A bispecific monomeric nanobody induces spike trimer dimers and neutralizes SARS-CoV-2 in vivo

Leo Hanke, Hrishikesh Das, Daniel J. Sheward, Laura Perez Vidakovics, Egon Urgard, Ainhoa Moliner-Morro, Changil Kim, Vivien Karl, Alec Pankow, Natalie L. Smith, Bartlomiej Porebski, Oscar Fernandez-Capetillo, Erdinc Sezgin, Gabriel K. Pedersen, Jonathan M. Coquet, B. Martin Hällberg (), Ben Murrell () and Gerald M. McInerney ()
Additional contact information
Leo Hanke: Karolinska Institutet
Hrishikesh Das: Karolinska Institutet
Daniel J. Sheward: Karolinska Institutet
Laura Perez Vidakovics: Karolinska Institutet
Egon Urgard: Karolinska Institutet
Ainhoa Moliner-Morro: Karolinska Institutet
Changil Kim: Karolinska Institutet
Vivien Karl: Karolinska Institutet
Alec Pankow: Karolinska Institutet
Natalie L. Smith: Karolinska Institutet
Bartlomiej Porebski: Karolinska Institutet
Oscar Fernandez-Capetillo: Karolinska Institutet
Erdinc Sezgin: Karolinska Institutet
Gabriel K. Pedersen: Statens Serum Institut
Jonathan M. Coquet: Karolinska Institutet
B. Martin Hällberg: Karolinska Institutet
Ben Murrell: Karolinska Institutet
Gerald M. McInerney: Karolinska Institutet

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Antibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. This emphasizes the need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we describe the isolation of a nanobody that interacts simultaneously with two RBDs from different spike trimers of SARS-CoV-2, rapidly inducing the formation of spike trimer–dimers leading to the loss of their ability to attach to the host cell receptor, ACE2. We show that this nanobody potently neutralizes SARS-CoV-2, including the beta and delta variants, and cross-neutralizes SARS-CoV. Furthermore, we demonstrate the therapeutic potential of the nanobody against SARS-CoV-2 and the beta variant in a human ACE2 transgenic mouse model. This naturally elicited bispecific monomeric nanobody establishes an uncommon strategy for potent inactivation of viral antigens and represents a promising antiviral against emerging SARS-CoV-2 variants.

Date: 2022
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DOI: 10.1038/s41467-021-27610-z

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