A broadly neutralizing monoclonal antibody overcomes the mutational landscape of emerging SARS-CoV-2 variants of concern

Abstract

The emergence of new variants of SARS-CoV-2 necessitates unremitting efforts to discover novel therapeutic monoclonal antibodies (mAbs). Here, we report an extremely potent mAb named P4A2 that can neutralize all the circulating variants of concern (VOCs) with high efficiency, including the highly transmissible Omicron. The crystal structure of the P4A2 Fab:RBD complex revealed that the residues of the RBD that interact with P4A2 are a part of the ACE2-receptor-binding motif and are not mutated in any of the VOCs. The pan coronavirus pseudotyped neutralization assay confirmed that the P4A2 mAb is specific for SARS-CoV-2 and its VOCs. Passive administration of P4A2 to K18-hACE2 transgenic mice conferred protection, both prophylactically and therapeutically, against challenge with VOCs. Overall, our data shows that, the P4A2 mAb has immense therapeutic potential to neutralize the current circulating VOCs. Due to the overlap between the P4A2 epitope and ACE2 binding site on Spike-RBD, P4A2 may also be highly effective against a number of future variants.

Pharmacological potential of Withania somnifera (L.) Dunal and Tinospora cordifolia (Willd.) Miers on the experimental models of COVID-19, T cell differentiation, and neutrophil functions

“…The animals were shifted to ABSL3 1 day prior to the challenge. Live intranasal infection of SARS-CoV-2 SARS-Related Coronavirus 2, Isolate USA-WA1/2020) 10 5 PFU/ 100ml (for hamster) and 10 5 PFU/50ml (for mice) or with DMEM mock control was established with the help of catheter under mild anesthetized by using ketamine (150mg/kg) and xylazine (10mg/kg) intraperitoneal injection inside ABSL3 facility (29)(30)(31)(32)(33)(34). Experimental protocols related to handling and experimentation was approved by RCGM, institutional biosafety, and IAEC (IAEC/ THSTI/105) animal ethics committee.…”

Exploring the Potential of Broadly Neutralizing Antibodies for Treating SARS-CoV-2 Variants of Global Concern in 2023: A Comprehensive Clinical Review

“…The crystal structures of the COV44-62 and COV44-79 antigen-binding fragments, when combined with the SARS-CoV-2 fusion peptide, revealed a helical structure covering the arginine residue at the S2' cleavage site [ 59 ]. In contrast, Parray and colleagues recently announced the identification of a potent mAb, P4A2, that can effectively neutralize all current circulating VOCs, including Omicron [ 60 ]. By determining the crystal structure of the P4A2 Fab: RBD complex, the residues of the RBD were identified as part of the ACE 2-receptor-binding motif (RBM), which remains unchanged in all VOCs [ 60 ].…”

“…In contrast, Parray and colleagues recently announced the identification of a potent mAb, P4A2, that can effectively neutralize all current circulating VOCs, including Omicron [ 60 ]. By determining the crystal structure of the P4A2 Fab: RBD complex, the residues of the RBD were identified as part of the ACE 2-receptor-binding motif (RBM), which remains unchanged in all VOCs [ 60 ]. The specificity of P4A2 for SARS-CoV-2 and its VOCs was confirmed by the pan-coronavirus pseudotyped neutralization assay [ 60 ].…”

“…By determining the crystal structure of the P4A2 Fab: RBD complex, the residues of the RBD were identified as part of the ACE 2-receptor-binding motif (RBM), which remains unchanged in all VOCs [ 60 ]. The specificity of P4A2 for SARS-CoV-2 and its VOCs was confirmed by the pan-coronavirus pseudotyped neutralization assay [ 60 ]. Administration of P4A2 to K18-hACE2 transgenic mice provided both prophylactic and therapeutic protection against VOCs in the study [ 60 ].…”

“…The specificity of P4A2 for SARS-CoV-2 and its VOCs was confirmed by the pan-coronavirus pseudotyped neutralization assay [ 60 ]. Administration of P4A2 to K18-hACE2 transgenic mice provided both prophylactic and therapeutic protection against VOCs in the study [ 60 ]. These results suggest that P4A2 could serve as a potential treatment option for neutralizing currently circulating VOCs [ 60 ].…”