A human monoclonal antibody targeting the conserved staphylococcal antigen IsaA protects mice against Staphylococcus aureus bacteremia.

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.

[1]  S. Foster,et al.  Characterization of IsaA and SceD, Two Putative Lytic Transglycosylases of Staphylococcus aureus , 2007, Journal of bacteriology.

[2]  V. Fowler,et al.  Phase II, Randomized, Double-Blind, Multicenter Study Comparing the Safety and Pharmacokinetics of Tefibazumab to Placebo for Treatment of Staphylococcus aureus Bacteremia , 2006, Antimicrobial Agents and Chemotherapy.

[3]  S. Foster,et al.  Anti-Staphylococcus aureus immunotherapy: current status and prospects. , 2009, Current opinion in pharmacology.

[4]  D. Missiakas,et al.  Role of Protein A in the Evasion of Host Adaptive Immune Responses by Staphylococcus aureus , 2013, mBio.

[5]  J. D. Capra,et al.  Rapid generation of fully human monoclonal antibodies specific to a vaccinating antigen , 2009, Nature Protocols.

[6]  A. van Belkum,et al.  Characterization of the Humoral Immune Response during Staphylococcus aureus Bacteremia and Global Gene Expression by Staphylococcus aureus in Human Blood , 2013, PloS one.

[7]  S. Foster,et al.  Identification of in vivo-expressed antigens of Staphylococcus aureus and their use in vaccinations for protection against nasal carriage. , 2006, The Journal of infectious diseases.

[8]  R. Schelonka,et al.  A blinded, randomized, multicenter study of an intravenous Staphylococcus aureus immune globulin , 2006, Journal of Perinatology.

[9]  H. Harmsen,et al.  Mapping the Pathways to StaphylococcalPathogenesis by Comparative Secretomics , 2006, Microbiology and Molecular Biology Reviews.

[10]  Michel C Nussenzweig,et al.  Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. , 2008, Journal of immunological methods.

[11]  H. Bonarius,et al.  High anti-staphylococcal antibody titers in patients with epidermolysis bullosa relate to long-term colonization with alternating types of Staphylococcus aureus. , 2013, The Journal of investigative dermatology.

[12]  S. Cosgrove.  The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[13]  D. Goldmann,et al.  N Surface Polysaccharide Poly- Antibodies Specific for the Bacterial of Fully Human Monoclonal Aureus Staphylococcus Protective Activity against Characterization of the Opsonic And , 2005 .

[14]  Jan Maarten van Dijl,et al.  Synthetic Effects of secG and secY2 Mutations on Exoproteome Biogenesis in Staphylococcus aureus , 2010, Journal of bacteriology.

[15]  R. Schelonka,et al.  Clinical trial of safety and efficacy of INH-A21 for the prevention of nosocomial staphylococcal bloodstream infection in premature infants. , 2007, The Journal of pediatrics.

[16]  S. Cosgrove,et al.  The Impact of Methicillin Resistance in Staphylococcus aureus Bacteremia on Patient Outcomes: Mortality, Length of Stay, and Hospital Charges , 2005, Infection Control & Hospital Epidemiology.

[17]  Henry F. Chambers,et al.  Waves of resistance: Staphylococcus aureus in the antibiotic era , 2009, Nature Reviews Microbiology.

[18]  Partially overlapping substrate specificities of staphylococcal group A sortases , 2012, Proteomics.

[19]  A. Radbruch,et al.  Corrigendum: Generation of stable monoclonal antibody–producing B cell receptor–positive human memory B cells by genetic programming , 2016, Nature Medicine.

[20]  L. Cope,et al.  Characterization of the mechanism of protection mediated by CS-D7, a monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB) , 2012, Front. Cell. Inf. Microbio..

[21]  J. Köhl,et al.  Staphylococcus aureus Formyl Peptide Receptor–like 1 Inhibitor (FLIPr) and Its Homologue FLIPr-like Are Potent FcγR Antagonists That Inhibit IgG-Mediated Effector Functions , 2013, The Journal of Immunology.

[22]  R. Kontermann,et al.  Characterization of the biological anti-staphylococcal functionality of hUK-66 IgG1, a humanized monoclonal antibody as substantial component for an immunotherapeutic approach , 2014, Human vaccines & immunotherapeutics.

[23]  S. McAllister,et al.  Pulsed-Field Gel Electrophoresis Typing of Oxacillin-Resistant Staphylococcus aureus Isolates from the United States: Establishing a National Database , 2003, Journal of Clinical Microbiology.

[24]  C. Woods,et al.  Phase II, Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial of a Polyclonal Anti-Staphylococcus aureus Capsular Polysaccharide Immune Globulin in Treatment of Staphylococcus aureus Bacteremia , 2007, Antimicrobial Agents and Chemotherapy.

[25]  Patrick C. Wilson,et al.  Rapid cloning of high-affinity human monoclonal antibodies against influenza virus , 2008, Nature.

[26]  S. Engelmann,et al.  Proteomics uncovers extreme heterogeneity in the Staphylococcus aureus exoproteome due to genomic plasticity and variant gene regulation , 2010, Proteomics.

[27]  A. Troelstra,et al.  Dual effects of soluble CD14 on LPS priming of neutrophils , 1997, Journal of leukocyte biology.

[28]  F. Lowy.  Staphylococcus aureus infections. , 2009, The New England journal of medicine.

[29]  A. van Belkum,et al.  Immunotherapeutic approaches against Staphylococcus aureus. , 2011, Immunotherapy.

[30]  K. Ohlsen,et al.  Immunotherapeutic strategies to combat staphylococcal infections. , 2010, International journal of medical microbiology : IJMM.

[31]  M. Hecker,et al.  Profiling the surfacome of Staphylococcus aureus , 2010, Proteomics.

[32]  S. Terakubo,et al.  Subcellular Location of the Soluble Lytic Transglycosylase Homologue in Staphylococcus aureus , 2004, Current Microbiology.

[33]  Sarah Dubrac,et al.  Identification of Genes Controlled by the Essential YycG/YycF Two-Component System of Staphylococcus aureus , 2004, Journal of bacteriology.

[34]  J. Wehland,et al.  Functional Antibodies Targeting IsaA of Staphylococcus aureus Augment Host Immune Response and Open New Perspectives for Antibacterial Therapy , 2010, Antimicrobial Agents and Chemotherapy.

[35]  D. Galloway,et al.  Human Monoclonal Antibodies against Anthrax Lethal Factor and Protective Antigen Act Independently To Protect against Bacillus anthracis Infection and Enhance Endogenous Immunity to Anthrax , 2007, Infection and Immunity.

[36]  M. Hecker,et al.  Human antibody response during sepsis against targets expressed by methicillin resistant Staphylococcus aureus. , 2000, FEMS immunology and medical microbiology.

[37]  L. Boon,et al.  Distinctive Cytokines as Biomarkers Predicting Fatal Outcome of Severe Staphylococcus aureus Bacteremia in Mice , 2013, PloS one.