Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti–IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease

Abstract

Interleukin-6 (IL-6) plays pathologic roles in immune-inflammatory diseases such as rheumatoid arthritis (RA) and Castleman disease. By inhibiting IL-6 receptors (IL-6Rs), tocilizumab (a humanized anti-IL-6R antibody) ameliorates the symptoms of these diseases and normalizes acute-phase proteins, including Creactive protein (CRP). We found that tocilizumab treatment increased serum levels of IL-6 and soluble IL-6R (sIL-6R). To investigate the pathologic significance of these increases, we analyzed the kinetics of serum IL-6 and sIL-6R and the proportion of sIL-6R saturated with tocilizumab after tocilizumab administration in patients with RA and Castleman disease and then compared the results with the CRP values. Serum IL-6 and sIL-6R markedly increased after tocilizumab administration in both RA and Castleman disease. As long as free tocilizumab was detectable, sIL-6R was saturated with tocilizumab and IL-6 signaling was completely inhibited. We concluded that it is likely that sIL-6R increased because its elimination half-life was prolonged by the formation of tocilizumab/sIL-6R immune complex, and that free serum IL-6 increased because IL-6R-mediated consumption of IL-6 was inhibited by the unavailability of tocilizumab-free IL-6R. We also concluded that the increased level of free IL-6 during tocilizumab treatment closely reflects the actual endogenous IL-6 production and true disease activity. (Blood. 2008;112:3959-3964)

Sustainable Efficacy of Switching From Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis

“…Conversely, the percentage of patients who maintained sufficient trough concentrations of TCZ was decreased after switching, suggesting that the serum trough concentration of TCZ could not be maintained in certain patients with high body weights. It is conceivable that disease activity was increased because IL‐6 signal transduction could not be completely inhibited 14. In contrast, the trough concentration of TCZ and efficacy slightly increased after switching in patients with low body weights (<50 kg).…”

“…It has been reported that CRP level is normalized when the serum TCZ concentration is ≥1 μg/ml, because TCZ can be bound to ≥95% of soluble IL‐6 receptors 14. Serum TCZ concentrations can be indirectly monitored through CRP concentrations, although the serum TCZ concentration is substantially maintained with individual differences.…”

“…Serum TCZ concentrations were measured using the enzyme‐linked immunosorbent assay every 4 weeks throughout the double‐blind period and extension period 14.…”

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

“…Moreover, it has been shown that IL-6 stimulates the production of vascular endothelial growth factor in the synovium of RA patients, thus contributing to pannus formation (16). Recent studies of IL-6R inhibition using tocilizumab have shown good clinical responses in RA (3,17) and other immune-mediated diseases (3).…”

Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development

“…While this may be a tractable surrogate measurement for cell surface RO, the physiological relevance of soluble RO must be assessed. Another option is to quantify the accumulation of a ligand for the receptor in the circulation as an indirect measure of RO 29, 30, 31, 32. However, the natural ligand for the receptor may be unknown or, if known, may bind to multiple receptors, in which case, the ligand levels may not be increased following administration of drugs.…”