Epidermal growth factor receptor as a target for therapy with antireceptor monoclonal antibodies

Abstract

The epidermal growth factor (EGF) receptor is a potential target for antitumor therapy. Recent studies from many laboratories have found that this receptor is expressed in high levels on a variety of human tumor cells. Furthermore, the EGF receptor has been implicated in autocrine stimulation of cell growth in a number of experimental studies. We have produced anti-EGF receptor monoclonal antibodies (MAbs), which block the binding of EGF and transforming growth factor alpha (TGF-alpha), and can prevent ligand-stimulated activation of EGF receptor tyrosine kinase. These MAbs have been useful in studies of EGF receptor function. Experiments utilizing the MAbs to block ligand binding have demonstrated that autocrine stimulation of EGF receptor phosphorylation can occur via an extracellular pathway, involving TGF-alpha-mediated activation of EGF receptor on the surface of the cell. The capacity of anti-EGF receptor MAbs to inhibit cell proliferation has provided evidence of an autocrine stimulatory pathway in cultures of malignant human skin, breast, colon, and lung cells. Growth of a variety of human tumor xenografts can be inhibited in situations where autocrine dependency is demonstrable in cell culture. Imaging studies with anti-EGF receptor MAb labeled with indium 111 (111In) demonstrated selective uptake in xenografts expressing high receptor levels. Based on these observations, a phase I trial was carried out with 111In-labeled anti-EGF receptor MAb 225 IgG1 in patients with advanced squamous cell lung carcinoma, a tumor that invariably expresses large numbers of EGF receptors. In the case of squamous lung carcinoma, there is evidence that overexpression of EGF receptors correlates with worse clinical stage and worse prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)