Chimeric 7E3 Prevents Carotid Artery Thrombosis in Cynomolgus Monkeys

Background and Purpose We compared the current antithrombotic strategy of antiplatelet therapy with aspirin, and anticoagulant therapy with heparin, with a specific genetically engineered chimeric antibody (c7E3 Fab) directed against the human glycoprotein Ilb/IIIa receptor in an animal model of arterial thrombosis. Methods Anesthetized cynomolgus monkeys (Macaca fascicularis) were instrumented for monitoring of arterial blood pressure, heart rate, and carotid artery flow velocity. Animals were treated with saline (n=6), aspirin (25 mg PO daily for 3 days; n=6), heparin (100 U/kg IV plus infusion adjusted to maintain activated partial thromboplastin time at 2 to 3 times baseline; n=6), aspirin plus heparin (as administered separately, n=6), or c7E3 Fab (0.10 mg/kg IV, n=7; 0.15 mg/kg IV, n=6; 0.20 mg/kg IV, n=6; 0.25 mg/kg IV, n=6). Thrombus formation via anodal electrolytic stimulation (100 μA) to the intimal surface of the right carotid artery was initiated 15 minutes after drug administration and continued for 180 minutes. Electrolytic injury to the left carotid artery began 210 minutes after drug administration and continued for 180 minutes. Whole blood cell counts, glycoprotein Ilb/IIIa receptor blockade, ex vivo platelet aggregation, template bleeding time, and activated partial thromboplastin time were assessed at various time points throughout the experimental protocol. Results Hemodynamic and hematologic parameters were comparable among groups at baseline. Treatment with c7E3 Fab inhibited ex vivo platelet aggregation, increased bleeding time, decreased thrombus weight, and increased time to occlusion in a dose-dependent manner in both vessels. Treatment with aspirin, heparin, or the combination of aspirin plus heparin was ineffective for the prevention of carotid artery thrombosis in this model. Conclusions Inhibition of the platelet glycoprotein Ilb/IIIa receptor with c7E3 Fab was found to be safe and effective for the prevention of primary thrombus formation, whereas treatment with either aspirin or heparin or the combination of the two agents failed to protect against occlusive thrombus formation in cynomolgus monkeys.

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