CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity.
Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity.
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配体诱导的受体二聚化或寡聚化是一种广泛存在的机制，用于确保通讯特异性、保障受体激活，并促进跨细胞膜的信号转导放大。然而，细胞表面抗原诱导的多聚化（本文称为 AIM）尚未在嵌合抗原受体（CAR）工程中被有意识地利用，以丰富基于 T 细胞的疗法。
我们共同开发了 ciltacabtagene autoleucel（cilta-cel），其 CAR 串联整合了两个靶向 B 细胞成熟抗原（BCMA）的纳米抗体，用于治疗多发性骨髓瘤。
在此，我们阐明了一个结构与功能模型，其中 BCMA 诱导的 cilta-cel CAR 多聚化放大了针对骨髓瘤的 T 细胞介导细胞毒性。BCMA-纳米抗体复合物的晶体学分析揭示了抗原-抗体异源多聚化的原子细节，而分析超速离心和小角 X 射线散射则表征了溶液中相互依赖的 BCMA 并置和 CAR 并列。BCMA 诱导的纳米抗体 CAR 多聚化增强了针对骨髓瘤来源细胞的细胞毒性，同时提高了免疫突触形成和介导细胞毒性的细胞因子释放。
我们的结果为在设计下一代 CAR 时考虑 AIM 策略提供了框架。
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 antigen-induced 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.
在 PubMed 查看 → 出版商原文（DOI） 全文 PDF（PMC）· 可下载 治疗专题与资料阅读指南 资料来源与翻译说明 报告译文或资料问题 →
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