Designer small molecule control system based on Minocycline induced disruption of protein-protein interaction.

Jha, R.; Kinna, A.; Hotblack, A.; Bughda, R.; Bulek, A.; Gannon, I.; Ilca, T.; Allen, C.; Lamb, K.; Dolor, A.; Parekh, F.; Sillibourne, J.; Cordoba, S. P.; Onuoha, S. C.; Thomas, S.; Ferrari, M.; Pule, M.

doi:10.1101/2023.08.15.553207

bioRxiv · 10.1101/2023.08.15.553207

Designer small molecule control system based on Minocycline induced disruption of protein-protein interaction.

Jha, R.·Kinna, A.·Hotblack, A.·Bughda, R.·Bulek, A.·Gannon, I.·Ilca, T.·Allen, C.·Lamb, K.·Dolor, A.·Parekh, F.·Sillibourne, J.·Cordoba, S. P.·Onuoha, S. C.·Thomas, S.·Ferrari, M.·Pule, M.

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Abstract

A versatile, safe, and effective small-molecule control system is highly desirable for clinical cell therapy applications. Therefore, we developed a two-component small-molecule control system based on the disruption of protein-protein interactions using minocycline, an FDA-approved antibiotic with wide availability, excellent bio-distribution, and low toxicity. The system comprises an anti-minocycline single-domain antibody (sdAb) and a minocycline-displaceable cyclic peptide. Here we show how this versatile system can be applied to OFF-switch split CAR systems (MinoCAR) and universal CAR adaptors (MinoUniCAR) with reversible, transient, and dose-dependent suppression; to a tunable T cell activation module based on MyD88/CD40 signaling; to a controllable cellular payload secretion system based on IL-12 KDEL retention and as a cell/cell inducible junction. This work represents an important step forward in the development of a remote-controlled system to precisely control the timing, intensity, and safety of therapeutic interventions. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/553207v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1a16d73org.highwire.dtl.DTLVardef@1189ceeorg.highwire.dtl.DTLVardef@e70a57org.highwire.dtl.DTLVardef@580fa9_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Jha, R., Kinna, A., Hotblack, A., Bughda, R., Bulek, A., Gannon, I., Ilca, T., Allen, C., Lamb, K., Dolor, A., Parekh, F., Sillibourne, J., Cordoba, S. P., Onuoha, S. C., Thomas, S., Ferrari, M., Pule, M.. 2023-08-16. Designer small molecule control system based on Minocycline induced disruption of protein-protein interaction.. https://doi.org/10.1101/2023.08.15.553207

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