A fully human streptolysin O-neutralizing monoclonal antibody improves survival in a murine model of group A streptococcus necrotizing soft tissue infection

ABSTRACT Necrotizing soft tissue infections (NSTIs) caused by Streptococcus pyogenes (group A streptococcus [GAS]) are rapidly progressive, toxin-driven infections for which no targeted antitoxin therapies exist. Streptolysin O (SLO), a cholesterol-dependent cytolysin, is a key mediator of tissue injury, vascular occlusion, and immune dysfunction and, thus, represents a promising therapeutic target. Here, we isolated and characterized three fully human monoclonal antibodies (huMAbs) against SLO (C11, G4, and L17) from the memory B cells of a naturally immunized donor using antigen-specific B-cell enrichment. All three huMAbs bound SLO with high affinity and potently neutralized SLO-induced hemolysis in vitro . Mechanistic studies revealed that C11 and G4 inhibited SLO-membrane binding, whereas L17 protected host cells without blocking membrane binding. Despite similar neutralizing potency in vitro , only L17 significantly improved disease outcomes in vivo . In a murine model of GAS-NSTI, L17 reduced clinical disease severity and prolonged survival by approximately 130%. Together, these findings demonstrate that antibody-mediated neutralization of SLO can alter disease outcomes during GAS-necrotizing infection and support the potential of L17 as a clinically relevant antitoxin therapeutic candidate for GAS-NSTI.