Inhibition of IL-6 for the treatment of inflammatory diseases
Introduction
Interleukin-6 (IL-6) is a pleiotropic cytokine with various essential biological activities. It was initially identified as a T cell factor that induces B cells to differentiate to immunoglobulin-producing cells (i.e. B cell stimulatory factor-2 [BSF-2]), with the cDNA encoding human BSF-2 being cloned by Hirano et al. in 1986 [1]. Afterward, BSF-2 was found to be identical to the 26 kDa interferon β2 protein, a hybridoma/plasmacytoma growth factor and hepatocyte-stimulating factor that had been independently cloned as a different functional molecule by separate groups. These names were then unified as IL-6 [2]. The history of nomenclature indeed reflects the multiple biological actions of IL-6.
Because IL-6 has a wide range of biological activities on various target cells, deregulated overproduction of IL-6 causes various clinical symptoms and abnormal laboratory findings in vivo. Specifically, IL-6 plays important roles in the regulation of immune response and inflammation, and overproduction of IL-6 is involved in the pathology of inflammatory diseases such as rheumatoid arthritis (RA), Castleman’s disease, juvenile idiopathic arthritis and Crohn’s disease [3]. These diseases are often refractory to conventional therapy (i.e. corticosteroids and immunosuppressive agents). Recently, biological agents targeting tumor necrosis factor-α (TNFα) have been used successfully to treat some of these diseases 4., 5., 6.. However, patients do not always respond to TNFα inhibitors. They also have an increased risk of serious infectious diseases. Therefore, there is still a need for another therapeutic strategy for these refractory diseases. IL-6 is a distinct target molecule whose actions could be blocked to provide treatment in these cases.
Humanized anti-interleukin-6 receptor (IL-6R) antibody was created by grafting the complementarity-determining regions from mouse anti-IL-6R antibody to human IgG1 [7]. The antibody is less immunogenic in humans and shows a longer half-life when administered in vivo. In addition, it is equivalent to both original mouse and chimeric anti-IL-6R antibodies in terms of antigen binding and IL-6 blockade. The possibility of IL-6 inhibition as a treatment of inflammatory diseases is discussed in this review (Figure 1).
Section snippets
Pathogenic significance of IL-6 in rheumatoid arthritis
RA is the most frequently observed autoimmune disease, and is characterized by the synovial proliferation and destruction of bone and cartilage in the affected joints. Overproduction of IL-6 is thought to play a crucial role in the pathology of RA (Figure 2). IL-6 is responsible for the activation of auto-reactive T cells and the appearance of auto-reactive antibodies, including rheumatoid factors. IL-6, acting as a hepatocyte-stimulating factor, induces production of C-reactive protein (CRP),
Pathogenic significance of IL-6 in multicentric Castleman’s disease
Multicentric Castleman’s disease is an atypical lymphoproliferative disorder in which IL-6 is responsible for the clinical abnormalities. Castleman’s disease is classified as either the hyaline-vascular or plasma cell type according to the histopathological findings of the affected lymph nodes. Patients with the plasma cell type frequently have systemic inflammatory manifestations such as fever, fatigue, appetite loss and anemia, as well as abnormal laboratory findings such as
Conclusions
Molecular therapy targeting IL-6 has been shown, in clinical trials, to be therapeutically effective for inflammatory diseases such as RA, Castleman’s disease, juvenile idiopathic arthritis and Crohn’s disease. Clinical trials of humanized anti-IL-6R antibody for other diseases such as lupus erythematosus and multiple myeloma are also being conducted (Table 1). Humanized anti-IL-6R antibody, as well as other biologics, widens the choice of therapeutic strategies for these refractory diseases.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
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2019, European Journal of Medicinal ChemistryCitation Excerpt :However, dysregulation of IL-6 production contributes to the pathogenesis of several chronic inflammatory diseases [81,82]. Accordingly, efforts have been dedicated for development of candidate molecules inhibiting IL-6 [83]. To the best of our knowledge, the currently developed anti-IL-6 agents are mainly antibody biologics such as sarilumab, which was approved in 2017 by FDA for treatment of rheumatoid arthritis [84,85].