Kageyama S, Yamamoto H, Nakazawa H, Yoshimoto R
Pharmaceutical Research Laboratories, Developmental Research Laboratories, Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-8681, Japan.
Thromb Res. 2001 Mar 1;101(5):395-404. doi: 10.1016/s0049-3848(00)00430-8.
The antithrombotic and antihaemostatic effects of the monoclonal antibody against human vWF (AJvW-2 Fab) were investigated in comparison with those of the monoclonal antibody against platelet GPIIb/IIIa (abciximab) in dogs. The ex vivo platelet aggregation and template bleeding time were measured before, 5, 90, 210 min and 24 h after injection of either AJvW-2 Fab or abciximab in anesthetized beagle dogs. Plasma concentration, vWF occupancy and plasma vWF antigen level were also measured by ELISA. In addition, the antithrombotic effect was evaluated in a canine model of repetitive coronary thrombosis (Folts model). AJvW-2 Fab significantly inhibited the ex vivo botrocetin-induced platelet aggregation at 0.18 mg/kg (53% plasma vWF occupancy) and also inhibited cyclic flow reductions (CFRs) at 0.06 mg/kg (31% occupancy). A significant prolongation of the bleeding time was observed at 1.8 mg/kg (95% occupancy), which was 30 times as high as the antithrombotic effective dose. Whereas, abciximab significantly inhibited both the ex vivo ADP-induced platelet aggregation and CFRs at 0.8 mg/kg, which was the minimally effective dose, also resulting in a significant prolongation of the bleeding time. These results suggest that blockade of the GPIb-vWF axis with AJvW-2 Fab leads to the inhibition of thrombus formation in the stenosed coronary arteries without less bleeding time prolongation than the GPIIb/IIIa blockade with abciximab.
在犬类中，比较了抗人血管性血友病因子单克隆抗体（AJvW-2 Fab）与抗血小板糖蛋白IIb/IIIa单克隆抗体（阿昔单抗）的抗血栓形成和抗止血作用。在麻醉的比格犬中，于注射AJvW-2 Fab或阿昔单抗前、注射后5分钟、90分钟、210分钟及24小时测量体外血小板聚集和模板出血时间。还通过酶联免疫吸附测定法测量血浆浓度、血管性血友病因子占有率及血浆血管性血友病因子抗原水平。此外，在重复性冠状动脉血栓形成犬模型（福尔茨模型）中评估抗血栓形成作用。AJvW-2 Fab在剂量为0.18 mg/kg（血浆血管性血友病因子占有率为53%）时可显著抑制体外蛇毒诱导的血小板聚集，在剂量为0.06 mg/kg（占有率为31%）时也可抑制周期性血流减少（CFRs）。在剂量为1.8 mg/kg（占有率为95%）时观察到出血时间显著延长，该剂量是抗血栓形成有效剂量的30倍。而阿昔单抗在剂量为0.8 mg/kg（最低有效剂量）时可显著抑制体外二磷酸腺苷诱导的血小板聚集和CFRs，同时也导致出血时间显著延长。这些结果表明，用AJvW-2 Fab阻断糖蛋白Ib-血管性血友病因子轴可抑制狭窄冠状动脉中的血栓形成，且与用阿昔单抗阻断糖蛋白IIb/IIIa相比，出血时间延长较少。
