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：
10582584
负责人：
Scot Randy Weinberger
金额：
$ 59.16万
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/10582584
关键词：
Achievement Adverse Drug Experience Report Amino Acid Substitution Amino Acids Antibodies Appearance 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 Marketing 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 Software Validation 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 manufacture 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 II阶段SBIR提案，标题为“软件确定蛋白质成型异质性和蛋白质表达保真度，建立在非常成功的第一阶段计划，并将生产出强大，易于使用的软件包装，独特地评估了生物疗法蛋白表达的精度。在过去的三十年中，全球生物制药市场有繁荣，2015年的销售额超过1760亿美元。结构和生物制药的功能活性取决于其的各个方面生产和环境。存在不当结构的蛋白质的存在与不良药物反应（ADR）有关，范围从患者的症状范围对发病和死亡的刺激。 ADR的外观已经提醒生物制药行业，蛋白质结构在生物治疗学的安全和功能。生物药物重组蛋白表达本质上容易出现低水平导致由氨基酸失物构成引起的序列变异的误差。这表达系统和文化条件会影响蛋白质产品质量属性，例如翻译的保真度和翻译后修改。这些蛋白质变体以多种方式影响产品质量：功能改变；改变活动;配体/底物结合改变；干扰蛋白质折叠导致蛋白质聚合;血清半衰期减少；治疗效率降低；和不需要的患者免疫响应。效率和患者安全的担忧是必要的需要表征这些低级蛋白质变体。通过实现我们的目标，我们的第二阶段提案将提供生物制药研究人员一种有价值的新软件工具，将检测不需要的生物治疗性表达变体可以表现为广告药物反应。我们的软件将使研究人员能够发现蛋白质表达和翻译后的存在以一种简单的方式变体，因此他们不仅了解这些的本质改变，但也可以改善放射性伪影的表达过程。