Development of Antibody Therapeutics against Flaviviruses

Abstract

Recent outbreaks of Zika virus (ZIKV) highlight the urgent need to develop efficacious interventions against flaviviruses, many of which cause devastating epidemics around the world. Monoclonal antibodies (mAb) have been at the forefront of treatment for cancer and a wide array of other diseases due to their specificity and potency. While mammalian cell-produced mAbs have shown promise as therapeutic candidates against several flaviviruses, their eventual approval for human application still faces several challenges including their potential risk of predisposing treated patients to more severe secondary infection by a heterologous flavivirus through antibody-dependent enhancement (ADE). The high cost associated with mAb production in mammalian cell cultures also poses a challenge for the feasible application of these drugs to the developing world where the majority of flavivirus infection occurs. Here, we review the current therapeutic mAb candidates against various flaviviruses including West Nile (WNV), Dengue virus (DENV), and ZIKV. The progress of using plants for developing safer and more economical mAb therapeutics against flaviviruses is discussed within the context of their expression, characterization, downstream processing, neutralization, and in vivo efficacy. The progress of using plant glycoengineering to address ADE, the major impediment of flavivirus therapeutic development, is highlighted. These advancements suggest that plant-based systems are excellent alternatives for addressing the remaining challenges of mAb therapeutic development against flavivirus and may facilitate the eventual commercialization of these drug candidates.

High Level Production of Monoclonal Antibodies Using an Optimized Plant Expression System

“…One active area of research in antibody development focuses on the production of therapeutic mAbs against flaviviruses. The Flaviviridae family contains over 53 viruses, including many major health pathogens such as Dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, and ZIKV which create a significant global public health burden (Sun et al, 2018). For Dengue alone, it is estimated that there are over 390 million cases annually.…”

“…Antibodies made in glycoengineered plants have been successfully used to treat Ebola virus disease in rhesus macaques and humans (Olinger et al, 2012;Lyon et al, 2014;Qiu et al, 2014) and the first in-human clinical trials have been carried out using plant-made antibodies (Ma et al, 2015). High expressing, safe, and efficacious plant-made antibody therapies have also been developed for dengue virus (Dent et al, 2016), West Nile virus (Sun et al, 2018), and chikungunya virus (Hurtado et al, 2019), while a variety of antibody-based immune complex vaccines have been developed in plants and shown promising efficacy in mouse immunization trials (Chargelegue Abbreviations: BeYDV, bean yellow dwarf virus; mAb, monoclonal antibody; ZIKV, Zika virus; GFP, green fluorescent protein; YFP, yellow fluorescent protein; CFP, cyan fluorescent protein; TSP, total soluble protein; g/kg LFW, grams recombinant protein per kilogram leaf tissue fresh weight. et al, 2005;Pepponi et al, 2014;Kim et al, 2015;Mason, 2016;Webster et al, 2018;Diamos et al, 2019b).…”

Flavivirus Receptors: Diversity, Identity, and Cell Entry

“…E-DIII domain's importance is highlighted by the fact that a vast majority of potent, neutralizing antibodies has been mapped to this region. Nevertheless, anti-DI and DII antibodies, although less potent, show broader cross-reactivity and form a major pool of anti-E protein specific immonoglobulins ( 13 ). Receptor binding is followed by clathrin-mediated endocytosis ( 14 ), which is considered to be a major mechanism of flavivirus cell entry, although there are exceptions described below.…”

Broad dengue neutralization in mosquitoes expressing an engineered antibody

“…Due to similarities within viral families, this research could have far-reaching consequences for rendering mosquitoes resistant to other arboviruses like ZIKV and CHIKV by using similar genetic engineering strategies to develop scFv-based transgenes. Multiple potent antibodies that effectively neutralize these various mosquito-borne viruses have also been identified in the last decade [77][78][79][80][81]. Although not all of these will confer robust viral resistance when expressed in vivo in mosquitoes, the availability of diverse, well-characterized antibodies of this sort, largely as a result of antibody therapeutic development efforts [78], should allow for the identification of those that function within the desired context.…”

“…Multiple potent antibodies that effectively neutralize these various mosquito-borne viruses have also been identified in the last decade [77][78][79][80][81]. Although not all of these will confer robust viral resistance when expressed in vivo in mosquitoes, the availability of diverse, well-characterized antibodies of this sort, largely as a result of antibody therapeutic development efforts [78], should allow for the identification of those that function within the desired context. Given the increasing incidence of disease caused by these viruses and the resulting global health implications, such scFv-based transgenes coupled with gene-drive systems [34] can provide an effective, sustainable, and comprehensive strategy for reducing the impact of arboviral mosquito-borne diseases.…”