A simeprevir-inducible molecular switch for the control of cell and gene therapies

Stacey E. Chin, Christina Schindler, Lisa Vinall, Roger B. Dodd, Lisa Bamber, Sandrine Legg, Anna Sigurdardottir, D. Gareth Rees, Tim I. M. Malcolm, Samantha J. Spratley, Cecilia Granéli, Jonathan Sumner and Natalie J. Tigue ()
Additional contact information
Stacey E. Chin: Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
Christina Schindler: Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
Lisa Vinall: Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
Roger B. Dodd: Biologics Engineering, Oncology R&D, AstraZeneca
Lisa Bamber: Biologics Engineering, Oncology R&D, AstraZeneca
Sandrine Legg: Biologics Engineering, Oncology R&D, AstraZeneca
Anna Sigurdardottir: Biologics Engineering, Oncology R&D, AstraZeneca
D. Gareth Rees: Biologics Engineering, Oncology R&D, AstraZeneca
Tim I. M. Malcolm: Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
Samantha J. Spratley: Biologics Engineering, Oncology R&D, AstraZeneca
Cecilia Granéli: Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca
Jonathan Sumner: Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
Natalie J. Tigue: Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Chemical inducer of dimerization (CID) modules can be used effectively as molecular switches to control biological processes, and thus there is significant interest within the synthetic biology community in identifying novel CID systems. To date, CID modules have been used primarily in engineering cells for in vitro applications. To broaden their utility to the clinical setting, including the potential to control cell and gene therapies, the identification of novel CID modules should consider factors such as the safety and pharmacokinetic profile of the small molecule inducer, and the orthogonality and immunogenicity of the protein components. Here we describe a CID module based on the orally available, approved, small molecule simeprevir and its target, the NS3/4A protease from hepatitis C virus. We demonstrate the utility of this CID module as a molecular switch to control biological processes such as gene expression and apoptosis in vitro, and show that the CID system can be used to rapidly induce apoptosis in tumor cells in a xenograft mouse model, leading to complete tumor regression.

Date: 2023
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DOI: 10.1038/s41467-023-43484-9

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