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2020-05-23| COVID-19

An Old SARS Antibody May Well be Our Weapon against COVID-19

by Sahana Shankar
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By Sahana Shankar, Ph.D. Candidate

Scientists from Humabs Biomed and the University of Washington, Seattle, demonstrate that monoclonal antibody from a SARS survivor can effectively neutralize the SARS-CoV-2 virus. The antibody is now under testing and development at Vir Biotechnology.

In the face of the current global healthcare crisis, accelerated research into a potential vaccine for COVID-19 has seen the emergence of many monoclonal antibodies (mAbs), which could potentially prevent the entry of the SARS-CoV-2 virus by blocking its S protein from binding to the ACE2 receptor. Previous work into coronaviruses and more recent characterization of the SARS-CoV-2 virus has established that the viruses of the subgenus sarbecovirus enter the host cells via binding of the homotrimeric spike (S) glycoprotein on the viral surface to host cell receptor.

 

Similarities Between SARS and COVID-19

Early sequence alignment showed that SARS-CoV-2 is similar to the SARS-causing virus SARS-CoV and binds to the same host cell receptor at the same receptor – ACE2 (Angiotensin-Converting Enzyme 2) to gain entry into the host. Their spike glycoprotein is 97.2% identical, suggesting their mode of infection would be similar too. Following this train of thought, researchers from Humabs Biomed SA, Switzerland, and the University of Washington, Seattle isolated memory B cells of individuals who recovered from the SARS infection in 2003 to test for antibodies that could neutralize the SARS-CoV-2 virus.

In the current study, the team analyzed multiple mAbs isolated from the peripheral blood of a SARS-CoV survivor to characterize them for effective binding with SARS-CoV and SARS-CoV-2 S protein. They further confirmed that the binding was specific to the sarbecovirus subgenus and highly sensitive to the SARS-CoV and SARS-CoV-2 receptor binding domains, indicating there is no cross-reactivity with other viruses.

 

S309 – A 17-Year-Old Antibody

One mAb, the S309 IgG, was able to bind to immobilized SARS-CoV-2 S domain at subpicomolar affinity and was a likely candidate to test for antiviral activity. To further elucidate the mechanism of S309 binding to SARS-CoV-2, the authors studied the Fab fragment’s crystal structure at 3.3 Å and cryoEM reconstruction of the S309 bound to the SARS-CoV-2 S ectodomain trimer. CryoEM analysis revealed that the S ectodomain trimer exists in open and closed states, and the S309 mAb could be docked into the closed conformation. The structural data explained why the mAb could recognize both SARS-CoV and SARS-CoV-2 S domains since 17 of the 22 residues of the mAb-binding epitope are strictly conserved. The mAb did not hinder binding of the S domain with the host receptor since the epitope is distinct from the receptor-binding motif and accessible both in the open and closed S domain conformations.

To test for the antiviral activity of the S309 mAb, the investigators used both the S309 Fab fragment and S309 IgG. Both demonstrated similar potencies at IC50 values. S309 IgG could neutralize the virus 100% and the Fab 80% suggesting that the Fc fragment is important for some of the downstream effector mechanisms in the host cell. Fc is known for eliciting Antibody-dependent cell cytotoxicity (ADCC) driven by the NK (Natural Killer) cells. The S309 IgG initiated the ADCC of SARS-CoV-2 transfected cells expressing the FcRIIIa receptors, indicating that the Fc fragment of S309 is what confers it the specificity and robust immune response in host cells and it could be engineered to enhance antiviral activity.

Based on the panel of mAbs used in the study, the authors mapped the antigenic sites on the SARS-CoV and SARS-CoV-2 S domains based on their binding with different mAbs and identified 4 sites. One of them was within the receptor-binding domain and targeted by 3 different mAbs. The other three were targeted by 6 other mAbs. Since these mAbs have low cross-reactivity, a mAb cocktail could enhance SARS-CoV-2 neutralization. The data indeed showed a synergistic effect of S309 coupled with either S304 or S315. S304 bound to 2 sites on the S domain and S315 targeted a single site. They were weakly immunizing in isolation but were very potent in combination with S306.

This study, published in the journal Nature, is a proof-of-concept for mAb cocktails to treat COVID-19, providing a blueprint for robust vaccine design. California-based Vir Biotechnology is currently developing the S309 antibody and fast-tracking it towards clinical evaluations. Its two promising antibody candidates, VIR-7831 and VIR-7832, are based on S309. Immediately after the publication of this study, Vir’s shares rocketed to US$ 40.1 per share from its previous closing price of US$ 30.35 on May 15th.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: COVID-19: Moderna Registers Positive Phase 1 Results for mRNA Vaccine

References
  1. https://www.nature.com/articles/s41586-020-2349-y
  2. https://newsroom.uw.edu/news/antibody-neutralizes-sars-and-covid-19-coronaviruses
  3. https://investors.vir.bio/news-releases/news-release-details/identification-and-characterization-potential-therapeutic-covid

 

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