Imaging the distribution of an antibody-drug conjugate constituent targeting mesothelin with 89Zr and IRDye 800CW in mice bearing human pancreatic tumor xenografts

摘要

Mesothelin is a tumor differentiation antigen expressed by epithelial tumors, including pancreatic cancer. Currently, mesothelin is being targeted with an antibody-drug conjugate (ADC) consisting of a mesothelin-specific antibody coupled to a highly potent chemotherapeutic drug. Considering the toxicity of the ADC and reduced accessibility of pancreatic tumors, non-invasive imaging could provide necessary information. We therefore developed a zirconium-89 (⁸⁹Zr) labeled anti-mesothelin antibody (⁸⁹Zr-AMA) to study its biodistribution in human pancreatic tumor bearing mice. Biodistribution and dose-finding of ⁸⁹Zr-AMA were studied 144 h after tracer injection in mice with subcutaneously xenografted HPAC. MicroPET imaging was performed 24, 72 and 144 h after tracer injection in mice bearing HPAC or Capan-2. Tumor uptake and organ distribution of ⁸⁹Zr-AMA were compared with nonspecific ¹¹¹In-IgG. Biodistribution analyses revealed a dose-dependent ⁸⁹Zr-AMA tumor uptake. Tumor uptake of ⁸⁹Zr-AMA was higher than ¹¹¹In-IgG using the lowest tracer dose. MicroPET showed increased tumor uptake over 6 days, whereas activity in blood pool and other tissues decreased. Immunohistochemistry showed that mesothelin was expressed by the HPAC and CAPAN-2 tumors and fluorescence microscopy revealed that AMA-800CW was present in tumor cell cytoplasm. ⁸⁹Zr-AMA tumor uptake is antigen-specific in mesothelin-expressing tumors. ⁸⁹Zr-AMA PET provides non-invasive, real-time information about AMA distribution and tumor targeting.