Targeted signal-amplifying enzymes enhance MRI of EGFR expression in an orthotopic model of human glioma

Cancer Res. 2011 Mar 15;71(6):2230-9. doi: 10.1158/0008-5472.CAN-10-1139. Epub 2011 Jan 18.


Epidermal growth factor receptor (EGFR) imaging in brain tumors is essential to visualize overexpression of EGFRvIII variants as a signature of highly aggressive gliomas and to identify patients that would benefit from anti-EGFR therapy. Seeking imaging improvements, we tested a novel pretargeting approach that relies on initial administration of enzyme-linked anti-EGFR monoclonal antibodies (mAb; EMD72000) followed by administration of a low-molecular-weight paramagnetic molecule (diTyr-GdDTPA) retained at the site of EGFR mAb accumulation. We hypothesized that diTyr-GdDTPA would become enzyme activated and retained on cells due to binding to tissue proteins. In support of this hypothesis, mAb-enzyme conjugates reacted with both membrane-isolated wild-type (wt) EGFR and EGFRvIII, but they bound primarily to EGFRvIII-expressing cells and not to EGFRwt-expressing cells. In vivo analysis of magnetic resonance (MR) tumor signal revealed differences in MR signal decay following diTyr-GdDTPA substrate administration. These differences were significant in that they suggested differences in substrate elimination from the tissue which relied on the specificity of the initial mAb binding: a biexponential signal decay was observed in tumors only upon preinjection with EGFR-targeted conjugates. Endpoint MRI in this setting revealed detailed images of tumors which correlated with immunohistochemical detection of EGFR expression. Together, our findings suggest an improved method to identify EGFRvIII-expressing gliomas in vivo that are best suited for treatment with therapeutic EGFR antibodies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / metabolism
  • Antibodies, Monoclonal, Humanized
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • ErbB Receptors / chemistry
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Gadolinium DTPA / chemistry
  • Gadolinium DTPA / metabolism
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / pathology
  • Horseradish Peroxidase / chemistry
  • Horseradish Peroxidase / metabolism
  • Humans
  • Image Enhancement
  • Magnetic Resonance Imaging / methods*
  • Mutation
  • Neoplasm Transplantation
  • Rats
  • Rats, Nude
  • Reproducibility of Results
  • Signal Processing, Computer-Assisted
  • Transplantation, Heterologous


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • epidermal growth factor receptor VIII
  • Horseradish Peroxidase
  • ErbB Receptors
  • Gadolinium DTPA
  • matuzumab