Nectin-2 is a cell adhesion molecule and virus receptor that is overexpressed in many different solid tumors (breast, prostate, ovarian, pancreas). Using a phage Fab library, we developed a fully human antibody, F1, against Nectin-2 that binds nectin2 dimers with high affinity (KD=1 nM) and undergoes rapid internalization. We commissioned Wuxi AppTec to generate F1-ADCs with 3 different cytotoxic payloads (DM1, MMAE, DXd). F1 conjugated to MMAE demonstrated the highest in vitro cytotoxicity across a panel of breast, pancreatic and ovarian cancer cell lines (IC₅₀ range 1.24-42.3 nM). In an MDA-MB-468 mouse xenograft model, this ADC fully suppressed tumor growth. Most importantly it also suppressed growth of metastatic primary tumor cultures from patients whose cancer has progressed on either Trodelvy, or Datroway, or Enhertu. Blavatnik funding will be used to perform additional IND enabling patient-derived organoid studies.