Agents which bind to epitopes of glycoprotein VI

Abstract

The present invention provides anti-thrombotic agents, methods for screening for said anti-thrombotics agents and methods of treating thrombotic and other cardiovascular disorders.

1 . A pharmaceutical formulation comprising monoclonal antibody hGP 5C4 or function-conservative fragments or variants thereof, which specifically bind to glycoprotein VI and a pharmaceutically acceptable excipient.  
     
     
         2 . The pharmaceutical formulation according to  claim 1 , wherein the monoclonal antibody hGP 5C4 or function-conservative fragments or variants thereof specifically bind to human glycoprotein VI.  
     
     
         3 . The pharmaceutical formulation according to  claim 1 , wherein the monoclonal antibody or function-conservative fragments thereof is purified from an antibody producing cell deposited as hGP 5C4 with DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen under Accession No. 2631, or progeny thereof.  
     
     
         4 . The pharmaceutical formulation according to  claim 1  wherein the monoclonal antibody or function-conservative fragment or variant thereof inhibits collagen-binding to human glycoprotein VI.  
     
     
         5 . A pharmaceutical formulation comprising a Fab fragment of the monoclonal antibody according to  claim 1 , which is hGP 5C4 Fab obtainable by papain digestion of hGP 5C4.  
     
     
         6 . A pharmaceutical formulation comprising a humanized antibody specifically binding to glycoprotein VI, which comprises a function conservative fragment or variant of the monoclonal antibody hGP 5C4.  
     
     
         7 . A pharmaceutical formulation comprising a fusion protein specifically binding to glycoprotein VI, which comprises an amino acid sequence of the antibody hGP 5C4 or of function-conservative fragments or variants thereof.  
     
     
         8 . A pharmaceutical formulation comprising a conjugate comprising an effector moiety and the monoclonal antibody hGP 5C4 or function-conservative fragments or variants thereof, which specifically bind to glycoprotein VI as defined in  claim 1 , a humanized form thereof or a fusion protein thereof.  
     
     
         9 . A hybridoma cell line deposited as hGP 5C4 with DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen under Accession number 2631, or a progeny thereof.  
     
     
         10 . A nucleic add coding for a polypeptide comprising at least 5 consecutive amino acids of the monoclonal antibody hGP 5C4 Fab and binding specifically to human glycoprotein VI.  
     
     
         11 . The nucleic acid according to  claim 11  which codes for monoclonal antibody hGP 5C4 Fab or function-conservative fragments or variants thereof, wherein said nucleic acid is obtainable from the hybridoma cell line according to  claim 9 .  
     
     
         12 . A method of treating or preventing acute or chronic vascular diseases associated with intraarterial and/or intravenous thrombosis comprising the use of the pharmaceutical formulation of  claim 1 , a humanized form thereof or a fusion protein thereof.  
     
     
         13 . The method of  claim 12 , wherein the medicament is for parenteral administration.  
     
     
         14 . An agent that binds to a ligand, the ligand consisting of one or a combination of: 
 (a) a peptide moiety of 5 to 15 amino acid residues including a sequence of contiguous amino acid residues selected from the sequence of contiguous amino acids from position 15 to position 39 of human GP VI protein as shown in  FIG. 35 ;    (b) a peptide moiety of 5 to 15 amino acid residues including a sequence of contiguous amino acid residues selected from the sequence of contiguous amino acids from position 73 to position 87 of human GP VI protein as shown in  FIG. 35 ;    (c) a peptide moiety of 5 to 15 amino acid residues including a sequence of contiguous amino acid residues selected from the sequence of contiguous amino acids from position 107 to position 121 of human GP VI protein as shown in  FIG. 35 .    
     
     
         15 . An agent that binds to a ligand, the ligand consisting of one or a combination of: 
 (a) a peptide moiety of 5 to 15 amino acid residues including a sequence of contiguous amino acid residues selected from the sequence of contiguous amino acids from position 15 to position 39 of human GP VI protein as shown in  FIG. 35 ;    (b) a peptide moiety of 5 to 15 amino acid residues including a sequence of contiguous amino add residues selected from the sequence of contiguous amino acids from position 73 to position 87 of human GP VI protein as shown in  FIG. 35 ;    (c) a peptide moiety of 5 to 15 amino acid residues including a sequence of contiguous amino acid residues selected from the sequence of contiguous amino acids from position 107 to position 121 of human GP VI protein as shown in  FIG. 35 , which is not monoclonal antibody hGP 5C4 or a fragment thereof other than a Fab′, a (Fab′) 2 , Fv or dsFv fragment.    
     
     
         16 . A ligand or peptide consisting of one or more of: 
 (a) a peptide moiety of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues including a sequence of contiguous amino acid residues selected from the sequence of contiguous amino acids from position 15 to position 39 of human GP VI protein as shown in  FIG. 35 ;    (b) a peptide moiety of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues including a sequence of contiguous amino add residues selected from the sequence of contiguous amino acids from position 73 to position 87 of human GP VI protein as shown in  FIG. 35 ;    (c) a peptide moiety of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino add residues including a sequence of contiguous amino add residues selected from the sequence of contiguous amino acids from position 107 to position 121 of human GP VI protein as shown in  FIG. 35 .