Lin et al. developed a flexible triple orthogonal linker platform to create multimodal targeting chimeras (Multi-TACs) that spatially coordinate immune cells within the tumor microenvironment through customizable linkers. The EGFR-CD3-PDL1 Multi-TAC, designed to co-engage T cells and dendritic cells at the tumor site, activated antigen-specific T cells and demonstrated robust antitumor efficacy in vitro, in several humanized mouse models, and in patient-derived tumor models. Multi-TAC was successfully expanded to enable tailored co-engagement of T–NK and T–myeloid cells, advancing immune-driven tumor control.
Contributed by Shishir Pant
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.
Author Info: (1) Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry o
Author Info: (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) Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China. (5) Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. (6) Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), First Department of Thoracic Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, China. (7) State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China. (8) Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), First Department of Thoracic Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, China. (9) Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, 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. (11) 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. (12) Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. (13) 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. (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. (15) Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. (16) 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. (17) Shenzhen Bay Laboratory, Shenzhen 518055, China. (18) Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China. (19) 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. (20) 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. (21) 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. (22) Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China. Electronic address: jzxi@pku.edu.cn. (23) 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.
