The discovery and development of belimumab: the anti-BLyS-lupus connection

Abstract

For the first time in more than 50 years, the US Food and Drug Administration has approved a drug specifically for the treatment of systemic lupus erythematosus (SLE). This drug, belimumab (Benlysta), is a human monoclonal antibody that neutralizes the B-cell survival factor, B-lymphocyte stimulator (BLyS). The approval of belimumab combined a pioneering approach to genomics-based gene discovery, an astute appreciation of translational medicine, a disciplined clinical strategy, a willingness to take calculated risks, a devoted cadre of patients and physicians and a healthy dose of serendipity. Collectively, these efforts have provided a model for the development of a new generation of drugs to treat the broad manifestations of SLE. However, as a substantial percentage of SLE patients do not respond to belimumab, further research is needed to better characterize the pathogenetic mechanisms of SLE, identify additional therapeutic targets, and develop effective and nontoxic novel agents against these targets.

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturebiotechnology.

Figures

Figure 1

Important milestones in belimumab (Benlysta) achieving FDA approval in SLE. RA, rheumatoid arthritis; SPA, special protocol assessment; BLA, biologics license application.

Figure 2

Coordinated development of BLyS and anti-BLyS (belimumab) for the treatment of aberrant B-cell function in CVI and SLE, respectively.

Figure 3

The effect of belimumab on the binding of BLyS to its receptors. (a) BLyS can bind to three receptors (BCMA, TACI, BR3 (also known as BAFF-R)), each of which being a distinct member of the TNF superfamily and each being expressed to different degrees on B cells, T cells and plasma cells. APRIL can bind to two of these receptors (BCMA, TACI) but not to the third (BR3). (b) Belimumab binds BLyS and blocks engagement of BLyS with BCMA, TACI and BR3. Belimumab does not bind APRIL, so engagement of APRIL with BCMA or TACI is not affected.