Abstract 2932: GNX1021, a novel ADC targeting glycans with branched Lewis B/Y, demonstrated preclinical tumor control activity in gastric cancer models and favorable safety

Background: Branched Lewis B/Y (bLeB/Y) is a unique tumor-associated glycan antigen overexpressed in a wide panel of solid tumors including gastric cancer. GNX1021 is a novel bLeB/Y-targeting ADC, linked to the potent antimitotic agent Monomethyl auristatin E (MMAE) via an enzyme-cleavable linker. The mAb backbone of GNX1021 has established safety profile in Ph1 oncology study. Disease control was maintained over 4 months as stable disease in 4/46 advanced solid tumor patients. This study presents in vitro pharmacodynamics and in vivo anti-tumor activity of GNX1021 in multiple gastric cancer models as well as its safety profile in rats. Methods: Target engagement was verified via ELISA, with detailed characterization of cell-binding, internalization, and cytotoxicity. Prevalence of bLeB/Y expression and other therapeutic targets are assessed through IHC over TMAs. Next, the in vivo efficacy was assessed in cell line-derived xenograft (CDX) models. MMAE-associated PD markers including Ki67 for cell proliferation and cleaved caspase-3 for apoptosis were characterized with IHC in the tumors isolated from CDX models. Nonclinical safety was evaluated in a pilot repeat-dose study of Sprague-Dawley (SD) rats. Results: The mAb of GNX1021 showed specific binding to bLeB/Y glycans without cross-reactivity to other types of glycans in ELISA. Among the positive-stained solid tumors, bLeB/Y showed high prevalence in 50% to 60% of overall gastric tumors tested, whereas HER2 had a limited expression in less than 10% of the same cohorts. In vitro cytotoxicity and internalization of GNX1021 was positively correlated with target expression in gastric cancer cells. Moreover, single administration of GNX1021 at low doses exhibited significant in vivo tumor burden reduction activity in high bLeB/Y-expressing gastric models, with sustained efficacy to the study end. The intratumoral activation of cleaved caspase-3 and down-regulation of Ki67 was observed along with tumor control as expected. Furthermore, hematotoxicity of GNX1021 was not detected with weekly administration at a preclinically efficacious low dose over 4 weeks. A mild reduction in neutrophils and reticulocytes was noted as the weekly dose increased to more than the double, while no detectable lesion in bone marrow was correlated with this observation. No obvious sign of hepatic and renal toxicity was identified. In general, GNX1021 was well tolerated in SD rats. Conclusions: GNX1021, a novel glycan-targeting ADC to branched Lewis B/Y, showed promising preclinical efficacy in gastric cancer models and favorable safety profile in SD rats. Through targeting such a unique glycan, GNX1021 demonstrated strong potential to address gastric cancer patients' unmet medical needs for novel targets. Citation Format: Yen-Ying Chen, Chia-Chun Chang, Wen-Han Lee, Ching-Kuei Chen, Ying-Rou Shen, Yu-Ting Lin, Chong-Wei He, Yu-Jeng Wang, Liang-Yirn Liu, Mei-Chun Yang, Tong-Hsuan Chang. GNX1021, a novel ADC targeting glycans with branched Lewis B/Y, demonstrated preclinical tumor control activity in gastric cancer models and favorable safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2932.