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

Zhuangzhi Zou, Jiao Shen, Diyuan Xue, Hongjia Li, Longxin Xu, Weian Cao, Wenyan Wang, Yang-Xin Fu () and Hua Peng ()
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Zhuangzhi Zou: Chinese Academy of Sciences
Jiao Shen: Chinese Academy of Sciences
Diyuan Xue: Tsinghua University
Hongjia Li: Chinese Academy of Sciences
Longxin Xu: Chinese Academy of Sciences
Weian Cao: Tsinghua University
Wenyan Wang: Tsinghua University
Yang-Xin Fu: Tsinghua University
Hua Peng: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49034-1

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