title: Development and Validation of a Small Single-domain Antibody That Effectively Inhibits Matrix Metalloproteinase 8.
abstract: A detrimental role for matrix metalloproteinase 8 (MMP8) has been identified in several pathological conditions, e.g., lethal hepatitis and the systemic inflammatory response syndrome. Since matrix MMP8-deficient mice are protected in the above-mentioned diseases, specific MMP8 inhibitors could be of clinical value. However, targeting a specific matrix metalloproteinase remains challenging due to the strong structural homology of matrix metalloproteinases, which form a family of 25 members in mammals. Single-domain antibodies, called nanobodies, offer a range of possibilities toward therapy since they are easy to generate, express, produce, and modify, e.g., by linkage to nanobodies directed against other target molecules. Hence, we generated small MMP8-binding nanobodies, and established a proof-of-principle for developing nanobodies that inhibit matrix metalloproteinase activity. Also, we demonstrated for the first time the possibility of expressing nanobodies systemically by in vivo electroporation of the muscle and its relevance as a potential therapy in inflammatory diseases.
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Delphine
authors.initials: D
authors.lastname: Demeestere
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Eline
authors.initials: E
authors.lastname: Dejonckheere
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Steeland
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Paco
authors.initials: P
authors.lastname: Hulpiau
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Haustraete
authors.affiliation: Cellular and Molecular Immunology Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Nick
authors.initials: N
authors.lastname: Devoogdt
authors.affiliation: Institute of Biochemistry, Unit for Degradomics of the Protease Web, University of Kiel, Kiel, Germany.
authors.forename: Rielana
authors.initials: R
authors.lastname: Wichert
authors.affiliation: Institute of Biochemistry, Unit for Degradomics of the Protease Web, University of Kiel, Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Elien
authors.initials: E
authors.lastname: Van Wonterghem
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Dewaele
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Griet
authors.initials: G
authors.lastname: Van Imschoot
authors.affiliation: Laboratory of Neuroplasticity and Neuroproteomics, Animal Physiology and Neurobiology, Department of Biology, K.U.Leuven, Leuven, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Aerts
authors.affiliation: Laboratory of Neuroplasticity and Neuroproteomics, Animal Physiology and Neurobiology, Department of Biology, K.U.Leuven, Leuven, Belgium.
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Arckens
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Saeys
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.affiliation: Inflammation Research Center, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Roosmarijn E
authors.initials: RE
authors.lastname: Vandenbroucke
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018274:Electroporation; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D062105:Molecular Docking Simulation; D061905:Single-Domain Antibodies / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D061905:Single-Domain Antibodies; D020784:Matrix Metalloproteinase 8