chain of a pathogenic anti-DNA monoclonal antibody that induces a systemic lupus erythematosus (SLE)-like disease in mice (hereinafter CDR-based peptide), a salt or a chemical derivative thereof;    (ii) an analog of a CDR-based peptide defined in (i), a salt or a chemical derivative thereof;    (iii) a dual synthetic peptide comprising two such peptides of (i) or analogs of (ii) covalently linked to one another either directly or through a short linking chain;    (iv) a peptide polymer comprising a plurality of sequences of said peptide (i) or analog thereof (ii); and    (v) a peptide polymer (iv) attached to a macromolecular carrier.    
     
     
         2 . A synthetic peptide according to  claim 1 , capable of: 
 (i) inhibiting specifically the proliferative response and cytokine secretion of T lymphocytes of mice that are high responders to SLE-inducing autoantibodies; or    (ii) inhibiting development of SLE in mice that are susceptible to SLE-induction by pathogenic autoantibodies.    
     
     
         3 . A synthetic peptide according to  claim 1  or  2 , being selected from the group consisting of peptides having the sequences I to V herein, wherein: 
 (i) the peptide of sequence I has the formula:  
                           T G Y Y X 1  X 2  X 3  X 4  X 5  Q S P E K S L E W I G   [I]                           
 wherein X 1  is Met, Ala or Val; X 2  is Gln, Asp, Glu or Arg; X 3  is Trp or Ala; X 4  is Val or Ser; and X 5  is Lys, Glu or Ala;  
 (ii) the peptide of sequence II has the formula:  
                           E I N P S T G G X 6  X 7  X 8  X 9  X 10  X 11  X 12  K A K   [II]               A T                         
 wherein X 6  and X 7  are each Thr, Val or Ala; X 8  is Tyr or Phe; X 9  is Asn or Asp; X 10  is Gln or Glu; and X 11  is Lys or Glu, and X 12  is Phe or Tyr;  
 (iii) the peptide of sequence III has the formula:  
                           Y Y C A R X 13  X 14  X 15  X 16  P Y A X 17  X 18  Y W G Q G S   [III]                           
 wherein X 13  is Phe, Thr or Gly; X 14  is Leu, Ala or Ser; X 15  is Trp or Ala; X 16  is Glu or Lys; X 17  is Met or Ala, and X 15  is Asp, Lys or Ser;  
 (iv) the peptide of sequence IV has the formula:  
                           G Y N X 19  X 20  X 21  X 22  X 23  X 24  S H G X 25  X 26  L E W I G   [IV]                           
 wherein X 19  is Met or Ala; X 20  is Asn, Asp or Arg; X 21  is Trp or Ala; X 22  is Val or Ser; X 23  is Lys or Glu; X 24  is Gln or Ala; X 25  is Lys or Glu, and X 26  is Ser or Ala; and  
 (v) the peptide of sequence V has the formula:  
                           Y Y C A R X 27  X 28  X 29  Y G X 30  X 31  X 32  G Q G   [V]               T L                         
 wherein X 27  is Ser or Phe; X 28  is Gly or Ala; X 29  is Arg, Ala or Glu; X 30  is Asn or Asp; X 31  is Tyr or Phe, and X 32  is Trp, His or Ala.  
 
     
     
         4 . A peptide according to  claim 3 , having a sequence Ia of the formula:  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   T G Y Y M Q W V K Q S P E K S L E W I G 
                   (Ia) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         5 . A peptide according to  claim 3 , having a sequence IIa of the formula:  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   E I N P S T G G T T Y N Q K F K A K A T 
                   (IIa) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         6 . A peptide according to  claim 3 , having a sequence IIIa of the formula:  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Y Y C A R F L W E P Y A M D Y W G Q G S 
                   (IIIa) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         7 . A peptide according to  claim 3 , having a sequence IVa of the formula:  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   G Y N M N W V K Q S H G K S L E W I G 
                   (IVa) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         8 . A peptide according to  claim 3 , having a sequence Va of the formula:  
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Y Y C A R S G R Y G N Y W G Q T L 
                   (Va) 
                     
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
     
     
         9 . A dual synthetic peptide according to  claim 1  or  2 , in which two different sequences I to V in  claim 3  are covalently linked to one another either directly or through a short linking chain.  
     
     
         10 . A dual synthetic peptide according to  claim 9 , in which two different sequences of the peptides Ia to Va are linked covalently.  
     
     
         11 . A peptide polymer according to  claim 1 , containing a plurality of identical sequences selected from the sequences I to V in  claim 3 .  
     
     
         12 . A pharmaceutical composition for the treatment of systemic lupus erythematosus comprising an effective amount of a synthetic peptide or peptide polymer according to any one of  claims 1  to  11 , and a pharmaceutically acceptable carrier.  
     
     
         13 . A pharmaceutical composition for the treatment of systemic lupus erythematosus comprising an effective amount of a mixture of at least two different peptides in accordance with any one of the  claims 3  to  10 .  
     
     
         14 . A method for the treatment of systemic lupus erythematosus comprising administering to a systemic lupus erythematosus patient an effective amount of a peptide or peptide polymer according to any one of  claims 1  to  11 .  
     
     
         15 . A method of selecting peptides capable of inhibiting the proliferative response of T lymphocytes from a SLE patient, comprising: 
 (i) synthesizing a peptide of at least 12 and at most 30 amino acid residues, having a sequence based on the CDR region of the heavy or light chain of a pathogenic anti-DNA monoclonal antibody that induces a SLE-like disease in mice, or an analog thereof;    (ii) testing said peptide or analog for its ability to inhibit the proliferative response of T cells from a SLE patient, or a T cell line or clone which is specific to the 16/6 Id anti-DNA monoclonal antibody to which the T cells are specific; and    (iii) selecting and producing said peptide only if it is capable of inhibiting said proliferative response.