Quantitative PET of EGFR expression in xenograft-bearing mice using ⁶⁴Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody

Purpose: Cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR) on the surface of cancer cells, was approved by the FDA to treat patients with metastatic colorectal cancer. It is currently also in advanced-stage development for the treatment of several other solid tumors. Here we report for the first time the quantitative positron emission tomography (PET) imaging of EGFR expression in xenograft-bearing mice using ⁶⁴Cu-labeled cetuximab. Methods: We conjugated cetuximab with macrocyclic chelating agent 1,4,7,10-tetraazadodecane-N′,N″N, N‴-tetraacetic acid (DOTA), labeled with ⁶⁴Cu, and tested the resulting ⁶⁴Cu-DOTA-cetuximab in seven xenograft tumor models. The tracer uptake measured by PET was correlated with the EGFR expression quantified by western blotting. The estimated human dosimetry based on the PET data in Sprague-Dawley rats was also calculated. Results: MicroPET imaging showed that ⁶⁴Cu-DOTA-cetuximab had increasing tumor activity accumulation over time in EGFR-positive tumors but relatively low uptake in EGFR-negative tumors at all times examined (<5%ID/g). There was a good correlation (R ² = 0.80) between the tracer uptake (measured by PET) and the EGFR expression level (measured by western blotting). Human dosimetry estimation indicated that the tracer may be safely administered to human patients for tumor diagnosis, with the dose-limiting organ being the liver. Conclusion: The success of EGFR-positive tumor imaging using ⁶⁴Cu-DOTA-cetuximab can be translated into the clinic to characterize the pharmacokinetics, to select the right population of patients for EGFR-targeted therapy, to monitor the therapeutic efficacy of anti-EGFR treatment, and to optimize the dosage of either cetuximab alone or cetuximab in combination with other therapeutic agents.