Safety and tolerability of 514G3, a True Human Anti-Protein A Monoclonal Antibody for the treatment of S. aureus Bacteremia.

Background:

Novel therapeutic approaches are urgently needed for the treatment of serious infections due to S. aureus. 514G3 is a True Human Monoclonal antibody (IgG3), targeting Staphylococcus Protein A (SpA), which was isolated and cloned from a healthy human donor. Treatment of S. aureus infection with a True Human Antibody is expected to be safe, with minimal side effects.

Methods:

Phase I, double blind, multicenter, randomized, placebo controlled, dose escalation study of 514G3 in patients hospitalized with S. aureus bacteremia. Eligible subjects received a single intravenous dose of 514G3 at 2, 10, or 40 mg/kg or placebo (3:1) along with standard antibiotic therapy. Subjects were followed for at least 14 days to assess adverse events (AEs), potential dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD). DLTs were defined as any grade 3 or greater AE assessed as probably or definitely related to therapy. The MTD was defined as the highest dose level with ≤1 DLT.

Results:

12 subjects received 514G3, and 4 placebo. Median age was 60, and 39% were female. Infection source was 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%). No DLTs occurred. The MTD was undefined, and 40 mg/kg was designated as the recommended phase 2 dose. The incidence of SAEs was lower in the 514G3 group than placebo, with 3 of 12 (25%) and 2 of 4 (50%) experiencing SAEs respectively. None of the SAEs were probably or definitely related to antibody therapy, and all were deemed to be related to worsening of the patients’ underlying condition.

Conclusion:

514G3 was safe and well tolerated at all dose levels tested. While the numbers are small, fewer SAEs in the 514G3 treatment group suggest a favorable side effect and tolerability profile. Safety and reduction of complications from S. aureus bacteremia will be explored further in a randomized controlled trial utilizing the 40 mg/kg dose that is adequately powered to demonstrate differences between treatment arms.