Protective Efficacy of Monoclonal Antibodies Neutralizing Alpha-Hemolysin and Bicomponent Leukocidins in a Rabbit Model of Staphylococcus aureus Necrotizing Pneumonia

Abstract

Staphylococcus aureus is a major human pathogen that causes a wide range of infections by producing an arsenal of cytotoxins. We found that passive immunization with either a monoclonal antibody (MAb) neutralizing alpha-hemolysin or a broadly cross-reactive MAb neutralizing Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysins HlgAB and HlgCB conferred only partial protection, whereas the combination of those two MAbs conferred significant protection in a rabbit model of necrotizing pneumonia caused by the USA300 methicillin-resistant S. aureus epidemic clone.

Hypersensitivity of MAIT cells to Leukocidin ED indicates a Staphylococcus aureus immune evasion mechanism targeting the innate effector cell response

“…It is interesting to note that several new treatments are in development against S. aureus infection including monoclonal antibodies aimed to neutralize S. aureus toxins [49]. In experimental animal models of infection in mice [50] and rabbits [51], the combination of monoclonal antibodies, including one targeting LukED, shows enhanced efficacy over single antibody administration with decreased bacterial burden [50] or increased survival [51]. In addition, new neutralizing agents called centyrins are able to block the binding of the five bicomponent leukocidins to their receptors and protect in vivo against S. aureus infection [52].…”

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

“…It has already been shown that the addition of just one target with a bispecific antibody improves Hu-mAb efficacy [55,59,60]. Further, there are now pentavalent antibodies and mAb cocktails that are also being explored to improve efficacy [73,74]. One can certainly envision a future, 5-10 years from now, where there could be a Hu-mAb antibody product, cocktail or multivalent molecule, which is developed for each bacterial pathogen that causes difficult-to-treat infections.…”

Exploring Virulence Factors and Alternative Therapies against Staphylococcus aureus Pneumonia

“…More promising results by the Diep group came from two studies conducted in a NP rabbit model. The first study showed that passive immunization using a combination of an Hla-specific mAb (suvratoxumab) with a cross-neutralizing leukocidin mAb (SAN177 or SAN481) reduced mortality to 7% and 0%, respectively ( Figure 1 B) [ 195 ]. The second study showed similar results when attenuated Hla (Hla H35L/H48L ), combined with two attenuated PVL components (described in [ 88 ]), were used for active immunization [ 86 ], where 100% protection from lethality was observed in immunized rabbits ( Figure 1 C).…”

“…*: also neutralizes enterotoxins A and B and toxic shock syndrome toxin 1. (1): [ 193 , 194 ]; (2): [ 195 ]; (3): [ 86 ]; (4): [ 74 , 196 ]; (5): [ 197 , 198 ]; (6): [ 199 ]; (7): [ 200 ]; (8): [ 201 ]. (i): [ 202 ]; (ii): [ 203 ]; (iii): [ 204 ]; (iv): [ 183 ]; (v): [ 205 ].…”

“…We will highlight some in the following paragraphs. 1): [193,194]; (2): [195]; (3): [86]; (4): [74,196]; (5): [197,198]; (6): [199]; (7): [200]; (8): [201]. (i): [202]; (ii): [203]; (iii): [204]; (iv): [183]; (v): [205].…”