The work: Rheumatoid arthritis (RA) is a common, chronic, painful and disabling autoimmune disease. Prior to the work of Drs. Feldmann and Maini, the treatment of RA was not based on understanding of which molecules were produced in excess. In the mid-1980’s, the team began work on unravelling which molecules might be the culprit of this disease in hopes of determining which targets would be ideal for treatment. Experiments in the laboratory on cells from joints of patients and in an animal model of RA demonstrated that tumor necrosis factor (TNF), a molecule belonging to the ‘cytokine’ family, was a major driver of inflammation and joint damage. They discovered a monoclonal antibody-based treatment that blocked the action of TNF and was safe and effective for treating in RA. Anti-TNF therapy works in most patients rapidly to reduce pain, improve mobility, reduce work disability, improve social functioning, and, when compared with patients on conventional synthetic drug treatments, reduces the risk of heart attacks, strokes and increases life expectancy. It has a major role in protecting joints from degeneration, thus maintaining good physical function and reducing the need for joint surgery.
The impact: They discovered the first treatment for RA, using monoclonal antibodies which are genetically engineered natural defense molecules. Not only was this a novel treatment, but it was the first demonstration of the efficacy of a biological therapy for a chronic autoimmune disease and led to the recognition by the pharmaceutical industry that biological drugs are a viable class of therapeutic agents that can compete with traditional chemical drugs. The effective results have not only transformed the treatment for patients, but have led to other successful anti-TNF treatments, and encouraged much further work using antibodies for treatment.
After training in medicine and realising that research was the path towards improving therapy, he studied for a PhD in immunology at the Walter and Eliza Hall Institute in Melbourne with Prof. Sir Gus Nossal. There he learnt to optimise immune responses in tissue culture, and also studied potent intercellular mediators, molecules later identified as cytokines, autoimmunity and immuneregulation.
In 1983, while working in Av Mitchison’s ICRF Tumour Immunology Unit at University College London, on reflecting about the new observations of upregulated MHC class II in local sites of autoimmunity (e.g. thyroid) he proposed that this reflected augmented antigen presentation. Since cytokines, especially interferons upregulate MHC antigens, in 1983 he published a hypothesis that upregulated cytokines and antigen presentation were key steps in the generation of a chronic autoimmune disease. This was a testable hypothesis, and was successfully tested on Grave’s thyroiditis by 1985-6. This led to collaboration with Ravinder Maini, relocation to the Kennedy Institute, and the exploration of what were critical cytokines in the most accessible human autoimmune disease, rheumatoid arthritis. New methods were developed to assess which cytokines were produced locally demonstrating that many pro-inflammatory cytokines were produced. To unravel which was the best target, he analysed cytokine regulation in dissociated rheumatoid arthritis synovial tissue, and found that blockade of TNF also downregulated IL-1 and other pro-inflammatory cytokines, indicating that TNF was the long sought after therapeutic target. This was validated in mouse arthritis, treatment given after disease onset. Thus there was a rationale for a proof-of-principle clinical trial of anti-TNF, and he was a leader with my colleague Prof. Sir Ravinder Maini of this and subsequent clinical trials which led to approval for anti-TNF therapy in rheumatoid arthritis. This success and that of other anti-TNF antibodies has made anti-TNF the best-selling drug class from 2012. He succeeded Ravinder Maini as Director of Kennedy Institute in 2002.
This work has led to his election to various national academies of science (e.g. Royal Society, Australian Academy of Science and the National Academy of Science, USA), and multiple prestigious prizes, mostly with his colleague Sir Ravinder Maini, e.g. Crafoord Prize of Royal Swedish Academy, the Albert Lasker Clinical Medical Research Award, Ernst Schering Prize, Paul Janssen prize.