Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin.
Tumor necrosis factors (TNF) alpha and beta are structurally related cytokines that mediate a wide range of immunological, inflammatory, and cytotoxic effects. During bacterial infection of the bloodstream (sepsis), TNF-alpha induction by bacterial endotoxin is thought to be a major factor contributing to the cardiovascular collapse and critical organ failure that can develop. Despite antibiotic therapy, these consequences of sepsis continue to have a high mortality rate in humans. Here we describe a potent TNF antagonist, a TNF receptor (TNFR) immunoadhesin, constructed by gene fusion of the extracellular portion of human type 1 TNFR with the constant domains of human IgG heavy chain (TNFR-IgG). When expressed in transfected human cells, TNFR-IgG is secreted as a disulfide-bonded homodimer. Purified TNFR-IgG binds to both TNF-alpha and TNF-beta and exhibits 6- to 8-fold higher affinity for TNF-alpha than cell surface or soluble TNF receptors. In vitro, TNFR-IgG blocks completely the cytolytic effect of TNF-alpha or TNF-beta on actinomycin D-treated cells and is markedly more efficient than soluble TNFR (24-fold) or monoclonal anti-TNF-alpha antibodies (4-fold) in inhibiting TNF-alpha. In vitro, TNFR-IgG prevents endotoxin-induced lethality in mice when given 0.5 hr prior to endotoxin and provides significant protection when given up to 1 hr after endotoxin challenge. These results confirm the importance of TNF-alpha in the pathogenesis of septic shock and suggest a clinical potential for TNFR-IgG as a preventive and therapeutic treatment in sepsis.
Ashkenazi
A
A
Department of Immunobiology, Genentech, Inc., South San Francisco, CA 94080.
Marsters
S A
SA
Capon
D J
DJ
Chamow
S M
SM
Figari
I S
IS
Pennica
D
D
Goeddel
D V
DV
Palladino
M A
MA
Smith
D H
DH
D000818:Animals; D000911:Antibodies, Monoclonal; D002470:Cell Survival / Q000187:drug effects; D002678:Chimera; D002872:Chromosome Deletion; D003001:Cloning, Molecular; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D007700:Kinetics; D007739:L Cells; D008233:Lymphotoxin-alpha / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D018124:Receptors, Tumor Necrosis Factor; D015183:Restriction Mapping; D012481:Salmonella Infections, Animal / Q000276:immunology / Q000517:prevention & control; D012772:Shock, Septic / Q000276:immunology / Q000517:prevention & control*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D008233:Lymphotoxin-alpha; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin