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: Kenji Kashima, Miho Watanabe, Yasuko Satoh, Junichi Hata, Nobuya Ishii, Yuko Aoki
• Journal: Cancer science (Cancer Sci) Vol. 103 Issue 12 Pg. 2144-52 (Dec 2012) ISSN: 1349-7006 [Electronic] England
• PMID: 22937829 (Publication Type: Journal Article)
• Copyright: © 2012 Japanese Cancer Association.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neutralizing
• Vascular Endothelial Growth Factor C
• Vascular Endothelial Growth Factor D

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Neutralizing (therapeutic use)
• Female
• Humans
• Lymphatic Metastasis
• Mice
• Mice, Inbred BALB C
• Neuroblastoma (drug therapy, metabolism, secondary)
• Vascular Endothelial Growth Factor C (antagonists & inhibitors, metabolism)
• Vascular Endothelial Growth Factor D (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays