Arming Immune Cell Therapeutics with Polymeric Prodrugs.

Advanced healthcare materials 2022 May

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Engineered immune cells are an exciting therapeutic modality, which survey and attack tumors. Backpacking strategies exploit cell targeting capabilities for delivery of drugs to combat tumors and their immune-suppressive environments. Here, a new platform for arming cell therapeutics through dual receptor and polymeric prodrug engineering is developed. Macrophage and T cell therapeutics are engineered to express a bioorthogonal single chain variable fragment receptor. The receptor binds a fluorescein ligand that directs cell loading with ligand-tagged polymeric prodrugs, termed "drugamers." The fluorescein ligand facilitates stable binding of drugamer to engineered macrophages over 10 days with 80% surface retention. Drugamers also incorporate prodrug monomers of the phosphoinositide-3-kinase inhibitor, PI-103. The extended release of PI-103 from the drugamer sustains antiproliferative activity against a glioblastoma cell line compared to the parent drug. The versatility and modularity of this cell arming system is demonstrated by loading T cells with a second fluorescein-drugamer. This drugamer incorporates a small molecule estrogen analog, CMP8, which stabilizes a degron-tagged transgene to provide temporal regulation of protein activity in engineered T cells. These results demonstrate that this bioorthogonal receptor and drugamer system can be used to arm multiple immune cell classes with both antitumor and transgene-activating small molecule prodrugs. © 2021 Wiley-VCH GmbH.

Citation

Ciana L López, Katherine J Brempelis, James F Matthaei, Kate S Montgomery, Selvi Srinivasan, Debashish Roy, Fei Huang, Shannon A Kreuser, Jennifer L Gardell, Ian Blumenthal, John Chiefari, Michael C Jensen, Courtney A Crane, Patrick S Stayton. Arming Immune Cell Therapeutics with Polymeric Prodrugs. Advanced healthcare materials. 2022 May;11(9):e2101944