Anti-thrombotic effects and bleeding risk of AJvW-2, a monoclonal antibody against human von Willebrand factor

1 A murine anti-human VWF monoclonal antibody, AJvW-2, was developed that inhibited the interaction between platelet glycoprotein Ib (GPIb) and von Willebrand factor (VWF) during the ristocetin-(IC50=0.7 +/- 0.1 mu g ml(-1)) and botrocetin-(IC50=1.8 +/- 0.3 mu g ml(-1)) induced aggregation of human platelets. 2 AJvW-2 inhibited the high shear stress (10.8 N m(-2)) induced aggregation of human platelets dose-dependently with an IC50=2.4 +/- 0.3 mu g ml(-1), but had no effect on low shear stress induced platelet aggregation (1.2 N m(-2)) up to 100 mu g ml(-1). 3 AJvW-2 also inhibited the high shear stress (5.0 N m(-2)) induced adhesion of human platelets to collagen I with the same efficacy (IC50=2.4 +/- 0.3 mu g ml(-1)), but had no effect at low shear conditions (1.5 N m(-2)). 4 AJvW-2 inhibited the botrocetin-induced aggregation of platelets from guinea-pig, rat, rabbit, dog and pig at the same concentration range as human platelets; it likewise also inhibited the high shear stress induced aggregation and adhesion to collagen I of guinea-pig platelets. 5 AJvW-2 prevented arterial thrombus formation in guinea-pigs at a dose of 100 mu g kg(-1) without prolonging the template bleeding time, whereas the GPIIb/IIIa antagonist lamifiban mediated inhibition of thrombosis at 1000 mu g kg(-1) was accompanied by a significant prolongation of the bleeding time. 6 These results suggest that AJvW-2 is a potent inhibitor of the GPIb-vWF interaction and a potential novel antithrombotic agent with lower bleeding risk than GPIIb/IIIa antagonists.