Topology-enabled long-acting interleukin-2 for advanced low-dose interleukin-2 therapy of autoimmune diseases

Jing Fang; Ruiling Feng; Xibao Tian; Xian Xiao; Bo Huang; Yuange Duan; Jian Lu; Zhanguo Li; Wen-Bin Zhang; Jing He

doi:10.59717/j.xinn-life.2026.100259

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Topology-enabled long-acting interleukin-2 for advanced low-dose interleukin-2 therapy of autoimmune diseases

1.
Beijing National Laboratory for Molecular Sciences, Peking University, Beijing 100871, China
2.
Key Laboratory of Polymer Chemistry & Physics of Ministry of Education, Peking University, Beijing 100871, China
3.
Center for Soft Matter Science and Engineering, Peking University, Beijing 100871, China
4.
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
5.
Beijing Key Laboratory of Non-invasive Diagnosis and Immunotherapy of Rheumatic Diseases, Peking University People’s Hospital, Beijing 100044, China
6.
Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing 100044, China
7.
Key Laboratory of Pest Monitoring and Green Management, Department of Entomology, College of Plant Protection, China Agricultural University, Beijing 100193, China
8.
State Key Laboratory of Protein and Plant Gene Research, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing 100871, China
9.
These authors contributed equally to the work

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Corresponding authors: wenbin@pku.edu.cn (W. Z.); hejing1105@126.com (J.H.); li99@bjmu.edu.cn (Z.L.)
Received Date: February 02, 2026

Accepted Date: September 21, 2026

Published Online: September 28, 2026

The Innovation Life https://doi.org/10.59717/j.xinn-life.2026.100259 | Cite this article

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PUBLIC SUMMARY

PUBLIC SUMMARY
1. Cyclic and catenated interleukin-2 (IL-2) with intact bioactivity are directly synthesized in living cells.
  
  These variants induce preferential Treg expansion to rebalance immunity.
  
  Extended serum half-life enables weekly low-dose treatment for three autoimmune diseases.
  
  Topology engineering overcomes protein therapeutic limits, offering a platform for next-generation biologics.

ABSTRACT

ABSTRACT

The therapeutic efficacy of protein biologics is often hampered by their rapid in vivo degradation and off-target effects. Interleukin-2 (IL-2), a cytokine promising for treating autoimmune diseases via regulatory T cell (Treg) expansion, exemplifies this challenge due to its short half-life and pleiotropic activity. Herein, we report a molecular-scale topology engineering strategy to overcome these limitations. By using split intein mediated ligation and genetically encoded entangling motif, p53dim (X), we constructed cyclic (c-IL-2) and catenated (cat-IL-2) variants of IL-2 via direct expression in E. coli. These topological proteins preserve the native conformation and receptor binding capacity of IL-2 with minimal to minor exogenous motifs, while exhibiting superior proteolytic stability and a dramatically extended serum half-life (approximately 4.5–5.0-fold longer than wt-IL-2). In murine models of three distinct autoimmune diseases (lupus, rheumatoid arthritis, and Sjögren’s syndrome), weekly administration of these topological IL-2 variants effectively rebalanced immunity, as evidenced by a marked expansion of Tregs and significant amelioration of tissue injury and clinical biomarkers. Transcriptomic profiling confirmed the induction of a tolerogenic program without systemic toxicity. This work establishes protein topology engineering as a minimalist, yet robust and generalizable platform to enhance the pharmacokinetics and functional specificity of therapeutic proteins, offering a powerful new modality for biologic drug development.
- chemical topology /
- protein catenane /
- systemic lupus erythematosus /
- low-dose /
- half-life

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REFERENCES

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Fang J., Feng R., Tian X., et al. (2026). Topology-enabled long-acting interleukin-2 for advanced low-dose interleukin-2 therapy of autoimmune diseases. The Innovation Life 4:100259. https://doi.org/10.59717/j.xinn-life.2026.100259

Fang J., Feng R., Tian X., et al. (2026). Topology-enabled long-acting interleukin-2 for advanced low-dose interleukin-2 therapy of autoimmune diseases. The Innovation Life 4:100259. https://doi.org/10.59717/j.xinn-life.2026.100259

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Topology-enabled long-acting interleukin-2 for advanced low-dose interleukin-2 therapy of autoimmune diseases

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ABSTRACT