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

• Published in: American journal of respiratory and critical care medicine Vol. 210; no. 1; pp. 35 - 46
• Main Authors: Long, Merete B., Gilmour, Amy, Kehl, Margaret, Tabor, David E., Keller, Ashley E., Warrener, Paul, Gopalakrishnan, Vancheswaran, Rosengren, Sanna, Crichton, Megan L., McIntosh, Eve, Giam, Yan Hui, Keir, Holly R., Brailsford, Wayne, Hughes, Rod, Belvisi, Maria G., Sellman, Bret R., DiGiandomenico, Antonio, Chalmers, James D.
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.07.2024
• Subjects: Adult; Aged; Antibodies, Bispecific - pharmacology; Antibodies, Bispecific - therapeutic use; Antigens, Bacterial; Bacterial infections; Bacterial Toxins; Bronchiectasis - immunology; Bronchiectasis - microbiology; Female; Humans; Immunoglobulins; Male; Middle Aged; Monoclonal antibodies; Neutrophils; Neutrophils - drug effects; Neutrophils - immunology; Pathogens; Pore Forming Cytotoxic Proteins; Pseudomonas aeruginosa - immunology; Pseudomonas Infections - immunology; Whole genome sequencing; infection; antibody; bronchiectasis; neutrophil
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.202308-1403OC

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 by neutrophils from patients with bronchiectasis and to prevent -associated cytotoxicity. isolates from a global bronchiectasis cohort (  = 100) underwent whole-genome sequencing to determine target prevalence. Functional activity of gremubamab against selected isolates was tested and . Patients with bronchiectasis (  = 11) and control subjects (  = 10) were enrolled, and the effect of gremubamab in peripheral blood neutrophil opsonophagocytic killing (OPK) assays against was evaluated. Serum antibody titers to Psl and PcrV were determined (  = 30; 19 chronic infection, 11 no known infection), as was the effect of gremubamab treatment in OPK and anti-cytotoxic activity assays. Psl and PcrV were conserved in isolates from chronically infected patients with bronchiectasis. Seventy-three of 100 isolates had a full locus, and 99 of 100 contained the gene, with 20 distinct full-length PcrV protein subtypes identified. PcrV subtypes were successfully bound by gremubamab and the monoclonal antibody-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 control subjects (OPK, +30.1 ± 7.6%). No evidence of competition between gremubamab and endogenous antibodies was found, with protection against -induced cytotoxicity and enhanced OPK demonstrated with and without addition of patient serum. Gremubamab enhanced bronchiectasis patient neutrophil phagocytosis and killing of and reduced virulence.