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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Targeting cell surface glucose-regulated protein 94 in gastric cancer with an anti-GRP94 human monoclonal antibody

  • Hyun Jung Kim (Department of Biopharmaceutical Chemistry, Kookmin University) ;
  • Yea Bin Cho (Department of Chemistry, Kookmin University) ;
  • Kyun Heo (Department of Biopharmaceutical Chemistry, Kookmin University) ;
  • Ji Woong Kim (Department of Biopharmaceutical Chemistry, Kookmin University) ;
  • Ha Gyeong Shin (Department of Biopharmaceutical Chemistry, Kookmin University) ;
  • Eun-bi Lee (Department of Biopharmaceutical Chemistry, Kookmin University) ;
  • Seong-Min Park (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center) ;
  • Jong Bae Park (Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center) ;
  • Sukmook Lee (Department of Biopharmaceutical Chemistry, Kookmin University)
  • Received : 2023.10.19
  • Accepted : 2024.02.14
  • Published : 2024.04.30
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Abstract

Gastric cancer (GC), a leading cause of cancer-related mortality, remains a significant challenge despite recent therapeutic advancements. In this study, we explore the potential of targeting cell surface glucose-regulated protein 94 (GRP94) with antibodies as a novel therapeutic approach for GC. Our comprehensive analysis of GRP94 expression across various cancer types, with a specific focus on GC, revealed a substantial overexpression of GRP94, highlighting its potential as a promising target. Through in vitro and in vivo efficacy assessments, as well as toxicological analyses, we found that K101.1, a fully human monoclonal antibody designed to specifically target cell surface GRP94, effectively inhibits GC growth and angiogenesis without causing in vivo toxicity. Furthermore, our findings indicate that K101.1 promotes the internalization and concurrent downregulation of cell surface GRP94 on GC cells. In conclusion, our study suggests that cell surface GRP94 may be a potential therapeutic target in GC, and that antibody-based targeting of cell surface GRP94 may be an effective strategy for inhibiting GRP94-mediated GC growth and angiogenesis.

Keywords

Acknowledgement

The authors declare that financial support was received for the research, authorship, and/or publication of this article from the Bio & Medical Technology Development Program of the National Research Foundation of Korea (grant numbers: NRF-2019M3E5D5065844 and NRF-2020M3A9I2107093) and the Korea Health Technology R&D Project of the Korea Health Industry Development Institute (grant number: HI22C0360) funded by the Korean government. The schematic representations in Fig. 3A were created using BioRender (https://www.biorender.com/).

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