Therapeutic targeting of the BAFF/APRIL axis in systemic lupus erythematosus

The B-cell activating factor (BAFF) axis comprises two ligands (BAFF and APRIL) and three receptors (BCMA, TACI, BR3). BAFF is a vital B-cell survival factor and overexpression of BAFF in both mice and humans is associated with systemic lupus erythematosus (SLE). The anti-BAFF monoclonal antibody (mAb), belimumab, was recently approved by the US FDA for the treatment of adult SLE patients, and three additional BAFF antagonists (atacicept, blisibimod, tabalumab) are presently being evaluated in SLE Phase-III trials.The general biological properties of the individual elements of the BAFF/APRIL axis are reviewed, with emphasis placed on molecular interactions and the potential relevance of each individual element to SLE.The success of belimumab, an agent which promotes only modest B-cell depletion, is contrasted with the failure of the anti-CD20 mAb rituximab, an agent which promotes profound B-cell depletion, and multiple arguments are offered to explain this apparent paradox. Real and perceived limitations to belimumab therapy are presented, and possibilities for other therapeutic agents that target specific elements of the BAFF/APRIL axis are discussed.