Week 2, March 2025: Neutralizing SARS-CoV-2, 6 Years On: Evolving Strategies and Insights

Six years after the emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), the landscape of viral neutralization has shifted significantly. Advances in antibody therapeutics, vaccine development, and immune response understanding have reshaped our approach to combating COVID-19 and its evolving variants. As researchers continue to refine strategies for long-term protection and pandemic preparedness, key questions remain: How effective are current neutralizing antibodies against new strains? 

Last week, a study led by researchers from Stanford University introduced bispecific antibodies (bsAbs) that target both the RBD and a conserved region in the amino-terminal domain (NTD) of the SARS-CoV-2 spike protein. By integrating these two specificities into a single antibody, they developed a promising therapeutic candidate capable of neutralizing a broad range of SARS-CoV-2 variants in vitro. One of these bsAbs, CoV2-biRN5, demonstrated protective effects in a mouse model when administered prophylactically, reducing viral loads post-infection. This underscores the potential of NTD-RBD bispecific antibodies as resilient next-generation therapeutics against evolving SARS-CoV-2 variants. 

Another recent article describes a broadly neutralizing antibody against the SARS-CoV-2 Omicron sub-variants BA.1, BA.2, BA.2.12.1, BA.4, and BA.5! The global spread of SARS-CoV-2 and its variant strains, including Alpha, Beta, Gamma, Delta, and now Omicron, pose a significant challenge. With the constant evolution of the virus, Omicron and its subtypes BA.1, BA.2, BA.3, BA.4, and BA.5 have developed the capacity to evade neutralization induced by previous vaccination or infection. This evasion highlights the urgency in discovering new monoclonal antibodies (mAbs) with neutralizing activity, especially broadly neutralizing antibodies (bnAbs), to combat the virus. In this study, researchers introduced a fully human neutralizing mAb, CR9, that targets Omicron variants. Structural analysis using cryo-electron microscopy (cryo-EM) revealed that CR9 binds to an epitope formed by RBD residues. With its strong potency and specificity, CR9 presents a promising therapeutic option for Omicron infections, emphasizing the ongoing necessity of monoclonal antibody discovery to combat COVID-19.

In the bioinformatics space last week, researchers from ETH Zurich published a paper in Nature about the discovery of deep mutational learning for the selection of therapeutic antibodies resistant to the evolution of Omicron variants of SARS-CoV-2. By constructing a diverse library of full-length Omicron BA.1 receptor-binding domains (RBDs) and screening for ACE2 and antibody binding, they trained ensemble deep-learning models to predict antibody binding and viral escape. This approach enabled the identification of optimal antibody combinations with complementary resistance to viral mutations. Using deep learning to analyze a vast sequence landscape, researchers demonstrated a method for selecting therapeutic antibodies that remain effective against current and future SARS-CoV-2 variants, offering a powerful strategy for long-term COVID-19 treatment.

Further along in drug development is the Phase 1 study evaluating the safety, tolerability, and pharmacokinetics of IN-006, a nebulized reformulation of regdanvimab, as an alternative to systemic antibody delivery for COVID-19. IN-006 is an inhaled antibody treatment for COVID-19. Regdanvimab, an IV-dosed human IgG1 mAb directed against the SARS-COV-2 spike protein receptor binding domain (RBD), was approved in the European Union for adults with COVID-19 who did not require supplemental oxygen and who were at increased risk of progression to severe COVID-19. From results published last month, the trial assessed single and multiple inhaled doses, with no serious adverse events reported. IN-006 achieved high nasal fluid concentrations, significantly exceeding the typical IC50 range for antiviral monoclonal antibodies, while serum levels remained low. These findings support further development of inhaled antibody therapies as a targeted and convenient approach for respiratory infections.