Software for Determining Proteoform Heterogeneity and Protein Expression Fidelity

GenNext技术第二阶段SBIR提案，题为“软件 确定蛋白质形式异质性和蛋白质表达保真度，”建立在一个 非常成功的第一阶段计划，并将产生一个强大的，易于使用的软件 软件包，它唯一地评估了生物蛋白质表达的精确度。 在过去的三十年里，全球生物制药市场 2015年销售额超过1760亿美元。结构和 生物药物的功能活性取决于其 生产与环境。结构不正确的蛋白质的存在， 与药物不良反应（ADR）有关，从患者症状性 刺激发病率和死亡。ADR的出现已经引起了 生物制药行业的关键作用，蛋白质结构中发挥作用， 生物治疗药物的安全性和功能。 生物制药重组蛋白表达固有地倾向于低水平表达。 氨基酸错误掺入导致序列变异的错误。的 表达系统和培养条件可影响蛋白质产品的质量 属性，如翻译保真度和翻译后修饰。这些 蛋白质变体以多种方式影响产品质量：功能改变; 活性;改变的配体/底物结合;扰动的蛋白质折叠，导致蛋白质 聚集;降低的血清半衰期;降低的治疗功效;和不期望的 病人的免疫反应。对疗效和患者安全性的担忧需要 需要对这些低水平的蛋白质变体进行表征。 在实现我们的目标后，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， 表达变异，可能表现为药物不良反应。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，使他们不仅了解这些性质的变化， 改变，但也可以改善表达过程，以消除这些文物。

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.