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积木。我们已经开发出一种简单而有效的方法来连接生命系统中的多肽和蛋白质，这是一种蛋白质强力胶。这条途径依赖于一种最初来自化脓性链球菌的表面蛋白。这种强力胶技术已经进入疫苗临床，并正在走向抗癌治疗的临床。然而，世界上大多数地区都经历了这种细菌的轻微感染，并产生了识别细菌表面蛋白的抗体。这种免疫反应是这种蛋白质强力胶成功用于新疗法的主要障碍。在这里，我们将开发我们的蛋白质强力胶的变体，它是人类免疫系统最低限度识别的。然后，我们将利用我们重新设计的强力胶来应对基于细胞的疗法的一个重要挑战。CAR-T细胞已经成为治疗B细胞癌的一种非常成功的疗法。然而，CAR-T细胞疗法在治疗T细胞癌方面并不成功。我们将应用我们的蛋白质强力胶来解决CAR-T细胞对抗T细胞癌症的限制因素。我们将建立对CAR-T细胞针对T细胞淋巴瘤细胞的激活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。使用重新设计的强力胶，我们还将建立针对癌症而不是所有T细胞的细胞表面标记的CAR-T细胞的有效靶向，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.