Chemically Programmable and Switchable CAR‐T Therapy. Issue 29 (18th May 2020)

• Record Type: Journal Article
• Authors: Qi, Junpeng; Tsuji, Kohei; Hymel, David; Burke, Terrence R.; Hudecek, Michael; Rader, Christoph; Peng, Haiyong
• Is Part Of: Angewandte Chemie international edition. Volume 59:Issue 29(2020)
• Page Start: 12178
• Page End: 12185
• Publication Date: 2020-05-18
• Subjects: antibodies -- antitumor agents -- cell-surface receptors -- CAR-Ts -- immunotherapy; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202005432
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : Fab‐ulous ! A novel small‐molecule‐controlled chimeric antigen receptor T cell (CAR‐T) therapy was developed based on a chemically programmed antibody fragment (Fab) as an on/off switch. As a proof‐of‐concept, a folate‐programmed Fab switch mediated potent and specific eradication of folate‐receptor‐expressing cancer cells by engaging CAR‐T cells in both in vitro and in vivo models of ovarian cancer.