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PET imaging of HER1-expressing xenografts in mice with 86Y-CHX-A″-DTPA-cetuximab

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

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 HER1-expressing metastatic colorectal cancer. Limitations in currently reported radiolabeled cetuximab for PET applications prompted the development of 86Y-CHX-A″-DTPA-cetuximab as an alternative for imaging HER1-expressing cancer. 86Y-CHX-A″-DTPA-cetuximab can also serve as a surrogate marker for 90Y therapy.

Methods

Bifunctional chelate, CHX-A″-DTPA was conjugated to cetuximab and radiolabeled with 86Y. In vitro immunoreactivity was assessed in HER1-expressing A431 cells. In vivo biodistribution, PET imaging and noncompartmental pharmacokinetics were performed in mice bearing HER1-expressing human colorectal (LS-174T and HT29), prostate (PC-3 and DU145), ovarian (SKOV3) and pancreatic (SHAW) tumor xenografts. Receptor blockage was demonstrated by coinjection of either 0.1 or 0.2 mg cetuximab.

Results

86Y-CHX-A″-DTPA-cetuximab was routinely prepared with a specific activity of 1.5–2 GBq/mg and in vitro cell-binding in the range 65–75%. Biodistribution and PET imaging studies demonstrated high HER1-specific tumor uptake of the radiotracer and clearance from nonspecific organs. In LS-174T tumor-bearing mice injected with 86Y-CHX-A″-DTPA-cetuximab alone, 86Y-CHX-A″-DTPA-cetuximab plus 0.1 mg cetuximab or 0.2 mg cetuximab, the tumor uptake values at 3 days were 29.3 ± 4.2, 10.4 ± 0.5 and 6.4 ± 0.3%ID/g, respectively, demonstrating dose-dependent blockage of the target. Tumors were clearly visualized 1 day after injecting 3.8–4.0 MBq 86Y-CHX-A″-DTPA-cetuximab. Quantitative PET revealed the highest tumor uptake in LS-174T (29.55 ± 2.67%ID/cm3) and the lowest tumor uptake in PC-3 (15.92 ± 1.55%ID/cm3) xenografts at 3 days after injection. Tumor uptake values quantified by PET were closely correlated (r2 = 0.9, n = 18) with values determined by biodistribution studies.

Conclusion

This study demonstrated the feasibility of preparation of high specific activity 86Y-CHX-A″-DTPA-cetuximab and its application for quantitative noninvasive PET imaging of HER1-expressing tumors. 86Y-CHX-A″-DTPA-cetuximab offers an attractive alternative to previously labeled cetuximab for PET and further investigation for clinical translation is warranted.

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Acknowledgments

This 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 small-animal PET scanner.

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Correspondence to Martin W. Brechbiel.

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Nayak, T.K., Regino, C.A.S., Wong, K.J. et al. PET imaging of HER1-expressing xenografts in mice with 86Y-CHX-A″-DTPA-cetuximab. Eur J Nucl Med Mol Imaging 37, 1368–1376 (2010). https://doi.org/10.1007/s00259-009-1370-z

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