Systemic lupus erythematosus: how are B-cell targeted therapies progressing? High-scoring review

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that primarily affects women
of childbearing age.

Patients with SLE produce too many autoantibodies and cytokines, leading to inflammation and organ damage
.

The important role of B cells in the pathogenesis of SLE

SLE is characterized by B cells reacting with autoantigens to produce autoantibodies
.
These autoantibodies can appear years before SLE clinically onset
.
Overproduction of autoantibodies leads to an inflammatory cascade and a massive immune response that ultimately leads to organ damage
in patients.
In addition to secreting autoantibodies, B cells secrete cytokines
that promote inflammation.

B cells and plasma cells (effector B cells) play an important role in the pathogenesis of SLE, and their associated antigens are the main therapeutic targets, such as CD19, CD20, CD40, etc.

Figure 1 Maturation process of B cells

A novel therapeutic drug for SLE targeting B cells

Treatment strategies targeting B cells include directly killing B cells, regulating B cell function, inhibiting molecules necessary for B cell growth and survival, and
accelerating autoantibody clearance.

Table 1 A brief summary of various B-cell clinical trials

Belliumab

The BLISS-52 and BLISS-76 trials were a phase 3 randomized, double-blind, placebo-controlled, multicenter study of berliumab, based on which the FDA approved the anti-BAFF monoclonal antibody beliumumab for the treatment of SLE
。 At week 52, the response rates for SRI(4) in the BLISS-52 trial were 43.
6% in the placebo group, 51.
4% in the 1 mg/kg berliumab group, and 57.
6% in the 10 mg/kg berliumab group, while in the BLISS-76 trial, the SRI(4) response rates were 33.
5% in the placebo group, 40.
6% in the 1 mg/kg berliumab group, and 43.
2%
in the 10 mg/kg berliumab group, respectively.

The FDA also approved the subcutaneous injection type of berliumab based on the results of the BLISS-SC test
.
In the BLISS-SC trial, SRI(4) was also used as the primary endpoint, and its efficacy data were comparable
to those of the BLISS-52 and BLISS-76 trials.

Tatesip

According to the results of the Phase 2 study, Thalacip has been approved for SLE indication
in China in March 2021.
The phase 2b trial of tetazep included 249 patients with moderate to severe SLE and received teltazep (80 mg, 160 mg, or 240 mg) or placebo in a 1:1:1:1 ratio, and at 48 weeks, the response rates of SRI(4) in each group were 33.
9% in the placebo group, 71% in the 80 mg tetazep group, 68.
3% in the 160 mg tetazep group, and 75.
8%
in the 240 mg tetazep group, respectively.

Rituximab

Based on the results of both the EXPLORER trial and the LUNAR trial, rituximab in the treatment of SLE or LN did not meet the primary endpoints
.
The EXPLORER trial was a phase 2/3 randomized, double-blind, placebo-controlled trial of 257 patients with moderate to severe active SLE to assess the safety and efficacy of rituximab
.
The primary endpoint was defined as the ability
of rituximab to trigger a pre-set clinical response at week 52.
At week 52, the main clinical response rate (12.
4% vs.
15.
9%), partial clinical response rate (17.
2% vs.
12.
5%) and overall effective rate (29.
6% vs.
28.
4%) were slightly different between the rituximab group and the
placebo group.

The LUNAR trial is a phase 3 randomized, double-blind, placebo-controlled trial in patients with lupus nephritis (LN) to assess the safety and efficacy of rituximab in combination with mycophenolate mofetil (MMF) and glucocorticoids
.
In the study, the overall (complete and partial) renal remission rate in the rituximab group was 56.
9%, higher than that in the placebo group of 45.
8%, but there was no statistically significant difference
.

With the introduction of glucocorticoids and immunosuppressants since the mid-1950s, the prognosis of patients with SLE has improved considerably, but there is still a large number of unmet
treatment needs.
Understanding SLE's immune system abnormalities paves the way
for identifying targets for drug development.
There is no doubt that substantial progress will be made in the future in creating safer and more effective treatments for SLE, which will lead to better treatments
for patients.

Reference: Arbitman L, Furie R, Vashistha H.
B cell-targeted therapies in systemic lupus erythematosus[J].
J Autoimmun.
2022 Aug 10:102873.
doi: 10.
1016/j.
jaut.
2022.
102873.
Epub ahead of print.
PMID: 35963808.