Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift - CEA - Commissariat à l’énergie atomique et aux énergies alternatives Accéder directement au contenu
Article Dans Une Revue mAbs Année : 2022

Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift

Résumé

Here, we report the molecular engineering of nanobodies that bind with picomolar affinity to both SARS-CoV-1 and SARS-CoV-2 receptor-binding domains (RBD) and are highly neutralizing. We applied deep mutational engineering to VHH72, a nanobody initially specific for SARS-CoV-1 RBD with little cross-reactivity to SARS-CoV-2 antigen. We first identified all the individual VHH substitutions that increase binding to SARS-CoV-2 RBD and then screened highly focused combinatorial libraries to isolate engineered nanobodies with improved properties. The corresponding VHH-Fc molecules show high affinities for SARS-CoV-2 antigens from various emerging variants and SARS-CoV-1, block the interaction between ACE2 and RBD, and neutralize the virus with high efficiency. Its rare specificity across sarbecovirus relies on its peculiar epitope outside the immunodominant regions. The engineered nanobodies share a common motif of three amino acids, which contribute to the broad specificity of recognition. Our results show that deep mutational engineering is a very powerful method, especially to rapidly adapt existing antibodies to new variants of pathogens.

Dates et versions

cea-03674232 , version 1 (20-05-2022)

Identifiants

Citer

Adrien Laroche, Maria Lucia Orsini Delgado, Benjamin Chalopin, Philippe Cuniasse, Steven Dubois, et al.. Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift. mAbs, 2022, 14 (1), pp.2076775. ⟨10.1080/19420862.2022.2076775⟩. ⟨cea-03674232⟩
1015 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More