Research and therapeutics-traditional and emerging therapies in systemic lupus erythematosus

Abstract

This review summarizes traditional and emerging therapies for SLE. Evidence suggests that the heterogeneity of SLE is a crucial aspect contributing to the failure of large clinical trials for new targeted therapies. A clearer understanding of the mechanisms driving disease pathogenesis combined with recent advances in medical science are predicted to enable accelerated progress towards improved SLE diagnosis and personalized approaches to treatment.

Keywords: B cells; biological therapies; clinical trials and methods; immunotherapy; systemic lupus erythematosus and autoimmunity.

Fig. 1

Biologic therapies and their targets in the immune system Shown are some of the common cytokines, pathways and functions of the immune system (in blue) known to be dysregulated in SLE and targeted by biologic therapies (in red). Plasmacytoid dendritic cells release type I IFNs, such as IFNα, in response to Toll-like receptor (TLR)9 stimulation induced by immune complexes. In SLE, immune complexes may be formed by autoantibodies, such as anti-DNA antibodies complexed to self-DNA. IFN-primed neutrophils release DNA in the form of neutrophil extracellular traps (NETs; [121]) or oxidized mitochondrial DNA after activation by anti-Sm or anti-RNP autoantibodies, which trigger the Fcγ receptor, TLR7 and reactive oxygen species pathways [122]. Studies suggest that SLE disease activity is associated with type I IFN activity, which is elevated in the periphery of most SLE patients. Sifalimumab, a human anti-IFNα mAb, and rontalizumab, a humanized IgG1 anti-IFNα mAb, have been developed to target this pathway. BAFF (CD257, BLyS, TNFSF13B) is a key B cell maturation and survival factor that is produced predominantly by myeloid lineage cells. BAFF has been assessed as a therapeutic target, diagnostic marker and prognostic indicator for SLE. Therapeutic agents include a unique peptibody, blisibimod, which has four domains that bind to BAFF fused to a human IgG1 Fc domain, and belimumab, a humanized IgG1 mAb, which has achieved US Food and Drug Administration approval for the treatment of SLE. Both agents block BAFF from binding to its receptors. Other B cell-targeted therapies are directed at CD19, CD20 and CD22 cell surface proteins. Rituximab is a humanized anti-CD20 mAb used for B cell depletion therapy and might be most effective in combination with anti-CD257 (BAFF) therapies. MEDI-551 is a humanized IgG1 mAb to CD19. MEDI-551 is predicted to be a more effective B cell depletion therapy than rituximab because CD19 is expressed by plasmablasts and long-lived plasma cells, unlike CD20, and might spare B regulatory cells. Epratuzumab, a humanized IgG1 mAb, enhances the inhibitory function of CD22 on B cells. Epratuzumab, acting through CD22 (Siglec-2), reduced B cell activity as determined by a number of parameters, including decreased expression of cell surface proteins, such as adhesion molecules, reduced cytokine production (e.g. IL-6 and TNF) and diminished migration and cell growth. Abatacept is composed of a human cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) protein joined to a human IgG1 Fc domain. Abatacept out-competes the CD28 receptor for binding to CD80 and CD86 ligands expressed by antigen-presenting myeloid cells, including B cells. CD28 is a key costimulatory molecule that delivers the ‘second signal’ required for antigen-induced T cell activation. Abatacept treatment can result in diminished T cell responses and T-dependent B cell antibody production. CD154 (CD40 ligand) is expressed on activated T cells and binds to the CD40 receptor on antigen-presenting cells. The CD154–CD40 interaction is important for T cell responses and T-dependent B cell responses. Thus, treatment with anti-CD154 can result in diminished T cell and humoral responses in an antigen-specific manner. IL-6 can be produced by a variety of cells and promotes inflammation and immune responses. Sirukumab, a human anti-IL-6 mAb, binds with high specificity and affinity to IL-6. Sirukumab prevents IL-6 from binding to the soluble and transmembrane forms of the IL-6 receptor, thus inhibiting IL-6-driven inflammation and immune responses. Tocilizumab, a humanized anti-IL-6 receptor mAb, likewise dampens IL-6-dependent responses, and it has been approved for the treatment of RA. Eculizumab is an anti-C5 mAb under study for SLE. Eculizumab may be beneficial for lupus nephritis in cases resistant to other therapies with evidence of C5 activation. This figure was adapted from Petri, M: Treat to Target(s)—the Lupus 12-Step Programme. A CME Programme for Rheumatologists 2015.