Summary
The in vivo activity of MA-16N7C2, the first monoclonal antibody that contains an
echistatin-like RGD-sequence and inhibits platelet glycoprotein (GP)IIb/IIIa function,
was determined in baboons. A dosefinding study assessing haemostatic variables such
as bleeding time and ex vivo platelet aggregation showed that doses of as low as 0.2-0.3
mg/kg resulted in a pronounced effect. The effects were dose-dependent and lasted
for several days, implying that MA-16N7C2 is a potent and long-acting GPIIb/IIIa inhibitor.
Following the initial studies, the antithrombotic 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, the antithrombotic effect was stronger 48 h after
a dose of 0.3 mg/kg administration 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 and after an extended
period, occupied GPIIb/IIIa may be internalised by the platelets. Upon platelet activation,
these receptors become reexposed but arc unable to participate in thrombus formation.
This is in contrast to unoccupied internal GPIIb/IIIa receptors early after a low
dose of MA-16N7C2.
