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.
Biomed Pharmacother. 2022 Jun;150:113051. doi: 10.1016/j.biopha.2022.113051. Epub 2022 May 10.
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.
结直肠癌（CRC）是全球危及生命的恶性肿瘤之一。因此，需要确定新的潜在治疗靶点和治疗方法来改善 CRC 患者的临床结果。在这项研究中，我们发现葡萄糖调节蛋白 94（GRP94）在 CRC 组织中过度表达，其高表达与微血管密度增加相关。接下来，通过噬菌体展示技术和连续的体外功能分离，我们生成了一种新型的人源单克隆抗体，该抗体特异性靶向细胞表面 GRP94，并显示出与曲妥珠单抗相当的优越内化活性。我们发现该抗体特异性抑制内皮细胞管形成，同时促进内皮细胞表面 GRP94 表达的下调。最后，我们证明该抗体可有效抑制 HCT116 人 CRC 细胞的肿瘤生长和血管生成，而在体内不会引起严重毒性。总之，这些发现表明细胞表面 GRP94 是 CRC 中一种新的潜在抗血管生成靶点，靶向内皮细胞表面的 GRP94 是抑制 CRC 肿瘤血管生成的有效策略。
