Low Density Lipoprotein Receptor Targeting Chimeras for Membrane Protein Degradation and Enhanced Drug Delivery

Antibody-based therapeutics encompass diverse modalities for targeting tumor cells, among which antibody-drug conjugates (ADCs) and extracellular targeted protein degradation (eTPD) specifically depend on efficient lysosomal trafficking for activity. However, many tumor antigens exhibit poor internalization, limiting ADC effectiveness. To address this, we developed low-density lipoprotein receptor-targeting chimeras (LIPTACs), leveraging the constitutive endocytic and recycling activity of the low-density LDLR to enhance lysosomal delivery. LIPTACs enable robust degradation of diverse extracellular membrane proteins, including neo-epitopes on RAS-driven cancer cells. Moreover, by coupling LIPTACs with cytotoxic payloads to generate degrader-drug conjugates, we achieve superior intracellular delivery and enhanced cytotoxicity compared to conventional ADCs.