Tackling COVID-19 with neutralizing monoclonal antibodies

Abstract

Monoclonal antibodies (mAbs) have revolutionized the treatment of several human diseases, including cancer and autoimmunity and inflammatory conditions, and represent a new frontier for the treatment of infectious diseases. In the last 20 years, innovative methods have allowed the rapid isolation of mAbs from convalescent subjects, humanized mice, or libraries assembled in vitro and have proven that mAbs can be effective countermeasures against emerging pathogens. During the past year, an unprecedentedly large number of mAbs have been developed to fight coronavirus disease 2019 (COVID-19). Lessons learned from this pandemic will pave the way for the development of more mAb-based therapeutics for other infectious diseases. Here, we provide an overview of SARS-CoV-2-neutralizing mAbs, including their origin, specificity, structure, antiviral and immunological mechanisms of action, and resistance to circulating variants, as well as a snapshot of the clinical trials of approved or late-stage mAb therapeutics.

Keywords: COVID-19; SARS-CoV-2; monoclonal antibody; neutralization; therapeutics.

Figure 1

Timeline of approval of mAbs for all indications (black) and for infectious disease (blue) Sotrovimab received EUA at the time of publication.

Figure 2

Fab-RBD complexes, epitopes, and Fc mutations of clinically relevant mAbs (A) Full spike (S) of SARS-CoV-2 (PDB: 6ZGG) is shown on the left, where ACE2 (pink cartoon) is modeled on the open-state RBD (gray space-filling model) (ACE-2 PDB: 6M0J); the structures of eight Fab-RBD complexes were determined by a combination of X-ray crystallography and/or cryoelectron microscopy (cryo-EM) analysis (Fabs shown as light-blue cartoons and RBD orientation fixed in the upward state shown on S trimer [left image]; see Table 1 for PDB accession numbers). ACE2 and mAb footprints are shown in blue and light green, respectively. Footprints on RBDs were defined according to 5 Å distance from ACE2- or mAb-contacting residues. The stem of N343 glycan is shown as a black sphere. mAbs are labeled using both their original and generic (nonproprietary) names. (B) Antigenic sites nomenclature (Ia–IV versus classes 1–4) according to Barnes et al., 2020a, Cohen et al. (2021), and Piccoli et al. (2020) and colored as in (A). (C) Sequences of the full RBD of SARS-CoV-2 (Wuhan-1 strain), where ACE2 and mAb footprints are highlighted in blue and light green, respectively, as in (A) and (B). The key RBD mutations found in VOCs/VOIs are boxed in red. (D) Structural representation of human IgG1 Fc where amino acids changed in COVID-19 mAbs in late development are shown as red spheres. N297-bound glycans are shown as blue spheres. List of Fc abbreviations: LALA, L234A/L235A (Hezareh et al., 2001; Xu et al., 2000); GAALIE, G236A/A330L/I332E (Weitzenfeld et al., 2019); YTE, M252Y/S254T/T256E (Dall’Acqua et al., 2002); LS: M428L/N434S (Zalevsky et al., 2010); TM, triple mutant in Fc, L234F/L235E/P331S (Oganesyan et al., 2008).

Figure 3

Full occupancy of binding to S trimer by the non-RBM mAb S309 Side (left) and top (right) views of a structural model of SARS-CoV-2 S trimer (gray) with two RBDs in the closed state (dark green) and one in the open state (light green monomer) based on PDB: 6WPT. S309 Fab bound to all three RBDs is modeled as full IgG1 (light blue), and ACE2 monomer (red) bound to the open RBD is shown as a ribbon diagram. This model illustrates how the non-RBM mAb S309 may shield S trimers to sterically prevent ACE2 binding on target cells. S309 is the precursor of VIR-7831, recently renamed sotrovimab.

Figure 4

Prevalence of VOCs over time Prevalence was calculated based on the cumulative counts of sequences retrieved from GISAID belonging to any of the listed VOCs over the total number of sequences deposited by month. GISAID sequences were filtered based on the quality of the sequences (<10% Xs) and the coverage of most of the S sequence (>80% full length). The Phylogenetic Assignment of Named Global Outbreak (PANGO) lineage designation (Rambaut et al., 2020) of each variant, along with the location where they were first identified, is indicated on the right.

Figure 5

Mutations on the SARS-CoV-2 S in VOCs and resistance profile of clinical mAbs (A) Ancestry tree of SARS-CoV-2 VOCs/VOIs. (B) Schematic of SARS-CoV-2 S and the mutation landscape in each VOC/VOI. Del, deletion; ins, insertion. (C) Neutralization of a selection of VOCs/VOIs by clinical-stage mAbs as reported previously (Baum et al., 2020b; Chen et al., 2021b, 2021c; Copin et al., 2021; Dejnirattisai et al., 2021; Dong et al., 2021; FDA (US Food and Drug Administration), 2020a, 2020b; Hoffmann et al., 2021; Liu et al., 2021b; McCallum et al., 2021a; Ryu et al., 2021; Starr et al., 2021b, 2021c; Thomson et al., 2021; Wang et al., 2021a, 2021b). Prediction of neutralization coverage is based on the presence of mutations in the available epitope of each mAb. mAbs developed clinically as cocktails are grouped.

Figure 6

Prophylactic and therapeutic approaches to COVID-19 Vaccines are listed in purple, and mAb-based prophylactic or therapeutic modalities completed successfully or in progress are shown in blue. Other therapeutic modalities are not shown.