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Hijacking Extracellular Targeted Protein Degrader-Drug Conjugates for Enhanced Drug Delivery

Fangzhu Zhao1, Yan Wu1, Kaitlin Schaefer1

  • 1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94158, United States.

Journal of the American Chemical Society
|October 15, 2025
PubMed

Insights

Degrader-drug conjugates (DDCs) enhance cancer treatment by combining antibody-drug conjugates and extracellular targeted protein degradation. DDCs improve lysosomal delivery and cytotoxicity, offering a next-generation therapeutic option.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • Antibody-based therapeutics are crucial for targeting tumor cells.
  • Antibody-drug conjugates (ADCs) and extracellular targeted protein degradation (eTPD) rely on lysosomal trafficking.
  • ADCs face limitations due to antigen internalization efficiency, while eTPD lacks cytotoxic potency.

Purpose of the Study:

  • To develop novel degrader-drug conjugates (DDCs) that overcome limitations of ADCs and eTPD.
  • To leverage eTPD's endocytic and recycling capabilities for enhanced lysosomal delivery.
  • To improve cytotoxic potency and broaden the utility of antibody therapeutics.

Main Methods:

  • Development of DDCs utilizing fast internalizing receptors: low-density lipoprotein receptor (LDLR) and chemokine receptor (CXCR7).
  • Assessment of lysosomal delivery efficiency and degradation of extracellular membrane proteins.
  • Evaluation of DDC cytotoxicity compared to conventional ADCs in vitro.

Main Results:

  • LDLR-based degraders demonstrated efficient and selective degradation of extracellular membrane proteins.
  • DDCs incorporating a cytotoxic payload exhibited enhanced cytotoxicity compared to conventional ADCs in vitro.
  • The dual modality of DDCs addresses internalization and potency challenges in current antibody therapeutics.

Conclusions:

  • DDCs represent a promising next-generation antibody therapeutic strategy.
  • This approach enhances lysosomal delivery and cytotoxic efficacy for cancer treatment.
  • DDCs offer broader utility and improved efficacy, expanding options for antibody-based therapies.

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