Design and evolution of deimmunized protein superglues to enhance modular cell therapy

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The generation of novel therapeutics often depends on improved tools to bridge and combine biological building-blocks. We have developed a simple and efficient route to link peptides and proteins in living systems, a kind of protein superglue. This route depends on a surface protein originally derived from the bacterium Streptococcus pyogenes. This superglue technology has reached the clinic for vaccines and is moving towards the clinic for anti-cancer therapeutics. However, most of the world experiences mild infection by this bacterium and generates antibodies that recognise the bacterium's surface proteins. Such an immune response is a major obstacle to the success of this protein superglue for new therapies. Here we will develop variants of our protein superglue that are minimally recognised by the human immune system. We will then make use of our re-engineered superglue towards an important challenge for cell-based therapies. CAR-T cells have become a highly successful therapy for cancers of B cells. However, CAR-T cell therapy has not been successful against cancers of T cells. We will apply our protein superglue to address limiting factors for CAR-T cells against T cell cancers. We will establish control over the extent and time-course of CAR-T cell activation against T cell lymphoma cells, which is important to avoid sometimes fatal immune over-activation. Using the re-engineered superglue, we will also establish the efficient targeting of the CAR-T cells against cell-surface markers that are specific to the cancer and not all T cells, which is key for avoiding dangerous immunodeficiency.