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 Geleick,Roger Murphy,Andrew M. Scott,Carol Caesar,Taija Makinen,Kari Alitalo,Steven A. Stacker +11 more
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TLDR
It is demonstrated, using bioassays for the binding and cross-linking of VEGFR-2 and V EGFR-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-2Abstract:
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.read more
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VEGF-D promotes the metastatic spread of tumor cells via the lymphatics.
Steven A. Stacker,Carol Caesar,Megan E. Baldwin,Gillian E. Thornton,Richard A. Williams,Remko Prevo,David A. Jackson,Shin-Ichi Nishikawa,Hajime Kubo,Hajime Kubo,Marc G. Achen +10 more
TL;DR: It is demonstrated that lymphatics can be established in solid tumors and implicates VEGF family members in determining the route of metastatic spread and could be blocked with an antibody specific for V EGF-D.
Journal ArticleDOI
Optical biosensors in drug discovery.
TL;DR: Advances in instrumentation and experimental design have led to the increasing application of optical biosensors in many areas of drug discovery, including target identification, ligand fishing, assay development, lead selection, early ADME and manufacturing quality control.
Journal ArticleDOI
Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF‐C/D receptor VEGFR‐3
Taija Makinen,Tanja Veikkola,Satu Mustjoki,Terhi Karpanen,Bruno Catimel,Edouard C. Nice,Lyn M. Wise,Andrew A. Mercer,Heinrich Kowalski,Dontscho Kerjaschki,Steven A. Stacker,Marc G. Achen,Kari Alitalo +12 more
TL;DR: It is shown that VEGFR‐3 stimulation alone protects the lymphatic endothelial cells from serum deprivation‐induced apoptosis and induces their growth and migration, and defines the critical role of VEGF‐C/VEG FR‐3 signalling in the growth and survival of lymphatichelial cells.
Journal ArticleDOI
Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3.
Taija Makinen,Lotta Jussila,Tanja Veikkola,Terhi Karpanen,Mikko I. Kettunen,Kalevi J. Pulkkanen,Risto A. Kauppinen,David A. Jackson,Hajime Kubo,Shin-Ichi Nishikawa,Seppo Ylä-Herttuala,Kari Alitalo +11 more
TL;DR: It is shown that a soluble form of VEGFR-3 is a potent inhibitor of Vascular endothelial growth factor (VEGF)-C and VEGF-D signaling, and when expressed in the skin of transgenic mice, it inhibits fetal lymphangiogenesis and induces a regression of already formed lymphatic vessels, though the blood vasculature remains normal.
Journal ArticleDOI
Lymphangiogenesis and cancer metastasis.
Steven A. Stacker,Marc G. Achen,Marc G. Achen,Lotta Jussila,Lotta Jussila,Megan E. Baldwin,Megan E. Baldwin,Kari Alitalo,Kari Alitalo +8 more
TL;DR: In this paper, the authors reviewed recent experimental and clinico-pathological data indicating that growth factors that stimulate lymphangiogenesis in tumours are associated with an enhanced metastatic process.
References
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Journal Article
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Journal ArticleDOI
Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo
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