23 Anti-CD20 therapy: where are we today?

To the surprise of the lupus community, the original B-cell depleting clinical trials with rituximab performed in systemic lupus (EXPLORER) and lupus nephritis (LUNAR) failed to achieve statistical significance. 1 2 Subsequent investigations suggested that failure to attain clinical response was related to inadequate B cell depletion, although this conclusion was based solely upon evaluation of peripheral blood.3 Confirmation of this theory was generated by investigators who compared B cell depletion in lymph nodes to peripheral blood in patients who had received rituximab prior to kidney transplantation.4 While B cells were depleted in peripheral blood, they were present in lymph nodes harvested at surgery. These observations made a case to develop therapies with greater capacity to deplete B cells, especially in tissues.Obinutuzumab is a humanized, type II anti-CD20 monoclonal antibody that has distinct properties rendering it capable of superior B-cell killing compared to rituximab.5 The NOBILITY trial, a phase 2 clinical trial in patients with proliferative lupus nephritis conducted to test the hypothesis that enhanced B-cell depletion with obinutuzumab would increase the rate of complete renal response (CRR) when added to background standard of care (SOC) compared to SOC alone, yielded robust results.6 The phase 3 REGENCY study, which also enrolled patients with proliferative lupus nephritis, demonstrated superiority of obinutuzumab plus SOC to SOC alone (obinutuzumab vs placebo CRR rates: 46.4% vs 33.1%, respectively; p=0.02).7 In summary, robust B-cell depletion with obinutuzumab was responsible for the attainment of significant effect sizes observed in NOBILITY and REGENCY. Various other B-cell depletion approaches are under investigation for SLE, including chimeric antigen receptor (CAR)-T cell therapy, T cell-engaging therapy, and monoclonal antibodies directed against CD19, B cell-activating factor (BAFF) receptor, or B-cell maturation antigen (BCMA).References Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase ii/iii systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62(1):222–33. doi: 10.1002/art.27233Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study. Arthritis Rheum. 2012;64(4):1215–26. doi: 10.1002/art.34359.Reddy V, Jayne D, Close D, et al. B-cell depletion in sle: clinical and trial experience with rituximab and ocrelizumab and implications for study design. Arthritis Res Ther. 2013;151(Suppl 1):S2. doi: 10.1186/ar3910.Gomez Mendez LM, Cascino MD, Garg J, et al. Peripheral blood B cell depletion after rituximab and complete response in lupus nephritis. Clin J Am Soc Nephrol. 2018;13(10):1502–09. doi: 10.2215/CJN.01070118.Reddy V, Klein C, Isenberg DA, et al. Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples. Rheumatology (Oxford) 2017;56(7):1227–37. doi: 10.1093/rheumatology/kex067.Furie RA, Aroca G, Cascino MD, 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;81(1):100–07. doi: 10.1136/annrheumdis-2021-220920.Furie RA, Rovin BH, Garg JP, et al. Efficacy and safety of obinutuzumab in active lupus nephritis. N Engl J Med. 2025;392(15):1471–83. doi: 10.1056/NEJMoa2410965.Learning Objectives At the end of this presentation participants will be able to:Discuss the shortcomings of rituximab in lupus clinical trialsDescribe modifications to anti-CD20 monoclonal antibodies that enhance their ability to deplete B cellsAnalyse obinutuzumab clinical trial results for lupus nephritis