Belimumab was approved by the U.S. FDA in March 2011 for treatment
of patients with active, autoantibody-positive, systemic lupus erythematosus
(SLE). Belimumab is a human sequence monoclonal antibody that binds
to human B lymphocyte stimulator protein (BLys; also known as BAFF,
THANK, TALL-1, TNFSF13B, and zTNF4), which is overexpressed in
SLE patients. BLys is expressed on the cell surface of monocytes, macrophages,
and monocyte-derived dendritic cells and is cleaved to form a soluble
cytokine that stimulates cell proliferation and antibody secretion in B
lineage cells that express the BLys receptor BAFF-R (also known as BR-3).
The precise function of two additional BLys receptors, TACI and BCMA, is
less clear. Belimumab inhibits BLys interaction with these three receptors
leading to measurable reductions in autoantibodies, such as anti-dsDNA,
and specific circulating B cell lineage compartments including antibody producing
plasma cells. Belimumab was discovered by screening molecules
from a phage display library of human single-chain Fv sequences for BLys
binding and functional blocking, followed by optimization of the lead
through the introduction of variant residues in VH CDR3.
