Mechanism of Action of Belimumab in Systemic Lupus Erythematosus
Belimumab is a fully human recombinant IgG1λ monoclonal antibody that specifically binds to soluble B-lymphocyte stimulator (BLyS, also known as BAFF) and prevents it from binding to its receptors on B cells, thereby inhibiting B-cell survival, differentiation, and maturation. 1, 2
Molecular Target and Binding
Belimumab specifically recognizes and inhibits the biological activity of soluble B-lymphocyte stimulator (BLyS/BAFF), a naturally occurring protein that stimulates B-lymphocytes to develop into mature B cells. 2, 3
The antibody blocks BLyS from binding to its receptors on B cells, which are critical for B-cell selection and survival. 3
Laboratory studies indicate that higher than normal levels of BLyS may contribute to the pathogenesis of autoimmune diseases such as SLE, making this an appropriate therapeutic target. 2
Impact on B-Cell Populations
By inhibiting BLyS binding, belimumab prevents the survival and differentiation of selected B-cell subsets without causing complete peripheral blood B-cell depletion. 1, 4
This mechanism differs fundamentally from rituximab (anti-CD20), which achieves complete peripheral blood B-cell depletion for relatively long periods. 4
The selective modulation rather than complete depletion explains why belimumab has no significant impact on vaccine immunogenicity in SLE patients, unlike rituximab which substantially impairs vaccine responses. 4
Clinical Relevance of the Mechanism
The inhibition of BLyS-mediated B-cell activation addresses a key pathogenic mechanism in SLE, where B cells play a central role in disease pathogenesis through autoantibody production and immune dysregulation. 3
This targeted approach allows for disease control while preserving some B-cell function, which maintains protective immunity and explains the acceptable safety profile with balanced adverse events compared to placebo. 4, 5
The mechanism is particularly effective in autoantibody-positive SLE patients, as these patients have evidence of active B-cell-mediated pathology that responds to BLyS inhibition. 6