Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3006-11. doi: 10.1073/pnas.1520175113. Epub 2016 Mar 2.

Cell-type-restricted anti-cytokine therapy: TNF inhibition from one pathogenic source.

Author information

1
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;
2
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;
3
Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia;
4
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;
5
Laboratory of Experimental Immunology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia;
6
Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany;
7
Institute of Biochemistry and Molecular Biology II, Medical-Faculty, Heinrich-Heine-University, 40225 Duesseldorf, Germany;
8
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RF, United Kingdom;
9
School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom;
10
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.
11
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.

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.

KEYWORDS:

TNF; anti-cytokine therapy; autoimmunity; bispecific antibody; humanized mice

PMID:
26936954
PMCID:
PMC4801281
DOI:
10.1073/pnas.1520175113
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Secondary source ID

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center