Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment

Feng Lin; Shenyi Yin; Zijian Zhang; Ying Yu; Haoming Fang; Zhen Liang; Rujie Zhu; Haitao Zhou; Jianjie Li; Kunxia Cao; Weiming Guo; Shan Qin; Yuxuan Zhang; Chenghao Lu; Han Li; Shibo Liu; Heng Zhang; Buqing Ye; Jian Lin; Yan Li; Xiaozheng Kang; Jianzhong Jeff Xi; Peng R Chen

doi:10.1016/j.cell.2024.10.016

Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment

Cell. 2024 Nov 2:S0092-8674(24)01198-X. doi: 10.1016/j.cell.2024.10.016. Online ahead of print.

Authors

Feng Lin¹, Shenyi Yin², Zijian Zhang³, Ying Yu², Haoming Fang⁴, Zhen Liang⁵, Rujie Zhu⁶, Haitao Zhou⁵, Jianjie Li⁷, Kunxia Cao⁸, Weiming Guo⁸, Shan Qin⁴, Yuxuan Zhang⁸, Chenghao Lu⁸, Han Li⁴, Shibo Liu⁸, Heng Zhang⁹, Buqing Ye², Jian Lin¹⁰, Yan Li¹¹, Xiaozheng Kang¹², Jianzhong Jeff Xi¹³, Peng R Chen¹⁴

Affiliations

¹ 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.
² Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China.
³ 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.
⁴ Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
⁵ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), First Department of Thoracic Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, China.
⁶ State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
⁷ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China.
⁸ 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.
⁹ Shenzhen Bay Laboratory, Shenzhen 518055, China.
¹⁰ 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; Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China. Electronic address: linjian@pku.edu.cn.
¹¹ 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. Electronic address: yanli@nju.edu.cn.
¹² 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; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), First Department of Thoracic Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, China. Electronic address: kangxz@cicams.ac.cn.
¹³ Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China. Electronic address: jzxi@pku.edu.cn.
¹⁴ 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; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: pengchen@pku.edu.cn.

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.

Keywords: T cell engager; antibody conjugates; bioorthogonal chemistry; dendritic cell engager; integrated immunotherapy; multi-cell co-engagement; multispecific drugs; triple orthogonal linker; tumor-immune microenvironment.