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

Vincent DussuptRajeshwer S SankhalaLetzibeth Mendez-RiveraSamantha M TownsleyFabian SchmidtLindsay WieczorekKerri G LalGina C DonofrioUrsula TranNathaniel D JacksonWeam I ZakyMichelle ZemilSarah R TritschWei-Hung ChenElizabeth J MartinezAslaa AhmedMisook ChoeWilliam C ChangAgnes HajduczkiNingbo JianCaroline E PetersonPhyllis A ReesMagdalena RutkowskaBonnie M SlikeChristopher N SelverianIsabella SwaffordI-Ting TengPaul V ThomasTongqing ZhouClayton J SmithJeffrey R CurrierPeter D KwongMorgane RollandEdgar DavidsonBenjamin J DoranzChristopher N MoresTheodora HatziioannouWilliam W ReileyPaul D BieniaszDominic Paquin-ProulxGregory D GromowskiVictoria R PolonisNelson L MichaelKayvon ModjarradM Gordon JoyceShelly J Krebs
Published in: Nature immunology (2021)
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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