Preclinical review of anti-tumor necrosis factor monoclonal antibodies

Abstract

To review the preclinical evidence for the role of tumor necrosis factor (TNF) in the pathogenesis of septic shock and to assess the preclinical efficacy of anti-TNF therapies for this clinical problem. The international English language literature from 1986 to the present formed the basis of this review. MEDLINE was used to identify pertinent in vitro and animal studies pertaining to the pathobiology of TNF and the use of anti-TNF therapies, with special emphasis on antibody approaches. Those studies that focused on the mechanisms of action of TNF, its role in the inflammatory cascade, and the potential uses of anti-TNF therapies were emphasized. Investigations that described animal and human results served as the primary database. Animal studies were selected based on the relevance of the model to the pathogenesis of the human clinical sepsis syndrome. Where they provided supportive evidence, patient studies were selected on the basis of study design. The administration of anti-TNF antibodies in baboons, monkeys, and other species that were administered lethal doses of bacteria or endotoxin suggest that this approach may limit organ damage and decrease the mortality rate caused by the septic shock syndrome. Therapy with anti-TNF monoclonal antibodies is reviewed. Bacterial challenge induces the release of TNF (among other mediators), which exerts both physiologic and toxic effects that may ultimately lead to organ dysfunction and death. New anti-TNF therapies such as anti-TNF antibodies appear to attenuate the injurious effects of TNF and promote survival in otherwise lethal septic shock animal models, suggesting a similar benefit might be obtained in the treatment of human septic shock.