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Relative antithrombotic effects of monoclonal antibodies targeting
different platelet glycoprotein-adhesive molecule interactions in nonhuman
primates
Y Cadroy, SR Hanson, AB Kelly, UM Marzec, BL Evatt, TJ Kunicki, RR Montgomery and LA Harker
Division of Hematology and Oncology, Emory University School of Medicine,
Atlanta, GA 30322.
The relative antithrombotic effectiveness of targeting glycoprotein (GP)
Ib-dependent versus GPIIb-IIIa-dependent platelet interactions has been
determined in baboons by measuring thrombus formation after infusing
comparable antihemostatic doses of anti-von Willebrand factor (vWF)
monoclonal antibody (MoAb) BB3-BD5, anti-GPIb MoAb AP1, and anti-
GPIIb-IIIa MoAb LJ-CP8 under conditions of arterial and venous flow (shear
rates of 750 to 1,000 seconds-1 and 100 seconds-1, respectively). Thrombus
formation was quantified as 111In-platelet deposition and 125I-fibrin
accumulation on segments of collagen-coated tubing interposed in chronic
exteriorized arteriovenous (AV) shunts for 40 minutes. In vitro, anti-vWF
MoAb BB3 BD5 (IgG) and anti-GPIb MoAb AP1 [IgG or F(ab)2 fragments]
inhibited ristocetin-induced platelet aggregation (IC50 50 nmol/L and 1
mumol/L, respectively), but neither of these MoAbs blocked platelet
aggregation induced by adenosine diphosphate (ADP) (P > .5). Conversely,
anti-GPIIb-IIIa MoAb LJ-CP8 inhibited platelet aggregation induced by ADP
(IC50 1 mumol/L, but failed to block ristocetin-induced platelet
aggregation (P > .5). In vivo, the intravenous infusion of anti-vWF MoAb
BB3 BD5 or anti-GPIIb- IIIa MoAb LJ-CP8 into baboons at doses that
abolished corresponding agonist-induced aggregation ex vivo (bolus
injections of 0.5 mg/kg and 10 mg/kg, respectively) prolonged template
bleeding times from baseline values of 4.0 +/- 0.3 minutes to > 27 +/- 4
minutes, and to > 26 +/- 4 minutes, respectively (P < .001 in both
cases), without affecting the peripheral platelet count (P > .5).
However, injection of anti-GPIb MoAb AP1 [10 mg/kg as IgG or 1 mg/kg as
F(ab)2 fragments] produced immediate irreversible thrombocytopenia (<
40,000 platelets/microL). Anti-GPIIb-IIIa MoAb LJ-CP8 abolished platelet
deposition and fibrin accumulation on collagen segments under both arterial
and venous flow conditions (P < .01 in all cases), whereas MoAb BB3 BD5
produced minimal inhibition of platelet deposition and no decrease in
fibrin accumulation at arterial shear rates and undetectable antithrombotic
outcomes at low shear. Thus, inhibiting GPIIb-IIIa-dependent platelet
recruitment abrogates both thrombus formation and platelet hemostatic
function at both venous and arterial shear rates. By contrast, interfering
with GPIb-vWF-dependent platelet interactions abolishes platelet hemostatic
function without producing corresponding antithrombotic effects.
Volume 83,
Issue 11,
pp. 3218-3224,
06/01/1994
Copyright © 1994 by The American Society of Hematology
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