Introduction of Cetuximab

Cetuximab (C225, IMC-C225) is an epidermal growth factor receptor (EGFR) binding Fab fragment. Cetuximab is chimerized from the Fv (variable; antigen-binding) regions of the myeloma cell line 225, a mouse monoclonal antibody (mAb) that blocks the ligand-binding site of the EGFR, and a human immunoglobulin G (IgG) constant region (framework) gene segment.

Cetuximab was approved by the Food and Drug Administration (FDA) in March 2006 for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapy. In July 2009, the FDA approved cetuximab for treatment of colon cancer with wild-type KRAS, since it had little or no effect in colorectal tumors harboring a KRAS mutation (this also applied to the EGFR antibody panitumumab). This was the first genetic test to guide treatment of cancer. The KRAS gene encodes a small G protein on the EGFR pathway. Cetuximab and other EGFR inhibitors only work on tumors in which KRAS is not mutated.

Cetuximab was approved by the Food and Drug Administration (FDA) in March 2006 for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in patients who have had prior platinum-based therapy. In July 2009, the FDA approved cetuximab (Erbitux) for treatment of colon cancer with wild-type KRAS, since it had little or no effect in colorectal tumors harboring a KRAS mutation (this also applied to the EGFR antibody panitumumab). This was the first genetic test to guide treatment of cancer. In July 2012, the FDA approved a real time PCR companion diagnostic test for KRAS, the Therascreen® KRAS test. The KRAS gene encodes a small G protein on the EGFR pathway. Cetuximab and other EGFR inhibitors only work on tumors in which KRAS is not mutated.

Mechanism of Action of Cetuximab

Cetuximab is the first of its kind to be approved for treating metastatic colorectal cancer. Cetuximab binds specifically to the EGFR (also known as erbB-1, HER1), which is expressed on both tumor and normal cells and competitively inhibits the binding of its natural ligands such as epidermal growth factor as well as other factors including transforming growth factor-α (TGF-α). Since the expression of EGFR is elevated on many types of solid tumor cells including those from the colon and rectum, Cetuximab’s inhibitory effect is more pronounced on tumor cells than on normal cells. Binding of Cetuximab to EGFR blocks the phosphorylation and activation of receptor-associated tyrosine kinase (normally following the binding of the natural ligands) and consequently leads to the inhibition of tumor cell growth, induction of apoptosis and a reduction in the production of matrix metalloproteinases and vascular endothelial growth factor. EGFR is a member of a subfamily of type I receptor tyrosine kinases that include HER1 (EGFR), HER2, HER3, and HER4. EGFR is actively expressed in some types of tissues including skin and hair follicles, which is the possible basis by which the use of Cetuximab results in the adverse reaction of a skin rash in a large percentage of patients (88%) after receiving the drug. In summary, Cetuximab inhibits receptor tyrosine kinase activity, endocytoses EGFR, inhibits cell cycle regulation, induces apoptosis, inhibits angiogenesis, inhibits invasion/metastasis, and inhibits cell repair or recovery after chemotherapy or radiation.

Fig.1 Mechanism of action of Cetuximab

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