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Mol Cancer Ther. 2019 Jul 10. pii: molcanther.0207.2019. doi: 10.1158/1535-7163.MCT-19-0207. [Epub ahead of print]

A Novel Anti-HER2 Antibody-Drug Conjugate XMT-1522 for HER2-Positive Breast And Gastric Cancers Resistant to Trastuzumab Emtansine.

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Translational Cancer Medicine Research Program, University of Helsinki.
Research Programs Unit, Translational Cancer Research and Laboratory Animal Centre, University of Helsinki.
University of Helsinki.
Faculty of Medicine and Health Technology, Tampere University.
Laboratory of Molecular Oncology, University of Helsinki.
Translational Cancer Medicine Research Program and Laboratory Animal Centre, University of Helsinki.
Department of Oncology, Helsinki University Hospital and University of Helsinki.
Laboratory of Molecular Oncology, University of Helsinki


Most patients with HER2-positive breast or gastric cancer exhibit primary or acquired resistance to trastuzumab emtansine (T-DM1), and such patients may have limited therapeutic options. XMT-1522 is a novel anti-HER2 antibody-drug conjugate. We compared XMT-1522 to T-DM1 in preclinical models. The effects of XMT-1522 and T-DM1 on cell survival and apoptosis were compared in six HER2-positive breast cancer or gastric cancer cell lines, of which three lines were T-DM1-sensitive (N-87, OE-19, JIMT-1) and three T-DM1-resistant (RN-87, ROE-19, SNU-216). We compared these agents also in the HER2-negative breast cancer cell line MCF-7, and in mouse RN-87 and JIMT-1 xenograft models. Cell survival was assessed using the AlamarBlue method and apoptosis with the Caspase-Glo 3/7 method. XMT-1522 inhibited the growth of all six HER2-positive cell lines. The proportions of cells that survived XMT-1522 treatment were smaller as compared to T-DM1, particularly in the T-DM1-resistant cell lines. XMT-1522 induced more cell apoptosis compared to T-DM1. While RN-87 and JIMT-1 xenograft tumors progressed on T-DM1 treatment, all tumors responded to XMT-1522, and all but one tumor disappeared during the XMT-1522 treatment. XMT-1522 had a strong anti-tumor effect on RN-87 and JIMT-1 xenografts that progressed on T-DM1. We conclude that XMT-1522 was effective in HER2-positive breast cancer and gastric cancer cell lines resistant to T-DM1, and in xenograft models resistant to T-DM1. The results support the testing of XMT-1522 in clinical trials in patients with HER2-positive cancer.

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