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Preformulation of New Biological Entities
Published in Sandeep Nema, John D. Ludwig, Parenteral Medications, 2019
Riccardo Torosantucci, Vasco Filipe, Jonathan Kingsbury, Atul Saluja, Yatin Gokarn
ADCs are mAbs that are covalently bound to cytotoxic chemicals via (semi)synthetic linkers. Such immune conjugates combine the antitumor potency of highly cytotoxic small-molecule drugs with the high selectivity and favorable pharmacokinetic profile of mAbs. The first ADC to gain FDA approval was gemtuzumab ozogamicin (Mylotarg®) in 2000. It is a recombinant, humanized anti-CD33 mAb covalently linked to the cytotoxic antitumor antibiotic calicheamicin for the treatment of patients with acute myeloid leukemia. Brentuximab vedotin (Adcetris®), approved in 2011, is an anti-CD30 chimeric mAb coupled through a protease-cleavable linker to the antimitotic agent monomethyl auristatin E and is approved to treat relapsed or refractory Hodgkin lymphoma and systemic anaplastic large-cell lymphoma. Ado-trastuzumab emtansine (Kadcyla®), approved in 2013, is a humanized anti-human epidermal growth factor receptor 2 (anti-HER2) mAb covalently linked to the microtubule inhibitory drug DM1 (a derivative of maytansine) and is approved for the treatment of HER2-positive metastatic breast cancer. More than 30 additional ADCs have entered clinical development (all for oncological indications), and there are an additional 30 in clinical trials [37].
Production of Life-Saving Drugs from Marine Sources
Published in Prasenjit Mondal, Ajay K. Dalai, Sustainable Utilization of Natural Resources, 2017
Cytotoxic agent maytansine (52), a benzoansamacrolide first isolated from the bark of the Ethiopian shrub Maytenus ovatus, leads to the formation of derivatives emtansine (54; also known as DM1) and ravtansine (55; also known as DM4) that bind to tubulin near the vinca alkaloid binding site. Trastuzumab emtansine (T-DM1; Roche in partnership with ImmunoGen) is an important ADC of emtansine to trastuzumab through a stable thioether linker that target human epidermal growth factor receptor (HER2; Figure 10.6).
Theranostic approaches in nuclear medicine: current status and future prospects
Published in Expert Review of Medical Devices, 2020
Luca Filippi, Agostino Chiaravalloti, Orazio Schillaci, Roberto Cianni, Oreste Bagni
Another molecular target of utmost importance for the management of BC is represented by HER-2. The HER family includes transmembrane proteins that activate intracellular signaling pathways in response to extracellular signals. The amplification of the HER2 gene has been found correlated with more aggressive tumors, characterized by high rate of proliferation and poor prognosis [80]. In patients submitted to anti-HER-2 therapy, the detection of HER-2 expression is of crucial importance to select those subjects who are more likely to benefit from the aforementioned treatments. In particular, trastuzumab (Herceptin; Genentech, South San Francisco, CA) represented the first humanized MoAb approved by FDA for the treatment of HER-2 positive BC. Trastuzumab, binding to the extracellular domain of HER-2, proved able to suppress tumor growth and proliferation through different mechanisms. Beyond trastuzumab, other drugs targeting HER-2 have been subsequently introduced such as pertuzumab (Perjeta; Genentech, South San Francisco, CA) and trastuzumab emtansine (T-DM1), in which trastuzumab is linked with DM-1, a potent inhibitor of microtubule polymerization [81].