Expansion of Regulatory T cells via an Engineered IL-2 Mutein to Suppress Autoimmune Glomerulonephritis.

Abstract

RATIONALE: Regulatory T (Treg) cells suppress autoimmunity and restrain inflammatory responses, showing promising potential in autoimmune glomerulonephritis (GN) therapy with minimizing nonspecific immunosuppression. Although low-dose interleukin-2 (IL-2) has been shown to promote Treg expansion, its clinical utility is constrained by its short half-life and concurrent effector T cell activation. METHODS: An IL-2 mutein STS718 was engineered by introducing point mutations and fusing it to a human IgG1 Fc domain. The molecular characteristics of STS718, including its affinity, selectivity, and half-life were evaluated.expansion of Treg cells by STS718 was assessed in mice and cynomolgus monkeys. Experimental autoimmune GN models, including crescentic GN and membrane GN, were established to test the therapeutic potential of STS718. The ability of STS718 to induce human functional Treg cells was confirmed using human naïve CD4T cells from donors and peripheral blood mononuclear cells (PBMCs) from autoimmune GN patients. RESULTS: STS718 exhibited a lower affinity for IL-2 receptor (IL-2Rβγ) and comparable affinity for IL-2Rαβγ compared with wild-type IL-2-Fc of human, rat, and mouse, as well as a prolonged half-life. STS718 expanded Treg cells in mice and cynomolgus monkeys in a manner that was dependent on either time or dose, without significantly affecting the effector T cell activation. Proof-of-concept experiments confirmed that sustained Treg expansion mediated by STS718 effectively suppressed the progression of autoimmune GN models, exhibiting superior efficacy compared to wild-type IL-2-Fc. In addition, the STS718 was capable of inducing the expansion of human functional Treg cells from either naïve CD4T cells of healthy donors or PBMCs from autoimmune GN patients. CONCLUSIONS: Collectively, these findings suggest that engineered IL-2 mutein which selectively expands Treg cellsholds significant promise as an alternative immunotherapeutic strategy for controlling autoimmune GN while reducing nonspecific immunosuppression.