Elevated BLyS levels have been implicated in abnormal B cell development, including (but not limited to) autoantibody production, lymphadenopathy development (75), and lymphomas (85). By specifically antagonizing the modulatory protein, BLyS-targeted agents provide an effective way to control B cell activity (Table 1). BLyS-specific targeted therapy specifically affects early-stage B cells in the periphery without affecting late-stage compartments, such as memory or bone marrow plasma cells, and without compromising the immune system (86).
Table 1
B cell–targeted therapies for SLE
Belimumab. Belimumab is a fully human monoclonal Ab (IgG1) that binds soluble BLyS (86) and inhibits its binding to TACI, BCMA, and BR3 (Table 1). The specificity and affinity of belimumab for BLyS suggests that it may decrease B cell survival that results from an abundance of BLyS. Preclinical data demonstrate a role for belimumab in inhibiting BLyS: the administration of belimumab was found to inhibit the effects of BLyS in mice expressing the exogenous human protein, including decreases in spleen weight and serum IgA levels (86). This effect may stem, at least in part, from an attenuation of class switching in autoreactive B cells. Recent nonclinical data have shown that anti-BLyS treatment appears to leave secondary immunity intact. A study of anti-BLyS treatment in mice determined that memory B cells, long-lived plasma cells, and secondary immune responses transiently rose, but remained whole, during and after exposure (87, 88). IgG-bearing memory B cells and natural Ab–secreting B cells were insensitive to anti-BLyS treatment, which suggests that they are BLyS independent and may be manipulated separately (57). A common phenomenon associated with BLyS-targeted therapies is the early transient rise in memory B cell numbers, which return to normal levels within 2 weeks after treatment (89).
The safety and efficacy of belimumab in SLE patients has been studied in a phase I randomized controlled clinical trial (90). In this dose-ranging study, belimumab treatment resulted in significantly greater percent reductions in CD20+ B cells than did placebo, consistent with the mechanism of action of this Ab. This reduction was observed in patients treated with 1 or 2 doses of belimumab versus placebo-treated patients. A similar percent decrease in serum Igs was observed in belimumab-treated patients compared with placebo-treated patients; however, this decrease did not reach statistical significance. Overall, there was no difference in disease activity — as assessed by Safety of Estrogens in Lupus Erythematosus: National Assessment–SLEDAI (SELENA-SLEDAI) score — between the 2 treatment groups, but this may be because of the short term of the trial. Belimumab was well tolerated in the phase I study, with the majority of adverse events (AEs) being mild to moderate in severity, and the incidence of AEs similar in the placebo and belimumab treatment groups. In addition, there was no increase observed in the number of infections in belimumab-treated patients versus patients given placebo (37% and 62% of the study population, respectively).
Belimumab appears to have a latency period before SLE disease improvement is seen, and clinical response was most evident in a subgroup of serologically active patients (91); each of these observations may account for the phase II trial not meeting its primary endpoint (Table 1). The long onset of efficacy for belimumab may be due to a slow off-time for BLyS at BR3, coupled with highly occupied receptors in SLE patients. A study of SLE patients showed reduced levels of available free BR3 on B cells in comparison with healthy controls (92). The reduced amount of available BR3 resulted in continuous receptor-ligand engagement. The slow off-time for BLyS at BR3, coupled with the abundance of BLyS, correlated with an increase in disease activity (92). BLyS also has a slow turnover rate, which may explain why there is a lag time or slower rate of disease response with belimumab treatment. The safety and efficacy of belimumab in SLE is currently being further validated in 2 large, global, phase III randomized controlled trials (BLISS 52 and BLISS 76; http://www.clinicaltrials.gov; trial nos. NCT00424476 and NCT00410384, respectively).
Atacicept. Atacicept (TACI-Ig) is a soluble, recombinant fusion protein of the human IgG1 Fc and the extracellular domain of the TACI receptor that binds BLyS and APRIL and inhibits their action on B cells (Table 1). Similar to BLyS blockade, atacicept administration in a murine model of SLE led to delayed onset in SLE disease progression and reductions in B cell populations, spleen size, and DC activation (93, 94). However, in parallel to the anti-BLyS data above, it appears that TACI blockade reduces IgM-producing, but not IgG-producing, plasma cells. Whether this same effect occurs in humans remains to be seen.
In a dose-escalating phase I clinical trial (95), patients with moderate SLE showed a trend toward clinical improvement, as assessed by SELENA-SLEDAI scores, after treatment with atacicept. The small patient number (n = 12) precludes a definitive conclusion regarding the effect of atacicept on disease activity, although dose-dependent reductions in mature and total B cell levels and Igs were observed. The reductions in B cells were sustained for up to 43 days in the single-dose group and up to 64 days in the repeated-dose group. Atacicept was well tolerated in this trial, with no significant differences in AE frequency or type observed between placebo and treatment groups. Although the number of infection-related events was similar in placebo and atacicept groups in the phase I trial, a recent phase II trial of atacicept in lupus nephritis was suspended because of a high risk of severe infections (96). A new phase II/III trial of atacicept in generalized SLE is currently open and recruiting patients (http://www.clinicaltrials.gov; trial no. NCT00624338).
Additional BLyS-targeted therapies. New biologic therapies targeted against BLyS are presently in development. These include BR3-Fc, AMG-623, and anti-BR3 Ab (Table 1). Of these, only BR3-Fc and AMG-623 have begun clinical trials, and while both appear to be well tolerated by patients, their efficacy in treating SLE and improving disease activity remains unknown (97, 98).
Other B cell–targeted therapies in SLE. Several therapies with a mechanism of action that targets B cells directly, in contrast to targeting BLyS, have also been tested in SLE patients and other autoimmune patients. Rituximab, ofatumumab, and epratuzumab have all demonstrated biological effect in SLE, while ocrelizumab has shown efficacy in RA (Table 1). Each of these has been shown to deplete the total population of peripheral B cells with less specificity than BLyS-targeted drugs. Furthermore, the depleted state of B cells may persist for up to 10 months after treatment is terminated (99).
It is reasonable to speculate that reducing the number of B cells with anti-CD20 Ab therapy may effectively elevate the concentration of free BLyS, leading to increased incidence of autoreactive B cells surviving selection (43). A recent study of non-SLE B cell disorders showed that treatment with rituximab resulted in a 5-fold increase in serum BLyS levels (P < 0.001; ref. 100). In addition, recent clinical data reflecting the measurement of BLyS levels and autoreactive Abs in SLE during rituximab therapy (n = 25) showed that patients with higher BLyS levels at baseline were more likely to harbor anti-Ro and anti-RNP/Sm Abs after treatment; patients in this subgroup were significantly more likely to experience an SLE disease flare within 1 year of cessation of therapy (101). In this study, patients with lower BLyS levels prior to anti-CD20 therapy fared better in the long term than did their higher-BLyS counterparts (101). These data suggest that certain patients, especially those with high baseline BLyS serum levels, may not be the ideal candidates for rituximab therapy.
