Abstract The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and its variants has posed a serious global public health emergency. Therapeutic interventions or vaccines are urgently needed to treat and prevent the further dissemination of this contagious virus. This study described the identification of neutralizing receptor‐binding domain (RBD)‐specific antibodies from mice through vaccination with a recombinant SARS‐CoV‐2 RBD. RBD‐targeted monoclonal antibodies (mAbs) with distinct function and epitope recognition were selected to understand SARS‐CoV‐2 neutralization. High‐affinity RBD‐specific antibodies exhibited high potency in neutralizing both live and pseudotype SARS‐CoV‐2 viruses and the SARS‐CoV‐2 pseudovirus particle containing the spike protein S‐RBD V367F mutant (SARS‐CoV‐2(V367F)). These results demonstrated that these antibodies recognize four distinct groups (I–IV) of epitopes on the RBD and that mAbs targeting group I epitope can be used in combination with mAbs recognizing groups II and/or IV epitope to make mAb cocktails against SARS‐CoV‐2 and its mutants. Moreover, structural characterization reveals that groups I, III, and IV epitopes are closely located to an RBD hotspot. The identification of RBD‐specific antibodies and cocktails may provide an effective therapeutic and prophylactic intervention against SARS‐CoV‐2 and its isolates. The neutralizing receptor‐binding domain‐specific antibodies from mice showed high affinity against SARS‐CoV‐2 live and pseudovirus particle bearing the wildtype and SV367F mutant protein. The antibodies selected for distinct epitopes on the RBD have different levels of competition capacity with ACE2 binding to RBD. The combination of them in usage could provide an effective way to control SARS‐CoV‐2 transmission.
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