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

Abstract

Synthetic peptides of at least 12 and at most 30 amino acid residues comprising a sequence consisting of, or found within, a complementarity-determining region (CDR) found in the heavy or light chain of the human anti-DNA 16/6Id monoclonal antibody, or a sequence obtained by replacement and/or deletion and/or addition of one or more amino residues to said sequence, and salts, chemical derivatives and polymers of said peptides can be used for immunomodulation of systemic lupus erythematosus-associated responses.

1 . A synthetic peptide selected from the group consisting of: 
 (a) a peptide of at least 12 and at most 30 amino acid residues comprising a sequence consisting of, or found within, a complementarity-determining region (CDR) found in the heavy or light chain of the human monoclonal anti-DNA 16/6Id antibody (hereinafter “hCDR sequence”), or a sequence obtained by: (i) replacement of one or more of the amino acid residues of the hCDR sequence by different amino acid residues; (ii) deletion of one or more amino acid residues from the hCDR sequence; and/or (iii) addition of one or more amino acid residues to the hCDR sequence , or a salt or a chemical derivative of said peptide;    (b) a dual synthetic peptide comprising two different ones of said peptide of (a) covalently linked to one another either directly or through a short linking chain;    (c) a peptide polymer comprising a plurality of sequences of said peptide of (a); and    (d) a peptide of (a) or a peptide polymer of (c) attached to a macromolecular carrier.    
     
     
         2 . A synthetic peptide according to  claim 1 , wherein said hCDR sequence comprises a sequence consisting of, or found within, a CDR found in the heavy chain of the human monoclonal anti-DNA 16/6Id antibody.  
     
     
         3 . A synthetic peptide according to  claim 1  or  2 , comprising further amino acid residues.  
     
     
         4 . A synthetic peptide according to  claim 3 , wherein said further amino acid residues are amino acid residues of the sequences of the human 16/6Id mAb flanking the hCDR sequences, or sequences obtained by replacement of one or more of the amino acid residues of the hCDR flanking sequences by different amino acid residues, by deletion of one or more amino acid residues from the hCDR flanking sequences and/or by addition of one or more amino acid residues to the hCDR flanking sequences.  
     
     
         5 . A synthetic peptide according to any one of  claims 2  to  4 , selected from the group consisting of: 
 (a) a peptide comprising a sequence consisting of, or found within, the sequence of SEQ ID NO:8, or a sequence obtained by: (i) replacement of one or more of the amino acid residues of said SEQ ID NO:8 by different amino acid residues; (ii) deletion of one or more amino acid residues from said SEQ ID NO:8;and/or (iii) addition of one or more amino acid residues to said SEQ ID NO:8, or a salt or a chemical derivative of said peptide;  
 (b) a dual synthetic peptide comprising two different ones of said peptide of (a) covalently linked to one another either directly or through a short linking chain;  
 (c) a peptide polymer comprising a plurality of sequences of said peptide of (a); and  
 (d) a peptide of (a) or a peptide polymer of (c) attached to a macromolecular carrier.  
 
     
     
         6 . A synthetic peptide according to  claim 5 , comprising a sequence consisting of, or found within, the sequence of SEQ ID NO:8, or a sequence obtained by: (i) replacement of one or more of the amino acid residues of said SEQ ID NO:8 by different amino acid residues; (ii) deletion of one or more amino acid residues from said SEQ ID NO:8; and/or (iii) addition of one or more amino acid residues to said SEQ ID NO:8.  
     
     
         7 . A synthetic peptide according to  claim 6  selected from a peptide consisting of the sequence of the SEQ ID NO: 11.  
     
     
         8 . A synthetic peptide according to  claim 7  selected from the peptides consisting of the sequences of the SEQ ID NO:12 to NO:18.  
     
     
         9 . The synthetic peptide according to  claim 7  consisting of the sequence of the SEQ ID NO:6.  
     
     
         10 . The peptide consisting of the sequence of SEQ ID NO:6.  
     
     
         11 . A synthetic peptide according to any one of  claims 2  to  4 , selected from the group consisting of: 
 (a) a peptide comprising a sequence consisting of, or found within, the sequence of SEQ ID NO:10, or a sequence obtained by: (i) replacement of one or more of the amino acid residues of said SEQ ID NO:10 by different amino acid residues; (ii) deletion of one or more amino acid residues from said SEQ ID NO:10; and/or (iii) addition of one or more amino acid residues to said SEQ ID NO:10, or a salt or a chemical derivative of said peptide;  
 (b) a dual synthetic peptide comprising two different ones of said peptide of (a) covalently linked to one another either directly or through a short linking chain;  
 (c) a peptide polymer comprising a plurality of sequences of said peptide of (a); and  
 (d) a peptide of (a) or a peptide polymer of (c) attached to a macromolecular carrier.  
 
     
     
         12 . A synthetic peptide according to  claim 11 , comprising a sequence consisting of, or found within, the sequence of SEQ ID NO:10, or a sequence obtained by: (i) replacement of one or more of the amino acid residues of said SEQ ID NO:10 by different amino acid residues; (ii) deletion of one or more amino acid residues from said SEQ ID NO:10; and/or (iii) addition of one or more amino acid residues to said SEQ ID NO:10.  
     
     
         13 . A synthetic peptide according to  claim 12  selected from a peptide consisting of the sequence of the SEQ ID NO:19.  
     
     
         14 . A synthetic peptide according to  claim 13  selected from the peptides consisting of the sequences of the SEQ ID NO:20 to NO:27.  
     
     
         15 . The synthetic peptide according to  claim 13  consisting of the sequence of the SEQ ID NO:7.  
     
     
         16 . The peptide consisting of the sequence of SEQ ID NO:7.  
     
     
         17 . A synthetic peptide according to any one of  claims 2  to  4 , selected from the group consisting of: 
 (a) a peptide comprising a sequence consisting of, or found within, the sequence of SEQ ID NO:9, or a sequence obtained by: (i) replacement of one or more of the amino acid residues of said SEQ ID NO:9 by different amino acid residues; (ii) deletion of one or more amino acid residues from said SEQ ID NO:9; and/or (iii) addition of one or more amino-acid residues to said SEQ ID NO:9, or a salt or a chemical derivative of said peptide;  
 (b) a dual synthetic peptide comprising two different ones of said peptide of (a) covalently linked to one another either directly or through a short linking chain;  
 (c) a peptide polymer comprising a plurality of sequences of said peptide of (a); and  
 (d) a peptide of (a) or a peptide polymer of (c) attached to a macromolecular carrier.  
 
     
     
         18 . A synthetic peptide according to  claim 17 , comprising a sequence consisting of, or found within, the sequence of SEQ ID NO:9, or a sequence obtained by: (i) replacement of one or more of the amino acid residues of said SEQ ID NO:9 by different amino acid residues; (ii) deletion of one or more amino acid residues from said SEQ ID NO:9; and/or (iii) addition of one or more amino acid residues to said SEQ ID NO:9.  
     
     
         19 . A dual synthetic peptide according to  claim 2 , in which two different peptides each comprising a sequence consisting of, or found within, a different CDR of the heavy chain of the human 16/6Id mAb, are covalently linked to one another either directly or through a short linking chain.  
     
     
         20 . A dual synthetic peptide according to  claim 19 , in which a peptide according to  claim 6  is covalently linked to a peptide according to  claim 12 .  
     
     
         21 . The dual synthetic peptide according  claim 20 , in which a peptide of SEQ ID NO:11 is covalently linked to a peptide of SEQ ID NO:19.  
     
     
         22 . The dual synthetic peptide, in which the peptide of SEQ ID NO:6 is covalently linked to the peptide of SEQ ID NO:7.  
     
     
         23 . A peptide polymer according to any one of  claims 1  to  4 , containing a plurality of identical sequences selected from the sequences of SEQ ID NO:6, 7, and 11-27.  
     
     
         24 . A pharmaceutical composition comprising at least one synthetic peptide or peptide polymer according to any one of  claims 1  to  23 , and a pharmaceutically acceptable carrier.  
     
     
         25 . A pharmaceutical composition comprising the peptide of the sequence of SEQ ID NO:6, and a pharmaceutically acceptable carrier.  
     
     
         26 . A pharmaceutical composition comprising the peptide of the sequence of SEQ ID NO:7, and a pharmaceutically acceptable carrier.  
     
     
         27 . A pharmaceutical composition according to any one of  claims 24  to  26 , for the treatment of systemic lupus elythematosus.  
     
     
         28 . A pharmaceutical composition according to any one of  claims 24  to  27 , adapted for oral, intravenous, subcutaneous, intraarticular, intramuscular, inhalation, intranasal, intrathecal, intraperitoneal, intradermal, transdermal or enteral administration.  
     
     
         29 . A method for the treatment of systemic lupus erythematosus (SLE) comprising administering to a SLE patient an effective amount of a peptide or peptide polymer according to any one of  claims 1  to  23 .  
     
     
         30 . A method according to  claim 29 , which comprises administering to said SLE patient an effective amount of the peptide of the SEQ ID NO:6.  
     
     
         31 . A method according to  claim 29 , which comprises administering to said SLE patient an effective amount of the peptide of the SEQ ID NO:7.  
     
     
         32 . A method for immunomodulation of systemic lupus erythematosus (SLE)-associated responses in a SLE patient, which comprises administering to said SLE patient an effective amount of an effective amount of a peptide or peptide polymer according to any one of  claims 1  to  23 .  
     
     
         33 . A method according to  claim 32 , which comprises down-regulating the levels of matrix metalloproteinase (MMP)-3 and/or MMP-9 activities in a SLE patient.  
     
     
         34 . A method according to  claim 32 , which comprises immunomodulating the level of a cytokine activity in a SLE patient.  
     
     
         35 . A method according to  claim 34 , which comprises down-regulating the level of IL-2 and/or IFN-γ activity in a SLE patient.  
     
     
         36 . A method according to  claim 34 , which comprises up-regulating the level of TGF-β activity in a SLE patient.  
     
     
         37 . A method according to any one of  claims 32  to  36 , which comprises administering to said SLE patient an effective amount of the peptide of the SEQ ID NO:6.  
     
     
         38 . A method according to any one of  claims 32  to  36 , which comprises administering to said SLE patient an effective amount of the peptide of the SEQ ID NO:7.  
     
     
         39 . A method for assessing the effectiveness of a drug in the treatment of a SLE-patient which comprises measuring at different intervals of time the levels of MMP-3 and/or MMP-9 in a blood sample obtained from said patient being treated with said drug, whereby a decreased level of MMP-3 and/or MMP-9 correlates with the effectiveness of the drug.  
     
     
         40 . A method for assessing the effectiveness of a drug in the treatment of a SLE patient which comprises measuring at different intervals of time the levels of IL-2 and/or IFN-γ in a blood sample obtained from said patient being treated with said drug, whereby a decreased level of IL-2 and/or IFN-γ correlates with the effectiveness of the drug.  
     
     
         41 . A method for assessing the effectiveness of a drug in the treatment of a SLE patient which comprises measuring at different intervals of time the level of TGF-β in a blood sample obtained from said patient being treated with said drug, whereby an increased level of TGF-β correlates with the effectiveness of the drug.