Immunotargets and Therapy for Systemic Lupus Erythematosus

Chi Chiu Mok

doi:10.2147/ITT.S485650

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Review

Immunotargets and Therapy for Systemic Lupus Erythematosus

Authors Mok CC

Received 22 February 2025

Accepted for publication 16 June 2025

Published 24 June 2025 Volume 2025:14 Pages 605—629

DOI https://doi.org/10.2147/ITT.S485650

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Michael Shurin

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Chi Chiu Mok

Department of Medicine and Geriatrics, Tuen Mun Hospital, Hong Kong

Correspondence: Chi Chiu Mok, Department of Medicine & Geriatrics, Tuen Mun Hospital, Tsing Chung Koon Road, New Territories, Hong Kong, SAR, People’s Republic of China, Tel +85224685386, Fax +85224569100, Email [email protected]

Abstract: The pathophysiology of systemic lupus erythematosus (SLE) is complex and involves most cell types of the innate and adaptive immune system. Impaired clearance of apoptotic bodies and self-antigens, dysregulated cytokine network and aberrated functions of the immune cells lead to overproduction of autoantibodies, activation of complements, immune complex deposition and tissue injury. Novel biological and newer generation immunosuppressive agents have been developed to target the B cells, T cells, T/B cell interaction, plasmacytoid dendritic cells and the cytokines. With the advances in the knowledge about the intracellular pathways, small molecules that inhibit the downstream signal transduction from surface receptors and intracellular protein degradation by the ubiquitin-proteasome system are being developed in the pipeline. This article summarizes the evidence of various immunotargets for the treatment of SLE. These novel agents target specific cellular mechanisms, and further works are necessary to stratify patients according to biomarkers to receive individualized therapies that could help maximize the clinical response. With the availability of more therapeutic choices, a combination approach to achieve synergistic effects while reducing adverse events by dosage reduction of individual drugs is being explored for SLE patients at risk of disease progression or refractory to conventional therapies.

Keywords: target, immune, therapeutics, novel, biologics, small molecules, lupus

Introduction

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that predominantly affects women in their childbearing age. The illness is characterized by periods of quiescence and flares, which are notoriously unpredictable The onset of SLE cannot be prevented and there is no cure. Despite the availability of new drugs and improvement in adjunctive therapies, the survival of SLE patients fails to improve further after the mid-1990s’.¹ Conventional immunomodulatory drugs, except for hydroxychloroquine, have not been shown to confer survival benefit in SLE,² probably related to their adverse effects, such as infective complications, which still account for more than 50% of the mortality in more recent cohorts of SLE patients.³ This calls for the development of novel therapeutic approaches with a better efficacy-to-toxicity balance.⁴

The pathogenesis of SLE remains obscure.⁵ A plethora of genetic, epigenetic and environmental factors, including infective agents, hormonal factors and ultraviolet light, are involved and lead to dysregulation of the innate and adaptive immune responses.⁶ Genome- wide association studies (GWAS) have identified more than 200 risk loci in SLE,⁷ many of which are related to antigen presentation, immune regulation and interferon (IFN) signalling.⁸ Abnormal epigenetic mechanisms such as DNA methylation, histone modification, noncoding RNAs and RNA methylation also contribute to the modification of gene expression.⁹ Pathological processes that are probably involved in the initiation and perpetuation of the immune perturbations in SLE include: (1) loss of self-tolerance and generation of autoreactive B cells and T cells, leading to the production of antinuclear (ANA) and other autoantibodies¹⁰ (2) defective clearance of apoptotic materials, nuclear antigens, nucleosomes and immune complexes (ICs) by macrophages and complements^6,11,12 (3) impaired neutrophil apoptosis and degradation of DNA, histones, cytoplasmic granules and other mediators inside the neutrophil extracellular traps (NETs).^13–16 These antigens activate the plasmacytoid dendritic cells (pDCs) via the toll-like receptors (TLR7/9) to produce type I interferons (IFNs) and interleukin (IL)-6, which in turn accelerate monocyte maturation, inhibit T cell apoptosis, increase proliferation and autoantibody production by B cells.^10,12 Increased activity of the myeloid dendritic cells¹⁷ and defective functions of the regulatory B (Bregs) and T cells (Tregs)^18–20 polarizes the T cells to differentiate into the proinflammatory phenotypes (Th1/Th17). The augmented autoantibody production and IC formation mediates tissue inflammation and organ damage in patients with SLE.

Despite the negative results from multiple clinical trials of SLE drugs, newer biologic and targeted small molecules continue to emerge from the pipeline²¹ (Table 1). This article reviews the various immune targets for novel SLE therapies (Figure 1).

Table 1 Immunotargets and Therapy of Systemic Lupus Erythematosus

Figure 1 Immune targets of SLE therapies: (1) B cells (CD19, CD20, CD22, BAFF, April, BAFF receptors [BAFF-R, BCMA, TACI], BCR, BTK, FcR, FcRn, ICOSL, CD40, CD80/86); (2) Plasma cells (immunoproteasomes, CD38, CAR-T, T cell engagers); (3) T cells (CD40L, CD28, calcineurin, mTOR, JAK/TYK-2, S1PR1, TCR, low-dose IL-2); (4) plasmacytoid dendritic cells (BDCA2, ILT7, TLR7/8); (5) cytokines (IFN, IL-12, IL-17, IL-23); and (6) complements (C5a, factor B).

Abbreviations: BAFF, B cell activation factor; APRIL, a proliferation-inducing ligand; BCMA, B-cell maturation antigen; TACI, transmembrane activator and CAML interactor; BCR, B cell receptor; BTK, Bruton’s tyrosine kinase; FcR, Fc receptor; FcRn, neonatal Fc receptor; ICOSL, inducible T cell costimulator ligand; CAR-T, chimeric antigen receptor T-cell immunotherapy; mTOR, mammalian target of rapamycin; JAK, Janus kinase; TYK2, tyrosine kinase 2; S1PR1, sphingosine-1-phosphate receptor 1; TCR, T cell receptor; IL, interleukin; BDCA2, blood dendritic cell antigen 2; ILT7, immunoglobulin-like transcript 7; TLR, toll-like receptor; IFN, interferon.

Targeting the B Cells

B cells are central in the pathophysiology of SLE because they produce pathogenic antibodies. In addition, they are capable of presenting self-antigens to activate the autoreactive T cells^22,23 and produce cytokines that amplify the inflammatory response.²⁰ A subset of IL-10 secreting Bregs that suppresses the inflammatory response are altered in SLE, which is coupled with an expansion of transitional B cells which are dependent on B cell activating factor (BAFF) for maturation and a subpopulation of autoreactive age-associated B cells (ABCs).^23,24

B cells can be targeted by direct depletion with monoclonal antibodies (anti-CD19, anti-CD20), engineered T cells (Chimeric Antigen Receptor T cells [CAR-T]) and dual action monoclonal antibodies, or indirect modulation via inhibition of growth factors (eg BAFF), costimulatory molecules and intracellular signalling pathways (eg Bruton’s tyrosine kinase [BTK]).²⁵

B-Cell Depletion

Anti-CD20

The chimeric anti-CD20 monoclonal antibody, rituximab, was first studied in SLE. In the pivotal randomized controlled trial (RCT) of active non-renal SLE, two courses of rituximab (1gm for 2 doses) on background standard of care (SOC) did not report benefit in disease activity reduction at week 52 compared with placebo (PBO).²⁶ Another RCT (LUNAR) of rituximab in lupus nephritis (LN) also failed to meet its primary end point of renal response at week 52 when added to glucocorticoid (GC) and mycophenolate mofetil (MMF).²⁷ While rituximab was more effective than PBO in improving anti-dsDNA and complement levels, neutropenia, leukopenia, hypotension, infusion reactions, herpes zoster, and opportunistic infections were more common. Despite the futility of these RCTs, rituximab continued to be used off-label to treat refractory SLE and LN, with clinical responses reported in 67–86% of patients.²⁸

Ocrelizumab is a fully humanized anti-CD20 biologic that was subsequently studied in SLE.^29,30 In two RCTs of non-renal SLE and LN, patients were randomly assigned to receive two courses of ocrelizumab (400 mg or 1000 mg for 2 doses 2-weekly and after 4 months) or PBO. Patients in the LN trial received the SOC with GC combined with either MMF (3g/day) or low-dose cyclophosphamide (CYC) followed by azathioprine (AZA). Both studies were terminated prematurely because of severe serious infections. An analysis of the data from patients who received study drug for ≥32 weeks showed that the overall renal response rate of the combined ocrelizumab groups was non-significantly higher than that of PBO.³⁰ The effect size was higher with ocrelizumab combining with CYC than MMF whereas serious infections were more common in the MMF/ocrelizumab group.

As the serious infections in the ocrelizumab studies were potentially related to the protocol-based high-dose of MMF being used in Asian patients, subsequent RCTs of anti-CD20 biologics in SLE adopted a lower dose of MMF and less intense background immunosuppression.³¹ Obinutuzumab is a recombinant humanized type II anti-CD20 monoclonal antibody that is glyco-engineered for greater affinity for the FcγRIII on effector cells, leading to enhanced antibody dependent cellular cytotoxicity (ADCC), direct B-cell killing, and less reliance on complement dependent cytotoxicity (CDC).³² Obinutuzumab is more effective than rituximab in depleting B cells and ameliorating LN in the lupus mice.³³

A Phase II RCT (NOBILITY) of 125 patients with active proliferative LN who were receiving a SOC of GC and MMF showed that the complete renal response (CRR) rate at week 52 through week 104 in the obinutuzumab arm was superior to PBO.³¹ Obinutuzumab was not associated with an increase in serious adverse events (SAEs), serious infections or deaths. Post-hoc analyses demonstrated that the anti-CD20 agent reduced the incidence of LN flares, first estimated glomerular filtration rate (eGFR) decline by 30% or 40%, and a composite outcome of treatment failure, doubling of serum creatinine, or death.³⁴ The Phase III RCT of obinutuzumab in 271 patients with active LN (REGENCY) confirmed its efficacy compared to PBO, in conjunction with GC and MMF, at week 76 in terms of CRR or CRR together with a maintenance prednisone dose of ≤7.5mg/day.³⁵ Despite the absence of unexpected safety signals, SAEs and infections were more frequent in obinutuzumab-treated patients. Greater adjusted between-group differences in the rate of CRR were observed in those patients with higher serological SLE activity, uP/Cr>3.0 and histological class IV±V disease.

A GC-free regimen consisting of rituximab (1 gram for 2 doses) and MMF (dosage adjusted by drug level) has been explored in a single arm prospective study of 50 patients with LN.³⁶ Complete or partial renal response was reported in 90% of patients treated with this regimen (RITUXILUP regimen) without concomitant oral prednisone over a median time of 37 weeks. As a planned RCT of this regimen was aborted (NCT01773616), it is hoped that the ongoing RCT of obinutuzumab/MMF versus GC/MMF in LN (OBILUP; NCT04702256) would provide new insights on the efficacy of this GC-free regimen in LN.

Anti-CD22

Epratuzumab is a human monoclonal antibody that targets the CD22 antigen on mature B cells, which is involved in the modulation of B-cell receptor (BCR) signalling, cellular activation and survival.³⁷ Compared to CD20, CD22 blockade is less cytotoxic. Epratuzumab diminished B cell proliferation, migration and production of inflammatory cytokines.³⁸ Early clinical trials showed that epratuzumab induced a modest depletion of peripheral B cells without significant effects on T cells, autoantibody or immunoglobulin levels.^39,40 Following a phase IIb PBO-controlled RCT of epratuzumab (ENBLEM) demonstrating safety and preliminary efficacy in SLE,^41,42 two subsequent phase III RCTs were conducted (EMBODY 1/2).⁴³ Unfortunately, the primary clinical improvement end point, BILAG-based combined lupus assessment [BICLA] at week 48, was not met, although adverse events (AEs) and treatment-emergent AEs (TEAEs) were not increased with treatment.

Anti-CD19 and T-Cell Engagers

Obexelimab is dual function, non-cytolytic monoclonal antibody that binds to CD19 and FcyRIIb to inhibit B cells and plasmablasts.⁴⁴ A phase II PBO-controlled RCT of obexelimab in 104 SLE patients with non-organ-threatening manifestations did not meet the primary end point of reaching week 32 without loss of improvement, although the time to this end point was prolonged with obexelimab compared to PBO.⁴⁵ B cells decreased by approximately 50% after anti-CD19 treatment and the presence of gene expression clusters with high B cell pathway modules were associated with longer time to loss of improvement. Another anti-CD19 monoclonal, inebilizumab, approved for treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients, is registered for a study in refractory SLE (NCT06570798).

The anti-CD3/anti-CD19 bispecific T cell engager (BiTE), blinatumomab, instigates CD3-positive T cells to target CD19-positive B cells,⁴⁶ leading to B cell elimination and concomitant reduction of T cells. Blinatumomab is effective against acute lymphoblastic leukemia and other B cell malignancies. As the drug targets both malignant and non-malignant lymphocytes, it may potentially cause the cytokine release syndrome and neurotoxicity similar to CAR-T therapy. Blinatumomab has been shown to be effective in refractory rheumatoid arthritis⁴⁷ and systemic sclerosis.⁴⁸ As the effect of blinatumomab mimics CAR-T but does not require preconditioning with lymphodepletion and chemotherapy, it is a more acceptable option in younger SLE patients.⁴⁹ Two studies of blinatumomab in refractory SLE have been registered (NCT06789107 and NCT06570798).

Teclistamab is a CD3/B-cell maturation antigen (BCMA) BiTE that is used to treat refractory myeloma.⁵⁰ Unlike CD3/CD19 BiTE, it has a capacity to deplete the long-lived plasma cells. Successful use of teclistamab has been reported in a patient with refractory SLE.⁵¹ Teclistamab led to a rapid depletion of peripheral-blood B cells by week 1 and eradication of marrow B cells and plasma cells by week 8. However, no clinical trials in SLE have been registered yet.

Car-t

CAR-T therapy involves the use of engineered T cells to target CD19 on B cells or BCMA on myeloma cells.^25,52 CAR-T depletes B cells profoundly, including the memory B cells, plasmablasts and plasma cells. Pilot studies of CD19-targeted CAR-T therapy showed good response in patients with severe or refractory SLE.⁵³ However, the procedure involves pre-conditioning with cyclophosphamide and fludarabine, which is undesirable for fertility and oncogenicity reasons. Moreover, it carries the risk of cytokine release and immune effector cell-associated neurotoxicity syndromes. Publication bias, relatively small number of SLE patients treated with CAR-T, lack of long-term data on safety and efficacy, and the general unavailability of this procedure are the major limitations of CAR-T in SLE.⁵

Long-Lived Plasma Cells

Long-lived plasma cells are capable of generating autoreactive immunologic memory and autoantibodies that are relevant for the pathogenesis of SLE.⁵⁴ In contrast to short-lived plasmablasts, they are resistant to conventional immunosuppressive and B cell depletion therapies because of the lack of CD19 and CD20 expression.⁵⁵ However, these plasma cells have upregulation of the autophagy pathways and the unfolded protein response, leading to the susceptibility to proteasome inhibition.²⁵ Targeting the immunoproteasomes and the cereblon E3 ligase in the ubiquitin-proteasome system (UPS), which is a major pathway for intracellular protein degradation, is a novel therapeutic approach in SLE.^56,57

Bortezomib is a non-selective inhibitor of both the constitutive and immune proteasomes. Case series have reported efficacy of bortezomib in conjunction with GCs for the treatment of refractory SLE manifestations, including LN.^58–62 Bortezomib depleted both short-lived and long-lived plasma cells in the peripheral blood and bone marrow, which was associated with improvement of anti-dsDNA level and proteinuria in LN.^58,60–62 However, the drug is limited by gastrointestinal toxicities, peripheral neuropathy and drug resistance on prolonged use.⁶³

Zetomipzomib is a highly selective immunoproteasome inhibitor with enhanced safety.⁶⁴ A phase Ib/II open study in 33 patients with active SLE despite stable background immunosuppression showed that subcutaneous zetomipzomib for 13 weeks improved disease activity, which was maintained for 12 weeks in 94% patients.⁶⁵ The drug was well tolerated and no neuropathy, prolonged gastrointestinal AEs were reported. Patients with LN recruited in this study also showed improvement in proteinuria after treatment for 24 weeks.⁶⁶ Unfortunately, a PBO-controlled phase IIb RCT (NCT05781750) to evaluate the efficacy and safety of zetomipzomib with SOC in LN was prematurely terminated for safety signals.

The protein cereblon is a substrate receptor of the cullin-ring ligase-4 E3 ubiquitin ligase complex, which tags polyubiquitin chains to degrade neo-substrate proteins that are disease promoting, such as transcription factors and tumor promoting proteins.⁶⁷ Cereblon E3 ligase modulators (CELMoDs) such as thalidomide, lenalidomide and pomalidomide synergize with the UPS to degrade Ikaros and Aiolos, which are transcriptional factors that regulate differentiation of lymphocytes, plasma cells and pDCs.^57,68 Moreover, as Ikaros and Aiolos are transcriptional suppressors of IL-2, their degradation leads to enhanced IL-2 and NK cell activity.⁶⁹

Thalidomide and lenalidomide have been used to treat refractory cutaneous lupus erythematosus (CLE), particularly subacute and chronic lesions.⁷⁰ Most published studies were small, retrospective and uncontrolled.^70–75 Moreover, thalidomide is limited by its poor intestinal absorption and the risk of peripheral polyneuropathy, which was reported in 15–80% of patients with no clear dose relationship.⁷⁰ Lenalidomide appeared to be less neurotoxic, but disease flares were common after drug discontinuation. Teratogenicity, potential cardiovascular AEs and thromboembolism,⁷⁶ are major deterrent of CELMoD use in SLE.

Iberdomide is a high affinity CELMoD. In a phase IIb RCT,⁷⁷ iberdomide treatment for 24 weeks in SLE patients significantly reduced the number of peripheral B cells and pDCs but increased Tregs and IL-2 production in a dose-dependent manner.⁷⁸ However, reduction in type I IFN gene signature occurred only in patients with high expression at baseline. These findings are consistent with the known immunomodulatory effects of iberdomide through enhanced degradation of Ikaros and Aiolos.

In a phase IIa PBO-controlled dose-escalating RCT of iberdomide in 42 patients with active SLE,⁷⁹ improvement in physicians’ global assessment (PGA) and Cutaneous Lupus Area and Severity Index Activity (CLASI-A) scores were observed with treatment. Safety was established and a subsequent phase II RCT of 288 active SLE patients confirmed efficacy of iberdomide 0.45mg compared to PBO in terms of SRI-4 response at week 24.⁸⁰ Subgroup analyses revealed higher effectiveness in patients with baseline SLEDAI ≥10, high Aiolos and IFN gene signature.^78,80 However, meaningful differences in most secondary end points, including CLASI-A score and joint counts, were not observed between iberdomide and PBO. AEs and SAEs were non-significantly higher in iberdomide-treated patients, with neutropenia and infections being the commonest. No peripheral neuropathy was reported. In patients with active CLE who participated in the above RCT,⁸⁰ significantly more iberdomide-treated (0.45mg) patients achieved ≥50% CLASI-A improvement from baseline to week 24 compared with PBO for subacute and chronic but not acute CLE lesions.⁸¹ Further clinical trials are necessary to confirm the efficacy of iberdomide in SLE, particularly for different subtypes of CLE.

There are alternative ways of targeting the plasma cells. Daratumumab is a monoclonal antibody that binds to CD38 expressed on plasma cells and plasmablasts. It depletes plasma cells and is approved for upfront combination therapy of myeloma.⁸² Successful treatment of refractory SLE by daratumumab has been reported.^83,84 However, there are no controlled trials in SLE yet. Felzartamab is another anti-CD38 monoclonal antibody that is being studied in primary membranous nephropathy.⁸⁵ A phase Ib study of felzartamab in LN has been registered (NCT06064929).

Targeting B-Cell Growth Factor

BAFF Inhibition

BAFF binds to three receptors on B cell surface, namely transmembrane activator and calcium modulator ligand interactor (TACI), BCMA and BAFF-R, which is essential for B cell maturation, survival, proliferation and immunoglobulin class switching.⁸⁶ BAFF mRNA and serum levels were elevated in SLE and correlated with disease activity.^87,88 APRIL (a proliferation-inducing ligand), a homolog of BAFF, is also important factor for survival and activation of B cells.⁸⁹ APRIL binds to TACI and BCMA receptors with a higher affinity than BAFF. Inhibition of the BAFF and/or APRIL promotes apoptosis and prevents maturation of the B cells.⁹⁰

Belimumab is a monoclonal antibody against BAFF that is approved for the treatment of SLE and LN. Pivotal RCTs in non-renal SLE confirmed benefit of belimumab when added to SOC in achieving the SRI-4 response.^91–94 Extension of the BLISS-52 and BLISS-72 RCTs^91,92 for up to 8 years showed sustained efficacy of belimumab and stable organ damage score in 88% of these patients.⁹⁵ Pooled data from RCTs confirmed superiority of belimumab to PBO when combined with SOC in the treatment of SLE⁹⁶ and a GC-sparing effect.⁹⁷ However, the efficacy of belimumab in reducing renal flare in patients treated for extra-renal activity appeared to be dependent on concomitant anti-malarial therapy.⁹⁸ For the treatment of LN, a large RCT reported significantly higher rate of primary end point renal response (PERR) when belimumab was combined to the SOC of either MMF or low-dose CYC when compared to PBO.⁹⁹ Efficacy was consistent in the Asian subpopulation¹⁰⁰ and across patients with newly diagnosed or relapsed LN.¹⁰¹ Open-label extension of this study for 28 weeks showed maintenance of the treatment response without new safety signals.¹⁰² A secondary analysis of the BLISS-LN trial showed that belimumab significantly reduced the risk of kidney-related events or death, renal flares and a sustained 30% or 40% decline in eGFR versus SOC alone.¹⁰³ However, kidney response to belimumab was not observed in patients with sub-epithelial deposits or a baseline uP/Cr of ≥3.0.

Tabalumab is a human monoclonal antibody against both soluble and membrane-bound BAFF.¹⁰⁴ Two identical PBO-controlled phase III RCTs of tabalumab in SLE with moderate to severe activity were conducted.^105,106 In the ILLUMINATE-1 study, the primary end point (SRI-5 rate) was not met at week 52, although significant improvement in anti-dsDNA and complements, reduction in total B cells, immunoglobulins and BAFF levels were achieved with tabalumab treatment.¹⁰⁵ In ILLUMINATE-2 study, the primary end point (SRI-5 at week 52) was met in the 120 mg (every 2 week) tabalumab arm.¹⁰⁶ In both RCTs, none of the secondary end points, which included time to first severe SLE flare and GC-sparing effect, supported efficacy of tabalumab. SAEs, TEAEs and mortality were not increased across the tabalumab arms, although depression and suicidal ideation was more common. A pooling of data of the two RCTs did not reveal significant benefit of tabalumab on various renal parameters.¹⁰⁷ Although the primary end point could have been met if SRI-4 had been used, further development of the drug was not pursued.

Blisibimod is a fusion protein comprising four BAFF binding domains linked to the N-terminus of the fragment crystallizable region (Fc) of a human antibody.¹⁰⁸ Following a phase II RCT showing efficacy of blisibimod at week 24 in terms of the SRI-5 response and a significant improvement in SLE serology and reduction in B cell count,¹⁰⁹ a phase III PBO-controlled RCT were performed (CHABLIS-SC1).¹¹⁰ This study recruited 442 SLE patients with high disease activity despite GCs and SOC. Unfortunately, the primary outcome, SRI-6 response at week 52, was not met. Exploratory end points that included SRI-4 and SRI-8 were also not significantly different between the blisibimod and PBO arms, including AEs and SAEs.

Atacicept (TACI-Ig) is a fusion protein that blocks the activity of both BAFF (soluble and membrane-bound) and APRIL.¹¹¹ Atacicept treatment in SLE patients reduced peripheral mature B cells and immunoglobulin levels in a dose-dependent manner.¹¹² A phase II/III PBO-controlled RCT of atacicept in patients with active LN was prematurely terminated for safety concerns.¹¹³ Another 52-week phase II/III PBO-controlled RCT of atacicept in 461 patients with active SLE did not meet the primary outcome of reduction in the incidence of a new BILAG A or B flare.¹¹⁴ The atacicept 150 mg arm was terminated prematurely because of increased serious infections. Atacicept reduced immunoglobulin levels and improved lupus serology. Patients with elevated serum levels of BAFF and APRIL showed a greater response in the reduction of SLE flares.¹¹⁵ Another 24-week phase IIb PBO-controlled RCT (ADDRESS II) involving 306 active SLE patients was repeated and did not show an increased incidence of TEAEs or SAEs as compared to PBO.¹¹⁶ Although the primary end point (SRI-4 at week 24) was not met, subgroups of patients with higher disease activity at baseline showed a significantly higher SRI-4 rates than PBO. However, further studies of atacicept were not pursued.

Telitacicept is another fusion protein that inhibits the binding of BAFF and APRIL to the TACI receptor.¹¹⁷ A multicenter phase II RCT involving 249 patients with active SLE conducted in China met the primary end point of having a significantly higher SRI-4 response at week 48 in all the 3 doses of telitacicept studied as compared to PBO. The drug was well tolerated with no increase in the incidence of AEs or SAEs.¹¹⁸ Telitacicept is currently licensed for SLE treatment in mainland China.

Anti-BAFF/Anti-CD20 Combination

The rebound increase in serum BAFF level after B cell depletion promotes reconstitution of autoreactive B cells that may be associated with SLE flares.¹¹⁹ Administration of a BAFF inhibitor after anti-CD20 therapy may retard full B-cell repopulation and production of SLE-specific autoantibodies.¹²⁰ A phase II open RCT (CALIBRATE) of 43 patients with recurrent or refractory LN showed that the addition of belimumab to the background GC/CYC/rituximab regimen caused a greater reduction in autoreactive naive B cells from baseline to week 48 compared to the no belimumab group without increasing AEs.¹²¹ However, the renal response rates were not significantly improved with belimumab/rituximab combination. Another phase II PBO-controlled RCT (Beat-Lupus) confirmed safety of rituximab and belimumab combination in 52 patients with refractory SLE manifestations (38% with LN).¹²² Belimumab-rituximab combination resulted in greater suppression of B-cell repopulation, anti-dsDNA levels, and reduced frequency of severe flares at week 52 compared to PBO.

In a more recent RCT (BLISS-BELIEVE) which recruited 263 patients with active SLE, combining rituximab with a background of SC belimumab while stopping concomitant immunosuppression led to a more profound drop in most B cell subsets, including memory B cells, and anti-dsDNA levels compared to PBO at week 52.¹²³ However, there was no significant difference between the combination group and the belimumab only group in the proportion of patients who achieved disease control at this time point, defined as a SLEDAI-2K ≤2 without immunosuppressants and a prednisone-equivalent dose of ≤5 mg/day. Of concern was an increased incidence of serious infections in the biologic combination group.

As the efficacy and safety of rituximab/belimumab combination is conflicting, further works are needed to re-evaluate this approach in different patient subgroups. A phase III open-label 2-year RCT (Synbiose-2) of rituximab/belimumab in patients with severe SLE, including LN, is in progress (NCT03747159).

Dual Mechanism Anti-BAFF

Ianalumab (VAY-736) is a human, decarboxylated antibody against the BAFF receptor (BAFF-R). It eliminates B cells via a dual mechanism of actions through enhancing ADCC and induction of B cell apoptosis via blockade of the BAFF/BAFF-R interaction.¹²⁴ A phase III PBO-controlled RCT of ianalumab in LN (SIRIUS-LN) is in progress (NCT05126277).

Rozibafusp alfa is a bispecific IgG2-peptide fusion designed to inhibit both BAFF and inducible T-cell costimulator ligand (ICOSL). A phase Ib RCT in rheumatoid arthritis showed safety and efficacy of rozibafusp as compared to PBO.¹²⁵ However, a phase IIb RCT in SLE was terminated because of futility of the interim results (NCT04058028).

Targeting B-Cell Signalling Pathway

The BTK is expressed in most hematopoietic cells, including the B cells and terminally differentiated plasma cells.¹²⁶ In B cells, BTK plays an essential role in the downstream signal pathways through the B-cell receptor¹²⁷ and enhances the sensitivity of the B cells to the toll-like TLR-mediated events that include cytokine and autoantibody production.¹²⁸ BTK expression was increased in peripheral blood mononuclear cells (PBMCs) of SLE patients and correlated with disease activity, including renal.¹²⁹ BTK inhibitors (BTKis) do not deplete B cells and the effects of BTK blockade in other immune cell types may enhance their therapeutic effects in SLE.

Evobrutinib, a highly selective oral BTKi, was studied in a phase II RCT of patients with active SLE despite SOC.¹³⁰ However, the study did not meet the primary end points of SRI-4 and SRI-6 at week 52 compared to PBO in the high disease activity subpopulation. No clinically meaningful differences in other secondary outcomes were observed either between evobrutinib and PBO, although the drug was well-tolerated. Another phase II dose-ranging study of fenebrutinib, a second-generation highly selective, reversible oral BTKi, was conducted in 260 SLE patients with moderate/severe activity who were receiving SOC.¹³¹ Although fenebrutinib reduced the BTK-dependent plasmablast RNA signature, anti-dsDNA, and IgG/IgM levels relative to PBO, the proportion of patients who achieved the SRI-4 and BICLA responses was not significantly higher in the treatment groups at week 48. However, SAEs were numerically more common in BTKi users. Orelabrutinib is a highly selective, irreversible oral BTKi that has been studied in a phase Ib/II RCT of 60 SLE patients in China.¹³² The primary outcome, SRI-4 response rate at week 12, was significantly higher in the treatment than PBO groups. Overall, AEs were mild to moderate and the majority of TEAEs were not severe. As the results of these three RCTs are discrepant, further phase III RCTs of the BTKis in SLE are needed.

Lipocalimab is a monoclonal antibody that binds with high affinity to block the neonatal Fc receptor (FcRn). It inhibits IgG recycling and reduces circulating IgG levels, including autoantibodies in a dose-dependent manner.¹³³ The biologic agent is being studied in primary Sjogren’s syndrome (NCT04969812),¹³⁴ rheumatoid arthritis, autoimmune hemolytic anemia, myasthenia gravis,¹³⁵ chronic inflammatory demyelinating polyneuropathy and severe hemolytic disease of the fetus and newborn.¹³⁶ Two studies of lipocalimab in SLE and LN have been registered (NCT04882878; NCT04883619).

Targeting T Cells

Calcineurin Inhibitors

The calcineurin inhibitors (CNIs) block T-cell activation through suppression of the calcium/calmodulin-dependent phosphatase calcineurin.¹³⁷ Cyclosporin A (CSA) and tacrolimus (TAC) have long been used in the treatment of SLE and LN.^138,139 TAC is preferred to CSA for SLE treatment because of fewer cosmetic, hypertensive and dyslipidemic AEs. Recent RCTs have established non-inferiority of TAC to MMF or intravenous pulse CYC as initial therapy of LN in terms of renal response at 6 months.^140,141 Moreover, low-dose combination of TAC and MMF has been shown to be more effective than intravenous CYC as initial therapy of LN at 6 months.¹⁴² Over 18 months, the rate of renal flares was similar between the MMF-TAC and CYC-AZA groups but the former was associated with a lower withdrawal rate due to AEs.¹⁴³ Addition of low-dose TAC to background MMF has also been shown to be effective in reducing proteinuria in refractory LN.^144,145 TAC does not affect the cell counts and is relatively safe during pregnancy.¹⁴⁶ Although long-term data on CNI nephrotoxicity are awaiting, TAC is commonly used for initial or maintenance treatment of SLE and LN in Asian countries.^147,148 In the latest 2024 Asia Pacific League of Association for Rheumatology (APLAR) consensus, CNI is one of the first-line agents recommended for initial treatment of LN.¹⁴⁹

Voclosporin is a chemical analog of CSA that has a stronger binding capacity to cyclophilin A, leading to a higher potency of calcineurin inhibition, faster elimination and less variability in plasma concentration.¹⁵⁰ A phase III PBO-controlled RCT of voclosporin in active LN showed efficacy of voclosporin in enhancing the CRR rate at week 52 when used in conjunction with MMF and GCs.¹⁵¹ SAE, serious infection and mortality was not significantly different between the voclosporin and PBO groups of patients. The results of this RCT corroborates that of the multi-target regimen in China in which upfront combination of CNI (TAC) with MMF was more effective than CYC in LN.¹⁴² While the cost-effectiveness of combined MMF and voclosporin for upfront combination therapy of LN has to be further evaluated,¹⁵² it is recommended for patients at risk of renal progression,^149,153 including refractory and frequently relapsing disease. Moreover, the CNIs may be more effective in ameliorating LN patients with heavy proteinuria and/or podocytopathy in kidney biopsy.¹⁵⁴

The mTOR Inhibitors

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that is essential for cell metabolism, growth and survival. Activation of the mTOR pathway in kidney tissues is reported in patients with active LN.¹⁵⁵ Inhibitors of mTOR, such as sirolimus and everolimus, are newer immunosuppressive agents that are used in kidney transplantation to prevent allograft rejection to facilitate sparing of the CNIs.¹⁵⁶ An open single-arm phase I/II study demonstrated efficacy of sirolimus in 40 patients with active SLE who were unresponsive or intolerant to SOC therapies in reducing disease activity and the dosage requirement of GCs at month 12.¹⁵⁷ Sirolimus was well tolerated, with only mild reduction in hemoglobin, neutrophil count and HDL-cholesterol level reported. Other case series of Caucasian and Asian patients with SLE also demonstrated efficacy and tolerability of sirolimus.^158,159 Meta-analysis of observational studies showed that sirolimus (1–3mg/day) treatment led to remission of SLE manifestations in 74% of patients.¹⁶⁰ Discontinuation of sirolimus occurred in 9.3% of patients due to reversible and mild AEs.

Inhibition of B/T Cell Co-Stimulation

Abatacept (CTLA4-Ig) is a recombinant fusion protein consisting of the extracellular domain of CTLA4 and a fragment of Fc domain of human IgG1. It binds to CD80 or CD86 with a higher affinity than CD28, thus hindering the co-stimulatory signal for T cell activation.¹⁶¹ In a phase IIb exploratory RCT, 175 patients with active non-renal SLE were randomized to receive abatacept or PBO,¹⁶² in addition to prednisone. The primary outcome of absence of new BILAG A or B flare at month 12 was not met, although treatment difference was greatest in patients with polyarthritis. Another PBO-controlled phase II/III multicenter RCT of abatacept in active proliferative LN on a background of GC and MMF also did not meet the primary end point of CRR at week 52.¹⁶³ In both RCTs, serious AEs and AEs such as herpes zoster and gastroenteritis, and withdrawal due to SAEs, were numerically more frequent in abatacept users. Another phase II RCT of active proliferative LN (ACCESS) also did not show benefit of abatacept over PBO in the CRR rate at week 24 when combined with prednisone and low-dose CYC as initial treatment.¹⁶⁴ However, the incidence of AEs and SAEs was not significantly increased with abatacept.

Interaction between CD40 ligand (CD40L or CD154) on activated T cells and CD40 on B cells is important for maintaining B cell functions such as B cell differentiation, germinal center formation, and antibody isotype switching.¹⁶⁵ Abnormal expression of CD40L in SLE patients might be associated with the generation of autoantibodies.^166,167 An anti-CD40L antibody, BG9588, has halted development because of increased risk of thromboembolism related to platelet activation.¹⁶⁸ Dapirolizumab pegol, a polyethylene glycol-conjugated antigen-binding (Fab0) fragment that lacks a functional Fc domain to reduce the risk of platelet activation, was developed to target the CD40L.¹⁶⁹ A phase IIb, PBO-controlled RCT of dapirolizumab in 182 SLE patients moderate-to-severe disease activity (RISE)¹⁷⁰ did not meet the primary end point of a dose-responsive BICLA responder rates at week 24, although the drug was well tolerated.

Targeting Dendritic Cells

The pDCs are the main producers of type I interferons (IFNs) which are important for the pathogenesis of SLE. Although pDCs constitute a small population of leukocytes in the peripheral blood, they accumulate in lesions of skin and other organs in patients with SLE.^171,172 Litifilimab is a monoclonal antibody that directs against blood dendritic cell antigen-2 (BDCA2) uniquely expressed on pDCs.¹⁷³ This interaction results in suppression of TLR-7/9-induced production of type I IFNs, other cytokines and chemokine by the pDCs.^173,174 Litifilimab also exhibits a dual effect on pDCs by internalization of surface low-affinity Fc gamma receptor (CD32a), thus preventing stimulation of the pDCs by DNA or RNA-containing immune complexes. A phase II PBO-controlled RCT (LILAC-A) of SLE patients with active arthritis or skin lesions showed a significantly greater reduction in active joint counts in the litifilimab 450mg group compared to PBO at week 24.¹⁷⁵ In the second part of this RCT (LILAC-B) that involved patients with active CLE, litifilimab was shown to be superior to PBO in the reduction of the CLASI-A score.¹⁷⁶ In both studies, most of the secondary end points did not support the results of the primary end point analyses. Litifilimab was associated with increased herpes zoster and other viral infections.

Daxdilimab is an IgG1 monoclonal antibody that binds to immunoglobulin-like transcript 7 (ILT7) on the surface of pDCs, leading to their depletion through the ADCC mechanism.¹⁷⁷ A Phase I study showed that daxdilimab profoundly reduced both circulating and tissue-resident pDCs, which was associated with reduced type I IFN activity and improvement in the CLASI-A score in patients with CLE.¹⁷⁷ No increased viral infection was observed with daxdilimab. A phase II trial in discoid lupus is in progress (NCT05591222).

Afimetoran is an antagonist of TLR7 and 8. A phase Ib study of afimetoran in 13 patients with CLE showed efficacy of the drug in suppressing the CLASI-A score, which was coupled with a reduction in expression of the TLR7/8 and IFN pathway genes and other cytokines.¹⁷⁸

Targeting Cytokines

Cytokines are secreted by immune cells for mutual communication and orchestration of the immune response.¹⁷⁹ They may exhibit pro-inflammatory or anti-inflammatory properties, or both, depending on the micro-environment. Cytokine production is dysregulated in SLE, which may the primary or secondary to the imbalance of the Th1/Th2 and Th17/Treg pathways.¹⁸⁰ A number of cytokines are over-expressed in patients with SLE, including the IFNs (IFNα, IFNγ), interleukins (IL-6/10/12/17/21/23) and BAFF.¹⁸¹ Targeting the cytokines by monoclonal antibodies and their downstream intracellular pathway by the Janus kinase inhibitors (JAKis) is an important approach in the treatment of SLE.

Anti-Interferon

IFNα promotes dendritic cell development, T cell activation, and autoantibody production by B cells.¹⁸² Levels of IFN-α, IFN-driven chemokines, and expression of IFN-regulated genes were elevated in SLE patients and correlated with clinical and serological disease activity and serum IL-10 levels.^183–185 Moreover, gain-of-function genetic variants in the type I IFN pathway have been associated with increased susceptibility to SLE.¹⁸⁶

Rontalizumab is a human monoclonal antibody that neutralizes 12 subtypes of IFNα but does not bind to IFNβ or IFNω.¹⁸⁷ A phase II PBO-controlled RCT did not meet the clinical end points of BILAG improvement and SRI response at week 24 in patients with active SLE.¹⁸⁸ Sifalimumab is another human IgG1κ monoclonal antibody that neutralizes most subtypes of IFNα. A phase II RCT in 431 SLE patients showed that the SRI-4 response rate at week 52 was superior in the 1200mg sifalimumab arm than PBO.¹⁸⁹ Improvement in joint counts and CLASI-A skin scores was also documented with sifalimumab treatment, although no changes in anti-dsDNA or C3/4 levels were observed. AEs were not increased with treatment except herpes zoster. Despite the encouraging results, the drug was not further developed.

Anifrolumab is a human monoclonal antibody that directs against the type I IFN receptor, thus blocking the signals from all type I IFNs, including IFNα, IFNβ, IFNε, IFNκ and IFNω.¹⁹⁰ Following a phase IIb RCT showing promising results and safety of anifrolumab,¹⁹¹ two pivotal phase III PBO-controlled RCTs were conducted.^192,193 In the TULIP-1 study, 457 patients with active non-renal SLE were randomized to receive two doses of anifrolumab and PBO in addition to the SOC.¹⁹² At week 52, the SRI-4 response rate was similar between anifrolumab and PBO groups. However, a secondary analysis of the BICLA response and the abolition of the treatment failure criterion of new prescription of non-steroidal anti-inflammatory drugs (NSAIDs) during the trial showed benefit of anifrolumab compared to PBO. In the TULIP-2 study, a modified primary end point of BICLA at week 52 was adopted.¹⁹³ Results showed a significant higher proportion of SLE patients achieved the BICLA response than PBO. Anifrolumab was subsequently approved for the treatment of moderate to severe SLE in addition to SOC.

Pooled data of the TULIP studies showed that anifrolumab treatment was associated with earlier, more frequent, more prolonged and sustained achievement of the low disease activity state (LLDAS)¹⁹⁴ and a sustained GC tapering effect compared to PBO.¹⁹⁵ Patient subgroups with larger treatment differences relative to PBO included those with baseline high IFN gene signature, abnormal serological markers and Asian ethnicity.¹⁹⁶ A 3-year extension of the TULIP studies revealed sustained efficacy of anifrolumab in the reduction of SLE activity and the cumulative GC doses without new safety signals.¹⁹⁷ However, anifrolumab treatment was associated with an increased incidence of herpes zoster and respiratory tract infections.¹⁹⁸

Anifrolumab has also been studied in LN. A phase II PBO-controlled RCT of 147 patients with active LN did not meet the primary outcome of improvement in the geometric mean of proteinuria at week 52 with anifrolumab.¹⁹⁹ However, secondary analysis indicated that using an intensified anifrolumab regimen (with loading doses), the CRR rate was significantly higher than that of PBO. While the incidence of SAEs was similar across all groups, herpes zoster was more common in anifrolumab users. An extension of this study for a further of 12 months demonstrated similar efficacy of anifrolumab over PBO without new safety signals.²⁰⁰ A phase III study of anifrolumab in LN is in progress (NCT05138133).

There are alternative ways of targeting IFNα in SLE. IFN-α-kinoid (IFN-K) is a recombinant human IFNα conjugated to an immunogenic carrier protein.²⁰¹ Active immunization of IFN-K disrupts B cell tolerance and generates neutralizing antibodies against all subtypes of IFNα. A phase I/II dose-escalating RCT of IFN-K in 28 patients with active SLE showed safety and immunogenicity of the drug.²⁰² IFN-K administration induced anti-IFNα antibodies in all subjects, with significantly higher anti-IFNα titers in IFN signature positive than negative patients. IFN-K significantly diminished the expression of IFN-induced genes, which was associated with improvement in C3 levels. A significant correlation was found between the neutralizing anti-IFNα titers and reduction in IFN scores compared to baseline.²⁰³

On the other hand, IFNα can also be antagonized by targeting the pDCs (Targeting Dendritic Cells above) or the intracellular downstream signal pathway by the JAKis (see below).

Anti-IL6

IL-6 is mainly secreted by activated macrophages and T cells and acts synergistically with the type I IFNs to activate B cells, leading to production of protective and pathogenic antibodies. Serum IL-6 levels were elevated in SLE patients and correlated with disease activity and anti-dsDNA level.²⁰⁴ A phase I study of tocilizumab in 16 SLE patients showed efficacy in improving disease activity, particularly arthritis, which was associated with reduction in anti-dsDNA,²⁰⁵ number of activated T and B cells, plasmablasts and post-switched memory B cells.²⁰⁶ Another anti-IL6 monoclonal antibody (sirukumab) was studied in a phase I PBO-controlled trial of 46 patients with SLE or CLE.²⁰⁷ Both tocilizumab and sirukumab treatment were associated with a dose-dependent reduction in neutrophil count and increase in infective complications.^205,207 In a phase II proof-of-concept PBO-controlled RCT of 25 patients with refractory LN, the renal response was not found to be superior in the treatment group at week 24.²⁰⁸ Moreover, in the sirukumab group, SAEs developed in 48% of patients through week 40, most of which were infective complications.

Anti-IL12/23

IL12 and IL23 play an essential role in inflammation and autoimmunity.²⁰⁹ In patients with SLE, a disease activity-related upregulation of serum IL12, IL-23 and IL-23 receptor levels, as well as the expression of the IL12/23 shared common p40 subunit as compared to healthy subjects has been demonstrated.^210–212 Ustekinumab is a fully human monoclonal antibody that inhibits the IL-12/23 p40 subunit and is approved for patients with skin psoriasis, psoriatic arthritis and inflammatory bowel disease. Despite the promising results from a phase II PBO-controlled RCT of ustekinumab in SLE,^213,214 a phase III RCT of 516 patients with active SLE was prematurely terminated due futility of the efficacy end point on interim analysis.²¹⁵ The AEs were consistent with the known safety profile of ustekinumab.

Guselkumab is a monoclonal antibody that targets IL-23p19 subunit. A phase II RCT in adult patients with active LN (histologic class III/IV) was prematurely terminated due to enrollment challenges.²¹⁶ At week 24, no differences in the primary renal efficacy endpoint and other secondary endpoints could be demonstrated between the guselkumab and PBO group of patients.

Low-Dose IL-2

IL-2 is a cytokine produced by activated CD4+ T cells that induces growth and proliferation of the T cells, NK and B cells.²¹⁷ High-dose IL-2 augments the anti-tumor effects of the cytotoxic T cells but also lead to undesirable effects due to the activation of other immune cells. However, low-dose IL-2 preferentially activates the Tregs, leading to immune suppression and tolerance.²¹⁸ Binding of IL-2 to the IL-2 receptor (IL-2R) triggers several downstream signalling pathways that include the JAK-STAT, phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) and the mitogen activated protein kinase (MAPK) that increase Treg proliferation and functional activity.²¹⁹ In addition, murine studies also indicated low-dose IL-2 could effectively deplete autoreactive follicular T helper cells and abolish the autoantibody response.²²⁰

A phase II PBO-controlled RCT of low-dose IL-2 in 100 SLE patients who were receiving SOC did not meet the primary outcome of SRI-4 response at week 12.²²¹ However, efficacy of low-dose IL-2 was shown after excluding 2 centers with 100% SRI-4 rate in the PBO arms. Another RCT of 60 SLE patients in China also did not meet the same primary end point at week 12.²²² However, at week 24, a significantly higher rate of SRI-4 response was observed with IL-2 treatment without increased serious infections. Another phase II PBO-controlled RCT of IL-2 (efavaleukin alfa) in patients with active non-renal SLE was prematurely terminated due to futility (NCT04680637).

The limitations of low-dose IL-2 include the short serum half-life, potential dose-dependent adverse effects, great variability in patients’ response at different dosages, as well as the lack of long-term safety data. Future study design should refine the dosage regimens, explore the prospect of combination with other novel agents, and nest the most appropriate patient subsets by biomarkers to receive IL-2 therapy.

Targeting Cytokine Downstream Pathways

Baricitinib

Baricitinib is a JAK1/2 inhibitor that has shown efficacy in a phase II RCT of SLE patients with active joint and/or skin disease.²²³ Both the primary efficacy endpoint (resolution of skin disease or arthritis at week 24) and secondary end points that included SRI-4 response and LLDAS were achieved in the baricitinib (4mg) group compared to PBO. Although baricitinib did not lead to a greater improvement in anti-dsDNA and C3,²²⁴ levels of IL-12 p40, IL-6, mRNA expression of STAT1-target, STAT2-target, and STAT4-target and multiple IFN responsive genes were reduced.²²⁵ Serious infections were more frequent in the baricitinib 4mg group relative to PBO. Two identical phase III RCTs of baricitinib in non-renal SLE (BRAVE 1/2) were subsequently performed.^226,227 The primary end point, SRI-4 response at week 52, was met in BRAVE-1 but not in BRAVE-2. All secondary endpoints were not met in both studies. Although the musculoskeletal and mucocutaneous domains on SLEDAI and BILAG improved significantly with baricitinib 4mg in BRAVE-1, result was not reproduced in BRAVE-2. The inconsistent results of these two RCTs render the efficacy of baricitinib in SLE inconclusive.²²⁸ A long-term extension study of baricitinib in SLE is in progress (SLE-BRAVE-X).

Upadacitinib

Upadacitinib is a selective JAK1 inhibitor that has been approved for rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, atopic dermatitis and inflammatory bowel disease.¹¹ The results of a PBO-controlled phase II RCT comparing the efficacy of two doses of upadacitinib, alone or in combination with elsubrutinib, a BTK inhibitor, was recently published.²²⁹ The low-dose upadacitinib/elsubrutinib and elsubrutinib arms were discontinued after an interim analysis showing lack of efficacy. More patients achieved the primary end point of SRI-4 and GC dose ≤10mg/day at week 24 with upadacitinib (30mg/day) and high-dose upadacitinib/elsubrutinib versus PBO. Secondary end points such as the rates of SRI-4, BICLA, LLDAS at week 24 and 48, and reduction of SLE flares were also in favor of these two treatment arms. No new safety signals were observed for upadacitinib or elsubrutinib.

Deucravacitinib

Deucravacitinib is a selective Tyk-2 inhibitor that blocks the downstream signalling of IL-12, IL-23, IL-10, and the type I IFNs.²³⁰ The phase II PBO-controlled RCT (PAISLEY) of deucravacitinib in 363 patients with active SLE (skin or joint) achieved the end point of SRI-4 at week 32.²³¹ Secondary endpoints such as SRI-4, BICLA and LLDAS at week 48 were also in favor of the deucravacitinib (3mg twice-daily) group. Moreover, significantly more patients in this group achieved a ≥50% reduction in the CLASI score and combined swollen/tender joint counts. Greater improvement in anti-dsDNA and complement levels was observed in the deucravacitinib groups across all dosages, but not PBO, which were associated with an improvement in IFN signature through 44 weeks. Deucravacitinib was well-tolerated, with no increase in infective complications, including herpes zoster, reported. Two phase III RCTs (POETYK SLE-1/2) are in progress (NCT05617677 and NCT05620407).

Targeting Other Cellular Mechanisms

Targeting the Complements

Complements play an essential role in clearance of immune complexes and apoptotic bodies in SLE. They also regulate the functions of T and B cells.²³² Activation of terminal complement is associated with disease activity and organ damage in SLE, particularly LN. Eculizumab is a monoclonal antibody targeting C5 complement and blocks its cleavage. A phase I study demonstrated safety in SLE patients.²³³ Case series have reported efficacy of eculizumab in SLE/LN with thrombotic microangiopathy (TMA) features or part of the atypical hemolytic uremic syndrome.^234,235 Avacopan is a complement 5a receptor (C5aR) antagonist approved as an adjunctive treatment for ANCA-related vasculitis. It is also being investigated for the treatment of C3 glomerulopathy, hidradenitis suppurativa and IgA nephropathy. However, no clinical trial of avacopan in SLE/LN has been registered yet. Iptacopan is an oral inhibitor against complement factor B in the alternative complement pathway. It regulates the cleavage of C3, generation of downstream effectors and the amplification of the terminal complement pathway. The drug is approved for paroxysmal nocturnal haemoglobinuria (PNH) and is being investigated in IgA nephropathy and C3 glomerulopathy.²³⁶ A phase II RCT in active LN has been registered (NCT05268289).

Targeting the S1PR1

Sphingosine 1-phosphate (S1P) is a bioactive metabolite of ceramide that binds to five G protein-coupled S1P receptors (S1PR1-S1PR5) and influences cell proliferation, survival, and migration.²³⁷ Among the S1PR isoforms, S1PR1 is expressed on leukocytes and endothelial cells and mediates lymphocyte trafficking, Treg/Th17 cell homeostasis, and vascular permeability.²³⁸ Four S1PR1 modulators (fingolimod, siponimod, ozanimod, and ponesimod) are approved for multiple sclerosis and two SIPR1 modulators (ozanimod and etrasimod) are approved inflammatory bowel disease.²³⁹ The S1PR1 modulators could be effective in reducing SLE activity by inhibiting the trafficking of autoreactive lymphocytes and Th17 cell differentiation, augmenting the number and function of the Tregs, and reducing production of autoantibodies.²⁴⁰ Moreover, these modulators could enhance the endothelial cell and blood-brain barrier functions, diminish adhesion molecule expression for leukocyte transmigration, and type I IFN production by pDCs in response to viral or oligonucleotides, which are potentially beneficial for renal, neuropsychiatric disease and atherosclerotic injury in SLE.²⁴¹

An open phase Ib safety trial of amiselimod in 17 SLE patients with mild/moderate activity reported lymphopenia after treatment in all patients but no serious infections, cardiac toxicity or SAEs were observed.²⁴² A proof-of-concept PBO-controlled RCT of oral cenerimod in 49 SLE patients with active mucocutaneous or musculoskeletal manifestations demonstrated efficacy in reducing serological and clinical activity at week 12 without increasing TEAEs.²⁴³ Reduction in lymphocyte count occurred in a dose-dependent manner and a small but non-clinically relevant drop of heart rate was observed in the first 6 hours of drug administration. A more recent phase II PBO-controlled dose-escalating RCT of cenerimod in 427 SLE patients with moderate/severe activity did not meet the primary end point of mSLEDAI-2K score improvement at month 6.²⁴⁴ However, cenerimod 4 mg reduced IFN-associated protein and gene signature biomarkers after treatment.²⁴⁵ Two phase III RCTs (OPUS-1/2) of cenerimod in SLE are in progress (NCT05648500, NCT05672576).

Synthetic Peptides and Immune Tolerizers

Abetimus sodium, consisting of four dsDNA epitopes conjugated to a non-immunogenic polyethylene glycol platform, crosslinks anti-dsDNA immunoglobulin receptors on B cell surface, triggering signal transduction pathways that result in apoptosis or anergy.²⁴⁶ However, two large phase III RCTs of SLE failed to show efficacy of this agent in reducing disease flares, although it was well tolerated and reduced anti-dsDNA levels.^247,248

Edratide is a peptide based on the sequence of the first complementarity-determining (CDR1) region of a pathogenic human anti-DNA monoclonal antibody (16/6 idiotype) that downregulates pathogenic cytokines, apoptosis, IFNα gene expression, but upregulates Tregs in PBMCs of SLE patients.^249,250 A 26-week phase II dose-escalating study of SLE patients with mild/moderate activity was terminated because of lack of efficacy.²⁵¹

Rigerimod (Lupuzor) is a 21-mer linear peptide issued from the small nuclear ribonucleoprotein U1-70K and phosphorylated at the Ser140 position.²⁵² It tolerizes CD4+T cells to react to self-antigens by binding to the MHC class II molecule on cell surface and through other unknown mechanisms.²⁵³ A phase IIa study demonstrated safety of rigerimod and improved clinical and serological SLE activity [122]. Another phase IIb RCT confirmed higher SRI response rate than PBO at week 12.²⁵⁴ However, the phase III 52-week RCT of rigerimod in SLE (NCT02504645) did not meet the primary end point.²⁵⁵

Laquinimod is a modulator of antigen presenting cells that directs T cells toward an anti-inflammatory phenotype through downregulation of the pro-inflammatory cytokines (IL-6/12/17/23/TNFα) but upregulation of IL-10. A phase IIa PBO-controlled RCT showed efficacy of laquinimod in improving renal function and proteinuria on a background of MMF and GCs.²⁵⁶ No increase in AEs and SAEs were observed in the laquinimod groups. Another study of laquinimod in lupus arthritis has been completed (NCT01085084).

Arsenic Trioxide

Arsenic trioxide (ATO) is now part of the standard treatment regimen for acute promyelocytic leukemia (PML). ATO binds to the PML-retinoic acid receptor (RAR)α fusion oncoprotein and enhances its proteasomal degradation, leading to senescence of the leukemic cells and restoration of terminal differentiation of the myeloid progenitors.²⁵⁷ The availability of an oral form of ATO has greatly reduced the incidence of cardiotoxicity compared to the intravenous preparation. Increasing evidence shows that ATO has anti-inflammatory properties that include modulation of Treg activation, Th1/Th2 and Th17/Treg balance, depletion of activated T cells and pDCs, and reduction of differentiation, autoantibody and cytokine production by B cells.²⁵⁷ A phase IIa open single-arm dose-escalating study of 11 SLE patients with refractory disease showed that 50% of patients could achieve a SRI-4 response after intravenous ATO treatment for 24 weeks.²⁵⁸ Neutropenia occurred in 20% of the patients. As oral ATO is more convenient and has a reduced toxicity profile, it has a great potential for the treatment of SLE.

Conclusion

Novel therapeutic agents that target different cell types, cytokines, receptors and intracellular pathways of the innate and adaptive immune systems are being developed and tested in patients with SLE. As B cells are pivotal in the production of autoantibodies, targeting B cells is one of the main strategies of SLE therapies in the past two decades. However, the clinical efficacy of B cell modulation in SLE has not been too impressive until the recent data from the newer generation anti-CD20, obinutuzumab, showing benefit in LN when combined with the SOC.³⁵ Previous RCTs of rituximab in non-renal SLE and LN^26,27 did not show efficacy although this biologic has been widely used to treat refractory SLE. Moreover, sequential or combination therapy of the anti-CD20 and anti-BAFF has not been shown to be effective in increasing the response rate in SLE and LN but carries a risk of increased infection.²⁵⁹ Clinical trials of anti-CD22, anti-CD19 in SLE are futile, and neither are other anti-BAFF agents such as blisibimod and tabalumab.²⁶⁰

The cytokine inhibitors show promise in SLE. Despite the futility of anti-IL6 and IL-12/23 trials,^208,215 belimumab and anifrolumab are anti-cytokine biologics approved for SLE at this juncture. Targeted small molecules have the advantage of lower production cost, convenience of oral administration and lack of immunogenicity.²¹ The oral jakinibs, proteasome inhibitors and cereblon modulators have shown preliminary success in SLE. The results of phase II studies of deucravacitinib and zetomipzomib in human SLE are encouraging. Iberdomide shows favorable phase II results in SLE, in particularly CLE lesions.

The clinical and serological heterogeneity of SLE is a major factor contributing to the failure of new drug trials in SLE. With the improvement in patient stratification by multi-omic approach, adjustment of background immunosuppressive regimens and study end points, the response rate and the effect size of SLE trials could be improved.²⁶⁰ A new era of SLE therapies is expected in the near future and the treat-to-target approach²⁶¹ is increasingly feasible in SLE. With the availability of these novel therapeutics and the improved patient selection, it is hoped that the effectiveness of SLE treatment could be improved so that patients can survive longer with improved quality of life.

Disclosure

The author reports no conflicts of interest in this work.

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Immunotargets and Therapy for Systemic Lupus Erythematosus

Introduction

Targeting the B Cells

B-Cell Depletion

Anti-CD20

Anti-CD22

Anti-CD19 and T-Cell Engagers

Car-t

Long-Lived Plasma Cells

Targeting B-Cell Growth Factor

BAFF Inhibition

Anti-BAFF/Anti-CD20 Combination

Dual Mechanism Anti-BAFF

Targeting B-Cell Signalling Pathway

Targeting T Cells

Calcineurin Inhibitors

The mTOR Inhibitors

Inhibition of B/T Cell Co-Stimulation

Targeting Dendritic Cells

Targeting Cytokines

Anti-Interferon

Anti-IL6

Anti-IL12/23

Low-Dose IL-2

Targeting Cytokine Downstream Pathways

Baricitinib

Upadacitinib

Deucravacitinib

Targeting Other Cellular Mechanisms

Targeting the Complements

Targeting the S1PR1

Synthetic Peptides and Immune Tolerizers

Arsenic Trioxide

Conclusion

Disclosure

References

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