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Structure of the Inmazeb cocktail and resistance to escape against Ebola virus

Rayaprolu, Vamseedhar and Fulton, Ben and Rafique, Ashique and Arturo, Emilia and Williams, Dewight and Hariharan, Chitra and Callaway, Heather and Parvate, Amar and Schendel, Sharon L. and Parekh, Diptiben and Hui, Sean and Shaffer, Kelly and Pascal, Kristen and Wloga, Elzbieta and Giordano, Stephanie and Copin, Richard and Franklin, Matthew and Boytz, RuthMabel and Donahue, Callie and Davey, Robert and Baum, Alina and Kyratsous, Christos A. and Saphire, Erica Ollmann (2022) Structure of the Inmazeb cocktail and resistance to escape against Ebola virus. . (Unpublished)

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Monoclonal antibodies can provide important pre- or post-exposure protection against disease for those not yet vaccinated or in individuals that fail to mount a protective immune response after vaccination. A key concern in use of monotherapy monoclonal antibody products lies in the high risk of mutagenic escape. Inmazeb (REGN-EB3), a three-antibody cocktail against Ebola virus, demonstrated efficacy in lessening disease course and improving survival in a randomized, controlled trial. Here we present the cryoEM structure at 3.1 Å of the Ebola virus glycoprotein, determined without symmetry averaging, in a simultaneous complex with eight Fab fragments of antibodies in the Inmazeb cocktail. This structure allows modeling of previously disordered portions of the glycan cap, maps the non-overlapping epitopes of Inmazeb, and illuminates the basis for complementary activities, as well as residues that are critical for resistance to escape by each component of this cocktail and other clinically relevant antibodies. We also provide direct evidence that, unlike monotherapy treatments, including those targeting conserved epitopes, the Inmazeb protects against the rapid emergence of EBOV escape mutants and supports the benefit of the combination approach.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper ItemJournal Article
Rayaprolu, Vamseedhar0000-0002-2823-2984
Fulton, Ben0000-0003-3531-0888
Rafique, Ashique0000-0003-4078-7242
Arturo, Emilia0000-0002-6911-129X
Williams, Dewight0000-0001-8942-8131
Callaway, Heather0000-0003-4003-3854
Parvate, Amar0000-0001-9282-5015
Schendel, Sharon L.0000-0002-5062-7261
Parekh, Diptiben0000-0002-1972-9462
Hui, Sean0000-0002-9870-6823
Shaffer, Kelly0000-0002-6212-1428
Pascal, Kristen0000-0003-4826-4606
Wloga, Elzbieta0000-0002-1494-9765
Giordano, Stephanie0000-0001-5879-3275
Copin, Richard0000-0001-7717-2183
Franklin, Matthew0000-0002-1482-0136
Boytz, RuthMabel0000-0002-8524-8376
Donahue, Callie0000-0002-4284-2914
Davey, Robert0000-0001-9168-2892
Baum, Alina0000-0001-7179-8679
Kyratsous, Christos A.0000-0002-2596-2906
Saphire, Erica Ollmann0000-0002-1206-7451
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. We gratefully acknowledge our funding from NIAID U19 AI142790, Consortium for Immunotherapeutics against Emerging Viral Threats (E.O.S, C.W.D.) and U.S. Department of Health and Health Services Contract No. HHSO100201700016C (Regeneron). A portion of this project has been funded in part with federal funds from the Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201700020C. We thank all the staff of the NIH who supported this study, in particular Kaleb Sharer, Russel Byrum, Jennifer Jackson, Sarah Klim, Danny Ragland, Marisa St Claire and Lisa Hensley. The authors would like to thank Kristen Tramaglini for continuous support with this project. Author Contributions: Conceptualization, E.O.S, C.A.K, A.B. Methodology, V.R, B.F, A.R, H.C, A.P, K.P, R.C, R.D Investigation, V.R, H.C, C.H, B.F, A.B, A.R, E.A, K.S, S.H, D.P, E.W, S.G, R.C, K.P, R.D, R.M.B, C.D Formal analysis, V.R, C.H, B.F, A.B, A.R, M.F, R.D, K.P Writing ± original draft, V.R, E.O.S., B.F., A.B. Writing ± review & editing, V.R, E.O.S, B.F, M.F, S.S, A.P, C.A.K, A.B Visualization, V.R, B.F., A.R., H.C. Supervision, E.O.S, C.A.K, M.F., A.B. Resources, E.O.S, D.W, C.A.K, A.B, A.R,. Funding Acquisition, E.O.S, C.A.K. Competing Interest Statement. Regeneron authors own options and/or stock of the company. C.A.K. is an officer of Regeneron
Funding AgencyGrant Number
NIHU19 AI142790
Department of Health and Human ServicesHHSO100201700016C
Department of Health and Human ServicesHHSO100201700020C
Record Number:CaltechAUTHORS:20230322-101630000.19
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:120312
Deposited By: George Porter
Deposited On:22 Mar 2023 18:15
Last Modified:22 Mar 2023 18:15

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