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

Ter Weele, E. J., Terwisscha van Scheltinga, A. G. T., Kosterink, J. G. W., Pot, L., Vedelaar, S. R., Lamberts, L. E., Williams, S. P., Lub de Hooge, M. N. & de Vries, E. G. E., 8-Dec-2015, In : Oncotarget. 6, 39, p. 42081-42090 10 p.

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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
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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