Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies
An antibody cocktail against SARS-CoV-2
Abstract
Anti-SARS-CoV-2 spike monoclonal antibodies | ||||||||
---|---|---|---|---|---|---|---|---|
Variants | REGN10989 | REGN10987 | REGN10933 | REGN10934 | REGN10964 | REGN10954 | REGN10984 | REGN10986 |
Wild-type | 7.23 × 10–12 | 4.06 × 10–11 | 4.28 × 10–11 | 5.44 × 10–11 | 5.70 × 10–11 | 9.22 × 10–11 | 9.73 × 10–11 | 9.91 × 10–11 |
Q321L | 1.46 × 10–11 | 5.02 × 10–11 | 6.85 × 10–11 | 6.84 × 10–11 | 5.65 × 10–11 | 2.32 × 10–10 | 2.75 × 10–10 | 2.06 × 10–10 |
V341I | 1.61 × 10–11 | 3.38 × 10–11 | 3.37 × 10–11 | 7.42 × 10–11 | 1.13 × 10–10 | 2.52 × 10–10 | 2.49 × 10–10 | 1.92 × 10–10 |
A348T | 7.33 × 10–12 | 2.98 × 10–11 | 4.13 × 10–11 | 1.42 × 10–10 | 3.52 × 10–11 | 1.84 × 10–10 | 2.01 × 10–10 | 1.03 × 10–10 |
N354D | 1.14 × 10–11 | 2.68 × 10–11 | 5.89 × 10–11 | 9.76 × 10–11 | 1.93 × 10–10 | 2.84 × 10–10 | 2.64 × 10–10 | 2.49 × 10–10 |
S359N | 4.30 × 10–12 | 2.41 × 10–11 | 2.12 × 10–11 | 3.04 × 10–11 | 6.83 × 10–11 | 1.09 × 10–10 | 1.23 × 10–10 | 8.91 × 10–11 |
V367F | 1.33 × 10–11 | 1.78 × 10–11 | 2.40 × 10–11 | 3.20 × 10–11 | 8.92 × 10–11 | 1.29 × 10–10 | 1.53 × 10–10 | 1.49 × 10–10 |
K378R | 1.21 × 10–11 | 2.40 × 10–11 | 3.52 × 10–11 | 4.65 × 10–11 | 6.19 × 10–11 | 1.65 × 10–10 | 1.88 × 10–10 | 1.54 × 10–10 |
R408I | 1.09 × 10–11 | 1.71 × 10–11 | 1.98 × 10–11 | 2.75 × 10–11 | 4.96 × 10–11 | 9.88 × 10–11 | 1.35 × 10–10 | 6.14 × 10–11 |
Q409E | 2.12 × 10–11 | 4.06 × 10–11 | 5.65 × 10–11 | 5.94 × 10–11 | 6.61 × 10–11 | 2.64 × 10–10 | 1.52 × 10–10 | 1.95 × 10–10 |
A435S | 1.10 × 10–11 | 3.88 × 10–11 | 4.71 × 10–11 | 8.07 × 10–11 | 7.90 × 10–11 | 2.11 × 10–10 | 2.18 × 10–10 | 1.51 × 10–10 |
K458R | 7.51 × 10–12 | 1.68 × 10–11 | 3.43 × 10–11 | 3.46 × 10–11 | 5.46 × 10–11 | 1.45 × 10–10 | 1.59 × 10–10 | 1.00 × 10–10 |
I472V | 2.27 × 10–11 | 4.18 × 10–11 | 9.17 × 10–11 | 9.40 × 10–11 | 1.01 × 10–10 | 3.44 × 10–10 | 2.61 × 10–10 | 2.24 × 10–10 |
G476S | 6.80 × 10–12 | 1.86 × 10–11 | 1.41 × 10–10 | 3.51 × 10–11 | 3.42 × 10–11 | 1.83 × 10–10 | 2.10 × 10–10 | 1.13 × 10–10 |
V483A | 8.78 × 10–12 | 2.60 × 10–11 | 1.54 × 10–11 | 4.43 × 10–11 | 4.50 × 10–11 | 1.12 × 10–10 | 1.71 × 10–10 | 9.70 × 10–11 |
Y508H | 1.71 × 10–11 | 2.75 × 10–11 | 4.77 × 10–11 | 6.73 × 10–11 | 1.02 × 10–10 | 2.05 × 10–10 | 2.83 × 10–10 | 2.01 × 10–10 |
H519P | 4.51 × 10–12 | 2.20 × 10–11 | 3.03 × 10–11 | 3.56 × 10–11 | 4.45 × 10–11 | 1.40 × 10–10 | 1.08 × 10–10 | 6.14 × 10–11 |
Anti-SARS-CoV-2 spike monoclonal antibodies | |||||||
---|---|---|---|---|---|---|---|
Escape mutants | REGN10989 | REGN10987 | REGN10933 | REGN10934 | REGN10933/10987 | REGN10989/10934 | REGN10989/10987 |
Wild-type | 7.27 × 10–12 | 3.65 × 10–11 | 5.57 × 10–11 | 5.99 × 10–11 | 3.28 × 10–11 | 8.27 × 10–12 | 1.22 × 10–11 |
K417E | 2.49 × 10–11 | 3.10 × 10–11 | 8.33 × 10–9 | 2.70 × 10–11 | 4.15 × 10–11 | 2.64 × 10–11 | 2.72 × 10–11 |
K444Q | 2.47 × 10–11 | NC | 7.81 × 10–11 | 5.38 × 10–9 | 1.23 × 10–10 | 4.19 × 10–11 | 4.82 × 10–11 |
V445A | 2.65 × 10–11 | NC | 8.82 × 10–11 | 1.42 × 10–10 | 1.54 × 10–10 | 4.08 × 10–11 | 5.74 × 10–11 |
N450D | 4.10 × 10–11 | 1.20 × 10–9 | 7.60 × 10–11 | NC | 1.88 × 10–10 | 6.04 × 10–11 | 5.37 × 10–11 |
Y453F | 2.77 × 10–11 | 1.04 × 10–10 | NC | 2.17 × 10–10 | 1.15 × 10–10 | 3.52 × 10–11 | 2.41 × 10–11 |
L455F | 1.77 × 10–11 | 3.87 × 10–11 | NC | 4.34 × 10–11 | 5.87 × 10–11 | 1.96 × 10–11 | 1.70 × 10–11 |
E484K | NC | 6.25 × 10–11 | 1.13 × 10–9 | NC | 6.19 × 10–11 | NC | 1.88 × 10–10 |
G485D | NC | 2.34 × 10–11 | 2.05 × 10–10 | 4.47 × 10–11 | 4.71 × 10–11 | 1.19 × 10–10 | 4.58 × 10–11 |
F486V | NC | 3.16 × 10–11 | NC | 3.50 × 10–11 | 8.8 × 10–11 | 1.29 × 10–10 | 6.96 × 10–11 |
F490L | 3.10 × 10–9 | 3.56 × 10–11 | 4.53 × 10–11 | 1.94 × 10–9 | 3.64 × 10–11 | 2.50 × 10–9 | 8.37 × 10–11 |
F490S | 2.23 × 10–10 | 4.42 × 10–11 | 6.63 × 10–11 | 8.91 × 10–9 | 3.4 × 10–11 | 4.2 × 10–10 | 6.58 × 10–11 |
Q493K | NC | 4.19 × 10–11 | NC | 3.45 × 10–10 | 3.24 × 10–11 | 4.55 × 10–10 | 5.94 × 10–11 |
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RE: Two or more anti-SARS-CoV-2 spike RBD antibody combination can restrict the generation of neutralization-evade mutants
To The Editor:
The scarcity of individualized molecular therapy for patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a high mortality rate for 2019 coronavirus disease (COVID-19) (1). Rapid mutational escape was found after the treatment of neutralizing monoclonal antibody (mAb) targeting SARS-CoV-2 spike receptor-binding domain (RBD). Two or more anti-SARS-CoV-2 spike RBD antibody combination can strengthen SARS-CoV-2 neutralization and may limit the generation of neutralization-evade mutants (2).
Yuan and colleague (3) first described CR3022 mAb, a neutralizing antibody previously isolated from a convalescent severe acute respiratory syndrome (SARS) patient, in complex with the RBD of the SARS-CoV-2 spike protein (3). Recent studies have demonstrated that the cross-reactive antibody CR3022 mAb has relatively strong binding capacity to SARS-CoV-2. CR3022 targets highly conserved cryptic epitope residues in RBD, which enables cross-reactive binding between SARS-CoV-2 and SARS-CoV RBD. A crucial finding is that the antibody binding sites between the two coronaviruses are highly analogous, with a distinction of only four amino acids in their structure. This high degree of similarity suggests that the site in RBD has an essential function that can be lost if the site undergoes major alterations. The fact that the binding site is highly conserved between SARS-CoV and SARS-CoV-2 also stipulates that antibodies that may be yet to be discovered can effectively neutralize these two viruses, and in the same way, may be able to disrupt a pandemic in the future (3).
Pinto and colleague (4) reported another neutralizing antibody, S309 mAb, isolated from a convalescent SARS patient; this antibody bound the conserved area of RBD of SARS-CoV and SARS-CoV-2. Importantly, the data showed that S309 could invalidate potentially all SARS-CoV-2 isolates known to be circulating to date. Furthermore, S309 mAb showed expansion neutralization in combination with other weakly neutralizing mAbs, which may decrease the risk of viral escape (4).
Baum and colleague (2) first reported an important finding that single neutralizing antibody induced escape mutants and antibody cocktail could prevent the rapid escape mutant. The authors reported that four individual neutralizing antibodies can cause multiple escape mutants; however, two neutralizing antibodies binding to distinct and non-overlapping regions of SARS-CoV-2 RBD avoided the escape mutant. However, no clinical trials have yet been reported. Nonetheless, SARS-CoV-2 neutralizing antibody cocktail therapy might be favorable to prevent future pandemics.
References
1. N. Vabre et al., Immunology of COVID-19: current state of the science. Immunity 52, 910–941 (2020).
2. A. Baum et al., Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 10.1126/science.abd0831 (2020).
3. M. Yuan et al., A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science 368, 630–633 (2020).
4. D. Pinto et al., Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 583, 290–295 (2020).