Software for Determining Proteoform Heterogeneity and Protein Expression Fidelity

用于确定蛋白质异质性和蛋白质表达保真度的软件

基本信息

批准号：
10379422
负责人：
Scot Randy Weinberger
金额：
$ 64.34万
依托单位：
GENNEXT TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379422
关键词：
Achievement Adverse Drug Experience Report Amino Acid Substitution Amino Acids Antibodies Appearance Base Sequence Binding Bioinformatics Biological Products Biological Response Modifier Therapy Cessation of life Code Complement Complex Computer software Consumption Dangerousness Data Detection Development Documentation Environment Financial Hardship Frequencies Goals Guidelines Half-Life Health Care Costs Healthcare Systems Heterogeneity Immune response Legal patent Ligands Link Liquid Chromatography Manufacturer Name Monoclonal Antibodies Morbidity - disease rate Morphologic artifacts Names Nature Patients Peptides Pharmacologic Substance Pharmacology Phase Play Post-Translational Protein Processing Procedures Process Production Proteins Recombinant Proteins Recombinants Research Research Personnel Role Safety Sales Serum Small Business Innovation Research Grant Software Tools Structure System Techniques Technology Testing Therapeutic Time Treatment Efficacy Validation Variant adverse drug reaction biopharmaceutical industry cell type detection limit expiration improved indexing infliximab irritation liquid chromatography mass spectrometry patient safety programs protein aggregation protein aminoacid sequence protein expression protein folding protein structure tandem mass spectrometry

项目摘要

The GenNext Technologies Phase II SBIR proposal entitled “Software for Determining Proteoform Heterogeneity and Protein Expression Fidelity,” builds upon a highly successful Phase I program, and will produce a robust, easy-to-use software package, that uniquely assesses the precision of biotherapeutic protein expression. During the last thirty years, the global market for biopharmaceuticals has prospered, achieving sales of more than $176 billion in 2015. The structure and functional activity of biopharmaceuticals are dependent on various aspects of their production and environment. The presence of proteins having improper structures has been linked to adverse drug reactions (ADR), which range from patient symptomatic irritation to morbidity and death. The appearance of ADR’s has alerted the biopharmaceutical industry to the critical role that protein structure plays in the safety and function of biotherapeutics. Biopharmaceutical recombinant protein expression is inherently prone to low-level errors resulting in sequence variants caused by amino acid misincorporation. The expression system and culturing conditions can influence protein product quality attributes, such as translational fidelity and post-translational modifications. These protein variants impact product quality in a number of ways: altered function; altered activity; altered ligand/substrate binding; perturbed protein folding leading to protein aggregation; decreased serum half-life; diminished therapeutic efficacy; and undesired patient immune response. Concerns for efficacy and patient safety necessitates the need to characterize these low-level protein variants. Upon achievement of our aims, our Phase II proposal will provide biopharmaceutical researchers a valuable, new software tool that will detect unwanted biotherapeutic expression variants that can manifest as adverse drug reactions. Our software will enable researchers to discover the presence of protein expression and post-translational variants in a facile manner so that they not only understand the nature of these alterations, but also may improve the expression process to eradicate these artifacts.

GenNext Technologies 第二阶段 SBIR 提案题为“Software for 确定蛋白质形式异质性和蛋白质表达保真度，”建立在第一阶段计划非常成功，并将产生一个强大、易于使用的软件包，独特地评估生物治疗蛋白质表达的精度。在过去的三十年里，全球生物制药市场发生了巨大的变化。蓬勃发展，2015 年销售额超过 1760 亿美元。生物制药的功能活性取决于其各个方面生产和环境中存在结构不当的蛋白质。与药物不良反应 (ADR) 有关，其中包括患者症状 ADR 的出现引起了人们的警惕。蛋白质结构在生物制药行业中发挥的关键作用生物治疗的安全性和功能。生物制药重组蛋白表达本质上容易出现低水平表达氨基酸错误掺入导致序列变异的错误。表达系统和培养条件会影响蛋白质产品的质量属性，例如翻译保真度和翻译后修饰。蛋白质变异通过多种方式影响产品质量：功能；活性；配体/底物结合扰乱蛋白质折叠；聚集；血清半衰期降低；以及不良反应；对患者免疫反应的担忧需要需要表征这些低水平的蛋白质变体。实现我们的目标后，我们的第二阶段提案将提供生物制药研究人员开发了一种有价值的新软件工具，可以检测不需要的生物治疗药物我们的软件会显示可能表现为药物不良反应的表达变异。使研究人员能够发现蛋白质表达和翻译后的存在以简单的方式识别变体，使他们不仅了解这些变体的本质改变，还可能改善表达过程以消除这些伪影。