A chimeric murine/human antibody Fab fragment directed against the platelet GPIIb/IIIa receptor enhances and sustains arterial thrombolysis with recombinant tissue-type plasminogen activator in baboons.

Abstract

Inhibition of the platelet glycoprotein (GP) IIb/IIIa receptor with the murine monoclonal antibody 7E3 abolishes ex vivo platelet aggregation, reduces thrombogenicity, and sustains arterial recanalization with recombinant tissue-type plasminogen activator (rt-PA). A chimeric murine/human Fab fragment of 7E3 (c7E3-Fab) has a markedly reduced immunogenicity, but its potency as an adjunct for thrombolysis with rt-PA has not been evaluated. The effects of a single intravenous bolus injection of aspirin (17 mg/kg) or c7E3-Fab (0.45 mg/kg) on thrombolysis and reocclusion induced with rt-PA were studied in groups of six baboons with femoral arterial thrombosis and superimposed high-grade stenosis. This dose of c7E3-Fab blocked 96 +/- 1% of the platelet GPIIb/IIIa receptors and abolished ADP-induced platelet aggregation. Bolus intravenous injections of rt-PA (0.25 mg/kg) were repeated at 15-minute intervals until reperfusion occurred (maximum of four injections). In the aspirin group, reperfusion was obtained within 51 +/- 16 minutes (mean +/- SD) but was rapidly followed by reocclusion within 6 +/- 9 minutes and by cyclic reflow and reocclusion. In the c7E3-Fab group, reperfusion was obtained within 25 +/- 8 minutes (P < .01 versus aspirin group) and was associated with a delayed reocclusion of 63 +/- 63 minutes (P < .05 versus aspirin group). Template bleeding times remained unchanged in the aspirin/rt-PA group but were markedly prolonged (to > 30 minutes) in the c7E3-Fab/rt-PA group.(ABSTRACT TRUNCATED AT 250 WORDS)

Chimeric 7E3 prevents carotid artery thrombosis in cynomolgus monkeys.

“…The findings offer the possibility that quantitation of receptor occupancy by c7E3 Fab may provide a reliable means of assessing the proper dose of the antibody and determination of its pharmacodynamics. The results of the present study confirm those presented recently by Kohmura et al 56 who reported on the efficacy of c7E3 Fab in the baboon. The latter authors noted that 0.45 mg/kg of the chimeric murine/human Fab fragment of the monoclonal antibody 7E3 enhanced and sustained arterial recanalization with recombinant tissue plasminogen activator.…”

“…The latter authors noted that 0.45 mg/kg of the chimeric murine/human Fab fragment of the monoclonal antibody 7E3 enhanced and sustained arterial recanalization with recombinant tissue plasminogen activator. As was the case in our study, Kohmura et al 56 also noted that aspirin (17 mg/kg IV) failed to prevent reocclusion of the femoral artery after successful thrombolysis, an observation that coincides with that reported in the present study.…”

Toward a New Frontier in Myocardial Reperfusion Therapy

“…[57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] Cumulatively, these studies have shown that the dose of fibrinolytic therapy can be substantially reduced to Ϸ50% or even 25% of the dose required in control experiments 57,58 and that fibrinolysis occurs much more rapidly and more completely and is much more stable, as reflected by the absence of cyclic flow variations or reocclusion once flow is restored. Nicolini and associates 65 showed that a low dose of a GP IIb/IIIa inhibitor combined with a low dose of a direct thrombin inhibitor (hirudin) also markedly facilitated coronary fibrinolysis in the canine electrolytic model.…”

High Levels of Platelet Inhibition With Abciximab Despite Heightened Platelet Activation and Aggregation During Thrombolysis for Acute Myocardial Infarction

“…This level of blockade corresponded to inhibition of ADP-induced platelet aggregation by Ϸ80% of baseline levels. 12,13 Whether this degree of blockade can be attained safely in the setting of AMI has not been fully explored. Doses of platelet GP IIb/IIIa antagonists in current clinical use have been selected on the basis of pharmacodynamic studies in patients undergoing elective percutaneous coronary interventions.…”