Radiolabeled Cetuximab Conjugates for EGFR Targeted Cancer Diagnostics and Therapy

Abstract

The epidermal growth factor receptor (EGFR) has evolved over years into a main molecular target for the treatment of different cancer entities. In this regard, the anti-EGFR antibody cetuximab has been approved alone or in combination with: (a) chemotherapy for treatment of colorectal and head and neck squamous cell carcinoma and (b) with external radiotherapy for treatment of head and neck squamous cell carcinoma. The conjugation of radionuclides to cetuximab in combination with the specific targeting properties of this antibody might increase its therapeutic efficiency. This review article gives an overview of the preclinical studies that have been performed with radiolabeled cetuximab for imaging and/or treatment of different tumor models. A particularly promising approach seems to be the treatment with therapeutic radionuclide-labeled cetuximab in combination with external radiotherapy. Present data support an important impact of the tumor micromilieu on treatment response that needs to be further validated in patients. Another important challenge is the reduction of nonspecific uptake of the radioactive substance in metabolic organs like liver and radiosensitive organs like bone marrow and kidneys. Overall, the integration of diagnosis, treatment and monitoring as a theranostic approach appears to be a promising strategy for improvement of individualized cancer treatment.

Immuno-PET Imaging and Radioimmunotherapy of 64Cu-/177Lu-Labeled Anti-EGFR Antibody in Esophageal Squamous Cell Carcinoma Model

“…For immuno-PET imaging, 64 Cu-labeled antibody is of particular interest because the half-life of 64 Cu (12.7 h) is suitable for targeting and clearance kinetics of antibodies (22). 177 Lu displays low-energy b --emission (497 keV, 78.7%) with minimal tissue penetration, making it suitable for therapy of small and metastatic tumors (23).…”

Combined cetuximab and celecoxib treatment exhibits a synergistic anticancer effect on human oral squamous cell carcinoma in vitro and in vivo

“…To evaluate the change in the apoptotic index, terminal transferase duTP nick end labeling (TuNEL) assay was used. HSC3 cells (1x10 5 cells/ml in 6-well plates) were cultured and treated with their respective half maximal inhibitory concentration (IC 50 ) values for CET, CXB, or both for 48 h. After fixation in 4% paraformaldehyde/PBS (pH 7.2) for 15 min at room temperature and permeabilization in a permeabilization buffer for 2-5 min, the assay was performed on cells on coverslips using a commercially available in situ apoptosis detection kit (In situ Cell Death Detection kit, POD, Roche Diagnostic, Branchburg, NJ, uSA). After applying anti-FITC HRP conjugate at 37˚C for 30 min, diaminobenzidine (DAB) was applied to generate an insoluble colored substrate at the site of DNA fragmentation for 10 min.…”

“…The lower chamber was filled with culture media containing 10% FBS. Cells (3x10 5 ) treated with the indicated drugs in low serum media [3:1 of DMEM:F12 with 0.5% (v/v) FCS and 2% (w/v) L-glutamine] in the inner chamber and KGM was used as a chemo-attractant. Plates were incubated for 16 h at 37˚C, and the invaded cells were observed with an immunofluorescence microscope by counting the cells that had invaded into the bottom of the cell culture insert.…”

“…Recently, novel treatments aimed to target specific molecules, such as epidermal growth factor receptor (EGFR), aberrantly expressed in OSCC, have been investigated and tested in clinical trials at several research centers with promising results (5). For many years, the EGFR has been investigated as a major target for the treatment of uncontrolled tumor growth (6).…”

PET of EGFR with 64Cu‐cetuximab‐F(ab′)2 in mice with head and neck squamous cell carcinoma xenografts

“…In the last decades, molecular imaging has played an important role as a noninvasive technique for patient selection, monitoring and prediction of outcome. EGFR-targeted biomarkers have been widely investigated; cetuximab and its analogues have been labeled with several radionuclides, including 111 In for single photon emission tomography (SPECT) and 124 I, 66 Ga, 89 Zr and 86 Y for positron emission tomography (PET) (9).…”