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

Abstract

Low dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokines preferential expansion of immunosuppressive regulatory T cells (TRegs). 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 TRegs 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 TRegs. 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 TReg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.