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. 2015 Oct 5;60(1):6-13.
doi: 10.1128/AAC.01802-15. Print 2016 Jan.

Generation and Characterization of ALX-0171, a Potent Novel Therapeutic Nanobody for the Treatment of Respiratory Syncytial Virus Infection

Laurent Detalle  1 , Thomas Stohr  2 , Concepción Palomo  3 , Pedro A Piedra  4 , Brian E Gilbert  5 , Vicente Mas  3 , Andrena Millar  6 , Ultan F Power  6 , Catelijne Stortelers  2 , Koen Allosery  2 , José A Melero  3 , Erik Depla  2
Affiliations

Generation and Characterization of ALX-0171, a Potent Novel Therapeutic Nanobody for the Treatment of Respiratory Syncytial Virus Infection

Laurent Detalle et al. Antimicrob Agents Chemother. .

Abstract

Respiratory syncytial virus (RSV) is an important causative agent of lower respiratory tract infections in infants and elderly individuals. Its fusion (F) protein is critical for virus infection. It is targeted by several investigational antivirals and by palivizumab, a humanized monoclonal antibody used prophylactically in infants considered at high risk of severe RSV disease. ALX-0171 is a trimeric Nanobody that binds the antigenic site II of RSV F protein with subnanomolar affinity. ALX-0171 demonstrated in vitro neutralization superior to that of palivizumab against prototypic RSV subtype A and B strains. Moreover, ALX-0171 completely blocked replication to below the limit of detection for 87% of the viruses tested, whereas palivizumab did so for 18% of the viruses tested at a fixed concentration. Importantly, ALX-0171 was highly effective in reducing both nasal and lung RSV titers when delivered prophylactically or therapeutically directly to the lungs of cotton rats. ALX-0171 represents a potent novel antiviral compound with significant potential to treat RSV-mediated disease.

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Figures

FIG 1
FIG 1
Microneutralization assay with ALX-0171, Nb017, and palivizumab. The capacities of ALX-0171, Nb017, and palivizumab to neutralize RSV-A Long (A) and RSV-B 18537 (B) were tested. The results shown depict the means of triplicate values ± SEs. OD, optical density.
FIG 2
FIG 2
Crystal structure representation of the F protein in its prefusion conformation. Ribbon representation of one prefusion F-protein protomer is shown in red, and the other two protomers are shown in surface representation in blue and green. The residues listed are those that were mutated in the tested RSV escape mutants and are shown in yellow. The figure was prepared by using ICM Molsoft (46) and was derived from the sequence with PDB accession number 4JHW (26).
FIG 3
FIG 3
Results of competitive-binding ELISAs. The inhibition concentration-response curves obtained when biotinylated ALX-0171 was incubated with increasing concentrations of either unlabeled ALX-0171 or palivizumab are shown. The results shown depict the means of triplicate values ± SEs.
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