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  3. Chemically engineered antibodies for autophagy-based receptor degradation

Chemically engineered antibodies for autophagy-based receptor degradation

  • Nat Chem Biol. 2025 Jan 9. doi: 10.1038/s41589-024-01803-1.
Binghua Cheng # 1 2 3,  Meiqing Li # 1 4,  Jiwei Zheng # 1 3,  Jiaming Liang 1 2 3,  Yanyan Li 1 2 3,  Ruijing Liang 1 3 4,  Hui Tian 1 5,  Zeyu Zhou 1 5,  Li Ding 1,  Jian Ren 1 2,  Wenli Shi 1,  Wenjie Zhou 1 5,  Hailiang Hu 5,  Long Meng 1 3,  Ke Liu 1 4,  Lintao Cai 6 7 8,  Ximing Shao 9 10,  Lijing Fang 11 12 13,  Hongchang Li 14 15 16
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, China.
  • 4 Sino-Euro Center of Biomedicine and Health, Shenzhen, China.
  • 5 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 6 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. lt.cai@siat.ac.cn.
  • 7 Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, China. lt.cai@siat.ac.cn.
  • 8 Sino-Euro Center of Biomedicine and Health, Shenzhen, China. lt.cai@siat.ac.cn.
  • 9 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. xm.shao@siat.ac.cn.
  • 10 Sino-Euro Center of Biomedicine and Health, Shenzhen, China. xm.shao@siat.ac.cn.
  • 11 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. lj.fang@siat.ac.cn.
  • 12 Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, China. lj.fang@siat.ac.cn.
  • 13 Sino-Euro Center of Biomedicine and Health, Shenzhen, China. lj.fang@siat.ac.cn.
  • 14 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. hc.li@siat.ac.cn.
  • 15 Key Laboratory of Biomedical Imaging Science and System, Chinese Academy of Sciences, Shenzhen, China. hc.li@siat.ac.cn.
  • 16 Sino-Euro Center of Biomedicine and Health, Shenzhen, China. hc.li@siat.ac.cn.
  • # Contributed equally.
PMID: 39789191 DOI: 10.1038/s41589-024-01803-1
Abstract

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.

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