Characterisation of anti‐alpha toxin antibody levels and colonisation status after administration of an investigational human monoclonal antibody, MEDI4893, against Staphylococcus aureus alpha toxin

Abstract Objectives MEDI4893 is a novel, long‐acting human monoclonal antibody targeting Staphylococcus aureus ( SA ) alpha toxin ( AT ). This report presents the results of the exploratory analyses from a randomised phase 1 dose‐escalation study in healthy human subjects receiving single intravenous MEDI 4893 doses or placebo. Methods Anti‐ AT antibodies and AT expression were measured as described previously. Nasal swabs were analysed by culture and PCR . Data were summarised by treatment groups and visits by using SAS System Version 9.3. Results Subjects receiving 2250 or 5000 mg of MEDI 4893 had the highest serum anti‐ AT neutralising antibody ( NA b) levels: approximately 180‐ to 240‐, 70‐ to 100‐ and sevenfold to 10‐fold higher than respective baseline levels at peak, 30 and 360 days, respectively. In these subjects, levels of serum anti‐ AT NA bs were >3.2 International Units (IU) mL −1 for at least 211 days. In the upper respiratory tract, anti‐ AT NA b levels increased with MEDI 4893 dose. No apparent effect of MEDI 4893 on SA nasal colonisation, hla gene sequence or AT expression was observed. Five AT variants were detected, their lytic activity was fully neutralised by MEDI 4893. Discussion Our results indicate that (1) MEDI 4893 administration at 2250 and 5000 mg would provide effective immunoprophylaxis against systemic SA disease; (2) MEDI 4983 distributes to the upper respiratory tract and retains neutralising activity against AT ; and (3) potential for emergence of MEDI 4893 resistance is low. Conclusion Intravenous administration of MEDI 4893 maintained levels of anti‐ AT NA bs in serum and nasal mucosa that may provide effective immunoprophylaxis against SA disease and support continued clinical development of MEDI 4893.