The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits glioma growth and angiogenesis in vivo

Maria Grazia Atzori, Lucio Tentori, Federica Ruffini, Claudia Ceci, Elena Bonanno, Manuel Scimeca, Pedro Miguel Lacal, Grazia Graziani

Research output: Contribution to journalArticle

Abstract

The vascular endothelial growth factor (VEGF) receptor-1 (VEGFR-1) is a tyrosine kinase receptor that does not play a relevant role in physiologic angiogenesis in adults, whereas 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 (D16F7 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 extracellular 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 extracellular 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 a single agent was well tolerated and significantly inhibited glioma growth (P < 0.001). Strikingly, in an intracranial orthotopic model, mice dosed with 20 mg/kg D16F7 demonstrated a 65% increase in median survival time compared with vehicletreated controls (P < 0.001) with a high percentage of longterm 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.

Original languageEnglish
Pages (from-to)77-86
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume364
Issue number1
DOIs
Publication statusE-pub ahead of print - Oct 12 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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