Tumor Necrosis Factor Antagonists: Some Historical Points
In early 2004 and over the last five years, TNF antagonists have come to be seen as the most remarkably effective therapies for rheumatoid arthritis (RA) in the history of the treatment of this disease. These agents include Etanercept (Enbrel), Infliximab (Remicade), and Adalimumab (Humira) all of which appear to be similarly effective for RA. Etanercept was the first agent approved, was fast-tracked by the FDA, and approved on Nov.2, 1998. Infliximab was second and was approved one year later (11/10/99). Adalimumab was approved on 12/31/2002. The literature on the clinical use of TNF antagonists that has accumulated within the last ten years is huge.
There are some questions not often addressed in the literature on the antagonists. Some of this information is important to understanding the history and immense scientific importance of TNF antagonism. I review several of these points here.
First, scientific work within this area has led to at least two major prestigious awards. The Albert Lasker award was presented to Professor Marc Feldmann and Sir Ravinder M Maini in 2003, who were credited with the discovery of anti-TNF therapy for the treatment of rheumatoid arthritis and other autoimmune diseases. This is only the third time that the Lasker award has been given for work in Rheumatology. The first was for the discovery of corticosteroids in 1949, the second for joint replacement therapy in 1974; and anti-TNF therapy is the third. Lasker awards, which are made in a wide range of scientific areas, have come to be known as “America’s Nobels”, and have been followed in 66 cases by award of the Nobel Prize. Professors Feldmann and Maini work at Imperial College, London, Kennedy Institute of Rheumatology division. In collaboration with Centocor inc, this work eventually led to approval of Remicade for clinical use in RA. The work of Feldmann and Maini introduced the concept of TNF-alpha being the key cytokine governing inflammatory reactions in rheumatoid joints. This idea was received with much doubt when it was first put forth in the 1980’s. The belief at that time was that many cytokines and inflammatory mediators were required to produce inflammation. Further studies silenced these doubts. Sir Ravinder commented: “The discovery that inhibiting just one molecule could make such a huge difference to the many sufferers of this terrible disease was a truly remarkable find.” TNF could then be viewed as a regulatory cytokine “with a pivotal role in controlling the production of IL-1 and other proinflammatory molecules in RA.”
In 1992 Feldmann and Maini performed the first clinical trial of anti-TNF therapy for RA. The antibody, which had been created at Centocor Inc, was initially called cA2, then infliximab (Remicade). Fortunately for the investigators, one of Feldmann’s former visiting scientists had joined Centocor with a position as research director, and learned of the antibody. It was given to 20 patients by Feldmann and Maini with dramatic improvement. Centocor was the first company to begin large scale anti-TNF antibody trials, but following the 1992 disclosure of the initial results, other companies entered the competition vigorously with their own anti-TNF agents. Success with RA led to trials with Crohn’s disease, juvenile RA, ankylosing spondylitis, psoriasis, psoriatic arthritis, and other inflammatory disorders, many of these successful, as the years have passed.
For their work, Feldmann and Maini have also been honored by award of the Crafoord Prize of the Royal Swedish Academy of Science in 2000. This prize was established in 1982 to promote basic research in a variety of sciences. One award is given a year. The award is currently 500,000 $US and is intended to fund further research by the prizewinner. Holger Crafoord, a Swedish industrialist donated the initial funds for the prize.
It is interesting to note that one year prior to the approval of Infliximab, Etanercept was approved and introduced for the treatment of RA. Credit for the creation of Etanercept goes to molecular biologist Raymond Goodwin PhD and biochemist Craig A Smith PhD who were with the Immunex Corporation in Seattle Washington. Dr. Smith joined Immunex in 1988. He resolved to clone a soluble receptor for TNF. The scientists applied for a patent and published their work in the May 25, 1990 issue of Science. The original expectation was that it would be useful in treating Gram negative sepsis and shock. Work soon revealed that it was effective in animal models of arthritis then in rheumatoid arthritis. It was the original work of Professors Feldmann and Maini that led to its use for rheumatoid Arthritis. The work of Goodwin and Smith led to a second major award.
The intellectual Properties Owners Association, which honors the very best American inventors, awarded the inventors of Enbrel the Inventor of the Year Award to Craig A. Smith, Raymond G. Goodwin, and M. Patricia Beckman “for their creative genius and their contribution to an improved quality of life for sufferers of rheumatoid arthritis”. This award was given in 2001. The IPO award is the oldest and best known award given to recent inventors. To be eligible, an invention must have been patented or first marketed in the preceding four years. Etanercept was first marketed in 1998.
Adalimumab (Humira) as a therapeutic candidate was developed by Knoll Pharmaceuticals in Germany. Abbott purchased Knoll, then further developed the candidate antibody D2E7 at the clinical level, and released it. There is no one inventor of Humira. The entire new product development team of Knoll (then Abbott) had input. Jochen Salfeld, PhD, was the Global Preclinical Director at Knoll, then Abbott. (Personal communication from Carl R Wilhelm of Abbott, 1/09/2004). George P Smith is credited as the originator of the phage display technique which was utilized in the development of Humira. (Science 1985, 288:1315-1317). Humira (adalimumab) was isolated by Cambridge Antibody Technology (CAT), using phage display technology. CAT is a leading biotechnology company, located near Cambridge, England, which has several monoclonal antibodies under review, and has alliances with a large number of companies to produce and commercialize human monoclonal antibodies. Adalimumab (Humira) is fully human, not chimeric, and hopefully will be less immunogenic than infliximab.This work was done in conjunction with Abbott Laboratories. Abbott owns exclusive worldwide rights to the product. Humira is the first human monoclonal antibody approved for therapeutic use in both the US and Europe.
At the time of this review, TNF antagonists have been given to 500,000 or more patients with RA with improvement in a majority of those treated. In addition to RA, the list of diseases that respond to these agents is rapidly gowing. These include other autoimmune diseases, JRA, granulomatous dieases (sarcoid), uveitis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn’s disease, and others. Not all of these are FDA approved for all TNF antagonists, but efforts to expand the list of approved diseases continue.
—Robert B. Buckingham, M.D.