Monoclonal antibodies to vascular endothelial growth factor-D block its interactions with both VEGF receptor-2 and VEGF receptor-3

Marc G. Achen, Sally Roufail, Teresa Domagala, Bruno Catimel, Edouard C. Nice, Detlef M. Geleick, Roger Murphy, Andrew M. Scott, Carol Caesar, Taija Makinen, Kari Alitalo, Steven A. Stacker

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Abstract

Vascular endothelial growth factor-D (VEGF-D), the most recently discovered mammalian member of the VEGF family, is an angiogenic protein that activates VEGF receptor-2 (VEGFR-2/Flk1/KDR) and VEGFR-3-(Flt4). These receptor tyrosine kinases, localized on vascular and lymphatic endothelial cells, signal for angiogenesis and lymphangiogenesis. VEGF-D consists of a central receptor-binding VEGF homology domain (VHD) and N-terminal and C- terminal propeptides that are cleaved from the VHD to generate a mature, bioactive form consisting of dimers of the VHD. Here we report characterization of mAbs raised to the VHD of human VEGF, D in order to generate VEGF-D antagonists. The mAbs bind the fully processed VHD with high affinity and also bind unprocessed VEGF-D. We demonstrate, using bioassays for the binding and cross-linking of VEGFR-2 and VEGFR-3 and biosensor analysis with immobilized receptors, that one of the mAbs, designated VD1, is able to compete potently with mature VEGF-D for binding to both VEGFR-2 and VEGFR-3 for binding to mature VEGF-D. This indicates that the binding epitopes on VEGF-D for these two receptors may be in close proximity. Furthermore, VD1 blocks the mitogenic response of human microvascular endothelial cells to VEGF-D. The anti-(VEGF-D) mAbs raised to the bioactive region of this growth factor will be powerful tools for analysis of the biological functions of VEGF-D.

Original languageEnglish
Pages (from-to)2505-2515
Number of pages11
JournalEuropean Journal of Biochemistry
Volume267
Issue number9
DOIs
Publication statusPublished - 1 Jan 2000
Externally publishedYes

Keywords

  • Angiogenesis
  • Inhibitor
  • Lymphangiogenesis
  • Monoclonal antibody
  • VEGF-D

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