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Antibodies From 5 People With COVID-19 Show "Exquisite Potency"
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Mark Mascolini
Nine neutralizing monoclonal antibodies (mAbs) isolated from 5 people with severe COVID-19 have "exquisite potency" against SARS-CoV-2, according to results published in Nature by an all-star roster from the United States and Hong Kong [1]. Identified neutralizing mAbs were about equally divided between distinct regions of the viral spike, the receptor-binding domain (RBD) and the N-terminal domain (NTD). But 2 targeted other unusual regions.
Led by senior authors Yaoxing Huang, Lawrence Shapiro, and David Ho, the research team notes that neutralizing mAbs primarily target the spike that thrusts from the surface of SARS-CoV-2 and links the virus to target cells. The spike has two subunits, S1 and S2. S1 has two subunits, RBD and NTD; S2 orchestrates virus-cell fusion after RBD snares the ACE2 receptor on cells. The authors note that other teams recently reported neutralizing mAbs that target RBD.
With colleagues from several US and Hong Kong institutions, Aaron Diamond AIDS Research Center scientists started their search for neutralizing mAbs by assembling a cohort of 40 people with PCR-confirmed SARS-CoV-2 infection. First the researchers tested plasma samples from all participants for neutralizing activity against SARS-CoV-2 pseudovirus. From this group of 40, the research team picked 5 people with the highest plasma virus-neutralizing titers. All 5 people were severely ill and needed mechanical ventilation for acute respiratory distress syndrome.
Starting with peripheral blood mononuclear cells, the cell-sorting strategy focused on live memory B cells that bound the SARS-CoV-2 spike trimer. (A trimer is a complex of three macromolecules.) Strategies that identified "high-confidence" antigen-specific mAbs yielded 6 such mAbs from 1 participant but 44 to 100 such mAbs from the other 4 people. After more sifting steps, the investigators eventually zeroed in on 19 neutralizing mAbs with promising potency. Nine mAbs clearly bound RBD, 8 bound NTD, and 2 bound neither RBD nor NTD and got labeled "other."
Nine mAbs had "exquisite potency" in neutralizing SARS-CoV-2 in vitro with 50% inhibitory concentrations (IC50s) of 0.7 to 9 ng/mL. These 9 top neutralizers included 4 mAbs targeting RBD, 3 directed to NTD, and 2 targeting undetermined spike trimer regions. A single participant contributed 5 of the superstrong 9 neutralizing mAbs.
The researchers tested one neutralizing mAb against SARS-CoV-2 in a hamster model of infection. Hamsters first got intraperitoneal injections of the mAb at doses of 0.3 or 1.5 mg/kg, or they got an inert solution. Twenty-four hours later, researchers challenged hamsters intranasally with 100,000 plaque-forming units of a SARS-CoV-2 strain. Evaluation of hamster lung tissue showed that the high-dose mAb lowered both viral RNA copy number and infectious virus titers 10,000-fold compared with lung from untreated hamsters. In other words, this experiment showed "complete elimination of infectious SARS-CoV-2 at a relatively modest antibody dose."
The authors highlight two other findings:
1. Epitope-mapping studies indicate that mAbs directed against the top of RBD strongly compete with ACE2 binding and potently neutralize virus, whereas mAbs directed against the sides of RBD do not compete with ACE2 and neutralize virus with less gusto.
2. Two identified potent mAbs did not home to RBD or NTD, a unique finding. One of these mAbs stretched from the top of one RBD to the top of another RBD.
The investigators propose that "several of our monoclonal antibodies with exquisite virus-neutralizing activity are promising candidates for development as modalities to treat or prevent SARS-CoV-2 infection."
Reference
1. Liu L, Wang P, Nair MS, et al. Potent neutralizing antibodies directed to multiple epitopes on SARS-CoV-2 spike. Nature (2020). Published 22 July. https://doi.org/10.1038/s41586-020-2571-7
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