Low-density lipoprotein receptor-targeting chimeras for membrane protein degradation and enhanced drug delivery

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• Antibody-based therapeutics like antibody-drug conjugates (ADCs) and extracellular targeted protein degradation (eTPD) are crucial for cancer treatment.
• Their efficacy relies on efficient lysosomal trafficking, but poor antigen internalization often limits conventional ADCs.
• Existing eTPD strategies also face challenges in achieving optimal cytotoxic potency.

Purpose of the Study:

• To develop a novel strategy to enhance lysosomal delivery for antibody-based therapeutics.
• To overcome the limitations of poor internalization in conventional ADCs.
• To improve the cytotoxic potency of extracellular targeted protein degradation strategies.

Main Methods:

• Development of low-density lipoprotein receptor-targeting chimeras (LIPTACs) that utilize the constitutive endocytic pathway of the low-density lipoprotein receptor (LDLR).
• Application of LIPTACs for efficient and selective degradation of extracellular membrane proteins.
• Generation of degrader-drug conjugates by coupling LIPTACs with cytotoxic payloads.

Main Results:

• LIPTACs demonstrated efficient and selective degradation of diverse extracellular membrane proteins.
• Coupling LIPTACs with cytotoxic payloads resulted in superior intracellular delivery and enhanced cytotoxicity compared to conventional ADCs.
• LDLR-mediated trafficking significantly improved the performance of both eTPD and ADC modalities.

Conclusions:

• LDLR-mediated trafficking via LIPTACs offers a powerful approach to enhance antibody-based cancer therapeutics.
• This dual modality strategy addresses key limitations of current ADCs and eTPD, improving intracellular delivery and cytotoxic potency.
• LIPTACs provide a versatile blueprint for next-generation antibody therapeutics with broader applicability and enhanced efficacy in cancer treatment.