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

• Published in: Scientific reports Vol. 11; no. 1; pp. 12987 - 14
• Main Authors: Kotaki, Tomohiro, Kurosu, Takeshi, Grinyo-Escuer, Ariadna, Davidson, Edgar, Churrotin, Siti, Okabayashi, Tamaki, Puiprom, Orapim, Mulyatno, Kris Cahyo, Sucipto, Teguh Hari, Doranz, Benjamin J., Ono, Ken-ichiro, Soegijanto, Soegeng, Kameoka, Masanori
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326/22/1295; 631/326/596/1413; Affinity; Animals; Antibodies; Antibodies, Monoclonal - biosynthesis; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antibody Affinity - immunology; Antigens, Viral - chemistry; Antigens, Viral - immunology; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Cross-reactivity; Dengue - drug therapy; Dengue - immunology; Dengue - virology; Dengue fever; Dengue Virus - drug effects; Dengue Virus - immunology; Epitope Mapping; Epitopes; Epitopes - chemistry; Epitopes - immunology; Health problems; Humanities and Social Sciences; Humans; Hybridomas; Maturation; Mice; Models, Molecular; Monoclonal antibodies; multidisciplinary; Mutation rates; Neutralization; Neutralization Tests; Protein Conformation; Recombinant Proteins; Science; Science (multidisciplinary); Structure-Activity Relationship; Variable region; Vector-borne diseases; α-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-92403-9

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 (NT 50  < 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 NT 50 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.