Introduction of Belimumab

Belimumab is a monoclonal antibody targeting BLyS (B-lymphocyte stimulator), a B-cell survival factor. BLyS is also known as B-cell activating factor (BAFF) and is known to induce B-cell proliferation, differentiation and immunoglobulin secretion.  Data from murine models of lupus and patients supports the role of BLyS as a therapeutic target in systemic lupus erythematosus (SLE). Belimumab was not effective in Phase II clinical trials for rheumatoid arthritis. It was moderately effective in Phase II trials for Sjögren syndrome. Belimumab received FDA approval for the treatment of SLE on March 9, 2011, despite concerns among advisory committee members that the improvement of 4 points on the SELENA-SLEDA scale was marginal, and despite reservations about additional deaths in the treatment group. It was subsequently approved in Canada and Europe as well.

Mechanism of Action of Belimumab

Systemic lupus erythematosus (SLE) is considered the prototypic autoimmune disease, with aberrations throughout the immune system resulting in diverse clinical manifestations. B cells are central in the pathogenesis of SLE, because they are precursors for plasma cells that secrete antibodies; they also present antigens to T cells and other B cells, and they secrete proinflammatory cytokines. B cells are activated by T cells. B cells and plasmacytoid dendritic cells can also be activated through endosomal toll-like receptors, some of which recognize DNA- and RNA-containing proteins. In patients with SLE, numbers of circulating plasma cells, plasma blasts, and late transitional B cells (a late stage of maturation in B cells) are increased. Higher-than-normal proportions of B cells and T cells are activated, and activation pathways are abnormal, favoring autoimmunity and inflammation. Regulatory cells of several types that suppress B cells and helper T cells are low in numbers or dysfunctional in most patients with SLE. Increased B-cell activation is due in part to increased levels of growth factors, including B-lymphocyte stimulator BLyS (also known as BAFF). BAFF is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. BLyS exists in both membrane-bound and soluble forms and is expressed by monocytes, macrophages and dendritic cells. BLyS can bind to 3 receptors, all of which are expressed by B lymphocytes, namely TACI (TNF transmembrane activator and calcium modulator and cyclophilin ligand interactor), BCMA (B lymphocyte maturation antigen) and BR3 (BAFF/BLyS receptor 3). A further TNF family member, APRIL, can also bind TACI and BCMA with biologic functions similar to BLyS. BAFF is required for B-cell survival, maturation, and activation; germinal-center formation; the development of B cells into plasma cells; and immunoglobulin production. Many of the subsets of maturing B cells are completely dependent on the binding of BAFF receptors by BLyS to survive and mature. Mature, activated B cells differentiate into plasma blasts or memory B cells; memory cells lack BAFF receptors. Belimumab binds to BAFF and reduces the number of circulating B cells. It is possible that belimumab binds primarily to circulating soluble BAFF and therefore does not induce the antibody-dependent cellular cytotoxicity (ADCC) that could be expected from this IgG1-type antibody.

Fig.1 Mechanism of action of Belimumab

For research use only. Not intended for any clinical use.