Drug Inhibition of GPIb.

Abstract SCI-38

The platelet-specific glycoprotein (GP)Ib, member of the GPIb/IX/V complex, is the main receptor for von Willebrand Factor (VWF), but also for a growing list of other ligands such as thrombin, coagulation factor XI and XII, Mac-1 and P-selectin. For VWF and GPIb to interact, VWF needs to undergo a conformational change. In the circulation, this is induced by shear forces that stretch VWF, especially when bound onto collagen at vascular lesions. As the contribution of VWF to platelet adhesion becomes more important with increasing shear forces, the idea emerged that inhibition of the GPIb-VWF interaction could actually result in an antithrombotic effect targeted to high shear arterioles or stenosed arteries, leaving hemostasis virtually unaffected in vessel beds with slower circulation. And in the mean time, a growing amount of evidence suggests that this could lead to a lower bleeding risk than what is seen with currently available antithrombotic agents. Several compounds have been tested in the past such as fragments of VWF, snake venoms and antibodies. We developed an anti-human GPIb monoclonal antibody, 6B4, that competes directly for the binding site of VWF. The humanized 6B4 Fab-fragment effectively prevented repetitive occlusions of the damaged and stenosed femoral artery in a baboon thrombosis model. Interestingly, only little prolongation of the template bleeding time and minimal increase in blood loss from a standardized incision was observed. This apparent larger therapeutic window of GPIb inhibitors could be particularly useful in ischemic stroke, where the utility of current platelet inhibitors and anticoagulants is significantly counterbalanced by the risk of intracerebral bleeding complications. Recent promising results in a mouse model of cerebral ischemia/reperfusion indeed show a significantly less severe stroke outcome using a GPIb-inhibitor, either administered before or, importantly, after cerebral artery occlusion. No increase in intracerebral hemorrhages was detected, in contrast to what is seen with e.g. GPIIb/IIIa inhibition. Finally, as antibodies may be useful for acute treatments but not for chronic applications, the identification of a GPIb-inhibiting nonamer peptide raises hopes towards development of orally available small molecule inhibitors.