Broad and potent neutralizing activity of human IgG1 LALA antibody against SARS-CoV-2 variants

The rapid outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has resulted in the coronavirus disease 2019 (COVID-19) pandemic. This pandemic has massively affected the healthcare system and economy globally. Scientists and policymakers have formulated many pharmaceutical and non-pharmaceutical strategies to contain the pandemic.

Study: Discovery of a SARS-CoV-2 Broadly-Acting Neutralizing Antibody with Activity against Omicron and Omicron + R346K Variants. Image Credit: Tatiana Shepeleva/Shutterstock

Background

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, SARS-CoV-2 has evolved due to mutations in the viral genome. Several SARS-CoV-2 variants have been classified as variants of concern (VOC) and variants of interest (VOI) by the World Health Organization, in accordance to their virulence, transmissibility, and ability to evade the anti-SARS-CoV-2 neutralizing antibodies (nAbs) induced via vaccination or natural infection.

Scientists have characterized the newly emerged Omicron VOC (B.1.1.529) that has become the dominant variant in many countries worldwide. In vitro studies associated with the Omicron variant using Vero cells, expressing human ACE2 and human TMPRSS2 for susceptibility to nAbs were performed. It was revealed that the Omicron strain is resistant to nAbs currently authorized or approved for clinical use (AFCU nAbs). AFCU nAbs include REGN10987 (imdevimab), LY-CoV555 (bamlanivimab), REGN10933 (casirivimab), and several other approved nAbs.

Recent studies have reported the emergence of a subset of Omicron viruses that contains an additional mutation in the spike protein at the R346K position in the receptor-binding domain (RBD). Previous studies have reported the presence of R346K mutation in SARS-CoV-2 Mu VOC. Scientists reported a decreased neutralization potency of Omicron+ R346K strain for all tested AFCU nAbs.

Previous studies that performed Omicron pseudotype neutralization assays revealed that the two of the antibodies in development, bebtelovimab, and BRII-198 (romlusevimab), were effective against the Omicron variant. BRII-198 exhibited a significantly decreased neutralizing activity against Omicron + R346K pseudoviruses.

However, not much evidence is available regarding the efficacy of bebtelovimab against Omicron + R346K pseudoviruses. The Omicron subvariant constitutes 23% of sequences submitted to GISAID. Therefore, there is an urgent need to develop effective nAbs that could protect individuals from SARS-CoV-2 VOCs.

An early COVID-19 treatment showed intravenous (IV) administration of nAbs is an effective way to treat severely infected COVID-19 patients. However, later scientists reported that another mode of delivery, i.e., intranasal (IN) delivery, could be more efficient for respiratory infection.

A new study

Researchers have shown that the production of human antibodies in transgenic animals has several advantages, such as enhanced diversity and clonal selection for antibody optimization. This enables the development of highly reactive and effective antibody therapeutics.

A new study published on the bioRxiv* preprint server has focused on the identification, in vitro binding, and potent neutralizing activity of STI-9167 (plutavimab) against live viruses and pseudotype viruses.

Scientists determined the efficacy of STI-9167 against several SARS-CoV-2 variants, including the Omicron and Omicron+ R346K variant. The K18ACE2 transgenic mouse model of COVID-19 disease helped determine the effect of STI-9167 when introduced via IN or IV. The studied mice were infected either with the original SARS-CoV-2, the Delta, or the Omicron strain.

The authors identified a pool of antibodies following immunization of mice with SARS-CoV-2 RBD protein obtained from the original SARS-CoV-2 strain. The antibody binding analysis and virus neutralization assays revealed that STI-9167 is effective against the SARS-CoV-2 original strain and several VOCs, including Delta, Omicron, and the Omicron+ R346K subvariant. The authors used virus pseudotypes to determine the STI-9167 activity against the Omicron +R346K subvariant. They also reported an excellent neutralizing ability of STI-9167 against the Mu variant. 

A previous study by the same group of researchers reported that nAb STI-2020, when administered via IN, showed higher efficacy in the SARS-CoV-2 preclinical models of pathogenesis. In this study, researchers reported that STI-9167 is effective in both delivery modes, i.e., IN and IV routes. 

The findings of this study are in line with previous studies, which revealed that the amount of virus replication found in the lungs following Omicron infection was reduced compared to the original SARS-CoV-2 variant and the Delta variant. Scientists reported that IN treatment with STI-9167, at a dose level of 5 mg/kg, in K18 ACE2 transgenic mice showed that the treated mice were protected 12 hours following the treatment. They measured the effectiveness of the treatment by comparing the weight loss and viral load in the treated and the control group of mice.

Conclusion

The authors reported that the phase 1 clinical studies associated with administering liquid drops of STI-2099 in the upper airways reported it to be safe. A phase 2 study has been completed in the US, and two other Phase 2 studies, are being conducted in Mexico and the United Kingdom. Encouraged by promising results, the cGMP drug product has been prepared to analyze its efficacy and safety in human clinical trials.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.