权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Biopharmaceutical proteins: biophysical studies of aggregation and their interactions with excipients

生物制药蛋白质：聚集及其与赋形剂相互作用的生物物理学研究

基本信息

批准号：
BB/M006913/1
负责人：
Jeremy Paul Derrick
金额：
$ 47.43万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM006913%2F1
关键词：
Biopharmaceutical proteins biophysical studies aggregation

项目摘要

Traditionally, drugs used to treat disease have been small molecules- these are relatively simple chemicals, perhaps consisting of fewer than a couple of hundred atoms. They are sufficiently small to be made by direct chemical synthesis. Although this type of drug is still widely used, more recently a different kind of medicine has been introduced. These drugs are much larger molecules- containing many thousands of atoms- and are generally proteins. They have significant advantages over small molecule medicines, and have extended the scope for treatment of disease. Therapeutic antibodies are a good example: they have been developed to treat a range of human diseases, including multiple sclerosis, autoimmune diseases and cancer. The method of manufacture of these drugs- or biopharmaceuticals- is different from their small molecule counterparts, however. They are too complex to be made by direct chemical synthesis; instead, they are frequently made from cultured mammalian cells. The use of this new kind of drug has raised its own types of problems. Large proteins are generally much less stable to certain conditions, such as heat, compared to their small molecule counterparts. Considerable effort is therefore expended by the manufacturers for each new biopharmaceutical medicine to find conditions under which it is stable, and thus prolong its 'shelf life'. A major source of deterioration in stored preparations of biopharmaceutical drugs is aggregation- this is a technical term which describes the propensity for proteins to bind to each other in solution. Aggregates are effectively 'clumps' of protein which are many times larger than the original protein, and form spontaneously under certain conditions. Boiling an egg induces a similar kind of behaviour- the egg white protein (albumin) is pulled apart by the elevated temperature and the individual protein chains adhere into a dense mesh. This becomes insoluble, which is why the albumin is transformed from a transparent, colourless liquid into a white solid. The presence of aggregates in the preparation of a biopharmaceutical drug can be deleterious to its function- it can reduce its efficacy and also, on some occasions, induce the production of antibodies in the patient in response to its administration. One way to reduce aggregation is to add certain small molecules- called 'excipients'- which have the effect of stabilising the biopharmaceutical drug. The way in which excipients function is complicated, however, and not well understood. This proposal seeks to investigate how they function, using a range of different experimental tools which are designed to measure the behaviour and structure of proteins in solution. We will conduct these measurements under different conditions and with selected excipients which are commonly used. The information we obtain will be used as a practical guide to help in stabilization of new biopharmaceutical drugs, as they are developed in the future. We will also develop specific methods which can be used to provide a practical guide during drug development. The project is a partnership between an academic grouping, who have expertise in the various methods employed, and MedImmune, who have extensive experience in developing these new kinds of medicine and bringing them to market.

传统上，用于治疗疾病的药物是小分子--这些是相对简单的化学物质，可能由不到几百个原子组成。它们足够小，可以通过直接化学合成来制备。虽然这种药物仍然被广泛使用，但最近已经引入了一种不同的药物。这些药物是更大的分子-包含数千个原子-通常是蛋白质。它们比小分子药物具有显著优势，并扩大了疾病治疗的范围。治疗性抗体就是一个很好的例子：它们已被开发用于治疗一系列人类疾病，包括多发性硬化症、自身免疫性疾病和癌症。然而，这些药物或生物药物的制造方法与它们的小分子对应物不同。它们太复杂了，不能通过直接化学合成来制造;相反，它们通常由培养的哺乳动物细胞制成。这种新药的使用也带来了它自己的问题。与它们的小分子对应物相比，大蛋白质通常对某些条件（例如热）不太稳定。因此，对于每种新的生物制药药物，制造商花费了相当大的努力来寻找其稳定的条件，从而延长其“保质期”。生物制药药物储存制剂劣化的主要来源是聚集-这是一个技术术语，描述了蛋白质在溶液中相互结合的倾向。聚集体实际上是蛋白质的“团块”，其比原始蛋白质大许多倍，并且在某些条件下自发形成。煮鸡蛋也会引起类似的行为--鸡蛋的白色蛋白（白蛋白）被升高的温度拉开，单个蛋白质链粘附成密集的网格。这就变成了不溶性的，这就是为什么白蛋白从透明的无色液体转变成白色固体的原因。在生物制药药物的制备中聚集体的存在可能对其功能有害-它可以降低其功效，并且在某些情况下，还诱导患者响应于其施用而产生抗体。减少聚集的一种方法是添加某些小分子-称为“赋形剂”-具有稳定生物制药药物的作用。然而，赋形剂发挥作用的方式是复杂的，并且没有很好地理解。该提案旨在研究它们如何发挥作用，使用一系列不同的实验工具来测量溶液中蛋白质的行为和结构。我们将在不同的条件下使用常用的选定辅料进行这些测量。我们获得的信息将被用作实用指南，以帮助稳定新的生物制药药物，因为它们在未来的发展。我们还将开发特定的方法，可用于在药物开发过程中提供实用指导。该项目是一个学术团体和MedImmune之间的合作伙伴关系，前者拥有各种方法的专业知识，后者在开发这些新型药物并将其推向市场方面拥有丰富的经验。