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Understanding how aggregation influences the immune response to recombinant protein therapeutic drugs

了解聚集如何影响重组蛋白治疗药物的免疫反应

基本信息

批准号：
BB/L006391/1
负责人：
Jeremy Paul Derrick
金额：
$ 58.79万
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：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FL006391%2F1
关键词：
Understanding how aggregation influences immune

项目摘要

Many human diseases, such as multiple sclerosis and cancer, are now treated successfully with drugs which are proteins, rather than small molecules. Protein drugs have the advantage that they are highly specific for a particular target: antibodies are a good example. They can be developed to bind with high affinity to block a specific receptor on the surface of a cell, inhibiting the progress of disease. The use of this new kind of drug in the clinic has grown rapidly over the last two decades, because protein drugs offer the potential for therapeutic intervention which would be difficult or impossible to replicate with small molecule medicines. Although these protein drugs are generally well-tolerated and have opened up exciting new avenues for the treatment of disease, this approach has come with a specific problem. Biotherapeutic proteins (even proteins which are designed to 'look' human) can be recognised as being foreign by the immune system of the patient. This can lead to production of antibodies within the patient which bind to the protein drug and prevent it from functioning effectively. In some cases, the consequences have been more severe, leading to serious adverse health effects in patients undergoing treatment. The origin of this problem lies in the way in which the immune system recognises 'foreign' molecules: a classic question in immunology is, 'why does the immune system not attack its own host's cells?' We now know that there are sophisticated systems for eliminating or inactivating immune cells which would recognise 'self' antigens, to prevent this from happening. This phenomenon is called 'tolerance'. Many protein drugs, although apparently identical to those produced by the host, nevertheless manage somehow to breakdown tolerance and provoke an immune response. It is still unclear exactly how this happens. The aim of this proposal is to investigate this phenomenon and, ultimately, to use the information obtained to inform the design and development of more effective protein drugs in the future. We will focus on one particular aspect which impacts on the immune response to protein drugs- a behaviour known as aggregation. Anyone who has ever boiled an egg is familiar with this behaviour: the white of the egg, after boiling, is solidified. Heat treatment pulls the structure of the protein (albumin) in the egg white apart and the individual protein chains adhere into a dense mesh. This type of behaviour is a general property of proteins, and a version of it can occur in preparations of protein drugs. The presence of aggregates in the preparation is important, as we know that they are very effective at influencing the complex cellular and molecular processes that lead to an immune response. Our proposal will investigate the different immunological responses induced by aggregates from a selection of drug-like proteins. In particular, we seek to determine how these different responses are influenced and modulated by aggregate size, which is the main criterion used to characterise them.

许多人类疾病，如多发性硬化症和癌症，现在用蛋白质而不是小分子的药物成功地治疗了。蛋白质药物的优势在于它们对特定目标具有高度特异性：抗体就是一个很好的例子。它们可以通过高亲和力结合来阻断细胞表面的特定受体，从而抑制疾病的进展。在过去的二十年里，这种新型药物在临床中的应用迅速增长，因为蛋白质药物提供了治疗干预的潜力，这是小分子药物难以或不可能复制的。尽管这些蛋白质药物通常耐受性良好，并为疾病治疗开辟了令人兴奋的新途径，但这种方法有一个特殊的问题。生物治疗蛋白（甚至是设计成“看起来”像人类的蛋白）可以被患者的免疫系统识别为外来物。这可能导致患者体内产生抗体，这些抗体与蛋白质药物结合并阻止其有效发挥作用。在某些情况下，后果更为严重，对正在接受治疗的病人造成严重的不良健康影响。这个问题的根源在于免疫系统识别“外来”分子的方式：免疫学中的一个经典问题是，“为什么免疫系统不攻击自己宿主的细胞？”我们现在知道，有复杂的系统可以消除或使识别“自身”抗原的免疫细胞失活，以防止这种情况发生。这种现象被称为“宽容”。许多蛋白质药物，虽然表面上与宿主产生的药物相同，但却设法打破耐受性并引起免疫反应。目前尚不清楚这是如何发生的。本提案的目的是调查这一现象，并最终利用所获得的信息为未来更有效的蛋白质药物的设计和开发提供信息。我们将重点关注影响蛋白质药物免疫反应的一个特定方面——一种被称为聚集的行为。任何煮过鸡蛋的人都熟悉这种行为：鸡蛋的蛋白在煮沸后凝固了。热处理使蛋白（白蛋白）的结构分开，单个蛋白链粘合成致密的网状结构。这种类型的行为是蛋白质的一般特性，它的一个版本可能发生在蛋白质药物的制剂中。在制备中存在聚集体是很重要的，因为我们知道它们在影响导致免疫反应的复杂细胞和分子过程方面非常有效。我们的建议将研究不同的免疫反应诱导的聚集体从药物样蛋白的选择。特别是，我们试图确定这些不同的反应是如何受到骨料大小的影响和调节的，骨料大小是用来描述它们的主要标准。