Targeting of the collagen-binding site on glycoprotein VI is not essential for in vivo depletion of the receptor.
Targeting of the collagen-binding site on glycoprotein VI is not essential for in vivo depletion of the receptor.
复制标题
糖蛋白 VI 上胶原蛋白结合位点的靶向对于体内受体的消耗并不是必需的。
DOI：
10.1182/blood-2002-10-3242
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发表时间：
2003
期刊：
影响因子：
20.3
通讯作者：
B. Nieswandt
中科院分区：
文献类型：
--
作者：
V. Schulte;Tamer Rabie;Miroslava Prostredná;Barsom Aktas;S. Grüner;B. Nieswandt
糖蛋白（GP）VI是血小板上一种重要的胶原受体，可作为抗血栓治疗的一个有吸引力的靶点。我们以前已经表明，对小鼠GPVI（JAQ1）的主要胶原结合位点的单克隆抗体（mAb）诱导受体的不可逆下调，因此，在体内的长期抗血栓保护。为了确定JAQ1的这种独特的体内作用是否基于其与GPVI上的配体结合位点的相互作用，我们产生了针对GPVI上不同表位的新mAb（JAQ2，JAQ3），并测试了它们的体外和体内活性。我们发现，没有一个单克隆抗体抑制血小板活化的胶原蛋白或胶原蛋白相关肽在体外。然而，出乎意料的是，注射任一抗体均以与JAQ1相同的功效和动力学诱导GPVI的消耗。重要的是，JAQ2和JAQ3的单价F（ab）片段也观察到这种效应，排除Fc部分或抗GPVI抗体的二聚体形式参与该过程。这表明，抗GPVI剂，无论其结合位点如何，通常可以诱导体内受体的下调。
Glycoprotein (GP) VI is an essential collagen receptor on platelets and may serve as an attractive target for antithrombotic therapy. We have previously shown that a monoclonal antibody (mAb) against the major collagen-binding site on mouse GPVI (JAQ1) induces irreversible down-regulation of the receptor and, consequently, long-term antithrombotic protection in vivo. To determine whether this unique in vivo effect of JAQ1 is based on its interaction with the ligand-binding site on GPVI, we generated new mAbs against different epitopes on GPVI (JAQ2, JAQ3) and tested their in vitro and in vivo activity. We show that none of the mAbs inhibited platelet activation by collagen or the collagen-related peptide in vitro. Unexpectedly, however, injection of either antibody induced depletion of GPVI with the same efficacy and kinetics as JAQ1. Importantly, this effect was also seen with monovalent F(ab) fragments of JAQ2 and JAQ3, excluding the involvement of the Fc part or the dimeric form of anti-GPVI antibodies in this process. This indicates that anti-GPVI agents, irrespective of their binding site may generally induce down-regulation of the receptor in vivo.