![]() With the successful development of linker technology that allows a cytotoxic agent to be stably connected to a monoclonal antibody, the potential use of maytansine was resurrected. It binds tubulin and prevents assembly of microtubules by promoting depolymerization and inhibiting polymerization. Emtansine, also called DM1, is a derivative of maytansine that was originally isolated from an Ethiopian plant, Maytenus ovatus, and shown to have antitumor activities. T-DM1 is an antibody-drug conjugate (ADC) composed of trastuzumab connected via a stable thioether linker (SMCC designated MCC after conjugation) to an average of 3.6 emtansine molecules. The relatively rapid development of this novel drug reflects both a need and an excitement for targeted therapies that spare normal tissues yet provide improved efficacy compared with traditional cytotoxics. T-DMI was granted US Food and Drug Administration (FDA) approval in 2013, only 5 years after the first publication. Preclinical data regarding T-DM1 were published in 2008 and the first clinical trial evaluating it was published in 2010. In contrast to trastuzumab, lapatinib is associated with significant toxicity including diarrhea and rash.Īdo-trastuzumab emtansine (T-DM1) is the first antibody-directed chemotherapy approved for a solid malignancy. Like trastuzumab, single-agent lapatinib induces a response in the minority of patients. The newer orally bioavailable small molecule tyrosine kinase inhibitor lapatinib (Tykerb® GlaxoSmithKline) that targets both HER2 and epidermal growth factor receptor (EGFR, HER1) offers patients with metastatic HER2+ breast cancer a treatment option after progression on trastuzumab-based therapy. In addition, de novo or acquired resistance to trastuzumab eventually occurs in most patients with advanced disease. As a result, trastuzumab is typically combined with chemotherapy to increase efficacy, which also increase toxicity. While trastuzumab is well tolerated, when given as monotherapy it only leads to tumor shrinkage in about 25% of patients. Data are now emerging, however, that show the HER2-targeted monoclonal antibody trastuzumab (Herceptin ®, Genentech, San Francisco, CA, USA) has significantly improved outcomes for patients diagnosed with this subtype of cancer. This genetic alteration has been associated with more aggressive disease behavior and worse clinical outcomes. Roughly a quarter of all breast cancers are distinguished by amplification of the human epidermal growth factor receptor-2 ( HER2) gene, leading to overexpression of the HER2 protein on cancer cells.
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