Comparative therapeutic potential of ALX-0171 and palivizumab against RSV clinical isolate infection of well-differentiated primary pediatric bronchial epithelial cell cultures

Abstract

Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections in young infants. There are no RSV-specific treatments available. Ablynx has been developing an anti-RSV F-specific Nanobody(R), ALX-0171. To characterise the therapeutic potential of ALX-0171 we exploited our well-differentiated primary pediatric bronchial epithelial cell (WD-PBEC)/RSV infection model, which replicates several hallmarks of RSV disease in vivo. Using 2 clinical isolates (BT2a; Memphis 37), we compared the therapeutic potential of ALX-0171 with palivizumab, which is currently prescribed for RSV prophylaxis in high-risk infants. ALX-0171 treatment (900 mM) at 24 h post-infection reduced apically released RSV titers to near or below the limit of detection within 24 h for both strains. Progressively lower doses resulted in concomitantly diminished RSV neutralisation. ALX-0171 was approximately 3 fold more potent in this therapeutic RSV/WD-PBEC model than palivizumab (mean IC50 = 346.9-363.6 nM and 1048-1090 nM for ALX-0171 and palivizumab, respectively), irrespective of the clinical isolate. When viral genomic copies (GC) were measured by RT-qPCR, the therapeutic effect was considerably less and GCs were only moderately reduced (0.62 - 1.28 Log10 copies/mL) by ALX-0171 treatment at 300 and 900 nM. Similar findings were evident for palivizumab. Therefore, ALX-0171 was very potent at neutralising RSV released from apical surfaces but only had a limited impact on virus replication. The data indicate a clear disparity between viable virus neutralisation and GC viral load, the latter of which does not discriminate between viable and neutralised RSV. This study validates the RSV/WD-PBEC model for the pre-clinical evaluation of RSV antivirals.