Zhang, B., Sun, J., Wang, Y., Ji, D., Yuan, Y., Li, S., Sun, Y., Hou, Y., Li, P., Zhao, L., Yu, F., Ma, W., Cheng, B., Wu, L., Hu, J., Wang, M., Song, W., Li, X., Li, H., … Zhang, X. (2021). Site-specific PEGylation of interleukin-2 enhances immunosuppression via the sustained activation of regulatory T cells. Nat Biomed Eng, 5, 1288-1305.
Abstract
The preferential activation of regulatory T (T(reg)) cells by interleukin-2 (IL-2), which selectively binds to the trimeric IL-2 receptor (IL-2R) on T(reg) cells, makes this cytokine a promising therapeutic for the treatment of autoimmune diseases. However, IL-2 has a narrow therapeutic window and a short half-life. Here, we show that the pharmacokinetics and half-life of IL-2 can be substantially improved by orthogonally conjugating the cytokine to poly(ethylene glycol) (PEG) moieties via a copper-free click reaction through the incorporation of azide-bearing amino acids at defined sites. Subcutaneous injection of a PEGylated IL-2 that optimally induced sustained T(reg)-cell activation and expansion over a wide range of doses through highly selective binding to trimeric IL-2R led to enhanced therapeutic efficacy in mouse models of lupus, collagen-induced arthritis and graft-versus-host disease without compromising the immune defences of the host against viral infection. Site-specific PEGylation could be used more generally to engineer cytokines with improved therapeutic performance for the treatment of autoimmune diseases.
Last updated on 02/17/2024