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A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential.

ABSTRACT: Zika virus (ZIKV), a mosquito-borne flavivirus, causes devastating congenital birth defects. We isolated a human monoclonal antibody (mAb), ZKA190, that potently cross-neutralizes multi-lineage ZIKV strains. ZKA190 is highly effective in vivo in preventing morbidity and mortality of ZIKV-infected mice. NMR and cryo-electron microscopy show its binding to an exposed epitope on DIII of the E protein. ZKA190 Fab binds all 180 E protein copies, altering the virus quaternary arrangement and surface curvature. However, ZIKV escape mutants emerged in vitro and in vivo in the presence of ZKA190, as well as of other neutralizing mAbs. To counter this problem, we developed a bispecific antibody (FIT-1) comprising ZKA190 and a second mAb specific for DII of E protein. In addition to retaining high in vitro and in vivo potencies, FIT-1 robustly prevented viral escape, warranting its development as a ZIKV immunotherapy.

SUBMITTER: Wang J

PROVIDER: S-EPMC5673489 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential.

Wang Jiaqi J Bardelli Marco M Espinosa Diego A DA Pedotti Mattia M Ng Thiam-Seng TS Bianchi Siro S Simonelli Luca L Lim Elisa X Y EXY Foglierini Mathilde M Zatta Fabrizia F Jaconi Stefano S Beltramello Martina M Cameroni Elisabetta E Fibriansah Guntur G Shi Jian J Barca Taylor T Pagani Isabel I Rubio Alicia A Broccoli Vania V Vicenzi Elisa E Graham Victoria V Pullan Steven S Dowall Stuart S Hewson Roger R Jurt Simon S Zerbe Oliver O Stettler Karin K Lanzavecchia Antonio A Sallusto Federica F Cavalli Andrea A Harris Eva E Lok Shee-Mei SM Varani Luca L Corti Davide D

Cell 20170901 1

Zika virus (ZIKV), a mosquito-borne flavivirus, causes devastating congenital birth defects. We isolated a human monoclonal antibody (mAb), ZKA190, that potently cross-neutralizes multi-lineage ZIKV strains. ZKA190 is highly effective in vivo in preventing morbidity and mortality of ZIKV-infected mice. NMR and cryo-electron microscopy show its binding to an exposed epitope on DIII of the E protein. ZKA190 Fab binds all 180 E protein copies, altering the virus quaternary arrangement and surface c ...[more]

PMID: 28938115

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Project description:BackgroundZika virus (ZIKV) infection is a global health problem, and its complications, including congenital Zika syndrome and Guillain-Barré syndrome, constitute a continued threat to humans. Unfortunately, effective therapeutics against ZIKV infection are not available thus far.MethodsWe screened the compounds collection consisting of 1789 FDA-approved drugs by a computational docking method to obtain anti-ZIKV candidate compounds targeting ZIKV RNA-dependent RNA polymerase (RdRp). SPR (BIAcore) assay was employed to demonstrate the candidate compounds' direct binding to ZIKV RdRp, and polymerase activity assay was used to determine the inhibitory effect on ZIKV RdRp-catalyzed RNA synthesis. The antiviral effects on ZIKV in vitro and in vivo were detected in infected cultured cells and in Ifnar1-/- mice infected by ZIKV virus using plaque assay, western blotting, tissue immunofluorescence, and immunohistochemistry.ResultsHere, we report that a first-in-class macrocyclic antibiotic, which has been clinically used to treat Clostridium difficile infection, fidaxomicin, potently inhibits ZIKV replication in vitro and in vivo. Our data showed that fidaxomicin was effective against African and Asian lineage ZIKV in a wide variety of cell lines of various tissue origins, and prominently suppressed ZIKV infection and significantly improved survival of infected mice. In addition, fidaxomicin treatment reduced the virus load in the brains and testes, and alleviated ZIKV-associated pathological damages, such as paralysis, hunching, and neuronal necrosis in the cerebra. Furthermore, our mechanistic study showed that fidaxomicin directly bound ZIKV NS5 protein and inhibited the RNA synthesis-catalyzing activity of ZIKV RdRp.ConclusionsOur data suggest that fidaxomicin may represent an effective anti-ZIKV agent. In the light that fidaxomicin is already a clinically used drug, there might be a promising prospect in the development of fidaxomicin to be an antiviral therapeutic.

Dataset Information

A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential.

Publications

A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential.

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