Interleukin-(IL)-6 is a multifunctional inflammatory mediator that is elevated in autoimmune disorders including reumatoid arthritis. This cytokine is produced by all kinds of cell types (e.g. lymphocytes, macrophages, fibroblasts, synoviocytes) and stimulates among others activation of T-cells, differentiation of B cells, maturation of megakaryocytes, and acute phase proteins, and haemopoiesis. IL-6 has local effects on the inflammatory process in joints and systemic effects including increased ESR, trombocytosis, and anaemia.
In order to exert its action on target cells, IL-6 binds to its soluble receptor sIL-6R (1). The receptor complex binds to the gp130 transmembrane receptor and becomes membrane bound (2). After dimerisation with a second gp130 protein, phosphorylation occurs and signal transduction routes via either STAT proteins or JAK proteins are activated (3). This results in altered gene transcription and expression (4); e.g. increased expression of other cytokines in rheumatoid arthritis pathology.
Tocilizumab (also known as myeloma receptor antibody, MRA) is a recombinant humanised anti-human monoclonal antibody of IgG1κ directed against the IL-6 receptor (IL-6R). The antibody specifically binds to the IL-6 binding site of both soluble sIL-6R and membrane-bound mIL-6R receptors with similar affinity (5).By inhibiting binding of IL-6 to its receptor and hence dimerisation and signal transduction, tocilizumab blocks IL-6 activity. The drug prevents IL-6 from binding to its receptor and dimerisation of the gp130 receptors and thus activation of the signal transduction routes (6). This eventually results in prevention of bone and cartilage destruction in RA.
Tocilizumab (MW of approximately 149 kDa) is specific to the IL-6R and shows no binding to structurally related cytokine receptors, nor does it have cross-reactive inhibitory effects on other cytokines.
The pleiotropic activity of IL-6 is reflected in the adverse effects profile. However, infections of upper respiratory tract, skin and gastrointestinal system are the most common risk with tocilizumab therapy. Tocilizumab suppresses the development of effective immunity to bacterial and viral infections, which is medicated by IL-6. Hepatic adverse effects include increased enzyme activity, transaminases, and hypercholesterolemia. Other events caused by decreased IL-6 activity include hypertension and neutropenia and leukopenia. The pharmacovigilance data indicate cases of cardiovascular disorders and malignancies, but this needs further investigations.
Tocilizumab (alone or in combination with methotrexate) is indicated for the treatment of moderate to severe rheumatoid arthritis (RA) in patients who have either failed to responded to, or who were intolerant to, previous therapy with one or more disease modifying anti-rheumatic drugs (DMARDs).
EPAR of tocilizumab.