Chemically Programmable and Switchable CAR‐T Therapy

Abstract

AbstractAlthough 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.