Targeted signal-amplifying enzymes enhance MRI of EGFR expression in an orthotopic model of human glioma.
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.
Department of Biomedical Engineering, Worcester Polytechnic Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Mohammed S
MS
Shazeeb
Christopher H
CH
Sotak
Michael
M
DeLeo
Alexei
A
Bogdanov
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019786:Gadolinium DTPA / Q000737:chemistry / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006735:Horseradish Peroxidase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007089:Image Enhancement; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009154:Mutation; D009368:Neoplasm Transplantation; D051381:Rats; D011923:Rats, Nude; D015203:Reproducibility of Results; D012815:Signal Processing, Computer-Assisted; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C410723:epidermal growth factor receptor VIII; D006735:Horseradish Peroxidase; D066246:ErbB Receptors; D019786:Gadolinium DTPA; C520777:matuzumab
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