Project Abstract Lysosome targeted chimeras (LYTACs) are a recently developed technology that enable targeted internalization and subsequent degradation of a cell surface antigen by engaging the cation- independent mannose-6-phosphate receptor (CI-M6PR). The modular design of LYTACs enable its implementation in other therapeutic antibody-based modalities including antibody-drug conjugates (ADCs). We will develop ADC/LYTACs, which consist of an ADC conjugated to CI-M6PR binding ligands, which will provide a supplemental internalization and efficient lysosomal trafficking route independent of the inherent characteristics of a tumor antigen. To reduce off-target cytotoxicity, the CI- M6PR binder will be carefully optimized and a two-component strategy will be tested where the tumor antigen is pre-treated by a non- internalizing ADC before clicking on the internalizing ligand in vitro. Further, prodrug analogues of the CI- M6PR ligand will be developed to enhance the pharmacokinetic properties of this new therapeutic modality. We envision that ADC/LYTACs will significantly expand the target space for ADCs to include highly specific yet poorly internalizing tumor antigens.