2. Academic Validation
  3. An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancer

An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancer

  • Biomed Pharmacother. 2022 Jun:150:113051. doi: 10.1016/j.biopha.2022.113051.
Yea Bin Cho 1,  Ji Woong Kim 1,  Kyun Heo 2,  Hyun Jung Kim 3,  Sumi Yun 4,  Hye Seung Lee 5,  Ha Gyeong Shin 6,  Hyunbo Shim 7,  Hanjin Yu 8,  Yun-Hee Kim 9,  Sukmook Lee 10
Affiliations

Affiliations

  • 1 Department of Chemistry, Kookmin University, Seoul 02707, Republic of Korea.
  • 2 Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Antibody Research Institute, Kookmin University, Seoul 02707, Republic of Korea.
  • 3 Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Republic of Korea.
  • 4 Samkwang Medical Laboratories, Department of Diagnostic Pathology, Seoul 06742, Republic of Korea.
  • 5 Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
  • 6 Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Republic of Korea.
  • 7 Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea.
  • 8 HauulBio, Chuncheon, Gangwon 24398, Republic of Korea.
  • 9 Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea; Division of Convergence Technology, Research Institute of National Cancer Center, Goyang 10408, Republic of Korea.
  • 10 Department of Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Department of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Antibody Research Institute, Kookmin University, Seoul 02707, Republic of Korea. Electronic address: [email protected].
PMID: 35658213 DOI: 10.1016/j.biopha.2022.113051
Abstract

Colorectal Cancer (CRC) is one of the life-threatening malignancies worldwide. Thus, novel potential therapeutic targets and therapeutics for the treatment of CRC need to be identified to improve the clinical outcomes of patients with CRC. In this study, we found that glucose-regulated protein 94 (GRP94) is overexpressed in CRC tissues, and its high expression is correlated with increased microvessel density. Next, through phage display technology and consecutive in vitro functional isolations, we generated a novel human monoclonal antibody that specifically targets cell surface GRP94 and shows superior internalizing activity comparable to trastuzumab. We found that this antibody specifically inhibits endothelial cell tube formation and simultaneously promotes the downregulation of GRP94 expression on the endothelial cell surface. Finally, we demonstrated that this antibody effectively suppresses tumor growth and angiogenesis of HCT116 human CRC cells without causing severe toxicity in vivo. Collectively, these findings suggest that cell surface GRP94 is a novel potential anti-angiogenic target in CRC and that antibody targeting of GRP94 on the endothelial cell surface is an effective strategy to suppress CRC tumor angiogenesis.

Keywords

Cell surface GRP94; Downregulation; Fully human antibody; Internalization; Tumor angiogenesis.

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