anti-tumour effects of a specific anti-adam17 antibody in an ovarian cancer model in vivo抗肿瘤作用的特定anti-adam17抗体卵巢癌模型体内.pdfVIP

Anti-Tumour Effects of a Specific Anti-ADAM17 Antibody in an Ovarian Cancer Model In Vivo 1 . 2. 1 2 Frances M. Richards * , Christopher J. Tape , Duncan I. Jodrell , Gillian Murphy 1 Pharmacology Drug Development Group, Cancer Research UK Cambridge Research Institute, and Department of Oncology, University of Cambridge, Cambridge, United Kingdom, 2 Proteases and Tumour Microenvironment Group, Cancer Research UK Cambridge Research Institute, and Department of Oncology, University of Cambridge, Cambridge, United Kingdom Abstract ADAM 17 (TNF-a 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-a 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-a. In vitro, 200 nM D1(A12) inhibited shedding of ADAM17 substrates TNF-a, TNFR1-a, TGF-a, amphiregulin (AREG), HB-EGF and IL-6Ra, from IGROV1-Luc cells, (4.7 nM IC50 for TNF-a 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