PMID- 22792380
OWN - NLM
STAT- MEDLINE
DCOM- 20130110
LR  - 20240210
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 7
DP  - 2012
TI  - Anti-tumour effects of a specific anti-ADAM17 antibody in an ovarian cancer model 
      in vivo.
PG  - e40597
LID - 10.1371/journal.pone.0040597 [doi]
LID - e40597
AB  - ADAM 17 (TNF-alpha converting enzyme, TACE) is a potential target for cancer therapy, 
      but the small molecule inhibitors reported to date are not specific to this ADAM 
      family member. This membrane-bound metalloproteinase is responsible for 
      ectodomain shedding of pathologically significant substrates including TNF-alpha and 
      EGFR ligands. The aim of this study was to evaluate the pharmacokinetics, 
      pharmacodynamics and anti-tumour efficacy of the first specific inhibitor, an 
      anti-human ADAM17 IgG antibody, clone D1(A12). We used intraperitoneal xenografts 
      of the human ovarian cancer cell line IGROV1-Luc in Balb/c nude mice, chosen 
      because it was previously reported that growth of these xenografts is inhibited 
      by knock-down of TNF-alpha. In vitro, 200 nM D1(A12) inhibited shedding of ADAM17 
      substrates TNF-alpha, TNFR1-alpha, TGF-alpha, amphiregulin (AREG), HB-EGF and IL-6Ralpha, from 
      IGROV1-Luc cells, (4.7 nM IC(50) for TNF-alpha shedding). In IGROV1-Luc xenografts in 
      vivo, D1(A12) IgG showed pharmacokinetic properties suitable for efficacy 
      studies, with a single i.p. dose of 10 mg/kg D1(A12) sufficient to maintain IgG 
      plasma and ascites fluid concentrations above 100 nM for more than 7 days. The 
      plasma half life was 8.6 days. Next, an efficacy study was performed, dosing 
      D1(A12) or anti-human TNF-alpha antibody infliximab at 10 mg/kg q7d, quantifying 
      IGROV1-Luc tumour burden by bioluminescence. D1(A12) IgG showed a significant 
      reduction in tumour growth (p = 0.005), 56% of vehicle control. Surprisingly, 
      D1(A12) did not reduce the concentration of circulating human TNF-alpha, suggesting 
      that another enzyme may compensate for inhibition of ADAM17 in vivo (but not in 
      vitro). However, D1(A12) did show clear pharmacodynamic effects in the mice, with 
      significant inhibition of shedding from tumour of ADAM17 substrates TNFR1-alpha, 
      AREG, and TGF-alpha (4-15-fold reductions, p<0.0001 for all three). Thus, D1(A12) has 
      anti-ADAM17 activity in vivo, inhibits shedding of EGFR ligands and has potential 
      for use in EGF ligand-dependent tumours.
FAU - Richards, Frances M
AU  - Richards FM
AD  - Pharmacology & Drug Development Group, Cancer Research UK Cambridge Research 
      Institute, and Department of Oncology, University of Cambridge, Cambridge, United 
      Kingdom. frances.richards@cancer.org.uk
FAU - Tape, Christopher J
AU  - Tape CJ
FAU - Jodrell, Duncan I
AU  - Jodrell DI
FAU - Murphy, Gillian
AU  - Murphy G
LA  - eng
GR  - 15678/CRUK_/Cancer Research UK/United Kingdom
GR  - C96/A8333/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120711
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antineoplastic Agents)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.86 (ADAM17 Protein)
RN  - EC 3.4.24.86 (ADAM17 protein, human)
RN  - EC 3.4.24.86 (Adam17 protein, mouse)
SB  - IM
MH  - ADAM Proteins/*immunology/metabolism
MH  - ADAM17 Protein
MH  - Animals
MH  - Antibodies, Monoclonal/administration & dosage/immunology/*pharmacology
MH  - Antibody Specificity/*immunology
MH  - Antineoplastic Agents/administration & dosage/immunology/*pharmacology
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Ovarian Neoplasms/drug therapy/immunology/*metabolism
MH  - Tumor Burden/drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC3394719
COIS- Competing Interests: The authors have read the journal's policy and have the 
      following conflicts: C.J. Tape and G. Murphy are named as inventors on a patent 
      application US61/438,354, covering the antibody used in these studies. This does 
      not alter the authors' adherence to all the PLoS ONE policies on sharing data and 
      materials. All the authors are employees of the University of Cambridge. The 
      authors declare that no other competing interests exist.
EDAT- 2012/07/14 06:00
MHDA- 2013/01/11 06:00
PMCR- 2012/07/11
CRDT- 2012/07/14 06:00
PHST- 2012/04/11 00:00 [received]
PHST- 2012/06/11 00:00 [accepted]
PHST- 2012/07/14 06:00 [entrez]
PHST- 2012/07/14 06:00 [pubmed]
PHST- 2013/01/11 06:00 [medline]
PHST- 2012/07/11 00:00 [pmc-release]
AID - PONE-D-12-10317 [pii]
AID - 10.1371/journal.pone.0040597 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(7):e40597. doi: 10.1371/journal.pone.0040597. Epub 2012 Jul 11.