Creating Clinically Relevant EGFR Antagonists

创造临床相关的 EGFR 拮抗剂

• 批准号: 6936885
• 负责人: PHILIP T PIENKOS
• 金额: $ 39.3万
• 依托单位: MOLECULAR LOGIX, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936885
• 关键词: affinity chromatography; athymic mouse; biological signal transduction; cell line; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; enzyme linked immunosorbent assay; epidermal growth factor; gel filtration chromatography; genetic library; growth factor receptors; inhibitor /antagonist; lead; peptide library; protein engineering; receptor binding; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Cancer is the second leading cause of death in the U.S., and is responsible for losses of over $100 billion per year due to medical costs and lost productivity. Abnormalities in the Epidermal Growth Factor Receptor (EGFR) system are recognized as a major cause of cancers and significant biomedical effort has been directed towards this target in a search for novel anti-cancer agents. In Phase I of this project we proposed the re-engineering of EGF to transform it from an agonist to an antagonist as the first stage of our Anti Cancer Ligand program. Computational analysis of the EGF sequence and scrutiny of EGF/EGFR interactions led to a rational program of site-directed mutagenesis, production, purification and analysis of EGF variants culminating in the successful accomplishment of the goals established in our Phase I SBIR grant, the identification of our early stage lead, a single point mutant with antagonist properties. In Phase II of this project we will confirm the therapeutic potential of that lead in mouse xenograft studies using the high-EGFR human cancer A431 cell line and then improve upon its potential through a program of affinity maturation using both phage display and rational modification. The high affinity antagonist will be tested in both in vitro and in vivo assays to demonstrate its efficacy against human tumor models and to demonstrate that its mode of action is consistent with its therapeutic properties. The identification of this pre-clinical drug lead is the ultimate goal of this proposed Phase II program, and the intellectual property generated in the course of this program will provide the basis for marketing this lead to the pharmaceutical industry.

描述（由申请人提供）：癌症是美国第二大死亡原因，每年因医疗费用和生产力损失造成超过 1000 亿美元的损失。表皮生长因子受体（EGFR）系统的异常被认为是癌症的主要原因，并且在寻找新型抗癌药物的过程中，大量的生物医学努力已针对这一目标。在该项目的第一阶段，我们建议对 EGF 进行重新设计，将其从激动剂转变为拮抗剂，作为我们抗癌配体计划的第一阶段。 EGF 序列的计算分析和 EGF/EGFR 相互作用的审查导致了 EGF 变体定点诱变、生产、纯化和分析的合理计划，最终成功实现了我们第一阶段 SBIR 资助中确立的目标，即鉴定我们的早期先导药物，具有拮抗特性的单点突变体。在该项目的第二阶段，我们将使用高 EGFR 人类癌症 A431 细胞系在小鼠异种移植研究中确认该先导物质的治疗潜力，然后通过使用噬菌体展示和合理修饰的亲和力成熟程序来提高其潜力。高亲和力拮抗剂将在体外和体内试验中进行测试，以证明其对人类肿瘤模型的功效，并证明其作用方式与其治疗特性一致。该临床前先导药物的鉴定是该二期计划的最终目标，该计划过程中产生的知识产权将为将该先导药物营销到制药行业提供基础。