Please use this identifier to cite or link to this item: http://hdl.handle.net/10553/114617
Title: Nanobodies Protecting from Lethal SARS-CoV-2 Infection Target Receptor Binding Epitopes Preserved in Virus Variants other than Omicron
Authors: Casasnovas, José M.
Margolles, Yago
Noriega, María A.
Guzmán, María
Arranz, Rocío
Melero, Roberto
Casanova, Mercedes
Corbera Sánchez, Juan Alberto 
Jiménez-de-Oya, Nereida
Gastaminza, Pablo
Garaigorta, Urtzi
Saiz, Juan Carlos
Martín-Acebes, Miguel Ángel
Fernández, Luis Ángel
UNESCO Clasification: 310903 Inmunología
Keywords: Coronavirus
Covid-19
Nanobodies
Neutralizing Antibodies
Sars-Cov-2 Variants
Issue Date: 2022
Project: PIE-RD-COVID 19 (No 202020E079)
PTI+ Salud Global REC_EU (No SGL 2103051, NextGenerationEU)
No SGL 2103053, NextGenerationEU
CRIOMECORR project (ESFRI-2019-01-CSIC-16)
Instruct Image Processing Center PID16168 and PID14989
Journal: Frontiers in Immunology 
Abstract: The emergence of SARS-CoV-2 variants that escape from immune neutralization are challenging vaccines and antibodies developed to stop the COVID-19 pandemic. Thus, it is important to establish therapeutics directed toward multiple or specific SARS-CoV-2 variants. The envelope spike (S) glycoprotein of SARS-CoV-2 is the key target of neutralizing antibodies (Abs). We selected a panel of nine nanobodies (Nbs) from dromedary camels immunized with the receptor-binding domain (RBD) of the S, and engineered Nb fusions as humanized heavy chain Abs (hcAbs). Nbs and derived hcAbs bound with subnanomolar or picomolar affinities to the S and its RBD, and S-binding cross-competition clustered them in two different groups. Most of the hcAbs hindered RBD binding to its human ACE2 (hACE2) receptor, blocked cell entry of viruses pseudotyped with the S protein and neutralized SARS-CoV-2 infection in cell cultures. Four potent neutralizing hcAbs prevented the progression to lethal SARS-CoV-2 infection in hACE2-transgenic mice, demonstrating their therapeutic potential. Cryo-electron microscopy identified Nb binding epitopes in and out the receptor binding motif (RBM), and showed different ways to prevent virus binding to its cell entry receptor. The Nb binding modes were consistent with its recognition of SARS-CoV-2 RBD variants; mono and bispecific hcAbs efficiently bound all variants of concern except omicron, which emphasized the immune escape capacity of this latest variant.
URI: http://hdl.handle.net/10553/114617
ISSN: 1664-3224
DOI: 10.3389/fimmu.2022.863831
Source: Frontiers in Immunology [EISSN 1664-3224], v. 13, (Abril 2022)
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