title: TLR4/MD-2 monoclonal antibody therapy affords protection in experimental models of septic shock.
abstract: 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 mug) 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.
authors.affiliation: NovImmune SA, Geneva, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Daubeuf
authors.forename: John
authors.initials: J
authors.lastname: Mathison
authors.forename: Stephan
authors.initials: S
authors.lastname: Spiller
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hugues
authors.forename: Suzanne
authors.initials: S
authors.lastname: Herren
authors.forename: Walter
authors.initials: W
authors.lastname: Ferlin
authors.forename: Marie
authors.initials: M
authors.lastname: Kosco-Vilbois
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
authors.forename: Richard
authors.initials: R
authors.lastname: Ulevitch
authors.forename: Greg
authors.initials: G
authors.lastname: Elson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D006801:Humans; D007167:Immunotherapy; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051218:Lymphocyte Antigen 96; D051379:Mice; D012772:Shock, Septic / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D015996:Survival Rate; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D008024:Ligands; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4