Researchers find target for monoclonal antibodies in S. aureus
Click Here to Manage Email Alerts
Monoclonal antibodies isolated from children with invasive Staphylococcal aureus were capable of broad neutralization against distantly related variants of the two-component leukotoxin, LukAB, researchers reported.
“LukAB is critical for S. aureus targeting and killing of human neutrophils and is abundantly produced in the setting of invasive human infection,” Monique Bennett, PhD, a junior faculty member in the pediatric infectious disease department at Vanderbilt University Medical Center, and colleagues reported. “LukAB is unique among S. aureus cytotoxins in that it exists in variant form across distantly related strains of clinically relevant S. aureus.”
The researchers said they isolated B cells from children with invasive S. aureus infections, including bacteremia or acute hematogenous osteomyelitis.
After Epstein-Barr virus transformation, cell supernatants were screened for LukAB binding and selected to generate monoclonal hybridomas. The monoclonal antibodies were assessed for binding and neutralizing function by in vitro cytotoxicity assays, and neutrophil-like HL-60 cells were cultured in the presence of human monoclonal antibodies and diverse allelic variants of LukAB.
There were 34 distinct human anti-LukAB monoclonal antibodies generated from three children with invasive S. aureus, the authors reported. Of those, 22% were isolated following infection with a strain belonging to clonal complex (CC) 8, which was consistent with the epidemic USA300 clone, whereas 78% were generated against CC5 strains.
They reported that all monoclonal antibodies neutralized LukAB from the same clonal complex as the infecting isolate. Twenty-three also demonstrated neutralization against other allelic variants.
Seven monoclonal antibodies were capable of broad, potent neutralization of LukAB variants from clinically relevant clonal complexes tested — CC8, CC30, CC45, CC75, CC1, CC5 and CC398.
“We found strong evidence of a conserved target (or targets) for antibody-mediated toxin neutralization across diverse strains of S. aureus,” the authors wrote. “This provides additional support for this toxin as a target of intervention, as some previous vaccine attempts were likely unsuccessful due to activity against a narrow subset of circulating S. aureus strains.”
S . aureus is among the most common causes of both superficial and invasive infection in children and adults. In the late 1990s, community-associated MRSA became a major driver of infections among otherwise healthy individuals.
Development of novel antibiotics to cover S. aureus, and specifically MRSA, has been a major focus of pharmaceutical companies in the last several years, and in large part has been successful. The development of antibody-based therapeutics, and ultimately an S. aureus vaccine to prevent invasive infections, has been much more challenging, however. Several reasons for this exist, including the complex interaction of S. aureus as part of the normal human microbiome, as well as a great deal of variation among S. aureus isolates.
Understanding how humans develop immunity to S. aureus may be the key to unlocking the mystery of how to develop effective S. aureus therapeutics and vaccines. Development of these therapies have the potential to greatly improve the quality of life of those who suffer from recurrent MRSA infections and be potentially lifesaving for those at high risk for invasive infection, including people with central lines, people receiving hemodialysis and people with other immunocompromising conditions.
Perspective
Back to Top
S. aureus is among the most common causes of both superficial and invasive infection in children and adults. In the late 1990s, community-associated MRSA became a major driver of infections among otherwise healthy individuals.
Development of novel antibiotics to cover S. aureus, and specifically MRSA, has been a major focus of pharmaceutical companies in the last several years, and in large part has been successful. The development of antibody-based therapeutics, and ultimately an S. aureus vaccine to prevent invasive infections, has been much more challenging, however. Several reasons for this exist, including the complex interaction of S. aureus as part of the normal human microbiome, as well as a great deal of variation among S. aureus isolates.
Understanding how humans develop immunity to S. aureus may be the key to unlocking the mystery of how to develop effective S. aureus therapeutics and vaccines. Development of these therapies have the potential to greatly improve the quality of life of those who suffer from recurrent MRSA infections and be potentially lifesaving for those at high risk for invasive infection, including people with central lines, people receiving hemodialysis and people with other immunocompromising conditions.
Collapse
Bennett M, et al. Abstract 31. Presented at: St. Jude/PIDS Pediatric Infectious Diseases Research Conference; March 4-6, 2021 (virtual meeting).
Read more about
Click Here to Manage Email Alerts