Branislav Kovacech, Lubica Fialova, Peter Filipcik, Rostislav Skrabana, Monika Zilkova, Natalia Paulenka-Ivanovova, Andrej Kovac, Denisa Palova, Gabriela Paulikova Rolkova, Katarina Tomkova, Natalia Turic Csokova, Karina Markova, Michaela Skrabanova, Kristina Sinska, Neha Basheer, Petra Majerova, Jozef Hanes, Vojtech Parrak, Michal Prcina, Ondrej Cehlar, Martin Cente, Juraj Piestansky, Michal Fresser, Michal Novak, Monika Slavikova, Kristina Borsova, Viktoria Cabanova, Bronislava Brejova, Tomas Vinar, Jozef Nosek, Boris Klempa, Ludek Eyer, Vaclav Honig, Martin Palus, Daniel Ruzek, Tereza Vyhlidalova, Petra Strakova, Blanka Mrazkova, Dagmar Zudova, Gizela Koubkova, Vendula Novosadova, Jan Prochazka, Radislav Sedlacek, Norbert Zilka, Eva Kontsekova. Monoclonal antibodies targeting two immunodominant epitopes on the Spike protein neutralize emerging SARS-CoV-2 variants of concern. EBioMedicine, 76:103818. 2022.

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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.