Prolonged inhibition of acute arterial thrombosis by high dosing of a monoclonal anti-platelet 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 glycoprotein (GP)IIb/IIIa function, was determined in baboons. A dose-finding 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 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.
Kotzé
H F
HF
Department of Haematology, University of the Orange Free State, Bloemfontein, South Africa.
Badenhorst
P N
PN
Lamprecht
S
S
Meiring
M
M
Van Wyk
V
V
Nuyts
K
K
Stassen
J M
JM
Vermylen
J
J
Deckmyn
H
H
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D001166:Arteriovenous Shunt, Surgical; D001760:Bleeding Time; D002415:Cats; D006224:Cricetinae; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides; D010215:Papio; D015539:Platelet Activation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000276:immunology; D011093:Polyethylene Terephthalates; D011817:Rabbits; D051381:Rats; D013552:Swine; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011093:Polyethylene Terephthalates; C047981:arginyl-glycyl-aspartic acid