. 2023 Jul 10;14:1235440. doi: 10.3389/fphar.2023.1235440

TABLE 1.

B-cell-targeted investigation for treatment of SLE.

Medicine	Mechanism of action	Trial	Trial phase	SLE population	Method of administration	Significant findings	Ref
Belimumab	Monoclonal antibody (IgG1) targeted soluble BAFF	BLISS-52	Ⅲ	SELENA-SLEDAI≥6	IV	Significantly higher SRI rate with belimumab 1 mg/kg and 10 mg/kg than with placebo	Navarra et al. (2011)
		BLISS-52	Ⅲ	Positive for anti-dsDNA or ANA	IV		Navarra et al. (2011)
		BLISS-76	Ⅲ	SELENA-SLEDAI≥6	IV	Significantly greater SRI response with belimumab 10 mg/kg at week 52 compared with placebo. There was no difference between groups when followed to 76 weeks	Furie et al. (2011)
		BLISS-76	Ⅲ	Positive for anti-dsDNA or ANA	IV		Furie et al. (2011)
		BLISS-LN	Ⅲ	LN	IV	Significantly more patients in the belimumab group (10 mg/kg) had a primary efficacy renal response and a complete renal response than in the placebo group at week 104	Furie et al. (2020)
		BLISS-LN	Ⅲ	LN	IV	Increases occurred in the proportions of patients achieving primary efficacy renal response and complete renal response from open-label baseline to week 28	Furie et al. (2022)
Tabalumab	Monoclonal antibody (IgG4) targeted soluble and membrane BAFF	ILLUMINATE-1	Ⅲ	SELENA-SLEDAI≥6	SC	No significant difference in SRI-5, time to first flare, or steroid-sparing effect in tabalumab-treated patients. Significant reductions in anti-dsDNA antibodies, increase in C3 and C4, and reductions in total B cells and immunoglobulins were observed with tabalumab	Isenberg et al. (2016)
		ILLUMINATE-1	Ⅲ	ANA positive	SC		Isenberg et al. (2016)
		ILLUMINATE-2	Ⅲ	SELENA-SLEDAI≥6	SC	Primary endpoint was met with 120 mg every 2 weeks. Key secondary endpoints were not met.	Merrill et al. (2016)
		ILLUMINATE-2	Ⅲ	ANA positive	SC		Merrill et al. (2016)
Blisibimod	Peptibody with 4 BAFF-binding targeted BAFF	PEARL-SC	Ⅱ	SELENA-SLEDAI≥6	SC	SRI-5 response rates were not significantly improved in the pooled blisibimod groups. Significant changes in anti-dsDNA antibodies, complement C3 and C4, and reductions in B cells were observed with blisibimod	Furie et al. (2015)
		PEARL-SC	Ⅱ	Positive for anti-dsDNA or ANA	SC		Furie et al. (2015)
		CHABLIS-SC1	Ⅲ	SELENA-SLEDAI≥6	SC	SRI-6 primary endpoint was not met. A significant steroid-sparing effect appeared with blisibimod-treated subjects and achieved corticosteroid taper. Blisibimod was associated with successful steroid reduction, decreased proteinuria and biomarker responses	Merrill et al. (2018a)
				Systemic corticosteroid
				Positive for anti-dsDNA or ANA
Atacicept	A fusion protein of TACI and Fc domain of human IgG1 targeted both BAFF and April	ADDRESS Ⅱ	Ⅱb	SLEDAI-2K ≥ 6	SC	The SRI-4 response rate was improved with atacicept 75mg and 150 mg at week 24 as compared with placebo. The post hoc analysis showed that only the cohort with high disease activity at baseline did meet the primary endpoint in patients receiving atacicept 150 mg	Merrill et al. (2018b), Morand et al. (2020b), Wallace et al. (2021)
Atacicept		ADDRESS Ⅱ	Ⅱb	Positive for anti-dsDNA or ANA	SC
Rituximab	Monoclonal antibody targeted surface CD20	EXPLORE	Ⅱ/Ⅲ	≥1 BILAG A score or ≥2 BILAG B scores	IV	No differences were noted between placebo and rituximab in the primary and secondary endpoints	Merrill et al. (2010b)
				Positive for ANA
				Stable use of 1 immunosuppressive drug
		LUNAR	Ⅲ	Class Ⅲ or Ⅳ LN according to the 2003 ISN/RPS	IV	The primary endpoint was not achieved. Statistically significant improvements in serum complement C3, C4 and anti-dsDNA level and reduction of proteinuria were observed among patients treated with rituximab	Rovin et al. (2012)
		LUNAR	Ⅲ	Positive for ANA	IV		Rovin et al. (2012)
Ofatumumab	Monoclonal antibody targeted surface CD20	Case series	-	Treated with ofatumumab for SLE/LN since 2012	IV	B cell depletion was achieved in 12/14 patients, serological markers of disease activity have improved. Half of the patients with LN achieved renal remission by 6 months. Ofatumumab is a useful alternative in rituximab-allergic patients	Masoud et al. (2018)
Ocrelizumab	Monoclonal antibody targeted surface CD20	BELONG	Ⅲ	Positive for ANA	IV	Overall renal response rates with ocrelizumab in patients with active LN were numerically superior to those with placebo. But ocrelizumab treatment was associated with a higher rate of serious infections	Mysler et al. (2013)
Ocrelizumab	Monoclonal antibody targeted surface CD20	BELONG	Ⅲ	Active LN	IV		Mysler et al. (2013)
Obexelimab	Monoclonal antibody targeted surface CD19 and increased affinity for FcγRIIb	-	Ⅱ	SLEDAI decrease ≥4 points or ≥1 grade decrease in ≥1 BILAG A or B score	IV	No significantly difference between groups in an efficacy evaluable population analysis. There was a significant difference in the intent to treat analysis at 169 days, but not at 225 days	Merrill et al. (2018c)
Epratuzumab	Monoclonal antibody targeted surface CD22	EMBLEM	Ⅱb	BILAG 2004 of grade A in ≥1 organ/system or grand B in ≥2 organs/systems	IV	Proportion of responders was higher in all epratuzumab groups than with placebo	Wallace et al. (2014)
		EMBLEM	Ⅱb	SLEDAI-2K ≥ 6	IV		Wallace et al. (2014)
		EMBODY 1 & 2	Ⅲ	Positive for anti-dsDNA or ANA	IV	No statistically significant difference in the primary end point between the groups	Clowse et al. (2017)
				SLEDAI-2K ≥ 6
				BILAG-2004 scores of grade A in ≥1 body system or grand B in ≥2 body system

Abbreviations: SLE: systemic lupus erythematosus; BAFF: B-cell-activation factor; TACI: transmembrane activator calcium moderator and cyclophilin lingand interactor; April: a proliferation-inducing ligand; BLISS: belimumab in subjects with SLE; IV: intravenous; SELENA-SLEDAI: Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index; dsDNA: double-stranded DNA; ANA: antinuclear antibodies; SRI: SLE, responder index; LN: lupus nephritis; SC: subcutaneous; SLEDAI-2K: SLE, disease activity index 2000; BILAG: british isles lupus assessment; ISN/RPS: International Society of Nephrology/Renal Pathology Society.