Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Rheumatol. Author manuscript; available in PMC 2012 May 1.
Published in final edited form as:
PMCID: PMC3154025

Targeting BLyS in rheumatic disease: the sometimes-bumpy road from bench to bedside


Purpose of review

BLyS family ligands and receptors are key players in the selection and survival of most mature B lymphocytes. The fundamental role of BLyS in transitional B cell selection, coupled with the relative BLyS-independence of memory B cells and plasma cells, suggests that BLyS may be a useful therapeutic target in strategies directed against pre-immune B cell pools. Several agents that target BLyS are in clinical trials now, and we summarize recent results here, with a focus on systemic lupus erythematosus (SLE).

Recent findings

Belimumab, a human neutralizing anti-BLyS monoclonal antibody, has delivered moderate but positive results in two separate phase III clinical trials for systemic lupus erythematosus (SLE), and was recently recommended for approval by an FDA advisory panel. Additional agents targeting BLyS or other members of this cytokine receptor family are also being tested in clinical trials.


Together, these trials should yield novel therapies for a debilitating and often intractable illness; and offer insights that in turn should foster subsequent generations of personalized, targeted therapies for rheumatic diseases.

Keywords: BLyS, BAFF, B cell targeted therapy, lupus, SLE


Over the last decade, steadily increasing evidence has implicated the BLyS (also known as BAFF) family of ligands and receptors in mediating the selection and survival of most mature B lymphocyte subsets (reviewed in [1]). A connection with rheumatic disease was made early, based on the development of frank humoral autoimmunity in BLyS transgenic mice and the elevated BLyS levels in SLE, RA, and Sjogren’s syndrome. This connection was strengthened by animal studies clearly linking BLyS with B cell tolerance and homeostasis (reviewed in [2]). Based on these observations, a variety of approaches have been developed to target BLyS and other members of this cytokine and receptor family in the treatment of rheumatic diseases. BLyS-targeted therapies are presently in clinical trials (summarized in Table 1). Among these, two independent phase III clinical trials in SLE with the human neutralizing anti-BLyS monoclonal antibody, belimumab (registered as Benlysta®), achieved their primary endpoints. The FDA and European Medicines Agency are currently conducting reviews, and in November 2010 an FDA advisory panel voted in favor of approving Benlysta as a therapy for SLE in the U.S. The FDA itself may give its final approval as early as the first quarter of 2011. This would make belimumab the first new drug approved for SLE in decades. Reaching this milestone, however, has not been without several bumps along the road.

Table 1
Summary of SLE clinical trial results with BLyS-targeting agentsa

BLyS family biology suggests targets in treating autoimmune disorders

The BLyS family is a subset of the TNF superfamily, and consists of two cytokines (ligands), BLyS and APRIL; and three receptors, BR3 (BAFF-R), TACI, and BCMA. Soluble trimeric BLyS can interact with all three receptors, whereas APRIL only interacts with TACI and BCMA. While the biological actions of all family members have been investigated, interrogation of the BLyS/BR3 axis has advanced most rapidly, probably because of the profound effects on mature B cells following experimental manipulation of BLyS or BR3, as well as the inferred relevance to autoimmunity [3]. In aggregate, these studies have shown that BLyS/BR3 signaling regulates homeostasis of the pre-immune B cell pool by governing the stringency of selection at late tolerance checkpoints and controlling the lifespan of primary B cells.

After immature B cells exit the bone marrow, they pass through a transitional checkpoint before joining the mature recirculating primary B cell pool. Under normal circumstances, only about one-third of these transitional B cells survive to maturity, with those B cells expressing self-reactive or polyreactive specificities being lost [4,5]. Since mature primary B cells require BLyS for survival, only B cells that compete effectively for BLyS persist through transitional development. Accordingly, elevated BLyS levels allow B cells that are otherwise at a survival disadvantage to pass the transitional checkpoint and become established in the mature follicular and marginal zone B cell pools [6]. Conversely, reducing available BLyS may augment the stringency of transitional selection and reduce mature B cell lifespan, leading to reduced mature B cell numbers.

Based on the phenotypes of knockout mice, neither the APRIL ligand nor the TACI and BCMA receptors play major roles in building or maintaining the mature naïve B cell compartment [79]. Nevertheless, both BLyS and APRIL have important, if subtle, functions during B cell activation and in the differentiation or maintenance of antigen-experienced subsets. APRIL can modulate certain aspects of B cell activation [10], and BLyS signaling can interact with TLR pathways, initiating processes that engender class switching [10,11]. Both BLyS and BR3 are required for optimal germinal center (GC) formation and kinetics (reviewed in [12]), and both BLyS and APRIL signaling through TACI modulate isotype switching [12,13]. Whether the selection of activated B cell subsets, particularly GC B cells, is affected by BLyS availability remains less clear.

Neither memory nor long-lived plasma cells rely solely on BLyS for their differentiation or survival [14**,15**]. Indeed, long-lived plasma cells and memory B cells are relatively resistant to BLyS depletion compared to naive precursors; however, unswitched (IgM-bearing) memory cells may retain some BLyS dependence [14]. Two studies show that BLyS works with inflammatory cytokines to drive human memory B cells to differentiate into plasma cells [16,17]. Animal studies show that APRIL signaling through BCMA is sufficient to support long-lived plasma cells in bone marrow [7]; and, consistent with their exclusive expression of BCMA, long-lived plasma cells can utilize either BLyS or APRIL for maintenance [15].

Many observations in humans implicate BLyS or BLyS family members in SLE pathogenesis, thereby suggesting them as potential therapeutic targets. For example, serum BLyS, APRIL, and BLyS/APRIL heterotrimer levels are elevated in many SLE patients (for examples, see [10,1821]), and TACI upregulation and BR3 downregulation on peripheral B cells have also been observed [22].

The pivotal role for BLyS in transitional B cell selection, the relative BLyS-independence of memory B cell populations, and the dysregulation of BLyS in SLE collectively suggest BLyS as a prime candidate in therapeutic strategies for disorders resulting from failed peripheral B cell tolerance, or for diseases whose pathology relies on continued input from the pre-immune B cell pools. [23]. In such cases, neutralizing BLyS would have the safety advantage of leaving B cell memory, long-lived plasma cells, and natural antibodies intact. Conversely, if (pathogenic) autoreactive B cells are a component of the memory compartment, then BLyS neutralization may not be efficacious.

Treatment with belimumab (a BLyS-neutralizing monoclonal antibody)

Despite the strong salutary effects of BLyS antagonists in murine SLE models [24,25], demonstrating similar efficacy in human SLE has proven difficult. The greatest experience to date with BLyS antagonists has accrued with belimumab, a fully human IgG1λ mAb that binds and neutralizes soluble BLyS [26]. Preclinical studies with belimumab in cynomolgus monkeys demonstrated no cage-side toxicities and reversible effects on B cell numbers in peripheral blood or secondary lymphoid tissues [27]. Moreover, no untoward effects were observed in either mothers or babies of cynomolgus monkeys given belimumab throughout pregnancy [28].

This relative safety has been reproduced in human subjects. Belimumab was shown to be safe in a randomized, double-blind, placebo-controlled phase-I trial in SLE, in which the prevalence of adverse events was no different between belimumab- and placebo-treated patients [29]. Of note, only modest reductions in peripheral blood B cells were observed among belimumab-treated patients. No clinical efficacy was demonstrated in this phase-I trial, but the small number of patients (n = 70) and very brief treatment schedules (single infusion or two infusions 3 weeks apart) and follow-up period (12 weeks after final infusion) precluded demonstration of clinical benefit.

Armed with the very favorable safety profile of belimumab in human subjects along with compelling studies in murine SLE that demonstrated in vivo therapeutic efficacy for BLyS antagonism [30,31], a 52-week, randomized, double-blind, placebo-controlled phase-II trial of belimumab in SLE (n = 449) was undertaken. Disappointingly, the trial failed to meet its co-primary endpoints (disease activity at 24 weeks and time to first flare during the 52 weeks) when considering the entire SLE cohort [32]. However, extensive post hoc analysis led to a novel composite index of clinical response (SLE responder index or SRI; [33]) and demonstrated significantly increased clinical response among belimumab-treated patients at 52 weeks (but not at 24 weeks) among the ~70% of patients who were “seropositive” (ANA titer ≥1:80 and/or positive for anti-dsDNA antibodies) at entry.

Given the failure of belimumab to meet either of the co-primary endpoints in the phase-II trial, the initiation of two separate large randomized, double-blind, placebo-controlled phase-III trials (BLISS-52, n = 865; and BLISS-76, n = 819) of belimumab in “seropositive” SLE was met with skepticism. Nonetheless, both of these phase-III trials met their primary endpoints (increased percentage of responders at 52 weeks). In each trial, patients were given standard-of-care (SOC) + placebo (control group) or SOC + belimumab at one of two doses (1 or 10 mg/kg at weeks 0, 2, 4, and every 4 weeks thereafter). In BLISS-52 (conducted largely in Asia, South America, and Eastern Europe), SRI response rates were 44% in the placebo group, 51% (p = 0.013) in the 1 mg/kg belimumab group, and reached 58% (p = 0.0006) in the 10 mg/kg belimumab group [34]. In BLISS-76 (conducted largely in the US, Canada, and Europe), SRI response rates were 34% in the placebo group, 41% (p = 0.09) in the 1 mg/kg belimumab group, and were 43% (p = 0.017) in the 10 mg/kg belimumab group [35]. Importantly, analysis of the combined 1864 SLE patients in both BLISS trials at 52 weeks pointed to reductions in disease activity and prevention of worsening across vital internal organ systems, including hematological and renal [36**].

More bumps in the road lay ahead, however. The response rates at 76 weeks among belimumab-treated patients were no longer significantly different from that of placebo-treated patients, although the trend to greater response persisted [35]. This raises questions regarding the “staying power” of belimumab (and, by implication, other BLyS antagonists). This may reflect a lack of power afforded by the study cohort, or alternatively, the duration of belimumab-driven clinical efficacy is truly finite. Although patients treated with belimumab over 5 years in open-label extension (1415 patient-years) have shown stable SRI response scores and declining rates of flares, these patients have had their concurrent medications adjusted as clinically warranted [37], so the actual contribution of belimumab to the long-term favorable outcome remains uncertain. Nonetheless, belimumab is highly likely to win FDA approval for the treatment of SLE.

Once belimumab is approved, the questions of which patients to treat and for how long will immediately arise. No definitive answers to these questions can be offered at present, but we can offer the following suggestions. First, since only seropositive, but not seronegative, patients experienced a significant clinical response in the phase-II trial [32], it may be prudent to limit belimumab therapy to seropositive patients. (The phase-III trials are not informative in this regard, since all patients enrolled were seropositive.) Second, since clinical benefit in the phase-II trial was observed among patients taking prednisone ≥7.5 mg (or its equivalent)/day but not among patients taking <7.5 mg/day [32], it may be prudent to limit belimumab to patients that require ≥7.5 mg/day for disease control. (Analyses from the phase-III trials are not yet available but should be highly informative.) Third, since the responder rate among belimumab-treated patients continued to rise throughout the 52-week double-blinded portion of the phase-II trial [33], it may be prudent to give patients at least a 12-month trial of belimumab. Given the loss of significant difference between belimumab-treated and placebo-treated patients at 76 weeks in the BLISS-76 trial [35], the utility of protracted treatment with belimumab remains an open question that, at present, might be best left to a case-by-case adjudication by the attending physician.

Treatment with atacicept (TACI-Ig fusion protein)

In addition to belimumab, several other BLyS antagonists are undergoing clinical evaluation in SLE. The one furthest advanced in clinical evaluation is atacicept, a fusion protein between one of the BLyS receptors (TACI) and the Fc portion of IgG. Atacicept, in contrast to belimumab, binds and neutralizes both BLyS and APRIL. Accordingly, its clinical effects could substantially differ from those of belimumab. Since the roles for APRIL in the development and maintenance of antigen-experienced B cell subsets and in SLE are speculative, predicting the outcome of neutralizing both BLyS and APRIL is difficult. Indeed, the broader impact on B lineage pools could potentially afford greater efficacy, but might also prove less effective or detrimental due to unintended adverse events.

Preclinical studies with atacicept in mice and cynomolgus monkeys documented reversible sub-total depletion of B cells and reduction in circulating Ig (especially IgM) levels, with the only apparent systemic toxicity being transient elevations in liver-derived transaminases (without any histological changes in the livers) [38]. In humans, favorable safety and tolerability were demonstrated in a randomized, double-blind, placebo-controlled phase-I trial of atacicept in SLE [39]. SLE patients (n = 49) received a single dose of atacicept (0.3, 1, 3, or 9 mg/kg) or placebo or four weekly doses of atacicept (1 or 3 mg/kg) or placebo. Dose-dependent reductions in peripheral blood B cells and in circulating Ig levels were noted, but, as the case with the phase-I trial of belimumab in SLE, clinical efficacy could not be demonstrated due to the limited treatment and limited follow-up period.

Of concern, an unacceptable safety profile (increased risk of severe infections) was observed in a subsequent trial involving patients with SLE nephritis who were concurrently taking mycophenolate mofetil and corticosteroids ( identifier NCT00573157). As a consequence, this trial was prematurely terminated. Despite this bump in the road with atacicept, a separate phase-II/III trial of atacicept in SLE has recently been initiated ( identifier NCT00624338). Whether atacicept ultimately achieves clinical success from efficacy and safety standpoints remains an open question.

Treatment with other BLyS antagonists

Limited clinical information is available with regard to a third BLyS antagonist being tested in clinical trials, A-623 (previously known as AMG 623), a fusion between the Fc portion of IgG and a peptide sequence selected for its ability to bind with high affinity to BLyS. In a double-blind, placebo-controlled phase-I trial, SLE patients received a single dose (n = 54) or 4 weekly doses (n = 63) of AMG 623 (0.3, 1, or 3 mg/kg subcutaneously or 6 mg/kg intravenously) or matching placebo [40]. A dose-independent decrease in naive and total peripheral blood B cells was accompanied by an actual increase in memory B cells. Clinical responses were not reported, so the relevance of the disparate changes among B cell subsets to clinical parameters remains unknown. Of note, a similar (transient) increase in circulating memory B cells has been observed in belimumab-treated patients [41], raising the possibility that individual B cell subpopulations may be differentially affected by all BLyS antagonists.

In any case, a phase-II trial of A-623 in SLE has been initiated. It had been suspended due to “structural failure identified in some product vials” ( identifier NCT01162681), but the problem has been overcome, and the trial has resumed recruiting subjects.

A fourth BLyS antagonist in clinical development for SLE is LY2127399, a monoclonal antibody that binds both soluble and membrane BLyS [42]. Two phase-III trials in SLE ( identifiers NCT01205438 and NCT01196091) have just begun recruiting patients. Since the role for membrane BLyS in SLE pathogenesis is far from certain, it remains to be determined whether neutralization of soluble + membrane BLyS (as with LY2127399) will have greater therapeutic efficacy than neutralization of soluble BLyS alone (as with belimumab).

3. Conclusion

B cells play both protective and pathogenic roles in human health and disease, and there is increasing evidence that they are functionally more heterogeneous than originally imagined [43**,44]. The pivotal roles played by BLyS and its receptors in B cell homeostasis, selection, and survival, as well as their more recently appreciated roles among antigen-experienced subsets, suggest many advantages as potential targets in the therapy of humoral autoimmunity. Despite the strong potential for diseases in which primary B cell pools are crucial to sustained pathogenesis, targeting BLyS may not be effective in disease states in which autoreactive clones have already populated memory and/or long-lived plasma cell pools. Indeed, it is tempting to speculate that variable efficacy of belimumab in SLE patients may reflect differences in B cell profiles, due to the etiology and/or stage of the disease; and that as experience with BLyS and related targets increases, it will eventually help us to distinguish these variables.

Key points

  • We outline the roles played by BLyS and other members of this cytokine/receptor family in the biology of B cells, to explain why BLyS is likely to be a key target in effective treatment of SLE.
  • This article provides a detailed summary of clinical trial experience with belimumab, a BLyS-neutralizing antibody that is likely to win FDA approval in 2011 for treatment of lupus.
  • In addition, we summarize progress with three additional BLyS antagonists in recent clinical trials.


Supported in part by NIH grants R01AR059103 (WS) and R01AI 073939 (MPC).


1. Cancro MP, D’Cruz DP, Khamashta MA. The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus. J Clin Invest. 2009;119:1066–1073. [PMC free article] [PubMed]
2. Miller JP, Stadanlick JE, Cancro MP. Space, selection, and surveillance: setting boundaries with BLyS. J Immunol. 2006;176:6405–6410. [PubMed]
3. Treml JF, Hao Y, Stadanlick JE, Cancro MP. The BLyS family: toward a molecular understanding of B cell homeostasis. Cell Biochem Biophys. 2009;53:1–16. [PMC free article] [PubMed]
4. Thien M, Phan TG, Gardam S, Amesbury M, Basten A, Mackay F, Brink R. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity. 2004;20:785–798. [PubMed]
5. Lesley R, Xu Y, Kalled SL, Hess DM, Schwab SR, Shu HB, Cyster JG. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity. 2004;20:441–453. [PubMed]
6. Hondowicz BD, Alexander ST, Quinn WJ, 3rd, Pagan AJ, Metzgar MH, Cancro MP, Erikson J. The role of BLyS/BLyS receptors in anti-chromatin B cell regulation. Int Immunol. 2007;19:465–47. [PubMed]
7. O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, Lin LL, Mantchev GT, Bram RJ, Noelle RJ. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199:91–98. [PMC free article] [PubMed]
8. Seshasayee D, Valdez P, Yan M, Dixit VM, Tumas D, Grewal IS. Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor. Immunity. 2003;18:279–288. [PubMed]
9. Castigli E, Scott S, Dedeoglu F, Bryce P, Jabara H, Bhan AK, Mizoguchi E, Geha RS. Impaired IgA class switching in APRIL-deficient mice. Proc Natl Acad Sci U S A. 2004;101:3903–3908. [PubMed]
10. Tangye SG, Bryant VL, Cuss AK, Good KL. BAFF, APRIL and human B cell disorders. Semin Immunol. 2006;18:305–317. [PubMed]
11. Davidson A. Targeting BAFF in autoimmunity. Curr Opin Immunol. 2010;22:732– 739. [PMC free article] [PubMed]
12. Kalled SL. Impact of the BAFF/BR3 axis on B cell survival, germinal center maintenance and antibody production. Semin Immunol. 2006;18:290–296. [PubMed]
13. Sakurai D, Hase H, Kanno Y, Kojima H, Okumura K, Kobata T. TACI regulates IgA production by APRIL in collaboration with HSPG. Blood. 2006;109:2961–2967. [PubMed]
14** Scholz JL, Crowley JE, Tomayko MM, Steinel N, O’Neill PJ, Quinn WJ, 3rd, Goenka R, Miller JP, Cho YH, Long V, et al. BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact. Proc Natl Acad Sci U S A. 2008;105:15517–15522. This paper showed that existing humoral memory and natural antibodies are spared by BLyS neutralization in a mouse model. [PubMed]
15** Benson MJ, Dillon SR, Castigli E, Geha RS, Xu S, Lam KP, Noelle RJ. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol. 2008;180:3655–3659. This paper showed that memory B cells are spared but long lived plasma cells are reduced, by neutralizing both BLyS and APRIL in a mouse model. [PubMed]
16. Doreau A, Belot A, Bastid J, Riche B, Trescol-Biemont MC, Ranchin B, Fabien N, Cochat P, Pouteil-Noble C, Trolliet P, et al. Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat Immunol. 2009;10:778–785. [PubMed]
17. Ettinger R, Sims GP, Robbins R, Withers D, Fischer RT, Grammer AC, Kuchen S, Lipsky PE. IL-21 and BAFF/BLyS synergize in stimulating plasma cell differentiation from a unique population of human splenic memory B cells. J Immunol. 2007;178:2872–2882. [PubMed]
18. Roschke V, Sosnovtseva S, Ward CD, Hong JS, Smith R, Albert V, Stohl W, Baker KP, Ullrich S, Nardelli B, et al. BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases. J Immunol. 2002;169:4314–4321. [PubMed]
19. Koyama T, Tsukamoto H, Miyagi Y, Himeji D, Otsuka J, Miyagawa H, Harada M, Horiuchi T. Raised serum APRIL levels in patients with systemic lupus erythematosus. Ann Rheum Dis. 2005;64:1065–1067. [PMC free article] [PubMed]
20. Zhang J, Roschke V, Baker KP, Wang Z, Alarcon GS, Fessler BJ, Bastian H, Kimberly RP, Zhou T. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol. 2001;166:6–10. [PubMed]
21. Stohl W. Systemic lupus erythematosus and its ABCs (APRIL/BLyS complexes) Arthritis Res Ther. 2010;12:111. [PMC free article] [PubMed]
22. Zhao LD, Li Y, Smith MF, Jr, Wang JS, Zhang W, Tang FL, Tian XP, Wang HY, Zhang FC, Ba DN, et al. Expressions of BAFF/BAFF receptors and their correlation with disease activity in Chinese SLE patients. Lupus. 2010;19:1534–1549. [PubMed]
23. Treml LS, Quinn WJ, 3rd, Treml JF, Scholz JL, Cancro MP. Manipulating B cell homeostasis: a key component in the advancement of targeted strategies. Arch Immunol Ther Exp (Warsz) 2008;56:153–164. [PMC free article] [PubMed]
24. Ramanujam M, Bethunaickan R, Huang W, Tao H, Madaio MP, Davidson A. Selective blockade of BAFF for the prevention and treatment of systemic lupus erythematosus nephritis in NZM2410 mice. Arthritis Rheum. 2010;62:1457–1468. [PMC free article] [PubMed]
25. Ding H, Wang L, Wu X, Yan J, He Y, Ni B, Gao W, Zhong X. Blockade of B-cell-activating factor suppresses lupus-like syndrome in autoimmune BXSB mice. J Cell Mol Med. 2010;14:1717–1725. [PubMed]
26. Baker KP, Edwards BM, Main SH, Choi GH, Wager RE, Halpern WG, Lappin PB, Riccobene T, Abramian D, Sekut L, et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 2003;48:3253–3265. [PubMed]
27. Halpern WG, Lappin P, Zanardi T, Cai W, Corcoran M, Zhong J, Baker KP. Chronic Administration of Belimumab, a BLyS Antagonist, Decreases Tissue and Peripheral Blood B-Lymphocyte Populations in Cynomolgus Monkeys: Pharmacokinetic, Pharmacodynamic and Toxicologic Effects. Toxicol Sci. 2006;91:586–599. [PubMed]
28. Auyeung-Kim DJ, Devalaraja MN, Migone TS, Cai W, Chellman GJ. Developmental and peri-postnatal study in cynomolgus monkeys with belimumab, a monoclonal antibody directed against B-lymphocyte stimulator. Reprod Toxicol. 2009;28:443–455. [PubMed]
29. Furie R, Stohl W, Ginzler EM, Becker M, Mishra N, Chatham W, Merrill JT, Weinstein A, McCune WJ, Zhong J, 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. [PMC free article] [PubMed]
30. Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, Xu W, Parrish-Novak J, Foster D, Lofton-Day C, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000;404:995–999. [PubMed]
31. Ramanujam M, Wang X, Huang W, Liu Z, Schiffer L, Tao H, Frank D, Rice J, Diamond B, Yu KO, et al. Similarities and differences between selective and nonselective BAFF blockade in murine SLE. J Clin Invest. 2006;116:724–734. [PMC free article] [PubMed]
32. Wallace DJ, Stohl W, Furie RA, Lisse JR, McKay JD, Merrill JT, Petri MA, Ginzler EM, Chatham WW, McCune WJ, 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. [PMC free article] [PubMed]
33. Furie RA, Petri MA, Wallace DJ, Ginzler EM, Merrill JT, Stohl W, Chatham WW, Strand V, Weinstein A, Chevrier MR, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009;61:1143–1151. [PMC free article] [PubMed]
34. Navarra S, Guzman R, Gallacher A, Levy RA, Li EK, Thomas M, Jimenez R, Leon M, Hall S, Lan JL, Nasonov E, Tanasescu C, Kim HY, Pineda L, Zhong ZJ, Freimuth W, Petri MA. BLISS-52 Study Group: Belimumab, a BLyS-specific inhibitor, reduced disease activity, flares and prednisone use in patients with active SLE: efficacy and safety results from the phase 3 BLISS-52 study. Arthritis Rheum. 2009;60:3859.
35. Furie R, Zamani O, Wallace D, Tegzova D, Petri M, Merrill JT, Chatham W, Stohl W, Schwarting A, Cooper S, Zhong ZJ, Freimuth W, Hough D, van Vollenhoven RF. BLISS-76 Study Group. Belimumab, a BLyS-specific inhibitor, reduced disease activity and severe flares in seropositive SLE patients: BLISS-76 study results through wk 76. Arthritis Rheum. 2010;62:S606.
36** Manzi S, Sanchez-Guerrero J, Merrill JT, Furie RA, Gladman D, Navarra S, Ginzler EM, D’Cruz D, Doria A, Cooper S, Zhong ZJ, Hough D, Freimuth W, Petri M. BLISS-52 and -76 Study Groups.: Belimumab, a BLyS-specific inhibitor, reduced disease activity across multiple organ domains: combined efficacy results from the phase 3 BLISS-52 and -76 studies. Arthritis Rheum. 2010;62:S607. This reports combined information from BLISS 52 and BLISS 76 trial data, indicating significant clinical efficacy over controls at 52 but not 76 weeks. [PMC free article] [PubMed]
37. Merrill JT, Wallace DJ, Furie RA, Petri MA, Stohl W, Chatham WW, McCune J, Weinstein A, McKay J, Zhong ZJ, Pineda L, Klein J, Freimuth W, Ginzler EM. LBSL02/99 Study Group. Five-year experience with belimimab, a BLyS-specific inhibitor, in patients with systemic lupus erythematosus (SLE) Arthritis Rheum. 2010:S608.
38. Carbonatto M, Yu P, Bertolino M, Vigna E, Steidler S, Fava L, Daghero C, Roattino B, Onidi M, Ardizzone M, et al. Nonclinical safety, pharmacokinetics, and pharmacodynamics of atacicept. Toxicol Sci. 2008;105:200–210. [PubMed]
39. Dall’Era M, Chakravarty E, Wallace D, Genovese M, Weisman M, Kavanaugh A, Kalunian K, Dhar P, Vincent E, Pena-Rossi C, 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;56:4142–4150. [PubMed]
40. Stohl W, Merrill JT, Looney RJ, Buyon J, Wallace DJ, Weisman M, Ginzler EM, Cooke B, Holloway D, Kuchimanchi K, Cheah TC, Rasmussen E, Ferbas J, Belouski SS, Zack DJ. Phase 1a single- and phase 1b multiple-dose studies of AMG 623 (an anti-BAFF peptibody) in systemic lupus erythematosus (SLE) Arthritis Rheum. 2008;58:S565–S566.
41. Stohl W, Hiepe F, Thomas M, Scheinberg M, Clarke A, Aranow C, Jimenez R, Wellborne F, Abud-Mendoza C, Hough D, Pineda L, Migone TS, Freimuth W, Chatham W. BLISS-52 and -76 Study Groups: Belimumab, a BLyS-specific inhibitor, significantly reduced autoantibodies, normalized low complement, and reduced selected B-cell populations in patients with seropositive systemic lupus erythematosus (SLE): the phase 3 BLISS studies. Arthritis Rheum. 2010;62:S480.
42. Kikly K, Manetta J, Smith H, Wierda D, Witcher D. Characterization of LY2127399, a neutralizing antibody for BAFF [abstract] Arthritis Rheum. 2009;60:693.
43** Anolik JH, Looney RJ, Lund FE, Randall TD, Sanz I. Insights into the heterogeneity of human B cells: diverse functions, roles in autoimmunity, and use as therapeutic targets. Immunol Res. 2009 Apr 7; This provides a thorough and cogent overview of human B cell heterogeneity and apparently opposing roles in autoimmunity, particularly SLE. [PMC free article] [PubMed]
44. Looney RJ, Anolik J, Sanz I. A perspective on B-cell-targeting therapy for SLE. Mod Rheumatol. 2010;20:1–10. [PubMed]