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

ObjectivesMEDI4893 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 MEDI4893 doses or placebo.MethodsAnti‐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.ResultsSubjects receiving 2250 or 5000 mg of MEDI4893 had the highest serum anti‐AT neutralising antibody (NAb) 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 NAbs were >3.2 International Units (IU) mL−1 for at least 211 days. In the upper respiratory tract, anti‐AT NAb levels increased with MEDI4893 dose. No apparent effect of MEDI4893 on SA nasal colonisation, hla gene sequence or AT expression was observed. Five AT variants were detected, their lytic activity was fully neutralised by MEDI4893.DiscussionOur results indicate that (1) MEDI4893 administration at 2250 and 5000 mg would provide effective immunoprophylaxis against systemic SA disease; (2) MEDI4983 distributes to the upper respiratory tract and retains neutralising activity against AT; and (3) potential for emergence of MEDI4893 resistance is low.ConclusionIntravenous administration of MEDI4893 maintained levels of anti‐AT NAbs in serum and nasal mucosa that may provide effective immunoprophylaxis against SA disease and support continued clinical development of MEDI4893.

Alanine scanning mutagenesis of the MEDI4839 (Suvratoxumab) epitope reduces alpha toxin lytic activity in vitro and S. aureus fitness in infection models

“…1A and B ) (23). These residues were highly conserved among ~1,250 diverse S. aureus clinical isolates (24–26). Alanine scanning mutagenesis of these 9 contact residues was conducted to determine their role in AT function and to gain insight into the effect these mutations have on MEDI4893 neutralizing activity.…”

“…Since mAbs do not affect bacterial growth directly, it is difficult or even impossible to study the emergence of resistance in vitro or in vivo over the time course of preclinical infection models. To begin to address the questions about circulating resistant S. aureus isolates, we conducted two studies in which the AT gene ( hla ) was sequenced from ~1,250 clinical isolates (24–26). In these collections, 58 different AT sequence types were identified and the anti-AT mAb MEDI4893, currently in Phase 2 clinical testing, effectively neutralized all lytic variants.…”

“…Of these clinical isolates, only 19 encoded an AT protein with a mutation in the MEDI4893 epitope which was effectively neutralized. During Phase 1 study, no AT variants with amino acid substitutions in MEDI4893-binding region were detected despite prolonged exposure of S. aureus strains to MEDI4893 due to its extended half-life (26). Because the MEDI4893 epitope is highly conserved and no MEDI4893-resistant mutants were observed thus far, we hypothesized that the AT AAs in the MEDI4893-binding epitope are important for AT function.…”

“…These results support the hypothesis that the MEDI4893 epitope in AT is important not only for AT lytic activity, but also for bacterial fitness in skin and lung infection models. Therefore, it is not surprising that only two MEDI4893 epitope variants (N188T and V190I) were identified in the collection of ~1,250 bloodstream and lung infection clinical isolates (24–26). Although the potential for emergence of MEDI4893 resistance appears to be low, further monitoring of AT sequence variants encoded by circulating clinical isolates is underway that will provide added information regarding AT sequence conservation and the fitness of strains expressing defective or inactive AT variants.…”

“…MEDI4893 binds with high affinity to a discontinuous epitope on AT (amino acids 177-200 and 261-27) and inhibits pore-formation by blocking toxin binding to target cell membranes (20, 23). Recent studies of diverse S. aureus clinical isolate collections (~1250 total) demonstrated that the AT gene, hla , is encoded by a majority (>99.5%) of isolates and 58 different AT sequence variants were identified (24–26). In these collections, the MEDI4893 epitope was highly conserved with only 19 isolates having mutations in the epitope.…”