Characterization, epitope identification and mechanisms of the anti-septic capacity of monoclonal antibodies against macrophage migration inhibitory factor

Abstract

Sepsis is characterized by uncontrolled inflammatory responses. Macrophage migration inhibitory factor (MIF) has been shown to play an important role in the progression of sepsis thus is a potential therapeutic target. The aim of this study is to produce IgG anti-MIF monoclonal antibodies (mAbs) with anti-septic abilities in vivo and to determine mechanisms of their function. We generated 8 IgG anti-MIF mAbs with high specificity and 3 of them showed potent protective abilities in murine lethal peritonitis induced by cecal ligation and puncture (CLP). One anti-MIF mAb, F11, showed 100% protection within 72 h after sepsis induction and 72% mice treated with this mAb survived up to 84 h with reduced lung and kidney pathology. F11 treatment also reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels in septic mice. We further found that all 8 anti-MIF mAbs recognized the same epitope located in the amino acid residue 1-20 region of the N terminus of the MIF protein. Three of the mAbs, F11 in particular, inhibited tautomerase activity in association with their protective effect on CLP mice. Thus, we have produced anti-MIF mAbs that protected mice from CLP-induced sepsis by recognizing the same epitope domains in MIF. These mAbs are promising candidates for further development of therapeutics against inflammatory diseases.