Antithrombotic efficacy of a novel murine antihuman factor IX antibody in rats.
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 x kg(-1) x h(-1)), dose-dependently prevented thrombosis of an injured rat carotid artery (FeCl(3)-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 x kg(-1) x 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.
Feuerstein
G Z
GZ
SmithKline Beecham Pharmaceuticals, Department of Cardiovascular Pharmacology, King of Prussia, PA 19406-0939, USA.
Patel
A
A
Toomey
J R
JR
Bugelski
P
P
Nichols
A J
AJ
Church
W R
WR
Valocik
R
R
Koster
P
P
Baker
A
A
Blackburn
M N
MN
D000758:Anesthesia; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology; D001157:Arterial Occlusive Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D001241:Aspirin / Q000494:pharmacology; D016063:Blood Loss, Surgical; D002339:Carotid Arteries; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D005164:Factor IX / Q000276:immunology* / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007501:Iron; D008297:Male; D008855:Microscopy, Electron, Scanning; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D005343:Fibrinolytic Agents; D007074:Immunoglobulin G; D005164:Factor IX; D006493:Heparin; D007501:Iron; D001241:Aspirin