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

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, Elisabeth G E de Vries

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Abstract

Mesothelin is a tumor differentiation antigen expressed by epithelial tumors, including pancreatic cancer. Currently, mesothelin is being targeted with an antibodydrug 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 (Zr-89) labeled anti-mesothelin antibody (Zr-89-AMA) to study its biodistribution in human pancreatic tumor bearing mice. Biodistribution and dose-finding of Zr-89-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 Zr-89-AMA were compared with nonspecific 111In-IgG. Biodistribution analyses revealed a dose-dependent Zr-89-AMA tumor uptake. Tumor uptake of Zr-89-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. Zr-89-AMA tumor uptake is antigen-specific in mesothelin-expressing tumors. Zr-89-AMA PET provides non-invasive, real-time information about AMA distribution and tumor targeting.

Original languageEnglish
Pages (from-to)42081-42090
Number of pages10
JournalOncotarget
Volume6
Issue number39
DOIs
Publication statusPublished - 8-Dec-2015

Keywords

  • mesothelin
  • pancreatic cancer
  • zirconium-89
  • PET imaging
  • IRDye 800CW
  • GROWTH-FACTOR
  • CANCER
  • PET
  • ZR-89-TRASTUZUMAB
  • BIODISTRIBUTION
  • EXPRESSION
  • THERAPY
  • MODELS

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