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The systemic inflammatory response to infection, which is initiated by activated myeloid cells, plays a key role in the lethal outcome. Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory mediator, released by myeloid cells, that underlies a common genetic susceptibility to different infections and septic shock. Accordingly, strategies that are aimed at inhibiting the action of MIF have therapeutic potential. Here, we report the isolation and characterization of tailorable, small, affinity\u2010matured nanobodies (Nbs; single\u2010domain antigen\u2010binding fragments derived from camelid heavy\u2010chain Abs) directed against MIF. Of importance, these bioengineered Nbs bind both human and mouse MIFs with nanomolar affinity. NbE5 and NbE10 inhibit key MIF functions that can exacerbate septic shock, such as the tautomerase activity of MIF (by blocking catalytic pocket residues that are critical for MIF's conformation and receptor binding), the TNF\u2010inducing potential, and the ability of MIF to antagonize glucocorticoid action. A lead NbE10, tailored to be a multivalent, half\u2010life extended construct (NbE10\u2010NbAlb8\u2010NbE10), attenuated lethality in murine endotoxemia when administered\n                    <jats:italic>via<\/jats:italic>\n                    single injection, either prophylactically or therapeutically. Hence, Nbs, with their structural and pharmacologic advantages over currently available inhibitors, may be an effective, novel approach to interfere with the action of MIF in septic shock and other conditions of inflammatory endorgan damage.\u2014Sparkes, A., De Baetselier, P., Brys, L., Cabrito, I., Sterckx, Y. G.\u2010J., Schoonooghe, S., Muyldermans, S., Raes, G., Bucala, R., Vanlandschoot, P., Van Ginderachter, J. A., Stijlemans, B. Novel half\u2010life extended anti\u2010MIF nanobodies protect against endotoxic shock. FASEB J. 32, 3411\u20133422 (2018).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201701189r","type":"journal-article","created":{"date-parts":[[2018,1,25]],"date-time":"2018-01-25T13:56:57Z","timestamp":1516888617000},"page":"3411-3422","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Novel half\u2010life extended anti\u2010MIF nanobodies protect against endotoxic shock"],"prefix":"10.1096","volume":"32","author":[{"given":"Amanda","family":"Sparkes","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology Vrije Universiteit Brussels  Brussels Belgium"},{"name":"Myeloid Cell Immunology Laboratory Flanders Institute for Biotechnology (VIB) Center for Inflammation Research  Brussels 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