Targeting von Willebrand factor and platelet glycoprotein Ib receptor.
Atherothrombotic events, such as acute coronary syndrome or stroke, are the result of platelet activation. Von Willebrand factor (vWF), a multimeric glycoprotein, plays a key role in aggregation of platelets, especially under high-shear conditions. Acting as bridging element or ligand between damaged endothelial sites and the glycoprotein Ib (GPIb) receptor on platelets, vWF is responsible for platelet adhesion and aggregation. This vWF activation and further platelet aggregation mainly occurs under high shear stress present in small arterioles or during deficiency of the vWF-cleaving protease ADAMTS13. There are several substances targeting vWF itself or its binding receptor GPIb on platelets. Two antibodies are directed against vWF: AJW200, an IgG4 humanized monoclonal antibody, and 82D6A3, a monoclonal antibody of the collagen-binding A-3 domain of vWF. ALX-0081 and ALX-0681 are bivalent humanized nanobodies targeting the GPIb binding site of vWF. Aptamers are oligonucleotides with drug-like properties that share some of the attributes of monoclonal antibodies. ARC1779 is a second-generation, nuclease-resistant aptamer, binding to the activated vWF A1 domain and ARC15105 is a chemically advanced follower with an assumed higher affinity to vWF. Antibodies targeting GPIbα are h6B4-Fab, a murine monoclonal antibody; GPG-290, a recombinant, chimeric protein containing the amino-terminal 290 amino acids of GPIbα linked to human IgG1 Fc; and the monoclonal antibody SZ2. There are a number of promising preclinical results and development of some agents (AJW 200, ARC1779 and ALX-0081) has already reached Phase II trials.
Medical University of Vienna, Department of Clinical Pharmacology, Waehringer Guertel 18-20, 1090 Vienna, Austria.
Christa
C
Firbas
Jolanta M
JM
Siller-Matula
Bernd
B
Jilma
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071120:ADAMTS13 Protein; D054058:Acute Coronary Syndrome; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D001606:Bernard-Soulier Syndrome / Q000188:drug therapy / Q000503:physiopathology; D001778:Blood Coagulation Disorders / Q000188:drug therapy* / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D058990:Molecular Targeted Therapy; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000037:antagonists & inhibitors* / Q000502:physiology; D011697:Purpura, Thrombotic Thrombocytopenic / Q000188:drug therapy / Q000503:physiopathology; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors* / Q000502:physiology
D000911:Antibodies, Monoclonal; D052157:Aptamers, Nucleotide; D008562:Membrane Glycoproteins; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human