7E3 F(ab′)2, an effective antagonist of rat αIIbβ3 and αvβ3, blocks in vivo thrombus formation and in vitro angiogenesis

Abciximab (c7E3 Fab. ReoPro (R)) blocks GPIIb/IIIa and alpha nu beta3 and inhibits thrombotic and proliferative events only in humans and nonhuman primates. The bivalent F(ab ')(2) fragment is an effective antithrombotic agent in canine models. In the present study, 7E3 F(ab ')(2) was also found to bind to rat GPIIb/IIla (K-D = 27 +/- 4 mug/mL) and alpha nu beta3 (K-D = 9 +/- 8 mug/mL). to block in vitro rat platelet aggregation (IC50 = 16 +/- 6 mug/mL). and to inhibit alpha nu beta3-mediated microvessel sprout formation in a rat aortic ring assay. Following administration of 7E3 F(ab ')(2) (4 mg/kg) to rats, platelet aggregation was completely blocked for up ro 6 h and thrombus formation in response to a rat abdominal aorta double crush injury was prevented. Effective chronic dosing was achieved with 6 mg/kg daily I.P. injections. In vitro mixing experiments indicated that 7E3 F(ab ')(2) redistributed to unlabeled platelets in 2 h, Ex vivo. 7E3 F(ab ')(2) was detected on platelets for up to 4 days after a single 4-mg/kg injection. These data suggest that 7E3 F(ab ')(2) may be a useful agent to study the effects of GPIIb/IIIa and alpha nu beta3 blockade in rat models of thrombosis and vascular disease.