177Lu-Labeled Antibodies for EGFR-Targeted SPECT/CT Imaging and Radioimmunotherapy in a Preclinical Head and Neck Carcinoma Model

Abstract

Epidermal growth factor receptor (EGFR) has been well characterized as an important target for cancer therapy. Immunotherapy based on EGFR-specific antibodies (e.g., panitumumab and cetuximab) has shown great clinical promise. However, increasing evidence has indicated that only a subgroup of patients receiving these antibodies will benefit from them, and even patients who do initially experience a major response may eventually develop therapeutic resistance. In this study, we investigated whether panitumumab and cetuximab can serve as delivery vehicles for tumor-targeted radionuclide therapy in a preclinical tumor model that did not respond to immunotherapy. The in vitro toxicity and cell binding properties of panitumumab and cetuximab were characterized. Both antibodies were conjugated with 1,4,7,10-tetraazadodecane-N,N′,N″,N‴-tetraacetic acid (DOTA) and radiolabeled with ¹⁷⁷Lu. Small-animal SPECT/CT, biodistribution, and radioimmunotherapy (RIT) studies of ¹⁷⁷Lu-DOTA–panitumumab (¹⁷⁷Lu-Pan) and ¹⁷⁷Lu-DOTA–cetuximab (¹⁷⁷Lu-Cet) were performed in the UM-SCC-22B tumor model. Both ¹⁷⁷Lu-Pan and ¹⁷⁷Lu-Cet exhibited favorable tumor targeting efficacy. The tumor uptake was 20.92 ± 4.45, 26.10 ± 5.18, and 13.27 ± 1.94% ID/g for ¹⁷⁷Lu-Pan, and 15.67 ± 3.84, 15.72 ± 3.49, and 7.82 ± 2.36% ID/g for ¹⁷⁷Lu-Cet at 24, 72, and 120 h p.i., respectively. RIT with a single dose of 14.8 MBq of ¹⁷⁷Lu-Pan or ¹⁷⁷Lu-Cet significantly delayed tumor growth. ¹⁷⁷Lu-Pan induced more effective tumor growth inhibition due to a higher tumor uptake. Our results suggest that panitumumab and cetuximab can function as effective carriers for tumor-targeted delivery of radiation, and that RIT is promising for targeted therapy of EGFR-positive tumors, especially for those tumors that are resistant to antibody-based immunotherapy.