title: Development of human neutralizing antibody to ADAMTS4 (aggrecanase-1) and ADAMTS5 (aggrecanase-2).
abstract: ADAMTS4 (aggrecanase-1) and ADAMTS5 (aggrecanase-2), members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family, are considered to play a key role in aggrecan degradation of articular cartilage in human osteoarthritis. Here, we developed a neutralizing antibody to these aggrecanases by screening human combinatorial antibody library. Among the five candidate antibodies, one antibody was immunoreactive with both ADAMTS4 and ADAMTS5, showing no or negligible cross-reactivity with 10 different related metalloproteinases of the ADAMTS, ADAM (a disintegrin and metalloproteinase) and MMP (matrix metalloproteinase) gene families. This antibody almost completely and partially inhibited aggrecanase activity of ADAMTS4 and ADAMTS5, respectively. It also suppressed the aggrecanase activity derived from interleukin-1-stimulated osteoarthritic chondrocytes. These data demonstrate that the antibody is specific to ADAMTS4 and ADAMTS5 and inhibits their aggrecanase activity at molecular and cellular levels, and suggest that this antibody may be useful for treatment of pathological conditions such as osteoarthritis.
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Shiraishi
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Mochizuki
authors.affiliation: GeneFrontier Corporation, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Miyakoshi
authors.affiliation: GeneFrontier Corporation, Chiba, Japan.
authors.forename: Kanehisa
authors.initials: K
authors.lastname: Kojoh
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan. Electronic address: okada@z6.keio.jp.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
mesh_terms: D051722:ADAM Proteins / Q000276:immunology*; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D061505:Cell Surface Display Techniques; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000276:immunology*; D006801:Humans; D011348:Procollagen N-Endopeptidase / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D004791:Enzyme Inhibitors; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human
keywords: ADAMTS4; ADAMTS5; Aggrecanase; Cartilage; Human antibody; Osteoarthritis