Controlled bridging at the immune synapse to modulate T cell activation

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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.