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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\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      . Mechanistic studies revealed that C11 and G4 inhibited SLO-membrane binding, whereas L17 protected host cells without blocking membrane binding. Despite similar neutralizing potency\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , only L17 significantly improved disease outcomes\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . 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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00575-26","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T14:25:46Z","timestamp":1784298346000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["A fully human streptolysin O-neutralizing monoclonal antibody improves survival in a murine model of group A streptococcus necrotizing soft tissue infection"],"prefix":"10.1128","volume":"70","author":[{"given":"Emily","family":"Price","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00mz0c648","id-type":"ROR","asserted-by":"publisher"}],"name":"Boise VA Medical 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