Neutralizing antibodies for the treatment of COVID-19

Abstract

More clinical trial data are needed to determine whether sera from COVID-19-convalescent patients and neutralizing monoclonal antibodies specific to SARS-CoV-2 antigens can prevent COVID-19 or reduce the severity of the disease in high-risk populations.

Fig. 1 ∣. Structures of the SARS-CoV-2 spike protein and the RBD.

a, Front and side views of the crystal structure of the SARS-CoV-2 chimeric RBD in a complex with the hACE2 receptor (PDB 6VW1). The RBD core is depicted in orange, the receptor-binding motif (RBM) in green and hACE2 in violet. b,c, Structures of the SARS-CoV-2 S protein trimer in the closed (b; PDB 6VXX) and partially open (c; PDB 6VYB) conformations. The RBD core from one S protomer is depicted in orange and its RBM in green. The rest of the trimeric spike is in light blue. d, Crystal structure of the SARS-CoV-2 RBD in a complex with the human antibody Fab CR3022 (PDB 6W41). The RBD core is depicted in orange and the RBM in green. The light and heavy chains of mAb CR3022 are in pink and blue, respectively.

Fig. 2 ∣. Generation of SARS-CoV-2 neutralizing antibodies, and potential mechanisms of action.

a, SARS-CoV-2 nAbs may be isolated from patients’ B cells, a library of human single-domain antibodies (sdAbs), or a library of nanobodies (Nbs). Different regions of the SARS-CoV-2 S protein are targeted by nAbs, including the RBD and NTD in the S1 subunit. SARS-CoV nAbs with cross-neutralization activity against SARS-CoV-2 may cross-react with the SARS-CoV-2 RBD or S2 subunit. Convalescent plasma from patients infected with SARS-CoV-2 could be used for the treatment of COVID-19. b, Potential mechanisms of action. (i) In the absence of nAbs, SARS-CoV-2 binds to the viral ACE2 receptor via the RBD, mediating viral entry into target cells. (ii) In the presence of RBD-specific nAbs, the antibodies bind to the RBD and inhibit RBD binding to ACE2, resulting in the inhibition of membrane fusion and the entry of the virus into the host cell. Some non-RBD-targeting nAbs may bind to the NTD, the S trimer or the S2 subunit (thus preventing conformational changes of S or inhibiting membrane fusion and viral entry). (iii) In the presence of nAbs with suboptimal or negligible neutralizing activity, the antibody-bound virions may enter cells (such as monocytes or macrophages) through the FcγR, leading to enhanced viral entry, viral replication or inflammation.