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.
Bibliographical noteFunding Information:
This work was supported by research grants from the Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean government ( NRF-2019M3E5D5065844, NRF-2020M3A9I2107093 ).
We would like to thank the National Research Foundation of the Republic of Korea for its grant support. This work was supported by the Laboratory Animal Research Facility in the National Cancer Center Korea. Graphical abstracts, Fig. 2 , and Fig. 4 were created with BioRender.com .
© 2022 The Authors
- Cell surface GRP94
- Fully human antibody
- Tumor angiogenesis