Controlled bridging at the immune synapse to modulate T cell activation

控制免疫突触桥接以调节 T 细胞激活

• 批准号: 2445956
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2445956
• 关键词: Controlled; bridging; immune; synapse; modulate

Bispecific antibodies are engineered proteins that are capable of sticking to two different targets simultaneously. This property engenders applications for bispecific antibodies in the control of diseases, which often involve complex interactions between molecules on the surface of the same cells, or between different cells. However, these target molecules exist in many different locations, abundances, shapes, and orientations, so bridging two targets may require the bispecific antibody to be in a specific geometry. Indeed, bispecific antibody activity has been shown to depend on the spatial relationship between the two target-recognising elements on the molecule, as well as their ability to twist and bend relative to each other. Current approaches to select the shape and size bispecific antibodies for a specific activity are limited by cumbersome and costly screening approaches, which require the constituent parts to be produced in niche or unscalable formats. Instead, we herein propose a modular approach to bispecific antibody synthesis using protein/peptide superglues to assemble any two peptide tag-linked target-binding entities onto a central, customisable protein architecture. Computationally-designed protein linkers of defined size and curvature will be introduced into the bispecific architecture to control the way in the bispecific antibodies interact with their targets, in order to fine-tune their biological effect. In this research, we aim to build a library of bispecific antibodies in unique geometries that target different combinations of proteins on the surface of T cells to enhance their killing activity in response to diseased cells over healthy cells.

双特异性抗体是一种工程蛋白质，能够同时附着在两个不同的靶点上。这一特性使双特异性抗体在疾病控制中得到了应用，疾病往往涉及同一细胞表面的分子之间或不同细胞之间的复杂相互作用。然而，这些靶分子存在于许多不同的位置、丰度、形状和方向，因此连接两个靶分子可能需要双特异性抗体处于特定的几何形状。事实上，双特异性抗体的活性已被证明取决于分子上两个靶标识别元件之间的空间关系，以及它们相互扭曲和弯曲的能力。目前为特定活性选择形状和大小的双特异性抗体的方法受到繁琐和昂贵的筛选方法的限制，这些方法要求组成部分以利基或不可扩展的形式生产。相反，我们在这里提出了一种模块化的方法来合成双特异性抗体，使用蛋白质/多肽超胶将任何两个多肽标签链接的靶标结合实体组装到一个中心的、可定制的蛋白质结构上。通过计算设计的确定大小和曲率的蛋白质连接物将被引入到双特异性结构中，以控制双特异性抗体与其靶标相互作用的方式，从而微调它们的生物学效应。在这项研究中，我们的目标是建立一个独特几何形状的双特异性抗体库，针对T细胞表面的不同蛋白质组合，以增强它们对疾病细胞的杀伤活性，而不是健康细胞。