title: Therapeutic activity of glycoengineered anti-GM2 antibodies against malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is a rare and highly aggressive neoplasm that arises from the pleural, pericardial, or peritoneal lining. Although surgery, chemotherapy, radiotherapy, and combinations of these therapies are used to treat MPM, the median survival of such patients is dismal. Therefore, there is a compelling need to develop novel therapeutics with different modes of action. Ganglioside GM2 is a glycolipid that has been shown to be overexpressed in various types of cancer. However, there are no published reports regarding the use of GM2 as a potential therapeutic target in cases of MPM. In this study, we evaluated the efficacy of the anti-GM2 antibody BIW-8962 as an anti-MPM therapeutic using in vitro and in vivo assays. Consequently, the GM2 expression in the MPM cell lines was confirmed using flow cytometry. In addition, eight of 11 cell lines were GM2-positive (73%), although the GM2 expression was variable. BIW-8962 showed a significant antibody-dependent cellular cytotoxicity activity against the GM2-expressing MPM cell line MSTO-211H, the effect of which depended on the antibody concentration and effector/target ratio. In an in vivo orthotropic mouse model using MSTO-211H cells, BIW-8962 significantly decreased the incidence and size of tumors. Additionally, the GM2 expression was confirmed in the MPM clinical specimens. Fifty-eight percent of the MPM tumors were positive for GM2, with individual variation in the intensity and frequency of staining. These data suggest that anti-GM2 antibodies may become a therapeutic option for MPM patients.
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Machino
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.forename: Kenji
authors.initials: K
authors.lastname: Kita
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Mami
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Yui
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Nan-Ya
authors.forename: Shigeru
authors.initials: S
authors.lastname: Iida
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Nakamura
authors.forename: Shotaro
authors.initials: S
authors.lastname: Iwakiri
authors.forename: Kazumi
authors.initials: K
authors.lastname: Itoi
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D005678:G(M2) Ganglioside / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy*; D000086002:Mesothelioma, Malignant; D016513:Mice, SCID; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000188:drug therapy*; D015202:Protein Engineering; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000596341:BIW-8962; D005678:G(M2) Ganglioside
keywords: Antibodies; antibody-dependent cell cytotoxicity; ganglioside GM2; mesothelioma; therapeutics