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Unique drug structure: Do you know the antibody-drug conjugation technology behind Trastuzumab emtansine?
Trastuzumab emtansine (trade name: Kadcyla) is an antibody-drug conjugate consisting of a covalent linkage between the humanized monoclonal antibody trastuzumab (Herceptin) and the cytotoxic drug DM1. The drug is used to treat patients with HER2-positive breast cancer, especially those who have developed resistance to traditional treatments. Its mechanism is different from trastuzumab alone in that it is able to enter cells through receptor-mediated internalization and release DM1 in lysosomes, leading to mitotic arrest and death of tumor cells.
Because this monoclonal antibody targets HER2, which is only overexpressed in cancer cells, the conjugate is able to specifically deliver the cytotoxic DM1 to tumor cells.
Medical purposes
In the United States, Trastuzumab emtansine is approved specifically for the treatment of HER2-positive metastatic breast cancer (mBC). These patients need to receive second-line treatment after receiving trastuzumab and a taxane (such as paclitaxel or docetaxel). According to the EMILIA study, a clinical trial in 991 patients who had already received trastuzumab and a taxane, patients who received trastuzumab emtansine had significantly improved progression-free survival and overall survival.
In clinical trials, the median overall survival for trastuzumab emtansine was 30.9 months, which was significantly higher than the 25.1 months for the combination of lapatinib and capecitabine.
Adverse reactions
In clinical trials, common adverse reactions of trastuzumab emtansine include fatigue, nausea, musculoskeletal pain, thrombocytopenia, etc. Some of the serious adverse events identified in the EMILIA study included liver toxicity and cardiac injury. Nonetheless, trastuzumab emtansine was better tolerated than lapatinib plus capecitabine. Severe toxicities occurred in 43% of patients receiving trastuzumab emtansine and in 59% of patients receiving lapatinib/capecitabine.
In the United States, trastuzumab emtansine carries a black box warning for liver toxicity, heart damage, and fetal harm to pregnant women.
Chemical Properties
As an antibody-drug conjugate, each molecule of trastuzumab emtansine consists of one trastuzumab molecule and several DM1 attachment molecules. SMCC (succinimidyl trans-4-(maleimidylmethyl)cyclohexane-1-carboxylate) is a heterofunctional cross-linking agent that can react with the amino residues of trastuzumab to form a covalent bond between the antibody and DM1. The formation of this structure enables DM1 to effectively bind to cellular microtubules, thereby inhibiting the division of tumor cells.
Historical evolution
Trastuzumab emtansine has been approved for use in the United States since 2013 as a treatment option for HER2-positive metastatic breast cancer. The drug showed significant potential to improve patient survival in clinical trials and received priority review by the FDA. Later, the drug was also approved in the UK and EU. Over time, research and clinical trials of this drug continue, particularly in early-stage breast cancer and other possible indications.
Society and Culture
In the UK, trastuzumab emtansine was not initially recommended by the National Health Service. However, after much negotiation and a secret discount deal, the drug was able to continue to be used in the UK healthcare system. In addition, the drug was renamed "ado-trastuzumab emtansine" in 2013 to avoid possible medication errors.
The drug's development process reflects current evolving trends in cancer treatment, including precision medicine for patient populations and the application of new approaches. So, how many new drugs or therapies may change the landscape of cancer treatment in the future?
