Data for: Dual cancer-selective lysosomally-targeted antibody–drug conjugates expand the ADC-druggable proteome — Stanford

Abstract: Antibody–drug conjugates (ADCs) are standard-of-care therapies for several types of cancer, with an expanding representation in clinical development pipelines.1 A key determinant of efficacy for most ADCs is their ability to internalize into the target cell and traffic to the lysosome, where the ADC payload released. However, this internalization process is target- and antibody-dependent, limiting therapeutic results and ADC target scope. Here we extend the lysosome-targeting chimera (LYTAC)2,3 concept to ADCs. We conjugated a lysosome-targeting polyspecific integrin-binding peptide (PIP)4,5 to ADCs, generating lysosomally targeted ADCs (LytADCs). Across three targets (HER2, EGFR, CA9), two cancer cell lines (SKOV-3, U-87 MG), and three payloads (MMAE, MMAF, Dxd), LytADCs were significantly more potent than the corresponding ADC in cell culture, 3D spheroid culture and in a murine xenograft model. Notably, the LytADC strategy converted an anti-CA9 ADC, a poor internalizer with no detectable cytotoxicity in 2D cell culture despite target expression, into a potent therapeutic in vitro and in vivo. LytADCs therefore expand the ADC-druggable target space to include cell surface antigens with poor intrinsic internalization properties.Preprint available at: https://doi.org/10.26434/chemrxiv-2025-bsc8l/v2Please find attached the raw data that supports the manuscript, including:IncuCyte microscopy data Flow cytometry data MS-based intact protein characterization raw data Proteomics raw data AKTA SEC data A custom UniDec version Raw in vivo data iISM microscopy raw dataMALDI data