Inhibitors of the interaction between von Willebrand factor and platelet GPIb/IX/V.
The formation of platelet-rich thrombi, a critical step in the pathogenesis of atherothrombotic events, is a multistep process involving several components, among which von Willebrand Factor (VWF) plays a central role. Ruptured atherosclerotic plaques expose subendothelial matrix proteins which bind VWF that represents a bridge between the injured blood vessel and activated platelets, playing a crucial role in platelet adhesion and aggregation, especially in conditions of high-shear rate. Due to these peculiarities, the binding of VWF to GPIbα is an attractive drug target. Here we summarize the present knowledge on the different classes of drugs targeting the VWF-GPIb interaction and we give an account of their level of clinical development. In particular, the following compounds are discussed: AJW200, an IgG4 humanized monoclonal antibody against VWF-A1; 82D6A3, a monoclonal antibody against VWF-A3; ALX-0081 and ALX-0681, bivalent humanized nanobodies targeting the VWF-A1 domain; ARC1779 and its advanced formulation ARC15105, second-generation aptamers that bind the VWF-A1 domain; h6B4-Fab, a murine monoclonal antibody, and GPG-290, a recombinant chimeric protein, both directed against GPIbα.
Division of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Via E. dal Pozzo, 06126, Perugia, Italy. grespa@unipg.it
Paolo
P
Gresele
Stefania
S
Momi
D000818:Animals; D052157:Aptamers, Nucleotide / Q000627:therapeutic use; D006801:Humans; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000037:antagonists & inhibitors* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology
C526287:ARC 1779; D052157:Aptamers, Nucleotide; C523730:GPG-290 protein; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D011993:Recombinant Fusion Proteins; D014841:von Willebrand Factor