Restoring the balance in autoimmunity: the promise of IL-2 mutein

Abstract

Abstract The development and function of regulatory T cells (Treg) relies on interleukin-2 (IL-2), and Treg efficiently compete with other cells for IL-2 by expressing the highest levels of the IL-2 receptor alpha-chain (CD25). Accordingly, defects in Treg and the IL-2 pathway have been reported in several autoimmune diseases including type 1 diabetes (T1D). Low-dose IL-2 therapy has shown promising results in autoimmunity; however, autoreactive immune cells can also be activated by IL-2, and the pleiotropic effects of IL-2 raise concerns regarding its widespread utility. Hence, there is a need to develop novel IL-2 based therapeutics with enhanced Treg-specificity. Hypothesizing that reduced IL-2 affinity for IL-2Rβ should increase dependency on high CD25 expression and enhance Treg-selectivity, we generated and screened twenty-eight Fc-fused murine IL-2 muteins (Fc.IL-2 mutein), and identified an optimized mutein that showed reduced signaling but prolonged association with CD25. In vivo, this optimal mutein led to greater enrichment and Ki-67 induction in Treg compared to wild-type (WT) IL-2, and reduced agonism of effector cells, resulting in an improved Treg:effector ratio. In the non-obese diabetic mouse model of T1D, we observed significant protection from disease in mice treated with Fc.IL-2 mutein compared to WT IL-2. The enhanced efficacy of the mutein was most pronounced at high doses, revealing preferential Treg stimulation across a wide dose range. Thus, Fc.IL-2 mutein treatment represents a safer and more efficient alternative for the WT IL-2 therapy, allowing for selective Treg enrichment and a targeted control of the autoimmune response.