title: Therapy with TLR7 agonists induces lymphopenia: correlating pharmacology to mechanism in a mouse model.
abstract: OBJECTIVE
  Synthetic TLR7 agonists have been proposed as oral replacements for interferonα (IFNα) therapy in the treatment of hepatitis C virus infection. However, adverse effects, such as lymphopenia and cardiovascular irregularities, have been observed in the clinical following treatment with TLR7 agonists. We wished to understand and characterise the relationship between TLR7 agonism and adverse effects.
  
  
  METHODS
  We compared responses to two prototypic TLR7 agonists (Resiquimod: R-848; and PF-04878691) in a mouse model and compared the responses to treatment with IFNα. We measured clinically relevant adverse effects such as lymphopenia and cardiovascular irregularities and related them to plasma drug levels and clinically relevant efficacy biomarkers such as the pro-inflammatory cytokine IP-10, 2'5'OAS and TLR7 receptor expression.
  
  
  RESULTS
  By 2 h post dose all agents had induced a dose-dependent transient lymphopenia. IFNα increased heart rate immediately following dosing, persisting for 5 h, whilst PF-04878691 induced significant reductions in blood pressure. Lymphopenia co-incided with maximum plasma drug levels, raised levels of IP-10 and the auto-induction of TLR7 expression in the blood and lymph nodes. Peak levels of 2'5'OAS occurred at 24 h post-dose and only at doses which also induced lymphopenia.
  
  
  CONCLUSIONS
  We conclude that systemic delivery of TLR7 agonists or IFNα induces similar exaggerated pharmacology, consistent with there being a narrow therapeutic window between efficacy and safety. This clinically validated mouse model will help to investigate whether more potent agonists or optimised dosing schedules, will be successful strategies for targeting TLR7 in patients.
authors.affiliation: Pfizer Ltd, Ramsgate Road, Sandwich, Kent, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Perkins
authors.forename: Tansi
authors.initials: T
authors.lastname: Khodai
authors.forename: Houria
authors.initials: H
authors.lastname: Mechiche
authors.forename: Peter
authors.initials: P
authors.lastname: Colman
authors.forename: Frances
authors.initials: F
authors.lastname: Burden
authors.forename: Carl
authors.initials: C
authors.lastname: Laxton
authors.forename: Nigel
authors.initials: N
authors.lastname: Horscroft
authors.forename: Tom
authors.initials: T
authors.lastname: Corey
authors.forename: Deborah
authors.initials: D
authors.lastname: Rodrigues
authors.forename: Jaiessh
authors.initials: J
authors.lastname: Rawal
authors.forename: Jonathan
authors.initials: J
authors.lastname: Heyen
authors.forename: Mark
authors.initials: M
authors.lastname: Fidock
authors.forename: Mike
authors.initials: M
authors.lastname: Westby
authors.forename: Helen
authors.initials: H
authors.lastname: Bright
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D000634:Aminoquinolines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000378:metabolism; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced* / Q000378:metabolism; D007093:Imidazoles / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D016898:Interferon-alpha / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011804:Quinolines; D013449:Sulfonamides / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D015415:Biomarkers; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D007093:Imidazoles; D016898:Interferon-alpha; C523097:N-(4-(4-amino-2-ethyl-1H-imidazo(4,5c)quinolin-1-yl)butyl)methanesulfonamide; D011804:Quinolines; D013449:Sulfonamides; D051199:Toll-Like Receptor 7; D015088:2',5'-Oligoadenylate Synthetase; C402365:resiquimod