title: Targeting human vasohibin-2 by a neutralizing monoclonal antibody for anti-cancer treatment.
abstract: There are two members of the vasohibin (VASH) family, VASH1 and VASH2. VASH1 is expressed mainly in endothelial cells to inhibit angiogenesis, whereas VASH2 is expressed mainly in cancer cells to stimulate tumor growth. The aim of the present study was to establish neutralizing monoclonal antibody (mAb) against human VASH2 and apply it as an anti-cancer treatment. We previously raised mAb against several synthetic peptides of hVASH1, and found that one of them exhibited neutralizing activity against hVASH1. Because of the similarity in the amino acid sequences between VASH1 and VASH2, we hypothesized that they shared the bioactive center. When we mutated four amino acids within the region, the mutant VASH2 lost its pro-angiogenic activity. Therefore, we raised mAb against a synthetic peptide overlapping the mutated amino acids of hVASH2, and isolated one clone (1760) that almost completely inhibited the stimulatory effect of hVASH2 on the migration of and tube formation by endothelial cells. When we used this clone 1760 antibody for cancer treatment, the peritoneal injection of it inhibited both tumor growth and angiogenesis in a mouse xenograft model of human cancer cells. In terms of anti-tumor activity, 25 mg/kg of clone 1760 was equivalent to 5 mg/kg of bevacizmab. From these results, we propose the targeting of human VASH2 with neutralizing mAb as a new strategy for cancer treatment.
authors.affiliation: Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.|Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Koyanagi
authors.affiliation: Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Komori
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Saga
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsubara
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sato
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D042501:Angiogenic Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control*; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; C574858:VASH2 protein, human; D000068258:Bevacizumab
keywords: Angiogenesis; monoclonal antibody; mutant protein; synthetic peptide; vasohibin-2