High-throughput single-cell analysis reveals fully human Omp38-specific monoclonal antibodies against Acinetobacter baumannii

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BACKGROUND: Acinetobacter baumannii (A. baumannii) is a significant global health threat, particularly in hospital environments, where it is often linked to severe infections. As the need for innovative therapeutic approaches grows, fully human monoclonal antibodies (mAbs) have gained attention because of their high specificity, reduced immunogenicity, and enhanced affinity for target antigens, which may improve clinical efficacy. METHODS: Using the Beacon platform, we isolated single B cells from immunized humanized genomic orthologs for antibody development (HUGO-Ab) mice to develop outer membrane protein (OMP)-specific mAbs. The variable regions of the selected mAbs were cloned into mammalian expression vectors containing constant human IgG1 regions to generate fully human mAbs. After identifying mAbs binding to Omp38 via ELISA, their binding ability to LAC-4 and the clinical isolates was further evaluated. Subsequently, the effects of these mAbs on A. baumannii adhesion and biofilm formation were tested, and their protective efficacy was assessed using a lethal infection model. Finally, bioinformatics methods were used to predict the binding conformation of mAb F2 to Omp38. RESULTS: Omp38-specific fully human mAb F2 potently and broadly bound to A. baumannii strains and inhibited bacterial adherence and biofilm formation. Binding modeling and conformational analysis revealed that F2 targets the extracellular region of Omp38 and forms stable hydrogen bonds with different strains, suggesting its potential for broad-spectrum binding to diverse A. baumannii strains. CONCLUSIONS: This study demonstrates the utility of high-throughput single-cell analysis and antibody engineering in developing fully human mAbs against A. baumannii, highlighting the potential of these novel fully human mAbs to advance therapeutic strategies and improve clinical outcomes for A. baumannii infections.

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