Higher Order Structure Analysis of Protein Therapeutics by Covalent Labeling MS

通过共价标记 MS 对蛋白质治疗药物进行高阶结构分析

• 批准号: 9139644
• 负责人: Eric Graban
• 金额: $ 27.73万
• 依托单位: RECLAIM PHARMACEUTICAL WASTE MANAGEMENT
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139644
• 关键词: 3-Dimensional; Accounting; Administrator; Amino Acids; Biotechnology; Businesses; Circular Dichroism; Client; Computer software; Data; Data Analyses; Detection; Drug Industry; Effectiveness; Ensure; Exposure to; Fee-for-Service Plans; Feedback; Fluorescence Spectroscopy; Formulation; Generic Drugs; Goals; Healthcare; High Pressure Liquid Chromatography; Higher Order Chromatin Structure; IgG1; Immunoglobulins; Indiana; Indium; Label; Lead; Legal patent; Location; Market Research; Marketing; Mass Spectrum Analysis; Massachusetts; Measurement; Measures; Methods; Molecular Structure; Monoclonal Antibodies; Output; Parents; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Positioning Attribute; Process; Production; Protein Analysis; Protein Engineering; Proteins; Research; Research Personnel; Resolution; Safety; Sales; Sampling; Services; Side; Small Business Innovation Research Grant; Somatropin; Staging; Stress; Structural Genes; Technology; Testing; Therapeutic; Time; Universities; Waste Management; Work; base; cost; design; drug development; drug efficacy; immunogenicity; improved; innovation; insight; light scattering; mass spectrometer; oxidation; patient safety; protein aggregate; protein structure; public health relevance; response; small molecule; success; therapeutic protein; three dimensional structure; tool; user-friendly

 DESCRIPTION (provided by applicant): Protein therapeutics are the fastest growing segment of the pharmaceutical market, accounting for one-third of the overall late stage drug development pipeline, and anticipated to represent 20% of the total pharmaceuticals market value by 2017. However, two significant challenges must be overcome to maximize patient benefit and access to biologic drugs: Patient immunogenicity remains a significant problem for biologic drugs, resulting in patient non-response rates of up to 70% or more over the course of long term treatment. Denatured and aggregated proteins in biologic drugs are a known cause for immunogenicity, so maintaining their 3D structure is therefore critical for ensuring patient safety and drug efficacy. Lack of low cost generic competition looms as a pressing issue with biologic drug patents worth more than $26 billion in annual US sales expiring before 2020. However, one challenge slowing FDA approval of biosimilar drug applications is the inability to ensure that the 3D structures of proposed biosimilars are the same as the original branded drug. Unfortunately, current analytical strategies are inadequate for delivering easy to obtain, high-resolution analyses of protein 3D structure. In response, ReclaimRx and its research partners at Indiana University and University of Massachusetts propose to develop a mass spectrometry method that uses labeling to detect changes in protein 3D structure. This method will be quick, easy to use, and high resolution. Preliminary studies have demonstrated the strong potential for success of the proposed labeling approach by detecting changes in the 3D structure of 3 proteins (β-2-microglobulin, human growth hormone, and immunoglobulin G1) in response to forced degradation conditions. Phase I efforts will build upon this work by demonstrating the feasibility of the proposed technology. This will be achieved through the following Specific Aims: 1) Demonstrate effective detection of the structural degradation of 3 proteins (EPO, human growth hormone, and an IgG1 mAb) in response to thermal and oxidative forced degradation conditions; and 2) Develop a software pipeline specifically designed for protein covalent labeling studies. The simplicity of this approach allows ReclaimRx, an Indiana-based small business, to commercialize this method via a fee-for-service offering, where client will send samples to be analyzed in ReclaimRx's facilities. This service will include data analysis via software that converts the MS files into user-friendly formats. Phase II efforts will focus on developing the technology as a kit that can be purchased to allow researchers to perform the analysis in their own lab, and further refining the software pipeline for commercial use and test conditions relevant to potential customers.

 描述（由申请人提供）：蛋白质治疗剂是医药市场增长最快的部分，占整个后期药物开发管道的三分之一，预计到2017年将占医药市场总价值的20%。然而，必须克服两个重大挑战，以最大限度地提高患者的利益和获得生物药物：患者免疫原性仍然是生物药物的一个重大问题，导致患者在长期治疗过程中的无应答率高达70%或更高。生物药物中变性和聚集的蛋白质是免疫原性的已知原因，因此保持其3D结构对于确保患者安全性和药物疗效至关重要。缺乏低成本的仿制药竞争是一个紧迫的问题，生物药物专利价值超过260亿美元，美国年销售额将在2020年前到期。然而，阻碍FDA批准生物仿制药申请的一个挑战是无法确保拟议生物仿制药的3D结构与原始品牌药物相同。不幸的是，目前的分析策略不足以提供易于获得的高分辨率蛋白质3D结构分析。对此，ReclaimRx及其在印第安纳州大学和马萨诸塞州大学的研究合作伙伴提出开发一种质谱方法，利用标记来检测蛋白质3D结构的变化。这种方法快速、易于使用且分辨率高。初步研究表明，通过检测3种蛋白质（β-2-微球蛋白、人生长激素和免疫球蛋白G1）在强制降解条件下的3D结构变化，所提出的标记方法具有很强的成功潜力。第一阶段的工作将以这项工作为基础，证明拟议技术的可行性。这将通过以下具体目标实现：1）证明有效检测3种蛋白质（EPO、人生长激素和IgG 1 mAb）在热和氧化强制降解条件下的结构降解; 2）开发专门为蛋白质共价标记研究设计的软件管道。这种方法的简单性使得印第安纳州的一家小型企业ReclaimRx能够通过收费服务产品将这种方法商业化，客户将发送样品在ReclaimRx的设施中进行分析。这项服务将包括数据分析 通过软件将MS文件转换为用户友好的格式。第二阶段的工作重点是将该技术开发为一个可以购买的工具包，以允许研究人员在自己的实验室中进行分析，并进一步完善软件管道，用于商业用途和与潜在客户相关的测试条件。