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

去免疫蛋白强力胶的设计和进化以增强模块化细胞疗法

• 批准号: MR/Y011910/1
• 负责人: Mark Howarth
• 金额: $ 136.29万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY011910%2F1
• 关键词: Design; evolution; deimmunized; protein; superglues

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.

新疗法的产生通常依赖于改进的工具来桥接和联合收割机生物构件。我们已经开发出一种简单而有效的途径来连接生命系统中的肽和蛋白质，一种蛋白质强力胶。这一途径依赖于最初来源于细菌化脓性链球菌的表面蛋白。这种强力胶技术已经进入了疫苗临床，并正在走向抗癌治疗的临床。然而，世界上大多数人都会受到这种细菌的轻度感染，并产生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，这些变体被人类免疫系统识别最低。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重要挑战。CAR-T细胞已经成为治疗B细胞癌症的一种非常成功的疗法。然而，CAR-T细胞疗法尚未成功对抗T细胞癌症。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细胞激活T细胞淋巴瘤细胞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很重要。使用重新设计的强力胶，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，这是避免危险免疫缺陷的关键。