The objective of this project is to bring into development a therapeutic biologic with improved efficacy in patients whose breast cancer does not over-express Her-2/neu at a high enough level to benefit from Herceptin?. A Her-2/neu stradobody lead has been identified which demonstrates significantly improved ADCC relative to the monoclonal antibody that shares an identical Fab. This contract proposal entails compound optimization and assessment in an ADCC assay, assessment of the lead compound produced in different cell types and conditions, and development of a xenotransplant assay with low over-expressing Her- 2/neu human tumor cells. At least twelve currently designed compounds will be produced and tested in the optimization process. Numerous academics and companies have attempted to improve Fc - Fc gamma receptor binding through glycosylation engineering and site directed mutagenesis of the Fc domains. The stradobodies, in contrast, represent a completely novel approach of cross-linking NK cell low affinity Fc gamma receptors via structural changes to the Fc region of the IgG 1 antibody. The result of this project will be the identification of a lead Her-2/neu stradobody to move forward into xenotransplant and IND-enabling studies.