Evolution of Anti-SARS-CoV-2 Therapeutic Antibodies

Abstract

Since the first COVID-19 reports back in December of 2019, this viral infection caused by SARS-CoV-2 has claimed millions of lives. To control the COVID-19 pandemic, the Food and Drug Administration (FDA) and/or European Agency of Medicines (EMA) have granted Emergency Use Authorization (EUA) to nine therapeutic antibodies. Nonetheless, the natural evolution of SARS-CoV-2 has generated numerous variants of concern (VOCs) that have challenged the efficacy of the EUA antibodies. Here, we review the most relevant characteristics of these therapeutic antibodies, including timeline of approval, neutralization profile against the VOCs, selection methods of their variable regions, somatic mutations, HCDR3 and LCDR3 features, isotype, Fc modifications used in the therapeutic format, and epitope recognized on the receptor-binding domain (RBD) of SARS-CoV-2. One of the conclusions of the review is that the EUA therapeutic antibodies that still retain efficacy against new VOCs bind an epitope formed by conserved residues that seem to be evolutionarily conserved as thus, critical for the RBD:hACE-2 interaction. The information reviewed here should help to design new and more efficacious antibodies to prevent and/or treat COVID-19, as well as other infectious diseases.

Keywords: Bamlanivimab; Bebtelovimab; COVID-19; Casirivimab; Cilgavimab; Etesevimab; Imdevimab; Regdanvimab; Sotrovimab; Tixagevimab; therapeutic antibodies; variants of concern.

Figure 1

Timeline of SARS-CoV-2 VOCs emergence (on top of the time bar) along with the first EUA by the FDA and/or EMA of the therapeutic antibodies (underneath the time bar).

Figure 2

Neutralization potency of the EUA-approved anti-COVID-19 antibodies when challenged with SARS-CoV-2 VOCs. The heat map is based on the neutralization values of pseudovirus assays against SARS-CoV-2 variants [42,43,44,45]. The values of NC₅₀ in ng/mL are depicted in the following color code: <20 (dark green), 21–100 (hunter green), 101–1000 (lime green), 1001–9999 (light green), >10,000 (orange).

Figure 3

Anatomy of the SARS-CoV-2 spike protein. Above: Schematic representation of the different domains in the subunit 1 and 2 of the SARS-CoV-2 spike. NTD, N-terminal domain (in purple); RBD, receptor binding domain (in light blue); RBM, receptor binding motif (in deep blue); FP, fusion peptide (in forest green); HR1, heptapeptide repeat sequence 1 (in blue); HR2, heptad repeat sequence 2 (in melon orange); TM, transmembrane domain (in pink); CT, cytoplasmic tail (in gold). Below: Two views related by 90° rotation of the surface of Spike homotrimer protein of SARS-CoV-2 in down conformation. Each monomer is colored in white, gray and colors.. The figures were prepared using PyMOL Molecular Graphics System version 2.4.1. Schrödinger, LLC, New York (https://pymol.org/2, accessed on 16 May 2022) using the coordinates of the PDB ID: 7BNM.

Figure 4

Connolly surface of the RBD with RBM motif in light blue. Side views on the top. RBM seen from the hACE-2 perspective on the bottom. The figure was generated using the coordinates with PDB ID: 7MZG in PyMOL Molecular Graphics System version 2.4.1. Schrödinger, LLC, New York (https://pymol.org/2, accessed on 16 May 2022).

Figure 5

Sequence alignment of the therapeutic antibodies. The second column corresponds to the name of the IGHV, IGKV, or IGLV germline genes. The third column is the number of putative somatic mutations, indicated in green squares in the sequences. The germline genes were assigned using Ig BLAST (https://www.ncbi.nlm.nih.gov/igblast/ accessed on 16 May 2022). The CDRs are indicated in gray squares as defined using Kabat’s numbering convention.

Figure 6

Conolly surface of SARS-CoV-2 RBD in the same view of Figure 3 showing the interface with ACE-2 and the epitopes recognized by the anti-SARS-CoV-2 therapeutic antibodies. Front and top view of the structural surface of the SARS-CoV-2 RBD shows the location of the Delta variant mutations (in red), Omicron variant mutations (in blue), and mutations in both variants (in purple). RBD residues that contact ACE-2 are indicated in orange, whereas the RBD residues protected by anti–SARS-CoV2 antibodies are indicated with different colors: Casirivimab (cyan); Imdevimab (purple); Bamlanivimab (yellow); Etesevimab (marine blue); Sotrovimab (green); Regdanvimab (red); Tixagevimab (forest green); Cilgavimab (raspberry); and Bebtelovimab (deep teal) PDB 7MZG. The figures were prepared using PyMOL Molecular Graphics System version 2.4.1. Schrödinger, LLC, New York (https://pymol.org/2, accessed on 16 May 2022).