Controlling protein self-assembly and stability using biological ions

ImmTAC分子是由Immunocore公司生产的一种有前途的新型双特异性治疗药物，可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效应功能的scFv抗体片段的融合体。与大多数下一代治疗药物一样，由于稳定性差、聚集水平高和表面吸附，ImmTACC分子难以制造。特别是，由于imtacc分子以低浓度施用，静脉注射袋或注射器的任何表面吸附都会导致对其预期剂量的控制不佳。一旦一种治疗药物进入开发阶段，控制其稳定性的主要途径就是添加赋形剂。然而，目前的方法并不令人满意，迫切需要新的，但生物安全的赋形剂。一个未开发的领域涉及模拟细胞如何通过使用生物亲水物来防止非特异性蛋白质聚集。例如，ATP不仅可以作为能量来源，还可以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。这项工作旨在通过阐明和测量潜在的生物分子相互作用来获得机制理解。虽然一个关键的结果是稳定治疗方法，但我们将深入了解细胞如何维持密集排列的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微妙变化驱动的。该跨学科项目结合了物理化学科学和生物科学方面的专业知识，提供更有效的治疗方法，改善患者的健康和福祉。由于生物制药部门主要使用有限数量的批准赋形剂，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堆积的大分子环境的稳定性，这部分依赖于小的多价离子，核苷酸就是一个很好的例子。如果成功，这项技术可以迅速转化为工业，从而显示出经济和社会影响。它建立在领先的学术团体和创新型生物技术公司的专业知识基础上，并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缺口，这将通过跨越工程和生命科学之间的界限的培训以及在蓬勃发展的生物制药设施的实践经验来解决。

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.