Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity  

作　　者：Yan Sun Xiu-Na Yang Shuang-Shuang Yang Yi-Zhu Lyu Bing Zhang Kai-Wen Liu Na Li Jia-Chen Cui Guang-Xiang Huang Cheng-Lin Liu Jie Xu Jian-Qing Mi Zhu Chen Xiao-Hu Fan Sai-Juan Chen Shuo Chen 

机构地区：[1]Shanghai Institute of Hematology,National Research Center for Translational Medicine,State Key Laboratory of Medical Genomics,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [2]Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China [3]Department of Hematology,Second Hospital of Dalian Medical University,Dalian 116023,China [4]National Facility for Protein Science Shanghai,Shanghai Advanced Research Institute,Chinese Academy of Sciences,Shanghai 201210,China [5]Legend Biotech China,Nanjing 211112,China [6]Shanghai Immune Therapy Institute,Shanghai Cancer Institute,State Key Laboratory of Oncogenes and Related Genes,Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China [7]Wondercel Biotechnology,Shenzhen 518052,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第1期259-270,共12页信号转导与靶向治疗（英文）

基　　金：supported by grants from the Double First-Class Project from the Ministry of Education(grant code:WF510162602);Innovative Research Team of High-Level Local Universities in Shanghai,Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(grant code:2019CXJQ01);Overseas Expertise Introduction Project for Discipline Innovation(111 Project;grant code:B17029);National Natural Science Foundation of China(grant numbers:82230006 and 81900206);Shanghai Shenkang Hospital Development Center(grant code:SHDC2020CR5002);Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine-ShanghaiTech University,Shanghai Pilot Program for Basic Research-Shanghai Jiao Tong University(grant code:21TQ1400226).

摘　　要：Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity,safeguarding receptor activation,and facilitating amplification of signal transduction across the cellular membrane.However,cell-surface antigeninduced multimerization(dubbed AIM herein)has not yet been consciously leveraged in chimeric antigen receptor(CAR)engineering for enriching T cell-based therapies.We co-developed ciltacabtagene autoleucel(cilta-cel),whose CAR incorporates two B-cell maturation antigen(BCMA)-targeted nanobodies in tandem,for treating multiple myeloma.Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity.Crystallographic analysis of BCMA–nanobody complexes revealed atomic details of antigen–antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution.BCMA-induced nanobody CAR multimerization enhanced cytotoxicity,alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release,towards myeloma-derived cells.Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

关 键 词：CYTOTOXICITY ANTIGEN ELEVATED 

分 类 号：R730[医药卫生—肿瘤]