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; 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

doi:10.18632/oncotarget.5877

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Research Papers:

Imaging the distribution of an antibody-drug conjugate constituent targeting mesothelin with ⁸⁹Zr 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 and Elisabeth G.E. de Vries

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Oncotarget. 2015; 6:42081-42090. https://doi.org/10.18632/oncotarget.5877

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Abstract

Eva J. ter Weele1,2, Anton G.T. Terwisscha van Scheltinga1,2, Jos G.W. Kosterink1,4, Linda Pot2, Silke R. Vedelaar2, Laetitia E. Lamberts2, Simon P. Williams5, Marjolijn N. Lub-de Hooge1,3, Elisabeth G.E. de Vries2

1Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands

2Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands

3Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, Netherlands

4Department of Pharmacy, Section of Pharmacotherapy and Pharmaceutical Care, University of Groningen, Groningen, Netherlands

5Department of Biomedical Imaging, Genentech, Inc., South San Francisco, CA, USA

Correspondence to:

Elisabeth G.E. de Vries, e-mail: [email protected]

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 (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.

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Research Papers:

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

Abstract

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