title: Development of DS-5573a: A novel afucosylated mAb directed at B7-H3 with potent antitumor activity.
abstract: B7-H3 is highly overexpressed in a variety of human clinical tumors, and its expression is significantly associated with poor outcomes. In our study, we aimed to develop new antitumor mAbs by employing cancer cell immunization, and succeeded in generating a mouse anti-human B7-H3 antibody (M30) that shows antitumor activity. M30 was humanized (Hu-M30), and an afucosylated Hu-M30 (DS-5573a) was also generated. To assess the potency of DS-5573a as a therapeutic mAb, we characterized this mAb and evaluated its antitumor activity in vitro and in vivo. Flow cytometry analysis showed that B7-H3 proteins were expressed on various types of cancer cell lines broadly, and DS-5573a binds to IgC1 and IgC2 domains of human B7-H3. Antibody-dependent cellular cytotoxicity activity of DS-5573a was drastically enhanced against medium to high B7-H3-expressing cancer cell lines MDA-MB-231 and NCI-H322. DS-5573a also induced high antibody-dependent cellular cytotoxicity activity against low B7-H3-expressing cancer cell line COLO205, whereas Hu-M30 induced little activity against it. In addition, DS-5573a was found to be a novel anti-B7-H3 antibody which showed antibody-dependent cellular phagocytosis activity. Furthermore, DS-5573a showed dose-dependent and significant antitumor efficacy (0.03-3 mg/kg) in MDA-MB-231-bearing SCID mice (which have functional natural killer cells and macrophages), but little antitumor efficacy in NOG mice (which lack natural killer cells and have reduced macrophage function). These results suggest that antitumor activity of DS-5573a is mediated by effector cells, and this mAb could be a promising antitumor therapy for patients with a wide range of B7-H3-expressing tumors.
authors.affiliation: Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Akiko
authors.identifier: http://orcid.org/0000-0002-7911-0573
authors.initials: A
authors.lastname: Nagase-Zembutsu
authors.affiliation: Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hirotani
authors.affiliation: Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Yamato
authors.affiliation: Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Yamaguchi
authors.affiliation: Oncology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Takata
authors.affiliation: New Modality Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Fukuchi
authors.affiliation: Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yazawa
authors.affiliation: Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Agatsuma
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D060887:B7 Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060887:B7 Antigens; C423237:CD276 protein, human; C000613983:DS-5573a
keywords: Antibody-dependent cellular cytotoxicity; B7-H3; DS-5573a; antibody-dependent cellular phagocytosis; therapeutic antibody