Ado-trastuzumab

Compound Name:Ado-trastuzumabMolecular Target:HER-2Molecular Structure:humanized IgG1? mAbLicensed Indication:HER-2 positive metastatic breast cancerManufacturer and/or Distributor:Genentech/; ImmunogenInitial FDA Approval2013SummaryAdo-trastuzumab emtansine is the novel formulation of the anti-HER2 monoclonal antibody trastuzumab (Herceptin®) covalently linked by a thioether to the microtubule inhibitory drug DM1, which is a maytansine derivative. After binding to HER2 on the surface of tumor cells, ado-trastuzumab emtansine is internalized into lysosomes, where the toxic moiety is released. DM1 then binds to tubulin to disrupt microtubule networks, which causes cell cycle arrest and mitotic death. Ado-trastuzumab emtansine also has some of the same in vitro activities as trastuzumab, including inhibition of HER-2 mediated signaling and shedding, and cytotoxicity by ADCC.

 Ado-trastuzumab emtansine is approved for treatment of patients with HER2-positive metastatic breast cancer who have previously been treated with trastuzumab and a taxane, separately or in combination. Subsequent to several phase II trials, approval was based on a single phase III randomized open-label trial comparing ado-trastuzumab emtansine to treatment with lapatinib plus capecitabine. Ado-trastuzumab emtansine provided improved overall survival and progression-free survival, as well as favorable responses by several other parameters. Clinical trials in other cancers, including gastric cancer, are ongoing. Gastric cancers overexpress HER2 15-20% of the time. The ToGA trial demonstrated that patients who where HER2-positive with advanced gastric and gastroesophageal junction adenocarcinoma had a statistically significant improvement in overall survival when given trastuzumab in combination with 5-FU/capecitabine and cisplatin compared to those not given trastuzumab. Work with cell lines also shows potential for use in HER-2 positive bladder cancer. 
Safety concerns include hepatotoxicity, left ventricular dysfunction, embryo-fetal toxicity, infusion reactions, thrombocytopenia, and pulmonary or neurotoxicity.References

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6. Hayashi T, Seiler R, Oo HZ, Jäger W, Moskalev I et al. Targeting HER2 with T-DM1, an Antibody Cytotoxic Drug Conjugate, is Effective in HER2 Over Expressing Bladder Cancer. J Urol 2015 Oct;194(4):1120-31. http://www.ncbi.nlm.nih.gov/pubmed/26047983

7. Yan H, Endo Y, Shen Y, Rotstein D, Dokmanovic M et al. Ado-trastuzumab emtansine targets hepatocytes via human epidermal growth factor receptor 2 to induce hepatotoxicity. Mol Cancer Ther. 2015 Dec 28. pii: molcanther.0580.2015. http://www.ncbi.nlm.nih.gov/pubmed/26712117

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