BIOMEDICAL (BASIC)

该项目的目的是开发一种治疗性生物制剂，改善乳腺癌患者的疗效，这些患者的Her-2/neu表达水平不足以从赫赛汀中获益。已经鉴定了Her-2/neu斯塔都体先导物，其证明相对于共享相同Fab的单克隆抗体显著改善的ADCC。该合同提案需要在ADCC试验中进行化合物优化和评估，评估在不同细胞类型和条件下产生的先导化合物，以及开发低过表达Her- 2/neu人肿瘤细胞的异种移植试验。在优化过程中，将生产和测试至少12种目前设计的化合物。许多学者和公司已经尝试通过Fc结构域的糖基化工程和定点诱变来改善Fc-Fc γ受体结合。相比之下，斯塔都体代表了通过对IgG 1抗体的Fc区的结构改变来交联NK细胞低亲和力Fc γ受体的全新方法。该项目的结果将是确定一种领先的Her-2/neu斯塔都体，以推进异种移植和IND使能研究。

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.