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.

Abstract

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 Ilb/Illa (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. (J. Clin. Invest.

Monitoring Platelet GP IIb/IIIa Antagonist Therapy

“…[5][6][7][8] These studies provided a framework for deciding on a dosing schedule for the first phase III study (EPIC). 9 Similar studies have been reported with some of the other GP IIb/IIIa antagonists.…”

Identification of glycoprotein IIb as the lipoprotein(a)-binding protein on platelets. Lipoprotein(a) binding is independent of an arginyl-glycyl-aspartate tripeptide located in apolipoprotein(a).

“…The latter was purified by enzymatic digestion of anti-CRGDGQSYRGT IgG with pepsin as described. 36 The F(ab') 2 fragment was extensively purified to ensure the absence of residual IgG or Fc fragments.…”

A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis

“…cent studies indicate that treatment with specific inhibitors of glycoprotein IIb/IIIa leads to better outcomes than does aspirin therapy. [23][24][25][26]41 It is conceivable that Pl A2 -positive patients would receive extra benefit from direct therapy with anti-glycoprotein IIb/IIIa, providing a rationale for decisions regarding the choice of antiplatelet therapy for patients with unstable coronary syndromes. 41 …”

“…6,8,9 Large trials have demonstrated a marked benefit of various inhibitors of platelet function in both preventing and reducing the mortality and morbidity associated with unstable coronary syndromes. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] Additional studies have linked ex vivo platelet reactivity to outcome in patients after myocardial infarction. 27 In sum, there is strong evidence that platelets, and glycoprotein IIb/IIIa in particular, have an important role in the pathogenesis of acute coronary syndromes.…”