Systemic lupus erythematosus (SLE) is a heterogeneous disease characterised by abnormalities in cellular and humoral immunity with clear hints that abnormalities of B lineage cells (B and plasma cells) are key drivers.

Clinical experiences with belimumab as a first approved targeted SLE treatment provide robust evidence that blocking BLyS/BAFF selectively interfering with B cell survival can change the course of the disease, including prevention of damage accrual. Recent failures of first generation anti-CD20 (rituximab, ocrelizumab) and BTK inhibitors (fenebrutinib/GDC-0853² and evobrutinib³) together with the occurrence of anergic B cells in SLE³ provide the rational for various innovative strategies. These include more profound targeting by second generation anti-CD20 modalities (obinutuzumab⁴) CD19 (CART, bispecific antibodies) or employing other immune targets, such as CD38 (daratumumab), or BAFFR (ianalumab).

In addition, enhancing regulatory B-cell functions may hold attractive opportunities. Such strategies have potential to reinstall the balance of pathogenic and protective B cells with the potential of more specific therapies. Moreover, these treatment targets should have the potential to overcome the status of anergic B cells holding promise to escape the detrimental chronic autoimmune process. In this context, targeting checkpoint molecules that downmodulate intracellular phosphatases, such as CD40 or other targets of this family on B cells, and enhancing Treg cells, may provide increased control of B-cell activation. Another potential innovative treatment modality could be the use of non-depleting bispecific antibodies may open more selective B cell subset targeting of enhancing the potency of depletion in the future.^{4 5}

References

1. Isenberg D, et al. Efficacy, safety, and pharmacodynamic effects of the bruton’s tyrosine kinase inhibitor, fenebrutinib (GDC-0853), in moderate to severe systemic lupus erythematosus: results of a phase 2 randomized controlled trial [abstract]. Arthritis Rheumatol 2019;71(Suppl 10). https://acrabstracts.org/abstract/efficacy-safety-and-pharmacodynamic-effects-of-the-brutons-tyrosine-kinase-inhibitor-fenebrutinib-gdc-0853-in-moderate-to-severe-systemic-lupus-erythematosus-results-of-a-phase-2-rando/. (Accessed March 5, 2022).

2. Wallace D, et al. Efficacy and safety of evobrutinib (M2951) in adult patients with systemic lupus erythematosus who received standard of care therapy: a phase II, randomized, double-blind, placebo-controlled dose ranging study [abstract]. Arthritis Rheumatol 2020;72(Suppl 10). https://acrabstracts.org/abstract/efficacy-and-safety-of-evobrutinib-m2951-in-adult-patients-with-systemic-lupus-erythematosus-who-received-standard-of-care-therapy-a-phase-ii-randomized-double-blind-placebo-controlled-dose-rang/. (Accessed March 5, 2022).

3. Weißenberg SY, et al. Identification and characterization of post-activated B cells in systemic autoimmune diseases. Front Immunol 2019 Sep 24;10:2136.

4. Furie RA, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2022 Jan;81(1):100–107.

5. Dang VD, et al. B- and plasma cell subsets in autoimmune diseases: translational perspectives. J Invest Dermatol 2022 Mar;142(3 Pt B):811–822.

Learning Objectives

• Discuss the translational concept of anergic (APA, immunosenescent) B cells in SLE

• Explain the impact of indirect targeting of B cells by anti-BLyS/BAFF treatment

• Discuss depleting versus non-depleting strategies of B cells in SLE

• Explain the concept of overcoming APA (immunosenescent) B cells and the rational of anti-CD40 treatment as a checkpoint modulatory concept