Abstract 355: A novel anti-HER2 antibody that displays superior synergetic effects in Trastuzumab mediated HER2-overexpressing tumor arrest

Abstract

Abstract The majority of patients with metastatic breast cancer on Trastuzumab, an anti-HER2 monoclonal antibody, generally develop resistance to the drug within a year after initiation of the treatment. Therefore, there is an unmet need for a novel agent to treat HER2 overexpressing breast cancers. Here we described a novel anti-HER2 humanized monoclonal antibody, 19H6-hu, which binds to HER2 ECD with high affinity and could inhibit the proliferation of multiple HER2-overexpressing cancer cell lines as a single agent, though, to a lesser degree when compared to Trastuzumab alone. Interestingly, when in combination with Trastuzumab, 19H6-hu exhibited much stronger potency in inhibition of BT474, N87 and SKBR3 cell growth relative to that of Perjeta in combination with Trastuzumab as well as in suppression of tumor growth in vivo when compared to Trastuzumab alone. Alanine scanning demonstrated that the antibody binds to an alpha-helix located within the domain III and in proximity to the domain IV of HER2 ECD, which is different from the known binding sites of Trastuzumab and Perjeta. Western blotting further confirmed that 19H6-hu in combination with Trastuzumab is more efficacious in blocking phosphorylation of ERK and phosphorylation of HER2 at Y1248 when compared to Trastuzumab in combination with Perjeta or applied alone. Thereby, our results highlight the functional variability of HER2 domains and provide a new insight into the design of HER2-targeting agents. Citation Format: Haomin Huang, xuesai zhang, jianhe Chen, Le Zhao, qingrou Li, zhenping zhu. A novel anti-HER2 antibody that displays superior synergetic effects in Trastuzumab mediated HER2-overexpressing tumor arrest [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 355.