Nanobody-Engineered Bispecific IL-18 Mimetics Drive Antitumor Immunity by Engaging CD8+ T Cells and Evading IL-18BP in Preclinical Models.

IF 12.1 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-07-16 DOI:10.1016/j.ymthe.2025.07.004

Yanyang Nan,Min Zhu,Qian Wang,Xiaoxue Du,Caili Xu,Yuping Huang,Yujie Liu,Shaoyuan Zhou,Yuluoyan Qiu,Xiao Chu,Dianwen Ju,Yakun Wan,Xuyao Zhang

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引用次数: 0

Abstract

Cytokines are promising in cancer immunotherapy, but their pleiotropic effects limit specificity and clinical utility. Through binding to IL-18Rα and IL-18Rβ, interleukin-18 (IL-18) stimulates innate lymphocytes and effector T cells for antitumor immunity. However, clinical trials of recombinant IL-18 have been hampered by IL-18 binding protein (IL-18BP), a secreted high-affinity decoy receptor. Here, we developed decoy-resistant bispecific nanobodies that maintain IL-18 signaling potential. Based on agonistic nanobodies targeting IL-18Rα and IL-18Rβ, bispecific nanobody A4B2-mdFc effectively enhanced CD8+ T cells responses with distinct transcriptomic profiles. Systemic delivery of A4B2-mdFc boosted CD8+ T cells infiltration and activation, demonstrating dose-dependent antitumor efficacy in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Interestingly, PDCD1 and CTLA-4 expressions were drastically increased on CD8+ T cells when treated with A4B2-mdFc. Injection of A4B2-mdFc significantly improved the antitumor efficacy of immune checkpoint inhibitors (ICIs) targeting both PD-1 and CTLA-4. Our findings demonstrated that nanobody-based bispecific IL-18 mimetics elicited superior antitumor activity via CD8+ T cells activation and IL-18BP resistance, providing the potential application of cytokine-targeting bispecific nanobody monotherapy or in combination with ICIs for cancer immunotherapy.

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纳米体工程双特异性IL-18模拟物通过参与CD8+ T细胞和逃避IL-18BP在临床前模型中驱动抗肿瘤免疫

细胞因子在肿瘤免疫治疗中的应用前景广阔，但其多效性限制了其特异性和临床应用。白细胞介素-18 （IL-18）通过与IL-18Rα和IL-18Rβ结合，刺激先天淋巴细胞和效应T细胞抗肿瘤免疫。然而，重组IL-18的临床试验一直受到IL-18结合蛋白（IL-18BP）的阻碍，IL-18结合蛋白是一种分泌的高亲和力诱饵受体。在这里，我们开发了抗诱饵的双特异性纳米体，以维持IL-18的信号传导潜力。基于靶向IL-18Rα和IL-18Rβ的激动性纳米体，双特异性纳米体A4B2-mdFc有效增强了CD8+ T细胞对不同转录组谱的反应。全身递送A4B2-mdFc增强了CD8+ T细胞的浸润和活化，在细胞系来源的异种移植（CDX）和患者来源的异种移植（PDX）模型中显示出剂量依赖性的抗肿瘤效果。有趣的是，当A4B2-mdFc处理CD8+ T细胞时，PDCD1和CTLA-4的表达急剧增加。注射A4B2-mdFc可显著提高靶向PD-1和CTLA-4的免疫检查点抑制剂（ICIs）的抗肿瘤效果。我们的研究结果表明，基于纳米体的双特异性IL-18模拟物通过CD8+ T细胞活化和IL-18BP抗性，引发了卓越的抗肿瘤活性，为细胞因子靶向双特异性纳米体单药治疗或与ICIs联合用于癌症免疫治疗提供了潜在的应用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.