Site-specific PEGylation of interleukin-2 enhances immunosuppression via the sustained activation of regulatory T cells.

Abstract

The preferential activation of regulatory T (Treg) cells by interleukin-2 (IL-2), which selectively binds to the trimeric IL-2 receptor (IL-2R) on Treg 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 Treg-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.

• Authors: Bo Zhang, Jiaqi Sun, Yan Wang, Dezhong Ji, Yeshuang Yuan, Shengjie Li, Yeting Sun, Yingqin Hou, Pengchong Li, Lidan Zhao, Fei Yu, Wenxiao Ma, Boyang Cheng, Ling Wu, Jin Hu, Min Wang, Wei Song, Xiaogang Li, Hao Li, Yunyun Fei, Hua Chen, Lihe Zhang, George C Tsokos, Demin Zhou, Xuan Zhang
• Journal: Nature biomedical engineering (Nat Biomed Eng) Vol. 5 Issue 11 Pg. 1288-1305 (11 2021) ISSN: 2157-846X [Electronic] England
• PMID: 34580438 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Cytokines
• Interleukin-2

Topics

• Animals
• Cytokines
• Immune Tolerance
• Immunosuppression Therapy
• Interleukin-2
• Mice
• T-Lymphocytes, Regulatory