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

Abstract

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. 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. Mice received saline resuscitation and imipenem administration every 12h (0-72h post-CLP). AZD9773 (or DigiFab control) was dosed 24, 36, 48 and 60h post-CLP. 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). 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.