肿瘤细胞治疗研究
英文原题：A Tetrameric Biotin-Avidin Scaffold Using Anti-CD19 (FMC63) Traptavidin Fusion Enables High-Avidity CAR-T Cells for Leukemia Therapy.
A Tetrameric Biotin-Avidin Scaffold Using Anti-CD19 (FMC63) Traptavidin Fusion Enables High-Avidity CAR-T Cells for Leukemia Therapy.
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CAR-T 细胞疗法在治疗血液系统恶性肿瘤方面展现出前景，但面临诸多局限，包括CAR-T 细胞激活不足。我们开发了一种新型四聚体CAR-T（tCAR-T）系统，靶向CD19，该抗原在血液系统恶性肿瘤中过表达。
我们将抗CD19 scFv与traptavidin连接，构建了四聚体抗体支架，随后工程化改造T细胞，使其表达CD8铰链区、CD8跨膜区、共刺激结构域（4-1BB、CD3）以及YFP，并通过生物素连接酶进行生物素化。tCAR-T 系统通过生物素-亲和素相互作用完成组装。这种四聚体排列显著增强了抗体亲和力，促进了更强的抗原结合，并对CD19+ B细胞淋巴母细胞系（包括Raji、Nalm-6和Ramos）表现出强效的细胞毒性。
值得注意的是，tCAR-T 与Kymriah相比表现出更优越的抗肿瘤活性，具有增强的细胞因子释放和改善的靶细胞清除能力。这一创新方法通过增强结合亲和力和模块化靶向灵活性提高了癌症治疗效果，表明tCAR-T 能够克服传统CAR-T 疗法的局限性，并凸显其改善癌症患者治疗结局的潜力。
Chimeric antigen receptor-T cell (CAR-T) therapy shows promise for treating hematologic malignancies but faces limitations including insufficient CAR-T cell activation.
We developed a novel tetramer CAR-T (tCAR-T) system targeting CD19, which is overexpressed in hematologic malignancies.
We created a tetrameric antibody scaffold by linking anti-CD19 scFv to traptavidin, then engineered T cells expressing CD8 hinge, CD8 transmembrane, costimulatory domains (4-1BB, CD3 ), and YFP, followed by biotinylation using biotin ligase. The tCAR-T system was assembled via biotin-avidin interaction. This tetrameric arrangement significantly enhanced antibody avidity, promoting stronger antigen engagement and demonstrating potent cytotoxicity against CD19 + B-cell lymphoblast lines including Raji, Nalm-6, and Ramos.
Notably, tCAR-T exhibited superior antitumor activity compared to Kymriah, with enhanced cytokine release and improved target cell elimination. This innovative approach improves cancer treatment efficacy through enhanced binding avidity and modular targeting flexibility, demonstrating that tCAR-T can overcome limitations of conventional CAR-T therapy and highlighting its potential to improve therapeutic outcomes for cancer patients.
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