Monoclonal anti‐TNFα Antibody as a Probe of Pathogenesis and Therapy of Rheumatoid Disease

作者：Ravinder Nath Maini, Michael J. Elliott, EIONULA M. BRENNAN, Richard O. Williams, Cong Chu, Ewa M Paleolog, PETER J. CHARLES, Peter Charles Taylor, Marc Feldmann · 发表于：Immunological Reviews · 年份：1995 · DOI：10.1111/j.1600-065x.1995.tb00070.x · 被引用次数：182 · 研究领域：Rheumatoid Arthritis Research and Therapies、Monoclonal and Polyclonal Antibodies Research、Systemic Lupus Erythematosus Research

Rheumatoid arthritis is a common cause of chronic disability for which current therapies are of limited value in controlling the disease process and outcome. Our initial approach to understanding the pathogenesis of RA and defining a novel therapeutic target was to investigate the role of cytokines by blocking their action with antibodies on cultured synovial-derived mononuclear cells in vitro. These investigations suggested that neutralization of TNF alpha with antibodies significantly inhibited the generation of other pro-inflammatory cytokines also over-produced, such as, IL-1, GM-CSF, IL-6 and IL-8. The implication that blockade of a single cytokine, TNF alpha might have far-reaching effects on multiple cytokines and thereby exert significant anti-inflammatory and protective effects on cartilage and bone of joints, was tested in arthritic DBA/1 mice immunized with collagen II. Impressive amelioration of joint swelling and joint erosions in this model encouraged clinical trials with a monoclonal anti-TNF alpha antibody. The cA2 chimeric anti-TNF alpha high-affinity antibody was initially tested in an open-label study at a dose of 20 mg/kg on 20 patients, with substantial and universal benefit. Subsequently, a randomized placebo-controlled double-blind trial was performed on 73 patients comparing a single intravenous injection of placebo (0.1% human serum albumin) with two doses of cA2. Using a composite disease activity index, at 4 weeks post infusion, 8% of patients recei...