title: Development of a complete human IgG monoclonal antibody to transferrin receptor 1 targeted for adult T-cell leukemia/lymphoma.
abstract: Iron is an essential nutrient for normal cell growth, and reprogramming of iron metabolism is essential to tumor cell survival and progression. HTLV-1-associated adult T-cell leukemia/lymphoma (ATLL) has no effective therapy and high levels of cell surface transferrin receptor 1 (TFR1) expression have been reported in ATLL by us and other groups. In this study, to develop a novel molecular-targeted therapy against TFR1 to modulate iron metabolism, we initially determined the expression pattern of several iron-related genes along with TFR1 and found that ATLL cells presented characteristic of an iron-deficiency state such as high expression of iron-regulatory protein 2 (IRP2) and low expression of its E3 ubiquitin-ligase, FBXL5. Therefore, we developed human IgG monoclonal antibodies to human TFR1 using a phage display method (ICOS method) to block the incorporation of the transferrin (TF)-iron complex into ATLL cells for inhibiting cell growth. One of the mAbs, JST-TFR09, presented its greater affinity to TFR1 on ATLL cells in flow cytometry (FCM) analysis than those of commercially available anti-TFR1 antibodies and identified high expression of TFR1 in most of the acute-type ATLL cells. Moreover, JST-TFR09 could interfere with binding between TFR1 and TF, which resulted in effective blockade of TFR1 internalization and induction of cell apoptosis by the treatment of ATLL cells with JST-TFR09. JST-TFR09 showed dual activities through direct cell cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC), and the treatment of JST-TFR09 significantly suppressed cell growth of ATLL cells with induction of apoptosis in in vitro and in vivo experiments. Thus, JST-TFR09 described here may become a promising therapeutic antibody for the treatment of ATLL.
authors.affiliation: Division of Tumor and Cellular Biochemistry, Department of Medical Science, Faculty of Medicine, University of Miyazaki, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Shimosaki
authors.affiliation: Division of Tumor and Cellular Biochemistry, Department of Medical Science, Faculty of Medicine, University of Miyazaki, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakahata
authors.affiliation: Division of Tumor and Cellular Biochemistry, Department of Medical Science, Faculty of Medicine, University of Miyazaki, Japan.
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ichikawa
authors.affiliation: Division of Gastroenterology and Hematology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kitanaka
authors.affiliation: Division of Gastroenterology and Hematology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Kameda
authors.affiliation: Division of Gastroenterology and Hematology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hidaka
authors.affiliation: Division of Gastroenterology and Hematology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kubuki
authors.affiliation: Division of Antibody Project, Institute for Comprehensive Medical Science, Fujita Health University, Japan.
authors.forename: Gene
authors.initials: G
authors.lastname: Kurosawa
authors.affiliation: Perseus Proteomics, Inc., Japan.
authors.forename: Lilin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Perseus Proteomics, Inc., Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sudo
authors.affiliation: Division of Gastroenterology and Hematology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.affiliation: Division of Tumor and Cellular Biochemistry, Department of Medical Science, Faculty of Medicine, University of Miyazaki, Japan. Electronic address: kmorishi@med.miyazaki-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Morishita
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000494:pharmacology; D007167:Immunotherapy; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D011990:Receptors, Transferrin / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C068126:CD71 antigen; D007074:Immunoglobulin G; D011990:Receptors, Transferrin
keywords: ADCC; Adult T-cell leukemia/lymphoma; Anti-transferrin receptor 1 antibody; Direct cytotoxicity; Phage display