Physico-chemical aspects of formulating next generation biologics, including TCRs (T cell receptors).

蛋白质类药物的配方是确保这些药物在给病人时的稳定性和有效性的一个重要方面。然而，我们对蛋白质-蛋白质相互作用和蛋白质-赋形剂相互作用的知识的基本差距使这一过程变得困难，因为该过程的合理化尚不可能。相反，许多配方是基于其他类似分子的先前成功进行的，或者实际上，由于找不到合适配方的分子，产品开发被放弃了。对于许多已经生产了很长时间的生物制剂（如胰岛素和igg），存在先验知识，并且大多数产品的配方相对简单。然而，下一代生物制剂使用不同的分子类型和新技术，现有的配方策略不那么有效或不存在。本项目将研究一类这样的下一代生物制剂，在免疫核心的开发管道。这些分子（tcr）在其生物学功能上具有足够的特异性，因此在最终药物产品中需要非常低浓度的分子。因此，在如何表征分子及其稳定性以及如何配制它们以减少蛋白质表面相互作用方面出现了许多新的挑战，这在低浓度配方中是一个更加困难的问题。利用布里斯托尔大学生物物理和软物质小组开发的一系列不同的分析工具和专业知识，我们将研究如何在低浓度制度下应用合适的技术（光谱学，光散射等），并研究特定的辅料，如糖，氨基酸和洗涤剂如何随着时间的推移影响产品的稳定性。

Formulation of protein-based drugs is an important aspect of ensuring stability and efficacy of these drugs when they are delivered to patients. However, fundamental gaps in our knowledge about protein-protein interactions and protein-excipient interactions make this process difficult, since rationalisation of the process is not yet possible. Instead, much formulation is conducted based on prior success with other similar molecules, or indeed product development is abandoned for molecules for which a suitable formulation cannot be found. For many biologics that have been produced for a long time (e.g. insulin and IgGs), prior knowledge exists and formulation for most products is relatively straightforward. However, next generation biologics use different molecule types and new technologies for which existing formulation strategies are not as effective or do not exist. This project will examine one such class of next generation biologics, in the development pipeline at Immunocore. These molecules (TCRs) are sufficiently specific in their biological function, that very low concentrations of molecules are required in the final drug product. Hence, a number of new challenges emerge in how to characterise the molecules and their stability and how to formulate them to reduce protein-surface interactions, which are a more difficult problem in low-concentration formulations. Using a range of different analytical tools and knowhow developed in the Biophysics and Soft matter group at the University of Bristol, we will examine how suitable technologies (spectroscopy, light scattering etc) may be applied in low concentration regimes and examine how specific excipients, such as sugars, amino acids and detergents impact on product stability over time.