Recombinant Human Hexamer-Dominant IgM Monoclonal Antibody to Ganglioside GM3 for Treatment of Melanoma
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- Yumiko Azuma
- 1Pharmaceutical Research Department III, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan;
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- Yuji Ishikawa
- 1Pharmaceutical Research Department III, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan;
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- Shigeto Kawai
- 1Pharmaceutical Research Department III, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan;
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- Toshiaki Tsunenari
- 1Pharmaceutical Research Department III, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan;
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- Hiroyuki Tsunoda
- 2Genome Antibody Research Department,
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- Tomoyuki Igawa
- 2Genome Antibody Research Department,
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- Shin-ichiro Iida
- 3Oncology Disease Area Department,
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- Masahiko Nanami
- 4Preclinical Research Department, and
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- Masami Suzuki
- 5Safety Assessment Department, Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan; and
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- Reiko F. Irie
- 6Department of Biotechnology Sciences, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California
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- Masayuki Tsuchiya
- 2Genome Antibody Research Department,
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- Hisafumi Yamada-Okabe
- 1Pharmaceutical Research Department III, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan;
抄録
<jats:title>Abstract</jats:title><jats:p>Purpose: L612, a human IgM monoclonal antibody produced by an EBV-transformed human B-cell line, binds to ganglioside GM3 and kills GM3-positive human melanoma cells in the presence of complement. It has been shown to be effective in some patients with late-stage melanoma. L612 consists of hexameric IgM (about 20%), pentameric IgM (about 74%), and other minor IgM molecules. Because hexameric IgM activates complement more effectively than pentameric IgM, we developed and evaluated a hexamer-dominant recombinant IgM for clinical applications.</jats:p><jats:p>Experimental Design: Chinese hamster ovary (CHO) cells were transfected with heavy- and light-chain genes of L612, with or without the joining-chain gene. Antitumor effects of the recombinant IgM secreted from CHO cells were evaluated in vitro and in vivo.</jats:p><jats:p>Results: Recombinant IgM secreted from CHO cells without the joining chain (designated CA19) was ∼80% hexameric, whereas recombinant IgM from CHO cells transfected with heavy-, light-, and joining-chain genes (designated CJ45) was about 90% pentameric. Both CA19 and CJ45 recombinant IgMs caused complement-dependent cytotoxicity against human and mouse melanoma cell lines, but the amount of CA19 required for 50% specific cytotoxicity was 5 to 10 times smaller. I.v. injection of CA19 compared with CJ45 or native L612 elicited more profound antitumor activity in nude rats bearing a GM3-positive mouse melanoma xenograft.</jats:p><jats:p>Conclusions: A hexamer-dominant human IgM against GM3 may provide a more potent treatment option for patients with GM3-positive melanoma.</jats:p>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 13 (9), 2745-2750, 2007-05-01
American Association for Cancer Research (AACR)
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キーワード
詳細情報 詳細情報について
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- CRID
- 1364233269258834688
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- ISSN
- 15573265
- 10780432
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- データソース種別
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- Crossref