Controlled bridging at the immune synapse to modulate T cell activation

双特异性抗体是一种工程蛋白，能够同时附着在两个不同的目标上。这种特性使双特异性抗体在疾病控制中的应用成为可能，这通常涉及到相同细胞表面分子之间或不同细胞之间复杂的相互作用。然而，这些目标分子存在于许多不同的位置、丰度、形状和方向，因此桥接两个目标可能需要双特异性抗体具有特定的几何形状。事实上，双特异性抗体的活性已被证明取决于分子上两个目标识别元素之间的空间关系，以及它们相互扭曲和弯曲的能力。目前选择特定活性的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，这些筛选方法要求组成部分以利基或不可扩展的形式生产。相反，我们在此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/肽超胶将任何两个肽标签连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。计算设计的确定大小和曲率的蛋白质连接体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，以微调其生物效应。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细胞表面不同的蛋白质组合，以增强其对患病细胞的杀伤活性，而不是健康细胞。

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.