Anticancer agent - panitumumab
The epidermal growth factor receptor (EGFR) is closely associated with a number of cancerous processes, including angiogenesis, autonomous cell growth and invasion.
The epidermal growth factor receptor (EGFR) is closely associated with a number of cancerous processes, including angiogenesis, autonomous cell growth and invasion.
It is a transmembrane glycoprotein that has an intracellular domain with tyrosine kinase activity for signal transduction, and an extracellular ligand blocking domain. It is this ligand binding that activates the receptor and triggers its signalling pathways, which activate or modulate cellular processes. EGFR is overexpressed in many different malignant cells, so if it were inhibited this could have an anticancer effect.
One way of approaching this inhibition is with a monoclonal antibody designed to interfere with the ligand binding process. This closely targeted approach should minimise the toxicity to healthy cells, and Abgenix has developed the monoclonal antibody panitumumab which is designed to do just this.1
Several Phase II trials have been carried out, including a two-part study in patients with metastatic kidney cancer.2 The subjects were given four dose levels - 1.0, 1.5, 2.0 and 2.5mg/kg of panitumumab in the first part, with patients who had failed or not been able to receive IL2 - interferon alfa therapy being given eight weekly infusions. Those whose disease stabilised or responded continued to receive weekly infusions for eight months, until progression occurred. A total of 88 patients received at least one dose, and 95% had an overexpression of EGFR. All the patients completed the first eight week cycle; three achieved partial and two a minor response, and half the patients achieved disease stabilisation.
A further study looked at its potential use in refractory metastatic colon cancer.3 A total of 148 patients were given 2.5mg/kg a week, and after eight weeks there was a 10% overall response rate, with 38% achieveing stable disease. The median overall survival was eight months, and median overall time to progression two months.
In another trial, an open label dose escalating study, patients with advanced non small cell lung cancer were given sequential weekly doses of 1.0, 2.0 or 2.5 mg/kg, plus standard paclitaxel and carboplatin every three weeks.4 Median overall survival was 17 months.