© 1999 American Heart Association, Inc.
Thrombosis |
Antithrombotic Efficacy of a Novel Murine Antihuman Factor IX Antibody in Rats
From SmithKline Beecham Pharmaceuticals, Departments of Cardiovascular Pharmacology (G.Z.F., J.R.T., A.J.N., R.V., P.K.), Protein Biochemistry (A.P.), Experimental Pathology (P.B.), and Structural Biology (A.B., M.N.B.), King of Prussia, Pa; and Green Mountain Antibodies (W.R.C.) Burlington, Vt
Correspondence to Michael N Blackburn, PhD, Department of Structural Biology, UE-0447, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, Box 1539, King of Prussia, PA 19406-0939. E-mail michael_blackburn{at}sbphrd.com
Abstract—A murine antihuman factor IX monoclonal antibody (BC2) has been generated and evaluated for its capacity to prolong the activated partial thromboplastin time (aPTT) in vitro and ex vivo and to prevent arterial thrombosis in a rat model in vivo. BC2 extended aPTT to a maximum of 60 to 80 seconds at 100 to 1000 nmol/L in vitro (rat and human plasma, respectively) and ex vivo (rat) after dosing of rats up to 6 mg/kg in vivo. BC2, administered as bolus (1 to 6 mg/kg) followed by infusion (0.3 to 2 mg · kg-1 · h-1), dose-dependently prevented thrombosis of an injured rat carotid artery (FeCl3-patch model), increased time to artery occlusion, and reduced incidence of vessel occlusion. BC2 efficacy in preventing arterial thrombosis exceeded that of heparin (bolus 15 to 120 U/kg followed by infusion 0.5 to 4.0 U · kg-1 · min-1), whereas the latter rendered the blood incoagulable (aPTT>1000 seconds). BC2 demonstrated complete antithrombotic efficacy also as a single bolus given either as prevessel or postvessel injury as evidenced by reduction of thrombus mass (from 4.18±0.49 to 1.80±0.3 mg, P<0.001), increasing vessel patency time (from 14.9±0.9 minutes to 58.3±1.7 minutes, P<0.001) and decreasing incidence of vessel occlusion from 100% to 0% in vehicle- versus BC2-treated rats, respectively. BC2 (3 mg/kg, IV) administered in a single bolus resulted in 50% reduction in thrombus mass (P<0.01), extended vessel patency time (P<0.001), extended aPTT only 4-fold, and had no effect on blood loss via a tail surgical wound; heparin, at doses that reduced thrombus mass to a similar extent, extended aPTT beyond 1000 seconds (over 500-fold) and increased blood loss from 1.8±0.7 to 3.3±0.6 mL (P<0.001). These data suggest that BC2 may provide enhanced therapeutic efficacy in humans at lesser interference with blood hemostasis than heparin.
Key Words: thrombosis • coagulation • factor IX • heparin • aspirin • monoclonal antibodies
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