title: A human monoclonal antibody targeting the conserved staphylococcal antigen IsaA protects mice against Staphylococcus aureus bacteremia.
abstract: Due to substantial therapy failure and the emergence of antibiotic-resistant Staphylococcus aureus strains, alternatives for antibiotic treatment of S. aureus infections are urgently needed. Passive immunization using S. aureus-specific monoclonal antibodies (mAb) could be such an alternative to prevent and treat severe S. aureus infections. The invariantly expressed immunodominant staphylococcal antigen A (IsaA) is a promising target for passive immunization. Here we report the development of the human anti-IsaA IgG1 mAb 1D9, which was shown to bind to all 26 S. aureus isolates tested. These included both methicillin-susceptible and methicillin-resistant S. aureus (MSSA and MRSA, respectively). Immune complexes consisting of IsaA and 1D9 stimulated human as well as murine neutrophils to generate an oxidative burst. In a murine bacteremia model, the prophylactic treatment with a single dose of 5 mg/kg 1D9 improved the survival of mice challenged with S. aureus isolate P (MSSA) significantly, while therapeutic treatment with the same dose did not influence animal survival. Neither prophylactic nor therapeutic treatment with 5 mg/kg 1D9 resulted in improved survival of mice with S. aureus USA300 (MRSA) bacteremia. Importantly, our studies show that healthy S. aureus carriers elicit an immune response which is sufficient to generate protective mAbs against invariant staphylococcal surface antigens. Human mAb 1D9, possibly conjugated to for example another antibody, antibiotics, cytokines or chemokines, may be valuable to fight S. aureus infections in patients.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: s.vandenberg@erasmusmc.nl.
authors.forename: Sanne
authors.initials: S
authors.lastname: van den Berg
authors.affiliation: IQ Therapeutics, Groningen, The Netherlands.
authors.forename: Hendrik P J
authors.initials: HP
authors.lastname: Bonarius
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kok P M
authors.initials: KP
authors.lastname: van Kessel
authors.affiliation: IQ Therapeutics, Groningen, The Netherlands.
authors.forename: Goffe S
authors.initials: GS
authors.lastname: Elsinga
authors.affiliation: IQ Therapeutics, Groningen, The Netherlands.
authors.forename: Neeltje
authors.initials: N
authors.lastname: Kooi
authors.affiliation: IQ Therapeutics, Groningen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Westra
authors.affiliation: Lanthio Pharma, Groningen, The Netherlands.
authors.forename: Tjibbe
authors.initials: T
authors.lastname: Bosma
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: van der Kooi-Pol
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Danny G A M
authors.initials: DG
authors.lastname: Koedijk
authors.affiliation: IQ Therapeutics, Groningen, The Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Groen
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jan Maarten
authors.initials: JM
authors.lastname: van Dijl
authors.affiliation: Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Girbe
authors.initials: G
authors.lastname: Buist
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Irma A J M
authors.initials: IA
authors.lastname: Bakker-Woudenberg
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism*; D016470:Bacteremia / Q000382:microbiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D007116:Immunization, Passive / Q000379:methods; D008807:Mice, Inbred BALB C; D013203:Staphylococcal Infections / Q000382:microbiology / Q000517:prevention & control*; D016019:Survival Analysis; D016896:Treatment Outcome; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; C417673:IsaA antigen, staphylococcus; D037521:Virulence Factors
keywords: Bacteremia; Efficacy; Human monoclonal antibody; IsaA; Mouse; Staphylococcus aureus