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bioRxiv (Cold Spring Harbor Laboratory)

Reprogramming CAR T-Cells with designed bioPROTACs

Vivek S. Peche, Sebastian Kenny, Tae Gun Kang, Brian Coventry, Tian Mi, Inna Goreshnik, Mariana Garcia Sanchez, Reid Martin, Macey Smith, Dionne K. Vafeados, Rahul S. Kathayat, Yu Kaiwen, Zuo-Fei Yuan, Long Wu, Anthony A. High, Andrew N. Nemecek, Elizabeth Wickman, Adeleye Oluwatosin Adeshakin, Francesca Ferrara, Robert E. Throm, Taosheng Chen, Ben Youngblood, David A. Baker, Stephen M Gottschalk

Curated by Papers for Protein Design Using Deep Learning · 6. Function to Structure · 6.3 RoseTTAFold-based

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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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