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Marc Feldmann, Fionula Brennan, Ewa Paleolog, Peter Taylor, Ravinder Maini
Kennedy Institute of Rheumatology
London, UK

Anti TNFa Antibody (cA2) Therapy in Rheumatoid Arthritis: Clinical Results and Mechanism of Action

The rationale for anti TNFa therapy has been documented and published in many reviews. The clinical results of anti TNFa antibody therapy in rheumatoid arthritis have been very satisfying, with several open and placebo controlled studies all demonstrating a marked degree of clinical benefit and thus verifying that TNFa is a therapeutic target in rheumatoid arthritis. More recent clinical studies have focused on long-term treatment. A clinical trial of 5 doses of cA2 has been completed. This showed clinical benefit in 70% of patients treated with 3 or 10 mg/kg, which lasted for more than 12 weeks after cessation of therapy. Most impressive was the degree of improvement, with a few patients entering clinical remission. Especially at low doses of antibody there was synergy with a low dose of the anti-rheumatic drug methotrexate. One of the possible impediments to long-term treatment with antibodies is the development of an anti-idiotype response to the antibody. With repeated dosing, in this trial, it was found that there was an inverse dose-response curve, much less antibody at high doses of cA2. With methotrexate these were also reduced, and thus this trial revealed two strategies for mimimizing immunogenicity.

The mechanism of action of cA2 was investigated. Three mechanisms of action are already apparent. First is downregulation of the cytokine network in vivo. Second is a reduction of leucocyte trafficking into joints, which could be a major mechanism. Third is a regulation in angiogenic mediators. The actions at multiple steps in the disease process may explain the marked clinical efficacy of blocking a single cytokine.