University of Cambridge School of Clinical Medicine Cambridge Biomedical Campus, Cambridge, UK.
IAVI, Chelsea and Westminster Hospital, London, UK.
Nat Commun. 2024 Sep 12;15(1):7979. doi: 10.1038/s41467-024-52357-8.
The use of monoclonal antibodies for the control of drug resistant nosocomial bacteria may alleviate a reliance on broad spectrum antimicrobials for treatment of infection. We identify monoclonal antibodies that may prevent infection caused by carbapenem resistant Acinetobacter baumannii. We use human immune repertoire mice (Kymouse platform mice) as a surrogate for human B cell interrogation to establish an unbiased strategy to probe the antibody-accessible target landscape of clinically relevant A. baumannii. After immunisation of the Kymouse platform mice with A. baumannii derived outer membrane vesicles (OMV) we identify 297 antibodies and analyse 26 of these for functional potential. These antibodies target lipooligosaccharide (OCL1), the Oxa-23 protein, and the KL49 capsular polysaccharide. We identify a single monoclonal antibody (mAb1416) recognising KL49 capsular polysaccharide to demonstrate prophylactic in vivo protection against a carbapenem resistant A. baumannii lineage associated with neonatal sepsis mortality in Asia. Our end-to-end approach identifies functional monoclonal antibodies with prophylactic potential against major lineages of drug resistant bacteria accounting for phylogenetic diversity and clinical relevance without existing knowledge of a specific target antigen. Such an approach might be scaled for a additional clinically important bacterial pathogens in the post-antimicrobial era.
使用单克隆抗体来控制耐药性医院获得性细菌可能会减轻对广谱抗生素治疗感染的依赖。我们确定了可能预防耐碳青霉烯鲍曼不动杆菌引起感染的单克隆抗体。我们使用人免疫受体小鼠（Kymouse 平台小鼠）作为人 B 细胞检测的替代物，建立一种公正的策略来探测临床相关鲍曼不动杆菌的抗体可及靶标景观。在用鲍曼不动杆菌衍生的外膜囊泡（OMV）免疫 Kymouse 平台小鼠后，我们鉴定了 297 种抗体，并分析了其中 26 种抗体的功能潜力。这些抗体针对脂寡糖（OCL1）、Oxa-23 蛋白和 KL49 荚膜多糖。我们鉴定了一种识别 KL49 荚膜多糖的单克隆抗体（mAb1416），证明其具有预防体内保护作用，可预防与亚洲新生儿脓毒症死亡率相关的耐碳青霉烯鲍曼不动杆菌谱系。我们的端到端方法鉴定了具有预防潜力的功能性单克隆抗体，可以针对耐药性细菌的主要谱系提供预防作用，这些谱系具有系统发育多样性和临床相关性，而无需针对特定靶抗原的现有知识。在抗菌药物后时代，这种方法可能会扩展到其他具有临床重要性的细菌病原体。
