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    University - Student Department: Chemistry Position: Graduate

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  • Mail Code: 5080

All Publications

  • Directed evolution of genetically encoded LYTACs for cell-mediated delivery. Proceedings of the National Academy of Sciences of the United States of America Yang, J. L., Yamada-Hunter, S. A., Labanieh, L., Sotillo, E., Cheah, J. S., Roberts, D. S., Mackall, C. L., Bertozzi, C. R., Ting, A. Y. 2024; 121 (13): e2320053121

    Abstract

    Lysosome-targeting chimeras (LYTACs) are a promising therapeutic modality to drive the degradation of extracellular proteins. However, early versions of LYTAC contain synthetic glycopeptides that cannot be genetically encoded. Here, we present our designs for a fully genetically encodable LYTAC (GELYTAC), making our tool compatible with integration into therapeutic cells for targeted delivery at diseased sites. To achieve this, we replaced the glycopeptide portion of LYTACs with the protein insulin-like growth factor 2 (IGF2). After showing initial efficacy with wild-type IGF2, we increased the potency of GELYTAC using directed evolution. Subsequently, we demonstrated that our engineered GELYTAC construct not only secretes from HEK293T cells but also from human primary T-cells to drive the uptake of various targets into receiver cells. Immune cells engineered to secrete GELYTAC thus represent a promising avenue for spatially selective targeted protein degradation.

    View details for DOI 10.1073/pnas.2320053121

    View details for PubMedID 38513100

  • Directed Evolution of Genetically Encoded LYTACs for Cell-Mediated Delivery. bioRxiv : the preprint server for biology Yang, J. L., Yamada-Hunter, S. A., Labanieh, L., Sotillo, E., Cheah, J. S., Roberts, D. S., Mackall, C. L., Ting, A. Y., Bertozzi, C. R. 2023

    Abstract

    Lysosome-targeting chimeras (LYTACs) are a promising therapeutic modality to drive the degradation of extracellular proteins. However, early versions of LYTAC contain synthetic glycopeptides that cannot be genetically encoded. Here we present our designs for a fully genetically encodable LYTAC (GELYTAC), making our tool compatible with integration into therapeutic cells for targeted delivery at diseased sites. To achieve this, we replaced the glycopeptide portion of LYTACs with the protein insulin like growth factor 2 (IGF2). After showing initial efficacy with wild type IGF2, we increased the potency of GELYTAC using directed evolution. Subsequently, we demonstrated that our engineered GELYTAC construct not only secretes from HEK293T cells but also from human primary T-cells to drive the uptake of various targets into receiver cells. Immune cells engineered to secrete GELYTAC thus represent a promising avenue for spatially-selective targeted protein degradation.

    View details for DOI 10.1101/2023.11.14.567117

    View details for PubMedID 38014030

    View details for PubMedCentralID PMC10680704