Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
University of Chinese Academy of Sciences, 100049, Beijing, China.
Nat Commun. 2024 Jun 3;15(1):4701. doi: 10.1038/s41467-024-49034-1.
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-1CD8T 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.
免疫检查点阻断（ICB）疗法通过减轻肿瘤浸润淋巴细胞（TIL）的免疫抑制作用而发挥作用，但通常不足以完全重新激活这些功能失调的 TIL。尽管白细胞介素 12（IL-12）已与 ICB 联合使用以提高疗效，但这仍然受到与这种细胞因子全身给药相关的严重毒性的限制。在这里，我们设计了一种由抗 PD-1 抗体和小鼠低亲和力 IL-12 突变体-2（αPD1-mIL12mut2）组成的融合蛋白。αPD1-mIL12mut2 的系统给药具有强大的抗肿瘤活性，且毒性可检测。在机制上，αPD1-mIL12mut2 通过高亲和力αPD-1 介导的低亲和力 IL-12 的顺式结合，优先激活肿瘤浸润的 PD-1CD8T 细胞。此外，αPD1-mIL12mut2 治疗还具有抑制远端肿瘤以及转移的远隔效应。总的来说，αPD1-mIL12mut2 治疗可诱导强烈的全身抗肿瘤反应，同时减少副作用。
