Novel combination therapy for rheumatoid arthritis: efficacy of anti-CD3 antibody enhanced by p38 inhibitor (Work packages 1-4)

Anti-CD3 therapy has the potential to have long-lasting efficacy for patients with type 1 diabetes following a brief course of therapy, which if translated to the treatment of RA could reduce or even remove the need for frequent biologic therapy with all the associated financial and healthcare benefits. However, its pathway into the clinic has been hampered by variable responses and side effects, the latter caused by inflammatory cytokine release. This application outlines a proof-of-mechanism study to determine whether the side effects of the anti-CD3 therapeutic antibody Otelixizumab (OTX) could be mitigated and clinical response enhanced, by co-administration of an inhibitor of the inflammatory nodal kinase p38.

The applicants aim to investigate the ability of OTX combined with the p38 inhibitor Losmapimod (also developed by GSK) to induce functionally suppressive T-regulatory (Treg) cell subsets in peripheral blood mononuclear cells (PBMC) from rheumatoid arthritis (RA) patients in vitro. The applicants will also analyse the impact of this combination on cytokine release (both pro- and anti-inflammatory) by PBMC from RA patients. Different doses of OTX and Losmapimod will be tested to maximise induction of Treg whilst minimising cytokine release. These investigations will extend existing studies to include patients with psoriatic arthritis where pilot data indicates similar results as observed in RA PBMC. In addition, the effects of this combination on synovial fluid cells will be assessed.