Kageyama Shunsuke, Yamamoto Hiroshi, Nakazawa Harumi, Matsushita Junko, Kouyama Tetsuya, Gonsho Akinori, Ikeda Yasuo, Yoshimoto Ryota
Developmental Research Laboratories, Pharmaceutical Research Laboratories, Ajinomoto Co, Inc, Kanagawa, Japan.
Arterioscler Thromb Vasc Biol. 2002 Jan;22(1):187-92. doi: 10.1161/hq0102.101520.
The interaction between platelet glycoprotein Ib and von Willebrand factor (vWF) plays a crucial role in platelet-mediated thrombus formation under high-shear-stress conditions. The aim of this study was to investigate the antiplatelet profile of a humanized anti-vWF monoclonal antibody, AJW200. In vitro studies were performed with a modified cone-and-plate viscometer and human platelets. AJW200 inhibited high-shear-stress-induced platelet adhesion, aggregation, and thrombin generation, but it did not have such effects under low-shear-stress conditions. Although abciximab inhibited platelet aggregation under both shear stress conditions, it did not inhibit platelet adhesion and thrombin generation. In addition, the pharmacokinetics and pharmacodynamics of AJW200 were evaluated in cynomolgus monkeys. Sustained inhibition of ristocetin-induced platelet aggregation was observed over 24 hours, 6 days, and 2 weeks after a single bolus injection of 0.3, 1, and 3 mg/kg, respectively. Moderate prolongation of the bleeding time was observed at the doses of 1 and 3 mg/kg. Abciximab markedly prolonged the bleeding time at 0.4 mg/kg, at which concentration complete inhibition of ADP-induced platelet aggregation was observed. These results suggest that glycoprotein Ib-vWF blockade with AJW200 results in a sustained antiplatelet effect without extensive prolongation of the bleeding time, probably due to a shear-stress-dependent inhibitory action.
血小板糖蛋白Ib与血管性血友病因子（vWF）之间的相互作用在高剪切应力条件下血小板介导的血栓形成过程中起着关键作用。本研究的目的是探究人源化抗vWF单克隆抗体AJW200的抗血小板特性。使用改良的锥板粘度计和人血小板进行了体外研究。AJW200抑制了高剪切应力诱导的血小板黏附、聚集和凝血酶生成，但在低剪切应力条件下没有此类作用。尽管阿昔单抗在两种剪切应力条件下均抑制血小板聚集，但它不抑制血小板黏附和凝血酶生成。此外，还在食蟹猴中评估了AJW200的药代动力学和药效学。分别在单次静脉注射0.3、1和3mg/kg后24小时、6天和2周观察到对瑞斯托霉素诱导的血小板聚集的持续抑制。在1和3mg/kg剂量下观察到出血时间适度延长。阿昔单抗在0.4mg/kg时显著延长出血时间，在此浓度下观察到对ADP诱导的血小板聚集的完全抑制。这些结果表明，用AJW200阻断糖蛋白Ib-vWF会导致持续的抗血小板作用，而不会使出血时间过度延长，这可能归因于剪切应力依赖性抑制作用。
