A broadly neutralizing germline-like human monoclonal antibody against dengue virus envelope domain III

Hu, Dan; Zhu, Zhongyu; Li, Shun; Deng, Yong-Qiang; Wu, Yanling; Zhang, Nana; Puri, Vinita; Wang, Chunyu; Zou, Peng; Liu, Cheng; Tian, Xiaolong; Wang, Yulu; Zhao, Qi; Li, Wei; Prabakaran, Ponraj; Yang, Feng; Cardosa, Jane; Qin, Cheng‐Feng; Zhou, Xiaohui; Dimitrov, Dimiter S.; Ying, Tianlei

doi:10.1371/journal.ppat.1007836

Cited by 33 publications

(27 citation statements)

References 69 publications

(75 reference statements)

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“…Recent advances in monoclonal antibody isolation and characterization (Boonyaratanakornkit and Taylor, 2019; Corti and Lanzavecchia, 2014) have accelerated the identification of bNAbs, including those against flaviviruses. Examples include antibodies d488 (Li et al, 2019) and m366 (Hu et al, 2019), which were cloned from B cells of rhesus macaques receiving an experimental DENV vaccine and from healthy flavivirus-naive humans, respectively, and antibody DM25-3, which was isolated from a mouse immunized with a mature form of DENV2 virus-like particles (Shen et al, 2018). Although these antibodies were cross-reactive against DENV1-4, they demonstrated only moderate potency.…”

Section: Introductionmentioning

confidence: 99%

Broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

Durham

Agrawal

Waltari

et al. 2019

eLife

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Eliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To define bNAb targets, we characterized 28 antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified J9 and J8, two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies showed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against DENV with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested that J9 and J8 followed divergent somatic hypermutation pathways, and that a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a new epitope that can be exploited for vaccine design.

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Section: Introductionmentioning

confidence: 99%

Broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

Durham

Agrawal

Waltari

et al. 2019

eLife

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“…However, during the natural course of infection, the serological response to the E glycoprotein is highly serotype cross-reactive and predominantly targets epitopes containing highly conserved residues, for instance, the fusion loop of the domain II [31]. In addition, high-avidity and highly neutralizing antibodies against DENV, bind to domain III (DIII) of the E glycoprotein, which is implicated in DENV binding to its cognate receptor [36,37]. These antibodies appear to be most effective at providing protection from infection and/or disease [38][39][40].…”

Section: Antibody Response To Denv Infectionmentioning

confidence: 99%

Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II - DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis

Puerta-Guardo¹,

Biering²,

Harris³

et al. 2020

Dengue Fever in a One Health Perspective

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Severe disease is associated with serial infection with DENV of different serotypes. Thus, primary DENV infections normally cause asymptomatic infections, and secondary heterotypic infections with a new DENV serotype potentially increase the risks of developing severe disease. Despite many proposed hypotheses trying to explain it, the exact immunological mechanism leading to severe dengue disease is unknown. In turn, severe manifestations are believed to be a consequence of the combinations of many immunopathogenic mechanisms involving viral and host factors leading to increased pathogenesis and disease. Of these mechanisms, the adaptive immune response has been proposed to play a critical role in the development of severe dengue manifestations. This includes the effect of non-neutralizing but enhancing antibodies produced during primary infections, which results in enhanced-DENV infection of Fc-γ-receptor-expressing cells (e.g. monocytes and macrophages) during DENV heterotypic exposure in a phenomenon called antibody-dependent enhancement (ADE); the increased activation of memory T cells during secondary infections, which has low affinity for the current infecting serotype and high affinity for a past infection with a different serotype known as the original antigenic sin; the unbalanced production of pro-inflammatory cytokines that have a direct effect on vascular endothelial cells resulting in plasma leak in a phenomenon known as cytokine storm; and the excessive activation of the complement system that causes exacerbated inflammatory responses, increasing disease severity. In addition to the adaptive immune responses, a secreted viral factor known as the nonstructural protein 1 (NS1) has been recently proposed as the missing corner piece of the DENV pathogenesis influencing disease. This Part II of the chapter will discuss the interplay between the distinct host adaptive immune responses and viral factors that together contribute to the development of DENV pathogenesis and severe disease.

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“…Thus, one of three mutations [L234A + L235A (LALA), D265A, and N297A] was introduced to the Fc region of the best neutralizing HuMAb, 3G9, to disrupt the interaction with Fc receptors [39]. We chose to test three mutations, because the effect of Fc-modification during the in vivo animal experiment varied depending on the study group [40][41][42][43][44][45]. These three mutations are described as being the same in terms of the effect on loss of binding to Fc receptors and should not compromise antibody neutralizing potency [46] or shorten the halflife significantly [47].…”

Section: Recombinant Igg Construction and Evaluationmentioning

confidence: 99%

An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus within vivotherapeutic potency

Kotaki

Kurosu

Grinyo

et al. 2020

Preprint

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Dengue virus (DENV), from the genus flavivirus of the family flaviviridae, causes serious health problems globally. Human monoclonal antibodies (HuMAb) can be used to elucidate the mechanisms of neutralization and antibody-dependent enhancement (ADE) of DENV infections, leading to the development of a vaccine or therapeutic antibodies. Here, we generated eight HuMAb clones from an Indonesian patient infected with DENV. These HuMAbs exhibited the typical characteristics of weak neutralizing antibodies including high cross-reactivity with other flaviviruses and targeting of the fusion loop epitope (FLE). However, one of the HuMAbs, 3G9, exhibited strong neutralization ability (NT50 < 0.1 µg/ml) and possessed a high somatic hyper-mutation rate of the variable region, indicating affinity-maturation. Administration of this antibody significantly improved the survival rate of interferon-α/β/γ receptor knockout C57BL/6 mice after a lethal DENV challenge. Additionally, Fc-modified 3G9 molecules that had lost their in vitro ADE activity showed significantly enhanced therapeutic potency in vivo and competed strongly with an ADE-prone antibody in vitro. Taken together, the affinity-matured FLE-targeting antibody 3G9 exhibits several promising features for therapeutic application including a low NT50 value, potential for pan-flavivirus infection treatment, and suppression of ADE. This study demonstrates the therapeutic potency of affinity-matured FLE-targeting antibodies.

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A broadly neutralizing germline-like human monoclonal antibody against dengue virus envelope domain III

Cited by 33 publications

References 69 publications

Broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

Broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II - DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis

An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus within vivotherapeutic potency

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