Perspectives on the development of neutralizing antibodies against SARS-CoV-2

Abstract

SARS-CoV-2 gains entry to human cells through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore, the receptor binding domain (RBD) of the S protein is the primary target for neutralizing antibodies. Selection of broad-neutralizing antibodies against SARS-CoV-2 and SARS-CoV is attractive and might be useful for treating not only COVID-19 but also future SARS-related CoV infections. Broad-neutralizing antibodies, such as 47D11, S309, and VHH-72, have been reported to target a conserved region in the RBD of the S1 subunit. The S2 subunit required for viral membrane fusion might be another target. Due to their small size and high stability, single-domain antibodies might have the ability to be administered by an inhaler making them potentially attractive therapeutics for respiratory infections. A cocktail strategy combining two (or more) antibodies that recognize different parts of the viral surface that interact with human cells might be the most effective.

Keywords: COVID-19; SARS-CoV; SARS-CoV-2; neutralizing antibody; spike (S) protein.

Figure 1

Development of neutralizing antibodies for treating COVID-19. In the receptor binding stage, the S1 subunit of SARS-CoV-2 binds human ACE2 on the host cell surface. Antibodies that bind the RBD domain on the S1 subunit might block the interaction of the RBD and the ACE2. Cross-reactive antibodies (e.g., 47D11, S309, and VHH-72) that bind highly conserved epitopes on the RBDs of SARS-CoV and SARS-CoV-2 could have broad neutralization activities against viral infection. In the viral fusion stage, after the cleavage of S1 subunit, the viral fusion peptide (FP) on the S2 subunit inserts into the host cell membrane, inducing the conformational change of the S2 subunit, which forms a six-helix bundle (6-HB) with the HR1 and HR2 trimers. Antibodies (e.g., 1A9 against SARS-CoV) that target the HR domains might block viral fusion. Ab, antibody.