title: Cell-type-restricted anti-cytokine therapy: TNF inhibition from one pathogenic source.
abstract: Overexpression of TNF contributes to pathogenesis of multiple autoimmune diseases, accounting for a remarkable success of anti-TNF therapy. TNF is produced by a variety of cell types, and it can play either a beneficial or a deleterious role. In particular, in autoimmunity pathogenic TNF may be derived from restricted cellular sources. In this study we evaluated the feasibility of cell-type-restricted TNF inhibition in vivo. To this end, we engineered MYSTI (Myeloid-Specific TNF Inhibitor)--a recombinant bispecific antibody that binds to the F4/80 surface molecule on myeloid cells and to human TNF (hTNF). In macrophage cultures derived from TNF humanized mice MYSTI could capture the secreted hTNF, limiting its bioavailability. Additionally, as evaluated in TNF humanized mice, MYSTI was superior to an otherwise analogous systemic TNF inhibitor in protecting mice from lethal LPS/D-Galactosamine-induced hepatotoxicity. Our results suggest a novel and more specific approach to inhibiting TNF in pathologies primarily driven by macrophage-derived TNF.
authors.affiliation: Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; Laboratory of Experimental Immunology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia;
authors.forename: Grigory A
authors.initials: GA
authors.lastname: Efimov
authors.affiliation: Laboratory of Experimental Immunology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia; Research Group Inflammation Biology, German Rheumatism Research Center, a Leibniz Institute, 10117 Berlin, Germany; Department of Immunology, Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 199991, Russia;
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Kruglov
authors.affiliation: Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia;
authors.forename: Zoya V
authors.initials: ZV
authors.lastname: Khlopchatnikova
authors.affiliation: Laboratory of Experimental Immunology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia; Department of Immunology, Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 199991, Russia;
authors.forename: Fedor N
authors.initials: FN
authors.lastname: Rozov
authors.affiliation: Laboratory of Experimental Immunology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia;
authors.forename: Vladislav V
authors.initials: VV
authors.lastname: Mokhonov
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical-Faculty, Heinrich-Heine-University, 40225 Duesseldorf, Germany;
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RF, United Kingdom;
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
authors.affiliation: School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom;
authors.forename: Martin
authors.initials: M
authors.lastname: Stacey
authors.affiliation: Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia;
authors.forename: Marina S
authors.initials: MS
authors.lastname: Drutskaya
authors.affiliation: Department of Immunology, Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 199991, Russia; Laboratory of Molecular Biotechnologies, Institute of Gene Biology, Russian Academy of Sciences, Moscow 119334, Russia.
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Tillib
authors.affiliation: Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; Laboratory of Experimental Immunology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia; Research Group Inflammation Biology, German Rheumatism Research Center, a Leibniz Institute, 10117 Berlin, Germany; Department of Immunology, Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 199991, Russia; sergei@nedos.net.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D018033:Antibodies, Bispecific / Q000235:genetics / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000276:immunology; D000918:Antibody Specificity; D000937:Antigen-Antibody Reactions; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology; D002162:Camelus / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005688:Galactosamine / Q000633:toxicity; D005813:Genes, Synthetic; D006801:Humans; D007739:L Cells; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018033:Antibodies, Bispecific; D057134:Antibodies, Neutralizing; D000943:Antigens, Differentiation; D000954:Antigens, Surface; D022801:Complementarity Determining Regions; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen; D005688:Galactosamine
keywords: TNF; anti-cytokine therapy; autoimmunity; bispecific antibody; humanized mice