Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis.
Autoantibody production and immune complex deposition within the kidney promote renal disease in patients with lupus nephritis. Thus, therapeutics that inhibit these pathways may be efficacious in the treatment of systemic lupus erythematosus. Bruton's tyrosine kinase (BTK) is a critical signaling component of both BCR and FcR signaling. We sought to assess the efficacy of inhibiting BTK in the development of lupus-like disease, and in this article describe (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-[2,4-difluorophenoxy]phenyl)-1H-pyrazole-4-carboxamide (PF-06250112), a novel highly selective and potent BTK inhibitor. We demonstrate in vitro that PF-06250112 inhibits both BCR-mediated signaling and proliferation, as well as FcR-mediated activation. To assess the therapeutic impact of BTK inhibition, we treated aged NZBxW_F1 mice with PF-06250112 and demonstrate that PF-06250112 significantly limits the spontaneous accumulation of splenic germinal center B cells and plasma cells. Correspondingly, anti-dsDNA and autoantibody levels were reduced in a dose-dependent manner. Moreover, administration of PF-06250112 prevented the development of proteinuria and improved glomerular pathology scores in all treatment groups. Strikingly, this therapeutic effect could occur with only a modest reduction observed in anti-dsDNA titers, implying a critical role for BTK signaling in disease pathogenesis beyond inhibition of autoantibody production. We subsequently demonstrate that PF-06250112 prevents proteinuria in an FcR-dependent, Ab-mediated model of glomerulonephritis. Importantly, these results highlight that BTK inhibition potently limits the development of glomerulonephritis by impacting both cell- and effector molecule-mediated pathways. These data provide support for evaluating the efficacy of BTK inhibition in systemic lupus erythematosus patients.
Immunoscience, Pfizer Research, Cambridge, MA 02140;
Andrew L
AL
Rankin
Nilufer
N
Seth
Sean
S
Keegan
Tatyana
T
Andreyeva
Tim A
TA
Cook
Jason
J
Edmonds
Nagappan
N
Mathialagan
Micah J
MJ
Benson
Jameel
J
Syed
Yutian
Y
Zhan
Stephen E
SE
Benoit
Joy S
JS
Miyashiro
Nancy
N
Wood
Shashi
S
Mohan
Elena
E
Peeva
Shashi K
SK
Ramaiah
Dean
D
Messing
Bruce L
BL
Homer
Kyri
K
Dunussi-Joannopoulos
Cheryl L
CL
Nickerson-Nutter
Mark E
ME
Schnute
John
J
Douhan
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D018858:Germinal Center / Q000166:cytology; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D007668:Kidney / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008814:Mice, Inbred NZB; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011961:Receptors, Fc; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
C585580:5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-(2,4-difluorophenoxy)phenyl)-1H-pyrazole-4-carboxamide; D010880:Piperidines; D011720:Pyrazoles; D011961:Receptors, Fc; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse