PROTECTION AGAINST LETHAL ESCHERICHIA-COLI BACTEREMIA IN BABOONS (PAPIO-ANUBIS) BY PRETREATMENT WITH A 55-KDA TNF RECEPTOR (CD120A)-IG FUSION PROTEIN, RO-45-2081

Fusion proteins of the human 55-kDa TNF receptor extracellular domain with hinge and C2/C3 constant domains of human IgG1 or lgG3 heavy chai ns were tested in a primate sepsis model. Twenty-four baboons received 4.6, 1.0, or 0.2 mg/kg of TNFR5-G(1,3), or placebo, before the admini stration of a lethal dose of live Escherichia coli, Treatment with TNF R5-G(1,3), decreased 5-day mortality from 88% in the placebo group to 12% in the TNFR5-G(1,3)-treated animals (p < 0.01 by Fisher's exact te st). Treatments with TNFR5-G(1) and TNFR5-G(3) in doses from 0.2 to 4. 6 mg/kg were efficacious. Free plasma TNF was neutralized by all treat ments, but inactive TNF/TNFR5-G(1,3) complexes remained in circulation for prolonged periods. TNFR5-G(1,3) treatments attenuated the hemodyn amic disturbances, reduced fluid requirements, and decreased the syste mic IL-1 beta, IL-6, and IL-8 responses. In addition, TNFR5-G(1,3) tre atment shortened the granulocytopenia and reduced the loss of cellular TNF receptors from granulocytes. The decrease in fibrinogen concentra tions and increase in prothrombin and partial thromboplastin times wer e significantly attenuated by TNFR5-G(1,3) treatment. TNFR5-G(1,3) tre atment markedly attenuated the rise in plasma lactate concentration. H istologic studies of TNFR5-G(1,3) revealed dose-dependent protection a gainst tissue injury by Escherichia coli administration.