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Identification of Novel Epitopes with Agonistic Activity for the Development of Tumor Immunotherapy Targeting TRAIL-R1

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-1/2 (TRAIL-R1/R2), also known as death receptors, are expressed in a wide variety of tumor cells. Although TRAIL can induce cell apoptosis by engaging its cognate TRAIL-R1/R2, some tumor cells are or become resistant to TRAIL t...

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Autores principales: Guo, Lu, Sun, Xin, Hao, Zhichao, Huang, Jingjing, Han, Xiaojian, You, Yajie, Li, Yaying, Shen, Meiying, Ozawa, Tatsuhiko, Kishi, Hiroyuki, Muraguchi, Atsushi, Jin, Aishun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595084/
https://www.ncbi.nlm.nih.gov/pubmed/28900492
http://dx.doi.org/10.7150/jca.19918
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author Guo, Lu
Sun, Xin
Hao, Zhichao
Huang, Jingjing
Han, Xiaojian
You, Yajie
Li, Yaying
Shen, Meiying
Ozawa, Tatsuhiko
Kishi, Hiroyuki
Muraguchi, Atsushi
Jin, Aishun
author_facet Guo, Lu
Sun, Xin
Hao, Zhichao
Huang, Jingjing
Han, Xiaojian
You, Yajie
Li, Yaying
Shen, Meiying
Ozawa, Tatsuhiko
Kishi, Hiroyuki
Muraguchi, Atsushi
Jin, Aishun
author_sort Guo, Lu
collection PubMed
description Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-1/2 (TRAIL-R1/R2), also known as death receptors, are expressed in a wide variety of tumor cells. Although TRAIL can induce cell apoptosis by engaging its cognate TRAIL-R1/R2, some tumor cells are or become resistant to TRAIL treatment. Monoclonal antibodies (mAbs) against TRAIL-R1/R2 have been developed to use as potential antitumor therapeutic agents instead of TRAIL. However, TRAIL-R1/R2-based tumor therapy has not yet been realized. We previously generated a series of fully human monoclonal antibodies against TRAIL-R1 (TR1-mAbs) that induced tumor cell apoptosis. In this study, we identified the antigenic binding sites of these TR1-mAbs and proposed two major epitopes on the extracellular domain of TRAIL-R1. The analysis revealed that the epitopes of some TR1-mAbs partially overlaps with the beginning of TRAIL-binding sites, and other epitopes are located within the TRAIL-binding region. Among these mAbs, TR1-422 and TR1-419 mAbs have two antigenic binding sites that bound to the same binding region, but they have different essential amino acid residues and binding site sizes. Furthermore, we investigated the apoptosis activity of TR1-419 and TR1-422 mAbs in the form of IgG and IgM. In contrast to the IgG-type TR1-419 and TR1-422 mAbs, which enhanced and inhibited TRAIL-induced apoptosis, respectively, both IgM-type TR1-419 and TR1-422 mAb strongly induced cell apoptosis with or without soluble TRAIL (sTRAIL). Moreover, the results showed that IgM-type TR1-419 and TR1-422 mAbs alone can sufficiently activate the extrinsic and intrinsic apoptosis signaling pathways and suppress tumor growth in vivo. Consequently, we identified two antigenic binding sites with agonistic activity, and their specific IgM-type mAbs exhibited strong cytotoxic activity in tumor cells in vitro and in vivo. Thus, these agonistic antigenic binding sites may be useful for the development of effective Ab-based drugs or Ab-based cell immunotherapy for various human solid tumors.
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spelling pubmed-55950842017-09-12 Identification of Novel Epitopes with Agonistic Activity for the Development of Tumor Immunotherapy Targeting TRAIL-R1 Guo, Lu Sun, Xin Hao, Zhichao Huang, Jingjing Han, Xiaojian You, Yajie Li, Yaying Shen, Meiying Ozawa, Tatsuhiko Kishi, Hiroyuki Muraguchi, Atsushi Jin, Aishun J Cancer Research Paper Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-1/2 (TRAIL-R1/R2), also known as death receptors, are expressed in a wide variety of tumor cells. Although TRAIL can induce cell apoptosis by engaging its cognate TRAIL-R1/R2, some tumor cells are or become resistant to TRAIL treatment. Monoclonal antibodies (mAbs) against TRAIL-R1/R2 have been developed to use as potential antitumor therapeutic agents instead of TRAIL. However, TRAIL-R1/R2-based tumor therapy has not yet been realized. We previously generated a series of fully human monoclonal antibodies against TRAIL-R1 (TR1-mAbs) that induced tumor cell apoptosis. In this study, we identified the antigenic binding sites of these TR1-mAbs and proposed two major epitopes on the extracellular domain of TRAIL-R1. The analysis revealed that the epitopes of some TR1-mAbs partially overlaps with the beginning of TRAIL-binding sites, and other epitopes are located within the TRAIL-binding region. Among these mAbs, TR1-422 and TR1-419 mAbs have two antigenic binding sites that bound to the same binding region, but they have different essential amino acid residues and binding site sizes. Furthermore, we investigated the apoptosis activity of TR1-419 and TR1-422 mAbs in the form of IgG and IgM. In contrast to the IgG-type TR1-419 and TR1-422 mAbs, which enhanced and inhibited TRAIL-induced apoptosis, respectively, both IgM-type TR1-419 and TR1-422 mAb strongly induced cell apoptosis with or without soluble TRAIL (sTRAIL). Moreover, the results showed that IgM-type TR1-419 and TR1-422 mAbs alone can sufficiently activate the extrinsic and intrinsic apoptosis signaling pathways and suppress tumor growth in vivo. Consequently, we identified two antigenic binding sites with agonistic activity, and their specific IgM-type mAbs exhibited strong cytotoxic activity in tumor cells in vitro and in vivo. Thus, these agonistic antigenic binding sites may be useful for the development of effective Ab-based drugs or Ab-based cell immunotherapy for various human solid tumors. Ivyspring International Publisher 2017-08-02 /pmc/articles/PMC5595084/ /pubmed/28900492 http://dx.doi.org/10.7150/jca.19918 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Guo, Lu
Sun, Xin
Hao, Zhichao
Huang, Jingjing
Han, Xiaojian
You, Yajie
Li, Yaying
Shen, Meiying
Ozawa, Tatsuhiko
Kishi, Hiroyuki
Muraguchi, Atsushi
Jin, Aishun
Identification of Novel Epitopes with Agonistic Activity for the Development of Tumor Immunotherapy Targeting TRAIL-R1
title Identification of Novel Epitopes with Agonistic Activity for the Development of Tumor Immunotherapy Targeting TRAIL-R1
title_full Identification of Novel Epitopes with Agonistic Activity for the Development of Tumor Immunotherapy Targeting TRAIL-R1
title_fullStr Identification of Novel Epitopes with Agonistic Activity for the Development of Tumor Immunotherapy Targeting TRAIL-R1
title_full_unstemmed Identification of Novel Epitopes with Agonistic Activity for the Development of Tumor Immunotherapy Targeting TRAIL-R1
title_short Identification of Novel Epitopes with Agonistic Activity for the Development of Tumor Immunotherapy Targeting TRAIL-R1
title_sort identification of novel epitopes with agonistic activity for the development of tumor immunotherapy targeting trail-r1
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595084/
https://www.ncbi.nlm.nih.gov/pubmed/28900492
http://dx.doi.org/10.7150/jca.19918
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