In a recent study posted to the bioRxiv* preprint server, researchers reported a new monoclonal antibody (mAb), P2G3, which significantly neutralized the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant.
Background
The coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2, to date, has been responsible for more than 470 million infections and over six million deaths globally. SARS-CoV-2’s uncontrolled spread has resulted from the emergence of several variants of concern (VOC) with increased transmission and resilience to host immune responses.
The SARS-CoV-2 B.1.1.529.1 (Omicron) VOC which emerged in late 2021 has a high rate of transmission, significant resistance to approved clinical human mAbs, and low sensitivity towards vaccine-elicited immunity. Further, Omicron has replaced the previously worldwide dominant SARS-CoV-2 Delta VOC. All of this might be due to the presence of more than 15 additional mutations in the receptor-binding domain (RBD) of the Omicron variant compared to existing VOCs. This scenario urges the need for rapid development of therapeutic and preventative modalities against COVID-19.
About the study
In the current study, the researchers investigated the presence of anti-SARS-CoV-2 spike (S) antibodies in serum samples of over 100 donors. The team concentrated solely on a single SARS-CoV-2-infected individual who received two shots of the COVID-19 messenger ribonucleic acid (mRNA)-1273 vaccine and had the greatest serum antibody levels with outstanding breadth against a screen of SARS-CoV-2 variants in a trimeric S-angiotensin-converting enzyme 2 (ACE2) surrogate neutralization evaluation.
Supernatants of B cell clones were evaluated for high-affinity S binding molecules. This led to the selection of six clones for mAb synthesis using paired light and heavy chains in ExpiCHO cells [non-engineered subclone screened and isolated from Chinese hamster ovary (CHO)-S cells]. The six purified mAbs were then profiled. Cross-competitive SARS-CoV-2 S RBD binding investigations were performed employing a panel of clinically authorized anti-SARS-CoV-2 mAbs (REGN10987 and REGN10933 of Regeneron, AZD1061, and AZD8895 of AstraZeneca, Adagio’s ADG-2, and sotrovimab (S309) of Vir/GSK) and mAbs discovered earlier by the authors.
Blood mononuclear cells and serum samples used in the present study were collected from the participants of ImmunoVax and ImmunoCov studies conducted by the Immunology and Allergy Service, Lausanne University Hospital, Switzerland. The SARS-CoV-2 VOCs evaluated in the present work included initial SARS-CoV-2 D614G strain and Gamma, Beta, Delta, Omicron, and Alpha VOCs.
Results
The results indicated that the human mAb, P2G3, derived from COVID-19 convalescent and vaccinated individuals exhibited high efficiency in neutralizing SARS-CoV-2 VOCs. P2G3 had picomolar-range neutralizing activity against SARS-CoV-2 Omicron BA.2, BA.1.1, BA.1, and all other existing variants. Thus, P2G3 was significantly more potent than all the currently approved anti-COVID-19 mAbs. P2G3 fragment antigen-binding (Fab) combined with the Omicron S has unique binding characteristics towards both up and down spike trimer conformations in an epitope that partly coincides with the RBD but was different from those bound with every other known mAbs.
Due to its unique angle of attack and epitope, P2G3 was able to surmount all the Omicron mutations that prevent other anti-SARS-COV-2 mAbs from neutralizing them. As a result, P2G3 offered complete prophylactic immunity in the monkey model challenged with SARS-CoV-2 Omicron.
At last, while the team was able to separate the SARS-CoV2 mutants that were resistant to neutralization by P2G3 or P5C3 in vitro, priorly outlined widely active Class 3 and 1 mAbs, respectively, they discovered that these viruses were poorly infectious in the wild and that their key mutations were exceedingly rare. The scientists were able to show that P2G3 and P5C3 proficiently cross-neutralized each other’s escapes. Thus, the authors state that this cocktail of mAbs has considerable potential to safeguard against Omicron and other SARS-CoV-2 VOCs in both therapeutic and prophylactic contexts.
Conclusions
The study findings demonstrated the discovery of an anti-SARS-CoV-2 mAb named P2G3 (belongs to Class 3 mAbs) exhibiting exceptional potency and breadth for neutralization of all SARS-CoV-2 VOCs, such as the novel Omicron BA.2 and BA.1 variants. The authors proposed passive immunization using the P5C3 and P2G3 mAbs with prolonged half-lives via two or three injections each year. They may concurrently adhere to highly conserved and unique epitopes on the SARS-CoV-2 S as a very appealing COVID-19 prophylactic approach for immunocompromised patients.
The extensively active P5C3 and P2G3 mAbs’ combination has the prospects to be a superlative anti-COVID-19 mAb cocktail for therapeutic and prophylactic interventions against all prevailing SARS-CoV-2 VOCs following efficient development and licensing. This was due to their crystallizable fragment (Fc)-triggered functional activity, potent neutralization, and proven in vivo protection. Moreover, the P5C3 and P2G3 mAbs cocktail’s breadth of action implies that they may be able to neutralize several SARS-CoV-2 VOCs that are yet to emerge.
*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.
