Identification of Anti-Alpha Toxin Monoclonal Antibodies That Reduce the Severity of Staphylococcus aureus Dermonecrosis and Exhibit a Correlation between Affinity and Potency

Abstract

Staphylococcus aureus alpha toxin (AT) is an important virulence determinant and may be a valid target for immunoprophylaxis

Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

“…To gain a better understanding about strain coverage of the anti-AT MAb clinical candidate MEDI4893 (29,34), its neutralization capacity was assessed against all of the isolates producing functional alpha-toxin. MEDI4893 effectively neutralized each of the different toxin variants.…”

“…In murine S. aureus skin and soft tissue infection models, both active immunization with a nontoxigenic alpha-toxin mutant and passive immunization with alpha-toxinspecific antiserum or IgG significantly improved survival and reduced disease severity (27,(32)(33)(34). Antibodies against alpha-toxin were both necessary and sufficient for protection against soft tissue infection and were inversely associated with bacterial counts (32) and had a protective role in keratitis (35).…”

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

“…The use of animal serum containing antibodies that target bacterial antigens was a common therapeutic approach pre-dating the development of small molecule antibiotics, 7 but technological advances in antibody discovery, including B-cell cloning from human patients, 8 has invigorated research into monoclonal antibody (mAb)-based antibiotics. Anti-infective biologics with novel mechanisms of action targeting S. aureus alpha toxin, 9,10 protective antigen of Bacillus anthracis , 11 toxins A and B from Clostridium difficile , 12 and Pseudomonas aeruginosa cell wall components 13,14 are currently approved or in clinical development. The presence of cell wall glycopolymers, particularly in Gram-positive bacteria, shields many epitopes that might confer bactericidal activity from antibodies and other host-defense molecules, 15 but these cell wall polysaccharides also represent a potential target for mAb therapeutics.…”

Antibodies toStaphylococcus aureuscapsular polysaccharides 5 and 8 perform similarlyin vitrobut are functionally distinctin vivo

“…17,24 Polyclonal antibodies to the staphylococcal CPs protect mice against bacteremia but not lethal pneumonia, 25 whereas antibodies to S. aureus Hla protect mice against lethal pneumonia but not bacteremia. 21,22,25 We showed previously that polyclonal CP5-specific antibodies protected against experimental bacteremia induced by four different serotype 5 isolates. 25 In this study, the CP5 backbone-specific 4C2 mAb protected mice against experimental Reynolds (CP5) bacteremia.…”

“…Hla mAbs reduced the severity and tissue damage associated with staphylococcal skin infections and necrotizing pneumonia in preclinical studies. [20][21][22] A human mAb that neutralizes both Hla and four staphylococcal leukocidins 23 is beginning a phase 2 clinical trial for the prevention of S. aureus pneumonia in mechanically ventilated subjects. Because of the complexity of S. aureus pathogenesis and the diversity of staphylococcal infections, it is likely that immunoprophylaxis with mAbs will need to target multiple staphylococcal antigens.…”