Antibody targeting of cathepsin S inhibits angiogenesis and synergistically enhances anti-VEGF.
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.
Ward
Claire
C
Drug Discovery, Fusion Antibodies Ltd, Belfast, United Kingdom.
Kuehn
Diana
D
Burden
Roberta E
RE
Gormley
Julie A
JA
Jaquin
Thomas J
TJ
Gazdoiu
Mihaela
M
Small
Donna
D
Bicknell
Roy
R
Johnston
James A
JA
Scott
Christopher J
CJ
Olwill
Shane A
SA
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*
D020533:Angiogenesis Inhibitors; D000906:Antibodies; D042461:Vascular Endothelial Growth Factor A; D002403:Cathepsins; C028217:cathepsin S
Genes Dev. 2006 Mar 1;20(5):543-56
16481467
Oncologist. 2004;9 Suppl 1:36-42
15178814
Clin Cancer Res. 2009 Oct 1;15(19):6042-51
19789302
N Engl J Med. 2004 Jun 3;350(23):2335-42
15175435
Cancer Res. 2002 Jul 15;62(14):4015-22
12124335
Immunity. 1999 Feb;10(2):207-17
10072073
BMC Biochem. 2009 Sep 22;10:23
19772638
J Biol Chem. 2006 Mar 3;281(9):6020-9
16365041
Nat Rev Cancer. 2006 Oct;6(10):764-75
16990854
Cancer Res. 2007 Aug 1;67(15):7378-85
17671208
Nat Rev Clin Oncol. 2009 Aug;6(8):465-77
19581909
Mol Cancer Ther. 2008 Mar;7(3):538-47
18347141
J Invest Dermatol. 1992 Dec;99(6):683-90
1361507
Cancer Res. 2000 Oct 1;60(19):5565-70
11034104
Clin Cancer Res. 2007 Feb 15;13(4):1253-9
17317837
Cancer Cell. 2009 Mar 3;15(3):167-70
19249675
Circ Res. 2003 Mar 21;92(5):493-500
12600886
Cancer Lett. 1997 Nov 11;119(2):227-35
9570376
Cancer Cell. 2009 Mar 3;15(3):220-31
19249680
Nat Rev Clin Oncol. 2009 Jul;6(7):395-404
19424102
Cancer Res. 2006 Jan 1;66(1):198-211
16397233
J Clin Invest. 2006 Oct;116(10):2610-21
17016557
Cell. 2000 Jan 7;100(1):57-70
10647931
Cancer Res. 2008 Jul 15;68(14):5501-4
18632597
Immunity. 1999 Feb;10(2):197-206
10072072
Br J Cancer. 2005 May 9;92(9):1696-701
15841086