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Chemically engineered antibodies for autophagy-based receptor degradation.

Binghua Cheng1,2,3, Meiqing Li1,4, Jiwei Zheng1,3

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We developed AUTABs (autophagy-inducing antibodies) for degrading cell surface proteins via autophagy. This platform bypasses traditional limitations, offering a versatile and simpler approach to protein degradation in drug discovery.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted protein degradation is a promising therapeutic strategy.
  • Current methods using bifunctional degraders face limitations due to complexity and reliance on specific cellular machinery like lysosome-shuttling receptors or E3 ubiquitin ligases.

Purpose of the Study:

  • To develop a novel platform for plasma membrane protein degradation.
  • To overcome the limitations of existing targeted protein degradation strategies.

Main Methods:

  • Engineered antibodies, termed AUTABs (autophagy-inducing antibodies), were developed.
  • AUTABs were covalently conjugated with polyethylenimine (PEI).
  • The platform was validated by targeting various clinically important receptors and using a PEI-tagged secondary nanobody approach.

Main Results:

  • AUTABs effectively degrade target receptors through autophagy.
  • The degradation process is self-sufficient, independent of lysosome-shuttling receptors or E3 ubiquitin ligases.
  • The platform demonstrated broad applicability across different receptors and experimental setups.

Conclusions:

  • AUTABs provide a novel strategy for directing plasma membrane proteins to autophagic degradation.
  • This platform offers advantages in ease of generation, cell-type independence, and broad applicability.
  • AUTABs represent a significant advancement in targeted protein degradation for drug discovery.