Development of DS‐5573a: A novel afucosylated mAb directed at B7‐H3 with potent antitumor activity

Autor: Mitsuhiro Yazawa, Kenji Hirotani, Toshinori Agatsuma, Shu Takahashi, Akiko Nagase-Zembutsu, Michiko Yamato, Junko Yamaguchi, Makoto Yoshida, Takehiko Takata, Keisuke Fukuchi
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
B7 Antigens
medicine.drug_class
Antineoplastic Agents
Monoclonal antibody
Antibodies
Monoclonal
Humanized
Flow cytometry
03 medical and health sciences
Mice
0302 clinical medicine
Antibody‐dependent cellular cytotoxicity
In vivo
Cell Line
Tumor
Medicine
Animals
Humans
B7‐H3
Antibody-dependent cell-mediated cytotoxicity
Immunity
Cellular
biology
medicine.diagnostic_test
business.industry
Effector
Macrophages
DS‐5573a
antibody‐dependent cellular phagocytosis
Antibody-Dependent Cell Cytotoxicity
Antibodies
Monoclonal
General Medicine
Original Articles
In vitro
030104 developmental biology
Drug Discovery and Delivery
Oncology
030220 oncology & carcinogenesis
therapeutic antibody
Cancer cell
Immunology
Cancer research
biology.protein
Leukocytes
Mononuclear
Original Article
Female
Antibody
business
Zdroj: Cancer Science
ISSN: 1349-7006
1347-9032
Popis: 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.
Databáze: OpenAIRE
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