Modular design of synthetic receptors for programmed gene regulation in cell therapies.

Autor:	Zhu I; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA., Liu R; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA., Garcia JM; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA., Hyrenius-Wittsten A; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA; Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund 221 84, Sweden., Piraner DI; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA., Alavi J; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA., Israni DV; Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA 02215, USA., Liu B; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA; Department of Anesthesia, University of California, San Francisco, San Francisco, CA 94110, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA., Khalil AS; Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA 02215, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Roybal KT; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Gladstone UCSF Institute for Genetic Immunology, San Francisco, CA 94107, USA; UCSF Cell Design Institute, San Francisco, CA 94158, USA. Electronic address: kole.roybal@ucsf.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2022 Apr 14; Vol. 185 (8), pp. 1431-1443.e16.
DOI:	10.1016/j.cell.2022.03.023
Abstrakt:	Synthetic biology has established powerful tools to precisely control cell function. Engineering these systems to meet clinical requirements has enormous medical implications. Here, we adopted a clinically driven design process to build receptors for the autonomous control of therapeutic cells. We examined the function of key domains involved in regulated intramembrane proteolysis and showed that systematic modular engineering can generate a class of receptors that we call synthetic intramembrane proteolysis receptors (SNIPRs) that have tunable sensing and transcriptional response abilities. We demonstrate the therapeutic potential of the receptor platform by engineering human primary T cells for multi-antigen recognition and production of dosed, bioactive payloads relevant to the treatment of disease. Our design framework enables the development of fully humanized and customizable transcriptional receptors for the programming of therapeutic cells suitable for clinical translation. Competing Interests: Declaration of interests I.Z., R.L., and K.T.R. are co-inventors on patents for synthetic receptors (PRV 62/905,258, 62/905,262, 62/905,266, 62/905,268, 62/905,251, and 62/905,263). R.L. and K.T.R. are co-inventors on patents for synthetic receptors PRV 62/007,807. R.L., I.Z., D.I.P., D.V.I., A.S.K., and K.T.R. are co-inventors for synthetic receptors PRV 63/007,795. K.T.R. is a co-founder of Arsenal Biosciences, consultant, SAB member, and stockholder. K.T.R. is an inventor on patents for synthetic Notch receptors (WO2016138034A1 and PRV/2016/62/333,106) and receives licensing fees and royalties. The patents were licensed by Cell Design Labs and are now part of Gilead. He was a founding scientist/consultant and stockholder in Cell Design Labs, now a Gilead company. K.T.R. holds stock in Gilead. K.T.R. is on the SAB of Ziopharm Oncology and an advisor to Venrock. A.S.K. is a scientific advisor for and holds equity in Senti Biosciences and Chroma Medicine and is a co-founder of Fynch Biosciences and K2 Biotechnologies. B.L. is an inventor on patents (WO2017095823A1 and US20180369409A1) held by University of California that cover ALPPL2-targeted anticancer therapy and ALPPL2-targeting antibodies. Unrelated to this work, B.L. is a founder and stockholder of Fortis Therapeutics and Vivace Therapeutics and a consultant for Merck Sharpe & Dohme. (Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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