机构:[1]Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院[2]Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院[3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院[4]Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院
Adapter switches are commonly developed to control the activation process of CAR-T cells. However, these affinity-based adapter switches cannot control the exhaustion level of CAR-T cells, which leads to a reduction of antitumor activity. To overcome this hurdle, we developed a CAR system based on split intein-mediated protein trans-splicing. In this system, a split C-intein-mediated adapter switch (SIMAS) containing a CD19 antibody splices with an N-intein motif engineered on T-cell receptors to incorporate CD19 antibodies into T-cell receptors site-specifically, which generates protein trans-splicing-based integrated CAR-T (protinCAR-T) cells. Importantly, trans-splicing does not activate CAR-T cells, thus reducing exhaustion level. Only the binding of protinCAR-T cells to tumor cells and cell motility activate protinCAR-T cells, which have good antitumor activity in vivo. Generally, we developed a novel CAR system that enables tuning of CAR-T-cell activity, which provides solutions to address the safety and efficacy barriers of CAR-T-cell therapy.
基金:
National Natural Science Foundation of China (21977076,82100354, and 82470284) and the Science and Technology Department of Sichuan Province (2023NSFSC1637 and 2023NSFSC0002).
语种:
外文
PubmedID:
中科院(CAS)分区:
出版当年[2025]版:
大类|1 区医学
小类|1 区药物化学
最新[2025]版:
大类|1 区医学
小类|1 区药物化学
第一作者:
第一作者机构:[1]Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.[2]Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.[3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.[4]Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu 610041, China.
通讯作者:
通讯机构:[1]Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.[2]Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.[3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.[4]Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu 610041, China.
推荐引用方式(GB/T 7714):
Jiang Yunhan,Zhou Meng,Cheng Mengdi,et al.Universal Protein Trans-Splicing-Based CAR System Enabling CAR-T Cells with Reduced Exhaustion and Enhanced Efficacy[J].Journal Of Medicinal Chemistry.2025,68(7):7166-7179.doi:10.1021/acs.jmedchem.4c02697.
APA:
Jiang Yunhan,Zhou Meng,Cheng Mengdi,Fan Dongmei,Jiang Weiqing...&Yang Tao.(2025).Universal Protein Trans-Splicing-Based CAR System Enabling CAR-T Cells with Reduced Exhaustion and Enhanced Efficacy.Journal Of Medicinal Chemistry,68,(7)
MLA:
Jiang Yunhan,et al."Universal Protein Trans-Splicing-Based CAR System Enabling CAR-T Cells with Reduced Exhaustion and Enhanced Efficacy".Journal Of Medicinal Chemistry 68..7(2025):7166-7179