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: 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
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 39 Pg. 42081-90 (Dec 08 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26536664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Benzenesulfonates
• GPI-Linked Proteins
• IRDye 800CW
• Immunoconjugates
• Indoles
• Msln protein, mouse
• Radioisotopes
• Zirconium
• Mesothelin

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacokinetics)
• Benzenesulfonates (chemistry, pharmacokinetics)
• Cell Line, Tumor
• Cytoplasm (metabolism)
• GPI-Linked Proteins (antagonists & inhibitors, immunology, metabolism)
• Humans
• Immunoconjugates (immunology, pharmacokinetics)
• Immunohistochemistry
• Indoles (chemistry, pharmacokinetics)
• Male
• Mesothelin
• Mice, Inbred BALB C
• Mice, Nude
• Microscopy, Fluorescence
• Pancreatic Neoplasms (diagnostic imaging, metabolism, pathology)
• Positron-Emission Tomography (methods)
• Radioisotopes (chemistry, pharmacokinetics)
• Time Factors
• Tissue Distribution
• Transplantation, Heterologous
• Zirconium (chemistry, pharmacokinetics)