title: Entire CD3ε, δ, and γ humanized mouse to evaluate human CD3-mediated therapeutics.
abstract: 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.
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Research Division, Fuji Gotemba Research Labs., 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Otoya
authors.initials: O
authors.lastname: Ueda
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Research Division, Fuji Gotemba Research Labs., 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Naoko A
authors.initials: NA
authors.lastname: Wada
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Research Division, Kamakura Research Labs., 200, Kajiwara, Kamakura, Kanagawa, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kinoshita
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Research Division, Fuji Gotemba Research Labs., 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hino
authors.affiliation: Chugai Research Institute for Medical Science, Inc. 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Kakefuda
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Research Division, Fuji Gotemba Research Labs., 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ito
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Research Division, Fuji Gotemba Research Labs., 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Fujii
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Research Division, Kamakura Research Labs., 200, Kajiwara, Kamakura, Kanagawa, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Noguchi
authors.affiliation: Chugai Research Institute for Medical Science, Inc. 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Kiyoharu
authors.initials: K
authors.lastname: Sato
authors.affiliation: Chugai Research Institute for Medical Science, Inc. 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morita
authors.affiliation: Chugai Research Institute for Medical Science, Inc. 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tateishi
authors.affiliation: Chugai Research Institute for Medical Science, Inc. 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Chugai Research Institute for Medical Science, Inc. 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Goto
authors.affiliation: Chugai Research Institute for Medical Science, Inc. 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawase
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Research Division, Fuji Gotemba Research Labs., 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kato
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Research Division, Kamakura Research Labs., 200, Kajiwara, Kamakura, Kanagawa, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hattori
authors.affiliation: Chugai Pharmabody Research Pte. Ltd., 3 Biopolis Drive, #07 - 11 to 16, Synapse, 138623, Singapore.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nezu
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Translational Clinical Research Division, 1-1 Nihonbashi-Muromachi 2-Chome, Chuo-ku, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishiguro
authors.affiliation: Chugai Pharmaceutical Co., Ltd., Research Division, Fuji Gotemba Research Labs., 1-135, Komakado, Gotemba, Shizuoka, Japan.
authors.forename: Kou-Ichi
authors.initials: KI
authors.lastname: Jishage
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; C452842:CD3 antigen, gamma chain; C472562:CD3delta antigen; C485468:Cd3e protein, mouse