Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogenic human coronavirus that belongs to the sarbecovirus lineage of the genus Betacoronavirus. The ancestor strain has evolved into a number of variants of concern, with the Omicron variant of concern now having many distinct sublineages. The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use. Many are in preclinical and clinical development, and a few have been approved for emergency use. Here we summarize neutralizing antibodies that target four key regions within the SARS-CoV-2 spike (S) protein, namely the N-terminal domain and the receptor-binding domain in the S1 subunit, and the stem helix region and the fusion peptide region in the S2 subunit. Understanding the characteristics of these broadly neutralizing antibodies will accelerate the development of new antibody therapeutics and provide guidance for the rational design of next-generation vaccines.

Fig. 1. Neutralizing antibodies directed against the SARS-CoV-2 spike protein.

a | Schematic representation of the main domains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein. Arrows denote S1/S2 and S2′ protease cleavage sites. b | Different groups of neutralizing antibodies (nAbs) that target the S protein. Representative nAbs targeting the S1 N-terminal domain (NTD), S1 receptor-binding domain (RBD), and S2 stem helix (SH) and S2 fusion peptide (FP) regions are shown with the S protein depicted in the RBD ‘up’ conformation. c | RBD-directed nAbs can be divided into four main classes depending on the epitopes they target in the RBD of the S protein. For each class, one representative nAb bound to the RBD monomer is shown: class 1, CB6; class 2, LY-CoV555; class 3, S309; class 4, CR3022. CD, connector domain; CH, central helix; CT, cytoplasmic tail; HR, heptad repeat; SD, subdomain; TM, transmembrane domain.

Fig. 2. Structures of neutralizing antibodies bound to the SARS-CoV-2 spike protein.

Three-dimensional modelling is used here to depict the complexes of representative neutralizing antibodies (nAbs) interacting with their targets in the S1 and S2 subunits of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein. a | S1 N-terminal domain (NTD) nAbs, supersite (S2M28, Protein Data Bank (PDB) ID 7LY3). b | S1 NTD nAbs, non-supersite (5-7, PDB ID 7RW2). c | S1 receptor-binding domain (RBD) nAbs, class 1 (CB6, PDB ID 7C01). d | S1 RBD nAbs, class 2 (LY-CoV555, PDB ID 7KMG). e | S1 RBD nAbs, class 3 (S309, PDB ID 7TLY). f | S1 RBD nAbs, class 4 (CR3022, PDB ID 7JN5). g | S2 stem helix (SH) nAb (S2P6, PDB ID 7RNJ). h | S2 fusion peptide (FP) nAb (76E1, PDB ID 7X9E).