Exploiting human immune repertoire transgenic mice for protective monoclonal antibodies against antimicrobial resistant Acinetobacter baumannii

Stephen Baker, Aishwarya Krishna, Sophie Higham, Plamena Naydenova, Siobhan O’Leary, Josefin Bartholdson Scott, Katherine Harcourt, Sally Forrest, David Goulding, To Nguyen Nguyen, Nguyen Duc Toan, Elizaveta Alekseeva, Qingqing Zhou, Ilaria Andreozzi, Barbara Sobotic, Hannah Craig, Vivian Wong, Nichola Forrest-Owen, Dana Moreno Sanchez, Claire Pearce, Leah Roberts, Simon Watson, Simon Clare, Mili Estee Torok, Gordon Dougan, Paul Kellam, John S. Tregoning and Stephen T. Reece ()
Additional contact information
Stephen Baker: University of Cambridge School of Clinical Medicine Cambridge Biomedical Campus
Aishwarya Krishna: Babraham Research Campus
Sophie Higham: Norfolk Place
Plamena Naydenova: University of Cambridge School of Clinical Medicine Cambridge Biomedical Campus
Siobhan O’Leary: Babraham Research Campus
Josefin Bartholdson Scott: Babraham Research Campus
Katherine Harcourt: University of Cambridge School of Clinical Medicine Cambridge Biomedical Campus
Sally Forrest: University of Cambridge School of Clinical Medicine Cambridge Biomedical Campus
David Goulding: Wellcome Sanger Institute
To Nguyen Nguyen: Monash University
Nguyen Duc Toan: Children’s Hospital 1
Elizaveta Alekseeva: Babraham Research Campus
Qingqing Zhou: Babraham Research Campus
Ilaria Andreozzi: Babraham Research Campus
Barbara Sobotic: Babraham Research Campus
Hannah Craig: Babraham Research Campus
Vivian Wong: Babraham Research Campus
Nichola Forrest-Owen: Babraham Research Campus
Dana Moreno Sanchez: Babraham Research Campus
Claire Pearce: Babraham Research Campus
Leah Roberts: European Bioinformatics Institute (EMBL-EBI)
Simon Watson: Babraham Research Campus
Simon Clare: University of Cambridge School of Clinical Medicine Cambridge Biomedical Campus
Mili Estee Torok: University of Cambridge School of Clinical Medicine Cambridge Biomedical Campus
Gordon Dougan: University of Cambridge School of Clinical Medicine Cambridge Biomedical Campus
Paul Kellam: Babraham Research Campus
John S. Tregoning: Norfolk Place
Stephen T. Reece: Babraham Research Campus

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52357-8

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