Generation and characterization of human monoclonal antibodies specific to dengue virus NS1 protein as therapeutic agents

Abstract

Dengue fever, a cause of dengue virus infection, is one of the major public health issues worldwide and particularly in tropical and subtropical areas. Symptomatic infection of dengue disease has been ranged from flu-like illness to severe dengue disease called Dengue Hemorrhagic Fever (DHF) /Dengue Shock Syndrome (DSS). The severe disease, including vascular leakage, thrombocytopenia and bleeding, is frequently related to high viral titer and secondary infection. Interestingly, anti-NS1 antibodies have been considered to play a pivotal role in dengue pathogenesis resulting in severe dengue progression. In this study, four distinguishing characteristics of anti-NS1 human monoclonal antibodies (HuMAbs) that recognize NS1 C-terminal residue and no cross-reactivity to human thrombin and human microvascular endothelial cell line (HMEC-1), were previously generated from patients harbouring secondary dengue virus (DENV) 2 infection at the convalescent stage. These HuMAbs were investigated for the promising activity of NS1 HuMAbs-associated dengue pathogenesis including DENV NS1-induced cell cytolysis and viral replication via complement pathway, endothelial permeability and cytokines/chemokines secretion in HMEC-1 cells. As a result, NS1-specific HuMAbs exhibited therapeutic effects by neutralizing DENV and attenuating the replication of DENV 2 via a complement mechanism in endothelial cells. Interestingly, we found that not only HuMAbs against DENV NS1 caused complement-mediated cell lysis of infected cells but these HuMAbs also significantly decreased endothelial leakage and reduced cytokines production. Our findings suggest the novel potential of DENV NS1 human monoclonal antibodies as a therapeutic option against dengue disease.