Abstract 5290: BSI-001, a novel anti-HER2 antibody exhibiting potent synergistic efficacy with trastuzumab

Abstract

Abstract Background: Trastuzumab and pertuzumab are anti-HER2 antibodies that bind to two different epitopes of HER2. Although pertuzumab itself did not exhibit substantial clinical benefit as monotherapy, it was approved to be used in combination with trastuzumab because of its ability to enhance the clinical efficacy of trastuzumab. Currently, the combination of trastuzumab and pertuzumab is being used as first-line treatment for HER2-positive metastatic breast cancer. However, while the combination of trastuzumab and pertuzumab has been effective, there is still opportunity for greater effectiveness by identifying anti-HER2 mAbs that will be better synergistic partners of trastuzumab, allowing for better efficacy and/or broader indications. Methods: A SynAb࣪ Platform was used to identify BSI-001, an anti-HER2 mAb, through trastuzumab-based synergistic functional screening. A competitive ELISA was used to perform epitope binning of the anti-HER2 antibodies. BSI-001 was further characterized in combination with trastuzumab for its bioactivity in vitro, including inhibition of cell proliferation and antigen-mediated internalization of HER2 positive cell lines. The synergistic effect of BSI-001 with trastuzumab was also evaluated in trastuzumab-resistant cell lines. Multiple animal models were then employed to investigate the synergistic antitumor activity of the combination in vivo. Results: BSI-001 is the best functional partner of trastuzumab identified through the SynAb࣪ platform. BSI-001 binds to a unique epitope, distinct from the binding epitopes of trastuzumab and pertuzumab. It exhibits superior bioactivity and efficacy in vitro and in vivo when combined with trastuzumab. The combination of BSI-001 and trastuzumab inhibits HER2-positive cancer cell growth more potently than that of trastuzumab and pertuzumab. The combination of BSI-001 with trastuzumab also shows inhibition of cell growth of the trastuzumab-resistant cell line BT-474 Clone 5, whereas the combination of pertuzumab and trastuzumab did not. In addition, BSI-001 is able to synergize with trastuzumab to promote antigen-antibody internalization. In animal models, BSI-001 demonstrates superior synergistic antitumor activity when combined with trastuzumab as compared to pertuzumab. Summary: The combination of BSI-001 and trastuzumab showed significantly better in vitro and in vivo activity than the combination of trastuzumab and pertuzumab. In addition, because of the activity of the BSI-001/trastuzumab combination in a trastuzumab-resistant cancer cell line, there is the potential for this combination to be used to treat patients with trastuzumab-resistant cancer or patients who experienced relapse following trastuzumab and pertuzumab treatment. Citation Format: Shukai Xia, Zeyu Peng, Xiaoyu Ding, Wanjian Gu, Yujie Zhong, Jinyu Liu, Hongyan Li, Xiaoyao Hao, Xiaodong F. Liu, Mark Z. Ma, Lan Luo, Chunni Zhang, Mingjiu Chen. BSI-001, a novel anti-HER2 antibody exhibiting potent synergistic efficacy with trastuzumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5290.