Controlling protein self-assembly and stability using biological ions

利用生物离子控制蛋白质自组装和稳定性

• 批准号: 2777806
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2777806
• 关键词: Controlling; protein; self; assembly; stability

ImmTAC molecules are a promising new class of bispecific therapeutics produced by Immunocore for applications in oncology and as new treatments for infectious diseases. They are fusions of a T cell receptor (TCR) and a scFv antibody fragment with anti-CD3 effector function. As with most next-generation therapeutics, ImmTACC molecules are difficult to manufacture due to poor stability, high aggregation levels, and adsorption to surfaces. In particular, as ImmTACC molecules are administered at low concentrations, any surface adsorption to IV bags or syringes leads to poor control over their intended dose. Once a therapeutic is in development, the main route for controlling stability is through adding excipients. Current approaches, however, are not satisfactory and there is an urgent need for novel, but biologically safe excipients. One unexplored area involves mimicking how cells prevent non-specific protein aggregation through the use of biological hydrotropes. For example, ATP is proposed to not only function as an energy source, but also to maintain protein solubility in vivo. In this project, we will explore using biological molecules as stabilization agents in formulations. The work aims to gain a mechanistic understanding from elucidating and measuring the underlying bio-molecular interactions. While a key outcome is to stabilize therapeutics, we will gain insights about how cells maintain stability of densely packed protein environments and the formation of membraneless organelles, which is driven by subtle changes to protein solubility.The interdisciplinary project combines expertise in physicochemical sciences and biosciences for delivering more effective treatments that improve patient health and well-being. Because the biopharmaceutical sector has predominantly used a limited number of approved excipients, much room for innovation exists. Here, we explore exploiting the ways cells have naturally evolved to maintain the stability of densely-packed macromolecular environments, which relies, in part, on small multivalent ions, a good example being nucleotides. If successful, the technology could be rapidly translated into industry thereby demonstrating economic and societal impact. It builds upon expertise of leading academic groups and an innovative biotechnology company and combines state of the art analytical capabilities for advancing the reputation and leadership in UK formulation science. There exists a gap in well-trained bioformulation scientists, which will be addressed through training that crosses boundaries between engineering and life sciences combined with hands-on experience at a thriving biopharmaceutical facility.

ImmTAC分子是Immunocore生产的一类有前途的新型双特异性治疗剂，用于肿瘤学和感染性疾病的新治疗。它们是T细胞受体（TCR）和具有抗CD3效应子功能的scFv抗体片段的融合体。与大多数下一代治疗剂一样，ImmTACC分子由于稳定性差、聚集水平高和表面吸附而难以制造。特别地，当ImmTACC分子以低浓度施用时，对IV袋或注射器的任何表面吸附导致对其预期剂量的不良控制。一旦治疗药物处于开发阶段，控制稳定性的主要途径是通过添加赋形剂。然而，目前的方法并不令人满意，迫切需要新型但生物安全的赋形剂。一个未探索的领域涉及模拟细胞如何通过使用生物水溶助长剂来防止非特异性蛋白质聚集。例如，ATP不仅被认为是一种能量来源，而且还被认为是维持蛋白质在体内的溶解度。在这个项目中，我们将探索在配方中使用生物分子作为稳定剂。这项工作的目的是从阐明和测量潜在的生物分子相互作用中获得一个机械的理解。虽然关键成果是稳定治疗方法，但我们将深入了解细胞如何维持密集蛋白质环境的稳定性和无膜细胞器的形成，这是由蛋白质溶解度的细微变化驱动的。该跨学科项目结合了物理化学科学和生物科学的专业知识，提供更有效的治疗方法，改善患者的健康和福祉。由于生物制药行业主要使用有限数量的批准辅料，因此存在很大的创新空间。在这里，我们探索利用细胞自然进化的方式来维持密集包装的大分子环境的稳定性，这在一定程度上依赖于小的多价离子，一个很好的例子是核苷酸。如果成功，该技术可以迅速转化为工业，从而展示经济和社会影响。它建立在领先的学术团体和创新生物技术公司的专业知识基础上，结合了最先进的分析能力，以提高英国配方科学的声誉和领导地位。在训练有素的生物制剂科学家方面存在差距，这将通过跨越工程和生命科学之间界限的培训以及在蓬勃发展的生物制药设施中的实践经验来解决。