Therapeutic antibodies as a treatment option for dengue fever

Abstract

Dengue fever is the most prevalent mosquito-borne viral disease globally with about 100 million cases of acute dengue annually. Severe dengue infection can result in a life-threatening illness. In the absence of either a licensed vaccine or antiviral drug against dengue, therapeutic antibodies that neutralize dengue virus (DENV) may serve as an effective medical countermeasure against severe dengue. However, therapeutic antibodies would need to effectively neutralize all four DENV serotypes. It must not induce antibody-dependent enhancement of DENV infection in monocytes/macrophages through Fc gamma receptor (FcγR)-mediated phagocytosis, which is hypothesized to increase the risk of severe dengue. Here, we review the strategies and technologies that can be adopted to develop antibodies for therapeutic applications. We also discuss the mechanism of antibody neutralization in the cells targeted by DENV that express Fc gamma receptor. These studies have provided significant insight toward the use of therapeutic antibodies as a potentially promising bulwark against dengue.

Current Status of Dengue Therapeutics Research and Development

“…The use of intravenous immunoglobulins has, however, not been carefully explored for the treatment of severe dengue, given its antiinflammatory properties. However, the risk of antibody-dependent enhancement could pose some concerns on the use of pooled polyclonal preparation as it may contain subneutralizing levels of antibodies and, paradoxically, enhance infection instead [68–70]. …”

The mechanistic role of antibodies to dengue virus in protection and disease pathogenesis

“…Primates have a complex FcγR system consisting of FcγRI family (FcγRIA, FcγRIB, FcγRIC), FcγRII family (FcγRIIA, FcγRIIBI, FcγRIIBII, FcγRIIBIII, FcγRIIC), and FcγRIII family (FcγRIIIA, FcγRIIIB). Each FcγR subtype has its own distinct properties and thus have different effects on DENV neutralization or enhancement [73]. As the majority of the monocytes express FcγRI, FcγRIIA, and FcγRIIB, these are the main FcγRs that have an impact on antibody-opsonized DENV infection or neutralization (Table 1).…”

“…For instance, differential levels of cytokines can influence FcγR expression. FcγRI expression has been shown to be upregulated by interferon γ (IFNγ) which can affect stoichiometry required for DENV neutralization [73,106,107]. In contrast, interleukin-4, interleukin-10 and transforming growth-factor-B (TGB-B) downregulate activating FcγRs but enhances the inhibitory FcγRIIB [108,109] which can potentially impact on the neutralization of immune complexes mediated by cross-reactive antibodies [102].…”

Utility, Limitations, and Future of Non-Human Primates for Dengue Research and Vaccine Development

“…Recently, it has been shown the effectiveness of using MAbs to control dengue infection in mice, and in vitro methods have been developed that predict the ability of modified MAbs to act therapeutically against antibody-enhanced disease in vivo (151). The potential of these therapeutics tools in humans and alternatives for improvement have been extensively reviewed (152). However, few studies have been conducted in NHP.…”