Abstract 1559: Assessing efficacy of anti-glypican-1antibody-drug conjugate as potential therapeutic approach for gastric cancer

Abstract Background: Despite significant advancements in cancer treatment, gastric cancer (GC) still has a high incidence and mortality rate. Antibody-drug conjugates (ADCs) are emerging as viable treatment option for GC. We previously identified glypican-1 (GPC1) as a novel cancer antigen in esophageal squamous cell carcinoma using quantitative protein expression profiling analysis focused on plasma membrane proteins, and recognized it as a potential target for ADCs.Glypican-1 (GPC1), a cell surface proteoglycan, has gained interest for its role in tumor growth and as a potential biomarker. This study evaluated the efficacy of an ADC comprising a humanized anti-GPC1 monoclonal antibody with monomethyl auristatin E (GPC1-ADC) to target GPC1 in GC. Methods: GPC1 expression was assessed in GC cell lines and tissues. The cytotoxic efficacy of GPC1-ADC and its mechanism of action were evaluated using comprehensive in vitro assays. Further, in vivo efficacy was assessed in xenograft mouse models, focusing on tumor growth inhibition and its performance against peritoneal dissemination. Results: In vitro, GPC1-ADC exhibited significant cytotoxicity against GPC1-positive cell lines by inducing cell cycle arrest and apoptosis. Additionally, GPC1-ADC exhibited promising bystander-killing activity through cancer-associated fibroblasts, underscoring its potential to target the heterogeneous tumor cell microenvironment characteristics of GC. In vivo, GPC1-ADC significantly inhibited tumor growth, demonstrating a substantial therapeutic effect in a peritoneal dissemination model. Immunohistochemical analysis of tumor specimens from patients with GC revealed that 90.2% of differentiated types and 66.7% of poorly differentiated types exhibit high GPC1 expression. High GPC1 expression in tumor samples was significantly related to poorer clinical outcomes for progression-free and overall survival. Conclusions: GPC1-ADC exerts a direct antitumor effect on GPC1-positive GC cells. Additionally, GPC1-ADC can impact GPC1-negative cells via GPC1-positive stromal cells. This mechanism is likely owing to the characteristics of MMAE, which has a bystander effect as the payload of GPC1-ADC. Our results suggest that GPC1-ADC may be a potential therapeutic candidate for GPC1-positive GC. Citation Format: Yuji Suzuki, Satoshi Serada, Kota Kawabata, Tsuyoshi Takahashi, Yuichiro Doki, Tetsuji Naka. Assessing efficacy of anti-glypican-1antibody-drug conjugate as potential therapeutic approach for gastric cancer [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 1559.