Monoclonal Antibodies Against the Staphylococcus aureus Bicomponent Leukotoxin AB Isolated Following Invasive Human Infection Reveal Diverse Binding and Modes of Action.

Thomsen IP, Sapparapu G, James DBA, Cassat JE, Nagarsheth M, Kose N, Putnam N, Boguslawski KM, Jones LS, Wood JB, Creech CB, Torres VJ, Crowe JE
J Infect Dis. 2017 215 (7): 1124-1131

PMID: 28186295 · PMCID: PMC5426380 · DOI:10.1093/infdis/jix071

The 2-component leukotoxin LukAB is critical for Staphylococcus aureus targeting and killing of human neutrophils ex vivo and is produced in the setting of human infection. We report 3 LukAB-specific human monoclonal antibodies (mAbs) with distinct mechanisms of toxin neutralization and in vivo efficacy. Three hybridomas secreting mAbs with anti-LukAB activity (designated SA-13, -15, and -17) were generated from B cells obtained from a 12-year-old boy with S. aureus osteomyelitis. Each of the 3 mAbs neutralized LukAB-mediated neutrophil toxicity, exhibited differing levels of potency, recognized different antigenic sites on the toxin, and displayed at least 2 distinct mechanisms for cytotoxic inhibition. SA-15 bound exclusively to the dimeric form of the toxin, suggesting that human B cells recognize epitopes on the dimerized form of LukAB during natural infection. Both SA-13 and SA-17 bound the LukA monomer and the LukAB dimer. Although all 3 mAbs potently neutralized cytotoxicity, only SA-15 and SA-17 significantly inhibited toxin association with the cell surface. Treatment with a 1:1 mixture of mAbs SA-15 and SA-17 resulted in significantly lower bacterial colony counts in heart, liver, and kidneys in a murine model of S. aureus sepsis. These data describe the isolation of diverse and efficacious antitoxin mAbs.

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MeSH Terms (17)

Animals Antibodies, Bacterial Antibodies, Monoclonal B-Lymphocytes Bacterial Proteins Child Female Humans Hybridomas Leukocidins Male Mice Mice, Inbred BALB C Neutrophils Regression Analysis Staphylococcal Infections Staphylococcus aureus

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