Biological rationale for HER2/neu (c-erbB2) as a target for monoclonal antibody therapy

Abstract

The physical characteristics of tumor antigens that would make the most ideal targets for antibody therapeutics include cell surface expression; high, stable expression levels in tumor cells; low or absent expression in normal tissues; lack of a soluble form of the antigenic target; and lack of internalization of the antigen/antibody complex. HER2/neu is a 185-kd surface membrane protein that is overexpressed in approximately 25% of human breast cancers due to amplification of the HER2 gene. Overexpression of the gene results in ligand-independent activation of HER2 kinase, causing mitogenic signal transduction and increased cell proliferation. Consequently, patients with this alteration have a worse clinical prognosis. Trastuzumab (Herceptin; Genentech, Inc, So. San Francisco, CA), a humanized anti-HER2 monoclonal antibody, has significant clinical activity against metastatic breast cancers with HER2/neu overexpression, despite the fact that the p185HER2 protein product lacks some of the ideal characteristics of tumor antigens listed above. We propose that the efficacy of trastuzumab may be explained on the basis of its effects on signal transduction, which is independent from its immune mechanism(s) of action. Furthermore, trastuzumab is synergistic with some chemotherapeutic drugs, resulting in improved therapeutic efficacy. Thus, in the case of trastuzumab, a clear distinction may be drawn between the use of monoclonal antibodies as immuneactive agents and their use to achieve a desired cellular/biochemical activity.