Engineered Antibody EGFR Antagonist Cancer Therapeutics

描述(由申请人提供)：该生物工程研究伙伴关系将开发生物分子分析和设计工具，用于设计用于癌症治疗的下一代治疗性抗体。多年来，产生抗体来结合在肿瘤细胞中表达增加的靶点一直是一种很有前途的治疗方法。然而，抗体结合可以产生各种不同的细胞反应，最终控制肿瘤细胞将需要仔细研究抗体结合和细胞反应之间的关系，以便设计适当的结合特性来产生所需的反应。在这里提出的研究中，针对表皮生长因子受体(EGFR)的抗体将通过定向进化、计算机对接预测和对改变的EGFR信号、二聚化和运输的细胞反应的定量分析来指导。EGFR在多种上皮性肿瘤中高表达，而封闭抗体目前通过临床免疫反应和筛选试验的局限性而不是这些初始抗体药物的合理设计而进展顺利，因此体内疗效的分子机制尚不完全清楚。以特定的EGFR表面为靶点的抗体旨在最大限度地发挥受体拮抗和下调作用，应该会产生更好的治疗效果。这项拟议的研究将开发适用于针对广泛目标的抗体设计方法，特别是细胞表面受体。BRP团队整合了蛋白质工程、细胞生物工程、计算蛋白质生物物理学候选人的专业知识；工程蛋白质/蛋白质识别的通用工具；并将通过结合定量细胞生物学和蛋白质工程开发生物响应修改的分析方法。

DESCRIPTION (provided by applicant): This Bioengineering Research Partnership will develop biomolecular analysis and design tools for engineering next-generation therapeutic antibodies for cancer therapies. Generating antibodies to bind targets whose expression is increased in tumor cells has been a promising therapeutic approach for many years. However, antibody binding can produce a variety of different cellular responses and, ultimately, control over tumor cells will require careful study of the relationship between antibody binding and cellular response so that appropriate binding properties can be engineered to produce desired responses. In the research proposed here, antibodies against epidermal growth factor receptor (EGFR) will be isolated and engineered by directed evolution, guided by computational docking predictions and quantitative analysis of cellular responses to altered EGFR signaling, dimerization, and trafficking. EGFR is overexpressed in a broad spectrum of epithelial cancers, and blocking antibodies are currently progressing favorably through clinical immune response and limitations of screening assays rather than rational design for these initial antibody drugs, and consequently the molecular mechanism of efficacy in vivo is not fully understood. Targeting specific EGFR surfaces with antibodies designed to maximize receptor antagonism and downregulation should result in greater therapeutic efficacy. The proposed research will develop approaches applicable to antibody design against a broad range of targets, particularly cell surface receptors. The BRP team integrates expertise in protein engineering, cellular bioengineering, computational protein biophysics candidates; generic tools for engineering protein/protein recognition; and will develop analytical approaches to biological response modification via combined quantitative cell biology and protein engineering.