Targeting of the collagen-binding site on glycoprotein VI is not essential for in vivo depletion of the receptor.
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.
Schulte
Valerie
V
Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
Rabie
Tamer
T
Prostredna
Miroslava
M
Aktas
Barsom
B
Grüner
Sabine
S
Nieswandt
Bernhard
B
D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000276:immunology / Q000502:physiology*; D003094:Collagen / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D010980:Platelet Membrane Glycoproteins / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism*; D038981:Receptors, Collagen / Q000737:chemistry / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000502:physiology
D010980:Platelet Membrane Glycoproteins; D038981:Receptors, Collagen; D017452:Receptors, IgG; C098341:platelet membrane glycoprotein VI; D003094:Collagen