Novel half-life extended anti-MIF nanobodies protect against endotoxic shock

What is it about?

Macrophage migration inhibitory factor (MIF) is a key player in many inflammatory diseases and septic shock in particular. Given its involvement in mechanisms underlying sepsis and septic shock, MIF represents an attractive therapeutic target for treatment of these pathologies. Though different strategies aimed at inhibiting MIF's action have been documented such as small molecule inhibitors (i.e. ISO-1), monoclonal antibodies (mAbs) against MIF or DNA-based MIF vaccination strategies, these approaches require either repetitive dosing due to the rapid clearance of the molecules or large amounts of humanized Abs, which could generate undesirable local and systemic side-reactions. Therefore, we investigated the use of Nanobodies® (Nbs), which are single-domain antigen-binding fragments (~15kDa) derived from camelid heavy-chain antibodies, as a new approach to block MIF-mediated biological effects. We report herein the isolation and characterization of tailorable, small, affinity-matured Nbs that exhibit cross-reactivity towards mouse and human MIF with nanomolar affinity. Two Nbs (NbE5 and NbE10) inhibit key MIF functions that can exacerbate septic shock, such as MIF's tautomerase activity, MIF's TNF-inducing potential and MIF's ability to antagonize glucocorticoid action. We further designed half-life extended, multivalent constructs of the lead inhibitory candidate (NbE10) that in an in vivo murine model attenuated lethal endotoxemia. Collectively, our results demonstrate that Nbs with their structural and pharmacologic advantages over currently available inhibitors may be an effective novel approach to interfere with MIF's action in septic shock and other conditions of inflammatory end-organ damage.

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