ISPO

Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

New rituximab (IDEC-C2B8) glycosylated variants with increased antibody-dependent cellular cytotoxicity: A general technology

J Jean-Mairet, P Umaña, JE Bailey

Institute of Biotechnology, ETH-Zürich, Switzerland

Unconjugated mAbs can be useful medicines for the treatment of cancer, as demonstrated by FDA-approved rituximab and trastuzumab. In spite of the achievements of these two drugs, there is currently a large interest in obtaining higher specific antibody activity than what is typically afforded by unconjugated mAb therapy. One way to obtain large increases in potency, while maintaining a simple production process and potentially avoiding significant, undesirable side effects, is to enhance the natural, cell-mediated effector functions of mAbs by engineering their oligosaccharide component. The glycosylation pattern of monoclonal antibodies is largely known to affect their biological performance including antibody-dependent cellular cytotoxicity (ADCC), but until recently only decreased ADCC activity, when eliminating or modifying the N-linked carbohydrate moiety, had been observed. Here we describe a general approach to significantly increase the in vitro ADCC activity of unconjugated IgGs by engineering the glycosylation pattern in the Fc region of monoclonals. The glycosylation pattern of rituximab (IDEC-C2B8) and an anti-neuroblastoma antibody (chCE7) were engineered in CHO cells with tetracycline-regulated expression of GnTIII. This enzyme catalyzes the formation of bisected oligosaccharides. In vitro ADCC activity of differently glycosylated antibody preparations correlated with the level of Fc-associated bisected oligosaccharides, and these preparations had significantly higher in vitro ADCC activity than non-modified or marketed counterparts. The ADCC-increasing strategy presented here should be applicable both those antibodies which already have significant ADCC activity in the absence of bisected oligosaccharides, and to the large group of mAbs with fine tumour specificities but unable to trigger effector functions of sufficient potency to be clinically useful.

For more information, contact jean@biotech.biol.ethz.ch

Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on cell cycle inhibitors.

http://www.cancerprev.org/Journal/Issues/24/101/108/3842