Recent advances in the development of anti-HER2 antibodies and antibody-drug conjugates

Abstract

Human epidermal growth factor receptor 2 (HER2)-targeted therapies have revolutionized the treatment of HER2-positive breast cancer, both in the metastatic and early stage settings. While trastuzumab and lapatinib had been the mainstays of treatment in combination with chemotherapy, innate and acquired resistance to these therapies occur. More recently, two additional HER2-directed therapies have been approved for HER2-positive breast cancer. Pertuzumab is a humanized monoclonal antibody that binds to the extracellular portion of the receptor on a domain distinct from the binding site of trastuzumab. The addition of pertuzumab to trastuzumab results in synergistic tumor cell inhibition and has been shown to significantly improve clinical outcomes for patients with HER2-positive metastatic breast cancer (MBC) compared to trastuzumab plus chemotherapy alone. In addition, ado-trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate linking trastuzumab with the cytotoxic maytansinoid, DM1, is an effective treatment for HER2-positive breast cancer that has progressed on other HER2-directed therapies. Both pertuzumab and T-DM1 are relatively well tolerated. This review presents the mechanisms of action as well as phase I, II and III clinical data describing the safety and efficacy of pertuzumab and T-DM1 for HER2-positive breast cancer.

Keywords: Human epidermal growth factor receptor 2 (HER2); T-DM1; antibody-drug conjugate; breast cancer; pertuzumab.

Figure 1

Schematic of the binding sites on human epidermal growth factor receptor 2 (HER2) for FDA-approved HER2-directed therapies. HER2 is a transmembrane receptor. Activation of HER2 results in cell signaling through the MAPK (RAS, RAF, MEK, and ERK) pathway and PI3K/Akt/mTOR pathways, leading to cellular proliferation. Trastuzumab and T-DM1 binds to the juxtamembrane domain of HER and inhibits cell signaling. T-DM1 is then endocytosed and DM-1 is released within the cell, where it can exert its cytotoxic effect via inhibiting microtubule function. In contrast pertuzumab binds domain II of the extracellular domain of HER2, preventing receptor heterodimerization with HER1, HER3, and HER4, and cell signaling. The tyrosine kinase inhibitor lapatinib binds the intracellular adenosine triphosphate binding domain of HER1 and HER2 and results in inhibition of cell signaling.