Open AccessDevelopment of DS ‐5573a: A novel afucosylated mA b directed at B7‐H3 with potent antitumor activity
Author(s) -
NagaseZembutsu Akiko,
Hirotani Kenji,
Yamato Michiko,
Yamaguchi Junko,
Takata Takehiko,
Yoshida Makoto,
Fukuchi Keisuke,
Yazawa Mitsuhiro,
Takahashi Shu,
Agatsuma Toshinori
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12915
Subject(s) - cytotoxicity , antibody , flow cytometry , in vivo , antibody dependent cell mediated cytotoxicity , cell culture , cancer research , in vitro , cancer , cancer immunotherapy , cancer cell , biology , immunotherapy , pharmacology , immunology , chemistry , immune system , biochemistry , genetics , microbiology and biotechnology
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 mA bs 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 mA b, we characterized this mA b 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 COLO 205, 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 mA b could be a promising antitumor therapy for patients with a wide range of B7‐H3‐expressing tumors.