title: Comprehensive screening for antigens overexpressed on carcinomas via isolation of human mAbs that may be therapeutic.
abstract: Although several murine mAbs that have been humanized became useful therapeutic agents against a few malignancies, therapeutic Abs are not yet available for the majority of the human cancers because of our lack of knowledge of which antigens (Ags) can become useful targets. In the present study we established a procedure for comprehensive identification of such Ags through the extensive isolation of human mAbs that may become therapeutic. Using the phage-display Ab library we isolated a large number of human mAbs that bind to the surface of tumor cells. They were individually screened by immunostaining, and clones that preferentially and strongly stained the malignant cells were chosen. The Ags recognized by those clones were isolated by immunoprecipitation and identified by MS. We isolated 2,114 mAbs with unique sequences and identified 21 distinct Ags highly expressed on several carcinomas. Of those 2,114 mAbs 356 bound specifically to one of the 21 Ags. After preparing complete IgG(1) Abs the in vitro assay for Ab-dependent cell-mediated cytotoxicity (ADCC) and the in vivo assay in cancer-bearing athymic mice were performed to examine antitumor activity. The mAbs converted to IgG(1) revealed effective ADCC as well as antitumor activity in vivo. Because half of the 21 Ags showed distinct tumor-specific expression pattern and the mAbs isolated showed various characteristics with strong affinity to the Ag, it is likely that some of the Ags detected will become useful targets for the corresponding carcinoma therapy and that several mAbs will become therapeutic agents.
authors.affiliation: Division of Antibody Project, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
authors.forename: Gene
authors.initials: G
authors.lastname: Kurosawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Akahori
authors.forename: Miwa
authors.initials: M
authors.lastname: Morita
authors.forename: Mariko
authors.initials: M
authors.lastname: Sumitomo
authors.forename: Noriko
authors.initials: N
authors.lastname: Sato
authors.forename: Chiho
authors.initials: C
authors.lastname: Muramatsu
authors.forename: Keiko
authors.initials: K
authors.lastname: Eguchi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Matsuda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takasaki
authors.forename: Miho
authors.initials: M
authors.lastname: Tanaka
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Iba
authors.forename: Susumu
authors.initials: S
authors.lastname: Hamada-Tsutsumi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ukai
authors.forename: Mamoru
authors.initials: M
authors.lastname: Shiraishi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Maiko
authors.initials: M
authors.lastname: Kurosawa
authors.forename: Sally
authors.initials: S
authors.lastname: Fujiyama
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Takahashi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Kato
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Mizoguchi
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Shamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuda
authors.forename: Mototaka
authors.initials: M
authors.lastname: Sugiura
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Hattori
authors.forename: Shuichi
authors.initials: S
authors.lastname: Miyakawa
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Shiroki
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Hoshinaga
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Hayashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugioka
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kurosawa
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D000951:Antigens, Neoplasm / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000175:diagnosis / Q000276:immunology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007167:Immunotherapy / Q000295:instrumentation / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000175:diagnosis / Q000276:immunology*; D019151:Peptide Library
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D019151:Peptide Library; D066246:ErbB Receptors