[HTML][HTML] Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity

B Zhang, J Sun, Y Yuan, D Ji, Y Sun, Y Liu… - … and Targeted Therapy, 2023 - nature.com
B Zhang, J Sun, Y Yuan, D Ji, Y Sun, Y Liu, S Li, X Zhu, X Wu, J Hu, Q Xie, L Wu, L Liu…
Signal Transduction and Targeted Therapy, 2023nature.com
Abstract Interleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune
responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical
consequences. Here, we report a strategy that exploited genetic code expansion-guided
incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine (FSY) into
IL-2 for proximity-enabled covalent binding to IL-2Rα to selectively promote Treg activation.
We found that FSY-bearing IL-2 variants, such as L72-FSY, covalently bound to IL-2Rα via …
Abstract
Interleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical consequences. Here, we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine (FSY) into IL-2 for proximity-enabled covalent binding to IL-2Rα to selectively promote Treg activation. We found that FSY-bearing IL-2 variants, such as L72-FSY, covalently bound to IL-2Rα via sulfur-fluoride exchange when in proximity, resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells. Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation, as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3 (LAG-3) and enhanced expression of programmed cell death protein-1 (PD-1). Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease (GvHD) resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment. The efficacy of L72-FSY was further improved by N-terminal PEGylation, which increased its circulatory retention for preferential and sustained effects. This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.
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