TITLE: NEDD9 Monoclonal Antibody Therapeutic for Pulmonary Thromboembolic Disease
TYPE OF AWARD: Drive
CLINICAL AREA: Biologic
INSTITUTION: Brigham and Women’s Hospital
DESCRIPTION: Increased platelet-endothelial 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 non-specific coagulation proteins, and are associated with elevated rates of off-target effects (e.g., intracranial hemorrhage). Developing a pulmonary vascular-specific 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 P-selectin to modulate platelet-endothelial 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 pro-thrombotic NEDD9 peptide sequence (mAb-NEDD9). Go/No-go 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 mAb-NEDD9, and iii) demonstrate that the mAb-NEDD9 inhibits platelet adhesion to pulmonary artery endothelial cells in vitro and inhibits thrombosis, vascular remodeling, and pulmonary hypertension in PAH/CTEPH animal models in vivo. Deliverables from this project will be well positioned for early clinical testing.