Antithrombotic efficacy of a novel murine antihuman factor IX antibody in rats

A murine antihuman factor IX monoclonal antibody (BC2) has been generated a nd evaluated for its capacity to prolong the activated partial thromboplast in 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 1 00 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 bol us(1 to 6 mg/kg) followed by infusion (0.3 to 2 mg . kg(-1) . h(-1)), lose- dependently prevented thrombosis of an injured rat carotid artery (FeCl3-pa tch model), increased time to artery occlusion, and reduced incidence of ve ssel occlusion. BC 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 sing le bolus given either prevessel or postvessel injury as evidenced by reduct ion of thrombus mass (from 4.18+/-0.49 to 1.80+/-0.3 mg, P<0.001), increasi ng vessel patency time (from 14.9+/-0.9 minutes to 58.3+/-1.7 minutes,P<0.0 01) and decreasing incidence of vessel occlusion from 100% to 0% in vehicle - versus BC2-treated rats, respectively. BC2 (3 mg/kg, TV) administered in a single bolus resulted in 50% reduction in thrombus mass (P<0.01), extende d vessel patency time (P<0.001), extended aPTT only LC-fold, and had no eff ect on blood loss via a tail surgical wound; heparin, at doses that reduced thrombus mass to a similar extent, extended aPTT beyond 1000 seconds lover 500-fold) and increased blood loss from 1.8+/-0.7 to 3.3+/-0.6 mt (P<0.001 ). These data suggest that BC2 may provide enhanced therapeutic efficacy in humans at lesser interference with blood hemostasis than heparin.