Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3–mediated therapeutics

T cell–mediated immunotherapy is an attractive strategy for treatment in various disease areas. In this therapeutic approach, the CD3 complex is one of the key molecules to modulate T cell functions; however, in many cases, we cannot evaluate the drug candidates in animal experiments because the the...

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Autores principales: Ueda, Otoya, Wada, Naoko A., Kinoshita, Yasuko, Hino, Hiroshi, Kakefuda, Mami, Ito, Tsuneo, Fujii, Etsuko, Noguchi, Mizuho, Sato, Kiyoharu, Morita, Masahiro, Tateishi, Hiromi, Matsumoto, Kaoru, Goto, Chisato, Kawase, Yosuke, Kato, Atsuhiko, Hattori, Kunihiro, Nezu, Junichi, Ishiguro, Takahiro, Jishage, Kou-ichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377452/
https://www.ncbi.nlm.nih.gov/pubmed/28368009
http://dx.doi.org/10.1038/srep45839
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author Ueda, Otoya
Wada, Naoko A.
Kinoshita, Yasuko
Hino, Hiroshi
Kakefuda, Mami
Ito, Tsuneo
Fujii, Etsuko
Noguchi, Mizuho
Sato, Kiyoharu
Morita, Masahiro
Tateishi, Hiromi
Matsumoto, Kaoru
Goto, Chisato
Kawase, Yosuke
Kato, Atsuhiko
Hattori, Kunihiro
Nezu, Junichi
Ishiguro, Takahiro
Jishage, Kou-ichi
author_facet Ueda, Otoya
Wada, Naoko A.
Kinoshita, Yasuko
Hino, Hiroshi
Kakefuda, Mami
Ito, Tsuneo
Fujii, Etsuko
Noguchi, Mizuho
Sato, Kiyoharu
Morita, Masahiro
Tateishi, Hiromi
Matsumoto, Kaoru
Goto, Chisato
Kawase, Yosuke
Kato, Atsuhiko
Hattori, Kunihiro
Nezu, Junichi
Ishiguro, Takahiro
Jishage, Kou-ichi
author_sort Ueda, Otoya
collection PubMed
description T cell–mediated immunotherapy is an attractive strategy for treatment in various disease areas. In this therapeutic approach, the CD3 complex is one of the key molecules to modulate T cell functions; however, in many cases, we cannot evaluate the drug candidates in animal experiments because the therapeutics, usually monoclonal antibodies specific to human CD3, cannot react to mouse endogenous Cd3. Although immunodeficient mice transfused with human hematopoietic stem or precursor cells, known as humanized mice, are available for these studies, mice humanized in this manner are not completely immune competent. In this study we have succeeded in establishing a novel mouse strain in which all the three components of the Cd3 complex — Cd3ε, Cd3δ, and Cd3γ — are replaced by their human counterparts, CD3E, CD3D, and CD3G. Basic immunological assessments have confirmed that this strain of human CD3 EDG–replaced mice are entirely immune competent, and we have also demonstrated that a bispecific antibody that simultaneously binds to human CD3 and a tumor-associated antigen (e.g. ERBB2 or GPC3) can be evaluated in human CD3 EDG–replaced mice engrafted with tumors. Our mouse model provides a novel means to evaluate the in vivo efficacy of human CD3–mediated therapy.
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spelling pubmed-53774522017-04-10 Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3–mediated therapeutics Ueda, Otoya Wada, Naoko A. Kinoshita, Yasuko Hino, Hiroshi Kakefuda, Mami Ito, Tsuneo Fujii, Etsuko Noguchi, Mizuho Sato, Kiyoharu Morita, Masahiro Tateishi, Hiromi Matsumoto, Kaoru Goto, Chisato Kawase, Yosuke Kato, Atsuhiko Hattori, Kunihiro Nezu, Junichi Ishiguro, Takahiro Jishage, Kou-ichi Sci Rep Article T cell–mediated immunotherapy is an attractive strategy for treatment in various disease areas. In this therapeutic approach, the CD3 complex is one of the key molecules to modulate T cell functions; however, in many cases, we cannot evaluate the drug candidates in animal experiments because the therapeutics, usually monoclonal antibodies specific to human CD3, cannot react to mouse endogenous Cd3. Although immunodeficient mice transfused with human hematopoietic stem or precursor cells, known as humanized mice, are available for these studies, mice humanized in this manner are not completely immune competent. In this study we have succeeded in establishing a novel mouse strain in which all the three components of the Cd3 complex — Cd3ε, Cd3δ, and Cd3γ — are replaced by their human counterparts, CD3E, CD3D, and CD3G. Basic immunological assessments have confirmed that this strain of human CD3 EDG–replaced mice are entirely immune competent, and we have also demonstrated that a bispecific antibody that simultaneously binds to human CD3 and a tumor-associated antigen (e.g. ERBB2 or GPC3) can be evaluated in human CD3 EDG–replaced mice engrafted with tumors. Our mouse model provides a novel means to evaluate the in vivo efficacy of human CD3–mediated therapy. Nature Publishing Group 2017-04-03 /pmc/articles/PMC5377452/ /pubmed/28368009 http://dx.doi.org/10.1038/srep45839 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Ueda, Otoya
Wada, Naoko A.
Kinoshita, Yasuko
Hino, Hiroshi
Kakefuda, Mami
Ito, Tsuneo
Fujii, Etsuko
Noguchi, Mizuho
Sato, Kiyoharu
Morita, Masahiro
Tateishi, Hiromi
Matsumoto, Kaoru
Goto, Chisato
Kawase, Yosuke
Kato, Atsuhiko
Hattori, Kunihiro
Nezu, Junichi
Ishiguro, Takahiro
Jishage, Kou-ichi
Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3–mediated therapeutics
title Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3–mediated therapeutics
title_full Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3–mediated therapeutics
title_fullStr Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3–mediated therapeutics
title_full_unstemmed Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3–mediated therapeutics
title_short Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3–mediated therapeutics
title_sort entire cd3ε, δ, and γ humanized mouse to evaluate human cd3–mediated therapeutics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377452/
https://www.ncbi.nlm.nih.gov/pubmed/28368009
http://dx.doi.org/10.1038/srep45839
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