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.

Keywords::

• antibody
• antibody-dependent enhancement
• dengue
• neutralization
• therapeutics

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Global prevalence of dengue remains high due to ineffective vector control. There is currently no licensed vaccine or antiviral drug against dengue.

• • Therapeutic antibodies are increasingly used for the treatment of infectious diseases as they are well-established and well tolerated by humans.

• • Human antibodies that potently neutralize dengue virus (DENV) bind quaternary epitopes on DENV E protein and could be used therapeutically against homologous serotype of dengue.

• • Administering an antibody cocktail may lower the risk of neutralization escape viruses. Inclusion of antibodies targeting complex epitopes may act against viral strain differences more effectively.

• • DENV neutralizing antibodies prioritized for therapeutic development should possess high affinity for accessible epitopes, and prevent intracellular viral fusion.

• • Measurement of DENV neutralization in monocytes better distinguishes serotype-specific from cross-reactive antibodies.

• • Serotype-specific antibodies are a good candidate for therapeutic antibodies as they inhibit intracellular viral fusion, and reduce risk of antibody-dependent enhancement (ADE).

• • High dose administration of cross-reactive antibodies can also impede ADE and reduce pro-inflammatory responses that underlie severe dengue.

• • Fc modifications to improve therapeutic antibody half-life and C1q binding can enhance effector function of antibodies and reduce the risk of ADE.

Notes