Abstract
Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.
Highlights
Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies targeting multiple sites of vulnerability on the coronavirus spike glycoprotein
We cultivated rVSV/SARS-CoV-2/GFP in the presence of single N-terminal domain (NTD) and receptor-binding domain (RBD) monoclonal antibodies (mAbs), and subsequently selected for resistant viral populations that replicated to high levels, as expected (Fig. 5f)
NTD-targeting and RBD-targeting mAbs were capable of mediating Fc effector functions, with a unique ability of NTD neutralizing mAbs to leverage complement deposition
Summary
Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Binding to NTD, RBD and the S trimer strongly correlated with plasma neutralization of pseudotyped SARS-CoV-2 virions (pseudotyped lentivirus (pSV); Extended Data Fig. 1a).
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