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 CD4+CD25+Foxp3+ regulatory T cells (nTreg) play vital roles in controlling excessive inflammatory responses and prevent autoimmune disease. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of nTreg by direct binding to its high affinity receptor consisting of three subunits, IL2R? (CD25), IL2R? (CD122) and ?c (CD132). Recent clinical trial shows that treatment with low-dose IL2 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 APT602, a fusion protein of human serum albumin (HSA) and IL-2 produced in mammalian cells. The unglycosylated fusion protein (85kD) improves solubility and the in vitro potency by 5 fold and extends plasma half-life by 25 fold (5h). A single mutation was introduced to eliminate the interaction with endothelial cell and lower the risk of vascular leak syndrome. Hence, low-dose APT602 will enable safe, selective, and convenient stimulation of nTreg cells with high-affinity to IL2R??? receptors while minimizing activation of effector immune cells with intermediate affinity IL2R?? receptors. In the severe and irreversible PAH model induced by SU5416/hypoxia in rats, which resembles human PAH pathophysiology, characterized by systemic inflammation and oxidative stress, treatment with APT602 twice a week for 3 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 APT602 will achieve long-term improvement of pulmonary and RV function.
Specific Aim. Determine whether treatment of APT602 twice a week for 3 weeks, initiated 21 days after PAH induction, will safely reverse pulmonary and RV remodeling and function 12 weeks of follow up post the treatment in the rat model of SU5416/hypoxia-induced severe PAH.
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.
