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Strategies to therapeutically modulate cytokine action

Nature Reviews Drug Discovery volume 22, pages 827–854 (2023)Cite this article

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Abstract

Cytokines are secreted or membrane-presented molecules that mediate broad cellular functions, including development, differentiation, growth and survival. Accordingly, the regulation of cytokine activity is extraordinarily important both physiologically and pathologically. Cytokine and/or cytokine receptor engineering is being widely investigated to safely and effectively modulate cytokine activity for therapeutic benefit. IL-2 in particular has been extensively engineered, to create IL-2 variants that differentially exhibit activities on regulatory T cells to potentially treat autoimmune disease versus effector T cells to augment antitumour effects. Additionally, engineering approaches are being applied to many other cytokines such as IL-10, interferons and IL-1 family cytokines, given their immunosuppressive and/or antiviral and anticancer effects. In modulating the actions of cytokines, the strategies used have been broad, including altering affinities of cytokines for their receptors, prolonging cytokine half-lives in vivo and fine-tuning cytokine actions. The field is rapidly expanding, with extensive efforts to create improved therapeutics for a range of diseases.

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Fig. 1: Cytokine receptors and γc-family cytokines.
Fig. 2: Heterodimerization of the IL-2Rβ and γc cytoplasmic domains is crucial for signalling.
Fig. 3: Mechanisms of cytokine signalling, using IL-2 as a representative cytokine.
Fig. 4: Different approaches to triggering IL-2 signalling: antibodies, single-chain reagents and orthogonal cytokines.
Fig. 5: Super-IL-2 and partial agonists.

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Acknowledgements

This work is supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH.

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  1. Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Warren J. Leonard & Jian-Xin Lin

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Correspondence to Warren J. Leonard.

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W.J.L. is an inventor on patents related to IL-2 partial agonists. J.X.L. declares no competing interests.

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Leonard, W.J., Lin, JX. Strategies to therapeutically modulate cytokine action. Nat Rev Drug Discov 22, 827–854 (2023). https://doi.org/10.1038/s41573-023-00746-x

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