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

Background: Despite significant advancements in cancer treatment, gastric cancer (GC) continues to have a high incidence and mortality rate. Antibody-drug conjugates (ADCs) are emerging as a viable treatment option for GC. Glypican-1 (GPC1), a cell surface proteoglycan, has garnered interest for its role in tumor growth and its potential as a biomarker. This study evaluated the efficacy of an ADC comprising a humanized anti-GPC1 monoclonal antibody conjugated 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 and mechanism of action of GPC1-ADC were evaluated through comprehensive in vitro assays. In vivo efficacy was further 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 demonstrated promising bystander-killing activity via cancer-associated fibroblasts, highlighting its potential to target the heterogeneous tumor microenvironment characteristic of GC. In vivo, GPC1-ADC significantly inhibited tumor growth and demonstrated substantial therapeutic effects in a peritoneal dissemination model. Immunohistochemical analysis of tumor specimens from GC patients revealed that 90.2% of differentiated types and 66.7% of poorly differentiated types exhibited high GPC1 expression. High GPC1 expression in tumor samples was significantly associated with poorer progression-free and overall survival.

Conclusions: Our findings suggest that GPC1-targeting ADCs represent a promising therapeutic option for GPC1-positive GC.