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Translating IL-6 Biology Into Effective Treatments

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Translating IL-6 Biology Into Effective Treatments PERSPECTIVES of IL-6, IL-6R and glycoprotein 130 (gp130) (Fig. 2a). Moreover, both soluble Translating IL-6 biology into effective IL-6R (sIL-6R) and membrane- bound IL-6R (mIL-6R) can be part of the hexameric treatments complex; hence, the binding region of IL-6–IL-6R–gp130 was considered too Ernest H. Choy , Fabrizio De Benedetti, Tsutomu Takeuchi , Misato Hashizume, complex and broad for a small-molecule Markus R. John and Tadamitsu Kishimoto compound to inhibit the IL-6 signal pathway6,7. The aforementioned mIL-6R and Abstract | In 1973, IL-6 was identified as a soluble factor that is secreted by T cells sIL-6R forms are associated with so-called and is important for antibody production by B cells. Since its discovery more than classical signalling and trans- signalling 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in pathways, respectively, the details of which and corresponding avenues for immune regulation in health and dysregulation in many diseases. Targeting of the drug development have been reviewed IL-6 pathway has led to innovative therapeutic approaches for various rheumatic extensively elsewhere4. Both signalling diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult- onset routes involve phosphorylation of Janus Still’s disease, giant cell arteritis and Takayasu arteritis, as well as other conditions kinase 1 (JAK1), JAK2 and tyrosine kinase 2 such as Castleman disease and cytokine release syndrome. Targeting this pathway (TYK2), which can also be targeted has also identified avenues for potential expansion into several other indications, therapeutically with different molecules but are not the focus of this article4. The such as uveitis, neuromyelitis optica and, most recently , COVID-19 pneumonia. To decision to target IL-6R rather than IL-6 mark the tenth anniversary of anti- IL-6 receptor therapy worldwide, we discuss the itself was made, taking into consideration history of research into IL-6 biology and the development of therapies that target that concentrations of the receptor have less IL-6 signalling, including the successes and challenges and with an emphasis on interpatient variability than concentrations rheumatic diseases. of IL-6, potentially simplifying dose and regimen selection8,9. With concurrent advances in biotechnology, the two Cytokine inhibitors have transformed the by T cells was important for antibody groups decided to develop a humanized outcome of many chronic inflammatory production by B cells (Fig. 1); subsequently, monoclonal antibody targeting IL-6R10–12. diseases. A decade has passed since the this soluble factor was cloned as IL-6, which The resulting humanized antibody to approval of anti-IL-6 receptor (anti-IL-6R) turned out to have various roles in several IL-6R, tocilizumab, binds to mIL-6R and therapy, which is now used worldwide autoimmune diseases1,2. At the same time, sIL-6R and inhibits IL-6 signalling by in various rheumatic diseases, such researchers at Chugai Pharmaceutical preventing IL-6 from binding to IL-6R11,12. as rheumatoid arthritis (RA), juvenile were exploring new avenues for drug The therapeutic benefit of this antibody idiopathic arthritis (JIA), adult-onset Still’s development for autoimmune diseases. to IL-6R led to the development of several disease (AOSD), giant cell arteritis (GCA) In the late 1980s, the two groups started antibodies to IL-6 (sirukumab, olokizumab and Takayasu arteritis, as well as other to collaborate to further advance the and clazakizumab). conditions such as Castleman disease and understanding of the biological role of IL-6 cytokine release syndrome (CRS). To mark in various autoimmune diseases and the Initial therapeutic applications this anniversary, we discuss the 40-year development of IL-6 inhibitors as treatment As IL-6 is well known to have various history of translational research into IL-6 options. To increase their collaborative physiological roles, in considering IL-6 biology and the subsequent development potential, the two research groups even as a therapeutic target, its homeostatic of therapies targeting this pivotal cytokine moved to adjoining laboratories at Osaka role versus its pathogenic role in various pathway, which helps to inform future University. The university researchers autoimmune diseases was extensively biological and clinical research. led efforts to identify IL-6 signalling debated3,4. However, utilizing cell-based mechanisms and the biological effects assays, animal models and ex vivo serum From signalling to drug discovery of IL-6, whereas the company focused and tissue analyses, scientists identified The journey from the discovery of on developing and characterizing IL-6 several candidate diseases that might benefit IL-6 biology to the development of an IL-6 inhibitors as potential new treatments for from the use of IL-6 inhibition (Table 1). pathway inhibitor as a potential treatment autoimmune diseases3–5. A 1988 publication reported that IL-6 for various diseases started coincidentally The traditional approach of searching is an important growth factor in myeloma with the meeting of two research groups for small- molecule inhibitors proved cells13. Oncologists in France conducted an in Japan. In 1973, researchers at Osaka challenging when the research team found open- label clinical trial of a mouse anti-IL-6 University led by Tadamitsu Kishimoto that IL-6 signal transduction occurred in patients with multiple myeloma, the first reported that a soluble factor secreted through a hexameric high- affinity complex second most common type of blood cancer NATURE REVIEWS | RHEUMATOLOGY VOLUME 16 | JUNE 2020 | 335 PERSPECTIVES after leukaemia14. Although none of the efficacy in those patients who produced to the bortezomib–melphalan–prednisone patients treated had an improved outcome low concentrations of IL-6 (REF.15). More regimen would be beneficial to patients or achieved remission in the initial report than 20 years later, a clinical trial evaluated with newly diagnosed multiple myeloma; of the trial, post-hoc analysis revealed that whether the addition of a different chimeric however, this IL-6 inhibitor also failed to treatment with the anti-IL-6 showed some monoclonal antibody to IL-6, siltuximab, improve outcomes16. Experimental findings Soluble factor for stimulating 1973 Phase II clinical trial B cells discovered Phase III clinical trial Regulatory approval 1986 IL-6 cloned Trial failed to meet primary end point IL-6R cloned 1988 1989 gp130 cloned Il6 transgenic mouse generated Anti-IL-6R (mouse) generated 1992 1993 Anti-IL-6R (human) generated Il6-knockout mouse generated 1995 2004 Tocilizumab trial for Crohn’s disease Tocilizumab Tocilizumab trial approved for in Castleman 2006 Castleman disease disease (Japan) 2007 Tocilizumab pivotal trials in RA (2007–2010) Tocilizumab pivotal Tocilizumab approved for RA, trials in sJIA and pJIA 2008 (2008–2012) sJIA and pJIA (Japan) 2009 Tocilizumab approved for RA (EU) Tocilizumab approved for RA (USA) Tocilizumab trial in SLE 2010 2011 Tocilizumab approved for sJIA (EU and USA) Tocilizumab approved for pJIA (EU and USA) 2013 Siltuximab Siltuximab Siltuximab approved trial in Tocilizumab trial in 2014 trial in AS for Castleman multiple Castleman disease (EU and USA) myeloma disease Sarilumab trial in AS 2015 2016 Sirukumab trial in SLE Sarilumab pivotal trial in RA Tocilizumab Sarilumab Tocilizumab trial in approved for approved for Takayasu Sirukumab 2017 RA (EU, Japan GCA (EU and arteritis trial in RA and USA) USA) and Tocilizumab CRS (USA) trial in GCA 2018 Tocilizumab Tocilizumab Tocilizumab approved trial in SSc trial in AOSD for CRS (EU) Tocilizumab approved for 2019 CRS and AOSD (Japan) 2020 Tocilizumab trial in COVID-19 pneumonia 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. 336 | JUNE 2020 | VOLUME 16 www.nature.com/nrrheum PERSPECTIVES In 1989, a publication described IL-6 inhibition in RA management of RA named IL-6 pathway constitutive overproduction of IL-6 from The development path for an IL-6 inhibitor inhibitors as one of the preferred treatment the germinal centres of hyperplastic lymph for the treatment of RA, the most common options for patients for whom methotrexate nodes in patients with Castleman disease, chronic autoimmune disorder that primarily is inappropriate60. Interestingly, the clinical a lymphoproliferative disorder, and a affects joints, began in the early 1990s, benefits of IL-6 inhibition might be correlation of serum IL-6 concentrations when cell- based experiments revealed that attributable, in part, to the beneficial effects with clinical abnormalities17. Consistent with IL-6 might be involved in osteoporosis, of IL-6 inhibition on bone and cartilage these observations, transgenic mice cartilage destruction and synovial turnover, which are supported
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