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Title of Journal: Eur J Nucl Med Mol Imaging

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Abbravation: European Journal of Nuclear Medicine and Molecular Imaging

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Springer-Verlag

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10.1002/ajmg.10107

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1619-7089

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PET imaging of HER1expressing xenografts in mice

Authors: Tapan K Nayak Celeste A S Regino Karen J Wong Diane E Milenic Kayhan Garmestani Kwamena E Baidoo Lawrence P Szajek Martin W Brechbiel
Publish Date: 2010/02/13
Volume: 37, Issue: 7, Pages: 1368-1376
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Abstract

Cetuximab is a recombinant human/mouse chimeric IgG1 monoclonal antibody that binds to the epidermal growth factor receptor EGFR/HER1 Cetuximab is approved for the treatment of patients with HER1expressing metastatic colorectal cancer Limitations in currently reported radiolabeled cetuximab for PET applications prompted the development of 86YCHXA″DTPAcetuximab as an alternative for imaging HER1expressing cancer 86YCHXA″DTPAcetuximab can also serve as a surrogate marker for 90Y therapyBifunctional chelate CHXA″DTPA was conjugated to cetuximab and radiolabeled with 86Y In vitro immunoreactivity was assessed in HER1expressing A431 cells In vivo biodistribution PET imaging and noncompartmental pharmacokinetics were performed in mice bearing HER1expressing human colorectal LS174T and HT29 prostate PC3 and DU145 ovarian SKOV3 and pancreatic SHAW tumor xenografts Receptor blockage was demonstrated by coinjection of either 01 or 02 mg cetuximab86YCHXA″DTPAcetuximab was routinely prepared with a specific activity of 15–2 GBq/mg and in vitro cellbinding in the range 65–75 Biodistribution and PET imaging studies demonstrated high HER1specific tumor uptake of the radiotracer and clearance from nonspecific organs In LS174T tumorbearing mice injected with 86YCHXA″DTPAcetuximab alone 86YCHXA″DTPAcetuximab plus 01 mg cetuximab or 02 mg cetuximab the tumor uptake values at 3 days were 293 ± 42 104 ± 05 and 64 ± 03ID/g respectively demonstrating dosedependent blockage of the target Tumors were clearly visualized 1 day after injecting 38–40 MBq 86YCHXA″DTPAcetuximab Quantitative PET revealed the highest tumor uptake in LS174T 2955 ± 267ID/cm3 and the lowest tumor uptake in PC3 1592 ± 155ID/cm3 xenografts at 3 days after injection Tumor uptake values quantified by PET were closely correlated r2 = 09 n = 18 with values determined by biodistribution studiesThis study demonstrated the feasibility of preparation of high specific activity 86YCHXA″DTPAcetuximab and its application for quantitative noninvasive PET imaging of HER1expressing tumors 86YCHXA″DTPAcetuximab offers an attractive alternative to previously labeled cetuximab for PET and further investigation for clinical translation is warrantedThis research was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute Center for Cancer Research and the United States Department of Health and Human Services We are also grateful to Jurgen Seidel and Michael Green National Cancer Institute National Institutes of Health Bethesda MD for technical input on the operations of NIH ATLAS smallanimal PET scanner


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