Human antibody-based chemically induced dimerizers for cell therapeutic applications.

Autor: Hill ZB; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA., Martinko AJ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.; Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, California, USA., Nguyen DP; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA., Wells JA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2018 Feb; Vol. 14 (2), pp. 112-117. Date of Electronic Publication: 2017 Dec 04.
DOI: 10.1038/nchembio.2529
Abstrakt: 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.
Databáze: MEDLINE
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