Software for Determining Proteoform Heterogeneity and Protein Expression Fidelity

GenNext Technologies第二阶段SBIR建议书，标题为 确定蛋白质形式的异质性和蛋白质表达的保真度 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 包，它独特地评估了生物治疗蛋白表达的精确度。 在过去的30年里，全球生物制药市场 蒸蒸日上，2015年销售额超过1760亿美元。它的结构和 生物制药的功能活性取决于它们的不同方面 生产和环境。具有不正确结构的蛋白质的存在 与药物不良反应(ADR)有关，从患者症状到 对发病率和死亡率的刺激。ADR的出现提醒了 蛋白质结构在生物制药工业中的关键作用 生物疗法的安全性和功能。 生物制药重组蛋白的表达天生就容易低水平 由于氨基酸错误结合而导致序列变异的错误。这个 表达系统和培养条件会影响蛋白质产品的质量 属性，如翻译保真度和翻译后修改。这些 蛋白质变体通过多种方式影响产品质量：改变功能；改变 活性；配体/底物结合的改变；干扰的蛋白质折叠导致蛋白质 聚集；血清半衰期减少；治疗效果减弱；以及不受欢迎 病人的免疫反应。出于对疗效和患者安全的考虑，有必要 需要确定这些低水平蛋白质变体的特征。 在我们的目标实现后，我们的第二阶段计划将提供生物制药 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疗法 可表现为药物不良反应的表达变体。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 以一种便捷的方式，以便他们不仅了解这些 改变，但也可能改善表达过程，以消除这些人工制品。

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.