title: Dual B cell immunotherapy is superior to individual anti-CD20 depletion or BAFF blockade in murine models of spontaneous or accelerated lupus.
abstract: OBJECTIVE
  To determine whether a combination of B cell depletion and BAFF blockade is more effective than monotherapy in treating models of spontaneous or accelerated systemic lupus erythematosus (SLE) in (NZB × NZW)F1 mice.
  
  
  METHODS
  Clinical parameters such as disease progression-free survival, proteinuria, and renal injury were assessed in models of spontaneous, interferon-α (IFNα)-accelerated, or pristane-accelerated lupus in (NZB × NZW)F1 mice. Treatment arms included anti-CD20 (B cell depletion), B lymphocyte stimulator receptor 3 fusion protein (BR-3-Fc) (BAFF blockade), the combination of anti-CD20 and BR-3-Fc, isotype control, or cyclophosphamide. In models of spontaneous, IFNα-accelerated, or pristane-accelerated lupus, mice were treated for 24 weeks, 8 weeks, or 12 weeks, respectively. Peripheral and resident B cell subsets and various autoantibodies were examined.
  
  
  RESULTS
  Compared to B cell depletion or BAFF blockade alone, combined therapy significantly improved disease manifestations in all 3 lupus models. In addition, marginal zone B cells, plasmablasts, and circulating and tissue plasma cells were decreased more effectively. Dual B cell immunotherapy also reduced multiple classes of pathogenic autoantibodies, consistent with its observed effectiveness in reducing immune complex-mediated renal injury.
  
  
  CONCLUSIONS
  Dual immunotherapy via B cell depletion and BAFF blockade is more efficacious than single agent immunotherapy in murine SLE models, and this combination treatment is predicted to be an effective strategy for immunotherapy in human SLE.
authors.affiliation: Genentech, Inc., South San Francisco, California.
authors.forename: WeiYu
authors.initials: W
authors.lastname: Lin
authors.forename: Dhaya
authors.initials: D
authors.lastname: Seshasayee
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.forename: Patrick
authors.initials: P
authors.lastname: Caplazi
authors.forename: Sami
authors.initials: S
authors.lastname: McVay
authors.forename: Eric
authors.initials: E
authors.lastname: Suto
authors.forename: Allen
authors.initials: A
authors.lastname: Nguyen
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Lin
authors.forename: Yonglian
authors.initials: Y
authors.lastname: Sun
authors.forename: Laura
authors.initials: L
authors.lastname: DeForge
authors.forename: Mercedesz
authors.initials: M
authors.lastname: Balazs
authors.forename: Flavius
authors.initials: F
authors.lastname: Martin
authors.forename: Ali A
authors.initials: AA
authors.lastname: Zarrin
mesh_terms: D058186:Acute Kidney Injury / Q000453:epidemiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000187:drug effects / Q000276:immunology*; D001323:Autoantibodies / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors* / Q000187:drug effects; D053265:B-Cell Activation Factor Receptor / Q000494:pharmacology / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D002452:Cell Count; D004195:Disease Models, Animal; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D015994:Incidence; D016898:Interferon-alpha / Q000009:adverse effects; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008814:Mice, Inbred NZB; D013729:Terpenes / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D001323:Autoantibodies; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D016898:Interferon-alpha; D013729:Terpenes; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse; C009042:pristane