This proposal seeks to advance recent basic discoveries made in our NHMRC project grant-funded work by performing proof-of-concept studies with therapeutic antibodies against the platelet thrombin receptor, PAR4, as a novel anti-thrombotic approach.
Arterial thrombosis causes heart attacks and ischaemic strokes and is the most common cause of death and disability in the world. Platelets are the cells that form arterial thrombi, and anti-platelet drugs are the mainstay of heart attack and stroke prevention. Yet current treatments have limited efficacy, even at best preventing fewer than 25% of lethal cardiovascular events. As a result there is a major clinical need for improved anti-platelet drugs. We have recently developed an approach with the potential to address this clinical need by targeting the platelet thrombin receptor, PAR4, with an inhibitory antibody.
In initial proof-of-principle studies, we developed a function-blocking anti-PAR4 polyclonal antibody and showed it causes anti-thrombotic effects: our antibody is a highly specific inhibitor of PAR4 and markedly impairs thrombosis in animal models and human blood. We have recently extended on these studies by partnering with Regeneron Pharmaceuticals to utilise their unique VelocImmune® technology to directly produce fully-human, function-blocking, anti-PAR4, monoclonal antibodies that are suitable for human therapies. We now have several candidates that bind to and inhibit human PAR4.
The current application seeks to perform the next stage proof-of-concept studies that will lead directly to clinical trial of these first-in-class agents. Specifically, we will:
1) Determine the binding characteristics and inhibitory activity of therapeutic antibodies targeting the human platelet thrombin receptor, PAR4;
2) Evaluate the anti-thrombotic efficacy of suitable therapeutic candidates.