TARGETING THE CO-INHIBITORY RECEPTOR G6B IN THROMBOSIS AND THROMBOCYTOPENIA – TARGITT

Platelet activation must be tightly regulated to allow a rapid response to vascular injury and invading pathogens, whilst preventing excessive bleeding and thrombosis. Central to these responses are the structurally-distinct immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors GPVI-FcRgamma-chain (GPVI) and FcgammaRIIA (CD32A), which mediate platelet activation to exposed extracellular matrix and immune complexes, respectively. However, sustained signalling from these receptors can have severe pathological consequences, leading to thrombosis, thrombocytopenia and paradoxical bleeding. The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6B, which binds heparan sulfates in the vessel wall has emerged as a critical inhibitor of platelet activation. Despite the major impact of immunotherapeutics targeting co-inhibitory receptors and their respective ligands in cancer therapy, they remain unexplored targets for regulating ITAM receptor-mediated platelet activation and thrombosis. The hypothesis underpinning TARGITT is that bispecific single-chain variable fragments (bi-scFv’s) that bind the ectodomains of G6B and either GPVI or CD32A can be used to regulate the threshold of platelet activation by mediating co-clustering of the ITIM-ITAM receptors, or blocking ligand engagement. Targeting G6B in this way provides a unique and selective means of regulating platelet reactivity to vascular injury and immune complexes with fewer bleeding side-effects compared with conventional inhibitors of activation receptors and signalling molecules. Preliminary findings demonstrating the inhibitory activities of G6B-GPVI and G6B-CD32A bi-scFv’s provide proof-of-concept of this strategy. The primary objective of TARGITT is to build on these findings and generate preclinical evidence of their efficacy in humanized mouse models, paving the way for a novel class of antithrombotic drugs targeting a physiological inhibitor of platelet activation.