title: Stimulation of angiogenesis and survival of endothelial cells by human monoclonal Tie2 receptor antibody.
abstract: Angiopoietin-1 (Ang1) and its endothelium-specific receptor, tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2), play critical roles in vascular development. Although the Ang1/Tie2 system has been considered a promising target for therapeutic neovascularization, several imitations of large-scale production have hampered the development of recombinant Ang1 for therapeutics. In this study, we produced a fully human agonistic antibody against Tie2, designated 1-4h, and tested the applicability of 1-4h as an alternative to native Ang1 in therapeutic angiogenesis. 1-4h significantly enhanced the phosphorylation of Tie2 in a dose- and time-dependent manner in human Tie2-expressing HEK293 cells and human umbilical vein endothelial cells. Moreover, 1-4h induced the activation of Tie2-mediated intracellular signaling such as AKT, eNOS, MAPK, and Focal Adhesion Kinase p125(FAK). In addition, 1-4h increased the chemotactic motility and capillary-like tube formation of endothelial cells in vitro and enhanced the survival of serum-deprived endothelial cells. Taken together, our data clearly suggest that a human Tie2 agonistic antibody is a potentially useful therapeutic approach for the treatment of several ischemic diseases including delayed-wound healing and ischemic heart and limb diseases.
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors.forename: Byungtae
authors.initials: B
authors.lastname: Hwang
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Jang-Seong
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Moon
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: In Cheul
authors.initials: IC
authors.lastname: Jeung
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors.forename: Na Geum
authors.initials: NG
authors.lastname: Lee
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors.forename: Jongjin
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Systems Immunology, College of Biomedical Science, and Institute of Antibody Research, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Hong
authors.affiliation: Center for Nanosafety Metrology, Korea Research Institute of Standards and Science Daejeon, Republic of Korea.
authors.forename: Young-Lai
authors.initials: YL
authors.lastname: Cho
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Haiyoung
authors.initials: H
authors.lastname: Jung
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Seon-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Hee Gu
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Won Kon
authors.initials: WK
authors.lastname: Kim
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Baek Soo
authors.initials: BS
authors.lastname: Han
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Bae
authors.affiliation: Department of Chemistry, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Sang J
authors.initials: SJ
authors.lastname: Chung
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea. Electronic address: lesach@kribb.re.kr.
authors.forename: Sang Chul
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea. Electronic address: sjick@kribb.re.kr.
authors.forename: Sang Jick
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea; Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea. Electronic address: jekmin@kribb.re.kr.
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Min
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019151:Peptide Library; D011485:Protein Binding / Q000187:drug effects; D042787:Receptor, TIE-2 / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D057127:Single-Chain Antibodies / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D019151:Peptide Library; D057127:Single-Chain Antibodies; D042787:Receptor, TIE-2
keywords: Agonistic antibody; Angiogenesis; Angiopoietin-1; Tie2 receptor