Abstract
ABSTRACTMEDI4893 is an investigational immunoglobulin G1(κ) 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 antidrug antibody (ADA) response of MEDI4893 following a single intravenous infusion in healthy adults 18 to 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. The MEDI4893 peak serum concentration increased dose proportionally from 77.2 μg/ml (225-mg dose) to 1,784 μg/ml (5,000-mg dose). The area under the concentration-time curve from 0 to 360 days also increased dose proportionally, from 4,840 μg · day/ml (225-mg dose) to 91,493 μg · day/ml (5,000-mg dose), indicating linear pharmacokinetics. MEDI4893's terminal half-life was estimated to be 80 to 112 days, which is approximately 4-fold longer than the half-lives of other human immunoglobulin G antibodies. The alpha-toxin-neutralizing activity in serum correlated highly with the MEDI4893 concentrations in serum. Three adults transiently tested positive for ADA on day 151, but this did not have an impact on MEDI4893 serum concentrations or the MEDI4893 safety profile; no subjects exhibited serum ADA at the study end. These data support the continued development of MEDI4893 for the prevention of S. aureus-mediated pneumonia. (This study has been registered at ClinicalTrials.gov under identifier NCT02296320.)
Highlights
MEDI4893 is an investigational immunoglobulin G1() monoclonal antibody that binds to and neutralizes alpha-toxin, a key Staphylococcus aureus virulence factor
MEDI4893 is an investigational human immunoglobulin G1() [IgG1()] monoclonal antibody that binds with a high affinity to and neutralizes S. aureus alpha-toxin, thereby diminishing S. aureus disease pathogenesis, as demonstrated in animal models of lethal pneumonia [8, 19]
MEDI4893 was derived from a previously described anti-alpha-toxin monoclonal antibody, LC10, and possesses a triple-amino-acid substitution (M252Y/S254T/T256E [YTE]) in the antibody Fc region that confers an extended serum half-life by increasing the affinity of antibody binding to the neonatal Fc receptor involved in lysosomal recycling of IgG molecules [21]
Summary
MEDI4893 is an investigational immunoglobulin G1() monoclonal antibody that binds to and neutralizes alpha-toxin, a key Staphylococcus aureus virulence factor. MEDI4893 is an investigational human immunoglobulin G1() [IgG1()] monoclonal antibody that binds with a high affinity to and neutralizes S. aureus alpha-toxin, thereby diminishing S. aureus disease pathogenesis, as demonstrated in animal models of lethal pneumonia [8, 19] This monoclonal antibody recognizes a highly conserved region of alpha-toxin that has been identified in Ͼ97% of S. aureus clinical isolates sequenced to date around the world [17, 20] and exerts its neutralizing activity through a dual mechanism: (i) it sterically blocks binding of alpha-toxin to the toxin’s cellular receptor, and (ii) it prevents alpha-toxin from adopting the pore-forming heptameric transmembrane conformation that is required for host cell lysis [19]. The YTE substitution does not interfere with the specificity of binding of antibody molecules to their target epitopes, as is evident in the ability of MEDI4893 to neutralize alpha-toxin by binding to the epitope involved in cell attachment and lytic pore formation [8, 19, 21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
