Comprehensive screening for antigens overexpressed on carcinomas via isolation of human mAbs that may be therapeutic.
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.
Kurosawa
Gene
G
Division of Antibody Project, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Akahori
Yasushi
Y
Morita
Miwa
M
Sumitomo
Mariko
M
Sato
Noriko
N
Muramatsu
Chiho
C
Eguchi
Keiko
K
Matsuda
Kazuki
K
Takasaki
Akihiko
A
Tanaka
Miho
M
Iba
Yoshitaka
Y
Hamada-Tsutsumi
Susumu
S
Ukai
Yoshinori
Y
Shiraishi
Mamoru
M
Suzuki
Kazuhiro
K
Kurosawa
Maiko
M
Fujiyama
Sally
S
Takahashi
Nobuhiro
N
Kato
Ryoichi
R
Mizoguchi
Yoshikazu
Y
Shamoto
Mikihiro
M
Tsuda
Hiroyuki
H
Sugiura
Mototaka
M
Hattori
Yoshinobu
Y
Miyakawa
Shuichi
S
Shiroki
Ryoichi
R
Hoshinaga
Kiyotaka
K
Hayashi
Nobuhiro
N
Sugioka
Atsushi
A
Kurosawa
Yoshikazu
Y
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
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D019151:Peptide Library; D066246:ErbB Receptors