Lin Feng, Yin Shenyi, Zhang Zijian, Yu Ying, Fang Haoming, Liang Zhen, Zhu Rujie, Zhou Haitao, Li Jianjie, Cao Kunxia, Guo Weiming, Qin Shan, Zhang Yuxuan, Lu Chenghao, Li Han, Liu Shibo, Zhang Heng, Ye Buqing, Lin Jian, Li Yan, Kang Xiaozheng, Xi Jianzhong Jeff, Chen Peng R
Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Shenzhen Bay Laboratory, Shenzhen 518055, China.
Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China.
Cell. 2024 Dec 26;187(26):7470-7491.e32. doi: 10.1016/j.cell.2024.10.016. Epub 2024 Nov 5.
Although immunotherapy has revolutionized cancer treatment, its efficacy is affected by multiple factors, particularly those derived from the complexity and heterogeneity of the tumor-immune microenvironment (TIME). Strategies that simultaneously and synergistically engage multiple immune cells in TIME remain highly desirable but challenging. Herein, we report a multimodal and programmable platform that enables the integration of multiple therapeutic modules into single agents for tumor-targeted co-engagement of multiple immune cells within TIME. We developed the triple orthogonal linker (T-Linker) technology to integrate various therapeutic small molecules and biomolecules as multimodal targeting chimeras (Multi-TACs). The EGFR-CD3-PDL1 Multi-TAC facilitated T-dendritic cell co-engagement to target solid tumors with excellent efficacy, as demonstrated in vitro, in several humanized mouse models and in patient-derived tumor models. Furthermore, Multi-TACs were constructed to coordinate T cells with other immune cell types. The highly modular and programmable feature of our Multi-TACs may find broad applications in immunotherapy and beyond.
尽管免疫疗法彻底改变了癌症治疗方式，但其疗效受多种因素影响，尤其是那些源自肿瘤免疫微环境（TIME）的复杂性和异质性的因素。同时并协同地作用于TIME中的多种免疫细胞的策略仍然非常值得期待，但具有挑战性。在此，我们报告了一个多模态且可编程的平台，该平台能够将多个治疗模块整合到单一药物中，以在TIME内对多种免疫细胞进行肿瘤靶向协同作用。我们开发了三正交连接子（T-Linker）技术，以整合各种治疗性小分子和生物分子作为多模态靶向嵌合体（Multi-TACs）。如在体外、几种人源化小鼠模型和患者来源的肿瘤模型中所证明的，EGFR-CD3-PDL1 Multi-TAC促进了T细胞与树突状细胞的协同作用，以优异的疗效靶向实体瘤。此外，构建了Multi-TACs以协调T细胞与其他免疫细胞类型。我们的Multi-TACs的高度模块化和可编程特性可能在免疫疗法及其他领域有广泛应用。
