A Bispecific Monoclonal Antibody Targeting Psl and PcrV Enhances Neutrophil-Mediated Killing of Pseudomonas aeruginosa in Patients with Bronchiectasis

Merete B. Long, Amy Gilmour, Margaret Kehl, David Tabor, Ashley E. Keller, Paul Warrener, Vancheswaran Gopalakrishnan, Sanna Rosengren, Megan L. Crichton, Eve McIntosh, Yan Hui Giam, Holly R. Keir, Wayne Brailsford, Rod Hughes, Maria G. Belvisi, Bret R. Sellman, Antonio DiGiandomenico (Lead / Corresponding author), James D. Chalmers (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    Abstract

    RATIONALE AND OBJECTIVES: Pseudomonas aeruginosa infection is associated with worse outcomes in bronchiectasis. Impaired neutrophil antimicrobial responses contribute to bacterial persistence. Gremubamab is a bivalent, bispecific monoclonal antibody targeting Psl exopolysaccharide and the type 3 secretion system component PcrV. This study evaluated the efficacy of gremubamab to enhance killing of P.aeruginosa by neutrophils from bronchiectasis patients and to prevent P.aeruginosa-associated cytotoxicity.

    METHODS: P.aeruginosa isolates from a global bronchiectasis cohort (n=100) underwent whole-genome sequencing to determine target prevalence. Functional activity of gremubamab against selected isolates was tested in-vitro and in-vivo. Patients with bronchiectasis (n=11) and controls (n=10) were enrolled and the effect of gremubamab in peripheral-blood neutrophil opsonophagocytic killing (OPK) assays against P.aeruginosa was evaluated. Serum antibody titers to Psl and PcrV were determined (n=30; 19: chronic P.aeruginosa infection, 11: no-known P.aeruginosa infection), as was the effect of gremubamab treatment in OPK and anti-cytotoxic activity assays.

    MEASUREMENTS AND RESULTS: Psl and PcrV were conserved in isolates from chronically-infected bronchiectasis patients. 73/100 isolates had a full psl locus and 99/100 contained the pcrV gene, with 20 distinct full-length PcrV protein subtypes identified. PcrV subtypes were successfully bound by gremubamab and the mAb mediated potent protective activity against tested isolates. Gremubamab increased bronchiectasis patient neutrophil-mediated OPK (+34.6±8.1%) and phagocytosis (+70.0±48.8%), similar to effects observed in neutrophils from controls (OPK:+30.1±7.6%). No evidence of competition between gremubamab and endogenous antibodies was found, with protection against P.aeruginosa-induced cytotoxicity and enhanced OPK demonstrated with and without addition of patient serum.

    CONCLUSION: Gremubamab enhanced bronchiectasis patient neutrophil phagocytosis and killing of P.aeruginosa and reduced virulence.

    Original languageEnglish
    JournalAmerican Journal of Respiratory and Critical Care Medicine
    Early online date16 May 2024
    DOIs
    Publication statusE-pub ahead of print - 16 May 2024

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