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 kinase 1 (Flk-1)/
kinase insert domain-containing receptor] play an important role in vascular permeability and
tumor angiogenesis. Previously, we reported on the development of anti-Flk-1 and antikinase insert domain-containing receptor
monoclonal antibodies (mAbs) that potently inhibit
VEGF binding and 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)
Matrigel plug and an
alginate-encapsulated
tumor cell (Lewis lung) assay in C57BL/6 mice. Systemic administration of DC101 every 3 days markedly reduced neovascularization of
Matrigel plugs and
tumor-containing
alginate beads in a dose-dependent fashion. Histological analysis of
Matrigel plugs showed reduced 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 mAb treatment significantly suppressed the growth of primary murine Lewis lung, 4T1 mammary, and
B16 melanoma tumors and growth of Lewis lung
metastases. DC101 also completely inhibited the growth of established epidermoid,
glioblastoma, pancreatic, and renal human
tumor xenografts. Histological examination of anti-Flk-1 mAb-treated
tumors showed evidence of decreased microvessel density,
tumor cell apoptosis, decreased
tumor cell proliferation, and extensive
tumor necrosis. These findings support the conclusion that anti-Flk-1 mAb treatment inhibits
tumor growth by suppression of
tumor-induced neovascularization and demonstrate the potential for therapeutic application of anti-
VEGF receptor antibody in the treatment of angiogenesis-dependent
tumors.