Jing Qing-Qing, Wen Jing, Ou Jian-Xia, He Yan-Ting, Zhang Yu-Ting, Rana Gul E, Wang Qi, Wang Gui-Feng, Wang Chun-He
Biotherapeutics Discovery Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Acta Pharmacol Sin. 2025 Aug 12. doi: 10.1038/s41401-025-01611-w.
Th1-type cytokines such as interleukin-2 (IL-2) and interleukin-12 (IL-12) are known for their potent antitumor activities, but their clinical application has been hindered by significant side effects. Immunocytokines (ICs) that combine cytokines with antibodies have shown favorable therapeutic and safety outcomes in clinical trials. In this study we first investigated the expression patterns and prognostic significance of IL13RA2 across various cancer types through a comprehensive analysis of the TIMER2 and TCGA datasets. Subsequently, we generated 52B8, a neutralizing antibody against interleukin-13 receptor alpha 2 (IL13RA2) as well as three ICs incorporating interleukin-2 (IL-2), interleukin-12 (IL-12), or both, designed as 52B8-IL2, 52B8-IL12 and 52B8-IL2/12, respectively. The ICs exhibited potent and dose-dependent anticancer activity both in vitro and in MC38-hIL13RA2-GFP and A375 tumor xenograft models in vivo. In addition, they exhibited significantly reduced side effects through targeted cytokine delivery as well as enhanced immune cell infiltration into tumors. Collectively, our results suggest that IL13RA2-targeting ICs represent a promising therapeutic strategy for the treatment of IL13RA2-positive tumors.
1型辅助性T细胞（Th1）细胞因子，如白细胞介素-2（IL-2）和白细胞介素-12（IL-12），以其强大的抗肿瘤活性而闻名，但其临床应用因显著的副作用而受到阻碍。将细胞因子与抗体结合的免疫细胞因子（IC）在临床试验中显示出良好的治疗效果和安全性。在本研究中，我们首先通过对TIMER2和TCGA数据集的全面分析，研究了IL13RA2在各种癌症类型中的表达模式和预后意义。随后，我们制备了52B8，一种针对白细胞介素-13受体α2（IL13RA2）的中和抗体，以及三种分别包含白细胞介素-2（IL-2）、白细胞介素-12（IL-12）或两者的免疫细胞因子，分别设计为52B8-IL2、52B8-IL12和52B8-IL2/12。这些免疫细胞因子在体外以及MC38-hIL13RA2-GFP和A375肿瘤异种移植体内模型中均表现出强大的、剂量依赖性的抗癌活性。此外，它们通过靶向细胞因子递送显著降低了副作用，并增强了免疫细胞向肿瘤内的浸润。总的来说，我们的结果表明，靶向IL13RA2的免疫细胞因子是治疗IL13RA2阳性肿瘤的一种有前景的治疗策略。
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