Targeted signal-amplifying enzymes enhance MRI of EGFR expression in an orthotopic model of human glioma
Department of Radiology; Graduate School of Biomedical Sciences; Department of Cell Biology
Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Brain Neoplasms; Cell Line, Tumor; Gadolinium DTPA; Glioma; Horseradish Peroxidase; Humans; Image Enhancement; Magnetic Resonance Imaging; Mutation; Neoplasm Transplantation; Rats; Rats, Nude; Receptor, Epidermal Growth Factor; Reproducibility of Results; Signal Processing, Computer-Assisted; Transplantation, Heterologous
Life Sciences | Medicine and Health Sciences
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.
DOI of Published Version
Cancer Res. 2011 Mar 15;71(6):2230-9. Epub 2011 Jan 18. Link to article on publisher's site
Shazeeb, Mohammed S.; Sotak, Christopher H.; DeLeo, Michael J. III; and Bogdanov, Alexei A. Jr., "Targeted signal-amplifying enzymes enhance MRI of EGFR expression in an orthotopic model of human glioma" (2011). University of Massachusetts Medical School. Senior Scholars Program. Paper 131.