Monoclonal antibody therapy for gram-negative sepsis: principles, applications, and controversies

Gram-negative sepsis is a common event in hospitalized patients and is a leading cause of death in the United States. Endotoxin (lipopolysaccharide, LPS), a component of the cell wall of gram-negative microorganisms, is responsible for the cascade of events leading to the sepsis syndrome consisting of fever, tachycardia, tachypnea, and evidence of organ hypoperfusion. The lipid A region of endotoxin produces most of these biologic and toxic effects. Monoclonal IgM antibodies directed against the lipid A portion of endotoxin (anti-LPS MoAb) have been developed for the treatment of gram-negative sepsis. Results of two large-scale clinical trials suggest that these antibodies offer clinically and statistically significant reductions in mortality by a factor of about one-third. However, in both trials, this apparent beneficial effect was limited to particular subsets of patients, and no overall benefit was seen. These considerations, in addition to the likely high cost of the agents, pose questions about their ultimate use in the treatment of patients with gram-negative sepsis. Nevertheless, the logic of the approach, the demonstration of efficacy in disease models, and the advances in modern techniques of molecular biology all suggest that these or other closely related products will play a significant role in the treatment of this disorder.