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.
OBJECTIVE
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.


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.


METHODS
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.


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).


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.
Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK, peter.newham@astrazeneca.com.
Peter
P
Newham
Daniel
D
Ross
Peter
P
Ceuppens
Shampa
S
Das
James W T
JW
Yates
Catherine
C
Betts
Jaimini
J
Reens
Kevin J
KJ
Randall
Richard
R
Knight
Jennifer S
JS
McKay
D000818:Animals; D002432:Cecum / Q000293:injuries / Q000601:surgery; D016207:Cytokines / Q000097:blood; D007140:Immunoglobulin Fab Fragments / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D008026:Ligation; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics / Q000276:immunology
C587873:AZD9773; D016207:Cytokines; D007140:Immunoglobulin Fab Fragments; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha