Update on D2E7: a fully human anti-tumour necrosis factor alpha monoclonal antibody.

Rheumatoid arthritis (RA) is characterised by persistent joint inflammation and concomitant joint destruction, and in severe cases with extra-articular manifestations, multiple joint involvement, and a significant reduction in life expectancy. In addition, functional decline and disability inevitably accompanies joint destruction. The extent to which most standard medical approaches have a positive impact on the course of rheumatoid disease is the subject of debate. Intense research eVort has focused on understanding cellular inflammatory mechanisms that may serve as therapeutic targets. Tumour necrosis factor á (TNFá) is a pleiotropic cytokine overproduced in rheumatoid joints primarily by macrophages. Although the causes of RA are not fully understood, TNFá seems to play a cardinal part in a variety of events in inflammatory synovitis and articular matrix degradation, and is therefore a prime target for directed immunotherapy in RA. 5 Accordingly, antibodies and soluble TNF receptors that bind TNFá with high specificity neutralise its activity and have been developed for use as therapeutic agents. However, current anti-TNFá treatments for RA may be limited by their capacity to elicit immune responses to their non-human elements or artificially fused human sequences. The high specificity neutralisation potency of a previously perfected murine monoclonal antibody was transferred to a fully human IgG1 antibody format (D2E7). D2E7, a high aYnity, recombinant, fully human anti-TNFá has no non-human or artificially fused human sequences. Therefore, D2E7 may have low immunogenicity and possibly greater therapeutic potential. D2E7 eVectively neutralised a broad range of TNF biological activities both in vitro and in vivo. For example, D2E7 inhibited binding of human TNFá to its p55 and p75 receptors on human cells and is highly selective for TNFá. It prevented severe polyarthritis in human TNFá expressing transgenic mice in a dose dependent manner and is currently being evaluated in clinical trials to treat RA.