Antithrombotic von willebrand factor (vwf) collagen bridging blockers

Abstract

The present invention clearly demonstrates that vWF-collagen interaction plays an important role in acute platelet-dependent arterial thrombus formation and that blockade of vWF-collagen interaction can induce complete abolition of thrombus formation in the injured and stenosed baboon femoral arteries. Accordingly, a blocker of vWF-collagen can be used as a compound for the prevention of acute arterial thrombotic syndromes or to manufacture medicines to prevention of acute arterial thrombotic syndromes.

1 . A ligand which is an antibody or an antigen recognizing fragment thereof binding specifically to the A3 domain of von Willebrand Factor (vWF) or an epitope thereof for use as a medicament.  
     
     
         2 . The ligand according to  claim 1 , further characterized in that it binds specifically to an epitope comprising amino acids located within the sequence spanning amino acids 974 to 989 within the A3 domain of vWF.  
     
     
         3 . The ligand according to  claim 2 , which binds to an epitope comprising amino acids PW (aa981-982) within the A3 domain of vWF.  
     
     
         4 . The ligand according to  claim 3 , which binds to an epitope comprising amino acids S, P W and R within the A3 domain of vWF.  
     
     
         5 . The ligand according to  claim 1 , which is further characterized in that it does not block the GPIb-vWF binding or GPIIb-IIIa receptor binding.  
     
     
         6 . The ligand according to anyone of  claims 1  to  5 , which is further characterized in that when said ligand is administered to a baboon by bolus intravenous administration at a dose corresponding to 300 microgram/kg of monoclonal antibody, it inhibits vWF binding to collagen at least up to 5 hours after injection.  
     
     
         7 . The ligand according to anyone of  claims 1  to  6 , further characterised in that said ligand ensures that it does not induce a severe decline in circulating vWF-levels or a severe drop in platelet count when the ligand is administered to a primate by bolus intravenous administration at a dose up to 600 microgram/kg.  
     
     
         8 . The ligand according to anyone of  claims 1  to  7 , further characterised in that said ligand ensures that bleeding time remains unchanged or that thrombocytopenia is not induced when said ligand is administered to a primate by bolus intravenous administration at a dose up to 600 microgram/kg.  
     
     
         9 . The ligand according to anyone of  claims 1  to  8 , further characterised in that said ligand induces vWF-occupancy and inhibits vWF-collagen binding when administered at a therapeutically effective dose up to 600 microgram/kg to a primate by bolus intravenous administration.  
     
     
         10 . The ligand according to anyone of  claims 1  to  9 , further characterised in that clotting time (Prothrombin Time (FT) or activated Partial Thromboplastin Time (aPTT)) remains unaffected, and vWF-collagen binding is inhibited and induces increased vWF-occupancy when said ligand is administered to a primate by bolus intravenous administration at a therapeutically effective dose up to 600 microgram/kg.  
     
     
         11 . The ligand according to anyone of  claims 1  to  10 , further characterised in that at a concentration of 1 μg/ml it completely inhibits platelet deposition on a collagen substrate at a shear rate of 1300 s −1  or higher.  
     
     
         12 . The ligand according to anyone of  claims 1  to  11  which, when administered to an individual as an antithrombotic agent, inhibits interaction of vWF with collagen and does not induce severe bleeding disorders at a minimal medicinal effective dose to exhibit antithrombotic action.  
     
     
         13 . The ligand according to any of  claims 1  to  12 , which, when administered to an individual as an antithrombotic agent, maintains circulating vWF-levels or platelet counts at a minimal medicinal dose effective to exhibit antithrombotic action.  
     
     
         14 . The ligand according to any of  claims 1  to  13 , which is a monoclonal antibody, deposited with the Belgian Collections of Micro-organisms, under accession number LMBP 5606CB or an antigen recognizing fragment thereof.  
     
     
         15 . An immunoconjugate comprising the ligand of any one of claims  1 - 14  and a thrombolytic agent.  
     
     
         16 . A pharmaceutical composition comprising the ligand of any one of claims  1 - 14  or the immunoconjugate of  claim 15  in admixture with a pharmaceutically acceptable carrier.