Development of monoclonal antibodies for the treatment of colorectal cancer

Abstract

The timeline for development, types, mechanisms of action, characteristics, and nomenclature of monoclonal antibodies used in cancer treatment; characteristics of the ideal target antigen; and currently available monoclonal antibody products for the treatment of colorectal cancer that target epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) are described. The development of monoclonal antibodies for cancer treatment has been a lengthy process, beginning more than a century ago. Monoclonal antibodies may be unconjugated or conjugated with a potent toxin or radioisotope. The immunogenicity of monoclonal antibodies depends on the species of the source, which is reflected in nomenclature. Progressive reductions in and eventual elimination of the mouse protein content in monoclonal antibodies led to decreases in immunogenicity and increases in plasma half-life as chimeric, humanized, and fully human monoclonal antibodies were developed. The isotype of the monoclonal antibody determines the mechanism of action and half-life while the specificity reflects affinity for the target antigen and cross reactivity with normal cells. The ideal target antigen for the monoclonal antibody is expressed in high numbers only on tumor cells, serves a function essential to cell survival, and is not shed or secreted. In colon cancer, EGFR is an ideal target as it is expressed in 25-77% of colorectal tumors, and it regulates cell division, repair, survival, and metastasis. Of the FDA-approved monoclonal antibodies targeting EGFR, panitumumab has a higher binding affinity, is more potent in inhibiting EGFR, has a longer half-life, and is less immunogenic than cetuximab. Beyond inhibiting cell surface signaling receptors, another approach of monoclonal antibodies in colorectal cancer is interfering with receptor stimuli, such a VEGF. VEGF is a ligand that binds to receptors on endothelial cell surfaces, resulting in angiogenesis. Currently, the only FDA-approved monoclonal antibody targeting VEGF is bevacizumab, which upon binding to the VEGF ligand, inhibits angiogenesis. Monoclonal antibody products currently available for the treatment of colorectal cancer are the result of years of research to identify therapeutic targets and develop safe and effective products. Ongoing research will continue to yield promising new targets and therapies.