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

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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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