Therapeutic activity of glycoengineered anti-GM2 antibodies against malignant pleural mesothelioma

Our plain-English summary of Therapeutic activity of glycoengineered anti-GM2 antibodies against malignant pleural mesothelioma, by Q. Li, W. Wang, Y. Machino, et al (Cancer Science, 2015).

The study

• Authors: Q. Li, W. Wang, Y. Machino, T. Yamada, K. Kita, M. Oshima, Y. Sekido, M. Tsuchiya, Y. Suzuki, K. Nan-Ya, S. Iida, K. Nakamura, S. Iwakiri, K. Itoi, S. Yano
• Journal: Cancer Science
• Published: 2015;106(1):102-7
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

In plain English

This laboratory and animal study tested whether an experimental antibody called BIW-8962 could act against malignant pleural mesothelioma. The antibody targets ganglioside GM2, a molecule found on cell surfaces. The study did not examine asbestos exposure. The authors first measured GM2 on 11 human mesothelioma cell lines. Four showed high levels, four showed low levels and three showed none, and none was found in the sarcomatoid cell lines. In lab dishes, the antibody combined with immune cells from four healthy volunteers significantly killed cells of the GM2-rich line MSTO-211H, and the killing increased as the proportion of immune cells rose. Mice then had these cells injected into the chest cavity. Tumors developed in 8 of 8 control mice, 7 of 8 mice given the antibody, and 4 of 8 mice given the antibody plus human immune cells. In that last group the median tumor weight was under 10 mg, compared with 550 mg in controls. Fluid around the lungs tended to decrease with the combination. Of 26 purchased patient tumor samples, 58% showed GM2, with no correlation with tissue type or stage. The authors concluded that anti-GM2 antibodies may become an effective therapy for mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study (cell lines and tissue staining) with an animal experiment in mice
• Who was studied: 11 human malignant pleural mesothelioma cell lines; male SCID mice injected in the chest cavity with MSTO-211H cells (8 per treatment group); frozen tumor samples from 26 mesothelioma patients purchased from Origene Technologies
• Exposure: No asbestos exposure was studied. The treatment tested was the non-fucosylated humanized anti-GM2 antibody BIW-8962, given intravenously to mice at 10 micrograms per animal on days 7 and 14, with or without human blood immune cells (mononuclear cells).
• Main results:
  • Of the 11 mesothelioma cell lines, GM2 levels were high (relative fluorescence greater than 10) in four (36%), low (2 to 10) in four (36%) and negative (less than 2) in three (28%).
  • No GM2 was detected in the sarcomatoid mesothelioma cell lines.
  • In lab dishes, BIW-8962 with immune cells from four healthy volunteers showed significant cell-killing (ADCC) activity against MSTO-211H cells at antibody concentrations of 1 and 10 micrograms per mL. The effect increased with the effector-to-target ratio (25, 50 and 100).
  • Complement-dependent killing (CDC) of mesothelioma cell lines was not observed even at 100 micrograms per mL of BIW-8962. The authors did not show these data.
  • In mice, chest tumors occurred in 8 of 8 controls (median weight 550 mg, range 380 to 650) and in 8 of 8 given immune cells alone (median 590 mg). They occurred in 7 of 8 given BIW-8962 alone (median 360 mg, range 0 to 590) and in 4 of 8 given BIW-8962 plus immune cells (median under 10 mg, range 0 to 510).
  • In mice, the combination of BIW-8962 and immune cells had a greater effect on tumor incidence and size than the antibody alone. Immune cells alone showed weak antitumor activity.
  • Pleural effusion (fluid around the lungs) tended to decrease with BIW-8962 plus immune cells. It occurred in 1 of 8 mice in that group versus 3 of 8 controls.
  • In the 26 patient tumor samples, GM2 was found in 58%, with large variation in staining intensity and frequency between patients.
  • No correlation was found between GM2 expression and tumor tissue type or stage in the patient samples.
• The authors' conclusion: The authors concluded that anti-GM2 antibodies may become an effective therapy for malignant pleural mesothelioma. They noted that a clinical study of BIW-8962 was under way.
• Limitations the authors state:
  • The authors noted that how the antibody distributes in human mesothelioma tumors has not been defined. Their dose estimates for people were extrapolated from other studies.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Neoplasm, Pericardial, Chemotherapy, Median Survival.

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