GPVI is an attractive target to develop new and safe antithrombotic with the following advantages:
pivotal role in atherothrombosis
inhibition of thrombus growth
inhibition of leucocyte recruitment
inhibition of platelet procoagulant activity
preservation of physiological haemostasis
minor risk of bleeding
no expected side effect
GPVI is a platelet membrane protein which belongs to the immunoglobulin superfamily and that is expressed exclusively by platelets and their precursor, the megacaryocytes.
GPVI is the receptor responsible for platelet activation by collagen and polymerized fibrin and as thus, it is involved in the initiation of thrombus formation.
GPVI contributes to the growth of the thrombus in two ways. First GPVI mediates platelet procoagulant activity via an initial adhesion to collagen followed by an activation leading to platelet secretion, recruitment of additional platelets and aggregation. Second GPVI behaves as a receptor for polymerized fibrin which lead to an amplification of thrombin generation and recruitment of circulating platelets.
A striking result was to discover that GPVI deficiencies do not provoke bleeding while it contributes to protect mice from thrombosis in different models. Furthermore, the founders were the first to identify a patient with a genetic deficiency in GPVI who do not presents any bleeding disorder.
Several model of thrombosis have been evaluated with the murine antibody 9O12 which was the prototype of the humanized drug candidate ACT017. In these models, 9O12 was able to decrease the process of thrombosis in vivo or to protect animals in a lethal model.
Furthermore, elevated plasma levels of soluble GPVI in patients with stroke suggest that GPVI is activated and processed in these patients.