A Novel Human Neutralizing mAb Recognizes Delta, Gamma and Omicron Variants of SARS-CoV-2 and Can Be Used in Combination with Sotrovimab

Abstract

The dramatic experience with SARS-CoV-2 has alerted the scientific community to be ready to face new epidemics/pandemics caused by new variants. Among the therapies against the pandemic SARS-CoV-2 virus, monoclonal Antibodies (mAbs) targeting the Spike glycoprotein have represented good drugs to interfere in the Spike/ Angiotensin Converting Enzyme-2 (ACE-2) interaction, preventing virus cell entry and subsequent infection, especially in patients with a defective immune system. We obtained, by an innovative phage display selection strategy, specific binders recognizing different epitopes of Spike. The novel human antibodies specifically bind to Spike-Receptor Binding Domain (RBD) in a nanomolar range and interfere in the interaction of Spike with the ACE-2 receptor. We report here that one of these mAbs, named D3, shows neutralizing activity for virus infection in cell cultures by different SARS-CoV-2 variants and retains the ability to recognize the Omicron-derived recombinant RBD differently from the antibodies Casirivimab or Imdevimab. Since anti-Spike mAbs, used individually, might be unable to block the virus cell entry especially in the case of resistant variants, we investigated the possibility to combine D3 with the antibody in clinical use Sotrovimab, and we found that they recognize distinct epitopes and show additive inhibitory effects on the interaction of Omicron-RBD with ACE-2 receptor. Thus, we propose to exploit these mAbs in combinatorial treatments to enhance their potential for both diagnostic and therapeutic applications in the current and future pandemic waves of coronavirus.

Comparative Analysis of a Human Neutralizing mAb Specific for SARS-CoV-2 Spike-RBD with Cilgavimab and Tixagevimab for the Efficacy on the Omicron Variant in Neutralizing and Detection Assays

“…We found that the high affinity binding of these mAbs to the Omicron variant is not retained, as no significant signals were observed at pM and low nM concentrations ( Figure 1 ). Thus, we tested them at higher concentrations in comparison with D3 mAb, which was reported to retain the ability to bind the Spike-Omicron variant in the nanomolar range [ 17 , 18 ].…”

“…To this aim, it could be useful to identify novel specific mAbs binding to unmutated epitopes of novel VOCs Spike-RBD or to combine different mAbs in order to potentiate their antiviral efficacy against new emerging variants. Here, we further characterized D3, a novel human mAb previously generated in our laboratory and characterized for its activity against the wild-type virus (Wuhan, China), UK, Delta and Gamma variants [ 17 , 18 ]. The aim was to investigate its ability to recognize also the other emerged Omicron subvariants to potentiate the therapeutic efficacy in combination with the approved mAbs or to exploit it for potential diagnostic applications.…”

“…Hence, we investigated on the ability of novel D3 mAb to recognize Omicron-derived RBD subvariants, either used as purified protein or expressed on pseudoviral particles in vitro, in comparison with the latter antibodies entered in clinical use for treatment of patients infected by SARS-CoV-2, such as Cilgavimab or Tixagevimab. Indeed, we previously compared its biological properties with Sotrovimab, Casirivimab and Imdevimab [ 18 ].…”

Recent Developments in the Understanding of Immunity, Pathogenesis and Management of COVID-19

“…The variable region of Sotrovimab binds to a highly conserved epitope of the SARS-CoV-2 spike protein in a region outside the highly mutagenic ACE2 receptor binding motif (Kd = 0.21 nM) and does not compete with human ACE2 receptor binding [ 148 ]. The highly conserved epitope targeted by Sotrovimab has been found on 99.8% of SARS-CoV-2 viruses which allows its use against mutagenic variants, including Omicron [ 149 ]. In May 2021, Sotrovimab received an Emergency Use Authorization in the United States for the treatment of mild to moderate SARS-CoV-2 in higher risk patients to prevent progression to severe symptoms [ 148 ].…”

Sotrovimab for treatment of COVID-19 infections

“…This highlighted the necessity of active, ongoing monitoring of mAB efficacy and amending treatment options accordingly based on the main variant causing SARS-CoV-2 infections. For the BA.2 sublineage, this includes use of bebtelovimab (LY-CoV1404) [17], or considering combination therapy with sotrovimab to ensure a broader spectrum of cover [18]. Overall, during the Delta pandemic, mAbs generally held significant promise in neutralizing the SARS-CoV-2 virus.…”