title: Antitumor activity of a novel anti-vascular endothelial growth factor receptor-1 monoclonal antibody that does not interfere with ligand binding.
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.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Graziani
authors.affiliation: Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Ruffini
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Tentori
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Manuel
authors.initials: M
authors.lastname: Scimeca
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Annalisa S
authors.initials: AS
authors.lastname: Dorio
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Atzori
authors.affiliation: Laboratory of Experimental Immunology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Failla
authors.affiliation: National Research Council of Italy (CNR), Institute of Molecular Biology and Pathology, Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Morea
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonanno
authors.affiliation: Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: D'Atri
authors.affiliation: Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome, Italy.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Lacal
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D000074322:Antineoplastic Agents, Immunological; D008024:Ligands; D008565:Membrane Proteins; C098069:PIGF protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: PlGF; VEGFR-1; angiogenesis; melanoma; monocyte/macrophage