Development of antibodies that interfere with the collagen-VWF-GPIb axis as new antithrombotics.
The epitope and the antithrombotic effect of 6B4, an antibody that inhibits GPIb, the receptor for von Willebrand Factor (VWF) on blood platelets, and of 82D6A3, an antibody against VWF that prevents the binding of VWF to collagen, were characterised. By using canine-human chimeras, alanine-scans, phage display, mutant analysis and modeling both the epitope of 6B4 in the N-terminal domain of GPIb, and of 82D6A3 in the VWF-A3 domain, could be mapped. As both epitopes furthermore are part of the ligand binding sites, this at once also explained the mechanism of the inhibition by the antibodies. Next both antibodies were tested in a thrombosis model in a stenosed artery in baboons, where they showed potent antithrombotic activities, without a noteworthy prolongation of the bleeding time. With this we thus could reveal two new strategies to prevent arterial thrombosis, which presumably may be safer than the currently available antiplatelet agents.
Deckmyn
H
H
Laboratory for Thrombosis Research, KULeuven Campus Kortrijk, Interdisciplinary Research Center, E. Sabbelaan 53--B 8500 Kortrijk.
Cauwenberghs
N
N
Wu
D
D
Depraetere
H
H
Vanhoorelbeke
K
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D000941:Antigens / Q000276:immunology; D003094:Collagen / Q000276:immunology / Q000378:metabolism*; D018604:Epitope Mapping; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000276:immunology* / Q000378:metabolism; D013927:Thrombosis / Q000517:prevention & control*; D014841:von Willebrand Factor / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000941:Antigens; D005343:Fibrinolytic Agents; D019038:Platelet Glycoprotein GPIb-IX Complex; C029417:Von Willebrand antigen; D014841:von Willebrand Factor; D003094:Collagen