A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice

Atherosclerosis is a chronic inflammatory disease caused by deposition of oxidative low-density lipoprotein in the arterial intima which triggers the innate immune response through myeloid cells such as macrophages. Regulatory T cells play an important role to control the progression or regression of atherosclerosis by resolving macrophage-mediated inflammatory functions. Interleukin-2 signaling is essential for homeostasis of regulatory T cells. Since recombinant Interleukin-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use, we constructed a fusion protein, designated HCW9302, containing two Interleukin-2 domains linked by an extracellular tissue factor domain. We found that HCW9302 exhibited a longer serum half-life with an approximately 1000-fold higher affinity for Interleukin-2 Receptor-alpha than Interleukin-2. HCW9302 could be administered to mice at a dosing range that expanded and activated regulatory T cells but not CD4 effector T cells. In atherosclerotic mouse model, HCW9302 treatment curtailed the progression of atherosclerosis through regulatory T cell activation and expansion, M2 macrophage polarization and myeloid-derived suppressor cell induction. HCW9302 treatment also lessened the proinflammation in aorta. Thus, HCW9302 is a potential therapeutic agent to expand and activate regulatory T cells for treatment of inflammatory and autoimmune diseases.