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Targeting the BLyS-APRIL signaling pathway in SLE
YCLIM-07071; No. of pages: 6; 4C: Clinical Immunology (2012) xx, xxx–xxx
available at www.sciencedirect.com
Clinical Immunology www.elsevier.com/locate/yclim
REVIEW
Targeting the BLyS-APRIL signaling pathway in SLE Antonio La Cava ⁎ Department of Medicine, University of California Los Angeles, 1000 Veteran Avenue 32-59, Los Angeles, CA 90095-1670, USA
Received 18 October 2012; accepted with revision 28 November 2012
KEYWORDS BLyS/BAFF; APRIL; Systemic lupus erythematosus (SLE)
Abstract The B lymphocyte stimulator (BLyS)- A PRoliferation-Inducing Ligand (APRIL) signaling pathway has an important role in the selection, maturation and survival of B cells and plays a significant role in the pathogenesis of systemic lupus erythematosus (SLE). The inhibition of BLyS, a survival factor for transitional and mature B cells, has recently proven to be successful in large phase III clinical trials that led to the approval of an anti-BLyS monoclonal antibody (belimumab) for the treatment of SLE. Yet, there is currently a need to both understand better the mechanisms of action of belimumab in SLE and better define the subsets of patients that are more likely to respond to the drug. © 2012 Elsevier Inc. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . BLyS and APRIL . . . . . . . . . . . . . . . . . . . . . 2.1. BLyS and APRIL receptors . . . . . . . . . . . . 3. Systemic lupus erythematosus (SLE) . . . . . . . . . . 3.1. BlyS in SLE . . . . . . . . . . . . . . . . . . . . 4. Belimumab . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Results from the clinical trials with belimumab 4.2. Considerations on the belimumab trials . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Fax: + 1 310 206 8606. E-mail address: [email protected]. 1521-6616/$ - see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clim.2012.11.010 Please cite this article as: A. La Cava, Targeting the BLyS-APRIL signaling pathway in SLE, Clin. Immunol. (2012), http://dx.doi.org/10.1016/ j.clim.2012.11.010
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1. Introduction BLyS and APRIL are two members of the TNF ligand superfamily. Together with their cognate receptors, BLyS and APRIL regulate B lymphocyte homeostasis and play important roles in certain autoimmune diseases and malignancies (e.g., lymphomas). In autoimmunity, the inhibition of BLyS protects from disease, possibly by reducing the survival of autoreactive B cells. This aspect has led to the targeting of the BLyS/APRIL pathway for the modulation of the aberrant production of autoantibodies that characterizes systemic lupus erythematosus (SLE). In particular, an antibody blocking soluble BLyS, called belimumab, was approved in 2011 by the FDA for the therapy of SLE after two phase III clinical trials showed that this biologic agent, in combination with standard of care, significantly reduced SLE disease activity and flare rates in patients with active SLE. Notwithstanding the benefits of belimumab in SLE, the mechanisms of action of this drug are only partially known, and it is not known how much of the deletion of transitional and naïve B cells can explain the observed efficacy of belimumab in SLE. Additional factors could include a modulation of antigen presentation to T cells, effects on T cell function, and/or an influence of belimumab on the production of cytokines and chemokines.
2. BLyS and APRIL BlyS (also called B cell activating factor, BAFF) is a B-cell survival factor that inhibits B cell apoptosis and favors B-cell proliferation and maturation, antibody production and IgG class switching [1–3]. APRIL mediates effects that are similar to those of BLyS. BLyS and APRIL are produced by monocytes/macrophages, dendritic cells, neutrophils, activated T cells, some B cells and non-hematopoietic cells [4]. Blys is synthesized as a homotrimeric transmembrane protein that can be cleaved into soluble homotrimers, or it can be found in soluble form as a circulating capsid-like structure of twenty trimers (a 60-mer) [5]. APRIL is a soluble protein but can also be found as a membrane-bound hybrid molecule called TWE-PRIL (formed by the trans-splicing of
Immature
Transitional
Naïve
TWEAK [TNF-related weak inducer of apoptosis] with APRIL) [6,7]. Heterotrimers of BLyS and APRIL, composed of one or two BLyS monomers with one or two APRIL monomers, are also commonly found and are typically elevated in the serum of SLE patients [8].
2.1. BLyS and APRIL receptors BLyS can bind to three different receptors that are expressed on B cells. One receptor is the BAFF receptor (BAFF-R or BR3) and is highly specific for BLyS. BAFF-R in humans is expressed by all B cells except bone marrow plasma cells [9]. BAFF-R is the predominant receptor on naïve and memory B cells [10,11]. Another receptor is called TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and is expressed on CD27 + memory B cells and bone marrow plasma cells. TACI is the predominant receptor on (MZ) zone B cells and short-lived plasma cells and acts as a negative regulator during B cell maturation. TACI deficiency in mice leads to defective B cell responses to T-independent antigens [12]. The third receptor is called BCMA (B lymphocyte maturation antigen), is expressed by some memory B cells and GC B cells and plasma cells, and influences the survival of long-lived bone marrow plasma cells [13,14]. BCMA is the predominant receptor on long-lived plasma cells, where it has an important role in cell survival, also in plasma blasts [15]. Interestingly, TACI and BCMA can bind to both BLyS and APRIL [6]. In terms of developmental expression, functional BLyS receptors on B cells appear at the transitional stage, thus affecting only the survival of mature B cells and making BlyS ineffective on the B-cell precursors that express CD20 ant not BLyS receptors (Fig. 1). Mechanistically, the signaling through BAFF-R controls B cell numbers by varying the proportion of cells that complete transitional B cell development, and by serving as the primary determinant of mature B cell longevity [16]. Additionally, studies on B cells from mice deficient in TACI, BCMA, and BAFF-R indicate that both TACI and BAFF-R transduce signals that result in isotype switching [17].
Germinal Center
Plasmablast
Plasmacell
Memory (MZ) BM Spleen LT Blood Gut, Tonsils
Fig. 1 Stages of B cell development and relative cell surface expression of BLyS/APRIL receptors. BAFF-R is represented as triangle(s), BCMA as rhomboid(s), and TACI as pentagon. Please cite this article as: A. La Cava, Targeting the BLyS-APRIL signaling pathway in SLE, Clin. Immunol. (2012), http://dx.doi.org/10.1016/ j.clim.2012.11.010
Targeting the BLyS-APRIL signaling pathway in SLE The effects of APRIL and BAFF on IL-6 and GM-CSF appear instead mediated by BCMA [18], a receptor that can also induce the arrest of cell growth [19].
3. Systemic lupus erythematosus (SLE) SLE has a multifactorial etiology that involves the contribution of only partly known environmental and genetic factors which act in concert with multiple abnormal immune responses. The disease affects multiple organs and tissues and is characterized by the presence of hyperactive B lymphocytes that produce autoantibodies against a variety of self cell-derived antigens (being responsible for most of the clinical and pathologic manifestations of the disease). The current management of SLE employs drugs that act non-specifically to reduce the inflammation and lymphocyte hyperactivity that typify the disease. These drugs, that include corticosteroids, anti-malarials and immunosuppressive agents, are not curative and mainly aim at preventing complications and/or flares that could lead to organ damage and a subsequent increased morbidity and mortality. The targeting of B lymphocytes has always been envisioned as a possibly valuable therapeutic opportunity in SLE because of the major role of these cells in the pathogenesis of the disease as producers of pathogenic autoantibodies. One modality to reduce the number of B cells – and thus the production of autoantibodies – has employed the use of an antibody that depletes CD20 + B cells, called rituximab, that failed to show therapeutic efficacy in two phase III randomized placebo-controlled trials [20]. Another approach has used an antibody to BLyS – called belimumab – to inhibit B cell function and survival, and it showed efficacy in two phase III clinical trials that led in 2011 to the FDA approval as a new therapeutic agent for SLE.
3.1. BlyS in SLE Transgenic mice that overexpress BLyS have an expansion of the peripheral B-cell pool and with age develop a lupus-like disease with elevated autoantibody titers and glomerulonephritis [21], whereas mice genetically deficient of BLyS lack most mature follicular and MZ B cells [11], and APRIL knockout mice have deficient plasma cell survival [6]. Circulating BLyS is elevated in New-Zealand Black × New-Zealand White (NZB × NZW)F1 (NZB/W) and MRL-lpr/lpr lupus-prone mice and correlates with disease progression [22]. Conversely, BLyS antagonism in lupus-prone mice ameliorates disease and improves mice survival by reducing anti-dsDNA antibody levels and renal disease [22,23]. In view of the fact that BLyS can also interact with BCMA, a soluble BCMA–Ig fusion protein made of the BCMA extracellular domain fused to a human IgG1 Fc was tested in NZB/W lupus mice and found to decrease the number of peripheral B cells, to delay proteinuria, and to extend mice survival [24]. Also, treatment with TACI-Ig of MRL-lpr/lpr lupus mice led to a reduction of serum autoantibodies and kidney pathology and extended mice survival [25]. In humans, increased serum concentrations of BLyS and APRIL are found in rheumatoid arthritis, systemic sclerosis and SLE, where they correlate with anti-dsDNA autoantibody
3 levels and disease activity [26,27]. Particularly, BLyS is elevated in the serum of 20–67% lupus patients, and APRIL is increased in 38–53% lupus patients [28,8].
4. Belimumab Belimumab is a recombinant human IgG1λ monoclonal antibody whose use is indicated in the treatment of adult SLE patients with active, seropositive disease that are concomitantly receiving standard therapy. It binds to soluble BLyS and prevents its binding to its receptors. Mechanistically, belimumab does not kill B cells directly because it does not cause antibody-dependent cell cytotoxicity and complement activation.
4.1. Results from the clinical trials with belimumab A randomized, double-blind, placebo-controlled, dose-ranging phase I trial with belimumab in 2001 included 70 SLE patients with mild-to-moderate disease activity and showed safety but no clinical efficacy [29]. However, belimumab reduced the circulating anti-dsDNA antibodies and the number of peripheral CD20 + B cells [29]. A phase II trial was then initiated with 449 patients with active SLE in the United States and Canada. Patients were divided into groups to receive three different i.v. doses of belimumab or placebo in combination with “standard of care” (SOC) therapy [30]. The results of the trial indicated safety tolerability, biologic activity and efficacy but a lack of improvement in lupus disease activity scores in patients receiving belimumab. However, it was observed a delay in the median time to first flare and an improvement in many secondary disease activity measures, including a decrease in the mean physician's global assessment (PGA), a trend toward an improvement in the short form 36 (SF-36) physical component (PCS) score, and the need of reduced corticosteroid use [30]. At the immune level, memory B cell and long-lived plasma cells were preserved, while naïve, activated and plasmacytoid B were depleted by belimumab, and serum antibody titers were significantly reduced [31]. Although the phase II clinical trial with belimumab did not meet its primary endpoint, two large phase III SLE studies were initiated in serologically active SLE patients after it was observed that seropositive patients (with ANA and/or anti-dsDNA antibodies) treated with belimumab had met the primary endpoints. In these two phase III trials, belimumab i.v. significantly reduced SLE disease activity, flare rates and prednisone dose in seropositive patients. The double-blind, placebo-controlled, international multi-center superiority trials (called BLISS-52 and BLISS-76) used as primary endpoint the patient response rate measured by the SLE responder index (SRI), a new procedure that had never been used before, to define an improvement of disease activity without worsening of symptoms and/or patient's wellbeing, and without new symptoms in previously unaffected organs [32]. BLISS-52 enrolled 865 patients from Asia, South America and Eastern Europe for 52 weeks, while BLISS-76 analyzed 819 patients from North America and Europe for 76 weeks (the data of BLISS-76 were also analyzed at 52 weeks). The
Please cite this article as: A. La Cava, Targeting the BLyS-APRIL signaling pathway in SLE, Clin. Immunol. (2012), http://dx.doi.org/10.1016/ j.clim.2012.11.010
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results of BLISS-52 showed higher SRI in the belimumab vs. placebo groups, disease improvement including a delay in the time or risk to flare, and a reduction of prednisone dose. Circulating anti-dsDNA, anti-Sm, anti-ribosomal P and anticardiolipin autoantibodies were significantly reduced by belimumab treatment, and C3 and C4 complement levels were increased [33]. The BLISS-76 study confirmed at 52 weeks safety and improvement in SRI for the belimumab group, but not by the 76th week. There was also no significant difference in the reduction of steroid dosage among the treatment groups. However, better responses in disease scoring and a reduced risk to flare were present after belimumab treatment at both 52 and 76 weeks. Mechanistically, belimumab deleted about 49% of activated CD20 +CD69 + B cells and about 24% of naïve B cells, with a less effective deletion of memory B cells, and about 44% of CD20 + B cells remained after treatment in the BLISS-76 study [34].
best candidate responders to belimumab, to address possible synergy of concomitant therapies, to limit side effects, and to study efficacy of other routes of administration (the s.c. route is currently under investigation in ongoing clinical trials). Also, belimumab has not yet been tested in lupus nephritis although the phase III clinical trials indicated a positive trend for belimumab in reducing renal flares and proteinuria [42]. The understanding of the above aspects will lead to tailored approaches with improved efficacy and limited side effects following the administration of this drug.
Conflict of interest statement The author has no potential financial conflict of interest related to this manuscript.
References 4.2. Considerations on the belimumab trials Belimumab modulates the signaling downstream of BAFF-R, that in humans is expressed on mature B cells, memory B cells and CD138 + plasmablasts (early plasma cells), but not on bone marrow CD138 + plasma cells (mature plasma cells) [35]. The BLISS-76 trial showed a reduction in CD20 + cells, naïve CD20 +CD27 − B cells, activated CD20 +CD69 + B cells, and CD20 +CD138 + plasmablasts [36,31]. Reductions were also seen in CD20 −/CD27 bright short-lived plasma cells and CD20 +/CD138 + plasma cells [36]. Of note, belimumab did not modulate secondary immune response to pneumococcal, tetanus and influenza vaccines, suggesting that long-lived plasma cells and memory B cells were not affected by belimumab treatment [37].
5. Conclusions Belimumab is the first biologic agent approved by the FDA for the treatment of SLE after more than 50 years but many questions about this drug remain open. Possibly important aspects of the action of belimumab have not yet been investigated, such as the effect of BlyS blockade on T cells despite BAFF-R is expressed on T cells [38] and the costimulation of T cells by BLyS is known to lead to cell proliferation and the secretion of cytokines including IL-2, TNF-α, IFN-γ, IL-5 and IL-13 [39]. Also, whether or not belimumab leaves intact the B10 (or IL-10 producing B cells) that suppress inflammation remains elusive [40]. What is known is that the lupus-like disease that develops in BlyS transgenic mice depends on Toll-like receptor (TLR) signaling because these mice, reconstituted with MyD88 −/− B cells, are protected from disease [41] (MyD88 is the common signaling element to many TLR). In this context, TLR stimulation upregulates BAFF-R expression in B cells for a potential synergy between BlyS and TLR stimulation. Clinically, the relevance of the effect of belimumab seems overall to be mild and the drug may be only intended for patients with no life-threatening forms of SLE, considering that the clinical trials lacked data on patients with organ involvement associated with mortality (proliferative nephritis and CNS). At present, there is the need to identify the
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[39] B. Huard, P. Schneider, D. Mauri, J. Tschopp, L.E. French, T cell costimulation by the TNF ligand BAFF, J. Immunol. 167 (2001) 6225–6231. [40] S. Fillatreau, C.H. Sweenie, M.J. McGeachy, D. Gray, S.M. Anderton, B cells regulate autoimmunity by provision of IL-10, Nat. Immunol. 3 (2002) 944–950. [41] J.R. Groom, C.A. Fletcher, S.N. Walters, S.T. Grey, S.V. Watt, M.J. Sweet, M.J. Smyth, C.R. Mackay, F. Mackay, BAFF and
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Please cite this article as: A. La Cava, Targeting the BLyS-APRIL signaling pathway in SLE, Clin. Immunol. (2012), http://dx.doi.org/10.1016/ j.clim.2012.11.010
available at www.sciencedirect.com
Clinical Immunology www.elsevier.com/locate/yclim
REVIEW
Targeting the BLyS-APRIL signaling pathway in SLE Antonio La Cava ⁎ Department of Medicine, University of California Los Angeles, 1000 Veteran Avenue 32-59, Los Angeles, CA 90095-1670, USA
Received 18 October 2012; accepted with revision 28 November 2012
KEYWORDS BLyS/BAFF; APRIL; Systemic lupus erythematosus (SLE)
Abstract The B lymphocyte stimulator (BLyS)- A PRoliferation-Inducing Ligand (APRIL) signaling pathway has an important role in the selection, maturation and survival of B cells and plays a significant role in the pathogenesis of systemic lupus erythematosus (SLE). The inhibition of BLyS, a survival factor for transitional and mature B cells, has recently proven to be successful in large phase III clinical trials that led to the approval of an anti-BLyS monoclonal antibody (belimumab) for the treatment of SLE. Yet, there is currently a need to both understand better the mechanisms of action of belimumab in SLE and better define the subsets of patients that are more likely to respond to the drug. © 2012 Elsevier Inc. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . BLyS and APRIL . . . . . . . . . . . . . . . . . . . . . 2.1. BLyS and APRIL receptors . . . . . . . . . . . . 3. Systemic lupus erythematosus (SLE) . . . . . . . . . . 3.1. BlyS in SLE . . . . . . . . . . . . . . . . . . . . 4. Belimumab . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Results from the clinical trials with belimumab 4.2. Considerations on the belimumab trials . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Fax: + 1 310 206 8606. E-mail address: [email protected]. 1521-6616/$ - see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clim.2012.11.010 Please cite this article as: A. La Cava, Targeting the BLyS-APRIL signaling pathway in SLE, Clin. Immunol. (2012), http://dx.doi.org/10.1016/ j.clim.2012.11.010
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1. Introduction BLyS and APRIL are two members of the TNF ligand superfamily. Together with their cognate receptors, BLyS and APRIL regulate B lymphocyte homeostasis and play important roles in certain autoimmune diseases and malignancies (e.g., lymphomas). In autoimmunity, the inhibition of BLyS protects from disease, possibly by reducing the survival of autoreactive B cells. This aspect has led to the targeting of the BLyS/APRIL pathway for the modulation of the aberrant production of autoantibodies that characterizes systemic lupus erythematosus (SLE). In particular, an antibody blocking soluble BLyS, called belimumab, was approved in 2011 by the FDA for the therapy of SLE after two phase III clinical trials showed that this biologic agent, in combination with standard of care, significantly reduced SLE disease activity and flare rates in patients with active SLE. Notwithstanding the benefits of belimumab in SLE, the mechanisms of action of this drug are only partially known, and it is not known how much of the deletion of transitional and naïve B cells can explain the observed efficacy of belimumab in SLE. Additional factors could include a modulation of antigen presentation to T cells, effects on T cell function, and/or an influence of belimumab on the production of cytokines and chemokines.
2. BLyS and APRIL BlyS (also called B cell activating factor, BAFF) is a B-cell survival factor that inhibits B cell apoptosis and favors B-cell proliferation and maturation, antibody production and IgG class switching [1–3]. APRIL mediates effects that are similar to those of BLyS. BLyS and APRIL are produced by monocytes/macrophages, dendritic cells, neutrophils, activated T cells, some B cells and non-hematopoietic cells [4]. Blys is synthesized as a homotrimeric transmembrane protein that can be cleaved into soluble homotrimers, or it can be found in soluble form as a circulating capsid-like structure of twenty trimers (a 60-mer) [5]. APRIL is a soluble protein but can also be found as a membrane-bound hybrid molecule called TWE-PRIL (formed by the trans-splicing of
Immature
Transitional
Naïve
TWEAK [TNF-related weak inducer of apoptosis] with APRIL) [6,7]. Heterotrimers of BLyS and APRIL, composed of one or two BLyS monomers with one or two APRIL monomers, are also commonly found and are typically elevated in the serum of SLE patients [8].
2.1. BLyS and APRIL receptors BLyS can bind to three different receptors that are expressed on B cells. One receptor is the BAFF receptor (BAFF-R or BR3) and is highly specific for BLyS. BAFF-R in humans is expressed by all B cells except bone marrow plasma cells [9]. BAFF-R is the predominant receptor on naïve and memory B cells [10,11]. Another receptor is called TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and is expressed on CD27 + memory B cells and bone marrow plasma cells. TACI is the predominant receptor on (MZ) zone B cells and short-lived plasma cells and acts as a negative regulator during B cell maturation. TACI deficiency in mice leads to defective B cell responses to T-independent antigens [12]. The third receptor is called BCMA (B lymphocyte maturation antigen), is expressed by some memory B cells and GC B cells and plasma cells, and influences the survival of long-lived bone marrow plasma cells [13,14]. BCMA is the predominant receptor on long-lived plasma cells, where it has an important role in cell survival, also in plasma blasts [15]. Interestingly, TACI and BCMA can bind to both BLyS and APRIL [6]. In terms of developmental expression, functional BLyS receptors on B cells appear at the transitional stage, thus affecting only the survival of mature B cells and making BlyS ineffective on the B-cell precursors that express CD20 ant not BLyS receptors (Fig. 1). Mechanistically, the signaling through BAFF-R controls B cell numbers by varying the proportion of cells that complete transitional B cell development, and by serving as the primary determinant of mature B cell longevity [16]. Additionally, studies on B cells from mice deficient in TACI, BCMA, and BAFF-R indicate that both TACI and BAFF-R transduce signals that result in isotype switching [17].
Germinal Center
Plasmablast
Plasmacell
Memory (MZ) BM Spleen LT Blood Gut, Tonsils
Fig. 1 Stages of B cell development and relative cell surface expression of BLyS/APRIL receptors. BAFF-R is represented as triangle(s), BCMA as rhomboid(s), and TACI as pentagon. Please cite this article as: A. La Cava, Targeting the BLyS-APRIL signaling pathway in SLE, Clin. Immunol. (2012), http://dx.doi.org/10.1016/ j.clim.2012.11.010
Targeting the BLyS-APRIL signaling pathway in SLE The effects of APRIL and BAFF on IL-6 and GM-CSF appear instead mediated by BCMA [18], a receptor that can also induce the arrest of cell growth [19].
3. Systemic lupus erythematosus (SLE) SLE has a multifactorial etiology that involves the contribution of only partly known environmental and genetic factors which act in concert with multiple abnormal immune responses. The disease affects multiple organs and tissues and is characterized by the presence of hyperactive B lymphocytes that produce autoantibodies against a variety of self cell-derived antigens (being responsible for most of the clinical and pathologic manifestations of the disease). The current management of SLE employs drugs that act non-specifically to reduce the inflammation and lymphocyte hyperactivity that typify the disease. These drugs, that include corticosteroids, anti-malarials and immunosuppressive agents, are not curative and mainly aim at preventing complications and/or flares that could lead to organ damage and a subsequent increased morbidity and mortality. The targeting of B lymphocytes has always been envisioned as a possibly valuable therapeutic opportunity in SLE because of the major role of these cells in the pathogenesis of the disease as producers of pathogenic autoantibodies. One modality to reduce the number of B cells – and thus the production of autoantibodies – has employed the use of an antibody that depletes CD20 + B cells, called rituximab, that failed to show therapeutic efficacy in two phase III randomized placebo-controlled trials [20]. Another approach has used an antibody to BLyS – called belimumab – to inhibit B cell function and survival, and it showed efficacy in two phase III clinical trials that led in 2011 to the FDA approval as a new therapeutic agent for SLE.
3.1. BlyS in SLE Transgenic mice that overexpress BLyS have an expansion of the peripheral B-cell pool and with age develop a lupus-like disease with elevated autoantibody titers and glomerulonephritis [21], whereas mice genetically deficient of BLyS lack most mature follicular and MZ B cells [11], and APRIL knockout mice have deficient plasma cell survival [6]. Circulating BLyS is elevated in New-Zealand Black × New-Zealand White (NZB × NZW)F1 (NZB/W) and MRL-lpr/lpr lupus-prone mice and correlates with disease progression [22]. Conversely, BLyS antagonism in lupus-prone mice ameliorates disease and improves mice survival by reducing anti-dsDNA antibody levels and renal disease [22,23]. In view of the fact that BLyS can also interact with BCMA, a soluble BCMA–Ig fusion protein made of the BCMA extracellular domain fused to a human IgG1 Fc was tested in NZB/W lupus mice and found to decrease the number of peripheral B cells, to delay proteinuria, and to extend mice survival [24]. Also, treatment with TACI-Ig of MRL-lpr/lpr lupus mice led to a reduction of serum autoantibodies and kidney pathology and extended mice survival [25]. In humans, increased serum concentrations of BLyS and APRIL are found in rheumatoid arthritis, systemic sclerosis and SLE, where they correlate with anti-dsDNA autoantibody
3 levels and disease activity [26,27]. Particularly, BLyS is elevated in the serum of 20–67% lupus patients, and APRIL is increased in 38–53% lupus patients [28,8].
4. Belimumab Belimumab is a recombinant human IgG1λ monoclonal antibody whose use is indicated in the treatment of adult SLE patients with active, seropositive disease that are concomitantly receiving standard therapy. It binds to soluble BLyS and prevents its binding to its receptors. Mechanistically, belimumab does not kill B cells directly because it does not cause antibody-dependent cell cytotoxicity and complement activation.
4.1. Results from the clinical trials with belimumab A randomized, double-blind, placebo-controlled, dose-ranging phase I trial with belimumab in 2001 included 70 SLE patients with mild-to-moderate disease activity and showed safety but no clinical efficacy [29]. However, belimumab reduced the circulating anti-dsDNA antibodies and the number of peripheral CD20 + B cells [29]. A phase II trial was then initiated with 449 patients with active SLE in the United States and Canada. Patients were divided into groups to receive three different i.v. doses of belimumab or placebo in combination with “standard of care” (SOC) therapy [30]. The results of the trial indicated safety tolerability, biologic activity and efficacy but a lack of improvement in lupus disease activity scores in patients receiving belimumab. However, it was observed a delay in the median time to first flare and an improvement in many secondary disease activity measures, including a decrease in the mean physician's global assessment (PGA), a trend toward an improvement in the short form 36 (SF-36) physical component (PCS) score, and the need of reduced corticosteroid use [30]. At the immune level, memory B cell and long-lived plasma cells were preserved, while naïve, activated and plasmacytoid B were depleted by belimumab, and serum antibody titers were significantly reduced [31]. Although the phase II clinical trial with belimumab did not meet its primary endpoint, two large phase III SLE studies were initiated in serologically active SLE patients after it was observed that seropositive patients (with ANA and/or anti-dsDNA antibodies) treated with belimumab had met the primary endpoints. In these two phase III trials, belimumab i.v. significantly reduced SLE disease activity, flare rates and prednisone dose in seropositive patients. The double-blind, placebo-controlled, international multi-center superiority trials (called BLISS-52 and BLISS-76) used as primary endpoint the patient response rate measured by the SLE responder index (SRI), a new procedure that had never been used before, to define an improvement of disease activity without worsening of symptoms and/or patient's wellbeing, and without new symptoms in previously unaffected organs [32]. BLISS-52 enrolled 865 patients from Asia, South America and Eastern Europe for 52 weeks, while BLISS-76 analyzed 819 patients from North America and Europe for 76 weeks (the data of BLISS-76 were also analyzed at 52 weeks). The
Please cite this article as: A. La Cava, Targeting the BLyS-APRIL signaling pathway in SLE, Clin. Immunol. (2012), http://dx.doi.org/10.1016/ j.clim.2012.11.010
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results of BLISS-52 showed higher SRI in the belimumab vs. placebo groups, disease improvement including a delay in the time or risk to flare, and a reduction of prednisone dose. Circulating anti-dsDNA, anti-Sm, anti-ribosomal P and anticardiolipin autoantibodies were significantly reduced by belimumab treatment, and C3 and C4 complement levels were increased [33]. The BLISS-76 study confirmed at 52 weeks safety and improvement in SRI for the belimumab group, but not by the 76th week. There was also no significant difference in the reduction of steroid dosage among the treatment groups. However, better responses in disease scoring and a reduced risk to flare were present after belimumab treatment at both 52 and 76 weeks. Mechanistically, belimumab deleted about 49% of activated CD20 +CD69 + B cells and about 24% of naïve B cells, with a less effective deletion of memory B cells, and about 44% of CD20 + B cells remained after treatment in the BLISS-76 study [34].
best candidate responders to belimumab, to address possible synergy of concomitant therapies, to limit side effects, and to study efficacy of other routes of administration (the s.c. route is currently under investigation in ongoing clinical trials). Also, belimumab has not yet been tested in lupus nephritis although the phase III clinical trials indicated a positive trend for belimumab in reducing renal flares and proteinuria [42]. The understanding of the above aspects will lead to tailored approaches with improved efficacy and limited side effects following the administration of this drug.
Conflict of interest statement The author has no potential financial conflict of interest related to this manuscript.
References 4.2. Considerations on the belimumab trials Belimumab modulates the signaling downstream of BAFF-R, that in humans is expressed on mature B cells, memory B cells and CD138 + plasmablasts (early plasma cells), but not on bone marrow CD138 + plasma cells (mature plasma cells) [35]. The BLISS-76 trial showed a reduction in CD20 + cells, naïve CD20 +CD27 − B cells, activated CD20 +CD69 + B cells, and CD20 +CD138 + plasmablasts [36,31]. Reductions were also seen in CD20 −/CD27 bright short-lived plasma cells and CD20 +/CD138 + plasma cells [36]. Of note, belimumab did not modulate secondary immune response to pneumococcal, tetanus and influenza vaccines, suggesting that long-lived plasma cells and memory B cells were not affected by belimumab treatment [37].
5. Conclusions Belimumab is the first biologic agent approved by the FDA for the treatment of SLE after more than 50 years but many questions about this drug remain open. Possibly important aspects of the action of belimumab have not yet been investigated, such as the effect of BlyS blockade on T cells despite BAFF-R is expressed on T cells [38] and the costimulation of T cells by BLyS is known to lead to cell proliferation and the secretion of cytokines including IL-2, TNF-α, IFN-γ, IL-5 and IL-13 [39]. Also, whether or not belimumab leaves intact the B10 (or IL-10 producing B cells) that suppress inflammation remains elusive [40]. What is known is that the lupus-like disease that develops in BlyS transgenic mice depends on Toll-like receptor (TLR) signaling because these mice, reconstituted with MyD88 −/− B cells, are protected from disease [41] (MyD88 is the common signaling element to many TLR). In this context, TLR stimulation upregulates BAFF-R expression in B cells for a potential synergy between BlyS and TLR stimulation. Clinically, the relevance of the effect of belimumab seems overall to be mild and the drug may be only intended for patients with no life-threatening forms of SLE, considering that the clinical trials lacked data on patients with organ involvement associated with mortality (proliferative nephritis and CNS). At present, there is the need to identify the
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