Abstract
Background Staphylococcus aureus is implicated in many opportunistic bacterial infections around the world. Rising antibiotic resistance and few alternative methods of treatment are just two looming problems associated with clinical management of S. aureus. Among numerous virulence factors produced by S. aureus, staphylococcal enterotoxin (SE) B is a secreted protein that binds T-cell receptor and major histocompatibility complex class II, potentially causing toxic shock mediated by pathological activation of T cells. Recombinant monoclonal antibodies that target SEB and block receptor interactions can be of therapeutic value.Methodology/Principal FindingsThe inhibitory and biophysical properties of ten human monoclonal antibodies, isolated from a recombinant library by panning against SEB vaccine (STEBVax), were examined as bivalent Fabs and native full-length IgG (Mab). The best performing Fabs had binding affinities equal to polyclonal IgG, low nanomolar IC50s against SEB in cell culture assays, and protected mice from SEB-induced toxic shock. The orthologous staphylococcal proteins, SEC1 and SEC2, as well as streptococcal pyrogenic exotoxin C were recognized by several Fabs. Four Fabs against SEB, with the lowest IC50s, were converted into native full-length Mabs. Although SEB-binding kinetics were identical between each Fab and respective Mab, a 250-fold greater inhibition of SEB-induced T-cell activation was observed with two Mabs.Conclusions/SignificanceResults suggest that these human monoclonal antibodies possess high affinity, target specificity, and toxin neutralization qualities essential for any therapeutic agent.
Highlights
Staphylococcus aureus is a common source of many diseases for both humans and domestic animals [1]
Virulence factor-specific antibodies derived from vaccination or employed as therapeutics represent a potential defense against bacterial diseases
Our results describe for the first time recombinantly-derived, human monoclonal antibodies against SEB that possess high affinity, target specificity, and therapeutic potential for superantigen-induced toxic shock
Summary
Staphylococcus aureus is a common source of many diseases for both humans and domestic animals [1] This bacterium presents a daunting medical problem due to increasing antibiotic resistance among nosocomial- and community-acquired isolates [2,3,4]. One type of virulence factor includes the staphylococcal enterotoxins (SEs), originally distinguished by serotyping methodology [7,8,9,10] These protein toxins can cause acute gastroenteritis and toxic shock syndrome. Among numerous virulence factors produced by S. aureus, staphylococcal enterotoxin (SE) B is a secreted protein that binds T-cell receptor and major histocompatibility complex class II, potentially causing toxic shock mediated by pathological activation of T cells. Recombinant monoclonal antibodies that target SEB and block receptor interactions can be of therapeutic value
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