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Novel half-life extended anti-MIF nanobodies protect against endotoxic shock. / Sparkes, Amanda; De Baetselier, Patrick; Brys, Lea; Cabrito, Inês; Sterckx, Yann G-J; Schoonooghe, Steve; Muyldermans, Serge; Raes, Geert; Bucala, Richard; Vanlandschoot, Peter; Van Ginderachter, Jo A; Stijlemans, Benoît.

In: The FASEB Journal, Vol. 32, No. 6, 06.2018, p. 3411-3422.

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Sparkes, Amanda ; De Baetselier, Patrick ; Brys, Lea ; Cabrito, Inês ; Sterckx, Yann G-J ; Schoonooghe, Steve ; Muyldermans, Serge ; Raes, Geert ; Bucala, Richard ; Vanlandschoot, Peter ; Van Ginderachter, Jo A ; Stijlemans, Benoît. / Novel half-life extended anti-MIF nanobodies protect against endotoxic shock. In: The FASEB Journal. 2018 ; Vol. 32, No. 6. pp. 3411-3422.

BibTeX

@article{f7d7898cd6e546f0b76f3c3d7c5a51d8,
title = "Novel half-life extended anti-MIF nanobodies protect against endotoxic shock",
abstract = "Sepsis-leading to septic shock-is the leading cause of death in intensive care units. 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-matured nanobodies (Nbs; single-domain antigen-binding fragments derived from camelid heavy-chain 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-inducing potential, and the ability of MIF to antagonize glucocorticoid action. A lead NbE10, tailored to be a multivalent, half-life extended construct (NbE10-NbAlb8-NbE10), attenuated lethality in murine endotoxemia when administered via 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 end-organ damage.-Sparkes, A., De Baetselier, P., Brys, L., Cabrito, I., Sterckx, Y. G.-J., Schoonooghe, S., Muyldermans, S., Raes, G., Bucala, R., Vanlandschoot, P., Van Ginderachter, J. A., Stijlemans, B. Novel half-life extended anti-MIF nanobodies protect against endotoxic shock.",
keywords = "LPS, MIF antagonist, Nbs",
author = "Amanda Sparkes and {De Baetselier}, Patrick and Lea Brys and In{\^e}s Cabrito and Sterckx, {Yann G-J} and Steve Schoonooghe and Serge Muyldermans and Geert Raes and Richard Bucala and Peter Vanlandschoot and {Van Ginderachter}, {Jo A} and Beno{\^i}t Stijlemans",
year = "2018",
month = "6",
doi = "10.1096/fj.201701189R",
language = "English",
volume = "32",
pages = "3411--3422",
journal = "The FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "6",

}

RIS

TY - JOUR

T1 - Novel half-life extended anti-MIF nanobodies protect against endotoxic shock

AU - Sparkes, Amanda

AU - De Baetselier, Patrick

AU - Brys, Lea

AU - Cabrito, Inês

AU - Sterckx, Yann G-J

AU - Schoonooghe, Steve

AU - Muyldermans, Serge

AU - Raes, Geert

AU - Bucala, Richard

AU - Vanlandschoot, Peter

AU - Van Ginderachter, Jo A

AU - Stijlemans, Benoît

PY - 2018/6

Y1 - 2018/6

N2 - Sepsis-leading to septic shock-is the leading cause of death in intensive care units. 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-matured nanobodies (Nbs; single-domain antigen-binding fragments derived from camelid heavy-chain 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-inducing potential, and the ability of MIF to antagonize glucocorticoid action. A lead NbE10, tailored to be a multivalent, half-life extended construct (NbE10-NbAlb8-NbE10), attenuated lethality in murine endotoxemia when administered via 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 end-organ damage.-Sparkes, A., De Baetselier, P., Brys, L., Cabrito, I., Sterckx, Y. G.-J., Schoonooghe, S., Muyldermans, S., Raes, G., Bucala, R., Vanlandschoot, P., Van Ginderachter, J. A., Stijlemans, B. Novel half-life extended anti-MIF nanobodies protect against endotoxic shock.

AB - Sepsis-leading to septic shock-is the leading cause of death in intensive care units. 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-matured nanobodies (Nbs; single-domain antigen-binding fragments derived from camelid heavy-chain 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-inducing potential, and the ability of MIF to antagonize glucocorticoid action. A lead NbE10, tailored to be a multivalent, half-life extended construct (NbE10-NbAlb8-NbE10), attenuated lethality in murine endotoxemia when administered via 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 end-organ damage.-Sparkes, A., De Baetselier, P., Brys, L., Cabrito, I., Sterckx, Y. G.-J., Schoonooghe, S., Muyldermans, S., Raes, G., Bucala, R., Vanlandschoot, P., Van Ginderachter, J. A., Stijlemans, B. Novel half-life extended anti-MIF nanobodies protect against endotoxic shock.

KW - LPS

KW - MIF antagonist

KW - Nbs

UR - http://www.scopus.com/inward/record.url?scp=85049216661&partnerID=8YFLogxK

U2 - 10.1096/fj.201701189R

DO - 10.1096/fj.201701189R

M3 - Article

VL - 32

SP - 3411

EP - 3422

JO - The FASEB Journal

JF - The FASEB Journal

SN - 0892-6638

IS - 6

ER -

ID: 39893843