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<p>Cell surface receptor-targeted protein degraders hold promise for drug discovery. However, their application is restricted because of the complexity of creating bifunctional degraders and the reliance on specific lysosome-shuttling receptors or E3 ubiquitin ligases. To address these limitations, we developed an autophagy-based plasma membrane protein degradation platform, which we term AUTABs (autophagy-inducing antibodies). Through covalent conjugation with polyethylenimine (PEI), the engineered antibodies acquire the capacity to degrade target receptors through autophagy. The degradation activities of AUTABs are self-sufficient, without necessitating the participation of lysosome-shuttling receptors or E3 ubiquitin ligases. The broad applicability of this platform was then illustrated by targeting various clinically important receptors. Notably, combining specific primary antibodies with a PEI-tagged secondary nanobody also demonstrated effective degradation of target receptors. Thus, our study outlines a strategy for directing plasma membrane proteins for autophagic degradation, which possesses desirable attributes such as ease of generation, independence from cell type and broad applicability.</p><p></p>

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Chemically engineered antibodies for autophagy-based receptor degradation

  • 期刊论文

  • 发表日期：

    2025年1月9日

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  • Binghua Cheng,
  • Meiqing Li,
  • Jiwei Zheng,
  • Jiaming Liang,
  • Yanyan Li,
  • Ruijing Liang,
  • Hui Tian,
  • Zeyu Zhou,
  • Li Ding,
  • Jian Ren,
  • Wenli Shi,
  • Wenjie Zhou,
  • Hailiang Hu,
  • Long Meng,
  • Ke Liu,
  • Lintao Cai,
  • Ximing Shao,
  • Lijing Fang,
  • Hongchang Li

摘要

Cell surface receptor-targeted protein degraders hold promise for drug discovery. However, their application is restricted because of the complexity of creating bifunctional degraders and the reliance on specific lysosome-shuttling receptors or E3 ubiquitin ligases. To address these limitations, we developed an autophagy-based plasma membrane protein degradation platform, which we term AUTABs (autophagy-inducing antibodies). Through covalent conjugation with polyethylenimine (PEI), the engineered antibodies acquire the capacity to degrade target receptors through autophagy. The degradation activities of AUTABs are self-sufficient, without necessitating the participation of lysosome-shuttling receptors or E3 ubiquitin ligases. The broad applicability of this platform was then illustrated by targeting various clinically important receptors. Notably, combining specific primary antibodies with a PEI-tagged secondary nanobody also demonstrated effective degradation of target receptors. Thus, our study outlines a strategy for directing plasma membrane proteins for autophagic degradation, which possesses desirable attributes such as ease of generation, independence from cell type and broad applicability.