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Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice

De Gasparo, Raoul and Pedotti, Mattia and Simonelli, Luca and Nickl, Petr and Muecksch, Frauke and Cassaniti, Irene and Percivalle, Elena and Lorenzi, Julio C. C. and Mazzola, Federica and Magrì, Davide and Michalcikova, Tereza and Haviernik, Jan and Honig, Vaclav and Mrazkova, Blanka and Polakova, Natalie and Fortova, Andrea and Tureckova, Jolana and Iatsiuk, Veronika and Di Girolamo, Salvatore and Palus, Martin and Zudova, Dagmar and Bednar, Petr and Bukova, Ivana and Bianchini, Filippo and Mehn, Dora and Nencka, Radim and Strakova, Petra and Pavlis, Oto and Rozman, Jan and Gioria, Sabrina and Camilla Sammartino, Josè and Giardina, Federica and Gaiarsa, Stefano and Pan-Hammarström, Qiang and Barnes, Christopher O. and Bjorkman, Pamela J. and Calzolai, Luigi and Piralla, Antonio and Baldanti, Fausto and Nussenzweig, Michel C. and Bieniasz, Paul D. and Hatziioannou, Theodora and Prochazka, Jan and Sedlacek, Radislav and Robbiani, Davide F. and Ruzek, Daniel and Varani, Luca (2021) Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice. Nature . ISSN 0028-0836. doi:10.1038/s41586-021-03461-y. (In Press) https://resolver.caltech.edu/CaltechAUTHORS:20210308-130543968

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Abstract

Neutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19). We developed a bispecific, IgG1-like molecule (CoV-X2) based on two antibodies derived from COVID-19 convalescent donors, C121 and C135. CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 neutralizes SARS-CoV-2 and its variants of concern, as well as the escape mutants generated by the parental monoclonals. In a novel animal model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41586-021-03461-yDOIArticle
https://rdcu.be/chH8NPublisherFree ReadCube access
https://doi.org/10.1101/2021.01.22.427567DOIDiscussion Paper
ORCID:
AuthorORCID
Barnes, Christopher O.0000-0003-2754-5951
Bjorkman, Pamela J.0000-0002-2277-3990
Nussenzweig, Michel C.0000-0003-0592-8564
Bieniasz, Paul D.0000-0002-2368-3719
Hatziioannou, Theodora0000-0002-7889-0766
Robbiani, Davide F.0000-0001-7379-3484
Varani, Luca0000-0002-0963-0987
Alternate Title:Bispecific antibody neutralizes circulating SARS-CoV-2 variants, prevents escape and protects mice from disease
Additional Information:© The Author(s), under exclusive licence to Springer Nature Limited 2021. Received 07 January 2021; Accepted 16 March 2021; Published 25 March 2021. Dedicated to the memory of the recently departed Prof. François Diederich. D.F.R., L.V., Q.P.H., F.B., L.C. have received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 101003650. This work was also support by SNF grant 31003A_182270 (L.V.); Lions Club Monteceneri (L.V.); George Mason University Fast Grant and IRB startup funds (D.F.R.); NIH U01 AI151698 for the United World Antiviral Research Network, UWARN (D.F.R., M.C.N.); NIH grant P01-AI138398-S1 (M.C.N., P.J.B.); 2U19AI111825 (M.C.N., D.F.R.); the Caltech Merkin Institute for Translational Research and P50 AI150464 (P.J.B.); R37-AI64003 (P.D.B.); R01AI78788 (T.H.); P.D.B. and M.C.N. are Howard Hughes Medical Institute Investigators. The study was also supported by: the Czech Academy of Sciences and Czech Ministry of Agriculture (RVO 68378050; R.S.; RVO0518; D.R.); Czech Ministry of Education, Youth and Sports and the European Regional Development Fund (LM2018126; CZ.1.05/2.1.00/19.0395 and CZ.1.05/1.1.00/02.0109; R.S.; CZ.02.1.01/0.0/0.0/15_003/0000495; D.R.); Czech Science Foundation (20-14325S, D.R.); the Bulgari Women & Science Fellowship in COVID-19 Research (F.Mu.); and by Ricerca Finalizzata from Ministry of Health, Italy (grants no. GR-2013-02358399; A.P.). We are grateful for the high-performance computing resources provided by CINECA, Dr. Sanzio Bassini, to Prof. Michael Hust, Dr. Federico Bertoglio, Fosca Bognuda and Elisa Restivo. We thank Vaclav Zatecka, Veronika Martinkova, and Linda Kutlikova for technical assistance and Dr. Vladimir Babak for help with statistical analyses. Data availability: The authors declare that data supporting the findings of this study are available within the paper and its supplementary information. All other data are available from the corresponding author upon reasonable request. Published data were taken from GenBank (https://www.ncbi. nlm.nih.gov/genbank/), UniProt (https://www.uniprot.org/), Protein Data Bank, PDB (https://www.rcsb.org/) and ViPR database (https:// www.viprbrc.org/). Source data are provided with this paper. Author contributions: R.D.G, M.Pe., L.S., F.Mu., J.C.L., F.Ma, D.M., C.I., E.P., S.D.G., M.Pa., F.B., D.M., S.Gi., C.O.B, F.B., J.C.S, F.G, S.Ga, designed and carried out experiments and analyzed results, produced plasmids, antibodies and viral proteins. P.N., T.M., J.H., V.H, B.M., N.P., A.F., J.T., V.I., M.Pa., D.Z., P.B., I.B., P.S., D.R., performed animal experiments and analyzed the results. L.V, D.F.R., D.R., Q.P.H., A.P., L.C., P.J.B., M.C.N., P.D.B., T.H. conceived and designed study and experiments and analyzed the results. P.N., T.M., R.N., O.P., J.P., J.R., R.S. conceived and designed the mouse model. L.V., D.F.R., D.R, R.D.G. wrote the manuscript with input from all co-authors. These authors contributed equally: Raoul De Gasparo, Mattia Pedotti. Competing interests: In connection with this work the Institute for Research in Biomedicine has filed a provisional patent application on which L.V. is inventor (PCT/EP2020/085342). The Rockefeller University has filed a provisional patent application on coronavirus antibodies on which D.F.R. and M.C.N. are inventors. Peer review information: Nature thanks Stanley Perlman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Group:COVID-19
Funders:
Funding AgencyGrant Number
European Research Council (ERC)101003650
Swiss National Science Foundation (SNSF)31003A_182270
Lions Club MonteceneriUNSPECIFIED
George Mason UniversityUNSPECIFIED
NIHU01 AI151698
NIHP01-AI138398-S1
NIH2U19AI111825
Caltech Merkin Institute for Translational ResearchUNSPECIFIED
NIHP50 AI150464
NIHR37-AI64003
NIHR01AI78788
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Czech Academy of SciencesUNSPECIFIED
Czech Ministry of AgricultureRVO 68378050
Czech Ministry of AgricultureRVO0518
Ministry of Education, Youth and Sports (Czech Republic)UNSPECIFIED
European Regional Development FundLM2018126
European Regional Development FundCZ.1.05/2.1.00/19.0395
European Regional Development FundCZ.1.05/1.1.00/02.0109
European Regional Development FundCZ.02.1.01/0.0/0.0/15_003/0000495
Czech Science Foundation20-14325S
Bulgari Women & Science Fellowship in COVID-19 ResearchUNSPECIFIED
Ricerca FinalizzataGR-2013-02358399
Ministero della Salute (Italy)UNSPECIFIED
DOI:10.1038/s41586-021-03461-y
Record Number:CaltechAUTHORS:20210308-130543968
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210308-130543968
Official Citation:De Gasparo, R., Pedotti, M., Simonelli, L. et al. Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice. Nature (2021). https://doi.org/10.1038/s41586-021-03461-y
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108344
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:08 Mar 2021 23:38
Last Modified:30 Mar 2021 17:53

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