CYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Conventional inhibitors often fail to address multiple pathogenic mechanisms of disease-causing proteins.
• Targeted protein degradation (TPD) offers a strategy to eliminate proteins and all their functions.
• Existing TPD strategies involve E3 ligases or endolysosomal pathway uptake.

Purpose of the Study:

• To introduce CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology for targeted protein degradation.
• To leverage a catalytic mechanism with the specificity and modular design of endolysosomal uptake.
• To enhance drug potency and reduce off-target tissue exposure risks.

Main Methods:

• CYpHER utilizes pH-dependent release of the target engager.
• The transferrin receptor (TfR) serves as the uptake receptor for rapid cycling.
• Demonstrated in vitro for EGFR and PD-L1, and in vivo for EGFR in non-small cell lung cancer models.

Main Results:

• CYpHER induces endolysosomal delivery of surface and extracellular targets.
• The technology allows for drug re-use, potentially increasing potency.
• TfR-based targeting enables application in tumors overexpressing TfR and potential CNS transport.

Conclusions:

• CYpHER technology provides a potent and durable TPD strategy.
• The approach combines catalytic efficiency with endolysosomal uptake advantages.
• This method shows promise for treating EGFR-driven cancers and other TfR-targeted diseases.