Repurposing Antibody-Drug Conjugates for Theranostic Targeting of Nectin-4 and TROP2 in Bladder Cancer

Abstract The application of antibody-drug conjugate (ADC) therapies in advanced bladder cancers may be improved through non-invasive molecular imaging and therapy with targeted radiation. Enfortumab and Sacituzumab, the antibody components for the ADCs PADCEV (Nectin-4 targeting) and TRODELVY (TROP2 targeting), were developed as ImmunoPET and radioimmunotherapeutic modalities in a HT1376 xenograft model of advanced bladder cancer. Both immuno-PET agents displayed distinct tumor uptake in vivo, with Sacituzumab showing higher accumulation (% ID/g) compared to Enfortumab, reflecting the higher TROP2 expression in this tumor model over Nectin-4. Further, both [177Lu]Lu-DOTA-Enfortumab and [177Lu]Lu-DOTA-Sacituzumab were effective in reducing the growth of tumors in vivo. The repurposing of well-validated ADC antibodies as theranostic radiopharmaceuticals is a promising approach for alternative or adjuvant therapies.