title: Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious Staphylococcus aureus Disease.
abstract: Staphylococcus aureus produces numerous virulence factors, each contributing different mechanisms to bacterial pathogenesis in a spectrum of diseases. Alpha toxin (AT), a cytolytic pore-forming toxin, plays a key role in skin and soft tissue infections and pneumonia, and a human anti-AT monoclonal antibody (MAb), MEDI4893*, has been shown to reduce disease severity in dermonecrosis and pneumonia infection models. However, interstrain diversity and the complex pathogenesis of S. aureus bloodstream infections suggests that MEDI4893* alone may not provide adequate protection against S. aureus sepsis. Clumping factor A (ClfA), a fibrinogen binding protein, is an important virulence factor facilitating S. aureus bloodstream infections. Herein, we report on the identification of a high-affinity anti-ClfA MAb, 11H10, that inhibits ClfA binding to fibrinogen, prevents bacterial agglutination in human plasma, and promotes opsonophagocytic bacterial killing (OPK). 11H10 prophylaxis reduced disease severity in a mouse bacteremia model and was dependent on Fc effector function and OPK. Additionally, prophylaxis with 11H10 in combination with MEDI4893* provided enhanced strain coverage in this model and increased survival compared to that obtained with the individual MAbs. The MAb combination also reduced disease severity in murine dermonecrosis and pneumonia models, with activity similar to that of MEDI4893* alone. These results indicate that an MAb combination targeting multiple virulence factors provides benefit over a single MAb neutralizing one virulence mechanism by providing improved efficacy, broader strain coverage, and protection against multiple infection pathologies.
  
  
  
  Alternative strategies to broad-spectrum antibiotics are required to combat the antibiotic resistance epidemic. Previous attempts at active or passive immunization against Staphylococcus aureus targeting single antigens have failed in clinical trials despite positive preclinical data. To provide broad disease and isolate coverage, an effective immunization strategy likely must target multiple virulence mechanisms of the pathogen. Herein, we tested a multimechanistic MAb combination targeting alpha toxin (AT) and clumping factor A (ClfA) that neutralizes AT-mediated cytotoxicity, blocks fibrinogen binding by ClfA, prevents bacterial agglutination, targets the bacteria for opsonophagocytic killing, and provides broad isolate coverage in a lethal-bacteremia model. Although each MAb alone was effective in bacteremia against some individual isolates, the MAb combination provided improved protection against other isolates. These results illustrate the importance of targeting multiple virulence mechanisms and highlight the potential for an MAb combination targeting AT and ClfA to effectively prevent S. aureus disease.
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA.
authors.forename: C
authors.initials: C
authors.lastname: Tkaczyk
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Hamilton
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sadowska
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Chang
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA.
authors.forename: P
authors.initials: P
authors.lastname: Chowdhury
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA.
authors.forename: R
authors.initials: R
authors.lastname: Buonapane
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA.
authors.forename: X
authors.initials: X
authors.lastname: Xiao
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA.
authors.forename: P
authors.initials: P
authors.lastname: Warrener
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mediavilla
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kreiswirth
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: Suzich
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA.
authors.forename: C K
authors.initials: CK
authors.lastname: Stover
authors.affiliation: MedImmune, a member of the AstraZeneca Group, Gaithersburg, Maryland, USA sellmanb@medimmune.com.
authors.forename: B R
authors.initials: BR
authors.lastname: Sellman
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology* / Q000302:isolation & purification; D057134:Antibodies, Neutralizing / Q000627:therapeutic use; D058491:Bacterial Load; D001427:Bacterial Toxins / Q000276:immunology*; D003030:Coagulase / Q000276:immunology*; D004195:Disease Models, Animal; D018922:HL-60 Cells; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D051379:Mice; D010587:Phagocytosis; D013203:Staphylococcal Infections / Q000097:blood / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000276:immunology*; D037521:Virulence Factors / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001427:Bacterial Toxins; C515944:ClfA protein, Staphylococcus aureus; D003030:Coagulase; D037521:Virulence Factors