title: Selective antibody intervention of Toll-like receptor 4 activation through Fc γ receptor tethering.
abstract: Inflammation is mediated mainly by leukocytes that express both Toll-like receptor 4 (TLR4) and Fc γ receptors (FcγR). Dysregulated activation of leukocytes via exogenous and endogenous ligands of TLR4 results in a large number of inflammatory disorders that underlie a variety of human diseases. Thus, differentially blocking inflammatory cells while sparing structural cells, which are FcγR-negative, represents an elegant strategy when targeting the underlying causes of human diseases. Here, we report a novel tethering mechanism of the Fv and Fc portions of anti-TLR4 blocking antibodies that achieves increased potency on inflammatory cells. In the presence of ligand (e.g. lipopolysaccharide (LPS)), TLR4 traffics into glycolipoprotein microdomains, forming concentrated protein platforms that include FcγRs. This clustering produces a microenvironment allowing anti-TLR4 antibodies to co-engage TLR4 and FcγRs, increasing their avidity and thus substantially increasing their inhibitory potency. Tethering of antibodies to both TLR4 and FcγRs proves valuable in ameliorating inflammation in vivo. This novel mechanism of action therefore has the potential to enable selective intervention of relevant cell types in TLR4-driven diseases.
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland, lshang@novimmune.com.
authors.forename: Limin
authors.initials: L
authors.lastname: Shang
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Daubeuf
authors.affiliation: the Cardiff University School of Medicine, Department of Child Health, University Hospital of Wales, Cardiff, United Kingdom.
authors.forename: Martha
authors.initials: M
authors.lastname: Triantafilou
authors.affiliation: the Cardiff University School of Medicine, Department of Child Health, University Hospital of Wales, Cardiff, United Kingdom.
authors.forename: Robin
authors.initials: R
authors.lastname: Olden
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Fabien
authors.initials: F
authors.lastname: Dépis
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Raby
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Herren
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Anaelle
authors.initials: A
authors.lastname: Dos Santos
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Pauline
authors.initials: P
authors.lastname: Malinge
authors.affiliation: the University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Dunn-Siegrist
authors.affiliation: INSERM UMR 699, Faculté de Médecine Paris Diderot, Site Xavier Bichat, 16 Rue Henri Huchard, Paris 75018 Cedex 18, France, and.
authors.forename: Sanae
authors.initials: S
authors.lastname: Benmkaddem
authors.affiliation: the Department of Pathology and Immunology, University of Geneva Medical School, Geneva 1211, Switzerland.
authors.forename: Antoine
authors.initials: A
authors.lastname: Geinoz
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Magistrelli
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Buatois
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Susana
authors.initials: S
authors.lastname: Salgado-Pires
authors.affiliation: the Department of Pathology and Immunology, University of Geneva Medical School, Geneva 1211, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
authors.affiliation: INSERM UMR 699, Faculté de Médecine Paris Diderot, Site Xavier Bichat, 16 Rue Henri Huchard, Paris 75018 Cedex 18, France, and.
authors.forename: Renato
authors.initials: R
authors.lastname: Monteiro
authors.affiliation: the University Hospitals of Geneva, 1211 Geneva, Switzerland.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Pugin
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Leger
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Ferlin
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Marie
authors.initials: M
authors.lastname: Kosco-Vilbois
authors.affiliation: the Cardiff University School of Medicine, Department of Child Health, University Hospital of Wales, Cardiff, United Kingdom.
authors.forename: Kathy
authors.initials: K
authors.lastname: Triantafilou
authors.affiliation: From the NovImmune SA, 14 Chemin des Aulx, 1228 Plan les Ouates, Switzerland.
authors.forename: Greg
authors.initials: G
authors.lastname: Elson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001665:Binding Sites; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D019281:Dimerization; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D021962:Membrane Microdomains / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000911:Antibodies, Monoclonal; D017452:Receptors, IgG; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: Fc gamma Receptor; Inflammation; Lipid Raft; Monoclonal Antibody; Toll-like Receptor (TLR); Toll-like Receptor 4; antibody
references.citation: Immunity. 2010 Apr 23;32(4):518-30
references.pmid: 20362473
references.citation: Nat Rev Immunol. 2008 Jan;8(1):34-47
references.pmid: 18064051
references.citation: Nature. 2009 Apr 30;458(7242):1191-5
references.pmid: 19252480
references.citation: Nat Immunol. 2010 Sep;11(9):814-9
references.pmid: 20711192
references.citation: Pharmacol Rev. 2009 Jun;61(2):177-97
references.pmid: 19474110
references.citation: Nat Clin Pract Rheumatol. 2007 Jul;3(7):382-90
references.pmid: 17599072
references.citation: J Exp Med. 1999 Jun 7;189(11):1777-82
references.pmid: 10359581
references.citation: Blood. 2012 Jun 14;119(24):5640-9
references.pmid: 22535666
references.citation: J Biol Chem. 2001 Mar 2;276(9):6591-604
references.pmid: 11096108
references.citation: Science. 2011 Aug 19;333(6045):1030-4
references.pmid: 21852502
references.citation: Sci Signal. 2011 Apr 19;4(169):ra24
references.pmid: 21505186
references.citation: J Immunol Methods. 2012 Jan 31;375(1-2):20-9
references.pmid: 21939661
references.citation: Annu Rev Biochem. 2007;76:141-65
references.pmid: 17362201
references.citation: Int Rev Immunol. 2011 Feb;30(1):16-34
references.pmid: 21235323
references.citation: J Biol Chem. 2007 Nov 30;282(48):34817-27
references.pmid: 17921137
references.citation: Immunol Rev. 2009 Nov;232(1):59-71
references.pmid: 19909356
references.citation: Biochem Biophys Res Commun. 2009 Oct 30;388(4):621-5
references.pmid: 19686699
references.citation: J Immunol. 2007 Nov 1;179(9):6107-14
references.pmid: 17947685
references.citation: Nat Immunol. 2010 May;11(5):373-84
references.pmid: 20404851
references.citation: MAbs. 2013 Sep-Oct;5(5):736-47
references.pmid: 23924795
references.citation: J Immunol. 2012 Apr 15;188(8):3584-93
references.pmid: 22427642
references.citation: Int Immunol. 2012 Aug;24(8):495-506
references.pmid: 22499954
references.citation: Immunol Lett. 2012 Mar 30;143(1):9-19
references.pmid: 22342996
references.citation: Cell Mol Life Sci. 2013 Oct;70(20):3847-69
references.pmid: 23430000
references.citation: Cell. 2004 Jul 23;118(2):229-41
references.pmid: 15260992
references.citation: Eur J Immunol. 2008 Jan;38(1):166-73
references.pmid: 18081038
references.citation: Eur J Immunol. 2001 Nov;31(11):3153-64
references.pmid: 11745332
references.citation: PLoS Pathog. 2009 Jun;5(6):e1000464
references.pmid: 19503602
references.citation: FEBS Lett. 2002 Dec 4;532(1-2):171-6
references.pmid: 12459484
references.citation: J Immunol. 2008 Jul 15;181(2):1245-54
references.pmid: 18606678
references.citation: J Innate Immun. 2010;2(3):204-15
references.pmid: 20375558
references.citation: Nature. 1997 Jul 24;388(6640):394-7
references.pmid: 9237759
references.citation: J Cell Sci. 2002 Jun 15;115(Pt 12):2603-11
references.pmid: 12045230
references.citation: J Biol Chem. 2009 Oct 2;284(40):27384-92
references.pmid: 19648648