TITLE: Molecular Imaging of Dysregulated Angiogenesis in Pulmonary Arterial Hypertension


INSTITUTION: Brigham and Women’s Hospital

DESCRIPTION:   Pulmonary arterial hypertension (PAH) is a disorder of elevated pulmonary vascular resistance characterized by progressive remodeling and obliteration of resistance-determining vessels of the pulmonary circulation.

Despite current therapies, transplant-free survival following the diagnosis of PAH remains slightly better than 50% at 5 years, due primarily to right heart failure.  Outcomes in PH could be improved with earlier diagnosis, and with deployment of therapies that directly target pulmonary vascular remodeling before irreversible changes have occurred.

Here we describe a pre-clinical development program for a positron emission tomography (PET) molecular imaging diagnostic test for PAH.  This strategy utilizes a radioisotope-conjugated (89-Zr) humanized monoclonal antibody directed against VEGF (bevacizumab) to detect abnormal angiogenic activity in the pulmonary vessels of individuals in the early stages of pulmonary vascular disease.  The rationale is based on histopathologic evidence of disordered angiogenic activity in the affected vessels of human disease, and molecular and histologic data from animal models of PAH demonstrating dysregulated angiogenic signaling.  Our molecular probe is retained avidly in remodeled small pulmonary arterioles and vascular lesions in a robust animal model of PAH, and binds avidly to vascular lesions in sectioned human lung tissues affected by PAH.

This pre-clinical development program would advance the first molecular imaging agent specifically designed for the diagnosis and management of pulmonary vascular disease, and provide a technology which would enable non-invasive identification of disease at earlier stages to permit earlier intervention, and could help to identify treatments which have the ability to modify the natural history of disease.