Fruitful Neutralizing Antibody Pipeline Brings Hope To Defeat SARS-Cov-2

Abstract

With the recent spread of severe acute respiratory syndrome coronavirus (SARS-CoV-2)_ infecting >16 million people worldwide as of 28 July 2020, causing >650 000 deaths, there is a desperate need for therapeutic agents and vaccines. Building on knowledge of previous outbreaks of SARS-CoV-1 and Middle East respiratory syndrome (MERS), the development of therapeutic antibodies and vaccines against coronavirus disease 2019 (COVID-19) is taking place at an unprecedented speed. Current efforts towards the development of neutralizing antibodies against COVID-19 are summarized. We also highlight the importance of a fruitful antibody development pipeline to combat the potential escape plans of SARS-CoV-2, including somatic mutations and antibody-dependent enhancement (ADE).

Keywords: COVID-19; SARS-CoV-2; antibody-dependent enhancement; drug resistance; neutralizing antibodies; viral escape.

Figure 1

SARS-CoV-2 Infection Depends on the Host Cell Receptor ACE2. (A) Cartoon representation of spike protein binding to ACE2 of the host cells. SARS-CoV-2 spike protein S binds to ACE2 through the receptor-binding domain (RBD) and is proteolytically activated by the human protease TMPRSS2, which loosens the structural constraints on the fusion peptide (FP) and initiates a cascade of refolding events (e.g., formation of the three-stranded coiled-coil) and facilitates membrane fusion and release of the viral genome. S protein, FP, HR1, HR2, ACE2, and TMPRSS2 are not drawn to scale. (B) Superimposition of ACE2–RBD structural complex (PDB 6M17) onto the spike protein trimer of SARS-CoV-2 (PDB 6VSB) with the RBD in the 'up' conformation. The spike protein is shown in ribbons with the RBD in green, the S1 domain in grey, and the S2 domain in blue. Abbreviations: HR1, heptad repeat 1; HR2, heptad repeat 2. Figure generated in Biorender (https://biorender.com/).

Figure 2

Crossreactivity of Antibodies S309, CR3022, and VHH-72 against the Receptor-Binding Domain (RBD) of SARS-CoV-1 and SARS-CoV-2 and Their Epitopes. (A) Superimposition of the RBD with four antibodies. The structures used for superimposition of S309 and CR3022 are with RBD of SARS-CoV-2 (PDB 6WPT [39] and PDB 6W41 [68]), whereas that of VHH-72 is with RBD of SARS-CoV-1 (PDB 6WAQ [70]). B38 is a SARS-CoV-2 specific antibody (PDB 7BZ5 [45]). RBD is shown in surface representation and antibodies are shown in ribbons. The molecular operating environment (MOE) program (Chemical Computing Group ULC, Montreal, QC, Canada; www.chemcomp.com/Products.htm) was used for structural superimposition. (B) Mapping of the epitopes of the four superimposed antibodies on the SARS-CoV-2 RBD surface. Epitope residues conserved between SARS-CoV-1 and -2 RBDs are shown in color corresponding to the respective antibody, and residue differences are shown in red. Note that the residue differences are depicted as residue numbers in the SARS-CoV-2 RBD. For example, K in position 444 in SARS-CoV-2 RBD is T in SARS-CoV-1 RBD, and is shown as K444T in the binding epitope of S309.

Figure 3

Mutations on SARS-CoV-2 Spike Protein and Effects on Neutralizing Antibodies. (A) Selected mutations of SARS-CoV-2 S protein observed in the current pandemic are highlighted. The S protein in the 'up' conformation is shown in ribbons. The enriched mutations are shown as spheres and are colored in cyan (S1 domain), red (RBD), and purple (S2). The non-enriched mutations in the RBD are shown in magenta. (B) Binding epitopes of SARS-CoV-2 RBD for antibodies B38 (PDB 7BZ5), S309 (PDB 6WPT), CR3022 (PDB 6W41), and VHH-72 (based on the superimposed structure of SARS-CoV-1, PDB 6WAQ) are shown where the residues depicted in stick representation (grey and magenta) are proposed to be involved in contacts between the RBD and the antibodies. Magenta sticks represent non-enriched mutations that have been sporadically detected in publicly available databases. Abbreviations: NTD, N-terminal domain; RBD, receptor-binding domain; S1 and S2, subunits.

Figure 4

Antibody-Dependent Enhancement (ADE) Observed with Poorly Neutralizing Antibodies. ADE is induced by low-affinity, low-quantity, poorly neutralizing antibodies against SARS-CoV-2. In the process, poorly neutralizing antibodies interact with SARS-CoV-2 and also with the Fc receptors (FcRs) of macrophages/monocytes. The antibody–virus complexes are internalized into the cells and eventually lead to increased production of proinflammatory cytokines, reduction of anti-inflammatory cytokines, and increased viral load. Figure generated with Biorender (https://biorender.com/).