Department of Immunology and Microbiology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 376 Boyles Street, Frederick, MD, 21702, USA.
Angew Chem Int Ed Engl. 2020 Jul 13;59(29):12178-12185. doi: 10.1002/anie.202005432. Epub 2020 May 18.
Although macromolecules on cell surfaces are predominantly targeted and drugged with antibodies, they harbor pockets that are only accessible to small molecules and constitutes a rich subset of binding sites with immense potential diagnostic and therapeutic utility. Compared to antibodies, however, small molecules are disadvantaged by a less confined biodistribution, shorter circulatory half-life, and inability to communicate with the immune system. Presented herein is a method that endows small molecules with the ability to recruit and activate chimeric antigen receptor T cells (CAR-Ts). It is based on a CAR-T platform that uses a chemically programmed antibody fragment (cp-Fab) as on/off switch. In proof-of-concept studies, this cp-Fab/CAR-T system targeting folate binding proteins on the cell surface mediated potent and specific eradication of folate-receptor-expressing cancer cells in vitro and in vivo.
尽管细胞表面的大分子主要是通过抗体靶向和药物治疗，但它们也存在只有小分子才能进入的口袋，这些口袋构成了一个丰富的结合位点子集，具有巨大的潜在诊断和治疗应用价值。然而，与抗体相比，小分子在生物分布上的限制较小、循环半衰期较短，并且无法与免疫系统进行通讯，这使其处于不利地位。本文介绍了一种赋予小分子招募和激活嵌合抗原受体 T 细胞（CAR-T）的能力的方法。该方法基于一个使用化学编程抗体片段（cp-Fab）作为开关的 CAR-T 平台。在概念验证研究中，这种针对细胞表面叶酸结合蛋白的 cp-Fab/CAR-T 系统在体外和体内介导了叶酸受体表达的癌细胞的有效和特异性清除。
