SIM0278, an IL-2 mutein that selectively expands regulatory T cells for the treatment of autoimmune disorders

Background Regulatory T cells (Tregs) are essential for maintaining immune tolerance, and their dysfunction contributes to autoimmune diseases. Interleukin-2 (IL-2)-based therapies aiming to expand Tregs are limited by a short half-life and broad immune activation. This study aims to develop a long-acting IL-2 variant with enhanced Treg selectivity for the treatment of autoimmune diseases. Methods Using a computation-driven protein engineering strategy, we designed an optimized IL-2 mutein to attenuate binding to IL-2 receptor (IL-2R) βγ while preserving high-affinity engagement with IL-2Rαβγ. The mutein was fused to a human Fc fragment to generate SIM0278. Its receptor binding profile, downstream signaling, and cellular selectivity were characterized in vitro . In vivo pharmacodynamics and therapeutic efficacy were evaluated in healthy mice, multiple autoimmune disease models and cynomolgus monkeys. Results Compared with wild type IL-2, SIM0278 maintained comparable activity toward IL-2Rαβγ while showing reduced activity toward IL-2Rβγ. This receptor response profile translated into preferential STAT5 activation in Tregs, with substantially reduced activation of conventional T cells and CD8 + T cells. In healthy mice, SIM0278 potently expanded Tregs. In models of delayed-type hypersensitivity, atopic dermatitis, graft-versus-host disease, and systemic lupus erythematosus, SIM0278 demonstrated robust, dose-dependent therapeutic effects, reducing inflammation, autoantibody production, and mortality. In cynomolgus monkeys, SIM0278 showed prolonged half-life with sustained and selective Treg expansion. Conclusion SIM0278 is a selective and long-acting Treg-biased IL-2 mutein fusion protein with promising therapeutic potential for various autoimmune diseases.