SIM0278, an IL-2 mutein that selectively expands regulatory T cells for the treatment of autoimmune disorders
Abstract
BackgroundRegulatory 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.MethodsUsing 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.ResultsCompared 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.ConclusionSIM0278 is a selective and long-acting Treg-biased IL-2 mutein fusion protein with promising therapeutic potential for various autoimmune diseases.
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BibTeX
@article{yan2026sim0278,
title = {{SIM0278, an IL-2 mutein that selectively expands regulatory T cells for the treatment of autoimmune disorders}},
author = {Yuxi Yan and Wenlu Yan and Zhenna Gao and Yiming Kou and Yulu Wang and Yingying Hu and Zhuoxiao Cao and Renhong Tang and Aik Han Goh and Xiaofeng Zhao},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.2004590},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.2004590},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SIM0278, an IL-2 mutein that selectively expands regulatory T cells for the treatment of autoimmune disorders
AU - Yuxi Yan
AU - Wenlu Yan
AU - Zhenna Gao
AU - Yiming Kou
AU - Yulu Wang
AU - Yingying Hu
AU - Zhuoxiao Cao
AU - Renhong Tang
AU - Aik Han Goh
AU - Xiaofeng Zhao
PY - 2026
DA - 2026/11/04
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.2004590
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.2004590
AB - BackgroundRegulatory 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.MethodsUsing 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.ResultsCompared 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.ConclusionSIM0278 is a selective and long-acting Treg-biased IL-2 mutein fusion protein with promising therapeutic potential for various autoimmune diseases.
SN - 1664-3224
ER -