Critical Review BAFF/BLyS Inhibitors: A New Prospect for Treatment of Systemic Lupus Erythematosus Kirsten Fairfax, Ian R. Mackay, and Fabienne Mackay Faculty of Medicine, Department of Immunology, Central Clinical School, Nursing and Health Sciences, Monash University, Melbourne, Australia Summary In November 2009, Human Genome Sciences and Glaxo- Smith Kline [HGS (Rockville, Maryland) and GSK, respec- tively] announced that Belimumab, a neutralizing antibody to the tumour necrosis factor (TNF)-like ligand, B-cell activating factor (BAFF belonging to the TNF family, also named BLyS), met the primary endpoints in two phase III clinical trials in sys- temic lupus erythematosus (SLE, lupus). In March 2011, Beli- mumab was approved by the US Federal Drug Agency for treatment of SLE patients; this was followed in May with ap- proval by the European Medicines Agency for use in the Euro- pean Union. This is an exciting development as it is the first successful late-stage clinical trial in SLE in over 40 years. In the light of this breakthrough, we review the key data and research outcomes and examine how blocking BAFF in patients with SLE significantly improves clinical outcomes. Ó 2012 IUBMB IUBMB Life, 64(7): 595–602, 2012 Keywords BAFF; Belimumab; BLyS; Lymphostat-B; Benlysta; Ata- cicept; B cells; T cells; IL-10; B1 B cells. INTRODUCTION BAFF appeared in the literature when it was cloned in 1999 (1–4). At that time, the pharmaceutical/biotech world had entered the era of DNA database mining, and a race for identifying the full sequence of new factors with potential as therapeutic targets was in progress. Considering the established clinical success of TNF inhibition, discovery of new genes belonging to the TNF family was an obvious focus of the data-mining effort. In 1999, four publications on BAFF were released within 2 months of each other, giving the molecule four different names, BLyS, BAFF, TALL-1, and THANK (1, 2–4). Of these four, two were of partic- ular interest, including a collaboration between Biogen (Cam- bridge, Massachusetts) (now BiogenIdec) and the University of Lausanne in Switzerland (2), and the other from HGS (Rockville, Maryland) (1) which concluded with the prophecy: ‘‘As such, BLyS, its receptor, or related antagonists may find medical utility in the treatment of B cell disorders associated with autoimmunity, neoplasia, or immunodeficiency syndromes’’ (1). These early articles were correct about the importance of BAFF in B cell biol- ogy, but the exact details of BAFF’s function in health, and its potential role in diseases was still lacking. The above articles pro- posed BAFF as an important co-stimulator of B cells, but it was not until later that year (1999) that Biogen scientists suggested that BAFF provided a critical B cell survival signal (rather than a proliferation signal), and that excess BAFF had a role in driving an autoimmune condition in mice which closely resembled SLE in humans (5). This last report thus became the first proof of concept that BAFF was indeed a therapeutic target, and that inhibitors of BAFF may have a use as a treatment for SLE (and potentially other autoimmune conditions). What was still unclear was how BAFF was driving autoimmunity. Another 10 years of research would be needed to obtain a much clearer picture as to how BAFF really works in health and autoimmunity. BAFF is produced by macrophages, neutrophils, and mono- cytes and is required for the survival of mature B cells (4, 6). Soluble BAFF adopts two forms, one typical of a TNF-family ligand, a homotrimer, and the other a capsid-like structure of twenty trimers (a 60-mer) (7). In 2000, research showed that BAFF was a survival factor in vitro for maturing peripheral B cells in mice, in particular splenic transitional B cells (8). This study proved highly predictive of the phenotype of mice lacking BAFF. As published in the following year, BAFF deficiency in mice led to loss of mature B cells from both the follicular and marginal zone B cell subsets as a result of a developmental block in the periphery at the early transitional (T1) B-cell stage (9, 10). Address correspondence to: Fabienne Mackay, PhD, Commercial Road, Department of Immunology, AMREP, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia. Tel: 1 61 3 9903 0712. Fax: 161 3 9903 0038. E-mail: Fabienne.Mackay@monash.edu Received 1 December 2011; accepted 3 April 2012 ISSN 1521-6543 print/ISSN 1521-6551 online DOI: 10.1002/iub.1046 IUBMB Life, 64(7): 595–602, July 2012