The rationale for BAFF inhibition in systemic lupus erythematosus

Abstract

BAFF (B-cell-activating factor) is a critical survival factor for transitional and mature B cells and is a promising therapeutic target for systemic lupus erythematosus (SLE). In 2010-2011, two phase 3 clinical trials showed that the addition of the anti-BAFF antibody belimumab to standard-of-care therapy in patients with moderately active SLE results in a better outcome at 52 weeks than standard-of-care therapy alone. Belimumab has been US Food and Drug Administration approved for the treatment of SLE, and other drugs that target BAFF are now in various stages of clinical testing. This review describes the function of BAFF and its homolog APRIL (a proliferation-inducing ligand) and addresses the rationale for the treatment of SLE with BAFF/APRIL inhibitors.

Fig 1

Proposed mechanisms of action of human BAFF and APRIL inhibitors: BAFF and APRIL bind differently to the three receptors (BAFF-R, TACI, and BCMA). Selective BAFF inhibitors block the interaction between BAFF and its receptors, leaving APRIL functions intact, whereas the dual BAFF/APRIL inhibitor atacicept (TACI-Ig) blocks the interaction of both BAFF and APRIL with all three receptors. The effect of the inhibitors on B-cell subsets is shown. Survival of cells in blue is not affected by BAFF or APRIL inhibition. Survival of cells in green is inhibited by selective BAFF inhibition. Survival of cells in orange is inhibited by dual BAFF/APRIL inhibition. The effect of BAFF inhibition on cells in gray is not known. BAFF inhibition may also alter the function of dendritic cells (DCs) and T cells and alter T-cell cytokine secretion. B1, B1 B cell; EF, extrafollicular focus; FO, follicular B cell; GC, germinal center; IL, interleukin; Imm, immature B cell; LPC, long-lived plasma cell; Mem, memory B cell; MZ, marginal zone B cell; SPC, short-lived plasma cell; T1, transitional type 1; T2, transitional type 2