Abstract B133: SEA technology: A novel strategy for enhancing antibody effector function

Abstract

Abstract The activity of monoclonal antibodies (mAbs) can be enhanced by a number of chemical and genetic strategies. We describe a novel strategy for enhancing antibody-dependent cellular cytotoxicity (ADCC) through modification of the mAb carbohydrate during expression, designated Sugar Engineered Antibody (SEA) technology. A series of small molecule fucose analogs were added to mAb-expressing Chinese hamster ovary (CHO) cells, with the resulting mAbs showing a significant reduction in their carbohydrate fucosylation. We demonstrate that these mAbs show a substantial increase in ADCC activity and an improvement in CD16 binding. We find that the mechanism of action is inhibition of GDP-mannose dehydratase (GMD), the first enzyme in de novo synthesis of GDP-fucose, leading to a depletion of substrate for the fucosyltransferase responsible for mAb carbohydrate fucosylation. We also demonstrate that this strategy yields mAbs with significantly reduced fucosylation in large scale CHO cell culture as well as in additional expression systems such as hybridomas and transient transfectants. Since genetic modification of the mAb-producing cell line is not required, SEA technology can be readily applied from the mAb screening to manufacturing stage to generate effector function enhanced therapeutic antibodies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B133.