Inhibition of B-cell activation and survival is another strategy for targeting the B-cell compartment. This approach could include blockade of costimulatory interactions that promote B-cell activation (e.g., anti-CD40L or CTLA4-Ig) or neutralization of B-cell survival factors/cytokines, such as B cell–activating factor belonging to the TNF family (BAFF). Belimumab is a fully human monoclonal antibody against BAFF. After initial encouraging results in a phase II trial in SLE, two phase III trials were initiated, have recently completed recruitment, and preliminary press releases from Human Genome Sciences and GlaxoSmithKline have reported favorable clinical responses compared with placebo (based on a composite SLE responder index). Given these initial reports, we should consider whether BAFF blockade would be expected to yield different results compared with anti-CD20. Indeed, this would be surprising given that both agents deplete B cells, with anti-CD20 causing even more pronounced B-cell depletion and likely better depletion of memory B-cell subsets. On the other hand, BAFF blockade may have additional effects on other immune cells important in SLE, including T cells and dendritic cells. Moreover, rituximab causes a compensatory increase in BAFF, which may theoretically have adverse effects on B-cell selection. Nevertheless, I suspect that the distinct trial results with BAFF blockade versus anti- CD20 in SLE are more related to trial design than biologic differences between the two therapies.
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Explore This IssueJanuary 2010
Another potential explanation for the disappointing results of B-cell depletion in SLE is the lack of effect on autoantibodies and long-lived plasma cells. Atacicept is a receptor fusion protein that blocks both BAFF and its related cytokine APRIL and may be unique in its dramatic effects on plasma cells, with reductions in total immunoglobulin (Ig) G, IgM, and autoantibodies in phase I studies in both RA and SLE.8 Because of its effects on plasma cells, transmembrane activator and calcium-modulating and cyclophilin ligand interactor (TACI)-Ig would appear to have great potential in autoantibody-mediated diseases. However, the challenge will be to eliminate autoantibody-producing plasma cells without increasing the risk of infection due to adverse effects on protective antibodies.
TABLE 2: Approaches to Target B Cells
B cell depletion
- Rituximab (anti-CD20)
- Ocrelizumab (humanized anti-CD20) (Phase III in RA and SLE)
- Anti-CD20 (small modular immunopharmaceutical [SIMP]) (Phase III in RA)
- Ofatumumab (anti-CD20 from humanized mice) (Phase III in RA)
- Epratuzumab (anti-CD22) (Phase II in SLE)
- Belimumab (anti-BAFF) (advanced development in RA, SLE)
- BR3-Fc (Phase I RA)
- Anti-BR3 (Phase I RA)
- Atacicept (TACI-Ig) (Phase I, II complete in RA and SLE)
Clinical Utilization and Safety
Given that B-cell depletion is irreversible until reconstitution occurs (and persists for long periods during which the patient may not make antibodies to infections or immunization), clinicians may be less comfortable using this therapeutic approach in RA instead of a TNF blockade, which can be stopped. However, a recent meta-analysis supports prior literature regarding the safety of B-cell depletion in that treatment of RA with rituximab was not associated with an increased incidence of serious infections, even after repeated courses, or with TNF blockade after B-cell depletion.9-11 The caveat here is that the database is relatively small for RA and even smaller for SLE. Moreover, there have been reports of fulminant hepatitis B reactivation and rare cases of PML. Thus, patients should be screened for hepatitis B prior to the use of rituximab, and viral prophylaxis should be considered in high-risk patients.