ArticleProtein science : a publication of the Protein Society2025
Engineering IGF2 for Lysosome-targeting chimeras development to target drug-resistant membrane proteins in tumor therapy.
Article in Protein science : a publication of the Protein Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Unlocking the "undruggable": current landscape and emerging frontiers in lysosomal receptor-mediated protein degradation.Drug delivery · 2026Review
- Lysosome-directed targeted protein degradation technologies for overcoming cancer drug resistance: mechanisms, design principles, and therapeutic opportunities.Drug delivery · 2026Review
- 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
- Lysosome-centered nanomedicine for cancer therapy: mechanisms, materials, and modalities.Journal of nanobiotechnology · 2026Review
- Targeted protein degradation dismantles undruggable targets to reverse immune evasion and therapy resistance in cancer.Frontiers in immunology · 2026Review
- Ketoboronate as a Minimal Covalent-Reversible Tag for Targeted Lysosomal Degradation of Extracellular and Membrane Proteins.Journal of the American Chemical Society · 2025Article
- 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
- VPS37A Activates the Autophagy-Lysosomal Pathway for TNFR1 Degradation and Induces NF-Oncology research · 2025Article
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Authors and funding
11 authors.
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Abstract
Lysosome-targeting chimeras (LYTACs) represent a promising approach for the targeted degradation of membrane proteins. Currently, two primary methods for LYTAC development involve chemically modified antibodies and wild-type insulin-like growth factor 2 (IGF2) fusion proteins (iLYTACs). However, LYTACs necessitate intricate chemical modification processes, while wild-type IGF2 in iLYTAC technology binds to IGF1R, potentially triggering carcinogenesis. To tackle this challenge, we introduce specific IGF2R-binding lysosomal targeting chimeras (sLYTACs), a novel technology utilizing engineered IGF2 mutant fusion antibodies for the degradation of endogenous membrane proteins. Diverging from iLYTACs, sLYTACs exhibit selective binding to IGF2R with increased affinity, significantly bolstering the anti-proliferative impact on drug-resistant tumor cells both in vitro and in vivo. By effectively degrading third-generation tyrosine kinase inhibitor-resistant EGFR mutants, masking binding epitope HER2, and concurrently targeting compensatory receptors interacting with these proteins, sLYTACs show great promise in drug development to overcome bypass signaling and combat drug resistance in tumors.
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