ReviewNovel approaches to the development of targeted therapeutic agents for systemic lupus erythematosus
Introduction
Systemic lupus erythematosus (SLE, lupus) is a chronic multisystem disease of unknown etiology [1], [2]. It affects all races though it is more common among African-Americans, Hispanics and Asians [1]. SLE is much more prevalent in females as compared to males (9:1 ratio) [2]. The prevalence of SLE is about 1:1000 females but it is increasing constantly due to both, a better early diagnosis and a better survival of lupus patients [1], [2]. Dysregulation of both, the innate and the adaptive immune systems play a role in SLE with the production of variety of autoantibodies and pro-inflammatory cytokines, impaired T cell function and enhanced apoptosis [1], [2], [3]. The clinical spectrum of lupus varies, ranging from mild mucocutaneous/musculoskeletal manifestations to life-threatening renal or neurologic disease [1], [2]. Disease activity and lupus organ involvement fluctuate along the time with flares and remissions (either spontaneous or induced by treatment) [1], [2]. Although the precise etiology of SLE is not fully defined yet, genetic, hormonal and environmental factors appear to play a role in the pathogenesis and course of the disease [3], [4].
The current "standard" treatment of SLE includes anti-malarial agents (mainly Hydroxychloroquine, HCQ), corticosteroids, immunoglobulins (IVIG) and cytotoxic immunosuppressive agents [1], [2], [5]. HCQ was shown to be effective in the treatment of mild to moderate mucocutaneous and musculoskeletal manifestations of lupus [5]. Corticosteroids, given orally or intravenously, are effective for almost all lupus related manifestations. However, the long-term adverse effects of the latter agents limit their usage. Recently, Thamer et al. demonstrated that a dose of as low as 6 mg prednisone per day increases the corticosteroids-induced organ damage by 50% [6]. Thus, a steroid sparing therapeutic approach is mandatory [7]. Other immunosuppressive agents such as Cyclophosphamide, Azathioprine, Methotrexate and Mycophenolate Mofetil were shown to be effective in the treatment of moderate to severe lupus manifestations (e.g. renal or CNS involvement) but these agents also have significant short and long term adverse effects [7]. Moreover, although the above treatment modalities are quite effective they are not specific for lupus and the control of disease activity with those agents remains suboptimal. Thus, in spite of treatment, lupus patients have active lupus related flares in substantial fractions of their life [7]. Therefore, there is an unmet need for alternative nontoxic effective and more lupus specific therapeutic approaches.
Based on the knowledge of the different dysregulated innate and adaptive immunological pathways involved in the pathogenesis of SLE, attempts have been made to develop biological therapies against targets that play a role in lupus. The various therapeutic means are at different stages of development. In general, they could be divided into non-specific and SLE specific means. The non-specific approaches could be further categorized as cell depleting agents and immunomodulatory means. In the present article we review the various biological therapeutic agents with a special focus on lupus antigen-specific therapeutic means.
Section snippets
B-cell targeted treatments
B cell activation with excess generation of immunoglobulins and autoantibodies is the hallmark of SLE [1], [2], [8]. Therefore, biological agents that target B cells and reduce their activity have been developed as potential candidates for the treatment of lupus [8].
BLyS targeted therapy
B lymphocyte stimulator (BLyS), also known as B cell activating factor (BAFF), is a 285 amino acid transmembrane protein (expressed on the surface of monocytes, macrophages, dendritic and activated T cells) that belongs to the tumor necrosis factor ligand superfamily [24], [25], [26]. Following a cleavage by purin protease, soluble active BLyS (17Kd protein) is released into the circulation [26]. The soluble BLyS can bind to three receptors (BCMR – B cell maturation antigen, TACI –
Inhibition of T-cell activation
The activation of T cells requires at least two independent signals. The first signal results from the engagement of the MHC complex and the antigen with the T cell receptor. The second activation signal is an antigen-independent event which involves an interaction of co-stimulatory molecules such as CD28 (expressed on T cells) and CD80/CD86 (expressed on antigen presenting cells such as DC, macrophages or B cells). Another co-stimulatory pathway is the interaction between CD40 (on B cells) and
Tocilizumab (anti IL-6 receptor mAb)
IL-6 is a multifactorial pro-inflammatory cytokine that was shown to play a role in the pathogenesis and treatment of murine lupus [52], [53]. Moreover, elevated levels of IL-6 were found in sera of active lupus patients [54]. Tocilizumab (Fig. 1; 8) is a fully humanized mAb against the IL-6 receptor that prevents binding of IL-6 to both, membrane and soluble receptors. A small phase I trial (16 lupus patients) suggested that Tocilizumab is safe and beneficial in SLE [55]. Further controlled
Eculizumab (Anti-C5 mAb)
The early complement components are essential for immune complex clearance whereas activation of the late components were shown to be associated with lupus exacerbations [66]. Eculizumab is a humanized IgG2/4 mAb directed against the complement protein C5, blocking the formation of the complement terminal membrane attack complex [66], [67]. This mAb was shown to ameliorate murine lupus [67]. A phase I trial with Eculizumab in 24 lupus patients demonstrated good safety profile but no clear
Therapeutic approaches for the specific treatment of SLE
The rationale behind attempting the development of antigen specific therapy for lupus as well as for other autoimmune diseases is to achieve the mean that will modulate only the disease specific pathogenic cells and pathways and will leave the rest of the immune system intact. Thus, in contrast to the current standard of care for lupus that suppresses large portions of the immune system, and unlike many of the newly therapeutic approaches that introduce agents that deplete large parts of the
Conclusions
The major progress made in recent years towards the understanding of the pathogenesis and development of SLE resulted in attempts to develop novel biological agents for the treatment of the disease. In this review we discussed a variety of biological therapies that are under different stages of development. The latter target different cell populations and molecules either by their depletion or by blocking inflammatory processes. Indeed, one of these biological agents, namely, Belimumab, that
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Present address: Rheumatology Institute, Sourasky Medical Center, Tel-Aviv, Israel.