Comprehensive screening for antigens overexpressed on carcinomas via isolation of human mAbs that may be therapeutic

Gene Kurosawa, Yasushi Akahori, Miwa Morita, Mariko Sumitomo, Noriko Sato, Chiho Muramatsu, Keiko Eguchi, Kazuki Matsuda, Akihiko Takasaki, Miho Tanaka, Yoshitaka Iba, Susumu Hamada-Tsutsumi, Yoshinori Ukai, Mamoru Shiraishi, Kazuhiro Suzuki, Maiko Kurosawa, Sally Fujiyama, Nobuhiro Takahashi, Ryoichi Kato, Yoshikazu MizoguchiMikihiro Shamoto, Hiroyuki Tsuda, Mototaka Sugiura, Yoshinobu Hattori, Shuichi Miyakawa, Ryoichi Shiroki, Kiyotaka Hoshinaga, Nobuhiro Hayashi, Atsushi Sugioka, Yoshikazu Kurosawa

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

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 IgG1 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 IgG1 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.

Original languageEnglish
Pages (from-to)7287-7292
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number20
DOIs
Publication statusPublished - 20-05-2008

All Science Journal Classification (ASJC) codes

  • General

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