Mapping aggregation-prone regions induced by extensional flow

蛋白质聚集对2000亿GB的生物制药行业来说是一个很大的问题，因为它可能对患者构成危险(蛋白质药物失去疗效和诱导免疫反应)，并可能增加上市时间，从而增加商品成本。在过去的四年里，我们已经证明了流体驱动的力量可以驱动模型蛋白质，如牛血清白蛋白(BSA)和包括G-CSF在内的生物制药以及那些基于IgG1支架的蛋白质的聚集。对于BSA，我们证明了施加的流体动力可以导致新的蛋白质表面暴露，具有更大的自亲和力，导致聚集。IGG的流动诱导聚集途径(S)仍未被探索，因此工业不能可靠地识别固有可制造的序列。随着抗体药物的偶联、下一代双特异性平台和基因治疗载体的出现，聚合技术已经对生物技术产业中蛋白质的巨大潜力的实现构成了更大的挑战。因此，Astbury结构和分子生物学中心与Medimmune之间的BBSRC CTP博士生项目的目标是应用利兹在蛋白质(非)折叠机制、分析质谱学和流体力学流动方面的独特专业知识来识别Medimmune专有生物制药的聚集界面。这项基础性研究最终将促进当前和下一代高价值生物药物的经济生产。

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.