Neutralizing antibodies for the prevention and treatment of COVID-19

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initiates the infection process by binding to the viral cellular receptor angiotensin-converting enzyme 2 through the receptor-binding domain (RBD) in the S1 subunit of the viral spike (S) protein. This event is followed by virus-cell membrane fusion mediated by the S2 subunit, which allows virus entry into the host cell. Therefore, the SARS-CoV-2 S protein is a key therapeutic target, and prevention and treatment of coronavirus disease 2019 (COVID-19) have focused on the development of neutralizing monoclonal antibodies (nAbs) that target this protein. In this review, we summarize the nAbs targeting SARS-CoV-2 proteins that have been developed to date, with a focus on the N-terminal domain and RBD of the S protein. We also describe the roles that binding affinity, neutralizing activity, and protection provided by these nAbs play in the prevention and treatment of COVID-19 and discuss the potential to improve nAb efficiency against multiple SARS-CoV-2 variants. This review provides important information for the development of effective nAbs with broad-spectrum activity against current and future SARS-CoV-2 strains.

Keywords: COVID-19; Monoclonal antibodies; Neutralization; SARS-CoV-2; Spike protein.

Fig. 1

Structural overview of the SARS-CoV-2 spike (S) protein. a Schematic diagram of the SARS-CoV-2 virion and its S protein. E envelope, M membrane, N nucleocapsid, ACE2 angiotensin-converting enzyme 2. b Cryo-EM structure of the SARS-CoV-2 S protein trimer (PDB 6VXX). The three subunits are colored orange, green, and blue. c Close-up views of the SARS-CoV-2 S receptor-binding domain (RBD) and N-terminal domain (NTD) in the S1 subunit. d Crystal structure of the SARS-CoV-2 RBD in complex with human ACE2 (PDB 6M0J). Human ACE2 is colored in light blue

Fig. 2

Generation of SARS-CoV-2-targeting human neutralizing monoclonal antibodies (nAbs) and their mechanisms of action. nAbs specific to SARS-CoV-2 can be generated by single B cell cloning (a) or phage display library screening (b). c nAbs targeting the receptor-binding domain (RBD) of the spike (S) protein bind to the RBD in the S1 subunit and block its binding with the angiotensin-converting enzyme 2 (ACE2) receptor, thus preventing virus entry into host cells through endocytosis or cell surface fusion processes. d nAbs targeting the N-terminal domain (NTD) in the S1 subunit or S2 bind to the NTD or S2 subunit, thus inhibiting the conformational change of the S protein or NTD or the formation of a 6-helix bundle (6-HB) structure mediated by heptad repeat region 1 (HR1) and HR2 in the S2 subunit, further blocking membrane fusion and virus entry into the host cell

Fig. 3

Structures of SARS-CoV-2 spike (S) in complex with N-terminal domain (NTD)-targeting neutralizing monoclonal antibodies (nAbs). a–e Cryo-EM structures of the SARS-CoV-2 S trimer bound to NTD-targeting nAbs a S2L28 (PDB 7LXZ), b S2M28 (PDB 7LY2), c S2X333 (PDB 7LXY), d 4-8 (PDB 7LQV), and e 4A8 (PDB 7C2L). f Crystal structure of the SARS-CoV-2 NTD in complex with the nAb S2M28 (PDB 7LY3)

Fig. 4

Structures of SARS-CoV-2 spike (S) in complex with receptor-binding domain (RBD)-targeting monoclonal antibodies (mAbs) with neutralizing activity (nAbs). a–e Cryo-EM structures of the SARS-CoV-2 S trimer bound to nAbs. a 2-4 with all three RBDs in the down conformation (PDB 6XEY), b P5A-1B9 with one RBD in the up conformation (PDB 7CZX), c P5A-3C12 with one or two RBDs in the up conformation, respectively (PDBs 7D0B and 7D0D), d P5A-2G7 with two RBDs in the up conformation (PDB 7CZW), and e P5A-1B8 with two or three RBDs in the up conformation, respectively (PDBs 7CZR and 7CZS). f–j Crystal structures of the SARS-CoV-2 RBD in complex with the nAbs f CT-P59 (PDB 7CM4), g CV07-270 (PDB 6XKP), h P2B-2F6 (PDB 7BWJ), i CV30 (PDB 6XE1), and j CB6 (PDB 7C01)