TNF ALPHA/IL1B MONOCLONAL ANTIBODY MICROSPHERE--LETHAL GRAM NEGATIVE PERITONITIS

SPID #: 18

SPID#: 18 Sepsis due to gram negative and gram positive bacteria is a significant clinical problem despite the advent of antibiotics. Even with effective antibiotic treatment, septic shock continues to be responsible for approximately 400,000 deaths per year in the United States alone. Hallmark complications of septic shock include cardiovascular collapse, increased vascular permeability, pulmonary dysfunction, fever, and alterations in lipoprotein lipase activity characterized by a wasting syndrome. The exact molecular events leading to the progression of sepsis are not clearly understood. However, recent studies have observed that the host response to the invading pathogen contributes to the pathogenesis of sepsis. The cytokines tumor necrosis factor alpha (TNFa) and interleukin-1 beta (1L-1B) have been implicated as principle immune modulators released from activated macrophages during experimental endotoxin shock. To date, the two primary models used in the majority of sepsis studies are either rats/mice or monkeys. The use of monoclonal antibodies (MoAb) against TNFa, given within minutes of an intravenous septic challenge, have been shown to be beneficial in reducing mortality of septic shock in nonhuman primates. However, there is no experimental data in nonhuman primates with septic shock using an infection model such as peritonitis, and clinical trials with monoclonal antibodies in humans with septic shock have been less effective than suggested by studies in the IV animal model. These studies, therefore, were initiated to establish a model of lethal, gram negative sepsis in the rhesus monkey by intraperitoneal inoculation of E. coli. Once established, this model will be used to evaluate the effect of various treatment regimens on blood levels of various cytokines (specifically TNFa and IL-1B), and on their ability to prevent death. The initial treatment to be evaluated will be the use of intravenous microencapsulated monoclonal antibodies to TNFa and IL-1B. Since the microcapsules will be targeted to monocytes/macrophages, a major source of the cytokines, it is believed that microencapsulation of the monoclonal antibodies will result in a much more effective treatment. Specific aims of these initial studies include (1) an assessment of the safety and toxicity of microcapsules administered intravenously; (2) a determination of the minimal effective in vivo dose of microencapsulated cytokine MoAb necessary to sufficiently blunt in vitro endotoxin stimulated cytokine release; (3) an assessment of the ability of microencapsulated cytokine MoAb to blunt in vivo cytokine production; and (4) a determination of the effectiveness of intravenous microencapsulated cytokine MoAb in preventing death following an intraperitoneal E. coli challenge in the rhesus monkey model.