MAST, Modular Activator and Silencer Therapeutics

人体产生的抗体可以识别细菌和病毒等不需要的入侵者的抗原。然后，这些抗体帮助指导免疫系统对抗入侵者并摧毁它们。抗体之所以能做到这一点，是因为它们有数百万种变体，每一种都对特定的目标具有独特的特异性，例如，一种特定类型的抗原只在一种细菌上显示。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，或者在科学实验中作为测量感兴趣产品数量的标记。事实上，这种情况发生得如此之大，以至于现在任何其他类型的蛋白质都不可能比不起眼的抗体对生物研究的进步和蛋白质疗法的发展做出更大的贡献。它几乎参与了所有可以想象的生物工程实验。即便如此，新的抗体应用仍然有巨大的潜力，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，每种抗体都赋予抗体新的和不同的能力。第一个平台将使抗体不仅能够结合靶标，还能改变其行为。有许多疾病是由蛋白质过度活跃或活性不足引起的，因此，能够制造出能够纠正目标蛋白质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更有可能结合和改变目标行为的抗体形状的库。第二和第三个平台将包含具有特殊功能的蛋白质阵列，这些功能可以将目标物送到细胞内的废物处理机器（降解物）中降解，或者像剪刀一样直接切割和破坏目标物（蛋白酶）。这些阵列将被设计成可以与任何抗体相连接。抗体可以用来引导这些蛋白质到一个特定的目标，在那里它们可以降解或破坏它。这些平台对于治疗任何一种特定蛋白质过度活跃并引发问题的疾病（如许多癌症中发生的情况）都是无价的，因此降解或摧毁它是一种理想的治疗方法。在这个项目中，我们汇集了抗体、降解物和蛋白酶的蛋白质工程专家团队，他们在人工智能、结构生物学、蛋白质进化和药理学分析筛选方面具有丰富的经验。据我们所知，目前还没有技术平台可以满足这里提出的三个目的。我们将制作、测试和验证这些平台。由于这三种平台都涉及赋予抗体新的能力，它们需要重叠的抗体生产和筛选方法，因此应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完全合理的，他们可以协同工作流程以确保项目目标的有效交付。然后，我们将把这些平台提供给英国学术界和工业界，以便他们也可以使用这些平台。此外，我们还与行业合作伙伴进行了接触，以获得他们的支持，包括潜在地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的抗体疗法的发展，并赋予英国生物科学部门权力。

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.