NEDD9 Monoclonal Antibody Therapeutic for Pulmonary Thromboembolic Disease
Project Abstract:
Increased plateletendothelial adhesion is a central pathobiological event underlying the pathogenesis of pulmonary arterial hypertension PAH and chronic thromboembolic pulmonary hypertension CTEPH Current therapies to treat thrombosis in PAH and CTEPH emphasize nonspecific coagulation proteins and are associated with elevated rates of offtarget effects eg intracranial hemorrhage Developing a pulmonary vascularspecific drug has several high impact and favorable advantages to current standard of care but such therapies not exist currently In this proposal we present novel data demonstrating that the substrate domain of the protein NEDD9 is a modifiable target to limit thrombosis selectively in the pulmonary circulation Specifically our data suggests that NEDD9 on the outward facing plasma membrane is increased by hypoxia selectively in human pulmonary artery endothelial cells which in turn functions as a target of platelet Pselectin to modulate plateletendothelial interactions in vitro and pulmonary thrombosis in vivo We propose experiments using PAH and CTEPH animal models and patient samples to profile the therapeutic effect of a novel monoclonal antibody against the prothrombotic NEDD9 peptide sequence mAbNEDD9 GoNogo decisions pivot points and milestone markers are detailed in the accompanying proposal Overall results of the proposed experiments aim to i establish NEDD9 as a druggable site to inhibit thrombosis in PAH and CTEPH ii develop a high quality mAbNEDD9 and iii demonstrate that the mAbNEDD9 inhibits platelet adhesion to pulmonary artery endothelial cells in vitro and inhibits thrombosis vascular remodeling and pulmonary hypertension in PAHCTEPH animal models in vivo Deliverables from this project will be well positioned for early clinical testing
