Chemically engineered antibodies for autophagy-based receptor degradation

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.