Antitumor activity of a novel anti-vascular endothelial growth factor receptor-1 monoclonal antibody that does not interfere with ligand binding

Grazia Graziani, Federica Ruffini, Lucio Tentori, Manuel Scimeca, Annalisa S. Dorio, Maria Grazia Atzori, Cristina M. Failla, Veronica Morea, Elena Bonanno, Stefania D'Atri, Pedro M. Lacal

Research output: Contribution to journalArticlepeer-review

Abstract

Vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase transmembrane receptor that has also a soluble isoform containing most of the extracellular ligand binding domain (sVEGFR-1). VEGF-A binds to both VEGFR-2 and VEGFR-1, whereas placenta growth factor (PlGF) interacts exclusively with VEGFR-1. In this study we generated an anti-VEGFR-1 mAb (D16F7) by immunizing BALB/C mice with a peptide that we had previously reported to inhibit angiogenesis and endothelial cell migration induced by PlGF. D16F7 did not affect binding of VEGF-A or PlGF to VEGFR-1, thus allowing sVEGFR-1 to act as decoy receptor for these growth factors, but it hampered receptor homodimerization and activation. D16F7 inhibited both the chemotactic response of human endothelial, myelomonocytic and melanoma cells to VEGFR-1 ligands and vasculogenic mimicry by tumor cells. Moreover, D16F7 exerted in vivo antiangiogenic effects in a matrigel plug assay. Importantly, D16F7 inhibited tumor growth and was well tolerated by B6D2F1 mice injected with syngeneic B16F10 melanoma cells. The antitumor effect was associated with melanoma cell apoptosis, vascular abnormalities and decrease of both monocyte/macrophage infiltration and myeloid progenitor mobilization. For all the above, D16F7 may be exploited in the therapy of metastatic melanoma and other tumors or pathological conditions involving VEGFR-1 activation.

Original languageEnglish
Pages (from-to)72868-72885
Number of pages18
JournalOncotarget
Volume7
Issue number45
DOIs
Publication statusPublished - 2016

Keywords

  • Angiogenesis
  • Melanoma
  • Monocyte/macrophage
  • PlGF
  • VEGFR-1

ASJC Scopus subject areas

  • Oncology

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