ArticleProceedings of the National Academy of Sciences of the United States of America2024
Directed evolution of genetically encoded LYTACs for cell-mediated delivery.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 26 citations in OpenAlex.
- Lysosome-directed targeted protein degradation technologies for overcoming cancer drug resistance: mechanisms, design principles, and therapeutic opportunities.Drug delivery · 2026Review
- Unlocking the "undruggable": current landscape and emerging frontiers in lysosomal receptor-mediated protein degradation.Drug delivery · 2026Review
- Recent advances in molecular mechanisms to improve the efficacy of CAR-T cell therapy for viral diseases, cancer, and autoimmune diseases.Stem cell research & therapy · 2026Review
- Engineering Antibodies into Targeted Chimeras: From Recognition Modules to Programmable Degraders.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Mapping and engineering the human cell-cell interactome.Nature biotechnology · 2026Review
- Article
- Pan-filovirus activity of an IGF2-fused monoclonal antibody: Impairment by IGF1R cross-engagement and rescue via IGF2 Y27L mutation.Virus research · 2026Article
- Potent and Selective IGF-IIR-Recruiting Bifunctional Molecules for Targeted Lysosomal Degradation of Extracellular and Membrane Proteins.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Glycan-based biological degraders targeting the cytokine immune axis.Communications biology · 2026Article
- Extracellular and Membrane Protein: Structure, Biological Functions, Diseases, and an Emerging Modality for Drug Discovery.MedComm · 2026Review
- Identifying a cancer therapeutic target: Cell-SELEX identifies a membrane protein for aptamer-mediated growth suppression.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Understanding the Role of H-Bonds in the Stability of Molecular Glue-Induced Ternary Complexes.Journal of chemical information and modeling · 2026Article
- Development of Prostate-Specific Lysosome-Targeting Degraders.Journal of the American Chemical Society · 2026Article
- Recent advances in targeting protein degradation for tumor immunotherapy.Journal of hematology & oncology · 2025Review
- Cancer Specific CAIX-Targeting Supramolecular Lysosome-Targeting Chimeras (Supra-LYTAC) for Targeted Protein Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- A Self-Assembling LYTAC Mediates CTGF Degradation and Remodels Inflammatory Tumor Microenvironment for Triple-Negative Breast Cancer Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Targeted degradation of extracellular proteins: state of the art and diversity of degrader designs.Journal of hematology & oncology · 2025Review
- Engineering IGF2 for Lysosome-targeting chimeras development to target drug-resistant membrane proteins in tumor therapy.Protein science : a publication of the Protein Society · 2025Article
- Directed evolution of genetically encoded LYTACs for cell-mediated delivery.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.