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

Autor: Tomasovic LM; Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Liu K; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA., VanDyke D; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA., Fabilane CS; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, USA., Spangler JB; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jamie.spangler@jhu.edu.; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jamie.spangler@jhu.edu.; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA. jamie.spangler@jhu.edu.; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jamie.spangler@jhu.edu.; Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA. jamie.spangler@jhu.edu.; Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA. jamie.spangler@jhu.edu.; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jamie.spangler@jhu.edu.; Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health, Baltimore, MD, USA. jamie.spangler@jhu.edu.
Jazyk: angličtina
Zdroj: BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy [BioDrugs] 2024 Mar; Vol. 38 (2), pp. 227-248. Date of Electronic Publication: 2023 Nov 24.
DOI: 10.1007/s40259-023-00635-0
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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