Inhibition of VEGF‐dependent angiogenesis and tumor angiogenesis by an optimized antibody targeting CLEC14a

• Published in: Molecular oncology Vol. 12; no. 3; pp. 356 - 372
• Main Authors: Kim, Taek‐Keun, Park, Chang Sik, Jang, Jihye, Kim, Mi Ra, Na, Hee‐Jun, Lee, Kangseung, Kim, Hyun Jung, Heo, Kyun, Yoo, Byong Chul, Kim, Young‐Myeong, Lee, Je‐Wook, Kim, Su Jin, Kim, Eun Sung, Kim, Dae Young, Cha, Kiweon, Lee, Tae Gyu, Lee, Sukmook
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-03-2018; John Wiley and Sons Inc; Wiley
• Subjects: angiogenesis; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Communication - drug effects; Cell Communication - immunology; Cell Line, Tumor; CLEC14a; Colorectal cancer; CTLD; Endothelium; Female; HCT116 Cells; Human Umbilical Vein Endothelial Cells; Humans; Immunoglobulin G - immunology; Immunoglobulin G - pharmacology; Lectins; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Monoclonal antibodies; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - immunology; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - immunology; Pancreatic cancer; Parenting; tumor angiogenesis; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; VEGF; Xenograft Model Antitumor Assays; South Korea; CLEC14a; CTLD; VEGF; angiogenesis; tumor angiogenesis
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12169

The C‐type lectin‐like domain of CLEC14a (CLEC14a‐C‐type lectin‐like domain [CTLD]) is a key domain that mediates endothelial cell–cell contacts in angiogenesis. However, the role of CLEC14a‐CTLD in pathological angiogenesis has not yet been clearly elucidated. In this study, through complementarity‐determining region grafting, consecutive deglycosylation, and functional isolation, we generated a novel anti‐angiogenic human monoclonal antibody that specifically targets CLEC14a‐CTLD and that shows improved stability and homogeneity relative to the parental antibody. We found that this antibody directly inhibits CLEC14a‐CTLD‐mediated endothelial cell–cell contact and simultaneously downregulates expression of CLEC14a on the surface of endothelial cells. Using various in vitro and in vivo functional assays, we demonstrated that this antibody effectively suppresses vascular endothelial growth factor (VEGF)‐dependent angiogenesis and tumor angiogenesis of SNU182 human hepatocellular carcinoma, CFPAC‐1 human pancreatic cancer, and U87 human glioma cells. Furthermore, we also found that this antibody significantly inhibits tumor angiogenesis of HCT116 and bevacizumab‐adapted HCT116 human colorectal cancer cells. These findings suggest that antibody targeting of CLEC14a‐CTLD has the potential to suppress VEGF‐dependent angiogenesis and tumor angiogenesis and that CLEC14a‐CTLD may be a novel anti‐angiogenic target for VEGF‐dependent angiogenesis and tumor angiogenesis.
An optimized antibody, deglyco C1 IgG, that targets CLEC14a‐CTLD may be an effective strategy for suppressing CLEC14a‐mediated VEGF‐dependent and tumor angiogenesis, which is closely associated with pathological angiogenesis.