Abstract
BAFF, a member of the TNF superfamily, has been recognized as a good target for autoimmune diseases. Belimumab, an anti-BAFF monoclonal antibody, was approved by the FDA for use in treating systemic lupus erythematosus. However, the molecular basis of BAFF neutralization by belimumab remains unclear. Here our crystal structure of the BAFF–belimumab Fab complex shows the precise epitope and the BAFF-neutralizing mechanism of belimumab, and demonstrates that the therapeutic activity of belimumab involves not only antagonizing the BAFF–receptor interaction, but also disrupting the formation of the more active BAFF 60-mer to favor the induction of the less active BAFF trimer through interaction with the flap region of BAFF. In addition, the belimumab HCDR3 loop mimics the DxL(V/L) motif of BAFF receptors, thereby binding to BAFF in a similar manner as endogenous BAFF receptors. Our data thus provides insights for the design of new drugs targeting BAFF for the treatment of autoimmune diseases.
Highlights
BAFF, a member of the TNF superfamily, has been recognized as a good target for autoimmune diseases
One BAFF–belimumab complex exists in an asymmetric unit, and the central BAFF trimer is bound by three belimumab Fab molecules through a crystallographic 3-fold axis, which is analogous to the structures of the BAFF–BAFF receptor 3 (BR3) and BAFF–B-cell maturation antigen (BCMA) complexes[6,7] (Fig. 1)
Belimumab has been characterized as targeting soluble BAFF only, whereas other BAFF antagonists, including tabalumab, blisibimod, and atacicept, can block both membrane-bound and soluble BAFF14
Summary
BAFF, a member of the TNF superfamily, has been recognized as a good target for autoimmune diseases. Soluble BAFF trimers can oligomerize to a virus-like assembly consisting of 20 trimers through trimer–trimer interactions via a long DE loop called a “flap” region, which is unique among TNFSF members[5,6,7]. This BAFF 60-mer is considerably more active than the trimer, possibly due to the clustering of BAFF receptors on the B-cell surface[8,9]. Other BAFF antagonists, including tabalumab (anti-BAFF antibody), blisibimod (anti-BAFF peptibody), and atacicept (TACI-IgG Fc fusion), are being or have been investigated in clinical trials for SLE14. These three biologics differ from belimumab in that they bind both membrane-bound and soluble BAFF, whereas belimumab binds only soluble BAFF14,26,27
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