Reprogramming CAR T-Cells with designed bioPROTACs

Peche, V. S.; Kenny, S.; Kang, T. G.; Coventry, B.; Mi, T.; Goreshnik, I.; Garcia Sanchez, M.; Martin, R.; Smith, M.; Vafeados, D.; Kathayat, R.; Kaiwen, Y.; Yuan, Z.-F.; Wu, L.; High, A.; Nemecek, A.; Wickmann, E.; Adeshakin, A.; Ferrara, F.; Throm, R.; Chen, T.; Youngblood, B.; Baker, D.; Gottschalk, S.

doi:10.64898/2026.02.21.706835

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bioRxiv · 10.64898/2026.02.21.706835

Reprogramming CAR T-Cells with designed bioPROTACs

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Abstract

Gene editing has been used to enhance CAR T-cell function by disrupting negative regulators but has limitations. Here we show that de novo-designed generated targeted degraders (bioPROTACs) provide an alternative approach. Expression of bioPROTACs in CAR T-cells targeting DNMT3A, a key regulator of T-cell exhaustion, phenocopied gene knockout. Our reversible, non-gene editing approach provides a tunable strategy to reprogram T-cell fate which should be broadly applicable for next-generation cell therapies.

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Peche, V. S., Kenny, S., Kang, T. G., Coventry, B., Mi, T., Goreshnik, I., Garcia Sanchez, M., Martin, R., Smith, M., Vafeados, D., Kathayat, R., Kaiwen, Y., Yuan, Z.-F., Wu, L., High, A., Nemecek, A., Wickmann, E., Adeshakin, A., Ferrara, F., Throm, R., Chen, T., Youngblood, B., Baker, D., Gottschalk, S.. 2026-02-22. Reprogramming CAR T-Cells with designed bioPROTACs. https://doi.org/10.64898/2026.02.21.706835

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