Summary Low dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine’s preferential expansion of immunosuppressive regulatory T cells (T Reg s). However, high toxicity, short serum half-life, and off-target immune cell activation limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating T Reg s over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leveraged structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), that potently and selectively activates and expands T Reg s. F5111 IC conferred protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a T Reg -biased immunotherapy that could be clinically translated for autoimmune disease treatment.

Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection