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Determination of the safety and efficacy of therapeutic neutralization of tumor necrosis factor-α (TNF-α) using AZD9773, an anti-TNF-α immune Fab, in murine CLP sepsis.
- Source :
-
Inflammation research : official journal of the European Histamine Research Society ... [et al.] [Inflamm Res] 2014 Feb; Vol. 63 (2), pp. 149-60. Date of Electronic Publication: 2013 Nov 17. - Publication Year :
- 2014
-
Abstract
- Objective and Design: TNF-α neutralization is associated with increased mortality in mouse cecal ligation puncture (CLP) models. AZD9773 is an ovine polyclonal human TNF-α immune Fab, with pharmacological properties that differ from previously studied anti-TNF-α agents. We explored the safety and efficacy of therapeutically administered AZD9773 in mouse CLP sepsis.<br />Methods: A moderate/severe-grade CLP model resulting in 20-30 % 5-day survival and a mild-grade CLP model resulting in ~70 % 5-day survival were established in human TNF-α transgene/murine TNF null (Tg1278/-/-) mice.<br />Treatment: Mice received saline resuscitation and imipenem administration every 12 h (0-72 h post-CLP). AZD9773 (or DigiFab control) was dosed 24, 36, 48 and 60 h post-CLP.<br />Results: Therapeutic dosing of AZD9773 in moderate/severe-grade CLP resulted in significantly increased survival (>70 %) compared with DigiFab (27 %, P < 0.05). Therapeutic dosing of AZD9773 in mild-grade CLP did not significantly affect survival outcome compared with DigiFab or imipenem alone (~60-70 % survival).<br />Conclusions: These data demonstrate that TNF-α neutralization can improve survival in moderate/severe CLP sepsis. TNF-α suppression in mild-grade models was not associated with survival benefit and did not increase 5-day mortality. These findings suggest that therapeutic benefit following TNF-α attenuation in models of sepsis may depend on model severity.
- Subjects :
- Animals
Cecum injuries
Cecum surgery
Cytokines blood
Immunoglobulin Fab Fragments blood
Immunoglobulin Fab Fragments pharmacology
Ligation
Lipopolysaccharides
Liver drug effects
Liver pathology
Male
Mice
Mice, Transgenic
Sepsis blood
Sepsis immunology
Tumor Necrosis Factor-alpha blood
Tumor Necrosis Factor-alpha genetics
Tumor Necrosis Factor-alpha immunology
Immunoglobulin Fab Fragments therapeutic use
Sepsis drug therapy
Tumor Necrosis Factor-alpha antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1420-908X
- Volume :
- 63
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Inflammation research : official journal of the European Histamine Research Society ... [et al.]
- Publication Type :
- Academic Journal
- Accession number :
- 24240228
- Full Text :
- https://doi.org/10.1007/s00011-013-0683-3