Abstract
INTRODUCTION: An Fc-mutated chimeric aglycosyl anti-CD3 monoclonal antibody (mAb), otelixizumab, has been used successfully to treat renal transplant rejection and type 1 diabetes, with reduced toxicity compared with traditional anti-CD3 therapies such as OKT3. The aim of this study was to seek preliminary safety data for otelixizumab in rheumatoid arthritis (RA). METHODS: A small Phase 1 experimental medicine study was performed in six participants with RA. The primary outcome measure was safety, with a focus on first-dose cytokine release reactions and extent of CD3(+) lymphopenia. Cytokine release was quantified using ELISA, and lymphocyte subsets by flow cytometry. In vitro whole blood assays were used to interrogate the mechanisms underlying the first-dose cytokine release reaction. Clinical progress following therapy was monitored as an exploratory outcome. RESULTS: All participants experienced a moderate first-dose cytokine release reaction. There was transient lymphopenia but no T-cell depletion, and a temporary CD8(+) T-cell lymphocytosis occurred in all participants. In those who completed therapy, a sustained reduction in CRP following treatment was noted. In an in vitro whole blood assay, designed to mirror in vivo cytokine release, there was a trend for reduced cytokine production in seropositive RA compared with seronegative RA, psoriatic arthritis, or healthy controls. CONCLUSIONS: At the dosing regimen used, otelixizumab was associated with an unexpected and significant first-dose reaction in participants with RA.