Glycoprotein (GP) VII 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 GPV1 (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 JAM. Importantly, this effect was also seen with monovalent F(ab) fragments of JAQ2 and JAW, 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. (C) 2003 by The American Society of Hematology.
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