Cetuximab
[CAS# 205923-56-4]

Identification

• Classification: API >> Antineoplastic agents >> Other antineoplastic agents
• Name: Cetuximab
• Synonyms: C 225; EGFR antibody; IMC 225; IMC-C 225
• Molecular Formula: C₆₄₈₄H₁₀₀₄₂N₁₇₃₂O₂₀₂₃S₃₆
• Molecular Weight: 145781.60
• CAS Registry Number: 205923-56-4
• SMILES: C1=CC=C(C=C1)CCON=CC2=CC=NC=C2

Properties

• Density: 1.0±0.1 g/cm³
• Boiling point: 371.9±44.0 ºC 760 mmHg

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P305+P351+P338

Discovory and Applicatios

Cetuximab is a chimeric monoclonal antibody developed for the targeted treatment of certain cancers by inhibiting the epidermal growth factor receptor (EGFR). EGFR is a transmembrane receptor tyrosine kinase that plays a central role in cell proliferation, survival, angiogenesis, and metastasis. Overexpression or dysregulation of EGFR is commonly observed in a variety of malignancies, including colorectal cancer and squamous cell carcinoma of the head and neck. The discovery and clinical application of cetuximab mark a significant advancement in targeted cancer therapy.

The development of cetuximab originated from efforts to design monoclonal antibodies that specifically block the ligand-binding domain of EGFR, thereby preventing the activation of downstream signaling pathways responsible for tumor growth and survival. Cetuximab is a recombinant chimeric antibody composed of the variable regions of a murine antibody (mAb 225) linked to human constant regions. This design was chosen to reduce immunogenicity while preserving high specificity for EGFR.

Cetuximab binds to the extracellular domain of EGFR with high affinity and competitively inhibits the binding of natural ligands such as epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). By blocking ligand-induced activation, cetuximab prevents receptor dimerization, autophosphorylation, and the activation of downstream signaling pathways, including the RAS-RAF-MEK-ERK and PI3K-AKT cascades. These pathways are crucial for cell proliferation and resistance to apoptosis. In addition to its inhibitory effects, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC), further contributing to its antitumor activity.

Cetuximab was first approved for clinical use in patients with EGFR-expressing metastatic colorectal cancer that is wild-type for KRAS. This is due to the finding that mutations in the KRAS gene, which lies downstream of EGFR, render tumor cells unresponsive to EGFR inhibition. Therefore, KRAS genotyping became a critical biomarker for selecting appropriate patients for cetuximab therapy. In colorectal cancer, cetuximab is used as monotherapy or in combination with chemotherapy regimens such as FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) to improve response rates and progression-free survival.

The second major indication for cetuximab is the treatment of squamous cell carcinoma of the head and neck. It is approved for use in combination with radiation therapy for locally or regionally advanced disease and as monotherapy for recurrent or metastatic cases that have progressed on prior platinum-based therapy. In this context, cetuximab improves locoregional control and overall survival, and it is one of the first biologic agents to demonstrate efficacy in head and neck cancer.

Beyond its approved uses, cetuximab has been investigated in a variety of other cancers where EGFR overexpression or dysregulation is present. However, clinical responses in other tumor types have been variable, highlighting the importance of molecular selection and combination strategies. Resistance to cetuximab can develop through multiple mechanisms, including mutations in downstream effectors, activation of alternative signaling pathways, or alterations in receptor trafficking.

Cetuximab is administered intravenously and is generally well tolerated, though it can be associated with adverse effects such as infusion reactions, skin rash, hypomagnesemia, and gastrointestinal disturbances. The skin rash, which often presents as an acneiform eruption, is considered a pharmacodynamic marker of EGFR inhibition and may correlate with therapeutic efficacy.

The discovery and development of cetuximab provided a clear example of rationally designed molecular-targeted therapy, shifting the paradigm of cancer treatment from nonspecific cytotoxic agents to more selective biologics. The experience with cetuximab has informed the development of newer EGFR-targeting agents and has contributed to a deeper understanding of molecular oncology and personalized medicine.