Inhibition of acute vascular thrombosis in chimpanzees by an anti-human tissue factor antibody targeting the factor X binding site.
Inhibition of acute vascular thrombosis in chimpanzees by an anti-human tissue factor antibody targeting the factor X binding site.
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DOI：
10.1160/th09-06-0400
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发表时间：
2010-01
影响因子：
6.7
通讯作者：
Wong HC
中科院分区：
文献类型：
--
作者：
Jiao JA;Kelly AB;Marzec UM;Nieves E;Acevedo J;Burkhardt M;Edwards A;Zhu XY;Chavaillaz PA;Wong A;Wong JL;Egan JO;Taylor D;Rhode PR;Wong HC
靶向因子VII（FVII）结合结构域的组织因子（TF）拮抗剂已被证明可以中断非人灵长类动物的急性血管血栓形成，而不会损害止血。在这项研究中，我们评估是否人/小鼠嵌合单克隆抗体（ALT-836，以前称为Sunol-cH 36）阻断组织因子的因子X/因子IX（FX/FIX）结合位点可以在黑猩猩动脉内膜切除术诱导的动脉血栓形成模型中获得类似的临床益处。在该模型中，在5只黑猩猩中，分别对右侧和左侧股浅动脉进行连续的动脉内膜切除术，间隔30天。在动脉内膜切除的股动脉中恢复血流之前立即静脉内注射ALT-836的推注（lmg/kg）。术前使用111 In-Oxine标记自体血小板，术后使用伽马照相机对动脉内膜切除术部位的111 In-血小板沉积进行成像。手术后30天，采集操作的动脉段进行通畅性分析。结果表明，ALT-836在减少急性血管血栓形成方面非常有效，与对照动物相比，治疗组的手术失血量和模板出血时间没有显著变化。这些数据表明，ALT-836是一种有效和安全的抗血栓形成剂，可预防TF引发的血管血栓形成，而不会影响止血。
Tissue factor (TF) antagonists targeting the factor VII (FVII) binding domain have been shown to interrupt acute vascular thrombus formation without impairing hemostasis in non-human primates. In this study, we evaluate whether a human/mouse chimeric monoclonal antibody (ALT-836, formerly known as Sunol-cH36) blocking the factor X/factor IX (FX/FIX) binding site of tissue factor could achieve similar clinical benefits in an arterial thrombosis model induced by surgical endarterectomy in chimpanzees. In this model, sequential surgical endarterectomies on right and left superficial femoral arteries were performed 30 days apart in five chimpanzees. A bolus (1 mg/kg) of ALT-836 was injected intravenously immediately preceding the restoration of flow in the endarterectomized femoral artery. Pre-surgical labeling of autologous platelets using 111In-Oxine and post-surgical gamma camera imaging of 111In-platelet deposition at endarterectomy sites was performed. The manipulated arterial segments were harvested for patency analysis 30 days following surgery. The results indicate that ALT-836 was highly effective at reducing acute vascular thrombosis, with no significant variations in surgical blood loss and template-bleeding time in the treated group compared to the control animals. These data suggest that ALT-836 is an effective and safe antithrombotic agent in preventing TF-initiated vascular thrombogenesis without compromising hemostasis.