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TLR4/MD-2 Monoclonal Antibody Therapy Affords Protection in Experimental Models of Septic Shock

Bruno Daubeuf^*, John Mathison, Stephan Spiller^1,, Stephanie Hugues, Suzanne Herren^*, Walter Ferlin^*, Marie Kosco-Vilbois^*, Hermann Wagner, Carsten J. Kirschning^1,, Richard Ulevitch and Greg Elson^2,*

^* NovImmune SA, Geneva, Switzerland; Department of Immunology, IMM-12, Scripps Research Institute, La Jolla, CA 92037; Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany; and Institut National de la Santé et de la Recherche Médicale U365, Institut Curie, rue d’Ulm, Paris, France

Overactivation of the immune system upon acute bacterial infection leads to septic shock. Specific bacterial products potently stimulate immune cells via toll-like receptors (TLRs). Gram-negative bacteria induce a predominantly TLR4-driven signal through LPS release. To neutralize LPS signaling in experimental models of sepsis, we generated mAbs toward the TLR4/myeloid differentiation protein-2 (MD-2) complex. The binding properties of an array of selected rat mAbs differed in respect to their specificity for TLR4/MD-2 complex. The specificity of one such mAb, 5E3, to murine TLR4 was confirmed by its recognition of an epitope within the second quarter of the ectodomain. 5E3 inhibited LPS-dependent cell activation in vitro and prevented proinflammatory cytokine production in vivo following LPS challenge in a dose-dependent manner. Furthermore, 5E3 protected mice from lethal shock-like syndrome when applied using both preventative and therapeutic protocols. Most notably, in the colon ascendens stent peritonitis model of polymicrobial abdominal sepsis, administration of a single dose of 5E3 (50 µg) protected mice against mortality. These results demonstrate that neutralizing TLR4/MD-2 is highly efficacious in protecting against bacterial infection-induced toxemia and offers TLR4/MD-2 mAb treatment as a potential therapy for numerous clinical indications.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ S.S. and C.J.K. are supported by German Research Foundation Grant SFB/TR-22-A5.

² Address correspondence and reprint requests to Dr. Greg Elson, NovImmune SA, 14, Chemin des Aulx, Plan-les-Ouates, Switzerland. E-mail address: gelson{at}novimmune.com

³ Abbreviations used in this paper: PAMP, pathogen-associated molecular pattern; MD-2, myeloid differentiation protein-2; CASP, colon ascendens stent peritonitis; PRR, pattern recognition receptor; LBP, LPS-binding protein; CBA, cytometric bead array.

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