1985. Pharmacokinetics of a Novel Monoclonal Antibody Targeting Staphylococcal Protein A in Patients Hospitalized with S. aureus Bacteremia
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Posters
  • 1985_IDWPOSTER.pdf (7.9 MB)
  • Background:

    S. aureus (SA) is a common cause of bacteremia (SAB) and carries a 20–40% mortality at 30days despite antibiotic therapy. While new therapeutic approaches are urgently needed, active and passive immunization strategies have failed due to SA immune evasion. Staphylococcus Protein A (ProA) binds human IgGs with high affinity via the Fc region, and prevents complement activation and binding of white blood cells necessary for phagocytosis. 514G3 binds specifically to ProA, was derived from an individual with natural anti-ProA titers, and is of an IgG3 subclass, which is not bound by ProA. It is therefore expected to bind ProA, while maintaining effector function, thus allowing for natural immune mediated clearance.

    Methods:

    Phase I, double blind, multicenter, randomized, placebo controlled, dose escalation study of 514G3 in adult patients hospitalized with SAB. Eligible subjects received a single intravenous dose of 514G3 at 2, 10, or 40 mg/kg or placebo (3:1) in conjunction with standard antibiotic therapy. Subjects were followed for at least 14 days, and blood for pharmacokinetic (PK) testing was collected daily. PK was assessed using ELISA and an opsonophagocytosis assay (OPA), which also measured 514G3 ability to mediate macrophage clearance of SA.

    Results:

    12 subjects received 514G3, and 4 placebo. The median age was 60, and 39% were female. Infection sources were: skin and soft tissue infection (6), phlebitis or catheter associated (4), unknown (3), and hemodialysis vascular access (3). MRSA was identified in 6 of 16 patients (38%). 514G3 half-life was 3.0, 5.0, and 4.8 days at the 2, 10, and 40 mg/kg dose levels, respectively. At the 40 mg/kg dose level, the mean maximum concentration was 820 mcg/ml post-infusion, and 120 mcg/ml at day 14. Serum concentration for ELISA and OPA measurements were consistent at the three 514G3 dose levels.

    Conclusion:

    Treatment with 514G3 demonstrated SA phagocytosis for patients hospitalized with SAB. The half-life was non-linear, suggesting target saturation at the lowest dose level. 514G3 may provide an effective adjunctive treatment for SAB and further study at the 40 mg/kg dose is warranted.

    Mark E. Rupp, MD, FIDSA, FSHEA, Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, Michael Stecher, MD, Clinical Regulatory, XBiotech USA, Inc, Austin, TX, John Mckinnon, MD, MSc, Medicine / Infectious Diseases, Henry Ford Hospital, Detroit, MI, Norma Jung, MD, University of Koln, Koln, Germany and Toan Huynh, MD, Carolinas Healthcare System/F.H. Sammy Ross Trauma Center, Charlotte, NC

    Disclosures:

    M. E. Rupp, None

    M. Stecher, XBiotech: Employee and Shareholder , Salary

    J. Mckinnon, None

    N. Jung, Labor Stein: Speaker's Bureau , Speaker honorarium
    Novartis: Speaker's Bureau , Speaker honorarium and travel grant
    Astellas: Consultant , travel grant
    Infectofos: Grant Investigator , Research grant

    T. Huynh, None

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