Abstract 4553: BSI-128 (AK2024) enhances trastuzumab function and potentiates trastuzumab-deruxtecan activity across HER2-positive preclinical models

Abstract Background: HER2-targeted therapy continues to evolve with the development of synergistic antibody combinations and novel payload-coupled modalities. Pertuzumab, the first approved trastuzumab-efficacy booster, demonstrates clinical benefit when combined with trastuzumab or trastuzumab-deruxtecan (T-Dxd) in HER2-positive breast cancer. BSI-128 (AK2024), a HER2-targeting monoclonal antibody identified through trastuzumab-synergy-based functional screening, has been characterized as a differentiated trastuzumab efficacy enhancer. Here, we further evaluate the synergistic cytotoxicity and anti-tumor activity of BSI-128 in combination with T-Dxd across HER2-positive in vitro and in vivo models. Methods: The binding epitope of BSI-128 was compared with trastuzumab, pertuzumab, and a competing antibody of similar epitope class HLX22 analog (synthetic antibody generated from published Henlius sequence). Trastuzumab-mediated cell binding, HER2 internalization, and antibody-dependent cell-mediated cytotoxicity (ADCC) in the presence of BSI-128 were assessed by flow cytometry, pH-sensitive internalization probes, and ADCC reporter assay. In vitro cytotoxicity assays for BSI-128 ± T-Dxd were performed using a 1:1 antibody ratio. In vivo synergy studies evaluated BSI-128 with sub-efficacious doses of T-Dxd in HER2-positive xenograft models. The efficacy comparisons were performed against pertuzumab and HLX22 analog. Results: BSI-128 engaged a HER2 epitope distinct from trastuzumab and pertuzumab and partially overlapping with the HLX22 analog. Despite epitope proximity, BSI-128 did not block trastuzumab binding, unlike the HLX22 analog. When combined at equal molar ratios, BSI-128 plus trastuzumab induced an approximate 2-fold increase in HER2 internalization compared with trastuzumab alone, and this enhancement exceeded that observed with pertuzumab or HLX22 analog combinations. Trastuzumab-mediated ADCC activity was maintained despite a 50% reduction in trastuzumab concentration when BSI-128 was added. Superior synergy of BSI-128 with trastuzumab relative to pertuzumab and HLX22 analog was confirmed in multiple HER2-positive in vitro and in vivo models. The presence of BSI-128 enhanced T-Dxd in vitro cytotoxicity by 2-fold in HER2-positive cells, whereas pertuzumab did not augment T-Dxd activity. BSI-128 also significantly potentiated the anti-tumor activity of T-Dxd in HER2-positive animal models. Conclusion: These data robustly support BSI-128 as a differentiated trastuzumab-synergy antibody with improved performance relative to pertuzumab and the competing synergy antibody when combined with T-Dxd. These findings support the clinical development of BSI-128 plus T-Dxd for HER2-positive gastric cancer and other T-Dxd-approved indications. BSI-128 is currently being evaluated in a Phase 1 clinical trial. Citation Format: Hui-Han Hu, Yinghui Dou, Hongyan Li, Liansheng Cheng, Jinyu Liu, Li Wei, Wenwen Dai, Daoqin Liu, Hui Wang, Ting Xu, Xiaoyao Hao, Yue Gao, Jinge Zhao, Yi Lu, Mingjiu Chen, Kedan Lin. BSI-128 (AK2024) enhances trastuzumab function and potentiates trastuzumab-deruxtecan activity across HER2-positive preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4553.