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

• Published in: Biomedicine & pharmacotherapy Vol. 150; p. 113051
• Main Authors: Cho, Yea Bin, Kim, Ji Woong, Heo, Kyun, Kim, Hyun Jung, Yun, Sumi, Lee, Hye Seung, Shin, Ha Gyeong, Shim, Hyunbo, Yu, Hanjin, Kim, Yun-Hee, Lee, Sukmook
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-06-2022; Elsevier
• Subjects: Cell surface GRP94; Downregulation; Fully human antibody; Internalization; Tumor angiogenesis; OCT; FDA; IHC; HRP; IgG; PFA; ICAM-1; GPT; FOLFIRI; CDR; BSA; TBS-T; TUNEL; SPR; ANOVA; FBS; BUN; FOLFOX; Downregulation; PBS; Cell surface GRP94; EGF; VEGF; rhGRP94; TMB; Tumor angiogenesis; TMA; DAPI; ER; hTNFα; GOT; GRP94; PBS-T; mAb; VCAM-1; Fully human antibody; CRC; scFv; TBIL; Internalization; CRE; MVD; SEM; HUVECs; PCR; 5-FU; ELISA; ERK
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.113051

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.
[Display omitted]
•Novel fully human monoclonal antibodies specific to GRP94 are developed using phage display technology.•An internalizing antibody has potent antiangiogenic activity in vitro and in vivo.•The antibody reduces HCT116 tumor growth without severe toxicity in vivo.•Endothelial cell surface GRP94 is a novel potential antiangiogenic target in CRC.•This antibody can be applied pharmaceutically to treat GRP94-mediated CRC.