Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors

Tumor angiogenesis is mediated by tumor-secreted angiogenic growth factors that interact with their surface receptors expressed on endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor [fetal liver kin ase 1 (Flk-1)/kinase insert domain-containing receptor] play an important r ole in vascular permeability and tumor angiogenesis. Previously, we reporte d on the development of anti-Flk-1 and antikinase insert domain-containing receptor monoclonal antibodies (mAbs) that potently inhibit VEGF binding an d receptor signaling. Here, we report the effect of anti-Flk-1 mAb (DC101) on angiogenesis and tumor growth. Angiogenesis in vivo was examined using a growth factor supplemented (basic fibroblast growth factor + VEGF) Matrige l plug and an alginate-encapsulated tumor cell (Lewis lung) assay in C57BL/ 6 mice. Systemic administration of DC101 every 3 days markedly reduced neov ascularization of Matrigel plugs and tumor-containing alginate beads in a d ose-dependent fashion. Histological analysis of Matrigel plugs showed reduc ed numbers of endothelial cells and vessel structures. Several mouse tumors and human tumor xenografts in athymic mice were used to examine the effect of anti-Flk-1 mAb treatment on tumor angiogenesis and growth. Anti-Flk-1 m Ab treatment significantly suppressed the growth of primary murine Lewis lu ng, 4T1 mammary, and B16 melanoma tumors and growth of Lewis lung metastase s. DC101 also completely inhibited the growth of established epidermoid, gl ioblastoma, pancreatic, and renal human tumor xenografts, Histological exam ination of anti-Flk-1 mAb-treated tumors showed evidence of decreased micro vessel density, tumor cell apoptosis, decreased tumor cell proliferation, a nd extensive tumor necrosis. These findings support the conclusion that ant i-Flk-1 mAb treatment inhibits tumor growth by suppression of tumor-induced neovascularization and demonstrate the potential for therapeutic applicati on of anti-VEGF receptor antibody in the treatment of angiogenesis-dependen t tumors.