| Autor: |
Yusheng Ou, Min Liu, Kai Zhan, Wanli Wu, Jiao Huang, Hanli Sun, Hongjun Zheng, Xiaohong Yu, Haiping Gong, Zhaosheng Han, Aiyuan Chen, Youping Liao, Yanmei Lin, Ge Liu, Qiuping Liu, Ruijuan Ma, Yingyi Mei, Xianqing Tang, Zhiming Weng, Jieyi Wu, Yun Ye, Tingting Zhang, Jiehong Chen, Lin Chen, Qingfeng Ding, Hui Fan, Jiajia Hu, Jinhua Huang, Lihong Huang, Qiaowei Li, Siyun Li, Jia Shi, Xiangpeng Tan, Xiaoling Wang, Ruirui Xiang, Qingjia Yan, Jianbin Zhang, Wenjing Zheng, Shi Zhong |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.10.12.511904 |
| Popis: |
The clinical success of T-cell receptor (TCR)-based immunotherapy depends on the efficacy and specificity of TCRs. Naturally occurring TCRs have limited anti-tumor potency due to their low affinity for tumor antigens. Affinity enhancement is a promising strategy to generate highly potent TCRs. However, it is concerned that affinity-enhanced TCRs are prone to lose specificity. We isolated low affinity TCRs specific for NY-ESO-1157-165/HLA-A*02:01 from peripheral blood mononuclear cells of healthy donors. An affinity-enhanced TCR candidate with optimal affinity and specificity was generated using phage display and an extensive set ofin vitroandin vivoassays. Alanine scanning mutagenesis showed that the TCR candidate retained specificity by making extensive contacts to the side chains of NY-ESO-1157-165peptide. Adoptive transfer of T cells engineered with this candidate (termed TAEST16001) significantly inhibited tumor growth in subcutaneous, metastatic, and patient-derived xenograft (PDX) mouse tumor models. This study demonstrates that sophisticated engineering and screening techniques can be utilized to generate a clinical candidate TCR with potent anti-tumor activity without losing specificity. TAEST16001 was approved by the Center for Drug Evaluation (CDE) as the first TCR-based immunotherapy clinical trial in China (ClinicalTrials.govIdentifier:NCT03159585). |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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