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

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 devel...

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Autores principales:	Tomohiro Kotaki, Takeshi Kurosu, Ariadna Grinyo-Escuer, Edgar Davidson, Siti Churrotin, Tamaki Okabayashi, Orapim Puiprom, Kris Cahyo Mulyatno, Teguh Hari Sucipto, Benjamin J. Doranz, Ken-ichiro Ono, Soegeng Soegijanto, Masanori Kameoka
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b08a284eec634976b8ba9f7d74a2d036
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spelling	oai:doaj.org-article:b08a284eec634976b8ba9f7d74a2d0362021-12-02T17:45:03ZAn affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency10.1038/s41598-021-92403-92045-2322https://doaj.org/article/b08a284eec634976b8ba9f7d74a2d0362021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92403-9https://doaj.org/toc/2045-2322Abstract 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.Tomohiro KotakiTakeshi KurosuAriadna Grinyo-EscuerEdgar DavidsonSiti ChurrotinTamaki OkabayashiOrapim PuipromKris Cahyo MulyatnoTeguh Hari SuciptoBenjamin J. DoranzKen-ichiro OnoSoegeng SoegijantoMasanori KameokaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tomohiro Kotaki Takeshi Kurosu Ariadna Grinyo-Escuer Edgar Davidson Siti Churrotin Tamaki Okabayashi Orapim Puiprom Kris Cahyo Mulyatno Teguh Hari Sucipto Benjamin J. Doranz Ken-ichiro Ono Soegeng Soegijanto Masanori Kameoka An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency
description	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.
format	article
author	Tomohiro Kotaki Takeshi Kurosu Ariadna Grinyo-Escuer Edgar Davidson Siti Churrotin Tamaki Okabayashi Orapim Puiprom Kris Cahyo Mulyatno Teguh Hari Sucipto Benjamin J. Doranz Ken-ichiro Ono Soegeng Soegijanto Masanori Kameoka
author_facet	Tomohiro Kotaki Takeshi Kurosu Ariadna Grinyo-Escuer Edgar Davidson Siti Churrotin Tamaki Okabayashi Orapim Puiprom Kris Cahyo Mulyatno Teguh Hari Sucipto Benjamin J. Doranz Ken-ichiro Ono Soegeng Soegijanto Masanori Kameoka
author_sort	Tomohiro Kotaki
title	An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency
title_short	An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency
title_full	An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency
title_fullStr	An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency
title_full_unstemmed	An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency
title_sort	affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b08a284eec634976b8ba9f7d74a2d036
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An affinity-matured human monoclonal antibody targeting fusion loop epitope of dengue virus with in vivo therapeutic potency

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