Neutralizing antibodies targeting SARS-CoV-2 spike protein

Abstract

SARS-CoV-2 causing the worldwide pandemic has changed people's life in multiple aspects dramatically since it's first identified in Wuhan, China at the end of 2019. While the numbers of infected patients and death toll keep vigorous increasing, curbing the progression of the pandemic is an urgent goal. Efforts have been made to search for prophylactic and therapeutic approaches including neutralizing antibodies development. By reviewing dozens of studies on anti-spike antibodies identification, we concluded that (1) promising therapeutic antibodies are being fished out by various approaches, such as screening of single B cells of convalescent patients, recombinant antibody library and B cells of immunized animals; (2) the epitopes are mainly RBD, but also some non-RBD domains, without the requisite of overlapping with ACE2 binding sites; (3) Neutralizing antibodies are convergent to a few germline genes, including IGHV3-30, IGHV3-53, IGHV3-66, with varying levels of somatic mutations. This review summarizes the progress in neutralizing antibodies development and the germline enrichment of effective antibodies, which will shed light on COVID-19 treatment and vaccine design.

Keywords: Antibody germline; COVID-19; SARS-CoV-2; Spike RBD; Therapeutic antibody.

Fig. 1

Schematic of spike structure and relevance to ACE2 binding. This figure is adapted from Wrapp et al. (2020) and Lan et al. (2020). (A) Schematic of spike structure of SARS-CoV-2 colored by domain and side views of spike of SARS-CoV-2. SS: signal sequence, S2′: S2′ protease cleavage site, FP: fusion peptide, HR1: heptad repeat 1, CH: central helix, CD: connector domain, HR2: heptad repeat 2, TM, transmembrane domain, CT: cytoplasmic tail. Arrows denote protease cleavage sites. (B) Overall structure of the SARS-CoV-2 RBD bound to ACE2. ACE2 - green; RBD core – cyan; RBM – red; disulfide bonds – sticks and indicated by arrows. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Variety of epitopes of antibody CR3022, S309, REGN10987, CC12.1 and S230 on spike RBD. Superimposition of RBD with five antibodies belong to different germlines was shown, RBD is displayed in surface representation and antibodies are shown in ribbons. The structure used for superimposition of CR3022 (wheat color, IGHV5-51) and S309 1N343 glycan is shown in sticks). Both REGN10987 (Limon color, PDB 6XDG) and S230 (Cyan color, PDB 6NB7) are antibodies of IGHV3-30 germline, and binds to different motif of RBD. Another antibody CC12.1 (Slate color, PDB 6XC2) of germline IGHV3-53 binds to similar epitope with that of S230.

Fig. 3

IGHV germline distribution of SARS-CoV-2 spike-targeting antibodies. (A) Christoph (Kreer et al., 2020) reported the frequencies of VH gene segments of clonal and non-clonal sequences from all 12 COVID-19 patients, NGS reference data from 48 healthy individuals (collected before the outbreak of SARS-CoV-2) are depicted in red line. Bar and line plots show as mean ± SD. (B) IGHV distribution of 294-RBD targeting antibodies from 12 literatures, analyzed by Yuan et al. (2020). (C) IGHV distribution of about 300 SARS-CoV-2 binding antibodies reported in the public database (http://opig.stats.ox.ac.uk/webapps/covabdab/#collapseOne) were analyzed, the data was due to June 20/2020. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)