title: Suppression of glomerulonephritis in lupus-prone NZB × NZW mice by RN486, a selective inhibitor of Bruton's tyrosine kinase.
abstract: OBJECTIVE
  Bruton's tyrosine kinase (BTK) plays a critical role in B cell development and function. We recently described a selective BTK inhibitor, RN486, that blocks B cell receptor (BCR) and Fcγ receptor signaling and is efficacious in animal models of arthritis. The aim of this study was to examine the potential efficacy of BTK in systemic lupus erythematosus (SLE), using an NZB × NZW mouse model of spontaneous SLE.
  
  
  METHODS
  Mice received RN486 or its vehicle (administered in chow) at a final concentration of 30 mg/kg for 8 weeks, starting at 32 weeks of age.
  
  
  RESULTS
  The administration of RN486 completely stopped disease progression, as determined by histologic and functional analyses of glomerular nephritis. The efficacy was associated with striking inhibition of B cell activation, as demonstrated by a significant reduction in CD69 expression in response to BCR crosslinking. RN486 markedly reduced the secretion of IgG anti-double-stranded DNA (anti-dsDNA) secretion, as determined by enzyme-linked immunosorbent and enzyme-linked immunospot assays. Flow cytometric analysis demonstrated depletion of CD138(high) B220(low) plasma cells in the spleen. RN486 inhibited secretion of IgG anti-dsDNA but not IgM anti-dsDNA, suggesting that pharmacologic blockade of BTK resembles the reported transgenic expression of low levels of endogenous BTK in B cells. In addition, RN486 may also impact the effector function of autoantibodies, as evidenced by a significant reduction in immune complex-mediated activation of human monocytes in vitro and down-regulation of the expression of macrophage-related and interferon-inducible genes in both the kidneys and spleens of treated mice.
  
  
  CONCLUSIONS
  Collectively, our data suggest that BTK inhibitors may simultaneously target autoantibody-producing and effector cells in SLE, thus constituting a promising therapeutic alternative for this disease.
authors.affiliation: Hoffmann-La Roche, Nutley, New Jersey.
authors.forename: Paola
authors.initials: P
authors.lastname: Mina-Osorio
authors.forename: Jacob
authors.initials: J
authors.lastname: LaStant
authors.forename: Natalie
authors.initials: N
authors.lastname: Keirstead
authors.forename: Toni
authors.initials: T
authors.lastname: Whittard
authors.forename: Julia
authors.initials: J
authors.lastname: Ayala
authors.forename: Stella
authors.initials: S
authors.lastname: Stefanova
authors.forename: Rosario
authors.initials: R
authors.lastname: Garrido
authors.forename: Nena
authors.initials: N
authors.lastname: Dimaano
authors.forename: Holly
authors.initials: H
authors.lastname: Hilton
authors.forename: Mario
authors.initials: M
authors.lastname: Giron
authors.forename: Kai-Yeung
authors.initials: KY
authors.lastname: Lau
authors.forename: Julie
authors.initials: J
authors.lastname: Hang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Postelnek
authors.forename: Yong
authors.initials: Y
authors.lastname: Kim
authors.forename: Soo
authors.initials: S
authors.lastname: Min
authors.forename: Alka
authors.initials: A
authors.lastname: Patel
authors.forename: John
authors.initials: J
authors.lastname: Woods
authors.forename: Meera
authors.initials: M
authors.lastname: Ramanujam
authors.forename: Julie
authors.initials: J
authors.lastname: DeMartino
authors.forename: Satwant
authors.initials: S
authors.lastname: Narula
authors.forename: Daigen
authors.initials: D
authors.lastname: Xu
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D037181:Lectins, C-Type / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008814:Mice, Inbred NZB; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017452:Receptors, IgG / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000936:Antigen-Antibody Complex; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D011505:Protein-Tyrosine Kinases; D017452:Receptors, IgG; D000099192:CD69 Antigens; C000625949:BTK protein, human; C000625951:Btk protein, mouse