86Y-CHX-A''-Diethylenetriamine pentaacetic acid-cetuximab

Excerpt

Epidermal growth factor (EGF) is a 53-amino acid cytokine (6.2 kDa) that is secreted by ectodermic cells, monocytes, kidneys, and duodenal glands (1). EGF stimulates growth of epidermal and epithelial cells. EGF and at least seven other growth factors and their transmembrane receptor kinases play important roles in cell proliferation, survival, adhesion, migration, and differentiation. The EGF receptor (EGFR) family consists of four transmembrane receptors, including EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), and HER4 (erbB-4) (2). HER1, HER3, and HER4 comprise three major functional domains: an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase domain. No ligand has been clearly identified for HER2; however, HER2 can be activated as a result of ligand binding to other HER receptors with the formation of receptor homodimers and/or heterodimers (3). HER1 as well as HER2 are overexpressed on many solid tumor cells such as breast, non–small-cell lung, head and neck, and colon cancers (4-6). The high levels of HER1 and HER2 expression on cancer cells are associated with a poor prognosis (7-10).

Trastuzumab, a humanized immunoglobulin G₁ (IgG₁) monoclonal antibody against the extracellular domain of recombinant HER2 (11), was labeled as ¹¹¹In-trastuzumab (12-14). C225, an anti-EGFR (HER1), mouse-human chimeric, monoclonal IgG₁ antibody, also known as erbitux and cetuximab, was labeled as ^99mTc-EC-C225 (15, 16) for imaging EGFR expression on solid tumors using single-photon emission computed tomography (SPECT). For evaluation as a positron emission tomography (PET) imaging agent for EGFR, ⁸⁶Y has been attached to cetuximab via CHX-A''-diethylenetriamine pentaacetic acid (CHX-A''-DTPA) to form ⁸⁶Y-CHX-A''-DTPA-cetuximab (17).