The molecular dissection of the immune system and the identification of druggable targets have played major roles in the biotechnology revolution. In particular, the evolution of therapeutic antibodies has witnessed advances from polyclonal horse serum to human monoclonal antibodies. The two biologics approved for systemic lupus erythematosus (SLE), anifrolumab^{1 2} and belimumab,^{3 4} are monoclonal antibodies directed against the type I interferon receptor and B Lymphocyte Stimulator, respectively. Yet other strategies employed in SLE drug development are relying on killing whole cells. Rituximab, an antibody directed against CD20, a cell surface molecule on B cells, is commonly used for the treatment of SLE despite the failures of the two registrational trials.^{5 6} Evidence has emerged that inadequate depletion of tissue resident B cells has been, in part, responsible for the lack of efficacy observed in clinical trials.^{7 8} The quest therefore is on to develop more effective measures to deplete B cells. Obinutuzumab is a monoclonal antibody that is also directed against CD20.⁹ However, it was engineered to provide more effective B cell killing. To pursue the hypothesis that more effective B cell depletion would yield better clinical efficacy, the NOBILITY trial in lupus nephritis was performed.⁹ While robust Phase II results were observed without any worrisome safety signals, the Phase III REGENCY trial will need to confirm these initial findings.¹⁰

Building on the evidence regarding the effectiveness of B-cell depletion in SLE, several novel approaches have been initiated. Borrowed from oncology, cell therapy has been effective for patients with lupus nephritis in early studies.^{11 12} Monoclonal antibodies directed against BCMA, CD19, or CD38, targets on various cell types of B cell lineage, are making their debut in the treatment of SLE. A rather unique design is the bispecific antibody, which includes two targets in its construct. One target is CD3, and the other target can be a molecule on a B cell (e.g. CD19 or CD20). Ligation of CD3 activates a T cell, and this activated T cell is then ‘introduced’ to the targeted B cell. Direct B-cell killing ensues, and the expectation is that this mechanism may be a more effective method to kill tissue resident B cells compared to traditional monoclonal antibodies that are highly dependent on antibody dependent cytotoxicity. Hence, they are known as bispecific T-cell engagers (BiTEs). A bispecific CD20/CD3 T-cell engaging antibody, known as mosunetuzumab, is in early development in SLE.¹³ In summary, with the goal of improving outcomes of our patients with SLE, the strategies to attack cells of the B cell lineage have expanded to include several novel approaches.

References

1. Furie R. Type i interferon inhibitor anifrolumab in active systemic lupus erythematosus (tulip-1): A randomised, controlled, Phase 3 trial. Lancet Rheumatol 2019;1:e208–e19.

2. Morand EF, Furie R, Tanaka Y, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020;382(3):211–21. doi: 10.1056/NEJMoa1912196.

3. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918–30. doi: 10.1002/art.30613.

4. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: A randomised, placebo-controlled, Phase 3 trial. Lancet. 2011;377(9767):721–31. doi: 10.1016/s0140-6736(10)61354-2.

5. 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.27233.

6. Rovin 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.

7. 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.

8. Md Yusof MY, Shaw D, El-Sherbiny YM, et al. Predicting and managing primary and secondary non-response to rituximab using b-cell biomarkers in systemic lupus erythematosus. Ann Rheum Dis. 2017;76(11):1829–36. doi: 10.1136/annrheumdis-2017-211191.

9. 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.

10. NCT04221477. A study to evaluate the efficacy and safety of obinutuzumab in patients with ISN/RPS 2003 Class III or IV lupus nephritis (regency) [Available from: https://classic.clinicaltrials.gov/ct2/show/NCT04221477] accessed 23 June 2024.

11. Muller F, Taubmann J, Bucci L, et al. CD19 CAR t-cell therapy in autoimmune disease – a case series with follow-up. N Engl J Med. 2024;390(8):687–700. doi: 10.1056/NEJMoa2308917.

12. Wang W, He S, Zhang W, et al. BCMA-CD19 compound CAR T cells for systemic lupus erythematosus: A Phase 1 open-label clinical trial. Ann Rheum Dis. 2024 doi: 10.1136/ard-2024-225785.

13. NCT05155345. A study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneously administered mosunetuzumab to participants with systemic lupus erythematosus [Available from: https://clinicaltrials.gov/study/NCT05155345?cond=Systemic%20Lupus%20Erythematosus&intr=Mosunetuzumab&rank=1] accessed 23 June 2024.

Learning Objectives

• Explain the limitations of current B-cell depleting antibodies

• Describe novel strategies to deplete B cells

• Discuss the application of Bispecific T-cell Engager antibodies to the treatment of SLE