Is sifalimumab a human anti-IFN alpha monoclonal antibody with a potential therapy for systemic lupus erythematosus?

Wang-Dong Xu, student,

Other Contributors:

August 22, 2011

Dear editor,

Merrill, et al. [1] reported that sifalimumab with safety profile and clinical activity was used in the phase I, multicentre, double-blind randomised study as an anti-IFN alpha monoclonal antibody in systemic lupus erythematosus (SLE), in which sifalimumab neutralized overexpression of the type I IFN signature in SLE patients in a dose-dependent manner as well as USP18/ESI-1 were inhibited, providing further evidence of a correlation between decreased IFN-inducible protein/gene expression and skin lesion improvement after a dose of sifalimumab. That indicated type I IFN may play an important role in the pathogenesis of SLE and blockade of IFN alpha may be a useful strategy for reducing disease activity.

In fact, therapy of anti-IFN alpha in SLE has been studied in other investigations. Yao, et al. [2] also revealed sifalimumab could neutralize overexpressed type I IFN signature in SLE patients in a dose-dependent manner. Dermal inflammation and certain proteins associated with IFN alpha/beta inducible gene expression (IP10, HERC5, ISG15) were decreased in the skin of sifalimumab-treated patients within two weeks of dosing.
Moreover, Yao, et al. [3] indicated that sifalimumab led to inhibition of excessively expressed type I IFN signature in WB (whole bolld) of patients. Meanwhile, downregulated CD4+ T cells, dendritic cells (DCs), plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) were detected, along with suppressed expression of both type I IFN-inducible mRNAs and protein occurred in skin lesions of SLE patients in another study.
Similarly, McBride, et al. [4] showed out another humanized IgG1 monoclonal antibody, rontalizumab, which might inhibit human IFN alpha also in dose-dependent inhibition of the type I IFN signature. In addition, two effective therapeutic agents in SLE, glucocorticoids and chloroquine, can downregulate the IFN signature or inhibit IFN alpha production by NIPC/pDC40; type I IFNAR-knockout experimental murine lupus models have a significantly reduced SLE disease [5].
Therefore, these results might suggest a potential role of anti-IFN alpha therapy for SLE, especially with sifalimumab. Although SLE is a chronic systemic autoimmune disease characterized by kinds of autoantibody production, complement activation and immune-complex deposition, since IFN alpha has been found to play an important role in the pathogenesis of SLE, researches are arising [6]. Some studies suggest that the decreased number of circulating pDCs may attribute to a migration of these cells to tissues, owing to an increased number of pDCs readily detected in renal tissue, skin and lymph nodes from lupus patients. These pDCs are activated in vivo and synthesize IFN alpha, indicating that these cells are responsible for the continuous IFN alpha production in lupus [7].

In conclusion, evidences suggest a posssible role of sifalimumab in the treatment of SLE, however, further studies are need to give comprehensive research.

References

1. Merrill JT, Wallace DJ, Petri M, et al. Safety pro?le and clinical activity of sifalimumab, a fully human anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double- blind randomised study. Ann Rheum Dis 2011 Jul 27.

2. Yao Y, Richman L, Higgs BW, et al. Neutralization of interferon-alpha/beta-inducible genes and downstream effect in a phase I trial of an anti-interferon-alpha monoclonal antibody in systemic lupus erythematosus. Arthritis Rheum 2009;60:1785-1796.

3. Yao Y, Higgs BW, Richman L, et al. Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFN alpha antibody, in systemic lupuserythematosus. Arthritis Res Ther 2010;12 (Suppl 1):S6.

4. McBride JM, Wallace DJ, Yao Z, et al. Dose-dependent modulation of interferon regulated genes with administration of single and repeat doses of Rontalizumab in a phase I, placebo controlled, double blind, dose escalation study in SLE [abstract 2072]. Arthritis Rheum 2009;60:S775-S776.

5. Ronnblom L, Pascual V. The innate immune system in SLE: type I interferons and dendritic cells. Lupus 2008;17:394-399.

6. Crow MK. Interferon-alpha: a therapeutic target in systemic lupus erythematosus. Rheum Dis Clin North Am 2010;36:173-186.

7. Ronnblom L, Alm GV, Eloranta ML. The type I interferon system in the development of lupus. Semin Immunol 2011;23:113-121.

Conflict of Interest

None declared