A broadly-neutralizing antibody against Ebolavirus glycoprotein that potentiates the breadth and neutralization potency of other antibodies

Francesca R Donnellan; Vamseedhar Rayaprolu; Pramila Rijal; Victoria O'Dowd; Amar Parvate; Heather Callaway; Chitra Hariharan; Dipti Parekh; Sean Hui; Kelly Shaffer; Ruben Diaz Avalos; Kathryn Hastie; Lisa Schimanski; Helena Müller-Kräuter; Thomas Strecker; Ariane Balaram; Peter Halfmann; Erica Ollmann Saphire; Daniel J Lightwood; Alain R Townsend; Simon J Draper

doi:10.1101/2024.06.21.600001

A broadly-neutralizing antibody against Ebolavirus glycoprotein that potentiates the breadth and neutralization potency of other antibodies

bioRxiv [Preprint]. 2024 Jun 25:2024.06.21.600001. doi: 10.1101/2024.06.21.600001.

Authors

Francesca R Donnellan^{1

2

3}, Vamseedhar Rayaprolu^{4

5}, Pramila Rijal^{6

7}, Victoria O'Dowd⁸, Amar Parvate^{4

9}, Heather Callaway^{4

10}, Chitra Hariharan⁴, Dipti Parekh⁴, Sean Hui^{4

11}, Kelly Shaffer^{4

12}, Ruben Diaz Avalos⁴, Kathryn Hastie⁴, Lisa Schimanski⁷, Helena Müller-Kräuter¹³, Thomas Strecker¹³, Ariane Balaram¹⁴, Peter Halfmann¹⁴, Erica Ollmann Saphire^{4

12}, Daniel J Lightwood⁸, Alain R Townsend^{6

7}, Simon J Draper^{1

2

3

15}

Affiliations

¹ Department of Biochemistry, University of Oxford, Dorothy Crowfoot Hodgkin Building, Oxford, OX1 3QU, UK.
² Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford, OX1 3QU, UK.
³ The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
⁴ Center for Vaccine Innovation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
⁵ Current affiliation: Pacific Northwest Cryo-EM Center, Oregon Health and Sciences University, Portland, OR 97201, USA.
⁶ Center for Translational Immunology, Chinese Academy of Medical Science Oxford Institute, Nuffield Department of Medicine, University of Oxford, OX3 7BN, UK.
⁷ MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, UK.
⁸ UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK.
⁹ Current affiliation: Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
¹⁰ Current affiliation: Chemistry & Biochemistry Building, Montana State University, Bozeman, MT 59717, USA.
¹¹ Current Affiliation: Department of Pathology & Immunology, Washington University School of Medicine. St. Louis MO 63110, USA.
¹² Department of Medicine. University of California San Diego. La Jolla, CA 92037, USA.
¹³ Institute of Virology, Philipps University Marburg, Hans-Meerwein-Straße 2, 35043 Marburg, Germany.
¹⁴ Influenza Research Institute, School of Veterinary Medicine, University of Wisconsin, Madison, WI, 53713, USA.
¹⁵ NIHR Oxford Biomedical Research Centre, Oxford, UK.

Abstract

Ebolavirus disease (EVD) is caused by multiple species of Ebolavirus. Monoclonal antibodies (mAbs) against the virus glycoprotein (GP) are the only class of therapeutic approved for treatment of EVD caused by Zaire ebolavirus (EBOV). Therefore, mAbs targeting multiple Ebolavirus species may represent the next generation of EVD therapeutics. Broadly reactive anti-GP mAbs were produced; among these, mAbs 11886 and 11883 were broadly neutralizing in vitro. A 3.0 Å cryo-electron microscopy structure of EBOV GP bound to both mAbs shows that 11886 binds a novel epitope bridging the glycan cap (GC), 3₁₀ pocket and GP2 N-terminus, whereas 11883 binds the receptor binding region (RBR) and GC. In vitro, 11886 synergized with a range of mAbs with epitope specificities spanning the RBR/GC, including 11883. Notably, 11886 increased the breadth of neutralization by partner mAbs against different Ebolavirus species. These data provide a strategic route to design improved mAb-based next-generation EVD therapeutics.

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