B cells targeting therapy in the management of systemic lupus erythematosus

Figures & data

Table 1. Target molecules for B cell therapies.

Molecule	Type	Location	Agents
CD19	Membrane receptor	All types of B cells including plasma cells	Anti-CD19 antibody
CD20	Membrane receptor	From pre-B cells to activated B cells	Anti-CD20 antibody
CD22	Membrane receptor	From pro-B cells to activated B cells	Anti-CD22 antibody
BAFF	Cytokine	Receptors expressed from immature B cells to plasma cells	Anti-BAFF antibody
APRIL	Cytokine	Receptors expressed from activated B cells to plasma cells	Anti-APRIL antibody
IL-6	Cytokine	Receptors expressed from activated B cells to plasmablasts	Anti-IL6 antibody
IL-6R	Membrane receptor	Activated B cells to plasmablasts	Anti-IL-6R antibody
Type 1 IFN	Cytokine	Interrupts BAFF from immature B cells to plasma cells	Anti-type 1 IFN antibody
IFNAR	IFN receptor	Blocks entire type 1 IFN signaling then inhibits induction of BAFF	Anti-IFNAR antibody
CD40L	Co-stimulatory molecules	T cells	Anti-CD40L antibody

APRIL: A proliferation-inducing ligand; BAFF: B cell activating factor; BCMA: B cell maturation antigen; CD40L: Cluster of differentiation 40 ligand; IFN: Interferon; IL-6: Interleukin-6; IFNAR: the type 1 IFN-α/β/ω receptor; IL-6R: Interleukin-6 receptor; TACI: Transmembrane activator and cyclophilin ligand interactor.

Table 2. Promising therapies targeting B cell surface antigens for SLE currently under investigation.

Agent	Type	Mechanism of action	Clinical trial development and status in SLE	Potentials/Outcomes	Severe side effects
XmAb5871	Humanized anti-CD19 monoclonal antibody	Inhibits B cell functions	Phase II, completed	Results analysis in progress	Unspecified
CD19 CARs	Anti-CD19 CARs	Engineered T cell receptors targeting CD19 on B cell and depleting B cells	Phase I, recruiting	T cells collected from patients, less toxicity	Poor expansion and early elimination of CARs, cytokines releasing syndromes
Rituximab	Chimeric anti-CD20 monoclonal antibody	Depletes B cell via ADCC, CDC, apoptosis, ADP	EXPLORER: Phase II/III in moderate to severe SLE, completed LUNAR: Phase III in active proliferative LN, completed RITUXILUP: Phase III in LN, terminated with unknown reasons ROOTS: Phase II in SLE with skin disease and arthritis, ongoing	High clinical response rate in more 20 open-label studies No significant difference in clinical response, measured by BILAG scores	Post-rituximab flares: high levels of anti-dsDNA antibodies and elevated circulating BAFF
Ocrelizumab	Humanized anti-CD20 monoclonal antibody	Depletes B cells via ADCC and CDC	BELONG: Phase III in SLE with LN, stopped prematurely due to serious infections BEGIN: Phase III in non-renal SLE, terminated due to unknown reasons	Overall renal response rates no significant difference compared to placebo group Does not produce HACA	Serious infections in the subgroup receiving background MMF
Obinutuzumab	Fully humanized anti-CD20 monoclonal antibody	Depletes B cells via ADCC and CDC	Phase III in SLE with proliferative LN, ongoing	Induces B cell cytotoxicity more efficient in in vitro whole blood assays in SLE	Unspecified
Epratuzumab	Humanized anti-CD22 monoclonal antibody	Enhances inhibitory function of CD22 on BCR and hence inhibits B cell activation	ALLEVIATE 1/2: Phase III in moderate to severe SLE, stopped prematurely due to interruption in drug supply EMBLEM: Phase IIb in moderate to severe SLE, completed EMBODY1/2: Phase III in moderate to severe SLE, completed	ALLEVIATE 1/2 and EMBODY1/2 failed to meet primary endpoint Extension study of EMBLEM reported improvements in disease activity, HRQOL and reduction of steroid doses	No significant difference compared to placebo group

ADCC: Antibody-dependent cell-mediated cytotoxicity; ADP: Antibody-dependent phagocytosis; APRIL: A proliferation-inducing ligand; BAFF: B cell activating factor; BCR: B cell receptor; CARs: Chimeric antigen receptors; CDC: Complement mediated cytotoxicity; CLL: Chronic lymphocytic leukemia; dsDNA: double-stranded deoxyribonucleic acid; FDA: United States Food and Drug Administration; HACA: Human anti-chimeric antibody; HRQOL: Health-related quality of life; LN: Lupus nephritis; MMF: Mycophenolate mofetil; MS: Multiple sclerosis; SLE: Systemic lupus erythematosus.

Table 3. Current ongoing trials of belimumab in SLE.

Name	Description	ClinicalTrials.gov Identifiers/Estimated participants	Estimated complete year/ Duration	Country
Continuation of BLISS-SC and HGS1006-C1115	Phase III: Efficacy and safety of belimumab in Northeast Asia	NCT01597622 N = 420	2018 (No results posted) 5 years	Japan, Republic of Korea
Belimumab Treatment Holiday and Treatment Re-start Study in Lupus Patients	Phase III: 24-week withdrawal followed by 28-week reintroduction of belimumab in SLE	NCT02119156	2018 (No results posted) 2 years	USA, China, Japan, Republic of Korea
BLAST	Phase IV: Effects of belimumab as single agent in SLE	NCT02270970 N = 20	2019 6 months	USA
BLISS-LN	Phase III: Efficacy, safety and tolerability of belimumab in adult LN	NCT01639339 N = 464	2020 2 years	USA, Argentina, Belgium, Brazil, Canada, China, Colombia, Czechia, France, Germany, Hong Kong, Hungary, Republic of Korea, Mexico, Netherlands, Philippines, Russian Federation, Spain, Taiwan, Thailand, UK
Belimumab (BENLYSTA^®) Pregnancy Registry	Effects of belimumab in pregnant women with SLE and infants born to mothers who were exposed to belimumab	NCT01532310 N = 500	2021 9 years	USA
BASE	Phase IV: Adverse events of special interest of belimumab in SLE	NCT01705977 N = 4018	2022 1–4 years	USA, Argentina, Australia, Brazil, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Estonia, Hong Kong, Hungary, Indonesia, Italy, Republic of Korea, Lithuania, Malaysia, Mexico, New Zealand, Norway, Peru, Philippines, Poland, Portugal, Romania, Russian Federation, Serbia, Slovakia, Spain, Switzerland, Taiwan, Thailand, Ukraine
Trial of Belimumab in Early Lupus	Phase IV: Effects of belimumab in early lupus	NCT03543839 N = 30	2023 2 years	USA
BENLYSTA^® Special Drug Use Investigation	Long-term safety of intravenous injection and subcutaneous injection belimumab in SLE	NCT03370263 N = 600	2025 1 year	Japan
SABLE	Long-tern safety and effectiveness of belimumab in SLE	NCT01729455 N = 3000	2025 12 years	USA, Argentina, Austria, Belgium, Canada, France, Germany, Israel, Italy, Portugal, Slovakia, Spain, Sweden
PLUTO	Phase II: Safety, pharmacokinetics and efficacy of belimumab in SLE pediatric patients	NCT01649765 N = 93	2028 5–10 years	USA, Argentina, Canada, Italy, Japan, Mexico, Netherlands, Peru, Poland, Russian Federation, Spain, UK

SLE: Systemic lupus erythematosus; UK: United Kingdom; USA: United States of America.

Table 4. Therapies targeting B cell survival factors, cytokines and co-stimulatory molecule for SLE currently under investigation.

Agent	Type	Mechanism of action	Clinical trial development and status in SLE	Potentials/Outcomes	Severe side effects
Tabalumab	Anti-BAFF monoclonal antibody	Targets both soluble and membrane-bound BAFF and inhibits B cells development	ILLUMINATE-1/2: Phase III, completed	ILLUMINATE-1 failed to meet primary endpoint ILLUMINATE-2 achieved primary endpoint but failed to meet secondary endpoints Drug development discontinued	Depression and suicidal ideation
Blisibimod	Anti-BAFF peptibody	Targets both soluble and membrane-bound BAFF and inhibits B cells development	PEARL-SC: Phase II in SLE, completed CHABLIS-SC1: Phase III in active SLE, completed CHABLIS7.5: Phase III in SLE, ongoing	Both studies failed to meet primary endpoint but reduced steroid dosage, levels of proteinuria and biomarkers	No significant difference compared to placebo group
Atacicept	Humanized TACI-antibody fusion protein	Targets BAFF and APRIL then inhibits B cells development	Phase II/III in LN, premature termination due to decline in serum IgG and serious infections APRIL-SLE: Phase II/III in moderate to severe SLE, premature termination due to fatal infections ADDRESS II: Phase IIb in active SLE, completed	ADDRESS II met primary end point particularly in high disease activity and serologically active SLE. Extension study showed a continued low flare trend in atacicept-treated patients	Broader immunosuppression Fatal infections in APRIL-SLE
RCT-18	Humanized TACI-antibody fusion protein	Targets BAFF and APRIL with strong binding capacity compared to atacicept	Phase IIb in moderate to severe SLE, ongoing	N/A	Unspecified
Sirukumab	Humanized anti-IL-6 monoclonal antibody	Binds to IL-6 then inhibits terminal differentiation of B cell into plasma cells	Phase I in SLE or CLE patients, completed Phase II in SLE with class III/IV lupus nephritis	Phase I study: Well tolerated with linear pharmacokinetics Phase II study: no overall improvement in proteinuria	Pneumonia and iatrogenic infection reported in phase II study
Tocilizumab	Humanized anti-IL-6R antibody	Blocks IL-6 from binding to its receptor	Phase I in SLE, completed	Preliminary data showed significant improvements of disease activity	Increased risk of infections and neutropenia
Vobarilizumab	Anti-IL-6R antibody with HAS domain	Blocks IL-6 from binding to its receptor	Phase II in moderate to severe SLE patients, completed	Longer half-life than tocilizumab Failed to meet primary endpoint	No significant difference compared to placebo group
Rontalizumab	Humanized anti-IFN-α monoclonal antibody	Prevents signaling through type 1 IFN receptor then inhibits induction of BAFF	Phase I in mild active SLE, completed ROSE: Phase II in moderate to severe SLE, completed	Phase I confirmed safety, pharmacokinetics profile and pharmacodynamics effects ROSE failed to meet primary end point but improved disease activity, reduced flares, decreased steroid use	No significant difference compared to placebo group
Sifalimumab	Fully humanized anti-IFN-α monoclonal antibody	Prevents signaling through type 1 IFN receptor then inhibits induction of BAFF	Phase IIb in moderate to severe SLE, completed Phase II in SLE, completed	All studies met primary end point but due to the modest treatment effects, drug development had been discontinued in favor of anifrolumab	No significant difference compared to placebo group
Anifrolumab	Fully humanized anti-IFNAR monoclonal antibody	Blocks entire type 1 IFN signaling then inhibits induction of BAFF	Phase II in moderate to severe SLE, completed Phase III studies in active SLE, ongoing	Phase II trial met primary endpoint and secondary endpoints, suggested that blocking entire IFN-I signaling is promising compared to targeting only IFN- α	No significant difference compared to placebo group
Dapirolizumab	Anti-CD40 ligand antibody conjugated to PEG	Blocks CD40 ligand on T cells and hence inhibits co-stimulatory effects on B cells	Phase I in SLE, completed Phase II in moderate to severe SLE, ongoing	Phase I showed good safety profile	Unspecified

APRIL: A proliferation-inducing ligand; BAFF: B cell activating factor; BCMA: B cell maturation antigen; CLE: Cutaneous lupus erythematosus; HAS: Human serum albumin; IFN: Interferon; IFNAR: the type 1 IFN-α/β/ω receptor; IL-6: Interleukin-6; IL-6R: Interleukin-6 receptor; N/A: Not available; PEG: Polyethylene glycol; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus; TACI: Transmembrane activator and cyclophilin ligand interaction.

Figure 1. Approaches to target B cells in SLE. One of the current strategies for SLE treatment include therapeutic modulation of B cell surface antigens (CD19, CD20 and CD22), B cell survival factors (BAFF, APRIL), cytokines (IL-6 and IFN) and their receptors (IL-6R and IFNAR) and co-stimulatory molecule (CD40L). Agents directly targeting on B cell surface antigens include: XmAb5871 which blocks CD19 and FcγRIIb on B cells and hence inhibits B cell functions, on the other hand engineered T cell receptors on T cell, CD19 CARs, blocks CD19 on B cell. Rituximab, ocrelizumab and obinutuzumab block CD20 and epratuzumab blocks CD22. The most developed approach which indirectly target B cells is inhibition of B cell survival factors. Belimumab, tabalumab and blisibimod block BAFF (closed circles). Atacicept and RCT-18 block BAFF and APRIL (open circles). Targeting cytokines or co-stimulatory molecule is another strategy to indirectly modulate B cells. Tocilizumab and vobarilizumab block IL-6R while sirukumab blocks directly IL-6 (closed triangles). Anifrolumab blocks IFNAR while rontalizumab and sifalimumab has specificity for blocking IFN-α (open triangles) but not IFN-ω (closed squares) and IFN-β (open squares) which also bind to IFNAR. Finally, dapirolizumab blocks CD40L disrupting CD40–CD40L interactions. APRIL: A proliferation-inducing ligand; BAFF: B-cell activating factor; BAFF-R: B-cell activating factor receptor; BCMA: B-cell maturation antigen; CARs: Chimeric antigen receptors; IL-6: Interleukin-6; IL-6R: interleukin 6 receptor; IFN: Interferon; IFNAR: the type 1 IFN-α/β/ω receptor; TACI: transmembrane activator and CAML interactor