Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections

用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征

• 批准号: MR/Y008693/1
• 负责人: Jeremy Brown
• 金额: $ 197.22万
• 依托单位: University College London
• 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%2FY008693%2F1
• 关键词: Isolation; characterisation; monoclonal; antibodies; treatment

The bacteria Acinetobacter baumannii causes severe lung and blood-borne infections in humans. It is one of the most highly resistant bacteria to antibiotics, and as a consequence A. baumannii infections have a very high mortality which approaches 50%. Overall, A. baumannii causes over 50,000 deaths per year across the globe, a number which is increasing. It is especially common in Asia with 15,000 deaths per year in Thailand alone, and at one of our research site hospitals the number of people with A. baumannii per year has increased from 100 in 2010 to over 500 in 2022. The World Health Organisation has made A. baumannii its top priority antibiotic resistant bacteria for which we need new treatments. One way of overcoming antibiotic resistance is to treat bacteria with antibodies, naturally occurring proteins that bind to invading microbes and boost the ability of the immune system to kill them. Antibody therapies are known to work for other microbes but are not available as yet for A. baumannii. We aim to fill this gap by developing an antibody treatment for A. baumannii. Over the past four years, we have identified antibodies to four A. baumannii proteins that we have shown bind strongly to the bacterial surface and can increase activity of the immune system against the bacteria. Importantly when given to mice these antibodies protected against A. baumannii infection, indicating they could be a good treatment for human infection. We now want to develop these antibodies for use in humans. To do so we need to obtain single specific antibodies for each of our protein targets which are called monoclonal antibodies, as these can then be produced in a factory in the large quantities needed for a treatment. We will isolate several monoclonal antibodies to each of our four A. baumannii proteins from either humans who have had previous A. baumannii infection and have developed an immune response to this bacteria, or from mice using vaccination experiments. We will then test each isolated monoclonal antibody to see how well they bind to and promote the immune systems ability to recognise and kill A. baumannii strains. We will also test each monoclonal antibody to see whether they can protect mice against A. baumannii infection. The most effective monoclonal antibodies will then be tested in combinations as our previous work suggests this will be more effective than a single antibody. In addition, we will collect data and samples on patients with A. baumannii infection at our hospital research site in Thailand. The information on the patients is needed so we can plan future clinical trials of a monoclonal antibody therapy; and samples from the patients will also help with the experiments investigating the monoclonal antibodies by providing white cells from which we can isolate monoclonal antibodies. At the end of the study we will have the data needed to decide which of the monoclonal antibodies and in which combination are likely to be the most effective treatment for A. baumannii infections. These monoclonal antibodies will in the future be developed into a clinical treatment for testing in humans.

细菌鲍曼尼菌的细菌会引起人类严重的肺和血传播感染。它是对抗生素最高度耐药的细菌之一，因此，鲍曼尼氏菌感染的死亡率很高，接近50％。总体而言，鲍曼尼曲霉每年在全球造成超过50,000人死亡，这一数字正在增加。仅在泰国，在亚洲尤为普遍，在我们的一家研究现场医院，每年有a。baumannii的人数已从2010年的100人增加到2022年的500多人。世界卫生组织使A. baumannii使我们的优先型抗生素耐药细菌为我们需要新的治疗方法。克服抗生素耐药性的一种方法是用抗体治疗细菌，自然存在的蛋白质结合到入侵微生物并增强免疫系统杀死它们的能力。众所周知，抗体疗法可用于其他微生物，但尚不可用于baumannii。我们旨在通过开发鲍曼尼曲霉的抗体处理来填补这一空白。在过去的四年中，我们已经鉴定出对四种鲍曼尼蛋白蛋白的抗体，它们已经显示出与细菌表面强烈结合的抗体，并可以增加免疫系统对细菌的活性。重要的是，当给小鼠时，这些抗体免受鲍曼尼曲霉感染的影响，这表明它们可能是人类感染的良好治疗方法。我们现在想开发这些抗体用于人类。为此，我们需要为我们的每种蛋白质靶标获取单克隆抗体的单一特异性抗体，因为这些抗体可以在工厂中以大量治疗所需的大量生产。我们将从以前曾患有鲍曼尼曲霉感染并使用疫苗接种实验的小鼠产生免疫反应的人类，将几种单克隆抗体分离为四种鲍曼尼蛋白蛋白中的每种单克隆抗体。然后，我们将测试每种孤立的单克隆抗体，以了解它们与识别和杀死鲍曼尼菌株的免疫系统的结合和促进能力。我们还将测试每种单克隆抗体，以查看它们是否可以保护小鼠免受鲍曼尼曲霉感染的侵害。然后，最有效的单克隆抗体将进行结合测试，因为我们先前的工作表明这将比单一抗体更有效。此外，我们将在泰国的医院研究站点收集有关鲍曼尼a。A.baumannii感染的患者的数据和样品。需要有关患者的信息，因此我们可以计划单克隆抗体治疗的未来临床试验；来自患者的样品还将通过提供白细胞来分离单克隆抗体的白细胞来帮助研究单克隆抗体的实验。在研究结束时，我们将拥有确定哪种单克隆抗体所需的数据，哪些组合可能是鲍曼尼曲霉感染最有效的治疗方法。将来，这些单克隆抗体将被发展为对人类测试的临床治疗方法。