Belimumab, a BLyS-specific inhibitor for the treatment of systemic lupus erythematosus

As B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), therapies targeting them may provide a valuable treatment for patients with SLE. One of the therapeutic strategies for B-cell targeting is through the inhibition of factors involved in the survival or differentiation of B cells. B-cell-activating factor (BAFF) or B-lymphocyte stimulator (BlyS; trademark of Human Genome Sciences, Rockville, MD, USA) has proven to be a key factor in the selection and survival of B cells. Belimumab is a fully human monoclonal antibody (immunoglobulin G1) that binds to soluble BAFF and inhibits it from binding to its receptors. To date, two phase III trials have demonstrated that belimumab in combination with standard of care significantly reduced SLE disease activity and SLE flare rates in patients with active SLE. In addition, it was generally well tolerated. This article reviews the immune mechanisms induced by the inhibition of BAFF/BLyS and the evidence-based clinical effectiveness of belimumab in SLE patients.     

贝利木单抗治疗系统性红斑狼疮的模型化疗效评价

目的:贝利木单抗是一种完全人源化IgGl-X单克隆抗体,可特异性结合可溶性B细胞刺激因子(BLyS),阻止BLyS与B细胞结合,促进B细胞凋亡,是FDA批准的第一个治疗系统性红斑狼疮(SLE)的新药。本研究基于该药物的全球临床文献数据,通过建模分析,评价贝利木单抗治疗SLE效应,定量表达其药效特征,并探索其潜在影响因素,从而建立贝利木单抗治疗SLE的疗效尺度,为治疗SLE的药物开发提供参照。方法:在Pubmed数据库中进行文献检索,纳入贝利木单抗治疗SLE的临床试验研究,提取受试者基线期人口学特征、用药剂量、给药方式、疗效和安全性等信息,建立分析数据库,再构建药效学模型,评价本药的药效特征。采用多种模型评价方法评价模型的稳健性。结果:最终有5篇含疗效文献纳入,涉及11个剂量组(N=3493)纳入模型构建;协变量筛选显示,种族(亚洲人群或非亚洲人群)、年龄、病程、Anti-dsDNA阳性对贝利木单抗治疗SLE的疗效无显著影响,最终未发现对模型参数有显著性影响的因素。模型评价显示本研究建立的模型能较好地描述贝利木单抗治疗SLE的量效关系。最终模型提示,疗效指标SRI应答率在第52周已接近峰值(约达峰值水平99%)。安慰剂组、贝利木单抗1 mg/kg静注、10 mg/kg静注和200 mg皮下注射在第52周的SRI应答率分别为46.1%、52.9%、57.9%和60.9%。扣除安慰剂效应后,贝利木单抗1 mg/kg静注、10 mg/kg静注和200 mg皮下注射在第52周的SRI应答率(药物纯效应)分别为6.8%、11.8%和14.8%。结论:贝利木单抗治疗SLE患者的疗效(SRI反应率)在第52周已接近峰值。贝利木单抗1 mg/kg静注、10 mg/kg静注和200 mg皮下注射在第52周的SRI应答率分别为52.9%、57.9%和60.9%。     

Belimumab Human Genome Sciences/Cambridge Antibody Technology/GlaxoSmithKline

Belimumab, the lead in a series of human monoclonal antibodies against the human protein B-lymphocyte stimulator (BLyS), is under development by Human Genome Sciences, Cambridge Antibody Technology and GlaxoSmithKline for the potential treatment of autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). By January 2006, belimumab had completed phase II clinical trials in SLE and RA; a phase III clinical SLE trial is scheduled to begin later this year.     

Targeting B lymphocyte stimulator in systemic lupus erythematosus and other autoimmune rheumatic disorders

B lymphocyte stimulator (BLyS) is a vital B cell survival factor. Overexpression of BLyS in mice can lead to systemic lupus erythematosus (SLE)-like disease and to Sjögren’s syndrome (SS)-like disease. Treatment of mice with established SLE with BLyS antagonists ameliorates disease progression and enhances survival. Moreover, similar treatment of mice with inflammatory arthritis ameliorates the ongoing inflammation and subsequent joint destruction. In humans, BLyS overexpression is common in patients with SLE, rheumatoid arthritis or SS. Results from a Phase I clinical trial with a BLyS antagonist in human SLE have shown the antagonist to be biologically active and safe. These features collectively point to BLyS as an attractive therapeutic target in human disease.     

Targeting B lymphocyte stimulator in systemic lupus erythematosus and other autoimmune rheumatic disorders

B lymphocyte stimulator (BLyS) is a vital B cell survival factor. Overexpression of BLyS in mice can lead to systemic lupus erythematosus (SLE)-like disease and to Sj?gren's syndrome (SS)-like disease. Treatment of mice with established SLE with BLyS antagonists ameliorates disease progression and enhances survival. Moreover, similar treatment of mice with inflammatory arthritis ameliorates the ongoing inflammation and subsequent joint destruction. In humans, BLyS overexpression is common in patients with SLE, rheumatoid arthritis or SS. Results from a Phase I clinical trial with a BLyS antagonist in human SLE have shown the antagonist to be biologically active and safe. These features collectively point to BLyS as an attractive therapeutic target in human disease.     

Belimumab: anti-BLyS human monoclonal antibody, anti-BLyS monoclonal antibody, BmAb, human monoclonal antibody to B-lymphocyte stimulator

Belimumab is a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS. Belimumab is in phase III trials for the treatment of systemic lupus erythematosus (SLE) and has completed a phase II trial in rheumatoid arthritis (RA); the product may also have potential in the treatment of other autoimmune disorders. In May 2001, Cambridge Antibody Technology (now MedImmune) completed its discovery programme and Human Genome Sciences identified belimumab as a candidate for clinical development. More than 1000 distinct human antibodies specific to BLyS were characterized by the collaboration.B-lymphocyte stimulator is a naturally occurring protein discovered by Human Genome Sciences that stimulates B-lymphocytes to develop into mature B cells. Laboratory studies have indicated that higher than normal levels of B-lymphocyte stimulator may contribute to the pathogenesis of autoimmune diseases, such as SLE and RA. Human Genome Sciences (HGS) and Cambridge Antibody Technology signed a collaborative agreement in August 1999 to study the B-lymphocyte stimulator as a human protein target. HGS is also developing other BLyS products. In March 2000, HGS and Cambridge Antibody Technology expanded their agreement into a 10-year collaboration and product development alliance, providing Human Genome Sciences with the right to use the antibody technology of Cambridge Antibody Technology to fully develop human antibodies for therapeutic and diagnostic purposes. Cambridge Antibody Technology will receive royalty payments on product sales from HGS, as well as the development and milestone payments it has already received. Belimumab will be manufactured in Human Genome Sciences' manufacturing facility, located in Rockville, MD, USA. HGS holds commercial rights to the drug. In July 2005, GlaxoSmithKline (GSK) exercised its co-development and co-promotion option to belimumab. In an agreement made in June 1996, HGS had granted a 50/50 co-development and co-promotion option to GSK for certain therapies that complete phase IIa trials successfully. The companies subsequently entered into a definite worldwide, co-development and commercialization agreement in August 2006, under which HGS will be responsible for conducting phase III trials of the product, with assistance from GSK. The companies will share equally phase III/IV development costs, sales and marketing expenses, and profits. In October 2007, Cambridge Antibody Technology was integrated into MedImmune. Both companies were previously independent subsidiaries of AstraZeneca. MedImmune is now the operationally independent biologics business unit of AstraZeneca. Human Genome Sciences intends to initiate a phase II trial of subcutaneous belimumab by mid-2008. Results from a phase II trial in 449 patients with SLE demonstrated that belimumab improved or stabilized SLE over 2.5 years. The phase II trial was a double-blind, placebo-controlled, multicentre study that evaluated the safety, optimal dosing, and preliminary efficacy of belimumab in patients with active SLE over 52 weeks initially, followed by a continuation phase for a total of 2.5 years. Belimumab has received fast-track designation for the treatment of SLE from the US FDA and has also been selected for inclusion in the agency's continuous Marketing Application Pilot 2 programme.     

Therapeutic targeting of B lymphocyte stimulator (BLyS) in the rheumatic diseases

B lymphocyte stimulator (BLyS) is a vital B cell survival factor. Overexpression of BLyS in mice can lead to clinical and serological features of systemic lupus erythematosus (SLE) and Sj?gren's syndrome (SS). Treatment with BLyS antagonists of mice with established SLE ameliorates disease progression and enhances survival. Moreover, similar treatment of mice with inflammatory arthritis ameliorates the ongoing inflammation and subsequent joint destruction. In humans, BLyS overexpression is common in patients with several rheumatic diseases, including SLE, rheumatoid arthritis (RA), Sj?gren's syndrome, scleroderma, Wegener's granulomatosis, and ANCA-associated vasculitis. Results from phase-II clinical trials with a BLyS antagonist in human SLE and RA have shown the antagonist to have biological and clinical activity along with a favorable safety profile. These features collectively point to BLyS as an attractive therapeutic target in human rheumatic diseases.     

Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: pharmacokinetic, pharmacodynamic, and toxicologic effects.

The tolerability, pharmacodynamic effects, and pharmacokinetics of belimumab (LymphoStat-B) were evaluated in cynomolgus monkeys. Belimumab is a fully human IgG1lambda antibody directed against B-lymphocyte stimulator (BLyS) protein. BLyS is a TNF family member that supports B-lymphocyte maturation and survival and has been implicated in the pathogenesis of autoimmune diseases and B-lymphocyte malignancies. Belimumab was developed to antagonize BLyS activity in autoimmune diseases and B-lymphocyte malignancies, where undesirable effects of B-lymphocyte activity may cause or contribute to disease. Pharmacodynamic effects of belimumab were monitored by immunophenotyping of peripheral blood. Pathology end points, including tissue immunophenotyping, are described after 13 and 26 weeks of treatment and after a 34-week treatment-free (recovery) period. Belimumab was safe and well tolerated in repeat-dose toxicology studies at 5-50 mg/kg for up to 26 weeks. Monkeys exposed to belimumab had significant decreases in peripheral blood B lymphocytes by 13 weeks of exposure, continuing into the recovery period, despite total lymphocyte counts similar to the controls. There were concomitant decreases in spleen and lymph node B-lymphocyte representation after 13 or 26 weeks of treatment with belimumab. Microscopically, monkeys treated with belimumab for 13 or 26 weeks had decreases in the number and size of lymphoid follicles in the white pulp of the spleen. All findings were generally reversible within a 34-week recovery period. These data confirm the specific pharmacologic activity of belimumab in reducing B lymphocytes in the cynomolgus monkey. The favorable safety profile and lack of treatment-related infections also support continued clinical development of belimumab.     

Belimumab: in systemic lupus erythematosus

Belimumab is a fully human recombinant IgG1λ monoclonal antibody that inhibits the binding of soluble B lymphocyte stimulator to B cells and hence prevents the survival and differentiation of selected B-cell subsets. It is available in the US, the EU and Canada for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity despite receiving standard therapy. At 52 weeks, a significantly greater proportion of belimumab 10?mg/kg than placebo recipients experienced a response as assessed by the SLE Responder Index (primary endpoint) in the randomized, double-blind, multinational, phase III BLISS-52 and BLISS-76 trials in patients with active seropositive SLE receiving standard therapy. A significantly greater proportion of belimumab than placebo recipients achieved a ≥4 point reduction in the SELENA-SLEDAI score at week 52 in both BLISS trials. However, the SLE Responder Index response rate was not significantly different between belimumab and placebo at 76 weeks in BLISS-76. Belimumab was generally well tolerated in the BLISS trials. During the double-blind periods of these trials and the phase II trial, twice as many deaths were reported with belimumab than placebo (six vs three). There were no meaningful differences between the incidence of serious infections and malignancies with belimumab or placebo.     

B-cell-targeted therapy for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex disease characterised by numerous autoantibodies and clinical involvement in multiple organ systems. The immunological events triggering the onset of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis of this disease has more recently gained prominence as a result of research in both mice and humans. Both antibody-dependent and -independent mechanisms of B cells are important in SLE. Autoantibodies contribute to autoimmunity by multiple mechanisms, including immune complex-mediated type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines such as interferon-alpha, tumour necrosis factor and interleukin-1. Suggested autoantibody-independent B-cell functions include antigen presentation, T-cell activation and polarisation, and dendritic-cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines, chemokines and lymphangiogenic growth factors, and by their critical contribution to lymphoid tissue development and organisation, including the development of ectopic tertiary lymphoid tissue. Given the large body of evidence implicating abnormalities in the B-cell compartment in SLE, a recent therapeutic focus has been to develop interventions that target the B-cell compartment by multiple mechanisms.Rituximab, a mouse-human chimeric monoclonal antibody against CD20 that specifically depletes B cells, has been studied the most extensively. Although promising open-label data await confirmation in ongoing multicentre placebo-controlled trials, a number of preliminary conclusions can be drawn. The adequacy of peripheral B-cell depletion depends on achieving high and sustained serum rituximab concentrations, pharmacokinetics that can be varied with treatment dose and factors that may affect drug clearance, such as human anti-chimeric antibodies. In SLE patients with effective B-cell depletion, the clinical response can be significant, with favourable responses observed in a diverse array of disease manifestations. Moreover, rituximab appears to have the potential to induce clinical remission in severe, refractory disease. B-cell depletion has the potential to induce disease amelioration by inhibiting autoantibody production and/or by interfering with other B-cell pathogenic functions. The fact that clinical improvement correlates with B-cell depletion and precedes by several months any decline in serum levels of relevant autoantibodies suggests a predominant effect of autoantibody-independent functions of B cells, although the subset of patients with disease remission ultimately also experience autoantibody normalisation. Significant questions remain about rituximab therapy in SLE, including the immunological determinants of treatment response and remission, the role of combination therapy, and the safety of repeated courses of rituximab. In addition, the efficacy and role of other B-cell-depleting approaches, such as humanised anti-CD20 antibodies and anti-CD22, remain to be defined.Another B-cell-targeted therapeutic approach is to block costimulatory interactions between T and B cells. Blockade of the CD40-CD40 ligand pathway has met with variable clinical benefit and unfortunate thromboembolic complications, although inhibition of the B7 pathway with cytotoxic T-lymphocyte antigen-4Ig is currently under early investigation in SLE clinical trials. Preliminary data on the treatment of SLE with belimumab, a fully human monoclonal antibody that specifically binds to and neutralises the B-lymphocyte stimulator (BLyS or B-cell-activating factor [BAFF]), are now available. In a phase II double-blind, placebo-controlled trial of the safety and efficacy of three different doses administered in addition to standard therapy, belimumab was well tolerated but reportedly did not meet primary efficacy endpoints. Blockade of BAFF is still viewed as a promising therapeutic approach and additional agents that interfere with the BAFF pathway are under study.Overall, therapies targeting B cells appear to be promising in the treatment of SLE, provide additional evidence for the importance of B cells to disease pathogenesis, and will continue to elucidate the diverse roles of B cells in this disease.     

B淋巴细胞刺激因子的药学前景

B淋巴细胞刺激因子(BlyS)是肿瘤坏死因子(TNF)超家族的一名新成员,它与某些免疫疾病的致病机制密切相关.从BlyS的生物学结构和功能入手,阐述与其相关的免疫缺陷病、自身免疫疾病和淋巴瘤等免疫疾病,以及B1yS治疗性蛋白、BlyS蛋白拮抗物、放射性BlyS蛋白的临床应用前景.     

霉酚酸酯在系统性红斑狼疮中的应用进展

霉酚酸酯作为一种新型免疫抑制剂，已经成功应用干预防器官移植过程中的急性移植物抗排斥反应．它也应用于治疗多种自身免疫性疾病。对系统性红斑狼疮的治疗主要集中在增殖性狼疮肾炎，目前霉酚酸酯正用于控制狼疮的其他症状，如狼疮病情活动、血液系统症状以及难治性皮肤性狼疮。现综述霉酚酸酯在治疗系统性红斑狼疮中的进展。     

Novel treatments for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease that is associated with the production of autoantibodies, and with considerable morbidity and mortality. There has been much interest in developing more specific therapies for this disease, which is currently managed with immunosuppressive drugs, predominantly corticosteroids, azathioprine, methotrexate and cyclophosphamide, in combination with hydroxychloroquine. Mycophenolate mofetil has been demonstrated to be as efficacious as cyclophosphamide in patients with lupus nephritis, and is being used increasingly in the clinic despite not being licensed for this indication. Novel methods of reducing autoantibody formation in SLE include the use of mAbs that modulate and/or deplete B-cells (anti-CD22 and anti-CD20 antibodies, respectively), or that interfere with the stimulatory effects of the soluble factor B-lymphocyte stimulator (anti-BLys antibodies). Alternative approaches include the use of atacicept (Merck Serono), a transmembrane activator and calcium modulator ligand interactor (TACI)-Ig fusion protein, which inhibits B-cell stimulation by binding to BLys and a profileration-inducing ligand (APRIL), or toleragens such as abetimus. Blocking costimulatory molecule interactions, such as the CD40-CD40 ligand interaction with mAbs and the CD28-B7 interaction with a soluble cytotoxic T-lymphocyte antigen 4 (CTLA-4)-IgG1 construct (abatacept), has also been attempted as a therapeutic strategy for SLE. The most promising strategy for a new drug for SLE is belimumab (Human Genome Sciences/GlaxoSmithKline), an anti-BLys antibody, as two phase III clinical trials with this drug recently met their primary endpoints. In this review, these novel approaches to the treatment of SLE, including the potential of targeting cytokine pathways involved in autoimmunity, are discussed.     

Challenges in bringing the bench to bedside in drug development for SLE

It is now widely accepted that the current standard of care for systemic lupus erythematosus (SLE) patients is inadequate. There has not been a new medication approved for this disease in thirty years. Attempts to develop and test new drugs have been ongoing since the mid-1990s, but have encountered formidable obstacles. Current models for lupus pathogenesis have provided a theoretical framework for understanding how heterogeneous genetic defects might combine in various ways to increase susceptibility to SLE in different individuals, and could have important implications for new drug development. With the current burst of drug discovery and increased public awareness of SLE, the impetus to overcome these obstacles has never been greater.     

Beyond transitional selection: New roles for BLyS in peripheral tolerance

B cell targeted therapies have enjoyed recent success in the treatment of systemic autoimmune diseases. Among these, Belimumab, which blocks the B cell survival cytokine BLyS, was recently approved for the treatment of Systemic Lupus Erythematosus. It is therefore important to consider the roles BLyS plays in B cell tolerance. Herein, we review how BLyS contributes to the negative selection of autoreactive B cell clones from the preimmune repertoire as well as its role in regulating both germinal center and extrafollicular peripheral B cell responses. We further examine the complex role of Toll-like receptors (TLRs) in humoral autoimmunity, pointing out potential crosstalk between BLyS and TLR pathways.     

早期应用贝利尤单抗治疗儿童系统性红斑狼疮的临床意义

目的:探讨早期应用贝利尤单抗(BLM)治疗儿童系统性红斑狼疮(SLE)的价值。 方法:选取我院肾脏风湿免疫科 2020-2021 年住院确诊为 SLE 的患儿 23 例,分为三组:对照组(初诊未用 BLM)7 例、初发组(初诊即用 BLM)7 例、复发组(复发才用BLM)9 例,分析三组患儿使用 BLM 前后相关炎症指标、系统性红斑狼疮疾病活动度(SLEDAI)评分、激素用量等变化,比较三组患儿临床疗效。 结果:儿童 SLE 使用 BLM 后激素用量、SLEDAI 评分、血沉均降低(P 均<0. 01),且初发组临床缓解时间、激素用量、SLEDAI 评分均小于对照组(P 均<0. 05);复发组临床缓解时间长于初发组(P<0. 05);临床缓解时间与病程呈正相关(r =0. 606,P<0. 05)。 结论:BLM 治疗儿童 SLE 安全有效,可减少激素用量,降低疾病活动度,且早期应用更易缓解疾病。     

Balancing efficacy and toxicity of novel therapies in systemic lupus erythematosus

Therapy of systemic lupus erythematosus has been facing the paradox of an overwhelming rate of trials testing novel potential therapeutic agents and the lack of US FDA approval of a single new drug for over five decades. Heterogeneity in disease phenotype, concomitant immunosuppressive medication and a lack of unequivocal hard end points for clinical trials have proven to be significant obstacles in establishing efficacy of candidate therapies. Nevertheless, combination regimens with already existing agents have shown efficacy with acceptable safety profiles, mainly in cases of refractory to conventional treatment disease. At the same time, positive results from trials with belimumab, an antibody that targets B cells, opened the way for approval of this agent for the treatment of lupus and lends hope for a new era in systemic lupus erythematosus therapeutics. Here, we review the latest advances in systemic lupus erythematosus therapy, focusing on the balance between efficacy and safety for combination therapeutic regimens and biologics under development.     

Balancing efficacy and toxicity of novel therapies in systemic lupus erythematosus

Therapy of systemic lupus erythematosus has been facing the paradox of an overwhelming rate of trials testing novel potential therapeutic agents and the lack of US FDA approval of a single new drug for over five decades. Heterogeneity in disease phenotype, concomitant immunosuppressive medication and a lack of unequivocal hard end points for clinical trials have proven to be significant obstacles in establishing efficacy of candidate therapies. Nevertheless, combination regimens with already existing agents have shown efficacy with acceptable safety profiles, mainly in cases of refractory to conventional treatment disease. At the same time, positive results from trials with belimumab, an antibody that targets B cells, opened the way for approval of this agent for the treatment of lupus and lends hope for a new era in systemic lupus erythematosus therapeutics. Here, we review the latest advances in systemic lupus erythematosus therapy, focusing on the balance between efficacy and safety for combination therapeutic regimens and biologics under development.     

Targeting the CXCR4/CXCL12 axis in systemic lupus erythematosus

Background: CXCR4 antagonists have garnered much interest as promising treatments for cancer metastases and HIV. Given its ability to attract multiple leukocyte subsets and stimulate B cell production and myelopoeisis, recent attention has been directed to these inhibitors in the treatment of autoimmune diseases, such as systemic lupus erythematosus (SLE). Objective: To assess the potential of CXCR4 antagonists in SLE. Methods: We reviewed literature on the expression of CXCR4 and its ligand CXCL12, and the effects of CXCR4 antagonists in murine and human SLE. Results/conclusions: CXCR4 and CXCL12 have been found at abundant levels in peripheral blood leukocyte subsets as well as immune and non-immune organs in lupus-prone murine models. While SLE patients have displayed upregulated, downregulated, or unchanged levels of CXCR4 in circulating blood lymphocytes, CXCR4 and CXCL12 were found prominently in the skin and kidney, suggesting that the ultimate destinations of CXCR4⁺ cells include these areas. CXCR4 antagonists have been explored in murine lupus models, in which disease severity and nephritis significantly improved. While clinical trials of CXCR4 antagonists in SLE have yet to be initiated, these inhibitors appear to have the potential to improve disease prognosis in severe lupus patients, particularly those with lupus nephritis.