Targeting SARS-CoV-2 Through Innovation

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Highlights:

• Interest in re-purposing neutralizing antibodies for therapeutic use against related viruses has been widely promoted by SARS-CoV-2
• An innovative research has focused on modifying a SARS-CoV-1 antibody for potent SARS-CoV-2 neutralization
• This offers hope for broader antibody discovery against similar viruses

Emergence of SARS-CoV-2 has sparked interest in repurposing neutralizing antibodies for potential therapeutics against related viruses, thereby offering promising insights for broader antibody discovery (1^✔).

Initial repurposing endeavors assessed monoclonal antibodies (mAbs) from 2003 SARS-CoV-1 and 2008 MERS survivors against SARS-CoV-2 (2^✔); however, none proved effective in efficiently neutralizing the virus.

‘Rise of SARS-CoV-2 has driven exploration into innovative approaches that hold promise for antibody discovery against diverse viruses.�#COVID-19, #SARS-CoV-2, #antibody’

Simultaneously, various teams extracted antibodies from humans infected with SARS-CoV-2 or animals vaccinated with SARS-CoV-2 spike (S) proteins (3^✔,4^✔).

Neutralizing Antibodies Repurposed for Viral Therapy

"The emergence of SARS-CoV-2 stimulated interest in repurposing neutralizing antibodies against related viruses for therapeutics. Zhao et al. used a rapid, affinity-maturation strategy to generate mutations within a neutralizing monoclonal antibody against SARS-CoV-1 isolated from a convalescent donor. The engineered antibodies were displayed on the surface of yeast, and clones with increased affinity for the SARS-CoV-2 S protein were isolated and characterized. A candidate engineered antibody blocked SARS-CoV-2 infection of cells in vitro and prophylactically protected hamsters from viral challenge, highlighting the potential of this approach for antibody discovery for other viruses," summarized the editor John F. Foley.

This study employs hybrid "refocusing" to engineer existing antibodies like CR3022, originally neutralizing SARS-CoV-1, for related virus targeting (1^✔).

SARS-CoV-1 Antibody Tailored!

By utilizing synthetic antibody maturation known as synthetic antibody maturation by multiple point loop library enrichments (SAMPLER), the team enhanced CR3022, a SARS-CoV-1-neutralizing antibody isolated in 2006 from a convalescent donor (1^✔).

Engineered CR3022 demonstrated SARS-CoV-2 neutralization and safeguarded against infection in a small animal model. Moreover, comprehensive sequencing and crystallographic analysis unveiled how the antibody adapts to sequence variations between SARS-CoV-1 and SARS-CoV-2 during the engineering process (1^✔).

Directed Evolution's Promise For Viral Defence

The study demonstrated the potential of antibody refocusing to generate potent neutralizing antibodies against new viruses or variants, leveraging closely related virus nAbs (1^✔).

By reengineering the SARS-CoV-1 nAb CR3022, the team achieved >1000-fold stronger affinity for the receptor binding domain (RBD) of SARS-CoV-2, leading to potent SARS-CoV-2 neutralization. Also, the protective effects in a small animal model, surpassing its neutralization of SARS-CoV-1 were evidenced by the study (1^✔).

Since affinity engineering takes under a month and doesn't rely on donor samples or structural information, this method complements traditional antibody discovery for swift response to pandemics (1^✔).

Thus, this workflow offers a blueprint to swiftly expand antibody neutralization across related yet resistant viruses.

References:

1. Broadening a SARS-CoV-1-neutralizing antibody for potent SARS-CoV-2 neutralization through directed evolution - (https:pubmed.ncbi.nlm.nih.gov/37582161/)
2. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody - (https:pubmed.ncbi.nlm.nih.gov/32065055/)
3. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model - (https:pubmed.ncbi.nlm.nih.gov/32540903/)
4. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody - (https:pubmed.ncbi.nlm.nih.gov/32422645/)

Source: Medindia

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