Humanized Staphylococcal Enterotoxin B (SEB)–Specific Monoclonal Antibodies Protect From SEB Intoxication and Staphylococcus aureus Infections Alone or as Adjunctive Therapy With Vancomycin

Varshney, Ankur Nandan; Wang, Xiaobo; MacIntyre, Jennifer; Zollner, Richard; Kelleher, Kerry; Коваленко, О. В.; Pechuan-Jorge, Ximo; Byrne, Fergus R.; Fries, Bettina C.

doi:10.1093/infdis/jiu198

Cited by 37 publications

(31 citation statements)

References 38 publications

(49 reference statements)

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“…Importantly, we have generated anti-SEl-K MAbs that now provide a tool that facilitates the study of SEl-K expression in vivo and its strain-dependent variability. Such MAbs could potentially be further developed for adjunctive therapy in the treatment of S. aureus disease as described for SEB-specific MAbs (22). Our analysis of predicted amino acid sequences from 39 S. aureus strains revealed the existence of at least 6 variants of SEl-K, including one that is conserved and unique to all examined USA300 strains.…”

Section: Discussionmentioning

confidence: 82%

Detection and Measurement of Staphylococcal Enterotoxin-Like K (SEl-K) Secretion by Staphylococcus aureus Clinical Isolates

et al. 2014

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SEl-K is commonly present in more than half of all Staphylococcus aureus clinical isolates and is present in almost all USA300 community-acquired methicillin-resistant S. aureus (CA-MRSA) isolates. Sequencing of the sel-k gene in over 20 clinical isolates and comparative analysis with all 14 published sel-k sequences indicate that there are at least 6 variants of the sel-k gene, including one that is conserved among all examined USA300 strains. Additionally, we have developed a highly sensitive enzyme-linked immunosorbent assay (ELISA) that specifically detects and measures SEl-K protein in culture supernatants and biological fluids. Quantification of in vitro SEl-K secretion by various S. aureus isolates using this novel capture ELISA revealed detectable amounts of SEl-K secretion by all isolates, with the highest secretion levels being exhibited by MRSA strains that coexpress SEB. In vivo secretion was measured in a murine thigh abscess model, where similar levels of SEl-K accumulation were noted regardless of whether the infecting strain exhibited high or low secretion of SEl-K in vitro. We conclude that SEl-K is commonly expressed in the setting of staphylococcal infection, in significant amounts. SEl-K should be further explored as a target for passive immunotherapy against complicated S. aureus infection. Staphylococcus aureus can express a large and diverse repertoire of virulence factors, including many different surface proteins, enzymes, and secreted toxins (1). Among the most potent of these virulence factors are the members of a family of secreted, heatstable proteins known as enterotoxins. More than 20 staphylococcal enterotoxins (SEs) have been discovered that demonstrate superantigenic (SAg) properties against T cells (2, 3). Superantigens can activate 20% to 50% of the T cell population by bypassing the traditional pathway of major histocompatibility complex (MHC)-dependent presentation of antigens to T cell receptors (TCRs). Instead, superantigens bind simultaneously to MHC class II (MHC-II) and TCRs, outside their antigen-binding groove, resulting in an excessive inflammatory response that can lead to toxic shock, multiorgan failure, and death. Superantigens are also associated with other immune-mediated diseases, including Kawasaki disease, atopic dermatitis, and chronic rhinosinusitis (4).The classical superantigens toxic shock syndrome toxin 1 (TSST-1), SEA, and SEB have been extensively studied due to their causative roles in toxic shock syndrome and food poisoning (5). However, advancements in sequencing methodologies have enabled the discovery of many more SEs whose roles in pathogenesis remain unknown (6). One of these toxins, SEl-K, has been shown to exhibit superantigenic properties, including V␤-specific T cell activation, pyrogenicity, emesis, and lethality in primates (7-9). Epidemiological studies have demonstrated the SEl-K-encoding genes to be among the most common SE genes in S. aureus clinical isolates (10-14). Additionally, SEl-K is the only SE gene to our knowledge that is si...

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Section: Discussionmentioning

confidence: 82%

Detection and Measurement of Staphylococcal Enterotoxin-Like K (SEl-K) Secretion by Staphylococcus aureus Clinical Isolates

et al. 2014

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“…Finally, mAb 20B1 has now also been humanized, and recent data document that this process retained efficacy and nanomolar range affinities (53). The product may be used prophylactically in the event of an imminent threat or immediately after suspected dissemination of SEB before the onset of cytokine storm.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, based on our data, the product could be used in a multivalent immune-protectant anti-toxin mixture, which should include mAb 14G8. Beyond neutralizing SEB toxin, mAb 20B1 has also been used as adjunctive therapy with antibiotics for treatment of S. aureus sepsis (53).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms Mediating Enhanced Neutralization Efficacy of Staphylococcal Enterotoxin B by Combinations of Monoclonal Antibodies

Dutta

Varshney

Franklin

et al. 2015

Journal of Biological Chemistry

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Background: Staphylococcal enterotoxin B is a potent superantigen that causes lethal toxic shock syndrome. Results: Ternary and binary complex of SEB with SEB specific mAbs identified three distinct epitopes. Conclusion: Two different mechanisms illustrate how cocktails of mAbs enhance neutralization efficacy. Significance: SEB neutralization via combination of mAbs is superior to monotherapy and can include non-neutralizing mAbs.

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“…This is surprising given the protective efficacy of hyperimmune-globulin preparations (35) and the overwhelming evidence with anti-infective Abs. They can work (36) as monotherapy, cocktails, or in combination with antimicrobial drugs (37). One problem may be that MAb cocktails commonly are more efficacious than monotherapy, especially if rapidly expanding pathogen populations are to be contained.…”

Section: Discussionmentioning

confidence: 99%

Antibody-Based Immunotherapy To Treat and Prevent Infection with Hypervirulent Klebsiella pneumoniae

Diago-Navarro

Calatayud-Baselga

Sun

et al. 2017

Clin Vaccine Immunol

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Hypervirulent Klebsiella pneumoniae (hvKp) strains are predicted to become a major threat in Asia if antibiotic resistance continues to spread. Anticapsular antibodies (Abs) were developed because disseminated infections caused by hvKp are associated with significant morbidity and mortality, even with antibiotic-sensitive strains. K1-serotype polysaccharide capsules (K1-CPS) are expressed by the majority of hvKp strains. In this study, K1-CPS-specific IgG Abs were generated by conjugation of K1-CPS to immunogenic anthrax protective antigen (PA) protein. Opsonophagocytic efficacy was measured in vitro and in vivo by intravital microscopy in murine livers. In vivo protection was tested in murine models, including a novel model for dissemination in hvKp-colonized mice. Protective efficacy of monoclonal antibodies (MAbs) 4C5 (IgG1) and 19A10 (IgG3) was demonstrated both in murine sepsis and pulmonary infection. In hvKp-colonized mice, MAb treatment significantly decreased dissemination of hvKp from the gut to mesenteric lymph nodes and organs. Intravital microscopy confirmed efficient opsonophagocytosis and clearance of bacteria from the liver. In vitro studies demonstrate that MAbs work predominantly by promoting FcR-mediated phagocytosis but also indicate that MAbs enhance the release of neutrophil extracellular traps (NETs). In anticipation of increasing antibiotic resistance, we propose further development of these and other Klebsiella-specific MAbs for therapeutic use.

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Humanized Staphylococcal Enterotoxin B (SEB)–Specific Monoclonal Antibodies Protect From SEB Intoxication and Staphylococcus aureus Infections Alone or as Adjunctive Therapy With Vancomycin

Abstract: SEB-neutralizing mAb 20B1 was successfully humanized. The mAb affects outcome by modulating the proinflammatory host response in both the sepsis and the intoxication models, which justifies further development.

Cited by 37 publications

References 38 publications

Detection and Measurement of Staphylococcal Enterotoxin-Like K (SEl-K) Secretion by Staphylococcus aureus Clinical Isolates

Detection and Measurement of Staphylococcal Enterotoxin-Like K (SEl-K) Secretion by Staphylococcus aureus Clinical Isolates

Mechanisms Mediating Enhanced Neutralization Efficacy of Staphylococcal Enterotoxin B by Combinations of Monoclonal Antibodies

Antibody-Based Immunotherapy To Treat and Prevent Infection with Hypervirulent Klebsiella pneumoniae

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