title: Inhibition of lymphatic metastasis in neuroblastoma by a novel neutralizing antibody to vascular endothelial growth factor-D.
abstract: Lymphatic spread is an important clinical determinant in the prognosis of many human cancers. The lymphangiogenic factor vascular endothelial growth factor-D (VEGF-D) is implicated in the promotion of lymphatic metastasis through the development of lymphatic vessels in some human cancers. In this study, we developed an anti-VEGF-D monoclonal antibody, cVE199, and investigated its in vitro properties, in vivo effects against tumors and possible target indications to evaluate its potential as a therapeutic antibody. The cVE199 molecule was revealed to have a specific binding reactivity against human VEGF-D, as well as a specific inhibitory activity against the binding of human VEGF-D to VEGFR-3. In addition, cVE199 was found to inhibit the biological activity of VEGF-D against lymphatic cells in vitro. Because we determined that a neuroblastoma cell line, SK-N-DZ, abundantly expressed VEGF-D, an in vivo efficacy study was performed using a xenograft model of SK-N-DZ. We found that cVE199 significantly decreased lymphatic metastasis of SK-N-DZ as well as lymphangiogenesis in primary lesions. Finally, we investigated VEGF-D expression in human neuroblastoma, finding that the molecule was expressed in 11 of 29 human neuroblastoma specimens (37.9%). In conclusion, we found that a novel anti-VEGF-D monoclonal antibody, cVE199, with specific reactivity against human VEGF-D, prevents lymphatic metastasis of neuroblastoma through the inhibition of lymphangiogenesis in an animal model. In addition, our results show that VEGF-D is expressed in some cases of human neuroblastomas, which suggests that cVE199 is a potential anti-metastasis therapeutic antibody in neuroblastoma treatment.
authors.affiliation: Department 2 of Pharmaceutical Research, Chugai Pharmaceutical Co. Ltd, Kanagawa, Japan. kashimaknj@chugai-pharm.co.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Kashima
authors.forename: Miho
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Satoh
authors.forename: Junichi
authors.initials: J
authors.lastname: Hata
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ishii
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D