Inhibition of tumor growth and metastasis by an immunoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular permeability factor121

Abstract

We elucidated the relationship between vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), which is a potent angiogenic factor, and the growth of primary and metastatic tumors using an immunoneutralizing monoclonal antibody against human VEGF/VPF121. The monoclonal antibody, MV303, suppressed the growth of human umbilical vein endothelial cells (HUVEC) induced by VEGF/VPF121 or VEGF/VPF165 but did not inhibit its growth induced by basic fibroblast growth factor. MV303 inhibited the binding of 125I-VEGF/VPF121 to HUVEC. We examined the effects of MV303 on tumor angiogenesis using a membrane chamber packed with the human fibrosarcoma cell line HT-1080 and implanted s.c. into BALB/c mice. The neovascularization induced by HT-1080 was inhibited by the i.v. injection of MV303 at a dose of 100 micrograms/mouse. Furthermore, the growth of solid tumors of s.c. implanted HT-1080 in BALB/c nude mice was almost completely inhibited by the i.v. and s.c. administration of MV303 ten times from day 1 at a dose of 100 micrograms/mouse (T/C values of tumor volume at day 18 were 0.20 and 0.18, respectively). Tumor growth was suppressed when MV303 was administered, even from eight days after tumor inoculation. MV303 suppressed the increase in lung weight caused by experimental metastasis with i.v. inoculation of cultured HT-1080 cells to BALB/c nude mice. The life spans of the mice treated with MV303 were significantly prolonged. These results indicated that VEGF/VPF played an important role in both primary and metastatic tumor growth as a tumor angiogenesis factor. MV303, an immunoneutralizing monoclonal antibody against VEGF/VPF, potently inhibited both primary and metastatic tumor growth with no marked side effects.