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

新疗法的产生往往依赖于改进的工具来连接和结合生物构建模块。我们已经开发了一种简单有效的途径来连接肽和蛋白质的生命系统，一种蛋白质超级胶。这一途径依赖于一种原来源于化脓性链球菌的表面蛋白。这种强力胶技术已经应用于疫苗的临床，并正在走向抗癌治疗的临床。然而，世界上大多数人都受到这种细菌的轻微感染，并产生识别细菌表面蛋白质的抗体。这种免疫反应是这种蛋白质超级胶在新疗法中取得成功的主要障碍。在这里，我们将开发我们的蛋白质超级胶的变体，它被人体免疫系统最低限度地识别。然后，我们将利用我们重新设计的强力胶来应对细胞疗法的一个重要挑战。CAR-T细胞已经成为一种非常成功的治疗B细胞癌的方法。然而，CAR-T细胞疗法尚未成功对抗T细胞癌。我们将使用我们的蛋白强力胶来解决CAR-T细胞对抗T细胞癌的限制因素。我们将建立对CAR-T细胞对T细胞淋巴瘤细胞激活的程度和时间过程的控制，这对于避免有时致命的免疫过度激活非常重要。使用这种重新设计的强力胶，我们还将建立CAR-T细胞对癌症特异性细胞表面标记物的有效靶向，而不是所有T细胞，这是避免危险的免疫缺陷的关键。

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.