Recent advances in immunotherapies for lupus nephritis

Abstract

Childhood-onset systemic lupus erythematosus (SLE) is characterized by increased rates of kidney involvement, termed lupus nephritis. Despite the significant morbidity and mortality associated with this disease, lupus nephritis trials have been plagued by repeated failures to meet clinical endpoints. However, improvements in trial design and the development of targeted approaches have begun to yield promising results, including two new FDA-approved lupus nephritis treatments since 2020. These include belimumab, a monoclonal antibody targeting the B cell survival cytokine BAFF (B cell activating factor), and voclosporin, a cyclosporin analog with improved pharmacokinetic characteristics. In this review, we will summarize the data supporting regulatory approval for these agents in lupus nephritis and highlight ongoing clinical trials targeting the diverse immunologic drivers of renal inflammation in SLE. While pediatric patients remain underrepresented in lupus clinical trials, given the increased severity of childhood-onset SLE and need for long-term protection from kidney damage, we anticipate the need for off-label use of these targeted therapies in the pediatric population. Future studies are needed to define optimal patient selection, drug combinations, and treatment duration in pediatric lupus nephritis.

Keywords: Immunosuppression; Induction therapy; Lupus nephritis; Pediatrics; Proliferative lupus nephritis; Systemic lupus erythematosus.

Figure 1:. Emerging drug targets for the treatment of lupus nephritis

Diagram depicting the multiple strategies currently being studies for the treatment of lupus nephritis, divided into five groups. 1) Inhibition of immune cell crosstalk: two separate drugs (Iscalimab and BI 655064) are examining whether blocking CD40:CD40L costimulatory signals prevents autoantibody formation and ameliorates lupus nephritis. Itolizumab targets the T cell activation molecule CD6. 2) Cytokine inhibition: multiple pro-inflammatory cytokines have been implicated in the pathogenesis of SLE and lupus nephritis. Studies are ongoing examining whether blocking type 1 interferon signals (Anifrolumab), BAFF activity (Lanalumab), or Th17 biology (IL-23: Guselkumab; IL-17A: Vunakizumab and Secukinumab) is an effective treatment strategy in lupus nephritis. 3) Plasma cell and/or autoantibody targeted therapies: the intra-glomerular deposition of autoantibody:autoantigen immune-complexes (IC) promotes glomerulonephritis. For this reason, independent strategies are being pursued to either deplete plasma cells (Daratumumab and KZR-616) or reduced serum IgG levels via blockade of the neonatal Fc receptor (FcRn; Nipocalimab). 4) Inhibition of the complement cascade: Given the putative role for complement as a driver of renal inflammation, complement C5 (Ravulizumab) and complement factor D (Vemircopan) inhibitors are being studied in active lupus nephritis. 5) Cell signaling inhibitors: Specific targets being pursued include: Bruton’s tyrosine kinase, a critical mediator of B cell receptor and Fc receptor signaling (Zanubrutinib); endosomal toll-like receptor signaling pathways (the antimalarial Artesunate); and the anti-metabolite Mizoribine. 6) B cell targeted therapies: including BAFF inhibitors (belimumab, ianalumab) and anti-CD20 depleting monoclonal Obinutuzumab.