Antitumor activity of anti-C-ERC/mesothelin monoclonal antibody in vivo

Our plain-English summary of Antitumor activity of anti-C-ERC/mesothelin monoclonal antibody in vivo, by K. Inami, M. Abe, K. Takeda, et al (Cancer Science, 2010).

The study

• Authors: K. Inami, M. Abe, K. Takeda, Y. Hagiwara, M. Maeda, T. Segawa, M. Suyama, S. Watanabe, O. Hino
• Journal: Cancer Science
• Published: 2010;101(4):969-74
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is an aggressive cancer often caused by chronic asbestos exposure, and its prognosis is very poor despite the therapies currently used. Due to the long latency period between asbestos exposure and tumor development, the worldwide incidence will increase substantially in the next decades. Thus, novel effective therapies are warranted to improve the prognosis. The ERC/mesothelin gene (MSLN) is expressed in wide variety of human cancers, including mesotheliomas, and encodes a precursor protein cleaved by proteases to generate C-ERC/mesothelin and N-ERC/mesothelin. In this study, we investigated the antitumor activity of C-ERC/mesothelin-specific mouse monoclonal antibody, 22A31, against tumors derived from a human mesothelioma cell line, ACC-MESO-4, in a xenograft experimental model using female BALB/c athymic nude mice. Treatment with 22A31 did not inhibit cell proliferation of ACC-MESO-4 in vitro; however, therapeutic treatment with 22A31 drastically inhibited tumor growth in vivo. 22A31 induced antibody-dependent cell-mediated cytotoxicity by natural killer (NK) cells, but not macrophages, in vitro. Consistently, the F(ab')(2) fragment of 22A31 did not inhibit tumor growth in vivo, nor did it induce antibody-dependent cell mediated cytotoxicity (ADCC) in vitro. Moreover, NK cell depletion diminished the antitumor effect of 22A31. Thus, 22A31 induced NK cell-mediated ADCC and exerted antitumor activity in vivo. 22A31 could have potential as a therapeutic tool to treat C-ERC/mesothelin-expressing cancers including mesothelioma.

In plain English

This was a laboratory study in cells and mice. It did not study asbestos exposure or people. The authors tested 22A31, a mouse antibody they had previously developed against C-ERC/mesothelin, a protein found on the surface of some cancer cells. Two human mesothelioma cell lines (ACC-MESO-4 and NCI-H226) carried the protein; a human liver cancer cell line (Huh7) did not. Tumors were grown under the skin of female nude mice, 3 to 5 per group. Injected into the abdomen, 22A31 did not significantly slow tumor growth. Injected directly into the tumors, it significantly slowed the growth of ACC-MESO-4 tumors, more so at higher doses, but not of Huh7 tumors. In lab dishes the antibody did not stop cancer cell growth by itself. It did enable natural killer (NK) cells, though not macrophages, to kill cells carrying the protein. A fragment of the antibody lacking its Fc portion did not slow tumors, and depleting NK cells in the mice weakened the effect. The authors concluded that 22A31 could have potential as a treatment for mesothelin-expressing cancers including 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 culture experiments plus a mouse xenograft (human tumor grown in mice) experiment testing an antibody treatment
• Who was studied: Female BALB/c athymic nude mice aged 7 weeks (from Charles River Japan), 3 to 5 per group in the main tumor experiments, carrying tumors from human mesothelioma cell lines ACC-MESO-4 and NCI-H226 or the human hepatocellular carcinoma line Huh7. Immune cells for the lab-dish tests came from Rag-2-deficient C57BL/6 mice.
• Exposure: No asbestos exposure was studied. The treatment was the anti-C-ERC/mesothelin mouse monoclonal antibody 22A31, compared with normal mouse IgG1 control antibody. It was given twice per week, 10 times, either into the abdominal cavity or directly into the tumor.
• Main results:
  • ACC-MESO-4 and NCI-H226 tumor cells expressed C-ERC/mesothelin, including after transplantation into nude mice; Huh7 cells did not.
  • In mice with ACC-MESO-4 tumors, injection of 22A31 into the abdominal cavity did not significantly inhibit tumor growth compared with control antibody.
  • Injection of 22A31 directly into the tumors significantly inhibited the growth of ACC-MESO-4 tumors, but not Huh7 tumors, compared with control antibody, and the effect was dose-dependent.
  • In lab dishes, 22A31 did not directly inhibit the growth of ACC-MESO-4 cells and did not induce complement-dependent killing of them.
  • 22A31 induced antibody-dependent cell-mediated killing (ADCC) of mesothelin-expressing cells with purified NK cells, but not with purified macrophages.
  • In mice, the F(ab')2 fragment of 22A31 did not inhibit growth of ACC-MESO-4 tumors compared with intact 22A31 (n = 5 per group).
  • The antitumor effect of 22A31 was inhibited when NK cells were depleted in the mice (n = 5 per group).
• The authors' conclusion: The authors concluded that 22A31 acted against C-ERC/mesothelin-expressing tumor cells through NK cell-mediated ADCC in mice, and that it could have potential as a therapeutic tool for C-ERC/mesothelin-expressing cancers including mesothelioma.
• Limitations the authors state:
  • Because athymic nude mice were used, the authors could not examine whether the treatment induced tumor-specific cytotoxic T cells.
  • Injection into the abdominal cavity had no significant antitumor effect. The authors suggested this was possibly due to insufficient antibody concentration within the tumor.
  • The roles of C-ERC/mesothelin in tumor cells are not yet clear, and the authors called for further studies.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelin, Monoclonal Antibody, Mesothelioma, Asbestos Exposure, Prognosis, Latency, Macrophage.

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