Abstract B019: Targeting branched Lewis B/Y glycans with GNX1021: A novel ADC approach for HER2-low gastric cancer

Abstract Background: Advanced gastric cancer remains a major clinical challenge due to limited therapeutic options and frequent resistance to existing treatments. Branched Lewis B/Y (bLeB/Y) is a novel tumor-associated glycan aberrantly expressed on cell surface proteins and lipids. Given glycans’ presentation across diverse membrane receptors, targeting bLeB/Y may offer broader therapeutic coverage and mitigate resistance mechanisms associated with current therapies. GNX1021 is a first-in-class antibody-drug conjugate (ADC) comprising a bLeB/Y-specific monoclonal antibody (GNX102) linked to monomethyl auristatin E (MMAE) via an enzyme-cleavable linker. This study investigates the functional role of bLeB/Y and evaluates the preclinical efficacy of GNX1021 in HER2-low gastric cancer. Methods: bLeB/Y expression was assessed via immunohistochemistry (IHC) on tumor tissue microarrays. Gene expression analysis employed qRT-PCR. GNX102-bLeB/Y interaction was characterized through X-ray crystallography and molecular docking. Protein and lipid carriers of bLeB/Y were identified via immunoprecipitation followed by mass spectrometry and confirmed by immunostaining. GNX1021 was evaluated in vitro for binding, internalization, and cytotoxicity, and in vivo using gastric cancer cell line-derived xenograft (CDX) models, as monotherapy or in combination with trastuzumab deruxtecan (T-DXd). Results: bLeB/Y was highly expressed in gastric, colorectal, and pancreatic cancers. In gastric cancer cells, expression of fucosyltransferases FUT1 and FUT4 strongly correlated with bLeB/Y levels. Structural studies revealed that GNX102 recognizes bLeB/Y through distinct variable regions, enabling specific glycan engagement. bLeB/Y was carried by multiple therapeutic targets involved in key oncogenic pathways, including HER2 and PD-L1. In vitro, GNX102 showed robust internalization and superior cytotoxicity compared to anti-HER2 agents in bLeB/Y-high gastric cancer cells. GNX1021 retained binding and cytotoxic activity in HER2-knockout gastric cancer cells, confirming HER2-independent mechanism. In vivo, single-dose administration of GNX1021 significantly suppressed tumor growth in bLeB/Y-high/HER2-low gastric CDX models. Notably, sequential treatment with T-DXd followed by GNX1021 led to enhanced tumor regression in the xenograft. Conclusion: GNX1021 is a novel glycan-targeting ADC with potent activity against gastric cancer, including HER2-low subtypes. By engaging the bLeB/Y broadly presented on key oncogenic receptors, GNX1021 shows promise as a monotherapy or in combination with protein targeted therapies including HER2-directed agents. These results support its potential to address unmet clinical needs in advanced gastric cancer. Citation Format: Yen-Ying Chen, Chia-Chun Chang, Wei-Chen Hsin, Wen-Han Lee, Kuan-Lun Huang, Hsuan-Hui Wu, Ya-Ni Shen, Chieh-Hsin Chen, Yu-Ting Lin, Ying-Rou Shen, Liang-Yirn Liu, Mei-Chun Yang, Tong-Hsuan Chang. Targeting branched Lewis B/Y glycans with GNX1021: A novel ADC approach for HER2-low gastric cancer [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 B019.