Cu-1,4,7,10-Tetraazacyclododecane-,','','''-tetraacetic acid-panitumumab

Epidermal growth factor (EGF) is a 53-amino-acid cytokine (6.2 kDa) 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 G (IgG) monoclonal antibody against the extracellular domain of recombinant HER2) (11) was labeled as In-trastuzumab (12-14). C225 (an anti-EGFR, mouse-human chimeric, monoclonal IgG antibody, also known as cetuximab) was labeled as Tc-EC-C225 (15, 16) for single-photon emission computed tomography (SPECT) imaging of EGFR expression on solid tumors. However, positron emission tomography (PET) offers better sensitivity, resolution, and quantification than SPECT (17). Cu ( = 12.7 h, β decay) is an attractive radionuclide for labeling cetuximab. Panitimumab has been approved by the United States Food and Drug Administration as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma. For evaluation as a PET imaging agent, Cu was attached to panitumumab 1,4,7,10-tetraazacyclododecane-,','','''-tetraacetic acid (DOTA) to form Cu-DOTA-panitumumab. Niu et al. (18) performed PET imaging studies in nude mice bearing human head and neck squamous cell carcinoma (HNSCC) tumors with different expressions of EGFR and found an unexpected inverse relationship with radioactivity accumulation and EGFR density in the tumors.