肿瘤细胞治疗研究
英文原题：Antibody format matters: A comparative analysis of VHH and scFv domains reveals superior in vivo CAR T cell function with VHH domains.
嵌合抗原受体（CAR）T细胞需要胞外靶向结构域来实现抗原特异性，通常是scFv。
嵌合抗原受体（CAR）T细胞需要胞外靶向结构域来实现抗原特异性，通常为scFv。VHH抗体因其尺寸更小、稳定性更好以及CDR3环结构，正逐渐成为替代性CAR结合区域。在此，我们通过免疫噬菌体展示文库生成并比较了靶向CD123的VHH和scFv抗体，基于可比的域靶向和动力学特征（K D范围 M 10 -9 -10 -11）选择了十对抗体。VHH抗体片段表现出改善的稳定性（Tm 50 7.85 C）、减少的聚集以及有利的表面电荷。在体外分析中，包含VHH的CAR比scFv来源的CAR表现出更高的IL2和IFN分泌，并在急性髓系白血病（AML）异种移植小鼠模型中显著增强生存并降低肿瘤负荷。对两种最常用抗体类别的全面比较为选择VHH作为首选CAR结合域提供了依据。
Chimeric antigen receptor (CAR) T cells require an extracellular targeting domain for antigen specificity, typically an scFv. VHH antibodies are emerging as alternative CAR binding regions due to their reduced size, improved stability, and CDR3 loop architecture. Herein, we generated and compared VHH and scFv antibodies targeting CD123, via immunized phage display libraries, selecting ten antibody pairs based on comparable domain targeting and kinetic profiles (K D range M 10 -9 -10 -11 ). The VHH antibody fragments showed improved stability (Tm 50 7.85 C), reduced aggregation, and a favorable surface charge. CARs incorporating a VHH demonstrated higher IL2 and IFN secretion than scFv-derived CARs during in vitro analysis and substantially enhanced survival and decreased tumor burden in a xenograft murine model of acute myeloid leukemia (AML). This comprehensive comparison of the two most adopted antibody classes provides a rationale for the selection of VHH as preferred CAR binding domains.
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