Sustained Delivery of IL-2 Using an Injectable Hydrogel Prevents Autoimmune Diabetes

IL-2 is a promising therapy for autoimmune type 1 diabetes (T1D), but the short half-life of injected IL-2 (less than 6 minutes) necessitates frequent injections and limits effective tissue exposure to IL-2. We have developed an injectable hydrogel for delivery of sustained release IL-2. This platform integrates clinical grade, commercially available materials, including collagen, hyaluronan, and heparin, that are thiolated and crosslinked into a hydrogel, to deliver IL-2 over time. This hydrogel degrades slowly over a two-week period in vivo while releasing IL-2 throughout this time. Moreover, we find that heparin or heparan sulfate binding of IL-2 potentiates IL-2 activity and promotes Foxp3+ regulatory T-cell (Treg) expansion in vitro in the setting of antigenic signals and TGF-beta. In the Non Obese Diabetic (NOD) mouse model of T1D, 3x/week IL-2 injections at a variety of concentrations failed to prevent autoimmune diabetes while once weekly IL-2 hydrogel delivery prevented disease in 70% of mice at 21 weeks of age. This treatment was associated with increased CD4+Foxp3+ Treg induction but no increase in CD8+ T-cells or activated CD4+FoxP3-CD25+ T-cells. Together these data suggest that IL-2 hydrogels could be a potent and valuable tool for use in IL-2 delivery protocols.