Engineered Antibody EGFR Antagonist Cancer Therapeutics

描述（由申请人提供）：该生物工程研究合作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，产生抗体结合肿瘤细胞中表达增加的靶标一直是一种很有前途的治疗方法。然而，抗体结合可以产生多种不同的细胞反应，最终，控制肿瘤细胞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分离和工程化，以计算对接预测和细胞对改变的EGFR信号，二聚化和运输的反应的定量分析为指导。EGFR在广泛的上皮性癌症中过表达，阻断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取得了良好进展，因此体内疗效的分子机制尚不完全清楚。针对特定的表皮生长因子受体表面设计抗体，以最大限度地发挥受体拮抗和下调作用，应该会产生更大的治疗效果。拟议的研究将开发适用于针对广泛靶标，特别是细胞表面受体的抗体设计的方法。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/蛋白识别通用工具；并将通过结合定量细胞生物学和蛋白质工程开发生物反应修饰的分析方法。

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.