Neutralization of antibody-enhanced dengue infection by VIS513, a pan serotype reactive monoclonal antibody targeting domain III of the dengue E protein.

Yadunanda Budigi,Zachary Shriver,Eugenia Z Ong,Gregory J Babcock,Eng Eong Ooi,Luke N Robinson,Alexander Winnett,Hwee Cheng Tan,Li Ching Ong,Kirk J Rowley,Sven Hobbie,Sylvie Alonso

doi:10.1371/journal.pntd.0006209

Abstract

Dengue virus (DENV) infection imposes enormous health and economic burden worldwide with no approved treatment. Several small molecules, including lovastatin, celgosivir, balapiravir and chloroquine have been tested for potential anti-dengue activity in clinical trials; none of these have demonstrated a protective effect. Recently, based on identification and characterization of cross-serotype neutralizing antibodies, there is increasing attention on the potential for dengue immunotherapy. Here, we tested the ability of VIS513, an engineered cross-neutralizing humanized antibody targeting the DENV E protein domain III, to overcome antibody-enhanced infection and high but brief viremia, which are commonly encountered in dengue patients, in various in vitro and in vivo models. We observed that VIS513 efficiently neutralizes DENV at clinically relevant viral loads or in the presence of enhancing levels of DENV immune sera. Single therapeutic administration of VIS513 in mouse models of primary infection or lethal secondary antibody-enhanced infection, reduces DENV titers and protects from lethal infection. Finally, VIS513 administration does not readily lead to resistance, either in cell culture systems or in animal models of dengue infection. The findings suggest that rapid viral reduction during acute DENV infection with a monoclonal antibody is feasible.

Highlights

Four serotypes of dengue virus (DENV1-4) are responsible for significant worldwide morbidity and mortality, with an estimated 390 million episodes of infection yearly [1]
In this study we demonstrate that VIS513, a monoclonal antibody therapeutic candidate that targets the dengue virus envelope protein, retains its anti-viral potency in the presence of preexisting antibodies, and is able to rescue mice from lethal infections
We find that the PRNT50 values for VIS513 are significantly lower than those for 4G2, comparable to those for 752–2 C8 and generally higher than those for 747(4) A11 (Table 1)

Summary

Introduction

Four serotypes of dengue virus (DENV1-4) are responsible for significant worldwide morbidity and mortality, with an estimated 390 million episodes of infection yearly [1]. DENV contains two structural proteins on its surface, envelope (E) and precursor membrane (prM). The prM protein covers the fusion loop during virus assembly to prevent premature fusion, and is subsequently cleaved by a furin-like protease leading to dissociation of the precursor “pr” portion from the virus. The cleavage process is imperfect, leading to a range of virus structures from completely immature (no prM cleavage), to partially mature, to fully mature (complete prM cleavage) [6,7]. The resulting mosaic of virus structures influences epitope accessibility and thereby affects the neutralizing activity of different classes of antibodies [7,8]

Methods

Results

Conclusion