title: TRAIL-receptor 1 IgM antibodies strongly induce apoptosis in human cancer cells in vitro and in vivo.
abstract: Agonistic tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-receptor-specific antibodies are attractive antitumor therapeutics. Recently, our group has generated several human monoclonal antibodies (mAbs) to TRAIL-receptor-1 (TRAIL-R1) (TR1-IgGs) using ISAAC technology. However, these TR1-IgGs did not demonstrate ideal apoptosis-inducing capacity in the absence of additional antibodies. To overcome this limitation, we class-switched the TR1-IgGs to TRAIL-R1 IgM antibodies (TR1-IgMs); TR1-IgMs might possess high valency and facilitate the crosslinking of the cell surface receptors. We showed that the TR1-IgMs bound TRAIL-R1, activated the caspase signal, and induced strong apoptosis (100-fold higher compared with the IgG form in one case) in human tumor cell lines without any additional crosslinking in vitro. We further demonstrated that these TR1-IgMs dramatically inhibited tumor growth in a xenograft model through the caspase activation cascade. These data suggest that TR1-IgMs may become potential immunotherapeutic agents for cancer therapy.
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama, Japan.
authors.forename: Xiuhong
authors.initials: X
authors.lastname: Piao
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamana
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama, Japan.
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Shitaoka
authors.affiliation: Department of Immunology, College of Basic Medical Sciences, Harbin Medical University , Nangang District , Harbin, China.
authors.forename: Aishun
authors.initials: A
authors.lastname: Jin
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishi
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Muraguchi
keywords: Antitumor therapeutics; IgM antibodies; TRAIL; TRAIL-R; crosslinking