Receptor-tuned Interleukin-2 Mutein Decouples Treg Expansion from ILC2-driven Cutaneous Inflammation
Anupama Sahoo, Cody Moorman, Mina Tsenkova, Yi Jing, Alexis Valdovinos, Xin Luo, Shiping Lu, Songyu Wang, Renee R. Hukkanen, Madeline Fort, Helen S.H. Tang, Ronya Primack, Shweta Mandavalli, Weiwen Deng
Anupama Sahoo, Cody Moorman, Mina Tsenkova, Yi Jing, Alexis Valdovinos, Xin Luo, Shiping Lu, Songyu Wang, Renee R. Hukkanen, Madeline Fort, Helen S.H. Tang, Ronya Primack, Shweta Mandavalli, Weiwen Deng
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Research In-Press Preview Immunology Inflammation

Receptor-tuned Interleukin-2 Mutein Decouples Treg Expansion from ILC2-driven Cutaneous Inflammation

Abstract

Low-dose interleukin-2 (IL-2) and IL-2 muteins are being developed to expand regulatory T cells (Tregs) for autoimmune disease therapy, but injection site reactions (ISRs) remain frequent and poorly understood. Here we show IL2Mut24, a murine surrogate of IL-2 receptor α (IL-2Rα, CD25)-biased IL-2 mutein, enhances Treg expansion yet paradoxically exacerbates cutaneous inflammation compared to wild-type IL-2. Using immunodeficient mice, antibody blockade and adoptive transfer, we identify group 2 innate lymphoid cells (ILC2s) as key drivers of IL-2-induced skin inflammation, defining a CD25-dependent innate activation axis that constrains immune tolerance. In cynomolgus monkeys, the CD25-biased IL-2 mutein efavaleukin alfa promotes greater peripheral Treg expansion than aldesleukin (recombinant human IL-2) but is accompanied by transient increases in IL-5 and dose-dependent ISRs, indicating conservation of this innate inflammatory program across species. To improve the therapeutic window, we engineer receptor clamps by linking IL2Mut24 to antibodies against CD25 to restrict IL-2 access to CD25. This receptor-tuned IL-2 preserves Treg selectivity, suppresses ISRs, and outperforms IL2Mut24 in experimental autoimmune encephalomyelitis by restraining Th17 responses. These findings reveal a conserved innate mechanism underlying IL-2–associated toxicity and establish receptor-tuning as a strategy to improve the safety and efficacy of IL-2–based immunotherapy.

Authors

Anupama Sahoo, Cody Moorman, Mina Tsenkova, Yi Jing, Alexis Valdovinos, Xin Luo, Shiping Lu, Songyu Wang, Renee R. Hukkanen, Madeline Fort, Helen S.H. Tang, Ronya Primack, Shweta Mandavalli, Weiwen Deng

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