In Vivo Induction of Regulatory T Cells via a Long-Lived IL-2 Mutein to Control Autoimmune Kidney Diseases

Background: Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. While low-dose interleukin-2 (IL-2) can expand and activate Tregs, its clinical applicability is limited by its short half-life and unintended stimulation of effector T cells. Methods: A novel IL-2 mutein STS718 was engineered by introducing point mutations at the CD122-binding interface and fusing it to an Fc domain. The molecular characteristics of STS718, including half-life and Treg selectivity, were evaluated by pharmacokinetics analysis. Experimental autoimmune glomerulonephritis models, including anti-glomerular membrane nephritis and membrane nephropathy, were established to test the therapeutic potential of STS718. ex vivo treatment of human naïve CD4 T cells from donors and peripheral blood mononuclear cells (PBMCs) from patients with autoimmune kidney diseases and in vivo administration to cynomolgus monkeys, were performed to confirm the potential of STS718 to induce human Tregs. Results: Compared to natural human IL-2, STS718 exhibited a Treg selectivity and prolonged half-life. In mice, STS718 dose-dependently expanded Tregs without affecting the differentiation of effector T cells, including Th1, Th2, Th17, and helper T cell. Proof-of-concept studies demonstrated that sustainable Treg expansion by STS718 effectively controlled the disease progression in autoimmune glomerulonephritis models, indicating the suppressive functions of STS718-induced Tregs. Furthermore, the STS718 was able to induce human Treg expansion in vitro and in vivo, as well as PBMCs of patients with autoimmune kidney diseases. Conclusion: The engineered IL-2 mutein STS718 can be used for successful induction of Tregs in vivo. These preclinical findings support the notion that low-dose IL-2 or its engineered muteins as a novel therapeutic approach in patients with autoimmune kidney diseases.