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(申请人提供)：蛋白质疗法是药品市场增长最快的部分，占整个晚期药物开发流水线的三分之一，预计到2017年将占整个药品市场价值的20%。然而，要最大限度地使患者受益和获得生物药物，必须克服两个重大挑战：患者的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反应率高达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结构对于确保患者的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，因为美国年销售额超过260亿美元的生物药物专利将在2020年前到期。然而，减缓FDA批准生物相似药物应用的一个挑战是无法确保拟议的生物仿制药的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容易获得的、高分辨率的蛋白质3D结构分析。对此，ReclaimRx及其在印第安纳大学和马萨诸塞大学的研究伙伴提议开发一种使用标记来检测蛋白质3D结构变化的质谱学方法。该方法具有快速、易用、分辨率高等特点。初步研究表明，通过检测3种蛋白质(β-2-微球蛋白、人类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大的成功潜力。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来实现：1)展示对3种蛋白质(EPO、人类生长激素和IgG1mAb)在热和氧化强迫降解条件下的结构降解的有效检测；以及2)开发专门为蛋白质共价标记研究设计的软件流水线。这种方法的简单性使总部位于印第安纳州的小企业ReclaimRx可以通过收费服务将这种方法商业化，客户将把样品送到ReclaimRx的设施进行分析。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。第二阶段的工作将集中于开发这项技术，作为一种可以购买的工具包，使研究人员能够在自己的实验室中进行分析，并进一步完善用于商业用途的软件管道和与潜在客户相关的测试条件。