Inhibition of VEGF ‐dependent angiogenesis and tumor angiogenesis by an optimized antibody targeting CLEC 14a

• Published in: Molecular oncology Vol. 12; no. 3; pp. 356 - 372
• Main Authors: Kim, Taek‐Keun, Park, Chang Sik, Jang, Jihye, Kim, Mi Ra, 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: Hoboken John Wiley & Sons, Inc 01-03-2018
• Subjects: Angiogenesis; Antibiotics; Bevacizumab; Cell adhesion & migration; Cloning; Colorectal carcinoma; Complementarity; Deglycosylation; Diabetic retinopathy; Endothelial cells; Enzymes; Epidermal growth factor; Glioma cells; Hepatocellular carcinoma; Immunoglobulins; Lectins; Monoclonal antibodies; Pancreatic cancer; Pancreatic carcinoma; Pharmaceuticals; Proteins; Targeted cancer therapy; Vascular endothelial growth factor; United States > US
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12169

The C‐type lectin‐like domain of
CLEC
14a (
CLEC
14a‐C‐type lectin‐like domain [
CTLD
]) is a key domain that mediates endothelial cell–cell contacts in angiogenesis. However, the role of
CLEC
14a‐
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
CLEC
14a‐
CTLD
and that shows improved stability and homogeneity relative to the parental antibody. We found that this antibody directly inhibits
CLEC
14a‐
CTLD
‐mediated endothelial cell–cell contact and simultaneously downregulates expression of
CLEC
14a 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
SNU
182 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
HCT
116 and bevacizumab‐adapted
HCT
116 human colorectal cancer cells. These findings suggest that antibody targeting of
CLEC
14a‐
CTLD
has the potential to suppress
VEGF
‐dependent angiogenesis and tumor angiogenesis and that
CLEC
14a‐
CTLD
may be a novel anti‐angiogenic target for
VEGF
‐dependent angiogenesis and tumor angiogenesis.