Broadly neutralizing antibodies against COVID-19

Abstract

The COVID-19 pandemic caused by SARS-CoV-2 has led to hundreds of millions of infections and millions of deaths, however, human monoclonal antibodies (mAbs) can be an effective treatment. Since SARS-CoV-2 emerged, a variety of strains have acquired increasing numbers of mutations to gain increased transmissibility and escape from the immune response. Most reported neutralizing human mAbs, including all approved therapeutic ones, have been knocked down or out by these mutations. Broadly neutralizing mAbs are therefore of great value, to treat current and possible future variants. Here, we review four types of neutralizing mAbs against the spike protein with broad potency against previously and currently circulating variants. These mAbs target the receptor-binding domain, the subdomain 1, the stem helix, or the fusion peptide. Understanding how these mAbs retain potency in the face of mutational change could guide future development of therapeutic antibodies and vaccines.

Figure 1

(a) Phylogenetic tree of SARS-CoV-2 previous VoCs (Wuhan, Alpha, Beta, Gamma, Delta, and Omicron BA.1) and currently dominant strains (BA.5, BQ.1, BA.2.75, and XBB). The tree is based on the amino acid sequences of the spike protein. (b) Regions of SARS-CoV-2 spike protein (in gray, PDB: 6XR8) targeted by 4 types of broadly neutralizing mAbs. The RBD, NTD, SD1, fusion peptide, and stem helix are colored in blue, cyan, green, red, and orange, respectively. (c) Cartoon representation of the RBD (left) and the surface representation of the RBD showing the locations of the left shoulder, neck, right shoulder, left flank, and right flank (right), PDB: 7BEI. The binding site of ACE2 on the RBD is colored in green.

Figure 2

(a and b) ACE2 footprint on the RBD. The RBD is colored in light gray and the ACE2 footprint in dark gray. (c–e) Mutations of SARS-CoV-2 variants in the RBD. Mutations from strain BQ.1 are colored in red and mutations from other strains that are not present in BQ.1 are colored in yellow. The ACE2 footprint is marked by black lines. (f) Different binding modes of four mAbs (LY-CoV555: blue, PDB: 7KMG; COVOX-384: red, PDB: 7BEP; REGN10987: magenta, PDB: 6XDG; Beta-27: yellow, PDB: 8BH5) with the RBD. (g) Binding region of Omi-42 (red) on the RBD, which is partially overlapped with the ACE2 footprint (marked by black lines). (h) Binding of the CDRs of Omi-42 with the RBD (CDRs of the heavy chain are colored in cyan and light chain in green), PDB: 7ZR7.

Figure 3

(a–c) Binding of the CDRs of COVOX-45, S2H97, and EY6A with the more conserved regions of the RBD (COVOX-45, PDB: 7PRY; S2H97, PDB: 7M7W; EY6A, PDB: 6ZCZ). (d and e) Different binding patterns of P008_60 (blue, PDB: 7ZBU), S3H3 (red, PDB: 7WD8), and SD1.040 (green, PDB: 8D48) with the SD1 (gray). The mutations T547K and A570D of the SD1 are labeled. The peptide 320–330 of the RBD that interacts with S3H3 is shown as an orange cartoon.

Figure 4

(a) Binding patterns of Fabs (red) with stem-helix peptide (yellow). (b) Different Fabs (blue) binding with fusion peptide (orange).