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The SARS-CoV-2 pandemic continues to affect lives around the globe. With no treatments currently available for COVID-19, vaccine and drug development are a priority. Many researchers are pursuing neutralizing antibodies to SARS-CoV-2 that would function to prevent the binding of the virus to its target cell receptors, leading to aggregation of virus particles and subsequent degradation of the virus through antibody-mediated immunomodulatory effects or complement activation.
Two recent articles published in Science have reported on the crystal structure of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein 1,2.
In the first publication, Wrapp et al. found that the binding affinity of the SARS-CoV-2 RBD to ACE2 is 10–20 times greater than the binding affinity of the earlier identified coronavirus, SARS-CoV. However, when neutralizing antibodies for the SARS-CoV RBD (clones S230, m396 and 80R) were tested against the new SARS-CoV-2 RBD, they showed no interaction.
In the second Science publication, Yuan et al. identified the crystal structure of the SARS-CoV-2 RBD 2. In this study, they used a combination of biolayer interferometry (BLI)and ELISA to show that a different SARS-CoV neutralizing antibody, the CR3022 clone, binds to the SARS-CoV-2 RBD, though with reduced affinity compared with the SARS-CoV RBD (KD 115±3 nM and < 0.1 nM for the SARS-CoV-2 and SARS-CoV RBD respectively) 2. This interaction of the CR3022 antibody with the SARS-CoV-2 spike protein was confirmed in a further report that stated that the RBD domain of the SARS-CoV-2 spike protein shows a higher affinity for the CR3022 clone than for the host receptor human ACE2 (KD=6.3 nM for CR3022 vs 15.2 nM for ACE2) 3. Other SARS-CoV neutralizing antibodies tested in this study (m396 and CR3014) showed limited affinity for the RBD domain of SARS-CoV-2.
Both the SARS-CoV-2 spike protein crystal structure and BLI studies suggest that the epitope of the CR3022 SARS-CoV-2 spike protein antibody does not overlap with the RBD-ACE2 binding site 1-3.
The RBD of the homotrimeric SARS-CoV-2 spike protein switches between ‘up’ and ‘down’ conformations like a hinge. ACE2 can only interact with the RBD when it is in the ‘up’ conformation. Similarly, the CR3022 antibody can only bind to the SARS-CoV-2 RBD when it is present in the ‘up’ conformation and requires that at least two of the spike protein subunits are in this conformation and slightly rotated to overcome steric hindrance at the antibody epitope 2. This conformational change in the SARS-CoV-2 spike protein may be physiologically significant as the CR3022 antibody can neutralize SARS-CoV, but did not neutralize SARS-CoV-2 in vitro at the highest tested dose in this study (400 µg/mL).
Recent analysis of the RBD of the spike protein in SARS-CoV-2 identified it as immunodominant and unique among known human and animal coronaviruses 4. Consequently, antibodies to this domain are likely to be highly specific to SARS-CoV-2, and could offer the basis for new COVID-19 antibody tests, revealing if an individual has been exposed to the virus.
Neutralizing therapies could be given to those exposed to the virus, such as a health and social-care workers, to prevent infection, as well as to patients already infected by the virus, to help treat and prevent disease progression. Although the study from Wrapp et al. reported that the CR3022 antibody did not neutralize the SARS-CoV-2 virus in vitro 1, it cannot be ruled out that CR3022 may protect against SARS-CoV-2 in vivo. Previous studies have seen comparable results for influzena A virus in which the viral HA protein shows a similar change in 'up' and 'down' conformations as the SARS-CoV-2 spike protein 5-7. Antibodies targeting influenza A virus HA on the surface of the trimer show no neutralizing effect in vitro, but are able to protect individuals against the attack of influenza A virus in vivo 8. Similarly, antibodies that do not neutralize in vitro but have protective effects in vivo have been observed for the herpes simplex virus 9, cytomegalovirus 10, alphavirus 11, and dengue virus 12. Further verification of the neutralizing capacity of the CR3022 SARS-CoV-2 spike protein antibody in animal models is required to fully understand the potential of this antibody in COVID-19.
Some have reported on the therapeutic potential of the CR3022 antibody to function in combination with a second antibody for the SARS-CoV-2 RBD, CR3014, which targets a different epitope on the RBD and overlaps with ACE2 binding 3, 13. Earlier research showed that in combination these antibodies could effectively control the immune escape caused by SARS-CoV to increase the host's resistance to attack from a range of mutant viral strains 13, suggesting such effects may also be seen with SARS-CoV-2.
Despite its unique binding mechanism to the SARS-CoV-2 spike protein and lack of overlap with the ACE-RBD, the CR3022 antibody for the SARS-CoV-2 spike protein may still effectively neutralize SARS-CoV-2 in vivo, or could be used as part of a neutralizing antibody combination for the treatment of COVID-19.
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