TY - JOUR T1 - THE ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-1 MONOCLONAL ANTIBODY D16F7 INHIBITS GLIOMA GROWTH AND ANGIOGENESIS IN VIVO JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.117.244434 SP - jpet.117.244434 AU - Maria Grazia Atzori AU - Lucio Tentori AU - Federica Ruffini AU - Claudia Ceci AU - Elena Bonanno AU - Manuel Scimeca AU - Pedro Miguel Lacal AU - Grazia Graziani Y1 - 2017/01/01 UR - http://jpet.aspetjournals.org/content/early/2017/10/12/jpet.117.244434.abstract N2 - The vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor that does not play a relevant role in physiological angiogenesis in adults, while it is important in tumor angiogenesis. In high-grade glioma VEGFR-1 expression by tumor endothelium and neoplastic cells contributes to the aggressive phenotype. We recently generated an anti-VEGFR-1 monoclonal antibody (mAb) characterized by a novel mechanism of action, since it hampers receptor activation without interfering with ligand binding. The mAb is able to inhibit chemotaxis and extra-cellular matrix invasion of glioma cells in vitro stimulated by VEGF-A, and by the VEGFR-1 selective ligand placental growth factor (PlGF). In this study we have investigated the influence of D16F7 on glioma growth and angiogenesis in vivo using C6 glioma cells transfected with the human VEGFR-1. D16F7 was able to inhibit receptor activation and migration and extra-cellular matrix invasion of C6 cells overexpressing the receptor in response to PlGF and VEGF-A. In nude mice, treatment with 10 and 20 mg/kg D16F7 as single agent was well tolerated and significantly inhibited glioma growth (p<0.001). Strikingly, in an intracranial orthotopic model, mice dosed at 20 mg/kg of D16F7 demonstrated a 65% increase in median survival time compared with vehicle-treated controls (p<0.001) with a high percentage of long-term survivors (46%). These effects were associated with glioma cell apoptosis and decreased tumor-associated vessel formation. Overall, these results highlight the therapeutic potential of D16F7 in glioma treatment, deserving further investigation after a humanization process as single agent or in combination therapies. ER -