PHARMACODYNAMIC STUDY OF F(AB')2 FRAGMENTS OF MURINE MONOCLONAL ANTIBODY-7E3 DIRECTED AGAINST HUMAN PLATELET GLYCOPROTEIN-IIB/IIIA IN PATIENTS WITH UNSTABLE ANGINA-PECTORIS

The pharmacodynamics of intravenous bolus injections of 0.05, 0.10, 0.15, and 0.20 mg/kg of F(ab′)2 fragments of the murine monoclonal antibody 7E3, 7E3-F(ab′)2, directed against the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor of human platelets, were studied in groups of four patients with unstable angina pectoris. With 0.20 mg/kg, the template bleeding time prolonged from 6.3±1.9 (mean±SD) to > 30 min; it subsequently decreased to 13±7.8 min after 12 h and to 8.3±1.5 min after 24 h. The number of unblocked GPIIb/IIIa receptors (preinfusion value, 32,000±3,000 per platelet) decreased to 13±7% of the preinfusion value 1 h after infusion, and then increased to 33±10% at 12 h, 44±8% at 24 h and 67±7% at 72 h. The logarithm of the bleeding time was inversely proportional with the residual GPIIb/IIIa receptors (r = 0.73, P < 0.0001). ADP-induced platelet aggregation (measured by changes in light transmittance in percent) decreased from 60±5% before infusion to 1.5±3% 1 h after infusion; it then increased to 29±3% after 24 h and 39±6% after 72 h. Platelet counts decreased by 16% at 1 h and returned to control values within 24 h. Proportionally smaller effects were seen at lower doses of 7E3-F(ab′)2. Antibody injection did not induce spontaneous bleeding. Angina was not observed during the first 12 h when the bleeding time was significantly prolonged, but occurred in 6 of the 16 patients within the next 3 d. 2 of the 16 patients developed low titers of IgG antibodies specific for 7E3-F(ab′)2. Thus 7E3-F(ab′)2 induces dose-related inhibition of platelet function; at a dose of 0.20 mg/kg, it causes profound inhibition of platelet aggregation and prolongation of the bleeding time, but no spontaneous bleeding.