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

// Eva J. ter Weele 1, 2 , Anton G.T. Terwisscha van Scheltinga 1, 2 , Jos G.W. Kosterink 1, 4 , Linda Pot 2 , Silke R. Vedelaar 2 , Laetitia E. Lamberts 2 , Simon P. Williams 5 , Marjolijn N. Lub-de Hooge 1, 3 , Elisabeth G.E. de Vries 2 1 Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands 2 Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands 3 Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, Netherlands 4 Department of Pharmacy, Section of Pharmacotherapy and Pharmaceutical Care, University of Groningen, Groningen, Netherlands 5 Department of Biomedical Imaging, Genentech, Inc., South San Francisco, CA, USA Correspondence to: Elisabeth G.E. de Vries, e-mail: e.g.e.de.vries@umcg.nl Keywords: mesothelin, pancreatic cancer, zirconium-89, PET imaging, IRDye 800CW Received: August 03, 2015      Accepted: October 16, 2015      Published: October 29, 2015 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 ( 89 Zr) labeled anti-mesothelin antibody ( 89 Zr-AMA) to study its biodistribution in human pancreatic tumor bearing mice. Biodistribution and dose-finding of 89 Zr-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 89 Zr-AMA were compared with nonspecific 111 In-IgG. Biodistribution analyses revealed a dose-dependent 89 Zr-AMA tumor uptake. Tumor uptake of 89 Zr-AMA was higher than 111 In-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. 89 Zr-AMA tumor uptake is antigen-specific in mesothelin-expressing tumors. 89 Zr-AMA PET provides non-invasive, real-time information about AMA distribution and tumor targeting.