Preclinical evaluation of 89Zr/177Lu-labeled amatuximab for theranostic application in pancreatic ductal adenocarcinoma

[Display omitted] Pancreatic ductal adenocarcinoma (PDAC) remains a significant clinical challenge, urgently requiring effective intervention strategies. In recent years, the application of radiopharmaceuticals has emerged as a promising modality for the accurate diagnosis and treatment of malignancies. Due to its high expression on pancreatic cancer cells, mesothelin (MSLN) has become an appealing target for radioimmunotherapy (RIT). In this study, we report the development of a novel radiotracer by conjugating amatuximab with zirconium-89 (89Zr) to facilitate the non-invasive detection of MSLN expression. Immuno-positron emission tomography (immunoPET) imaging demonstrated a specific accumulation of 89Zr-DFO- amatuximab in PANC-1-MSLN tumors. Subsequently, Lutetium-177 (177Lu)-labeled amatuximab was utilized for MSLN- targeted radioimmunotherapy (RIT), resulting in a significant suppression of PANC-1-MSLN xenograft growth. Furthermore, in vivo studies indicated that 177Lu-DOTA-amatuximab exhibited limited side effects. The development of 89Zr/177Lu-labeled amatuximab may provide novel insights into the formulation of precision diagnostic and therapeutic strategies for MSLN- overexpressing tumors, including PDAC.