What Are The Trends in The Treatment Of Biologics For Lupus Nephritis? Watch Chinese Scholars Summarize The Latest Developments

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by loss of immune tolerance, and lupus nephritis (LN) is one of the most common manifestations of severe organ damage and a significant cause of disability and death in patients. The current traditional immunosuppressive agents are not enough to meet the treatment needs of patients. In recent years, with the emergence of targeted therapy, several new biological agents have gradually entered the public eye and achieved specific curative effects

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In this context, Liu Xiuju, deputy director of the Pharmacy Department of the Second Hospital of Hebei Medical University, and her collaborators published a review in the journal Clin Exp Med. (impact factor 4.6), briefly summarizing the mechanism of action, efficacy, and safety of new biological agents in the LN field, including a variety of biological agents targeting B cells and T cells.

B cell BAFF/APRIL

Belimumab

Belimumab is a recombinant monoclonal antibody that was approved by the U.S. Food and Drug Administration (FDA) in December 2020 for the treatment of LN in adults. It inhibits B-lymphocyte stimulating factor (BAFF) and effectively blocks the production of autoantibodies by B cells, thereby suppressing autoimmune responses.

BLISS-LN is a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial for patients with active LN (NCT01639339), evaluating the efficacy and safety of belimumab combined with standard treatment. The results showed that the belimumab group had a significantly higher proportion of patients achieving an effective renal response than the placebo group at week 104 (p=0.03), and significantly reduced the level of anti-double-stranded DNA antibodies, while significantly increasing the levels of C3 and C4. Regarding safety, patients in the belimumab group had a significantly lower risk of kidney-related events or death than those in the placebo group (p=0.001).

Atacicept

Atacicept blocks BAFF and a proliferation-inducing ligand (APRIL), thereby eliminating B cells, reducing autoantibody levels, and suppressing autoimmune responses. APRIL-LN is a phase II/III clinical trial (NCT00573157) designed to evaluate the effect of atacicept in combination with standard of care in active LN. However, the trial was terminated early due to serious infectious complications in the first few treated patients. The post-hoc analysis showed that the patient received high-dose glucocorticoid as a basic treatment, which led to a significant decrease in IgG level on the first day after treatment, followed by serious infection complications, which suggested that attention should be paid to control when glucocorticoid was used as the basic treatment in the trial. dose.

B cell CD20

Rituximab

Rituximab (RTX) is a type I anti-CD20 monoclonal antibody that specifically binds to the B cell surface antigen CD20 and depletes B cells, thereby preventing the differentiation and activation of pathogenic B cells, reducing the production of autoantibodies and Antigen presentation. At the same time, the RTX-mediated cytotoxic process is complement- and antibody-dependent, highly selective for B cells, and thus does not damage normal immune cells.

LUNAR is a phase III clinical trial (NCT00282347) evaluating the efficacy and safety of RTX combined with standard therapy in 144 patients with LN. The results showed that there was no significant difference in the renal response rate between the RTX group and the placebo group, and the researchers speculated that the use of high-dose corticosteroids under standard treatment may have masked the therapeutic effect of RTX on the disease. Study-related adverse events did not differ significantly between the two groups, while the incidence of serious adverse events was significantly lower in the RTX group than in the placebo group.

RTX can be used as a complementary treatment to glucocorticoids and other immunosuppressants in a variety of refractory glomerular diseases including LN. Sometimes, clinicians also use RTX as a last resort to achieve a renal response.

Obotuzumab

Obotuzumab is a humanized type II anti-CD20 monoclonal antibody that has a different binding mode to the CD20 antigen than type I anti-CD20 antibodies. NOBILITY is a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial (NCT02550652), evaluating the efficacy of obotuzumab combined with standard therapy in 125 patients with proliferative LN. The results showed that the obotuzumab group helped to improve the clinical response of LN without increasing the incidence of serious adverse events. The results of the subsequent phase III clinical trial (NCT04221477) are expected to provide more substantial evidence for obinutuzumab in the treatment of LN.

Ocrelizumab

Ocrelizumab is a recombinant humanized anti-CD20 monoclonal antibody that selectively targets and eliminates CD20+ B cells in the peripheral circulation. In vitro tests showed that Ocrelizumab enhanced antibody-dependent cell-mediated cytotoxicity and decreased complement-dependent cytotoxicity compared with RTX. Phase III clinical trial BELONG (NCT00626197) evaluated the efficacy and safety of ocrelizumab in the treatment of active LN, but the trial was terminated early due to the high risk of infection in patients.

T cell CTLA‑4/CD40 

Abatacept

Abatacept is composed of human cytotoxic T cell-associated antigen 4 extracellular region (CTLA-4) and IgG1 antibody Fc fragment fusion protein. CTLA-4 can target dendritic cells or CD80/CD86 molecules on the surface of B cells, block the co-stimulatory interaction of CD80/CD86 and CD28 on T cells, prevent T cell activation, and limit B cell differentiation and autoantibodies generation. At present, phase II/III and phase III clinical trials have shown that the efficacy and safety of abatacept in the treatment of LN are not significantly different from those of placebo.

BI655064 is a human anti-CD40 monoclonal antibody that selectively blocks CD40-CD40L interaction. A phase II clinical trial (NCT02770170) evaluated the efficacy of three different doses of BI655064 combined with standard treatment for LN but did not meet the primary endpoint of the study.

Cytokine type I IFN–α

Anifrolumab

Anifrolumab is a fully human IgG1κ monoclonal antibody that binds to the IFN-α receptor and blocks all type I IFN signaling. TULIP-LN1 is a phase II clinical trial (NCT02547922) evaluating the efficacy and safety of nivolumab in patients with active grade III/IV LN but did not meet the primary endpoint.

A recent phase III clinical trial (NCT05138133) has been initiated, and 360 subjects are expected to be recruited, randomly receiving anifrolumab or placebo combined with standard treatment.

Cytokine IL‑6/IL-17 inhibitors, such as secukinumab and sirukumab, are considered to have potential in the treatment of LN. Two phase III clinical trials (NCT04181762 and NCT05232864) are currently ongoing to evaluate the long-term efficacy, safety, and tolerability of secukinumab in the treatment of LN. In addition, various drugs such as the complement inhibitors eculizumab and pegcetacoplan, the proteasome inhibitor bortezomib, and the Janus kinase inhibitor baricitinib have also been tried for the treatment of LN.

The purpose of LN treatment is to better protect the organs, reduce the recurrence rate and incidence of adverse events, and improve the quality of life of patients. Novel biologics have opened up new therapeutic avenues and provided more options for LN patients, especially those who do not respond well to traditional immunosuppressive therapy. Although the results of current clinical trials show that some biological agents have no significant effect on LN, most of them show good biological activity.

According to previous experience, the insignificant efficacy may be related to various factors such as the study design and sample size, the included population, the definition of the study endpoint, the background drugs used in combination, and the follow-up time. Therefore, it is still necessary for clinical researchers to fully understand the pathogenesis of LN, choose appropriate evaluation methods, and formulate a reasonable test plan. In conclusion, the efficacy and adverse events of biologics in the treatment of LN still need to be further explored through large-scale clinical trials and long-term follow-up.

Reference 

Cui W, Tian Y, Huang G, et al. Clinical research progress of novel biologics for the treatment of lupus nephritis[J]. Clin Exp Med. 2023 Jul 22. doi 10.1007/s10238-023-01143-9. Epub ahead of print. PMID: 37481481.