Cell

Small molecule

Chemical biology

Epitope

Biology

Cell signaling

Antibody

Chemistry

Phage display

Immunology

Signal transduction

Computational biology

Cell biology

Biochemistry

Nature Chemical Biology

Selections with a phage-displayed antibody library against an existing protein–small-molecule complex enabled the generation of antibody-based chemically induced dimerizers (AbCIDs) with the properties necessary for use in regulating cell therapies.                                                                 Chemically induced dimerizers (CIDs) have emerged as one of the most powerful tools for artificially regulating signaling pathways in cells; however, currently available CID systems lack the properties desired for use in regulating cellular therapies. Here, we report the development of human antibody-based chemically induced dimerizers (AbCIDs) from known small-molecule–protein complexes by selecting for synthetic antibodies that recognize the chemical epitope created by the bound small molecule. We demonstrate this concept by generating three antibodies that are highly selective for the BCL-xL–ABT-737 complex compared to BCL-xL alone. We show the potential of AbCIDs for application in regulating human cell therapies by using them to induce CRISPRa-mediated gene expression and to regulate CAR T-cell activation. We believe that the AbCIDs generated in this study will find application in regulating cell therapies and that the general method of AbCID development may lead to the creation of many new and orthogonal CIDs.

Human antibody-based chemically induced dimerizers for cell therapeutic applications