• Peter Newham, Daniel Ross, Peter Ceuppens, Shampa Das, James W T Yates, Catherine Betts, Jaimini Reens, Kevin J Randall, Richard Knight, and Jennifer S McKay.
• Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK, peter.newham@astrazeneca.com.
• Inflamm. Res. 2014 Feb 1;63(2):149-60.

Objective And DesignTNF-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.MethodsA 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.TreatmentMice 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.ResultsTherapeutic 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).ConclusionsThese 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.

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