Open AccessComprehensive screening for antigens overexpressed on carcinomas via isolation of human mAbs that may be therapeutic
Author(s) -
Gene Kurosawa,
Yasushi Akahori,
Miwa Morita,
Mariko Sumitomo,
Noriko Sato,
Chiho Muramatsu,
Kaoru Eguchi,
Kazuki Matsuda,
Akihiko Takasaki,
Miho Tanaka,
Yoshitaka Iba,
Susumu Hamada-Tsutsumi,
Yojiro Ukai,
Mamoru Shiraishi,
Kazuhiro Suzuki,
Maiko Kurosawa,
Sally Fujiyama,
Nobuhiro Takahashi,
Ryoichi Kato,
Yoshito Mizoguchi,
Mikihiro Shamoto,
Hiroyuki Tsuda,
M. Sugiura,
Yoshinobu Hattori,
Shuichi Miyakawa,
Ryoichi Shiroki,
Kiyotaka Hoshinaga,
Nobuhiro Hayashi,
Atsushi Sugioka,
Yoshikazu Kurosawa
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0712202105
Subject(s) - antibody dependent cell mediated cytotoxicity , in vivo , monoclonal antibody , antigen , cytotoxicity , immunostaining , cell culture , cancer research , in vitro , immunoprecipitation , biology , microbiology and biotechnology , cancer , antibody , phage display , immunology , immunohistochemistry , biochemistry , genetics
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 IgG1 Abs thein vitro assay for Ab-dependent cell-mediated cytotoxicity (ADCC) and thein vivo assay in cancer-bearing athymic mice were performed to examine antitumor activity. The mAbs converted to IgG1 revealed effective ADCC as well as antitumor activityin 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.