1. Monoclonal antibodies targeting two immunodominant epitopes on the Spike protein neutralize emerging SARS-CoV-2 variants of concern.
- Author
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Kovacech B, Fialova L, Filipcik P, Skrabana R, Zilkova M, Paulenka-Ivanovova N, Kovac A, Palova D, Rolkova GP, Tomkova K, Csokova NT, Markova K, Skrabanova M, Sinska K, Basheer N, Majerova P, Hanes J, Parrak V, Prcina M, Cehlar O, Cente M, Piestansky J, Fresser M, Novak M, Slavikova M, Borsova K, Cabanova V, Brejova B, Vinař T, Nosek J, Klempa B, Eyer L, Hönig V, Palus M, Ruzek D, Vyhlidalova T, Strakova P, Mrazkova B, Zudova D, Koubkova G, Novosadova V, Prochazka J, Sedlacek R, Zilka N, and Kontsekova E
- Subjects
- Angiotensin-Converting Enzyme 2 chemistry, Angiotensin-Converting Enzyme 2 genetics, Angiotensin-Converting Enzyme 2 metabolism, Animals, Antibodies, Monoclonal therapeutic use, Antigenic Drift and Shift, Antineoplastic Agents, Immunological therapeutic use, COVID-19 virology, Disease Models, Animal, Humans, Kinetics, Lung pathology, Mice, Mutation, Neutralization Tests, Protein Binding, SARS-CoV-2 genetics, SARS-CoV-2 isolation & purification, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus metabolism, COVID-19 Drug Treatment, Antibodies, Monoclonal immunology, Antineoplastic Agents, Immunological immunology, Immunodominant Epitopes immunology, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus immunology
- Abstract
Background: The emergence of new SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) that harbor mutations in the viral S protein raised concern about activity of current vaccines and therapeutic antibodies. Independent studies have shown that mutant variants are partially or completely resistant against some of the therapeutic antibodies authorized for emergency use., Methods: We employed hybridoma technology, ELISA-based and cell-based S-ACE2 interaction assays combined with authentic virus neutralization assays to develop second-generation antibodies, which were specifically selected for their ability to neutralize the new variants of SARS-CoV-2., Findings: AX290 and AX677, two monoclonal antibodies with non-overlapping epitopes, exhibit subnanomolar or nanomolar affinities to the receptor binding domain of the viral Spike protein carrying amino acid substitutions N501Y, N439K, E484K, K417N, and a combination N501Y/E484K/K417N found in the circulating virus variants. The antibodies showed excellent neutralization of an authentic SARS-CoV-2 virus representing strains circulating in Europe in spring 2020 and also the variants of concern B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). In addition, AX677 is able to bind Omicron Spike protein just like the wild type Spike. The combination of the two antibodies prevented the appearance of escape mutations of the authentic SARS-CoV-2 virus. Prophylactic administration of AX290 and AX677, either individually or in combination, effectively reduced viral burden and inflammation in the lungs, and prevented disease in a mouse model of SARS-CoV-2 infection., Interpretation: The virus-neutralizing properties were fully reproduced in chimeric mouse-human versions of the antibodies, which may represent a promising tool for COVID-19 therapy., Funding: The study was funded by AXON Neuroscience SE and AXON COVIDAX a.s., Competing Interests: Declaration of interests All authors affiliated with AXON COVIDAX a.s., AXON Neuroscience SE, AXON Neuroscience R&D Services SE (BKo, LF, PF, RSk, MZ, NP-I, AK, DP, GPR, KT, NTC, KM, PM, VP, KS, NB, JH, MPr, OC, MC, JP, MF, MN, NZ, EK) receive a salary from or were employed by the respective companies. Biomedical Research Center, the employer of MS and BKl, received reimbursement from AXON Neuroscience SE for neutralization assays performed according to the research contract. KB, VC, BB, TVi, JN, LE, VH, MPa, DR, TVy, PS, BM, DZ, GK, VN, JP and RSe have no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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