B-cell Biology and Related Therapies in Systemic Lupus Erythematosus

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Role of B cells in SLE

Although multiple immunologic abnormalities are important for the development and clinical expression of SLE, a large body of evidence strongly points to the B cell as a critical player in the pathogenesis of this disease.5

Therapeutic targeting of the B-cell compartment

Several different approaches to targeting B cells have been used: (1) BCD with monoclonal antibodies against B-cell–specific molecules (eg, anti-CD20), (2) induction of negative signaling in B cells (eg, anti-CD22); (3) blocking B-cell survival and activation factors (eg, anti-BAFF), and (4) blocking costimulatory interactions between B and T cells. Many of these agents are currently undergoing formal testing in clinical trials or are under development (Table 2).

Anti-CD20 Monoclonal Antibody

The largest body of clinical data regarding BCD involves anti-CD20 targeted therapy with the monoclonal antibody rituximab. CD20 is a member of the tetraspan family of integral membrane proteins71 and is specifically expressed on immature, naive, memory, and GC B cells, but not on early pre-B cells or PCs. In vitro rituximab can kill B cells by complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and induction of apoptosis.72 Studies in a murine model of human CD20

Other B-cell Depleting Antibodies

Other monoclonal antibodies that target CD20 are in various phases of development, including ocrelizumab (humanized anti-CD20) (Table 2). Theoretically, a fully human antibody may be better tolerated during infusions because of less immunogenicity. This could translate into more complete BCD especially in SLE, in which HACAs are more common after rituximab. The trial of ocrelizumab in lupus nephritis may answer the question of synergy with cyclophosphamide given that a subset of patients will

Summary

Recent controlled clinical trials of B-cell targeting agents in SLE have had variable benefit but have contributed to our understanding of how to conduct trials in lupus and have recently shown promise. New agents capable of affecting long-lived PCs are now being developed.123 These agents should allow eradication of autoantibodies, but will need to be used carefully to prevent infectious complications and to ensure that autoimmune PCs do not repopulate the long-lived PC compartment. The effect

Acknowledgments

The authors thank Andreea Coca for expert review of the manuscript and Inaki Sanz and Gregg Silverman for input on figures. The collaborations and thoughtful discussions with colleagues, especially Inaki Sanz and John Looney, are gratefully noted.

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    • Cited by (0)

    Dr Anolik has been supported by several grants including U19 Autoimmunity Center of Excellence AI56390, R01 AI077674-01A1, the Lupus Foundation of American, and the Lupus Research Institute. Dr Anolik has received grants from Amgen Pharmaceuticals, Genentech, Proteolix, and Vaccinex. She has served as a consultant for Genentech and Roche.

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