Current Rheumatology Reports

, Volume 14, Issue 4, pp 303–309 | Cite as

Biologic Differences Between Various Inhibitors of the BLyS/BAFF Pathway: Should We Expect Differences Between Belimumab and Other Inhibitors in Development?

SYSTEMIC LUPUS ERYTHEMATOSUS (JT MERRILL, SECTION EDITOR)

Abstract

For the first time in more than 50 years, the US Food and Drug Administration has approved a drug specifically for the treatment of systemic lupus erythematosus (SLE). This drug, belimumab, is a monoclonal antibody that neutralizes the B-cell survival factor, B-lymphocyte stimulator (BLyS). Although belimumab has demonstrated a very favorable safety profile, many SLE patients have failed to clinically improve from belimumab therapy. Three additional BLyS antagonists (atacicept, blisibimod, tabalumab) are currently undergoing clinical testing. These antagonists subtly differ from belimumab in their biologic targets, and each is administered through a route (subcutaneous) that differs from the route through which belimumab is currently delivered (intravenous). Whether these differences will have meaningful consequences for efficacy and safety remains to be determined.

Keywords

APRIL Atacicept BCMA Belimumab Blisbimod (A-623) BLyS/BAFF BR3 Systemic lupus erythematosus Tabalumab (LY2127399) TACI SLE 

References

Papers of particular interest, published recently, have been highlighted as: • of Importance •• of Major Importance

  1. 1.
    Moore PA, Belvedere O, Orr A, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999;285:260–3.PubMedCrossRefGoogle Scholar
  2. 2.
    Schneider P, MacKay F, Steiner V, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999;189:1747–56.PubMedCrossRefGoogle Scholar
  3. 3.
    Nardelli B, Belvedere O, Roschke V, et al. Synthesis and release of B-lymphocyte stimulator from myeloid cells. Blood. 2001;97:198–204.PubMedCrossRefGoogle Scholar
  4. 4.
    Laabi Y, Gras M-P, Brouet J-C, et al. The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed. Nucleic Acids Res. 1994;22:1147–54.PubMedCrossRefGoogle Scholar
  5. 5.
    von Bülow G-U, Bram RJ. NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily. Science. 1997;278:138–41.CrossRefGoogle Scholar
  6. 6.
    Thompson JS, Bixler SA, Qian F, et al. BAFF-R, a novel TNF receptor that specifically interacts with BAFF. Science. 2001;293:2108–11.PubMedCrossRefGoogle Scholar
  7. 7.
    Yan M, Brady JR, Chan B, et al. Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency. Curr Biol. 2001;11:1547–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Thompson JS, Schneider P, Kalled SL, et al. BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population. J Exp Med. 2000;192:129–35.PubMedCrossRefGoogle Scholar
  9. 9.
    Do RKG, Hatada E, Lee H, et al. Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. J Exp Med. 2000;192:953–64.PubMedCrossRefGoogle Scholar
  10. 10.
    Batten M, Groom J, Cachero TG, et al. BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med. 2000;192:1453–65.PubMedCrossRefGoogle Scholar
  11. 11.
    Rolink AG, Tschopp J, Schneider P, Melchers F. BAFF is a survival and maturation factor for mouse B cells. Eur J Immunol. 2002;32:2004–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Litinskiy MB, Nardelli B, Hilbert DM, et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol. 2002;3:822–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Bossen C, Tardivel A, Willen L, et al. Mutation of the BAFF furin cleavage site impairs B-cell homeostasis and antibody response. Eur J Immunol. 2011;41:787–97.PubMedCrossRefGoogle Scholar
  14. 14.
    Mackay F, Woodcock SA, Lawton P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999;190:1697–710.PubMedCrossRefGoogle Scholar
  15. 15.
    Khare SD, Sarosi I, Xia X-Z, et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci U S A. 2000;97:3370–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Gross JA, Johnston J, Mudri S, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000;404:995–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Cheema GS, Roschke V, Hilbert DM, Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum. 2001;44:1313–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang J, Roschke V, Baker KP, et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol. 2001;166:6–10.PubMedGoogle Scholar
  19. 19.
    Petri M, Stohl W, Chatham W, et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 2008;58:2453–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Jacob CO, Pricop L, Putterman C, et al. Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupus-prone New Zealand Mixed 2328 mice deficient in BAFF. J Immunol. 2006;177:2671–80.PubMedGoogle Scholar
  21. 21.
    Jacob N, Guo S, Mathian A, et al. B cell and BAFF dependence of IFN-α-exaggerated disease in systemic lupus erythematosus-prone NZM 2328 mice. J Immunol. 2011;186:4984–93.PubMedCrossRefGoogle Scholar
  22. 22.
    Hahne M, Kataoka T, Schröter M, et al. APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. J Exp Med. 1998;188:1185–90.PubMedCrossRefGoogle Scholar
  23. 23.
    Marsters SA, Yan M, Pitti RM, et al. Interaction of the TNF homologues BLyS and APRIL with the receptor homologues BCMA and TACI. Curr Biol. 2000;10:785–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Yu G, Boone T, Delaney J, et al. APRIL and TALL-1 and receptors BCMA and TACI: system for regulating humoral immunity. Nat Immunol. 2000;1:252–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Rennert P, Schneider P, Cachero TG, et al. A soluble form of B cell maturation antigen, a receptor for the tumor necrosis factor family member APRIL, inhibits tumor cell growth. J Exp Med. 2000;192:1677–83.PubMedCrossRefGoogle Scholar
  26. 26.
    Roschke V, Sosnovtseva S, Ward CD, et al. BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases. J Immunol. 2002;169:4314–21.PubMedGoogle Scholar
  27. 27.
    Varfolomeev E, Kischkel F, Martin F, et al. APRIL-deficient mice have normal immune system development. Mol Cell Biol. 2004;24:997–1006.PubMedCrossRefGoogle Scholar
  28. 28.
    Castigli E, Scott S, Dedeoglu F, et al. Impaired IgA class switching in APRIL-deficient mice. Proc Natl Acad Sci U S A. 2004;101:3903–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Stein JV, López-Fraga M, Elustondo FA, et al. APRIL modulates B and T cell immunity. J Clin Invest. 2002;109:1587–98.PubMedGoogle Scholar
  30. 30.
    • Jacob CO, Guo S, Jacob N, et al. Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice. Arthritis Rheum 2012; 64:1610–9. This is the first and only study to date in human or murine SLE to examine the effects of APRIL neutralization/elimination (without concurrent neutralization/elimination of BLyS) on development of SLE features. Google Scholar
  31. 31.
    Ramanujam M, Wang X, Huang W, et al. Similarities and differences between selective and nonselective BAFF blockade in murine SLE. J Clin Invest. 2006;116:724–34.PubMedCrossRefGoogle Scholar
  32. 32.
    Lesley R, Xu Y, Kalled SL, et al. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity. 2004;20:441–53.PubMedCrossRefGoogle Scholar
  33. 33.
    Thien M, Phan TG, Gardam S, et al. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity. 2004;20:785–98.PubMedCrossRefGoogle Scholar
  34. 34.
    Ota M, Duong BH, Torkamani A, et al. Regulation of the B cell receptor repertoire and self-reactivity by BAFF. J Immunol. 2010;185:4128–36.PubMedCrossRefGoogle Scholar
  35. 35.
    Nikbakht N, Migone T-S, Ward CP, Manser T. Cellular competition independent of BAFF/B lymphocyte stimulator results in low frequency of an autoreactive clonotype in mature polyclonal B cell compartments. J Immunol. 2011;187:37–46.PubMedCrossRefGoogle Scholar
  36. 36.
    Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113:4834–40.PubMedCrossRefGoogle Scholar
  37. 37.
    • Watanabe R, Ishiura N, Nakashima H, et al. Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity. J Immunol 2010;184:4801–4809. This study demonstrated that the B10 subset of B cells has regulatory activity and plays a role in modulating disease activity in murine SLE. PubMedCrossRefGoogle Scholar
  38. 38.
    • Iwata Y, Matsushita T, Horikawa M, et al.: Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 2011;117:530–541. This study documented the human equivalent of murine B10 regulatory cells. By implication, indiscriminate depletion of B cells would eliminate these regulatory cells and could be counterproductive in the treatment of human SLE. PubMedCrossRefGoogle Scholar
  39. 39.
    Sutherland APR, Ng LG, Fletcher CA, et al. BAFF augments certain Th1-associated inflammatory responses. J Immunol. 2005;174:5537–44.PubMedGoogle Scholar
  40. 40.
    • Zhou X, Xia Z, Lan Q, et al.: BAFF promotes Th17 cells and aggravates experimental autoimmune encephalomyelitis. PLoS ONE 2011;6:e23629. This study documented the ability of BLyS to directly act upon T cells and to promote generation of proinflammatory Th17 cells. The ramification for SLE is that therapeutic neutralization of BLyS may not only be beneficial by inhibiting pathogenic autoreactive B cells, but may also be beneficial by inhibiting generation of pathogenic Th17 cells. PubMedCrossRefGoogle Scholar
  41. 41.
    Baker KP, Edwards BM, Main SH, et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 2003;48:3253–65.PubMedCrossRefGoogle Scholar
  42. 42.
    Furie R, Stohl W, Ginzler EM, et al. Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Arthritis Res Ther. 2008;10:R109.PubMedCrossRefGoogle Scholar
  43. 43.
    • Wallace DJ, Stohl W, Furie RA, et al.: A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum 2009;61:1168–1178. The post-hoc analysis of this phase 2 study of belimumab in SLE set the stage for the seminal phase 3 studies that ultimately led to approval of belimumab by the FDA. PubMedCrossRefGoogle Scholar
  44. 44.
    •• Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:721–31. The BLISS-52 [44••] and BLISS-76 [45••] trials are the successful phase 3 studies in SLE that led to approval of belimumab by the FDA. PubMedCrossRefGoogle Scholar
  45. 45.
    •• Furie R, Petri M, Zamani O, et al.: A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63:3918–3930. The BLISS-52 [44••] and BLISS-76 [45••] trials are the successful phase 3 studies in SLE that led to approval of belimumab by the FDA. PubMedCrossRefGoogle Scholar
  46. 46.
    Merrill JT, Furie RA, Wallace DJ, et al. Sustained disease improvement and safety profile over the 1500 patient-year experience (6 years) with belimumab in patients with systemic lupus erythematosus (SLE). Arthritis Rheum. 2011;63:S222–3.CrossRefGoogle Scholar
  47. 47.
    •• Furie RA, Petri MA, Wallace DJ, et al.: Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum 2009;61:1143–1151. This paper describes the development of the novel SLE Responder Index (SRI), the instrument that was utilized in the BLISS-52 and BLISS-76 trials and that is now being utilized in several other SLE clinical trials. PubMedCrossRefGoogle Scholar
  48. 48.
    Stohl W, Jacob N, Quinn III WJ, et al. Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity. J Immunol. 2008;181:833–41.PubMedGoogle Scholar
  49. 49.
    Carter RH, Zhao H, Liu X, et al. Expression and occupancy of BAFF-R on B cells in systemic lupus erythematosus. Arthritis Rheum. 2005;52:3943–54.PubMedCrossRefGoogle Scholar
  50. 50.
    Dall’Era M, Chakravarty E, Wallace D, et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum. 2007;56:4142–50.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of RheumatologyUniversity of Southern California Keck School of MedicineLos AngelesUSA

Personalised recommendations