1. Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations.
- Author
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Dussupt V, Sankhala RS, Mendez-Rivera L, Townsley SM, Schmidt F, Wieczorek L, Lal KG, Donofrio GC, Tran U, Jackson ND, Zaky WI, Zemil M, Tritsch SR, Chen WH, Martinez EJ, Ahmed A, Choe M, Chang WC, Hajduczki A, Jian N, Peterson CE, Rees PA, Rutkowska M, Slike BM, Selverian CN, Swafford I, Teng IT, Thomas PV, Zhou T, Smith CJ, Currier JR, Kwong PD, Rolland M, Davidson E, Doranz BJ, Mores CN, Hatziioannou T, Reiley WW, Bieniasz PD, Paquin-Proulx D, Gromowski GD, Polonis VR, Michael NL, Modjarrad K, Joyce MG, and Krebs SJ
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal metabolism, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing metabolism, Antibodies, Viral immunology, Antibodies, Viral metabolism, Binding Sites genetics, COVID-19 metabolism, COVID-19 prevention & control, Disease Models, Animal, Dose-Response Relationship, Drug, Epitope Mapping, Epitopes chemistry, Epitopes immunology, Epitopes metabolism, Humans, Mice, Transgenic, Neutralization Tests, Protein Binding, Protein Conformation, SARS-CoV-2 genetics, SARS-CoV-2 metabolism, Sequence Homology, Amino Acid, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus metabolism, Survival Analysis, Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, COVID-19 immunology, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus immunology
- 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., (© 2021. The Author(s).)
- Published
- 2021
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