Recombinant human hexamer-dominant IgM monoclonal antibody to ganglioside GM3 for treatment of melanoma.

Abstract

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 approximately 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.

• Authors: Yumiko Azuma, Yuji Ishikawa, Shigeto Kawai, Toshiaki Tsunenari, Hiroyuki Tsunoda, Tomoyuki Igawa, Shin-ichiro Iida, Masahiko Nanami, Masami Suzuki, Reiko F Irie, Masayuki Tsuchiya, Hisafumi Yamada-Okabe
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 9 Pg. 2745-50 (May 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17473208 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• G(M3) Ganglioside
• L612 monoclonal antibody
• Recombinant Proteins

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• CHO Cells
• Cell Line, Tumor
• Cricetinae
• Cricetulus
• G(M3) Ganglioside (immunology)
• Humans
• Melanoma (chemistry, drug therapy, pathology)
• Recombinant Proteins (therapeutic use)
• Skin Neoplasms (chemistry, drug therapy, pathology)