ARX788, a novel anti-HER2 antibody-drug conjugate, shows anti-tumor effects in preclinical models of trastuzumab emtansine-resistant HER2-positive breast cancer and gastric cancer. (31st March 2020)

• Record Type: Journal Article
• Authors: Barok, Mark; Le Joncour, Vadim; Martins, Ana; Isola, Jorma; Salmikangas, Marko; Laakkonen, Pirjo; Joensuu, Heikki
• Is Part Of: Cancer letters. Volume 473(2020)
• Page Start: 156
• Page End: 163
• Publication Date: 2020-03-31
• Subjects: Human epidermal growth factor receptor 2 -- T-DM1 -- Xenograft -- Apoptosis -- Drug resistance; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.12.037
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The majority of HER2-positive breast or gastric cancers treated with T-DM1 eventually show resistance to this agent. We compared the effects of T-DM1 and ARX788, a novel anti-HER2 antibody-drug conjugate, on cell growth and apoptosis in HER2-positive breast cancer and gastric cancer cell lines sensitive to T-DM1, gastric cancer cell lines resistant to T-DM1, HER2-negative breast cancer cell lines, and T-DM1-resistant xenograft models. ARX788 was effective in T-DM1-resistant in vitro and in vivo models of HER2-positive breast cancer and gastric cancer. ARX788 showed a pronounced growth inhibitory effect on all five HER2-positive cell lines tested, of which two gastric cancer cell lines had acquired resistance to T-DM1. ARX788 evoked more apoptotic events compared to T-DM1. While JIMT-1 and RN-87 xenograft tumors progressed on T-DM1 treatment, all such tumors responded to ARX788, and four out of the six JIMT-1 tumors and nine out of the twelve RN-87 tumors disappeared during the ARX788 treatment. Mice treated with ARX788 survived longer than those treated with T-DM1. The data support evaluation of ARX788 in patients with HER2-positive breast cancer or gastric cancer including cancers that progress during T-DM1 therapy. Highlights: ARX788 (Ambrx Inc.) is a novel anti-HER2 antibody-drug conjugate. ARX788 had more potent anti-cancer efficacy than T-DM1 on the HER2positive cancer cell lines tested. ARX788 had substantial anti-cancer efficacy in T-DM1-resistant breast cancer and gastric cancer xenograft models. HER2-positive cancer bearing mice treated with ARX788 survived longer than mice treated with T-DM1. ARX788 shows promise for becoming a therapeutic option for patients with HER2-positive breast cancer or gastric cancer.