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Ref Type Journal Article
PMID (31292166)
Authors Le Joncour V, Martins A, Puhka M, Isola J, Salmikangas M, Laakkonen P, Joensuu H, Barok M
Title A Novel Anti-HER2 Antibody-Drug Conjugate XMT-1522 for HER2-Positive Breast and Gastric Cancers Resistant to Trastuzumab Emtansine.
Journal Molecular cancer therapeutics
Vol 18
Issue 10
Date 2019 10
URL
Abstract Text 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 with T-DM1, particularly in the T-DM1-resistant cell lines. XMT-1522 induced more cell apoptosis compared with 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 antitumor 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
XMT-1522 HER2 (ERBB2) Antibody 47 XMT-1522 is an antibody-drug conjugate comprising an ERBB2 (HER2)-targeted antibody linked to auristatin, which delivers the cytotoxic agent to Erbb2 (Her2)-expressing tumor cells, potentially resulting in decreased tumor growth (PMID: 31292166).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 positive breast cancer sensitive XMT-1522 Preclinical - Cell line xenograft Actionable In a preclinical study, XMT-1522 demonstrated improved efficacy compared to Kadcyla (ado-trastuzumab emtansine), inhibited growth of Erbb2 (Her2)-positive breast cancer cells in culture, resulted in tumor regression and prolonged survival in cell line xenograft models (PMID: 31292166). 31292166
ERBB2 positive stomach cancer sensitive XMT-1522 Preclinical - Cell line xenograft Actionable In a preclinical study, XMT-1522 demonstrated improved efficacy compared to Kadcyla (ado-trastuzumab emtansine), inhibited growth of Erbb2 (Her2)-positive gastric cancer cell lines in culture, resulted in tumor regression and prolonged survival in cell line xenograft models (PMID: 31292166). 31292166