Abstract B069: Humanized cancer-specific anti-HER2 monoclonal antibodies exerted antitumor activities in human breast cancer xenograft models

Abstract Introduction: Developing cancer-specific monoclonal antibodies (mAbs) that exhibit both high antitumor activity and low adverse effects is critical for reducing the risk of adverse events. Recently, we developed an anti-HER2 cancer-specific monoclonal antibody (clone H2CasMab-2, mouse IgG1), which binds to a locally misfolded region of HER2. Methods and Results: We investigated the in vitro and in vivo antitumor efficacy of three versions of H2CasMab-2: the mouse IgG2a (H2CasMab-2-mG2a), the mouse-human chimera (H2CasMab-2-hG1), and the humanized IgG1 (humH2CasMab-2). Every version of H2CasMab-2 showed lower ADCC against the breast cancer cells than trastuzumab, whereas they exhibited significantly higher CDC in breast cancer cells than trastuzumab. Furthermore, they demonstrated in vivo antitumor effects against breast cancer xenografts, which are consistent with those of trastuzumab. In immunohistochemistry, H2Mab-250 demonstrated higher sensitivity against several cancers compared to the universally used anti-HER2 detection kits, such as PATHWAY anti-HER2 (4B5) or HercepTest. Conclusion: These findings highlight the distinct roles of ADCC and CDC in the antitumor effects of H2CasMab-2 and trastuzumab, suggesting a potential direction for the clinical development of H2CasMab-2 for the treatment of HER2-positive tumors. Citation Format: Yukinari Kato, Hiroyuki Suzuki, Mika K. Kaneko. Humanized cancer-specific anti-HER2 monoclonal antibodies exerted antitumor activities in human breast cancer xenograft models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B069.