Regulatory T cell expansion by a highly CD25-dependent IL-2 mutein arrests ongoing autoimmunity

Interleukin-2 (IL-2) controls the function of regulatory T cells (Treg), and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although Treg-enhancing IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need to develop IL-2-based therapeutics with improved Treg-specificity. We targeted conserved residues in IL-2 that interact with the IL-2-receptor beta-chain, and identified an optimal IL-2 mutein with reduced potency, but enhanced Treg selectivity over a wide dose-range due to increased dependence on the CD25 IL-2-receptor subunit. Surprisingly, despite being a weaker agonist of IL-2 receptor signaling in vitro, the IL-2 mutein induced more robust and sustained Treg cell expansion compared to wild-type IL-2 in vivo. This increased potency is due to enhanced cell surface retention of CD25-associated IL-2 mutein, which results in prolonged IL-2R signaling and reduced target-mediated drug clearance. IL-2 mutein treatment potently arrested ongoing autoimmunity and induced durable disease protection in a setting in which wild-type IL-2 rapidly accelerated disease development. Thus, with carefully tuned affinity for specific receptor components, IL-2 muteins enable selective Treg enrichment, resulting in safe and targeted control of the autoimmune response.