Vascular endothelial growth factor receptor 1 (VEGFR-1), a tyrosine kinase receptor, has been shown to be a potential therapeutic target for treatment of tumors and angiogenesis-associated diseases. VEGFR-1 is activated by the ligands VEGF-A, VEGF-B and placental growth factor (PlGF). Studies have shown that VEGFR-1 plays not only an important role in regulating pathological angiogenesis for tumor growth but also a functional role in directly promoting growth of certain cancer cells. Our studies have demonstrated a role of VEGFR-1 in growth of breast cancer in experimental models. Here, we report antitumor activity of a fully human neutralizing monoclonal antibody against human VEGFR-1. . A panel of human monoclonal antibodies specific to VEGFR-1 was generated from the KM strain of human Ig transgenic mice (Medarex). The variable regions of the antibodies were engineered into a high expression vector for production of fully human IgG1 κ antibody. One clone designated IMC-18F1 with high affinity (KD = 54 pM) efficiently blocked binding of PlGF and VEGF to VEGFR-1 with an IC50 of 0.5 and 0.8 nM, respectively. IMC-18F1 inhibited ligand-induced phosphorylation of VEGFR-1 and activation of MAP kinase and Akt downstream signaling pathways in VEGFR-1 expressing endothelial and human breast cancer cell lines. The antibody also inhibited VEGF and PlGF-stimulated growth of breast carcinoma cells in vitro. Treatment of mice with IMC-18F1 significantly suppressed growth of human breast tumors in several xenograft models. Histology analysis showed that the antitumor effect was a result of MAPK and /or Akt signaling inhibition and tumor cell necrosis induced by anti-VEGFR-1 treatment. These results indicate that targeting VEGFR-1 by a specific monoclonal antibody is a promising therapeutic approach to human breast cancer and warrant further investigation.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]