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Recombinant Human Hexamer-Dominant IgM Monoclonal Antibody to Ganglioside GM3 for Treatment of Melanoma

Authors' Affiliations: ¹ Pharmaceutical Research Department III, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan; ² Genome Antibody Research Department, ³ Oncology Disease Area Department, ⁴ Preclinical Research Department, and ⁵ Safety Assessment Department, Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan; and ⁶ Department of Biotechnology Sciences, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California

Requests for reprints: Hisafumi Yamada-Okabe, Pharmaceutical Research Department III, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530 Japan. Phone: 81-467-45-4382; Fax: 81-467-45-6782; E-mail: okabehsf{at}chugai-pharm.co.jp.

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.

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.

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.

Conclusions: A hexamer-dominant human IgM against GM3 may provide a more potent treatment option for patients with GM3-positive melanoma.

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				Article on Recombinant Human Hexamer-Dominant IgM Monoclonal Antibody to Ganglioside GM3 for Treatment of Melanoma Clin. Cancer Res., July 1, 2007; 13(13): 4029 - 4031. [Full Text] [PDF]