Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment

Affiliations

• 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
• Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
• Department of Thoracic Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
• Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210061, China
• National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China
• Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
• Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), First Department of Thoracic Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, China
• State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
• Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China

PMID:  39504957  DOI: 10.1016/j.cell.2024.10.016

Abstract

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.

尽管免疫疗法在癌症治疗领域取得了突破性进展，但其疗效依然受到多种因素的影响，尤其是肿瘤免疫微环境（TIME）的复杂性和多样性。如何在TIME中同时激活多种免疫细胞，从而协同发挥抗肿瘤作用，依然是一个理想但具有挑战性的策略。在此，我们开发了一种多模式、可编程的平台，能够将多种治疗模块整合至单一制剂中，从而在TIME中实现多种免疫细胞的肿瘤靶向协同激活。我们引入了三重正交偶联臂（T-Linker）技术，用于整合多种治疗性小分子和生物分子，构建出多模式靶向嵌合体（Multi-TACs）。例如，EGFR-CD3-PDL1 Multi-TAC可同时激活T细胞和树突状细胞，针对实体肿瘤表现出显著的疗效，并在体外实验、多种人源化小鼠模型以及患者来源的肿瘤模型中获得了良好的效果。此外，Multi-TACs还可用于协调T细胞与其他类型的免疫细胞的共同作用。我们的Multi-TACs具有高度模块化和可编程的特点，在免疫治疗及其他相关领域具有广泛的应用潜力。

关键词：正交偶联臂，T-Linker，肿瘤，免疫疗法，微环境，RHM03002，佰乐博，佰乐博生物