Biological characterization of a novel class of toll-like receptor 7 agonists designed to have reduced systemic activity

被引:30
作者
Biffen, M. [2 ]
Matsui, H. [4 ]
Edwards, S. [2 ]
Leishman, A. J. [2 ]
Eiho, K. [4 ]
Holness, E. [2 ]
Satterthwaite, G. [2 ]
Doyle, I. [2 ]
Wada, H. [3 ]
Fraser, N. J. [2 ]
Hawkins, S. L. [2 ]
Aoki, M. [4 ]
Tomizawa, H. [4 ]
Benjamin, A. D. [2 ]
Takaku, H. [4 ]
McInally, T. [3 ]
Murray, C. M. [1 ]
机构
[1] AstraZeneca Plc, Alderley Pk SK10 4TF, Cheshire, England
[2] AstraZeneca R&D Charnwood, Dept Biosci, Loughborough, Leics, England
[3] AstraZeneca R&D Charnwood, Dept Med Chem, Loughborough, Leics, England
[4] Dainippon Sumitomo Pharma Co Ltd, Pharmacol Res Lab, Osaka, Japan
关键词
allergy; cytokines; lung; reporter cell; mononuclear cells; splenocytes; TLR7; CYTOKINE INDUCTION; MODIFIED ADENINE; IMMUNE-RESPONSE; HUMAN TLR7; ASTHMA; RECOGNITION; DERIVATIVES; PREVALENCE; EFFICACY; CELLS;
D O I
10.1111/j.1476-5381.2011.01790.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
BACKGROUND AND PURPOSE Toll-like receptor 7 (TLR7) agonists have potential in the treatment of allergic diseases. However, the therapeutic utility of current low molecular weight TLR7 agonists is limited by their systemic activity, resulting in unwanted side effects. We have developed a series of TLR7-selective antedrugs, including SM-324405 and AZ12441970, which contain an ester group rapidly cleaved in plasma to reduce systemic exposure. EXPERIMENTAL APPROACH Agonist activity at TLR7 of the parent ester and acid metabolite was assessed in vitro in reporter cells and primary cells from a number of species. Pharmacokinetics following a dose to the lungs was assessed in mice and efficacy evaluated in vivo with a mouse allergic airway model. KEY RESULTS Compounds were selective agonists for TLR7 with no crossover to TLR8 and were metabolically unstable in plasma with the acid metabolite showing substantially reduced activity in a number of assays. The compounds inhibited IL-5 production and induced IFN-alpha, which mediated the inhibition of IL-5. When dosed into the lung the compounds were rapidly metabolized and short-term exposure of the 'antedrug' was sufficient to activate the IFN pathway. AZ12441970 showed efficacy in a mouse allergic airway model with minimal induction of systemic IFN-alpha, consistent with the low plasma levels of compound. CONCLUSIONS AND IMPLICATIONS The biological and metabolic profiles of these TLR7-selective agonist 'antedrug' compounds are consistent with a new class of compound that could be administered locally for the treatment of allergic diseases, while reducing the risk of systemic side effects.
引用
收藏
页码:573 / 586
页数:14
相关论文
共 34 条
[1]   Special Issue: Guide to Receptors and Channels, 5th Edition Abstracts [J].
Alexander, Stephen P. H. ;
Mathie, Alistair ;
Peters, John A. .
BRITISH JOURNAL OF PHARMACOLOGY, 2011, 164 :S1-+
[2]   Environmental exposure to endotoxin and its relation to asthma in school-age children [J].
Braun-Fahrländer, C ;
Riedler, J ;
Herz, U ;
Eder, W ;
Waser, M ;
Grize, L ;
Maisch, S ;
Carr, D ;
Gerlach, F ;
Bufe, A ;
Lauener, RP ;
Schierl, R ;
Renz, H ;
Nowak, D ;
von Mutius, E .
NEW ENGLAND JOURNAL OF MEDICINE, 2002, 347 (12) :869-877
[3]   Chronic asthma-induced airway remodeling is prevented by toll-like receptor-7/8 ligand S28463 [J].
Camateros, Pierre ;
Tamaoka, Meiyo ;
Hassan, Muhannad ;
Marino, Rafael ;
Moisan, Jacques ;
Marion, Dominique ;
Guiot, Marie-Christine ;
Martin, James G. ;
Radzioch, Danuta .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2007, 175 (12) :1241-1249
[4]   Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA [J].
Diebold, SS ;
Kaisho, T ;
Hemmi, H ;
Akira, S ;
Sousa, CRE .
SCIENCE, 2004, 303 (5663) :1529-1531
[5]   First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agionist, to activate innate immune responses in patients with advanced cancer [J].
Dudek, Arkadiusz Z. ;
Yunis, Caria ;
Harrison, Lester I. ;
Kumar, Sandeep ;
Hawkinson, Ronald ;
Cooley, Sarah ;
Vasilakos, John P. ;
Gorski, Kevin S. ;
Miller, Jeffrey S. .
CLINICAL CANCER RESEARCH, 2007, 13 (23) :7119-7125
[6]   The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF-4878691) [J].
Fidock, M. D. ;
Souberbielle, B. E. ;
Laxton, C. ;
Rawal, J. ;
Delpuech-Adams, O. ;
Corey, T. P. ;
Colman, P. ;
Kumar, V. ;
Cheng, J. B. ;
Wright, K. ;
Srinivasan, S. ;
Rana, K. ;
Craig, C. ;
Horscroft, N. ;
Perros, M. ;
Westby, M. ;
Webster, R. ;
van der Ryst, E. .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 2011, 89 (06) :821-829
[7]   Redirection of allergen-specific TH2 responses by a modified adenine through Toll-like receptor 7 interaction and IL-12/IFN release [J].
Fili, Lucia ;
Ferri, Simona ;
Guarna, Francesco ;
Sampognaro, Salvatore ;
Manuelli, Cinzia ;
Liotta, Francesco ;
Cosmi, Lorenzo ;
Matucci, Andrea ;
Vultaggio, Alessandra ;
Annunziato, Francesco ;
Maggi, Enrico ;
Guarna, Antonio ;
Romagnani, Sergio ;
Parronchi, Paola .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2006, 118 (02) :511-517
[8]   Synthetic TLR Agonists reveal functional differences between human TLR7 and TLR8 [J].
Gorden, KB ;
Gorski, KS ;
Gibson, SJ ;
Kedl, RM ;
Kieper, WC ;
Qiu, XH ;
Tomai, MA ;
Alkan, SS ;
Vasilakos, JP .
JOURNAL OF IMMUNOLOGY, 2005, 174 (03) :1259-1268
[9]   Signalling pathways leading to IFN-α production in human plasmacytoid dendritic cell and the possible use of agonists or antagonists of TLR7 and TLR9 in clinical indications [J].
Guiducci, C. ;
Coffman, R. L. ;
Barrat, F. J. .
JOURNAL OF INTERNAL MEDICINE, 2009, 265 (01) :43-57
[10]   Comparison of human B cell activation by TLR7 and TLR9 agonists [J].
Hanten, John A. ;
Vasilakos, John P. ;
Riter, Christie L. ;
Neys, Lori ;
Lipson, Kenneth E. ;
Alkan, Sefik S. ;
Birmachu, Woubalem .
BMC IMMUNOLOGY, 2008, 9 (1)