Anti-TNF therapy: past, present and future

Abstract

While for a century therapeutics has been dominated by small molecules, i.e. organic chemicals of ~400Da absorbable via the gut, this is no longer the case. There are now a plethora of important medicines which are proteins and injectable, which have dramatically improved the therapy of many inflammatory diseases and of cancer. Most of these are monoclonal antibodies, some are receptor Ig Fc fusion proteins, others are cytokines or enzymes. The key to this new aspect of therapeutics has been the filling of unmet needs, and the consequent commercial success, which promoted further research and development. The first 'biologic' for a common disease, rheumatoid arthritis (RA), was a monoclonal antibody, infliximab, to human tumour necrosis factor (TNF). This was based on our work, which is described in this review, summarizing how TNF was defined as a good target in RA, how it was developed is described here, as well as future indications for anti-TNF and related agents. Biologics are now the fastest growing sector of therapeutics.

Keywords: anti-cytokine therapy; atherosclerosis; fibrosis; fractures; rheumatoid arthritis.

Fig. 1.

1983: a new hypothesis for autoimmunity (e.g. Graves’ disease).

Fig. 2.

The importance of TNF for IL-1 production in RA, revealed by analysis of cytokine regulation in the presence of anti-TNF or anti-lymphotoxin in vitro (12).

Fig. 3.

Mechanism of action of infliximab. The TNF-dependent cytokine cascade is inhibited (‘cytokine washout’) in vivo after administration of infliximab (1 or 10mg kg⁻¹) to patients with RA (21).

Fig. 4.

How cytokine washout by infliximab is translated into clinical benefit (6, 11, 12, 17, 18, 20, 22). Abbreviations: CCP, cyclic citrullinated peptide; MMPs, matrix metalloproteins; RF, rheumatoid factor; XR, X-ray radiography.

Fig. 5.

Mechanism of action of infliximab. There is reduced polymorphonuclear-leucocyte trafficking after infliximab therapy in patients with RA (22).