PROLONGED INHIBITION OF ACUTE ARTERIAL THROMBOSIS BY HIGH DOSING OF AMONOCLONAL ANTIPLATETLET GLYCOPROTEIN IIB IIIA ANTIBODY IN A BABOON MODEL/

The in vivo activity of MA-16N7C2, the first monoclonal antibody that contains an echistatin-like RGD-sequence and inhibits platelet glycopr otein (GP)IIb/IIIa function, was determined in baboons. A dose-finding study assessing haemostatic variables such as bleeding time and ex vi vo platelet aggregation showed that doses of as low as 0.2-0.3 mg/kg r esulted in a pronounced effect. The effects were dose-dependent and la sted for several days, implying that MA-16N7C2 is a potent and long-ac ting GPIIb/IIIa inhibitor. Following the initial studies, the antithro mbotic effect of 0.1 and 0.3 mg/kg of the antibody, given as a bolus, was determined in a baboon model of platelet-dependent, arterial-type thrombus formation. In these studies, a thrombogenic device consisting of Dacron vascular graft material was inserted as extension segments into a permanent arteriovenous shunt. The results confirmed the potent and long-lasting antithrombotic effect of MA-16N7C2. Surprisingly, th e antithrombotic effect was stronger 48 h after a dose of 0.3 mg/kg ad ministration than on the day of treatment with 0.1 mg/kg, despite the fact that comparable numbers of GPIIb/IIIa receptors were occupied on resting platelets. We postulate that with the high dose of MA-16N7C2 a nd after an extended period, occupied GPIIb/IIIa may be internalised b y the platelets. Upon platelet activation, these receptors become reex posed but are unable to participate in thrombus formation. This is in contrast to unoccupied internal GPIIb/IIIa receptors early after a low dose of MA-16N7C2.