title: Antitumor activity of anti-C-ERC/mesothelin monoclonal antibody in vivo.
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.
authors.affiliation: Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Inami
authors.forename: Masaaki
authors.initials: M
authors.lastname: Abe
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Hagiwara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maeda
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Segawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Suyama
authors.forename: Sumio
authors.initials: S
authors.lastname: Watanabe
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology*; D000090204:Mesothelin; D008654:Mesothelioma / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C413325:Erc protein, human; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; D008562:Membrane Glycoproteins; C000715528:Msln protein, mouse; D015513:Oncogene Proteins; D000090204:Mesothelin