Low-dose IL-2-based Immunomodulatory Therapy for PAH

DESCRIPTION provided by applicant Despite evidence that inflammatory mechanisms initiate and complicate pathophysiology in pulmonary arterial hypertension PAH no strategies have been developed to target the inflammatory cells involved Moreover it has been known for years that autoimmune diseases are associated with certain forms of PAH Hence novel therapy is urgently needed to attenuate chronic inflammation restore immune homeostasis and reverse adverse vascular remodeling in order to achieve a persistent improvement of pulmonary and right ventricular functions Naturally occurring thymus derived CD CD Foxp regulatory T cells nTreg play vital roles in controlling excessive inflammatory responses and prevent autoimmune disease Interleukin IL is the key cytokine for the generation survival and function of nTreg by direct binding to its high affinity receptor consisting of three subunits IL R CD IL R CD and c CD Recent clinical trial shows that treatment with low dose IL increased nTreg cells population and was associated with reversal of glucocorticoid refractory chronic graft versus host disease in patients who had undergone allogeneic hematopoietic stem cell transplantation We have designed APT a fusion protein of human serum albumin HSA and IL produced in mammalian cells The unglycosylated fusion protein kD improves solubility and the in vitro potency by fold and extends plasma half life by fold h A single mutation was introduced to eliminate the interaction with endothelial cell and lower the risk of vascular leak syndrome Hence low dose APT will enable safe selective and convenient stimulation of nTreg cells with high affinity to IL R receptors while minimizing activation of effector immune cells with intermediate affinity IL R receptors In the severe and andquot irreversibleandquot PAH model induced by SU hypoxia in rats which resembles human PAH pathophysiology characterized by systemic inflammation and oxidative stress treatment with APT twice a week for weeks effectively restored immune homeostasis and attenuated fibrosis which lead to reversal of lung and RV function In contrast neither bosentan FDA approved first line vasodilative therapy nor Gleevec effective but toxic in Phase III trial were safe or effective In this Phase I SBIR grant application we will determie whether transient treatment with APT will achieve long term improvement of pulmonary and RV function Specific Aim Determine whether treatment of APT twice a week for weeks initiated days after PAH induction will safely reverse pulmonary and RV remodeling and function weeks of follow up post the treatment in the rat model of SU hypoxia induced severe PAH PUBLIC HEALTH RELEVANCE We will determine whether transient or intermittent treatment with a novel and proprietary immunomodulatory drug will improve lung and heart functions in the clinically relevant animal models of human pulmonary arterial hypertension