Suvratoxumab (as known as MEDI4893) is a potent and long-acting human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody. This drug was developed by MedImmune to target Staphylococcus aureus alpha toxin (AT) that is currently in phase 2 clinical development for the prevention of S. aureus pneumonia in mechanically ventilated patients colonized with S. aureus in the lower respiratory tract. Suvratoxumab has been shown to prevent lethal S. aureus pneumonia, reduce the pathology associated with infection and accelerate pulmonary bacterial clearance even in the absence of concurrent antimicrobial therapy. Results from a phase 1, first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study demonstrated the safety and tolerability of MEDI4893.
Staphylococcus aureus is a Gram-positive coccus that causes serious infections of multiple organs, including the skin, soft tissues, respiratory tract, bone, joints, and endovascular system. S. aureus is the leading cause of hospital-acquired (nosocomial) pneumonia, including ventilator-associated pneumonia, resulting in significant morbidity, health care resource utilization, and death. An innovative approach to the prevention of S. aureus pneumonia could be the use of an anti-infective monoclonal antibody for immunoprophylaxis that targets a specific common virulence factor protein on S. aureus. Alpha toxin is a highly conserved, key virulence factor of S. aureus that functions as a cytolytic pore-forming toxin that, when released into the infected host, leads to tissue disruption, programmed cell death of leukocytes and endothelial cells, bacterial dissemination, and immune dysregulation. Thus, the neutralization of alpha-toxin should prevent the physiological damage caused by the toxin and limit the dissemination of S. aureus. Suvratoxumab is an investigational human immunoglobulin G1(κ) (IgG1, κ) monoclonal antibody that binds with a high affinity to and neutralizes S. aureus alpha toxin, thereby diminishing S. aureus disease pathogenesis, as demonstrated in animal models of lethal pneumonia. This monoclonal antibody recognizes a highly conserved region of alpha toxin that has been identified in >97% of S. aureus clinical isolates sequenced to date around the world and exerts its neutralizing activity through a dual mechanism: (i) it sterically blocks binding of alpha toxin to the toxin's cellular receptor, and (ii) it prevents alpha toxin from adopting the pore-forming heptameric transmembrane conformation that is required for host cell lysis. Suvratoxumab was derived from an anti-alpha toxin monoclonal antibody, LC10, and possesses a triple-amino-acid substitution (M252Y/S254T/T256E, YTE) in the antibody Fc region that confers an extended serum half-life by increasing the affinity of antibody binding to the neonatal Fc receptor involved in lysosomal recycling of IgG molecules. Importantly, the YTE substitution does not interfere with the specificity of binding of antibody molecules to their target epitopes, as is evident in the ability of suvratoxumab to neutralize alpha toxin by binding to the epitope involved in cell attachment and lytic pore formation.
Fig 1. Mechanism of Action of Suvratoxumab