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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.

Author information

1
Translational Cancer Medicine Research Program, University of Helsinki.
2
Research Programs Unit, Translational Cancer Research and Laboratory Animal Centre, University of Helsinki.
3
University of Helsinki.
4
Faculty of Medicine and Health Technology, Tampere University.
5
Laboratory of Molecular Oncology, University of Helsinki.
6
Translational Cancer Medicine Research Program and Laboratory Animal Centre, University of Helsinki.
7
Department of Oncology, Helsinki University Hospital and University of Helsinki.
8
Laboratory of Molecular Oncology, University of Helsinki barok.mark@gmail.com.

Abstract

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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