According to the most used classification, class I and II MAbs bind to amino acids contained within the receptor-binding motif, while class III and IV MAbs bind solely or predominantly to the RBD core (3)

According to the most used classification, class I and II MAbs bind to amino acids contained within the receptor-binding motif, while class III and IV MAbs bind solely or predominantly to the RBD core (3). Five MAb preparations have been authorized by the U.S. 34 studies, sotrovimab displayed a median 4.0-fold (interquartile range [IQR]: 2.6 to 6.9) reduction in activity against Omicron BA.1, and in 12 studies, it displayed a median 17-fold (IQR: 13 to 30) reduction in activity against Omicron BA.2. In 15 studies, the combination cilgavimab/tixagevimab displayed a median 86-fold (IQR: 27 to 151) reduction in activity against Omicron BA.1, and in six studies, it displayed a median 5.4-fold (IQR: 3.7 to 6.9) reduction in activity against Omicron BA.2. In eight studies against Omicron BA.1 and six studies against Omicron BA.2, bebtelovimab displayed no reduction in activity. Disparate results between assays were common. For authorized MAbs, 51/268 (19.0%) results for wild-type control variants and 78/348 (22.4%) results for Omicron BA.1 and BA.2 variants were more than 4-fold below or 4-fold above the median result for that MAb. Highly disparate results HJC0152 between published assays indicate a need for improved MAb susceptibility test standardization or interassay calibration. IMPORTANCE Monoclonal antibodies (MAbs) targeting the SARS-CoV-2 spike protein are among the most effective measures for preventing and treating COVID-19. However, SARS-CoV-2 Omicron variants contain many mutations in their spike receptor-binding domains, the target of all authorized MAbs. Therefore, determining the extent to which Omicron variants reduced MAb susceptibility is critical to preventing and treating COVID-19. We identified 51 studies that reported the susceptibility of the two main Omicron variants BA.1 and BA.2 to therapeutic MAbs in advanced clinical development, including eight authorized individual MAbs and three authorized MAb combinations. We estimated the degree to which different MAbs displayed reduced activity against Omicron variants. The marked loss of activity of many MAbs against Omicron variants underscores the importance of developing MAbs that target conserved regions of spike. Highly disparate results between assays indicate the need for improved MAb susceptibility test standardization. KEYWORDS: SARS-CoV-2, Omicron variant, monoclonal antibody, neutralization, spike protein, COVID-19, antiviral therapy, multidrug resistance INTRODUCTION HJC0152 Neutralizing antibodies (Abs) block the entry of virus into host cells and may also recruit host effector pathways to destroy virus-infected cells. Most SARS-CoV-2-neutralizing Abs identified in persons recovering from COVID-19 bind the surface-exposed spike receptor-binding domain (RBD) or N-terminal domain (NTD). The RBD is the main target of human neutralizing Abs and the sole target of those monoclonal antibodies (MAbs) that either have received emergency use authorization by the U.S. Food and Drug HJC0152 Administration or are in advanced clinical development. The RBD, which encompasses residues 306 to 534, alternates HJC0152 between a closed/down position and an open/up position. When in the up position, it binds to the human ACE2 receptor. Approximately 20 RBD residues form contacts with the human ACE2 receptor (1). The region of the RBD that contains these residues encompasses residues 438 to 506 and is called the receptor-binding motif, whereas the remainder of the RBD is called the RBD core. Although no two SARS-CoV-2-neutralizing MAbs have identical epitopes, those binding the RBD have been grouped into several classes depending on the location of their binding residues and whether they can bind the RBD in its up and/or down position (2,C4). According to the most used classification, class I and II MAbs bind to amino acids contained within the receptor-binding motif, while class III and IV MAbs bind solely RGS16 or predominantly to the RBD core (3). Five MAb preparations have been authorized by the U.S. FDA (5), two have been authorized in other countries, and 13 others are in phase II or III clinical trials (6). The combinations of bamlanivimab/etesevimab and casirivimab/imdevimab were authorized for outpatient treatment and postexposure prophylaxis in HJC0152 high-risk individuals. The combination cilgavimab/tixagevimab was authorized for preexposure prophylaxis in high-risk individuals. Sotrovimab and bebtelovimab were each authorized for the outpatient treatment of high-risk individuals. The Omicron BA.1 variant contains 15 RBD mutations including G339D, S371L, S373P, S375F,.

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