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Molecular Engineering of Interleukin-2 for Enhanced Therapeutic Activity in Autoimmune Diseases

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Abstract

The interleukin-2 (IL-2) cytokine plays a crucial role in regulating immune responses and maintaining immune homeostasis. Its immunosuppressive effects have been harnessed therapeutically via administration of low cytokine doses. Low-dose IL-2 has shown promise in the treatment of various autoimmune and inflammatory diseases; however, the clinical use of IL-2 is complicated by its toxicity, its pleiotropic effects on both immunostimulatory and immunosuppressive cell subsets, and its short serum half-life, which collectively limit the therapeutic window. As a result, there remains a considerable need for IL-2-based autoimmune disease therapies that can selectively target regulatory T cells with minimal off-target binding to immune effector cells in order to prevent cytokine-mediated toxicities and optimize therapeutic efficacy. In this review, we discuss exciting advances in IL-2 engineering that are empowering the development of novel therapies to treat autoimmune conditions. We describe the structural mechanisms of IL-2 signaling, explore current applications of IL-2-based compounds as immunoregulatory interventions, and detail the progress and challenges associated with clinical adoption of IL-2 therapies. In particular, we focus on protein engineering approaches that have been employed to optimize the regulatory T-cell bias of IL-2, including structure-guided or computational design of cytokine mutants, conjugation to polyethylene glycol, and the development of IL-2 fusion proteins. We also consider future research directions for enhancing the translational potential of engineered IL-2-based therapies. Overall, this review highlights the immense potential to leverage the immunoregulatory properties of IL-2 for targeted treatment of autoimmune and inflammatory diseases.

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This work was supported by funding from an Allegheny Health Network-Johns Hopkins Research Award (to Jamie B. Spangler), a Gabrielle’s Angel Foundation award (to Jamie B. Spangler), and a National Science Foundation CAREER award (2143160 to Jamie B. Spangler). Luke M. Tomasovic is supported by the NIH Medical Scientist Training Program (T32 GM136577). Derek VanDyke is supported by a Johns Hopkins-AstraZeneca Scholar award, an ARCS® Foundation Metro-Washington Chapter Scholar award, and a National Science Foundation Graduate Research Fellowship Program award. Charina S. Fabilane is supported by NIH T32 GM135131.

Conflicts of Interest

Derek VanDyke and Jamie B. Spangler are listed as co-inventors on a patent describing a Treg-biased IL-2-based therapy (International Publication Number WO2020264318A1). Luke M. Tomasovic, Kathy Liu, and Charina S. Fabilane have no conflicts of interest that are directly relevant to the content of this article.

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Tomasovic, L.M., Liu, K., VanDyke, D. et al. Molecular Engineering of Interleukin-2 for Enhanced Therapeutic Activity in Autoimmune Diseases. BioDrugs 38, 227–248 (2024). https://doi.org/10.1007/s40259-023-00635-0

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