Mapping aggregation-prone regions induced by extensional flow

绘制由拉伸流引起的易于聚集的区域

• 批准号: 2111955
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2111955
• 关键词: Mapping; aggregation; prone; regions; induced

protein aggregation is highly problematic to the £200bn biopharmaceutical industry as it can pose dangers to the patient (loss of efficacy of the protein drug and induction of the immune response) and can increase time-to-market and, therefore, cost of goods. Over the last four years, we have shown that fluid-driven forces can drive the aggregation of model proteins such as bovine serum albumin (BSA) and biopharmaceuticals including G-CSF and those based on IgG1 scaffolds. For BSA we showed that the hydrodynamic forces exerted can cause the exposure of a new protein surface with greater self-affinity, leading to aggregation. The flow induced aggregation pathway(s) of IgGs remain unexplored and consequently industry cannot reliably identify sequences that are inherently manufacturable. As antibody drug conjugates, next generation bi-specific platforms and gene therapy vectors are already posing an even greater manufacturing challenge, aggregation remains the major threat to the realisation of the enormous potentials of proteins in the bio-technology industry. The goal of this BBSRC CTP PhD studentship between the Astbury Centre for Structural and Molecular Biology and Medimmune, therefore, is to apply Leeds' unique expertise in protein (un)folding mechanisms, analytical mass spectrometry and hydrodynamic flow to identify the aggregation interfaces of Medimmune propriety biopharmaceuticals. This fundamental study will ultimately facilitate the economic production of current and next generation high-value bio-pharmaceuticals.

蛋白质聚集对于2000亿英镑的生物制药工业来说是非常成问题的，因为它可能对患者造成危险（蛋白质药物功效的丧失和免疫应答的诱导），并且可能增加上市时间，因此增加商品成本。在过去的四年里，我们已经证明，流体驱动力可以驱动模型蛋白质的聚集，如牛血清白蛋白（BSA）和生物药物，包括G-CSF和那些基于IgG 1支架。对于BSA，我们表明，施加的流体动力可以导致具有更大自亲和性的新蛋白质表面暴露，导致聚集。IgG的流动诱导的聚集途径仍然未被探索，因此工业上不能可靠地鉴定固有可制造的序列。由于抗体药物偶联物、下一代双特异性平台和基因治疗载体已经构成了更大的制造挑战，聚集仍然是生物技术行业实现蛋白质巨大潜力的主要威胁。因此，阿斯特伯里结构和分子生物学中心与Medimmune之间的BBSRC CTP博士研究生项目的目标是应用利兹在蛋白质（联合国）折叠机制，分析质谱和流体动力学流动方面的独特专业知识，以确定Medimmune专有生物药物的聚集界面。这项基础研究将最终促进当前和下一代高价值生物制药的经济生产。