Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

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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.

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Dussupt, V., Sankhala, R. S., Mendez-Rivera, L., Townsley, S. M., Schmidt, F., Wieczorek, L., … Krebs, S. J. (2021). Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations. Nature Immunology, 22(12), 1503–1514. https://doi.org/10.1038/s41590-021-01068-z

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