title: Btk inhibition treats TLR7/IFN driven murine lupus.
abstract: Bruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. In the pristane-induced DBA/1 lupus model, Btk inhibition suppressed arthritis, but autoantibodies and the IFN gene signature were not significantly affected; suggesting efficacy was mediated through inhibition of Fc receptors. In vitro studies using primary human macrophages revealed that Btk inhibition can block activation by immune complexes and TLR7 which contributes to tissue damage in SLE. Overall, our results provide translational insight into how Btk inhibition may provide benefit to a variety of SLE patients by affecting both BCR and FcR signaling.
authors.affiliation: TIP Immunology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA. Electronic address: Andrew.bender@emdserono.com.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Bender
authors.affiliation: TIP Immunology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Albertina
authors.initials: A
authors.lastname: Pereira
authors.affiliation: TIP Immunology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: TIP Immunology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Samy
authors.affiliation: TIP Immunology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Medicinal Chemistry, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Lesley
authors.initials: L
authors.lastname: Liu-Bujalski
authors.affiliation: Medicinal Chemistry, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Caldwell
authors.affiliation: Medicinal Chemistry, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Yi-Ying
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Medicinal Chemistry, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.affiliation: Biomolecular Pharmacology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Morandi
authors.affiliation: Biomolecular Pharmacology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Head
authors.affiliation: TIP Immunology Merck Serono, Frankfurter Strasse 250, A031/101 64293 Darmstadt, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Koehler
authors.affiliation: TIP Immunology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Melinda
authors.initials: M
authors.lastname: Genest
authors.affiliation: TIP Immunology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Shinji L
authors.initials: SL
authors.lastname: Okitsu
authors.affiliation: TIP Immunology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Daigen
authors.initials: D
authors.lastname: Xu
authors.affiliation: TIP Immunology, EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Grenningloh
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001168:Arthritis / Q000188:drug therapy / Q000473:pathology; D001323:Autoantibodies / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D033023:Foot Joints / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents; D007370:Interferon Type I / Q000276:immunology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009393:Nephritis / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011507:Proteinuria / Q000188:drug therapy / Q000473:pathology; D013729:Terpenes; D051199:Toll-Like Receptor 7 / Q000276:immunology
chemical_list: D001323:Autoantibodies; D007166:Immunosuppressive Agents; D007370:Interferon Type I; D047428:Protein Kinase Inhibitors; C495348:TLR7 protein, human; D013729:Terpenes; D051199:Toll-Like Receptor 7; C009042:pristane; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse
keywords: Bruton's tyrosine kinase; Interferon; Lupus; TLR7