Antibody-Drug Conjugates and T-DM1
AbstractHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer is an aggressive type of breast cancer with an inferior prognosis. Trastuzumab, a human monoclonal anti-HER2 antibody, was the first targeted agent for this breast cancer subtype. However, de novo and acquired trastuzumab resistance does occur, resulting in the need for other HER2-directed therapies. One approach has been the use of antibody drug conjugates (ADCs), which are cytotoxic drugs connected by chemical linkers to monoclonal antibodies that are specific for a tumor-associated antigen. This results in the preferential delivery of a drug to cancer cells while minimizing exposure to normal tissues. Ado-trastuzumab emtansine (T-DM1) is a novel ADC that consists of trastuzumab bound via a thioether linker to the cytotoxic agent, DM1, a highly potent antimitotic drug. Currently, T-DM1 is approved for patients with HER2-positive metastatic breast cancer who have previously received trastuzumab and a taxane, progressed on their most recent treatment in the locally advanced or metastatic setting, or are within 6 months of adjuvant trastuzumab for early-stage disease. It is currently being investigated in the neoadjuvant and adjuvant settings. This article provides a concise review of the clinical development, use, safety, and pharmacokinetics of T-DM1, as well as future research directions of T-DM1 in the field of HER2-directed therapies.
IntroductionHuman epidermal growth factor receptor 2 (HER2)-positive disease accounts for 20% to 25% of breast cancers, as represented by amplification of the HER2 gene and/or HER2 protein overexpression. This breast cancer subtype has an aggressive clinical course and inferior outcome.1,2 Trastuzumab is a humanized monoclonal anti-HER2 antibody that binds to the extracellular domain of HER2 and has significantly improved outcomes for patients with both early-stage and metastatic HER2-positive disease.3-5 Despite these significant advances, both de novo and acquired trastuzumab resistance occurs. Approximately 15% of women develop metastatic breast cancer (MBC) despite trastuzumab-based adjuvant therapy.6 This has led to the development of other HER2-directed therapies. Lapatinib, a potent small molecule dual tyrosine kinase inhibitor of HER2 and epidermal growth factor receptor (EGFR), was approved by the FDA in 2007 either in combination with capecitabine or trastuzumab for patients with HER2-positive MBC following disease progression on trastuzumab.7-10 In 2012, pertuzumab, a monoclonal antibody that binds subdomain II of the HER2 extracellular domain and blocks HER2 dimerization and signaling, was approved in combination with trastuzumab and docetaxel in the first-line setting for HER2-positive MBC (Figure).11,12 Most recently, the FDA provided accelerated drug approval for dual HER2 blockade in the neoadjuvant setting using pertuzumab and trastuzumab in combination with chemotherapy.13,14
Figure. Mechanisms of Action of HER2-Directed Agents for Breast Cancer
Human epidermal growth factor (EGF) receptors HER1, HER2, HER3, and HER4 are receptor tyrosine kinases that are involved in the signal transduction pathways that lead to cell survival and differentiation. Each of these receptors consists of three components: an extracellular binding domain, a transmembrane lipophilic segment, and a functional intracellular tyrosine kinase domain (with the exception of HER3). When a ligand of an EGF receptor binds to the extracellular binding domain, the tyrosine kinase domains are activated by both homodimerization and heterodimerization. The HER2 receptor is an orphan receptor and does not require the binding of a ligand for activation. HER2 is also the preferential dimerization partner of other members of the EGF family, and dimerization can be induced by receptor overexpression and mutation. Homo- and heterodimerization of the HER family leads to phosphorylation of the tyrosine kinase domain and activation of downstream signaling pathway, including the PI3K-AKT-mTOR and the RAF-MEK-MAPK pathways. Downstream effects include survival, proliferation, and increased vascular endothelial growth factor (VEGF). Anti-HER2 strategies include: (A) Trastuzumab is a monoclonal antibody that binds to the extracellular domain IV of the HER2 receptor. (B) Lapatinib is a dual tyrosine kinase inhibitor against HER2 and EGFR (HER1). (C) Pertuzumab is a monoclonal antibody that binds to extracellular domain II of HER2 and inhibits the dimerization of HER2 with other HER family receptors, especially HER3. The HER2-HER3 heterodimer is a strong activator of signaling through the PI3K-AKT-mTOR pathway. (D) T-DM1 is a novel antibody-drug conjugate of trastuzumab and DM1, a derivative of maytansine and a highly potent antimitotic drug. The drug binds to the extracellular domain of HER2, allowing for the selective delivery of DM-1 to HER2-overexpressing cells.