PET imaging of HER1-expressing xenografts in mice with 86Y-CHX-AaEuro3-DTPA-cetuximab

Cetuximab is a recombinant, human/mouse chimeric IgG(1) 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 Y-86-CHX-AaEuro(3)-DTPA-cetuximab as an alternative for imaging HER1-expressing cancer. Y-86-CHX-AaEuro(3)-DTPA-cetuximab can also serve as a surrogate marker for Y-90 therapy. Bifunctional chelate, CHX-AaEuro(3)-DTPA was conjugated to cetuximab and radiolabeled with Y-86. 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. Y-86-CHX-AaEuro(3)-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 Y-86-CHX-AaEuro(3)-DTPA-cetuximab alone, Y-86-CHX-AaEuro(3)-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 Y-86-CHX-AaEuro(3)-DTPA-cetuximab. Quantitative PET revealed the highest tumor uptake in LS-174T (29.55 +/- 2.67%ID/cm(3)) and the lowest tumor uptake in PC-3 (15.92 +/- 1.55%ID/cm(3)) xenografts at 3 days after injection. Tumor uptake values quantified by PET were closely correlated (r (2) = 0.9, n = 18) with values determined by biodistribution studies. This study demonstrated the feasibility of preparation of high specific activity Y-86-CHX-AaEuro(3)-DTPA-cetuximab and its application for quantitative noninvasive PET imaging of HER1-expressing tumors. Y-86-CHX-AaEuro(3)-DTPA-cetuximab offers an attractive alternative to previously labeled cetuximab for PET and further investigation for clinical translation is warranted.