title: Fully human monoclonal antibodies to TRAIL-R1 enhance TRAIL-induced apoptosis via activation of caspase-8 pathway.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic antibodies targeting TRAIL-receptors (TRAIL-Rs) can selectively induce apoptosis in cancer cells. However, they have limited antitumor efficacy in clinical trials. We previously generated ten fully human monoclonal Abs to TRAIL-receptor type 1 (TR1-mAbs) using immunospot array assay on a chip (ISAAC technology). We found that the TR1-mAbs exhibited different effects on TRAIL-induced apoptosis (enhanced or blocked apoptosis). Here, we further demonstrated that some mAbs competed with TRAIL for binding to TRAIL-R1 expressed on tumor cells that blocked TRAIL-induced apoptosis (B-TR1-Ab), whereas others did not compete with TRAIL that enhanced TRAIL-induced apoptosis (E-TR1-Ab). Combination of E-TR1-Ab (TR1-419) with TRAIL leads to enhanced antitumor activity in various tumor cells in vitro. E-TR1-419 and TRAIL could cooperate to upregulate the mRNA expression and protein levels of TRAIL-R1 and to promote caspase-8 cleavage and increased JNK phosphorylation. Our results suggest that combining E-TR1 Ab with TRAIL could provide a new therapeutic strategy for tumor immunotherapies.
authors.affiliation: Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin 150081, China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Hao
authors.affiliation: Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin 150081, China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin 150081, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150 Haping Street, Nangang District, Harbin 150001, China.
authors.forename: Meiying
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin 150081, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin 150081, China.
authors.forename: Yaying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150 Haping Street, Nangang District, Harbin 150001, China.
authors.forename: Da
authors.initials: D
authors.lastname: Pang
authors.affiliation: Division of Respiratory Disease, The Fourth Hospital of Harbin Medical University, 37 Yiyuan Street, Nangang District, Harbin 150001, China.
authors.forename: Shoude
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, 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, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Muraguchi
authors.affiliation: Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin 150081, China. Electronic address: aishunjin@ems.hrbmu.edu.cn.
authors.forename: Aishun
authors.initials: A
authors.lastname: Jin
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D053181:Caspase 8
keywords: Apoptosis; Fully human monoclonal antibodies to TRAIL-R1; TRAIL; TRAIL-R1; Tumor immunotherapy