An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency

Kotaki T., Kurosu T., Grinyo-Escuer A., Davidson E., Churrotin S., Okabayashi T., Puiprom O., Mulyatno K.C., Sucipto T.H., Doranz B.J., Ono K.-I., Soegijanto S., Kameoka M.

Department of Public Health, Kobe University Graduate School of Health Sciences, Kobe, Japan; Collaborative Research Center for Emerging and Re-Emerging Infectious Diseases, Institute of Tropical Disease, Airlangga University, Surabaya, Indonesia; Department of Virology I, National Institute of Infectious Diseases (NIID), Tokyo, Japan; Integral Molecular, Inc., Philadelphia, PA, United States; Mahidol-Osaka Center for Infectious Diseases (MOCID), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Medical & Biological Laboratories Co., Ltd., Tokyo, Japan; Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Japan


Abstract

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 (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 prolonged the survival of interferon-α/β/γ receptor knockout C57BL/6 mice after a lethal DENV challenge. Additionally, Fc-modified 3G9 that had lost their in vitro ADE activity showed 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 promising features for therapeutic application including a low NT50 value, potential for treatment of various kinds of mosquito-borne flavivirus infection, and suppression of ADE. This study demonstrates the therapeutic potency of affinity-matured FLE-targeting antibodies. © 2021, The Author(s).


Journal

Scientific Reports

Publisher: Nature Research

Volume 11, Issue 1, Art No 12987, Page – , Page Count


Journal Link: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85108321121&doi=10.1038%2fs41598-021-92403-9&partnerID=40&md5=965cf7a2d40fc063110b2576f08fe307

doi: 10.1038/s41598-021-92403-9

Issn: 20452322

Type: All Open Access, Gold, Green


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