Title | Site-specific PEGylation of interleukin-2 enhances immunosuppression via the sustained activation of regulatory T cells |
Authors | Zhang, Bo Sun, Jiaqi Wang, Yan Ji, Dezhong Yuan, Yeshuang Li, Shengjie Sun, Yeting Hou, Yingqin Li, Pengchong Zhao, Lidan Yu, Fei Ma, Wenxiao Cheng, Boyang Wu, Ling Hu, Jin Wang, Min Song, Wei Li, Xiaogang Li, Hao Fei, Yunyun Chen, Hua Zhang, Lihe Tsokos, George C. Zhou, Demin Zhang, Xuan |
Affiliation | Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, State Key Lab Complex Severe & Rare Dis, Beijing, Peoples R China Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing, Peoples R China Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll, Grad Sch, Beijing, Peoples R China Chinese Acad Med Sci & Peking Union Med Coll, Beijing Hosp, Grad Sch, Natl Ctr Gerontol,Peking Union Med Coll, Beijing, Peoples R China Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, Minist Educ,Key Lab, Beijing, Peoples R China Peking Univ, Ctr Soft Matter Sci & Engn, Beijing Natl Lab Mol Sci, Beijing, Peoples R China Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Rheumatol & Clin Immunol, Boston, MA 02115 USA |
Keywords | LOW-DOSE INTERLEUKIN-2 IN-VIVO SELECTIVE STIMULATION ALPHA-RECEPTOR IL-2 CYTOKINE ANTIBODIES EFFICACY SUBSETS GROWTH |
Issue Date | Sep-2021 |
Publisher | NATURE BIOMEDICAL ENGINEERING |
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. Orthogonally conjugating the cytokine interleukin-2 to poly(ethylene glycol) moieties at defined protein sites improves its pharmacokinetics and half-life as well as its therapeutic performance in mouse models of autoimmune diseases. |
URI | http://hdl.handle.net/20.500.11897/626191 |
ISSN | 2157-846X |
DOI | 10.1038/s41551-021-00797-8 |
Indexed | SCI(E) |
Appears in Collections: | 药学院 天然药物与仿生药物国家重点实验室 å å¦ä¸ å å å·¥ç¨ å¦é ¢ |