MEDI4893 is an investigational immunoglobulin G1K monoclonal antibody that specifically binds to and neutralizes alpha-toxin, a key Staphylococcus aureus virulence factor. A triple–amino acid substitution, M252Y/S254T/T256E, was engineered into the MEDI4893 Fc region to extend its serum half-life. A phase 1, double-blind, dose escalation study was designed to evaluate the safety, tolerability, pharmacokinetics, anti–alpha-toxin neutralizing activity, and anti-drug antibody (ADA) response of MEDI4893 following a single intravenous infusion in healthy adults 18–65 years of age. Thirty-three subjects were randomly assigned to receive MEDI4893 at 225 mg (n = 3), 750 mg (n = 3), 2,250 mg (n = 8), or 5,000 mg (n = 12) or placebo (n = 7) and were followed for 360 days. Adverse events were mild or moderate in severity; none were serious. MEDI4893 peak serum concentration increased dose proportionally from 77.2 μg/mL (225 mg) to 1,784 μg/mL (5,000 mg). Area under the concentration–time curve from 0 to 360 days also increased dose proportionally, from 4,840 μg•day/mL (225 mg) to 91,493 μg•day/mL (5,000 mg), indicating linear pharmacokinetics. MEDI4893's terminal half-life was estimated as 80–112 days, approximately fourfold longer than those of other human immunoglobulin G antibodies. Alpha-toxin–neutralizing activity in serum correlated highly with MEDI4893 concentrations in serum. Three adults tested positive transiently for ADA on day 151 without impact on MEDI4893 serum concentrations or safety profile; no subjects exhibited serum ADA at the study end. These data support continued development of MEDI4893 for the prevention of S. aureus-mediated pneumonia.
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