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: Shunsuke Shimosaki, Shingo Nakahata, Tomonaga Ichikawa, Akira Kitanaka, Takuro Kameda, Tomonori Hidaka, Yoko Kubuki, Gene Kurosawa, Lilin Zhang, Yukio Sudo, Kazuya Shimoda, Kazuhiro Morishita
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 485 Issue 1 Pg. 144-151 (03 25 2017) ISSN: 1090-2104 [Electronic] United States
• PMID: 28189691 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• CD71 antigen
• Immunoglobulin G
• Receptors, Transferrin

Topics

• Adult
• Antibodies, Monoclonal (immunology, pharmacology)
• Antigens, CD (genetics, immunology)
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Leukemic
• Humans
• Immunoglobulin G (immunology, pharmacology)
• Immunotherapy
• Leukemia-Lymphoma, Adult T-Cell (genetics, immunology, pathology, therapy)
• Receptors, Transferrin (genetics, immunology)
• Up-Regulation