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Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent

Author

Listed:
  • Pengju Wang

    (Zhengzhou University)

  • Xiaozhu Li

    (Institute of Biophysics, Chinese Academy of Sciences)

  • Jiwei Wang

    (Zhengzhou University)

  • Dongling Gao

    (Zhengzhou University)

  • Yuenan Li

    (Zhengzhou University)

  • Haoze Li

    (Zhengzhou University)

  • Yongchao Chu

    (Zhengzhou University)

  • Zhongxian Zhang

    (Zhengzhou University)

  • Hongtao Liu

    (Zhengzhou University)

  • Guozhong Jiang

    (Zhengzhou University)

  • Zhenguo Cheng

    (Zhengzhou University)

  • Shengdian Wang

    (Institute of Biophysics, Chinese Academy of Sciences)

  • Jianzeng Dong

    (The First Affiliated Hospital of Zhengzhou University)

  • Baisui Feng

    (Zhengzhou University
    The Second Affiliated Hospital of Zhengzhou University)

  • Louisa S. Chard

    (Queen Mary University of London)

  • Nicholas R. Lemoine

    (Zhengzhou University
    Queen Mary University of London)

  • Yaohe Wang

    (Zhengzhou University
    Queen Mary University of London)

Abstract

Interleukin-12 (IL-12) has emerged as one of the most potent agents for anti-tumor immunotherapy. However, potentially lethal toxicity associated with systemic administration of IL-12 precludes its clinical application. Here we redesign the molecule in such a way that its anti-tumor efficacy is not compromised, but toxic effects are eliminated. Deletion of the N-terminal signal peptide of IL-12 can effect such a change by preventing IL-12 secretion from cells. We use a newly designed tumor-targeted oncolytic adenovirus (Ad-TD) to deliver non-secreting (ns) IL-12 to tumor cells and examine the therapeutic and toxic effects in Syrian hamster models of pancreatic cancer (PaCa). Strikingly, intraperitoneal delivery of Ad-TD-nsIL-12 significantly enhanced survival of animals with orthotopic PaCa and cured peritoneally disseminated PaCa with no toxic side effects, in contrast to the treatment with Ad-TD expressing unmodified IL-12. These findings offer renewed hope for development of IL-12-based treatments for cancer.

Suggested Citation

  • Pengju Wang & Xiaozhu Li & Jiwei Wang & Dongling Gao & Yuenan Li & Haoze Li & Yongchao Chu & Zhongxian Zhang & Hongtao Liu & Guozhong Jiang & Zhenguo Cheng & Shengdian Wang & Jianzeng Dong & Baisui Fe, 2017. "Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01385-8
    DOI: 10.1038/s41467-017-01385-8
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    Cited by:

    1. Zhuangzhi Zou & Jiao Shen & Diyuan Xue & Hongjia Li & Longxin Xu & Weian Cao & Wenyan Wang & Yang-Xin Fu & Hua Peng, 2024. "Anti-PD-1 cis-delivery of low-affinity IL-12 activates intratumoral CD8+T cells for systemic antitumor responses," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Weiyue Ban & Mengchi Sun & Hanwei Huang & Wanxu Huang & Siwei Pan & Pengfei Liu & Bingwu Li & Zhenguo Cheng & Zhonggui He & Funan Liu & Jin Sun, 2023. "Engineered bacterial outer membrane vesicles encapsulating oncolytic adenoviruses enhance the efficacy of cancer virotherapy by augmenting tumor cell autophagy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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