BIOMEDICAL (BASIC)

该项目的目标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过度表达的水平不够高，无法从赫赛汀中获益。已经鉴定出Her-2/ new多体先导物，与具有相同Fab的单克隆抗体相比，其ADCC显著改善。该合同提案需要在ADCC试验中对化合物进行优化和评估，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/ new人类肿瘤细胞的异种移植试验。至少12种目前设计的化合物将在优化过程中生产和测试。许多学者和公司都试图通过糖基化工程和Fc结构域的定点诱变来改善Fc - Fc受体的结合。相反，交叉体通过改变IgG 1抗体Fc区的结构，代表了一种全新的交联NK细胞低亲和力Fc γ受体的方法。该项目的结果将是确定一个领先的Her-2/新体，以推进异种移植和ind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.