An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancer
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 (G...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332222004401 |
| _version_ | 1811253554305826816 |
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| author | Yea Bin Cho Ji Woong Kim Kyun Heo Hyun Jung Kim Sumi Yun Hye Seung Lee Ha Gyeong Shin Hyunbo Shim Hanjin Yu Yun-Hee Kim Sukmook Lee |
| author_facet | Yea Bin Cho Ji Woong Kim Kyun Heo Hyun Jung Kim Sumi Yun Hye Seung Lee Ha Gyeong Shin Hyunbo Shim Hanjin Yu Yun-Hee Kim Sukmook Lee |
| author_sort | Yea Bin Cho |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:52:47Z |
| format | Article |
| id | doaj.art-661ee168815b477d9ba998049b21b5b6 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-12T16:52:47Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-661ee168815b477d9ba998049b21b5b62022-12-22T03:24:21ZengElsevierBiomedicine & Pharmacotherapy0753-33222022-06-01150113051An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancerYea Bin Cho0Ji Woong Kim1Kyun Heo2Hyun Jung Kim3Sumi Yun4Hye Seung Lee5Ha Gyeong Shin6Hyunbo Shim7Hanjin Yu8Yun-Hee Kim9Sukmook Lee10Department of Chemistry, Kookmin University, Seoul 02707, Republic of KoreaDepartment of Chemistry, Kookmin University, Seoul 02707, Republic of KoreaDepartment 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 KoreaDepartment of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Republic of Korea; Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Republic of KoreaSamkwang Medical Laboratories, Department of Diagnostic Pathology, Seoul 06742, Republic of KoreaDepartment of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of KoreaDepartment of Biopharmaceutical Chemistry, Kookmin University, Seoul 02707, Republic of KoreaDepartment of Life Science, Ewha Womans University, Seoul 03760, Republic of KoreaHauulBio, Chuncheon, Gangwon 24398, Republic of KoreaDepartment 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 KoreaDepartment 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; Corresponding author at: Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Republic of Korea.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.http://www.sciencedirect.com/science/article/pii/S0753332222004401Cell surface GRP94Tumor angiogenesisFully human antibodyInternalizationDownregulation |
| spellingShingle | Yea Bin Cho Ji Woong Kim Kyun Heo Hyun Jung Kim Sumi Yun Hye Seung Lee Ha Gyeong Shin Hyunbo Shim Hanjin Yu Yun-Hee Kim Sukmook Lee An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancer Biomedicine & Pharmacotherapy Cell surface GRP94 Tumor angiogenesis Fully human antibody Internalization Downregulation |
| title | An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancer |
| title_full | An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancer |
| title_fullStr | An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancer |
| title_full_unstemmed | An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancer |
| title_short | An internalizing antibody targeting of cell surface GRP94 effectively suppresses tumor angiogenesis of colorectal cancer |
| title_sort | internalizing antibody targeting of cell surface grp94 effectively suppresses tumor angiogenesis of colorectal cancer |
| topic | Cell surface GRP94 Tumor angiogenesis Fully human antibody Internalization Downregulation |
| url | http://www.sciencedirect.com/science/article/pii/S0753332222004401 |
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