title: Depletion of autoreactive plasma cells and treatment of lupus nephritis in mice using CEP-33779, a novel, orally active, selective inhibitor of JAK2.
abstract: Accumulating evidence suggests that autoreactive plasma cells play an important role in systemic lupus erythematosus (SLE). In addition, several proinflammatory cytokines promote autoreactive B cell maturation and autoantibody production. Hence, therapeutic targeting of such cytokine pathways using a selective JAK2 inhibitor, CEP-33779 (JAK2 enzyme IC(50) = 1.3 nM; JAK3 enzyme IC(50)/JAK2 enzyme IC(50) = 65-fold), was tested in two mouse models of SLE. Age-matched, MRL/lpr or BWF1 mice with established SLE or lupus nephritis, respectively, were treated orally with CEP-33779 at 30 mg/kg (MRL/lpr), 55 mg/kg or 100 mg/kg (MRL/lpr and BWF1). Studies included reference standard, dexamethasone (1.5 mg/kg; MRL/lpr), and cyclophosphamide (50 mg/kg; MRL/lpr and BWF1). Treatment with CEP-33779 extended survival and reduced splenomegaly/lymphomegaly. Several serum cytokines were significantly decreased upon treatment including IL-12, IL-17A, IFN-α, IL-1β, and TNF-α. Anti-nuclear Abs and frequencies of autoantigen-specific, Ab-secreting cells declined upon CEP-33779 treatment. Increased serum complement levels were associated with reduced renal JAK2 activity, histopathology, and spleen CD138(+) plasma cells. The selective JAK2 inhibitor CEP-33779 was able to mitigate several immune parameters associated with SLE advancement, including the protection and treatment of mice with lupus nephritis. These data support the possibility of using potent, orally active, small-molecule inhibitors of JAK2 to treat the debilitative disease SLE.
authors: Cephalon, Inc., Worldwide Discovery Research, West Chester, PA 19380, USA.
authors: Lily D
authors: LD
authors: Lu
authors: Kristine L
authors: KL
authors: Stump
authors: Nate H
authors: NH
authors: Wallace
authors: Pawel
authors: P
authors: Dobrzanski
authors: Cynthia
authors: C
authors: Serdikoff
authors: Diane E
authors: DE
authors: Gingrich
authors: Benjamin J
authors: BJ
authors: Dugan
authors: Thelma S
authors: TS
authors: Angeles
authors: Mark S
authors: MS
authors: Albom
authors: Jennifer L
authors: JL
authors: Mason
authors: Mark A
authors: MA
authors: Ator
authors: Bruce D
authors: BD
authors: Dorsey
authors: Bruce A
authors: BA
authors: Ruggeri
authors: Matthew M
authors: MM
authors: Seavey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010950:Plasma Cells / Q000187:drug effects* / Q000276:immunology; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014230:Triazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000974:Antibodies, Antinuclear; C567989:CEP 33779; D016207:Cytokines; D004791:Enzyme Inhibitors; D011725:Pyridines; D014230:Triazoles; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2