Advances in the Research of Targeting B Cells for the Treatment of Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is a chronic, systemic autoimmune disease. The direct cause of SLE pathogenesis lies in the immune imbalance resulting from excessive B-cell activation. Targeting B-cells for treatment can inhibit their activation and proliferation, thereby reducing the production of autoantibodies. As such, B-cells have emerged as a novel therapeutic target for SLE in recent years. Currently, the clinical targets for B-cell-specific treatment of SLE primarily encompass B-cell surface antigens, B-cell-associated cytokines, and their accessory molecules, while intracellular small-molecule targeted drugs also show great clinical potential.

1. Anti-CD19 Targeted Therapy

CD19 is a transmembrane glycoprotein present on the surface of B-cells, spanning the entire developmental process from pre-B cells to plasma cells. It affects B-cell activation, signal transduction, and growth, and is involved in the transport of Ca2+ within B-cells. Consequently, CD19 is widely used for the diagnosis and prognosis of leukemia, lymphoma, and immune system-related diseases, and serves as an important target for immunotherapy. FcγR IIb, a low-affinity IgG receptor located on the surface of B-cells, functions as a reversible B-cell inhibitor.

Obexelimab (XmAb5871) is a bispecific antibody that exhibits binding specificity to two distinct target molecules: CD19 on the surface of B-cells and Fc receptor FcγRIIb. By targeting CD19, it inhibits B-cell activation and proliferation, eliminating autoantibody-secreting plasma cells. In synergy with FcγRIIb, it further suppresses antigen-presenting cell (APC) function, T-cell activation, and Toll-like receptor 9 (TLR9)-mediated signaling.

Anti-CD19 chimeric antigen receptor T-cell (anti-CD19 CAR-T) therapy involves genetically modifying T-lymphocytes to express chimeric antigen receptors (CARs) that target CD19, enabling them to identify and attack CD19+ B-cells.

2. Anti-CD20 Targeted Therapy

CD20 is a glycosylphosphorylated protein present on the surface of mature B-cells, with its expression limited to pre-B cells through memory B-cells, sparing the long-lived plasma cells. Since plasma cells maintain antibody production, administering CD20 inhibitors can virtually deplete peripheral B-cells without significantly reducing immunoglobulin levels.

① Rituximab (RTX) is a selective, human-mouse chimeric monoclonal antibody targeting CD20, featuring a human IgG1 domain and a murine CD20 variable region. It has become a standard therapeutic option for B-cell lymphomas expressing CD20 and for rheumatoid arthritis. The mechanism of RTX in treating SLE involves inducing apoptosis through antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity, thereby weakening autoimmune damage to the body by continuously depleting B-cells. Although RTX failed to meet the primary endpoints in two large randomized controlled trials for SLE (EXPLORER and LUNAR), numerous open-label studies of RTX for SLE have reported favorable efficacy. The 2019 EULAR guidelines recommend RTX for severe cases with renal, hematological, or neurological involvement, as well as for refractory SLE. A major concern with RTX is the development of human anti-chimeric antibodies (HACA), which can reduce drug efficacy and lead to treatment failure in subsequent administrations.

② Ocrelizumab (OCZ) is a new generation of Fc-modified, humanized anti-CD20 monoclonal antibody. Compared to RTX, OCZ exhibits higher ADCC activity and lower CDC effects in SLE patients, and does not induce the production of HACA. However, several clinical studies of OCZ in SLE were prematurely terminated due to serious adverse events, although preliminary results suggest that OCZ may have some efficacy in lupus nephritis (LN). Currently, the application of OCZ in SLE requires further validation through extensive clinical research.

③ Obinutuzumab (OBZ) is the latest generation of fully humanized, glycoengineered Fc type II anti-CD20 monoclonal antibody. Compared to type I anti-CD20 antibodies, OBZ has lower immunogenicity and higher affinity for FcγR III on effector cells, conferring upon it stronger ADCC and improved direct B-cell killing capabilities. Studies have confirmed that OBZ induces B-cell toxicity in vitro whole blood assays for rheumatoid arthritis and SLE with at least twice the efficiency of RTX. Currently, the results of a clinical trial investigating OBZ for the treatment of proliferative lupus nephritis (LN) indicate that OBZ contributes to improving clinical responses among patients with proliferative LN.

④ Ofatumumab is a fully humanized type I IgG1 monoclonal antibody against CD20, which has been approved for the treatment of chronic lymphocytic leukemia, autoimmune hemolytic anemia, and immune-mediated thrombocytopenia. Some case reports indicate that it can achieve better therapeutic effects in patients with SLE who are intolerant to RTX.

3.Anti-CD22 Targeted Therapy

CD22 membrane receptor is a B-cell-restricted adhesion molecule that forms a complex with the B-cell antigen receptor and functions as an inhibitory co-receptor. Epratuzumab is an anti-human CD22 IgG1 antibody that inhibits the activation and differentiation of B-cell subsets without significantly reducing the number of B cells. Therefore, compared to RTX, the risk of infection associated with epratuzumab is relatively lower. An extended study on long-term safety and effectiveness has shown that epratuzumab is well-tolerated in the treatment of SLE, leading to sustained improvement in disease activity and reduced steroid dosage. However, in two other Phase III clinical trials, epratuzumab did not demonstrate significant differences in treatment outcomes compared to placebo in patients with moderate to severe SLE, despite its specific immunomodulatory effects on B cells. Therefore, while epratuzumab may have acceptable safety in SLE patients, randomized controlled trials with larger sample sizes and longer follow-up periods are still needed to validate its efficacy.

4.Biologics Targeting B Lymphocyte Stimulator (BAFF) and Proliferation-Inducing Ligand (APRIL)

BAFF, also known as B Lymphocyte Stimulator (BLyS), belongs to the tumor necrosis factor family and regulates the homeostasis of B cells in peripheral blood. It interacts with BAFF receptors, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antigen (BCMA) on B cells, playing a crucial role in promoting B-cell survival, differentiation, and autoimmunity. In particular, studies in SLE have found that serum BAFF levels positively correlate with SLE disease activity.

① Belimumab was officially approved by the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) in March 2011 for the treatment of autoantibody-positive adult patients with active SLE who have received standard therapy. This marked the first biologic agent approved by the FDA for the treatment of SLE in over 50 years. Belimumab is a recombinant human IgG1-λ monoclonal antibody targeting BAFF. Its therapeutic effect in SLE is achieved primarily by interfering with the binding of BAFF to its receptors, inhibiting B-cell maturation and survival, reducing the number of plasma cells, and ultimately decreasing the production of autoantibodies. Currently, five large Phase III clinical studies on belimumab for the treatment of SLE have confirmed its tolerability and safety.

② Atacicept is a fully humanized recombinant fusion protein that binds to and neutralizes both BAFF and APRIL. Its unique tetravalent "protein body" structure exhibits higher affinity for BAFF. In a Phase III randomized controlled study among patients with active SLE, atacicept showed a statistically significant difference in reducing steroid dosage compared to the control group, and successfully decreased proteinuria and autoantibody levels with good tolerability. Although it failed to meet the primary endpoint, atacicept still demonstrated clinical efficacy. (Note: Blisibimod is likely a typo or misnomer; the intended term should be atacicept based on the context.)

③ Telitacicept is a novel recombinant fusion protein that neutralizes the activity of both BAFF and APRIL, thereby inhibiting the development and survival of plasma cells and mature B cells. In April 2020, the FDA granted telitacicept approval for the treatment of SLE. In March 2021, the National Medical Products Administration of China approved telitacicept for the treatment of adult patients with active autoantibody-positive SLE.

④ Blisibimod is a novel IgG1 monoclonal antibody that inhibits BlyS, possessing characteristics of both peptides and antibodies, and exhibits higher affinity for BAFF. Although a Phase II clinical trial using blisibimod in moderate to severe SLE did not meet its primary endpoint at Week 24, patients receiving the highest dose of blisibimod (200 mg weekly) showed a statistically significant difference in SLE Responder Index (SRI)-5 response rate at Week 20. In a Phase III clinical trial evaluating the efficacy and safety of blisibimod in SLE patients with lupus nephritis (LN), while the SRI-6 endpoint was not achieved, blisibimod successfully reduced glucocorticoid usage, proteinuria, and biomarker responses, with good tolerability.

5.Targeting Type I Interferon (IFN-I)

IFN-I is considered a key interferon in the pathogenesis of SLE, but different subclasses of IFN-I may have distinct functions in regulating SLE. Among them, IFN-α is produced by B cells and plasmacytoid dendritic cells, which can stimulate B-cell differentiation and promote autoantibody production by generating BAFF. Therefore, blocking the IFN-α signaling pathway can indirectly regulate B cells and reduce autoantibody generation. Anifrolumab is a fully humanized monoclonal antibody that binds with high specificity and affinity to the IFN-I receptor subunit 1, blocking both IFN-α and IFN-β signals. As a fully humanized IgG1κ monoclonal antibody, anifrolumab binds to IFNAR, inhibiting pro-inflammatory cytokines by blocking the IFN-I autoamplification loop, effectively suppressing IFN-I-dependent signaling, and thus inhibiting plasma cell differentiation. In a Phase II randomized controlled study in patients with moderate to severe SLE, anifrolumab effectively reduced oral corticosteroid use and met the primary endpoint. In a multinational, multicenter, Phase III double-blind randomized controlled study, SLE patients were stratified based on disease activity, IFN-stimulated gene (ISG) expression levels, and oral corticosteroid usage. Anifrolumab demonstrated significant efficacy compared to placebo, with sustained reductions in corticosteroid use, and patients with high ISG expression showed a better response to anifrolumab treatment.

6.Targeting CD40 Ligand (CD40L)

The interaction between CD40L on the surface of T cells and CD40 on B cells is crucial for the growth, differentiation, and activation of B cells. CD40L is broadly expressed on naive and activated CD4+ T cells as well as platelets. Targeting CD40L can affect B-cell function. Two monoclonal antibodies against CD40L, Ruplizumab and Toralizumab, were both discontinued in SLE studies due to thrombotic events. Dapirolizumab pegol, a pegylated anti-CD40L Fab fragment, does not have an Fc fragment and therefore cannot bind to platelet receptors, reducing the risk of platelet aggregation. In a Phase I trial involving SLE patients, no thromboembolic events were observed, and favorable efficacy was reported. A Phase II clinical trial investigating the efficacy and safety of Dapirolizumab in patients with moderate to severe SLE is ongoing, and its potential for treating SLE remains to be further clarified.

7.Targeting Molecular Targets within B Cells

Recently, the treatment of SLE has entered a new phase, which involves targeting molecules within pathogenic B cells. Bruton's tyrosine kinase (BTK) is a crucial component of the B-cell signaling pathway and plays multiple pathogenic roles in SLE, including promoting B-cell differentiation and autoantibody production. In some lupus models, small molecule inhibitors of BTK have been shown to effectively reduce autoantibody levels and alleviate kidney damage. Therefore, BTK inhibitors represent a promising therapeutic option for SLE. Evobrutinib is a novel, highly selective BTK inhibitor. In SLE mouse models, oral administration of Evobrutinib can reduce disease severity and histological damage, effectively improving symptoms in the kidney, skin, and nervous system. Currently, a Phase II clinical trial evaluating the efficacy and safety of Evobrutinib in the treatment of SLE is ongoing.

References

[1] Zhang Yingjie, Wang Chunfang. Research Progress in the Treatment of Systemic Lupus Erythematosus with B-Cell-Targeted Biologics [J]. China Medical Sciences, 2022, 12(19): 42-46.

[2] Li He, Yin Jing, Li Chongwei. Research Progress in the Treatment of Systemic Lupus Erythematosus with B-Cell-Targeted Therapies [J]. Journal of Shenyang Medical College, 2021, 23(05): 482-485.

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.