title: Pivotal involvement of Fcgamma receptor IIA in the neutralization of lipopolysaccharide signaling via a potent novel anti-TLR4 monoclonal antibody 15C1.
abstract: The mammalian Toll-like receptor (TLR) family has evolved to sense pathogens in the environment and protect the host against infection. TLR4 recognizes lipopolysaccharide (LPS) from Gram-negative bacteria and induces a signaling cascade that, when exaggerated, has been associated with severe sepsis. We have generated a TLR4-specific monoclonal antibody, 15C1, which neutralizes LPS-induced TLR4 activation in a dose-dependent manner. 15C1 potently blocks the effects of LPS on a panel of primary cells and cell lines in vitro. The binding of 15C1 was mapped to an epitope in the second portion of the extracellular region of TLR4, which has been shown previously to be functionally important in the recognition of LPS. Furthermore, we demonstrate a novel mechanism of inhibition, as the effects of 15C1 are partially Fc-dependent, involving the regulatory Fcgamma receptor IIA (CD32A). In addition to introducing 15C1 as a potent clinical candidate for use in the treatment of LPS-mediated indications, our work demonstrates a newly discovered pathway whose manipulation is pivotal in achieving optimal neutralizing benefit.
authors.affiliation: NovImmune SA, 1228 Plan-les-Ouates, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Dunn-Siegrist
authors.forename: Olivier
authors.initials: O
authors.lastname: Leger
authors.forename: Bruno
authors.initials: B
authors.lastname: Daubeuf
authors.forename: Yves
authors.initials: Y
authors.lastname: Poitevin
authors.forename: Fabien
authors.initials: F
authors.lastname: Dépis
authors.forename: Suzanne
authors.initials: S
authors.lastname: Herren
authors.forename: Marie
authors.initials: M
authors.lastname: Kosco-Vilbois
authors.forename: Yann
authors.initials: Y
authors.lastname: Dean
authors.forename: Jérôme
authors.initials: J
authors.lastname: Pugin
authors.forename: Greg
authors.initials: G
authors.lastname: Elson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D015703:Antigens, CD / Q000096:biosynthesis / Q000737:chemistry*; D002460:Cell Line; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000096:biosynthesis / Q000737:chemistry*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000939:Epitopes; C080568:Fc gamma receptor IIA; D008070:Lipopolysaccharides; D017452:Receptors, IgG; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4