BACKGROUND AND 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.
BACKGROUND AND 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: M D Fidock; B E Souberbielle; C Laxton; J Rawal; O Delpuech-Adams; T P Corey; P Colman; V Kumar; J B Cheng; K Wright; S Srinivasan; K Rana; C Craig; N Horscroft; M Perros; M Westby; R Webster; E van der Ryst Journal: Clin Pharmacol Ther Date: 2011-03-30 Impact factor: 6.875
Authors: Jongdae Lee; Christina C N Wu; Ki Jeong Lee; Tsung-Hsien Chuang; Kyoko Katakura; Yu-Tsueng Liu; Michael Chan; Rommel Tawatao; Michelle Chung; Carol Shen; Howard B Cottam; Michael M C Lai; Eyal Raz; Dennis A Carson Journal: Proc Natl Acad Sci U S A Date: 2006-01-30 Impact factor: 11.205
Authors: W Nicholas Haining; Jeffrey Davies; Holger Kanzler; Linda Drury; Thomas Brenn; John Evans; Jill Angelosanto; Steven Rivoli; Kate Russell; Suzanne George; Paul Sims; Donna Neuberg; Xiaochun Li; Jeffrey Kutok; Jeffrey Morgan; Patrick Wen; George Demetri; Robert L Coffman; Lee M Nadler Journal: Clin Cancer Res Date: 2008-09-01 Impact factor: 12.531
Authors: Brian C Keller; Cynthia L Johnson; Andrea Kaup Erickson; Michael Gale Journal: Cytokine Growth Factor Rev Date: 2007-08-16 Impact factor: 7.638
Authors: Alejandro Soza; James E Everhart; Marc G Ghany; Edward Doo; Theo Heller; Kittichai Promrat; Yoon Park; T Jake Liang; Jay H Hoofnagle Journal: Hepatology Date: 2002-11 Impact factor: 17.425
Authors: Hélène G Bazin; Laura S Bess; Mark T Livesay; Yufeng Li; Van Cybulski; Shannon M Miller; David A Johnson; Jay T Evans Journal: Bioorg Med Chem Lett Date: 2020-01-22 Impact factor: 2.823
Authors: Ching-Hsin Huang; Natalie Mendez; Oscar Hernandez Echeagaray; Joi Weeks; James Wang; Shiyin Yao; Sarah L Blair; Natalie Gude; William C Trogler; Dennis A Carson; Tomoko Hayashi; Andrew C Kummel Journal: Adv Ther (Weinh) Date: 2020-03-16
Authors: Stephan Menne; Daniel B Tumas; Katherine H Liu; Linta Thampi; Dalal AlDeghaither; Betty H Baldwin; Christine A Bellezza; Paul J Cote; Jim Zheng; Randall Halcomb; Abigail Fosdick; Simon P Fletcher; Stephane Daffis; Li Li; Peng Yue; Grushenka H I Wolfgang; Bud C Tennant Journal: J Hepatol Date: 2015-01-02 Impact factor: 25.083
Authors: Anissa S H Chan; Adria Bykowski Jonas; Xiaohong Qiu; Nadine R Ottoson; Richard M Walsh; Keith B Gorden; Ben Harrison; Peter J Maimonis; Steven M Leonardo; Kathleen E Ertelt; Michael E Danielson; Kyle S Michel; Mariana Nelson; Jeremy R Graff; Myra L Patchen; Nandita Bose Journal: PLoS One Date: 2016-11-03 Impact factor: 3.240
Authors: Jay T Evans; Laura S Bess; Sandra C Mwakwari; Mark T Livesay; Yufeng Li; Van Cybulski; David A Johnson; Hélène G Bazin Journal: ACS Omega Date: 2019-09-10