1. Imaging the distribution of an antibody-drug conjugate constituent targeting mesothelin with ⁸⁹Zr and IRDye 800CW in mice bearing human pancreatic tumor xenografts
- Author
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Eva J, ter Weele, Anton G T, Terwisscha van Scheltinga, Jos G W, Kosterink, Linda, Pot, Silke R, Vedelaar, Laetitia E, Lamberts, Simon P, Williams, Marjolijn N, Lub-de Hooge, and Elisabeth G E, de Vries
- Subjects
Male ,Cytoplasm ,IRDye 800CW ,Immunoconjugates ,Indoles ,Time Factors ,endocrine system diseases ,Transplantation, Heterologous ,pancreatic cancer ,zirconium-89 ,PET imaging ,Mice, Nude ,GPI-Linked Proteins ,Cell Line, Tumor ,parasitic diseases ,Animals ,Humans ,Tissue Distribution ,Radioisotopes ,Mice, Inbred BALB C ,Benzenesulfonates ,Antibodies, Monoclonal ,mesothelin ,Immunohistochemistry ,Pancreatic Neoplasms ,Microscopy, Fluorescence ,Positron-Emission Tomography ,Zirconium ,Research Paper - Abstract
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.
- Published
- 2015