title: Antibody targeting of cathepsin S inhibits angiogenesis and synergistically enhances anti-VEGF.
abstract: BACKGROUND
  Angiogenesis is a key hallmark of tumourigenesis and its inhibition is a proven strategy for the development of novel anti-cancer therapeutics. An important aspect of early angiogenesis is the co-ordinated migration and invasion of endothelial cells through the hypoxic tumour tissue. Cathepsin S has been shown to play an important role in angiogenesis as has vascular endothelial growth factor (VEGF). We sought to assess the anti-angiogenic effect of Fsn0503, a novel cathepsin S inhibitory antibody, when combined with anti-VEGF on vascular development.
  
  
  RESULTS
  Cathepsin S expression and secretion from endothelial cells was characterised using RT-PCR and western blotting. We further show that cathepsin S promotes pericellular hydrolysis of extracellular matrix components in the tumour microenvironment and facilitates endothelial invasion. The cathepsin S inhibitory antibody, Fsn0503, blocks extracellular proteolysis, inhibiting endothelial invasion and tube formation in cell-based assays. The anti-angiogenic effects of Fsn0503 were also shown in vivo where it significantly retarded the development of vasculature in human xenograft models. Furthermore, when Fsn0503 was combined with an anti-VEGF antibody, a synergistic inhibition of microvascular development was observed.
  
  
  CONCLUSIONS
  Taken together, this data demonstrates that the antibody-mediated targeting of cathepsin S represents a novel method of inhibiting angiogenesis. Furthermore, when used in combination with anti-VEGF therapies, Fsn0503 has the potential to significantly enhance current treatments of tumour neovascularisation and may also be of use in the treatment of other conditions associated with inappropriate angiogenesis.
authors.affiliation: Drug Discovery, Fusion Antibodies Ltd, Belfast, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Ward
authors.forename: Diana
authors.initials: D
authors.lastname: Kuehn
authors.forename: Roberta E
authors.initials: RE
authors.lastname: Burden
authors.forename: Julie A
authors.initials: JA
authors.lastname: Gormley
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jaquin
authors.forename: Mihaela
authors.initials: M
authors.lastname: Gazdoiu
authors.forename: Donna
authors.initials: D
authors.lastname: Small
authors.forename: Roy
authors.initials: R
authors.lastname: Bicknell
authors.forename: James A
authors.initials: JA
authors.lastname: Johnston
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Scott
authors.forename: Shane A
authors.initials: SA
authors.lastname: Olwill
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000494:pharmacology; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*
chemical_list: D020533:Angiogenesis Inhibitors; D000906:Antibodies; D042461:Vascular Endothelial Growth Factor A; D002403:Cathepsins; C028217:cathepsin S
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