Cytokines are singalling protein, peptide or glycoproteins molecules that are secreted by cells of immune system. They act of different cell types to regulate the immune response, inflammatory responses, cell growth, cell migration, fibrosis, and angiogenesis. Interleukines (IL) are a class of cytokines that are essential for the proper functioning of the immune system. Intital investigators believed that IL are only secreted and act on Leukocytes, therefore they were named as interleukins. In the cell, their synthesis is transient and are secreted rapidly. There are 40 IL known so far IL-1 to IL-40. They have attarcted a lot of therapeutic attention because of their essential nature and their ability to modulate the immune and repsonse. One such IL cytokine is targeted for the treatment of Rheumatoid arthrithis (RA) read more about RA here. This article will focus on the role of IL-6 in the pathogenesis of RA and current therpaeutic monoclonal antibodies (mAb) that target it.
RA is a common autoimmune disorders that affect approx. 0.5%–1% of adult population. It is characterised by the inflammation of synovium accompanied by articular bone and cartilage damage and systemic disorders.
IL-6: Cytokine IL6 is a dimeric glycopeptide of the type I cytokine family and is found to be elevated in RA. IL-6 is produced by the inflammed synovium and it accumulates in synovial fluid. It is also produced by T cells, B cells, monocytes, fibroblasts, osteoblasts and endothelial cells. IL-6 is a pro-inflammatory cytokine with pleitropic effects, as it influences the function of B cells, T cells, monocytes, platelets and liver.
IL-6 Signalling: Cytokines are secreted and are therefore in soluble form. The cytokine binding receptor protein for IL-6 is either soluble (sIL-6R) or membrane-bound (IL-6R). In both the scenarios the signal-transducing subunit is membrane bound glycoprotein 130 (gp130). In classical signalling, the IL-6 binds to membrane bound IL-6R and gp130 for further signal transduction. When the IL-6 binds to sIL-6R, which then interacts with homodimer of gp130 and induces signal transduction, it is called trans-signalling. It is especially useful in targeting a wide variety of cells that do not express IL-6R but only gp130.
Effects of IL-6 in RA: IL-6 is pro-inflammatory pleiotropic cytokine with several effects, some of them relevant to RA are outlined below.
- It induces B-cell differentiation into plasma cells and stimulates antibody production.
- It stimulates the production of TH17 cells from naïve T cells with support from cytokines IL-1b and IL-23.
- IL-6 activates neutrophils via membrane bound receptor IL-6R and promotes leukocyte infiltration to the inflammatory tissue (synovial joint). Neutrophils then mediate inflammation and secreting proteolytic enzymes, reactive oxygen intermediates causing joint destruction. Il-6 is strictly needed for the recruitement of mononuclear leukocytes.
- Infiltrated neutrophils release sIL-6R which induces local cells like endothelial cells to recruit more leukocytes and monocytes.
- It stimulates synviocytes to produce vascular endothelial growth factor (VEGF), which enhances inflammation by inducing vascular permeability, migration and proliferation of endothelial cells.
- IL-6 stimulates hematopoietic stem cells (granulocyte-macrophage lineage) to recruit osteoclasts. It is also knows to damage articular cartilage by trans signalling.
- Stimulates hepatic acute phase protein synthesis to produce C-reactive protein (CRP)
- It is also involved in inducing systemic effects of RA
- By unknown mechanism it also reduces the level of blood lipid, and cholesterol. Finally contributing to RA associated cardiac problems
Anti-IL-6 mAb therapy: Experiments in mouse models have shown that IL-6 is indispensable for the development of RA. This accompanied with the success of anti-IL-6 with IL-6R mAb in primates encouraged the development of therpay againtst IL-6 signalling. There are currently 2 therapeutic mAb drugs available for RA
1. Tocilizumab (Actemra or RoActemra) is used as a monotherapy for the treatment of severe cases of RA where no previous treatment or treatment with other disease modifying antirheumatic drugs (DMARDs) has been not successful. It is a humanized monoclonal antibody that works against soluble or membrane bound (anti-IL-6R) IL-6 receptor. This prevents IL-6 and IL-6R interaction and the subsequent signal transduction, thereby reducing inflammation and other symptoms of RA.
In clinical trails ~40% of the patients achieved remission i.e their symptoms disappeared. Upto 5 studies involving 4000 people showed a considerable advantage in using tocilizumab over placebo, TNF blockers or methotrexate irresponsive RA. Tocilizumab monotherapy was also found to be superior than to methotrexate (DMARD) or adalimumab monotherapy. After Tocilizumab administration the serum IL-6 level increase, due to accumulation of IL-6 as its receptor is blocked by Tocilizumab (anti-IL-6R), thereafter the IL-6 levels gradually decrease. It was approved in EU and USA in 2009 and 2010 respectively.
• Developed by Chugai Pharmaceutical Company in collaboration with Osaka University, Japan.
• Administered as injection or infusion.
• Classified as an immunosuppressant and interleukin inhibitor.
• Standard dose is every 4 weeks with 8 mg/kg of tocilizumab.
• Excipients: Sucrose, Polysorbate 80, Disodium phosphate dodecahydrate, Sodium dihydrogen phosphate dihydrate.
• Shelf life: 30 months
2. Sarilumab (Kevzara) is similar to Tocilizumab in its mode of action, safety and efficacy. Like Tocilizumab, it also binds to IL-6R (anti-IL-6R antibody). In contrast to Tocilizumab which is a humanized mAb, Sarilumab is a fully human mAb and thus has a lower immunogenecity. Sarilumab also has a longer in vivo half life and higher affinity for IL-6R. In the clinic it is used with methotrexate (a DMARD) when other treatments have not been successful and is succesful in reducing RA symtptoms associated with joints after 24 weeks of therapy. Clinical studies have also showed that Sarilumab + methotrexate is successful when adalimumab or methotrexate alone or other TNFa were intolerant or unable to adequately improve the symptoms of RA. It was approved in US and Europe in 2017
• Developed by Regeneron and Sanofi
• Administered as subcutaneous injection.
• Classified as an immunosuppressant and interleukin inhibitor.
• Standard dose: 200 mg every 2 week
• Excipients: Histidine, Arginine, Polysorbate 20, Sucrose
• Shelf life: 24 months
3. Sirukumab (Plivensia) was the only mAb against IL-6 for RA but it was withdrawn in 2017 because of the associated mortality due to infection and malignancies. Siltuximab was also a fully human mAb. A possible reason for the success of IL-6R therapy over IL-6 is due the presence of cellular pathways independent of RA that use IL-6 but not IL-6R.
4. Yet another anti-IL-6 mAb Siltuximab (Sylvant) is available in the market but its not used against RA because of insufficient evidence for its effectiveness against RA. It is rather used for multicentric Castleman’s disease when the patient is HIV and human herpesvirus-8 negative.