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Anti-PD-1 cis-delivery of low-affinity IL-12 activates intratumoral CD8+T cells for systemic antitumor responses

Author

Listed:
  • Zhuangzhi Zou

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jiao Shen

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Diyuan Xue

    (Tsinghua University)

  • Hongjia Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Longxin Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Weian Cao

    (Tsinghua University)

  • Wenyan Wang

    (Tsinghua University)

  • Yang-Xin Fu

    (Tsinghua University)

  • Hua Peng

    (Chinese Academy of Sciences
    Guangzhou Laboratory)

Abstract

Immune checkpoint blockade (ICB) therapies function by alleviating immunosuppression on tumor-infiltrating lymphocytes (TILs) but are often insufficient to fully reactivate these dysfunctional TILs. Although interleukin 12 (IL-12) has been used in combination with ICB to improve efficacy, this remains limited by severe toxicity associated with systemic administration of this cytokine. Here, we engineer a fusion protein composed of an anti-PD-1 antibody and a mouse low-affinity IL-12 mutant-2 (αPD1-mIL12mut2). Systemic administration of αPD1-mIL12mut2 displays robust antitumor activities with undetectable toxicity. Mechanistically, αPD1-mIL12mut2 preferentially activates tumor-infiltrating PD-1+CD8+T cells via high-affinity αPD-1 mediated cis-binding of low-affinity IL-12. Additionally, αPD1-mIL12mut2 treatment exerts an abscopal effect to suppress distal tumors, as well as metastasis. Collectively, αPD1-mIL12mut2 treatment induces robust systemic antitumor responses with reduced side effects.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49034-1
    DOI: 10.1038/s41467-024-49034-1
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    1. 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.
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