MAST, Modular Activator and Silencer Therapeutics

MAST，模块化激活剂和沉默剂疗法

• 批准号: BB/Y007816/1
• 负责人: Laura Itzhaki
• 金额: $ 178.33万
• 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=BB%2FY007816%2F1
• 关键词: MAST; Modular; Activator; Silencer; Therapeutics

The human body produces antibodies that recognize antigens on unwanted invaders such as bacteria and viruses. These antibodies then help direct the immune system against the invaders to destroy them. Antibodies can do this because there are millions of variations of them and each one has a unique specificity for a particular target, e.g., a particular type of antigen displayed only on one type of bacteria. This special property of antibodies has also allowed scientists to manipulate them to recognize many other useful targets of interest, for example in cancers, or to act as a marker to measure the amount of a product of interest in a scientific experiment. In fact, this has happened to such a degree that it is now unlikely any other type of protein has made a greater contribution to the advancement of biological research and the development of protein therapeutics than the humble antibody. It has been a participant in pretty much every biological engineering experiment conceivable. Even so, there remains huge potential for new antibody applications, and it is essential that the UK bioscience sector continues to be at the forefront of antibody technology development.Here we propose to expand the potential of antibody technologies by developing three new antibody platforms, each of which gives antibodies a new and different ability. The first platform will give antibodies the ability to not only bind a target but also change its behaviour. There are many diseases that are caused by proteins being overactive or underactive, and consequently, being able to make antibodies that can correct the activity level in a target protein would be enormously therapeutically useful. Currently, antibodies that bind a target are generally discovered from libraries of antibodies of all sorts of different shapes. Instead, we will create a library that is biased towards antibody shapes that are more likely to be able to bind and change a target's behaviour. The second and third platforms will instead contain arrays of proteins with specialised functions to either send a target to be degraded by the waste-disposal machinery inside a cell (degraders), or to act like scissors to directly cut up and destroy the target (proteases). These arrays will be designed so that they can be linked to any antibody of choice. The antibody can then be used to direct these proteins to a specific target where they can degrade or destroy it. These platforms will be invaluable for tackling any disease where a particular protein is overactive and causing problems, as occurs in many cancers, and so degrading or destroying it is an ideal therapeutic approach.For this project we have brought together a specialist team in protein engineering of antibodies, degraders, and proteases, with experience in artificial intelligence, structural biology, protein evolution, and pharmacological assay screening. To our knowledge there are no technology platforms currently available that fulfil the three purposes proposed here. We will make, test, and validate these platforms. Because all three platforms involve giving antibodies new abilities and they require overlapping methods for antibody production and screening it makes perfect sense to apply a team approach to developing these technologies together in parallel and employ a team of scientists with expertise in biochemistry or assay design, who can synergise workflows to ensure effective delivery of the project goals. We will then make the platforms available to UK academia and industry so that they can also use them. In addition, we have also engaged with industry partners to secure their support, including potentially aiding in screening of potential therapeutic leads. We believe that the creation of these technology platforms will facilitate the development of new antibody therapeutics and empower the UK bioscience sector.

人体产生抗体，识别有害入侵者（如细菌和病毒）上的抗原。然后，这些抗体帮助引导免疫系统对抗入侵者，摧毁它们。抗体可以做到这一点，因为它们有数百万种变体，每一种都对特定的靶点具有独特的特异性，例如，只在一种细菌上显示的特殊类型的抗原。抗体的这种特殊性质也使科学家能够操纵它们来识别许多其他有用的目标，例如在癌症中，或者作为标记物来测量科学实验中感兴趣的产物的量。事实上，这种情况已经发生到了这样一种程度，以至于现在不太可能有任何其他类型的蛋白质对生物学研究的进步和蛋白质疗法的发展做出比卑微的抗体更大的贡献。它几乎参与了所有可能的生物工程实验。尽管如此，新的抗体应用仍有巨大的潜力，英国生物科学部门继续走在抗体技术发展的最前沿是至关重要的。在这里，我们建议通过开发三种新的抗体平台来扩大抗体技术的潜力，每种抗体平台都赋予抗体一种新的不同的能力。第一个平台将使抗体不仅能够结合靶标，而且还能够改变其行为。有许多疾病是由蛋白质过度活跃或活性不足引起的，因此，能够制造可以纠正靶蛋白活性水平的抗体将在治疗上非常有用。目前，结合靶标的抗体通常是从各种不同形状的抗体库中发现的。相反，我们将创建一个偏向于抗体形状的库，这些抗体形状更有可能结合并改变目标的行为。第二个和第三个平台将包含具有专门功能的蛋白质阵列，要么发送目标通过细胞内的废物处理机制（降解剂）降解，要么像剪刀一样直接切割和破坏目标（蛋白酶）。这些阵列将被设计成使得它们可以连接到任何选择的抗体。然后，抗体可以用于将这些蛋白质引导到特定的目标，在那里它们可以降解或破坏它。这些平台对于解决任何特定蛋白质过度活跃并引起问题的疾病都是非常宝贵的，就像许多癌症一样，因此降解或破坏它是一种理想的治疗方法。和蛋白酶，具有人工智能、结构生物学、蛋白质进化和药理学分析筛选方面的经验。据我们所知，目前没有任何技术平台可以满足这里提出的三个目的。我们将开发、测试和验证这些平台。由于所有三个平台都涉及赋予抗体新的能力，并且它们需要重叠的抗体生产和筛选方法，因此采用团队方法并行开发这些技术并雇用具有生物化学或检测设计专业知识的科学家团队是非常有意义的，他们可以协同工作流程以确保有效实现项目目标。然后，我们将向英国学术界和工业界提供这些平台，以便他们也可以使用它们。此外，我们还与行业合作伙伴合作，以确保他们的支持，包括可能帮助筛选潜在的治疗线索。我们相信，这些技术平台的创建将促进新抗体疗法的开发，并为英国生物科学领域提供动力。