Functional antibodies targeting IsaA of Staphylococcus aureus

Functional antibodies targeting IsaA of staphylococcus aureus augment host immune response and open new perspectives for antibacterial therapy ABSTRACT 51 Staphylococcus aureus is the most common cause of nosocomial infections. Multiple 52 antibiotic resistance and severe clinical outcomes provide a strong rationale for 53 development of immunoglobulin-based strategies. Traditionally, novel immunological 54 approaches against bacterial pathogens involve antibodies directed against cell 55 surface exposed virulence-associated epitopes or toxins. In this study, w e generated 56 a monoclonal antibody targeting the housekeeping protein IsaA, a suggested soluble 57 lytic transglycosylase of S. aureus and tested its therapeutic efficacy in two 58 experimental mouse infection models. A murine anti-IsaA antibody of IgG1 subclass 59 (UK-66P) showed highest binding affinity in Biacore analysis. This antibody 60 recognizes all S. aureus strains tested including hospital-acquired and community-61 acquired methicillin-resistant S. aureus strains. Therapeutic efficacy in vivo was 62 analyzed in mice using a central-venous catheter-related infection model and a 63 sepsis survival model. In both models anti-IsaA IgG1 conferred protection to 64 staphylococcal infection. Ex vivo, UK-66P activates professional phagocytes and 65 induces highly microbicidal reactive oxygen metabolites in a dose-dependent 66 manner, resulting in bacterial killing. The study provides proof of concept that 67 monoclonal IgG1 antibodies with high-affinity to the ubiquitous expressed single 68 epitope IsaA are effective in the treatment of staphylococcal infection in different 69 mouse models. Anti-IsaA antibodies might be a useful component in an antibody-70 based therapeutic for prophylaxis or adjunctive treatment of human cases of S.