title: Imaging the distribution of an antibody-drug conjugate constituent targeting mesothelin with ⁸⁹Zr and IRDye 800CW in mice bearing human pancreatic tumor xenografts.
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.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.|Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Eva J
authors.initials: EJ
authors.lastname: ter Weele
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.|Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Anton G T
authors.initials: AG
authors.lastname: Terwisscha van Scheltinga
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.|Department of Pharmacy, Section of Pharmacotherapy and Pharmaceutical Care, University of Groningen, Groningen, Netherlands.
authors.forename: Jos G W
authors.initials: JG
authors.lastname: Kosterink
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Pot
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Silke R
authors.initials: SR
authors.lastname: Vedelaar
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Laetitia E
authors.initials: LE
authors.lastname: Lamberts
authors.affiliation: Department of Biomedical Imaging, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Williams
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.|Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Marjolijn N
authors.initials: MN
authors.lastname: Lub-de Hooge
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D001557:Benzenesulfonates / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000493:pharmacokinetics*; D007150:Immunohistochemistry; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D000090204:Mesothelin; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods; D011868:Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D015040:Zirconium / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000911:Antibodies, Monoclonal; D001557:Benzenesulfonates; D058851:GPI-Linked Proteins; C562366:IRDye 800CW; D018796:Immunoconjugates; D007211:Indoles; C000715528:Msln protein, mouse; D011868:Radioisotopes; D015040:Zirconium; D000090204:Mesothelin
keywords: IRDye 800CW; PET imaging; mesothelin; pancreatic cancer; zirconium-89