A Phase 1 Experimental Medicine Study of Anti-CD3 Monoclonal Antibody in Rheumatoid Arthritis

Introduction An Fc-mutated chimeric aglycosyl anti-CD3 (ChAglyCD3) 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.