Abstract
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.