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

鲍曼不动杆菌会导致人类严重的肺部和血液传播感染。它是对抗生素耐药性最高的细菌之一，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50,000多人死亡，这个数字还在增加。这在亚洲尤其常见，仅在泰国每年就有15,000人死亡，在我们的一家研究地点医院，每年感染鲍曼不动杆菌的人数从2010年的100人增加到2022年的500多人。世界卫生组织已将鲍曼不动杆菌列为其首要耐药细菌，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，抗体是一种自然产生的蛋白质，可以与入侵的微生物结合，提高免疫系统杀死它们的能力。抗体疗法已知对其他微生物有效，但尚不适用于鲍曼不动杆菌。我们的目标是通过开发一种针对鲍曼不动杆菌的抗体疗法来填补这一空白。在过去的四年里，我们已经鉴定出针对四种鲍曼不动杆菌蛋白的抗体，我们已经证明这些抗体与细菌表面结合得很强，可以提高免疫系统对细菌的活性。重要的是，当给小鼠注射这些抗体时，它们可以预防鲍曼不动杆菌的感染，这表明它们可能是治疗人类感染的一种很好的方法。我们现在想开发这些抗体用于人类。要做到这一点，我们需要为我们的每个蛋白质靶标获得单一的特异性抗体，这种抗体被称为单抗，因为这些抗体可以在工厂中大量生产，以便进行治疗。我们将从之前感染过鲍曼不动杆菌并对这种细菌产生免疫反应的人，或通过疫苗接种实验的小鼠身上，分离出针对我们的四种鲍曼不动杆菌蛋白的每一种的几种单抗。然后，我们将测试每一种分离的单抗，看看它们与免疫系统结合的情况如何，并促进免疫系统识别和杀死鲍曼不动杆菌菌株的能力。我们还将测试每一种单抗，看看它们是否能保护小鼠免受鲍曼不动杆菌的感染。然后将对最有效的单抗进行组合测试，因为我们之前的工作表明，这将比单一抗体更有效。此外，我们将在我们在泰国的医院研究地点收集鲍曼不动杆菌感染患者的数据和样本。患者的信息是需要的，这样我们就可以计划未来的单抗治疗的临床试验；患者的样本也将通过提供可以分离出单抗的白细胞来帮助研究单抗的实验。在研究结束时，我们将获得所需的数据，以确定哪种单抗及其组合可能是治疗鲍曼不动杆菌感染最有效的方法。这些单抗将来将被开发成临床治疗方法，用于人体试验。

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.