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

Jiaqi Wang; Marco Bardelli; Diego A. Espinosa; Mattia Pedotti; Thiam Seng Ng; Siro Bianchi; Luca Simonelli; Elisa X.Y. Lim; Mathilde Foglierini; Fabrizia Zatta; Stefano Jaconi; Martina Beltramello; Elisabetta Cameroni; Guntur Fibriansah; Jian Shi; Taylor Barca; Isabel Pagani; Alicia Rubio; Vania Broccoli; Elisa Vicenzi; Victoria Graham; Steven Pullan; Stuart Dowall; Roger Hewson; Simon Jurt; Oliver Zerbe; Karin Stettler; Antonio Lanzavecchia; Federica Sallusto; Andrea Cavalli; Eva Harris; Shee Mei Lok; Luca Varani; Davide Corti

doi:10.1016/j.cell.2017.09.002

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

Jiaqi Wang, Marco Bardelli, Diego A. Espinosa, Mattia Pedotti, Thiam Seng Ng, Siro Bianchi, Luca Simonelli, Elisa X.Y. Lim, Mathilde Foglierini, Fabrizia Zatta, Stefano Jaconi, Martina Beltramello, Elisabetta Cameroni, Guntur Fibriansah, Jian Shi, Taylor Barca, Isabel Pagani, Alicia Rubio, Vania Broccoli, Elisa VicenziVictoria Graham, Steven Pullan, Stuart Dowall, Roger Hewson, Simon Jurt, Oliver Zerbe, Karin Stettler, Antonio Lanzavecchia, Federica Sallusto, Andrea Cavalli, Eva Harris, Shee Mei Lok^*, Luca Varani, Davide Corti

^*Corresponding author for this work

Research & Technical Staff

Research output: Contribution to journal › Article › peer-review

97 Citations (Scopus)

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.

Original language	English
Pages (from-to)	229-241.e15
Journal	Cell
Volume	171
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2017.09.002
Publication status	Published - 21 Sept 2017

Bibliographical note

Funding Information:
We thank Victor A. Kostyuchenko and P. Robert Beatty for scientific discussion and Kuiama Lewandowski at PHE for the technical support in viral sequencing and Rocco D’Antuono for microscope assistance. We thank Fabio Benigni at Humabs for critical reading of the manuscript and Antonio Piralla from San Matteo Hospital in Pavia for helping in the sequencing of MARMs. We thank the European Virus Archive for consenting to the use of the ZIKV H/PF/2013 strain. The work was supported by Singapore Ministry of Education Tier 3 grant ( MOE2012-T3-1-008 ), National Research Foundation Investigatorship award ( NRF-NRFI2016-01 ), National Research Foundation Competitive Research Project grant ( NRF2016NRF-CRP001-063 ) and the Duke-NUS Signature Research Programme funded by the Ministry of Health, Singapore , awarded to S-M.L, and grant 5U19AI109761 from the US National Institutes of Health to Ian Lipkin and E.H. L.V. is grateful for support by G. Noseda, SNF grant 310030_166445 , 157699 , KFS-3728-08-2015 and Lions Club Monteceneri . A.L. is the scientific founder of Humabs BioMed SA. A.L. holds shares in Humabs BioMed. K.S., F.Z., S.J., E.C., M.B. and D.C. are employees of Humabs Biomed.

Publisher Copyright:
© 2017

Keywords

Zika
neutralizing antibody
serotherapy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2017.09.002

Cite this

Wang, J., Bardelli, M., Espinosa, D. A., Pedotti, M., Ng, T. S., Bianchi, S., Simonelli, L., Lim, E. X. Y., Foglierini, M., Zatta, F., Jaconi, S., Beltramello, M., Cameroni, E., Fibriansah, G., Shi, J., Barca, T., Pagani, I., Rubio, A., Broccoli, V., ... Corti, D. (2017). A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential. Cell, 171(1), 229-241.e15. https://doi.org/10.1016/j.cell.2017.09.002

@article{be8dc133dade4553a05a1788575e06cc,

title = "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.",

keywords = "Zika, neutralizing antibody, serotherapy",

author = "Jiaqi Wang and Marco Bardelli and Espinosa, {Diego A.} and Mattia Pedotti and Ng, {Thiam Seng} and Siro Bianchi and Luca Simonelli and Lim, {Elisa X.Y.} and Mathilde Foglierini and Fabrizia Zatta and Stefano Jaconi and Martina Beltramello and Elisabetta Cameroni and Guntur Fibriansah and Jian Shi and Taylor Barca and Isabel Pagani and Alicia Rubio and Vania Broccoli and Elisa Vicenzi and Victoria Graham and Steven Pullan and Stuart Dowall and Roger Hewson and Simon Jurt and Oliver Zerbe and Karin Stettler and Antonio Lanzavecchia and Federica Sallusto and Andrea Cavalli and Eva Harris and Lok, {Shee Mei} and Luca Varani and Davide Corti",

note = "Funding Information: We thank Victor A. Kostyuchenko and P. Robert Beatty for scientific discussion and Kuiama Lewandowski at PHE for the technical support in viral sequencing and Rocco D{\textquoteright}Antuono for microscope assistance. We thank Fabio Benigni at Humabs for critical reading of the manuscript and Antonio Piralla from San Matteo Hospital in Pavia for helping in the sequencing of MARMs. We thank the European Virus Archive for consenting to the use of the ZIKV H/PF/2013 strain. The work was supported by Singapore Ministry of Education Tier 3 grant ( MOE2012-T3-1-008 ), National Research Foundation Investigatorship award ( NRF-NRFI2016-01 ), National Research Foundation Competitive Research Project grant ( NRF2016NRF-CRP001-063 ) and the Duke-NUS Signature Research Programme funded by the Ministry of Health, Singapore , awarded to S-M.L, and grant 5U19AI109761 from the US National Institutes of Health to Ian Lipkin and E.H. L.V. is grateful for support by G. Noseda, SNF grant 310030_166445 , 157699 , KFS-3728-08-2015 and Lions Club Monteceneri . A.L. is the scientific founder of Humabs BioMed SA. A.L. holds shares in Humabs BioMed. K.S., F.Z., S.J., E.C., M.B. and D.C. are employees of Humabs Biomed. Publisher Copyright: {\textcopyright} 2017",

year = "2017",

month = sep,

day = "21",

doi = "10.1016/j.cell.2017.09.002",

language = "English",

volume = "171",

pages = "229--241.e15",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier",

number = "1",

}

Wang, J, Bardelli, M, Espinosa, DA, Pedotti, M, Ng, TS, Bianchi, S, Simonelli, L, Lim, EXY, Foglierini, M, Zatta, F, Jaconi, S, Beltramello, M, Cameroni, E, Fibriansah, G, Shi, J, Barca, T, Pagani, I, Rubio, A, Broccoli, V, Vicenzi, E, Graham, V, Pullan, S , Dowall, S , Hewson, R, Jurt, S, Zerbe, O, Stettler, K, Lanzavecchia, A, Sallusto, F, Cavalli, A, Harris, E, Lok, SM, Varani, L & Corti, D 2017, 'A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential', Cell, vol. 171, no. 1, pp. 229-241.e15. https://doi.org/10.1016/j.cell.2017.09.002

TY - JOUR

T1 - A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential

AU - Wang, Jiaqi

AU - Bardelli, Marco

AU - Espinosa, Diego A.

AU - Pedotti, Mattia

AU - Ng, Thiam Seng

AU - Bianchi, Siro

AU - Simonelli, Luca

AU - Lim, Elisa X.Y.

AU - Foglierini, Mathilde

AU - Zatta, Fabrizia

AU - Jaconi, Stefano

AU - Beltramello, Martina

AU - Cameroni, Elisabetta

AU - Fibriansah, Guntur

AU - Shi, Jian

AU - Barca, Taylor

AU - Pagani, Isabel

AU - Rubio, Alicia

AU - Broccoli, Vania

AU - Vicenzi, Elisa

AU - Graham, Victoria

AU - Pullan, Steven

AU - Dowall, Stuart

AU - Hewson, Roger

AU - Jurt, Simon

AU - Zerbe, Oliver

AU - Stettler, Karin

AU - Lanzavecchia, Antonio

AU - Sallusto, Federica

AU - Cavalli, Andrea

AU - Harris, Eva

AU - Lok, Shee Mei

AU - Varani, Luca

AU - Corti, Davide

N1 - Funding Information: We thank Victor A. Kostyuchenko and P. Robert Beatty for scientific discussion and Kuiama Lewandowski at PHE for the technical support in viral sequencing and Rocco D’Antuono for microscope assistance. We thank Fabio Benigni at Humabs for critical reading of the manuscript and Antonio Piralla from San Matteo Hospital in Pavia for helping in the sequencing of MARMs. We thank the European Virus Archive for consenting to the use of the ZIKV H/PF/2013 strain. The work was supported by Singapore Ministry of Education Tier 3 grant ( MOE2012-T3-1-008 ), National Research Foundation Investigatorship award ( NRF-NRFI2016-01 ), National Research Foundation Competitive Research Project grant ( NRF2016NRF-CRP001-063 ) and the Duke-NUS Signature Research Programme funded by the Ministry of Health, Singapore , awarded to S-M.L, and grant 5U19AI109761 from the US National Institutes of Health to Ian Lipkin and E.H. L.V. is grateful for support by G. Noseda, SNF grant 310030_166445 , 157699 , KFS-3728-08-2015 and Lions Club Monteceneri . A.L. is the scientific founder of Humabs BioMed SA. A.L. holds shares in Humabs BioMed. K.S., F.Z., S.J., E.C., M.B. and D.C. are employees of Humabs Biomed. Publisher Copyright: © 2017

PY - 2017/9/21

Y1 - 2017/9/21

N2 - 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.

AB - 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.

KW - Zika

KW - neutralizing antibody

KW - serotherapy

UR - http://www.scopus.com/inward/record.url?scp=85029651511&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.09.002

DO - 10.1016/j.cell.2017.09.002

M3 - Article

C2 - 28938115

AN - SCOPUS:85029651511

SN - 0092-8674

VL - 171

SP - 229-241.e15

JO - Cell

JF - Cell

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this