Mechanism of action of anti-HER2 monoclonal antibodies

The search for new methods of treating cancer, combined with advances in our understanding of carcinogenesis, molecular biology and technology, has resulted in the development of novel biologic agents with proven clinical efficacy. One such agent is trastuzumab (Herceptin), a humanized monoclonal antibody that targets the human epidermal growth factor receptor-2 (HER2). HER2 is a member of a family of receptors that interact with each other and various ligands to stimulate various intracellular signal transduction pathways involved in cell growth control. HER2 is overexpressed in 20%-30% of women with breast cancer and is associated with aggressive tumor characteristics and poor prognosis. Trastuzumab is the first humanized monoclonal antibody to be approved for therapeutic use and the first oncogene-targeted treatment with proven survival benefit in women with HER2-positive metastatic breast cancer. However, its mechanism of action has not been fully characterized and appears to be complex. This paper reviews current knowledge of the mechanism of action of trastuzumab, including HER2 protein downregulation, prevention of HER2-containing heterodimer formation, initiation of G1 arrest and induction of p27, prevention of HER2 cleavage, inhibition of angiogenesis, and induction of immune mechanisms. The significance of these mechanisms for selection of concomitant chemotherapy is also considered.