An anti-ASCT2 monoclonal antibody suppresses gastric cancer growth by inducing oxidative stress and antibody dependent cellular toxicity in preclinical models.

Glutamine is a major nutrient for cancer cells during rapid proliferation. Alanine-serine-cysteine (ASC) transporter 2 (ASCT2; SLC1A5) mediates glutamine uptake in a variety of cancer cells. We previously reported that KM8094, a novel anti-ASCT2 humanized monoclonal antibody, possesses anti-tumor efficacy in gastric cancer patient-derived xenografts. The aim of this study was to investigate the molecular mechanism underlying the effect of KM8094 and to further substantiate the preclinical feasibility of using KM8094 as a potential therapeutic agent against gastric cancer. First, ASCT2 was found to be highly expressed in cancer tissues derived from gastric cancer patients by an immunohistochemical analysis. Next, we performed in vitro studies using multiple gastric cancer cell lines and observed that several gastric cancer cells expressing ASCT2 showed glutamine-dependent cell growth, which was repressed by KM8094. We found that KM8094 inhibited the glutamine uptake, leading to the reduction of glutathione (GSH) level and the elevation of oxidative stress. KM8094 suppressed the cell cycle progression and increased the apoptosis. Furthermore, KM8094 exerted antibody dependent cellular cytotoxicity (ADCC) against human gastric cancer cells in vitro. Finally, in vivo studies revealed that KM8094 suppressed tumor growth in several gastric cancer xenografts. This effect was enhanced by docetaxel, one of the agents commonly used in gastric cancer therapy. Thus, our findings suggest that KM8094 is a potential new therapeutic agent for gastric cancer expressing ASCT2, which blocks the cellular glutamine metabolism and possesses ADCC activity.

Anti-tumor efficacy evaluation of a novel monoclonal antibody targeting neutral amino acid transporter ASCT2 using patient-derived xenograft mouse models of gastric cancer.

ASC amino acid transporter 2 (ASCT2), also known as solute linked carrier family 1 member A5 (SLC1A5) is a Na+-dependent glutamine/neutral amino acid transporter. ASCT2 acts as a high-affinity transporter of L-glutamine (Gln) and has been reported to be up-regulated in a variety of cancerous tissues including stomach, liver, and kidney. In this study, we evaluated anti-tumor efficacy of a novel anti-ASCT2 humanized monoclonal antibody, KM8094, which has a neutralizing activity against glutamine uptake, as a therapeutic antibody against gastric cancer and explored clinical predictive biomarker candidates by utilizing patient-derived xenograft (PDX) mouse models. Anti-tumor efficacy studies revealed that some of the PDX models used were responsive to KM8094 and the others were not. Interestingly, we observed a correlation between anti-tumor efficacy and low antigen expression as well as low basal levels of glutamine uptake, suggesting ASCT2 expression level could be a potential predictive biomarker for KM8094. We then further explored predictive biomarker candidates by multi-omics analysis on gastric cancer PDX mouse models. As a result, a few potential candidates such as TFF2, MUC13, and ANG were selected by gene expression and DNA methylation array analyses. In addition, metabolomics analysis revealed clear differences in intracellular energy status and redox status between responsive and non-responsive PDX models.