title: Btk-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell-associated damage in IFNα-driven lupus nephritis.
abstract: Systemic lupus erythematosus (SLE) is often associated with exaggerated B cell activation promoting plasma cell generation, immune-complex deposition in the kidney, renal infiltration of myeloid cells, and glomerular nephritis. Type-I IFNs amplify these autoimmune processes and promote severe disease. Bruton's tyrosine kinase (Btk) inhibitors are considered novel therapies for SLE. We describe the characterization of a highly selective reversible Btk inhibitor, G-744. G-744 is efficacious, and superior to blocking BAFF and Syk, in ameliorating severe lupus nephritis in both spontaneous and IFNα-accelerated lupus in NZB/W_F1 mice in therapeutic regimens. Selective Btk inhibition ablated plasmablast generation, reduced autoantibodies, and - similar to cyclophosphamide - improved renal pathology in IFNα-accelerated lupus. Employing global transcriptional profiling of spleen and kidney coupled with cross-species human modular repertoire analyses, we identify similarities in the inflammatory process between mice and humans, and we demonstrate that G-744 reduced gene expression signatures essential for splenic B cell terminal differentiation, particularly the secretory pathway, as well as renal transcriptional profiles coupled with myeloid cell-mediated pathology and glomerular plus tubulointerstitial disease in human glomerulonephritis patients. These findings reveal the mechanism through which a selective Btk inhibitor blocks murine autoimmune kidney disease, highlighting pathway activity that may translate to human SLE.
authors.affiliation: Departments of Immunology Discovery.
authors.forename: Arna
authors.initials: A
authors.lastname: Katewa
authors.affiliation: Departments of Immunology Discovery.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Bioinformatics and Computational Biology.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Hackney
authors.affiliation: Departments of Immunology Discovery.
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.affiliation: Translational Immunology.
authors.forename: Eric
authors.initials: E
authors.lastname: Suto
authors.affiliation: Biomarker Discovery OMNI.
authors.forename: Nandhini
authors.initials: N
authors.lastname: Ramamoorthi
authors.affiliation: Pathology.
authors.forename: Cary D
authors.initials: CD
authors.lastname: Austin
authors.affiliation: Biomarker Development.
authors.forename: Meire
authors.initials: M
authors.lastname: Bremer
authors.affiliation: Drug Metabolism and Pharmacokinetics.
authors.forename: Jacob Zhi
authors.initials: JZ
authors.lastname: Chen
authors.affiliation: Discovery Chemistry, at Genentech, South San Francisco, California, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Crawford
authors.affiliation: Gilead Sciences, Seattle, Washington, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Currie
authors.affiliation: Gilead Sciences, Seattle, Washington, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Blomgren
authors.affiliation: Translational Immunology.
authors.forename: Jason
authors.initials: J
authors.lastname: DeVoss
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: DiPaolo
authors.affiliation: Small Molecule Pharmaceutical Sciences.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hau
authors.affiliation: Biochemical and Cellular Pharmacology.
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Translational Immunology.
authors.forename: Justin
authors.initials: J
authors.lastname: Lesch
authors.affiliation: Biochemical and Cellular Pharmacology.
authors.forename: Laura E
authors.initials: LE
authors.lastname: DeForge
authors.affiliation: Translational Immunology.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Biochemical and Cellular Pharmacology.
authors.forename: Marya
authors.initials: M
authors.lastname: Liimatta
authors.affiliation: Small Molecule Pharmaceutical Sciences.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lubach
authors.affiliation: Biochemical and Cellular Pharmacology.
authors.forename: Sami
authors.initials: S
authors.lastname: McVay
authors.affiliation: Molecular Biology.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Biochemical and Cellular Pharmacology.
authors.forename: Allen
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Departments of Immunology Discovery.
authors.forename: Chungkee
authors.initials: C
authors.lastname: Poon
authors.affiliation: Biochemical and Cellular Pharmacology.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Clinical Pharmacology at Genentech, South San Francisco, California, USA.
authors.forename: Lichuan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Translational Immunology.
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Drug Metabolism and Pharmacokinetics.
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.affiliation: Discovery Chemistry, at Genentech, South San Francisco, California, USA.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Young
authors.affiliation: Biomarker Discovery OMNI.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Townsend
authors.affiliation: Departments of Immunology Discovery.
authors.forename: Karin
authors.initials: K
authors.lastname: Reif
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008814:Mice, Inbred NZB; D022423:Myeloid Cells / Q000378:metabolism*; D010950:Plasma Cells / Q000187:drug effects / Q000473:pathology*
chemical_list: D001323:Autoantibodies; D016898:Interferon-alpha; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse