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.

鲍曼不动杆菌会导致人类严重的肺部和血源性感染。它是对抗生素耐药性最强的细菌之一，因此鲍曼不动杆菌感染的死亡率非常高，接近 50%。总体而言，鲍曼不动杆菌每年在全球造成超过 50,000 人死亡，而且这个数字还在增加。这种疾病在亚洲尤其常见，仅泰国每年就有 15,000 人死亡，在我们的一家研究地点医院，鲍曼不动杆菌每年的感染人数已从 2010 年的 100 人增加到 2022 年的 500 多人。世界卫生组织已使鲍曼不动杆菌成为首要的抗生素抗性细菌，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，抗体是天然存在的蛋白质，可以与入侵的微生物结合并增强免疫系统杀死它们的能力。已知抗体疗法对其他微生物有效，但目前还无法用于鲍曼不动杆菌。我们的目标是通过开发鲍曼不动杆菌的抗体治疗来填补这一空白。在过去的四年中，我们已经鉴定出四种鲍曼不动杆菌蛋白的抗体，我们已证明它们与细菌表面牢固结合，并且可以增强免疫系统针对细菌的活性。重要的是，当给予小鼠这些抗体时，它们可以防止鲍曼不动杆菌感染，这表明它们可能是治疗人类感染的良好方法。我们现在希望开发这些抗体用于人类。为此，我们需要为每个蛋白质靶标获得单一特异性抗体，称为单克隆抗体，因为这些抗体可以在工厂中大量生产治疗所需的量。我们将从曾经感染过鲍曼不动杆菌并对该细菌产生免疫反应的人类或使用疫苗接种实验的小鼠中分离出针对我们的四种鲍曼不动杆菌蛋白中的每一种的几种单克隆抗体。然后，我们将测试每种分离的单克隆抗体，看看它们与免疫系统的结合程度如何，并促进免疫系统识别和杀死鲍曼不动杆菌菌株的能力。我们还将测试每种单克隆抗体，看看它们是否可以保护小鼠免受鲍曼不动杆菌感染。然后将组合测试最有效的单克隆抗体，因为我们之前的工作表明这将比单一抗体更有效。此外，我们还将在泰国的医院研究中心收集鲍曼不动杆菌感染患者的数据和样本。需要有关患者的信息，以便我们可以规划单克隆抗体疗法的未来临床试验；患者的样本也将通过提供白细胞来帮助研究单克隆抗体的实验，我们可以从中分离出单克隆抗体。在研究结束时，我们将获得所需的数据来决定哪种单克隆抗体以及哪种组合可能是治疗鲍曼不动杆菌感染的最有效方法。这些单克隆抗体将来将被开发成用于人体测试的临床治疗方法。