Tocilizumab, a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody, may play a role in treating systemic lupus erythematosus (SLE), according to preliminary pilot results¹ presented at the 69th Annual Meeting of the American College of Rheumatology in San Diego, California. The new agent, formerly known as MRA, is also being investigated in Castleman's disease, adult-onset Still's disease, and rheumatoid arthritis.

Murine studies have shown that IL-6 blockade prevents proteinuria and improves survival, and indirect evidence in humans has demonstrated that blocking IL-6 in the laboratory decreases anti-double-stranded DNA antibody production. Studies have also shown an increase in urinary IL-6 in active lupus nephritis.

In the phase I, open-label study, 14 SLE patients with mild-to-moderate disease activity were treated with biweekly infusions of tocilizumab (2 mg/kg, 4 mg/kg, or 8 mg/kg) for 12 weeks, then followed for 8 weeks after the last dose.

Compound considered biologically active

The new data showed that in vivo blockade of the IL-6 receptor decreases lymphocyte activation and alters B-cell and T-cell homeostasis by blocking differentiation and/or trafficking in patients with SLE, leading to normalization of the abnormal B- and T-cell subsets observed at baseline, according to study author Gabor Illei, MD, PhD, a rheumatologist at the National Institutes of Health in Bethesda, Maryland.

"Tocilizumab promptly and significantly decreased acute-phase reactants, suggesting that [the agent] is biologically active," Dr. Illei says. "It also alters B-cell and T-cell homeostasis in patients with lupus." At the end of treatment, most of the changes went back toward their baseline levels, he points out.

However, Dr. Illei explains to CIAOMed, "It is too early to speculate about the clinical efficacy or utility of tocilizumab in the treatment of SLE," as the study is still ongoing and researchers are planning to treat 16 patients.

Control blood was obtained from 12 healthy blood donors in the tocilizumab study. Peripheral blood mononuclear cells (PBMCs) were then isolated and phenotype analysis was carried out using flow cytometry. Pretreatment and week-12 values were compared and statistical significance was evaluated by paired t-test. Dr. Illei and colleagues also assessed differences in the response to IL-6 blockade between patients whose baseline values were within normal range and those who were outside the range.

According to the findings, acute-phase reactants decreased promptly and significantly during treatment. The frequency of both activated B (CD69+) and activated CD4+ and CD8+ T cells (HLADR+) also decreased with treatment (P <.05). In addition, IgD+CD27-naïve B-cell subsets increased (P <.05), whereas the frequency of IgD-CD27+ memory B-cell subsets and CD27highCD38highIgD- ISC decreased (P <.05).

In terms of T cells, the frequency of CD4+CD45RA+CCR7+ naïve T cells increased (P <.05). Most of the changes in all these subsets were observed primarily in patients whose baseline values were outside the normal range. The CD4+ or CD8+CD45RO+CCR7+ central memory cells and CD8+CD45RO+CCR7-effector memory cells decreased, with no difference between patients with normal or abnormal baseline values, the study found. Immunoglobulin levels remained in the normal range, but IgG3 and IgG4 subclasses decreased significantly. There was no consistent change in autoantibody levels, the study showed.

Reference

1. Shirota Y,  Yarboro C, Sims G, et al. The impact of in vivo anti-IL-6 receptor blockade on circulating T- and B-cell subsets in patients with systemic lupus erythematosus. Presented at: 69th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract 1884.