An Integrin-Targeting Peptide Enables Efficient Lysosomal Delivery of Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) are standard-of-care therapies for several types of cancer, with an expanding representation in clinical development pipelines. A key determinant of efficacy for most ADCs is their ability to internalize into the target cell, traffic to the lysosome, and release the toxic payload. This internalization and trafficking, however, is target- and antibody-dependent. Here we describe an approach to increase both the target selectivity and internalization ability of ADCs, leveraging recent advances in the extracellular targeted protein degradation space. Lysosome-targeting chimeras (LYTACs) are a class of molecules where a target binder is conjugated to a ligand for a lysosome trafficking receptor. LYTACs thereby deliver the target protein to the lysosome, leading to its degradation. We generated lysosomally-targeted ADCs (LytADCs) by attaching a polyspecific integrin-targeting peptide (PIP) to ADCs targeting several cancer-associated antigens. LytADCs were ~10x more efficient at cell-killing than the corresponding ADC, across three targets (HER2, EGFR, CA9), two different cancer cell lines (SKOV-3, U-87 MG), and in both 2D and 3D spheroid cell culture. These data suggest that LytADCs are a promising modality as next-generation ADCs.