Research Progress in the Treatment of Systemic Lupus Erythematosus with Belimumab

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unclear pathogenesis that can affect multiple organs throughout the body, primarily including the kidneys, joints, nervous system, and hematological system. Belimumab is a fully human immunoglobulin monoclonal antibody that binds to soluble B-lymphocyte stimulator (BLyS) and inhibits its biological activity. Currently, intravenous and subcutaneous formulations of belimumab have been approved for the treatment of active autoantibody-positive SLE patients over the age of 18, and its intravenous use has also been approved in children under the age of 5 in countries such as the United States, European Union, Brazil, China, Japan, and Russia. In 2020, belimumab became the first drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with active lupus nephritis (LN).

The Role of B Cells and BLyS in the Pathogenesis of Systemic Lupus Erythematosus (SLE)

Research has revealed that factors such as genetics, hormones, the environment, and abnormalities in the immune system all contribute to the development and progression of SLE, with cellular damage and abnormalities in humoral immunity playing pivotal roles. Disorders in T lymphocytes and abnormal activation of B lymphocytes lead to the production of multiple autoantibodies, which form immune complexes that deposit in organs and tissues, triggering various inflammatory responses and cellular damage, ultimately causing damage to affected organs. Extensive studies have demonstrated that excessive B lymphocyte reactivity plays a significant role in the pathogenesis of SLE, primarily through autoantibody formation, antigen presentation, and abnormal production of cytokines. Currently, 180 autoantibodies have been identified in SLE patients, most of which are high-affinity IgG antibodies, including anti-double-stranded DNA (anti-dsDNA) antibodies associated with disease activity and anti-Sm antibodies related to diagnosis. In addition to producing autoantibodies, B cells can also present self-antigens to activate T cells, producing proinflammatory cytokines and chemokines that amplify autoimmune reactions and inhibit the function of Treg cells. Genetic studies in SLE patients have also revealed a significant enrichment of susceptibility gene loci in B cell-related signaling pathways.

BLyS (B-lymphocyte stimulator) is a soluble ligand belonging to the tumor necrosis factor superfamily and serves as a crucial factor for B lymphocyte differentiation, homeostasis, and selection. BLyS can bind to three receptors, including BLyS receptor 3 (BR3, also known as BLYS-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antigen (BCMA). BLyS is the exclusive ligand for BR3, while TACI and BCMA can bind to both BLyS and a proliferation-inducing ligand (APRIL). BLyS signaling through BR3 facilitates the further differentiation of immature B lymphocytes into naive mature B lymphocytes, while the interaction of TACI and BCMA with APRIL plays a vital role in the survival of nascent plasma cells. In SLE patients, stimulation by self-antigens elevates BLyS levels, further promoting the survival of autoreactive B cells and the production of autoantibodies. Studies have shown that mutations in the TNFSF13B gene locus associated with SLE result in the formation of transcripts that are not repressed by corresponding microRNAs, leading to increased production of soluble BLyS, which promotes B cell activation and ultimately enhances humoral immune responses. In SLE, BLyS is primarily produced by monocytes, macrophages, dendritic cells, and activated T cells. Elevated levels of interferon-alpha (IFN-α) and interferon-gamma (IFN-γ) in SLE patients can stimulate dendritic cells and macrophages to produce BLyS, and estrogen can also upregulate BLyS expression.

SLE patients exhibit higher levels of BLyS in their peripheral blood compared to healthy individuals, and these levels correlate with autoantibody levels such as anti-double-stranded DNA and anti-histone antibodies. In lupus mouse models like NZBWF1 and MRL-lpr/lpr, peripheral BLyS levels increase as the disease progresses, emphasizing the crucial role of BLyS in the development and progression of SLE.

BLyS transgenic mice display an increase in peripheral B cells and effector T cells, along with SLE-like features, including the presence of numerous immune complexes and anti-nuclear antibodies in circulation and antibody deposits in the kidneys. Notably, BLYS-B6.Sle1 and BLYS-B6.Nba2 transgenic mice develop severe kidney damage as early as 3 months of age, significantly earlier than control mice. These observations in animal models of SLE suggest the effectiveness of anti-BLyS therapy.

In BXSB mice, treatment with BLYS-RIgG4 protein to block BLyS resulted in decreased BLyS levels and B cell counts in the peripheral blood. After 15 weeks of treatment, a reduction in proteinuria, alleviation of kidney pathological damage, and prolonged survival were observed. Similar results were seen in NZM.BLYS-/- mice with BLyS gene knockout. These findings highlight the potential therapeutic benefits of targeting BLyS in SLE management.

Belimumab and Systemic Lupus Erythematosus (SLE)

Given the role of BLyS in B cell-mediated autoimmune diseases, neutralizing BLyS has emerged as a potential new therapeutic approach for such disorders. As early as 2003, researchers utilized phage display technology and high-throughput sequencing to screen for antibodies against human BLyS, discovering that lymphostat-B (now known as belimumab, or belimumab) effectively inhibited BLyS-induced splenic B cell proliferation in vitro. This antibody was also validated in mouse and cynomolgus monkey models, demonstrating its high-affinity binding to BLyS and ability to block its biological activity.

In March 2011, the US Food and Drug Administration (FDA) approved belimumab for the treatment of adult patients with seropositive systemic lupus erythematosus (SLE). Belimumab is a fully human recombinant IgG1γ monoclonal antibody that binds to soluble BLyS, preventing its interaction with cellular receptors. By inhibiting the survival of B cells (including autoreactive B cells) and reducing their differentiation into immunoglobulin-producing plasma cells, belimumab decreases immune complex deposition without significantly impacting memory B cells or T cell populations. This minimal disruption to overall immune function makes belimumab the first FDA-approved biological agent for the treatment of SLE.

Studies have shown that the efficacy (after placebo effect removal) of belimumab administered as intravenous infusions at doses of 1 mg/kg and 10 mg/kg, and subcutaneous injections at 200 mg, were 6.8%, 11.8%, and 14.8% respectively at week 52 of treatment. The efficacy of 200 mg subcutaneous injection was slightly superior to that of 10 mg/kg intravenous infusion. The 200 mg subcutaneous injection administered once weekly achieved a higher steady-state trough concentration compared to the 10 mg/kg intravenous infusion administered once every 4 weeks. However, further clinical pharmacokinetic and pharmacodynamic studies are needed to explore the correlation between steady-state trough concentration and efficacy. Appropriate prophylactic medications should be administered before dosing to prevent infusion reactions and drug allergies. Currently, there is a lack of studies on the physical or biochemical compatibility of belimumab when combined with other medications, therefore, it is not recommended to administer this product simultaneously with other drugs through the same intravenous route.

The combination of belimumab with standard treatment regimens can effectively reduce disease activity in SLE patients, decrease the dosage of hormones, lower the risk of disease recurrence, and improve renal function and prognosis in LN patients. B-cell targeted therapy has provided a novel option for SLE treatment in recent years. As the first biological agent approved for the treatment of SLE, belimumab has demonstrated favorable efficacy and safety, offering a promising choice for SLE patients to achieve long-term disease remission with low-dose or even zero-dose hormone use. However, further long-term studies are still needed to evaluate some severe adverse events and long-term side effects, disease activity after discontinuation, and whether combining belimumab with other biological agents such as rituximab can achieve better efficacy and safety.

References

[1] Liao Yufang, Xie Tong. Research Progress on the Treatment of Systemic Lupus Erythematosus with Belimumab [J]. Contemporary Medicine Forum, 2023, (Issue 15).

[2] Yang Qingling, Xia Guangtao. New Progress in the Treatment of Systemic Lupus Erythematosus with Belimumab [J]. World Clinical Drugs, 2022, 43(01): 15-18.

[3] He Chengmei, Zhang Fengchun. Belimumab Monoclonal Antibody: A Novel Targeted Drug for the Treatment of Systemic Lupus Erythematosus [J]. Journal of Peking Union Medical College and Hospital, 2020, 11(02): 130-134.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.