Translating IL-6 biology into effective treatments

Abstract

In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovative therapeutic approaches for various rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis and Takayasu arteritis, as well as other conditions such as Castleman disease and cytokine release syndrome. Targeting this pathway has also identified avenues for potential expansion into several other indications, such as uveitis, neuromyelitis optica and, most recently, COVID-19 pneumonia. To mark the tenth anniversary of anti-IL-6 receptor therapy worldwide, we discuss the history of research into IL-6 biology and the development of therapies that target IL-6 signalling, including the successes and challenges and with an emphasis on rheumatic diseases.

Fig. 1. Timeline of the discovery of IL-6 and IL-6-targeted therapies.

The timeline shows progress in the field of IL-6 pathway inhibition following the initial identification of a B cell stimulation factor in 1973, and the more definitive biochemical and molecular studies carried out in the 1980s and 1990s, to clinical trials and approvals in various diseases in the 2000s and up to the present day. AOSD, adult-onset Still’s disease; AS, ankylosing spondylitis; CRS, cytokine release syndrome; GCA, giant cell arteritis; gp130, glycoprotein 130; IL-6R, IL-6 receptor; pJIA, polyarticular course juvenile idiopathic arthritis; RA, rheumatoid arthritis; sJIA, systemic juvenile idiopathic arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.

Fig. 2. Cell signalling pathways and the physiological role of IL-6 in diseases.

IL-6 participates in a broad spectrum of biological events, such as synovial inflammation, immune responses, haematopoiesis and acute-phase reactions. a | IL-6 binds to IL-6 receptor (IL-6R) and glycoprotein 130 (gp130) to form a hexameric complex. Both membrane-bound IL-6R and soluble IL-6R can be part of the hexameric complex and are associated with the classical signalling and trans-signalling pathways, respectively. Intracellular signalling pathways involve the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway. Pharmacological inhibitors of IL-6 signalling prevent IL-6 from binding to IL-6R by targeting either the cytokine itself or the receptor. b | In the context of disease, IL-6 can have both local inflammatory and systemic effects. Some of the manifestations of the diseases for which IL-6 inhibitors are approved could be explained by the effects of IL-6, on the basis of both preclinical and clinical data. IL-6 has been implicated in the pathogenesis of diseases, including rheumatoid arthritis, systemic juvenile idiopathic arthritis (sJIA), Castleman disease, giant cell arteritis, Takayasu arteritis and cytokine release syndrome, among others. c | As IL-6 has multiple roles in the dysfunction of the immune and inflammatory systems, anti-IL-6R therapy could relieve various symptoms such as fever, fatigue, pain, joint destruction, anaemia and others. CRP, C-reactive protein; MMP, matrix metalloprotease; RANKL, receptor activator of NF-κB ligand; SAA, serum amyloid A; T_eff cell, effector T cell; T_reg cell, regulatory T cell; VEGF, vascular endothelial growth factor.