Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice.
Phillip PymmAmy AdairLi-Jin ChanJames P CooneyFrancesca L MordantCody C AllisonEster LopezEbene R HaycroftMatthew T O'NeillLi Lynn TanMelanie H DietrichDamien DrewMarcel DoerflingerMichael A DenglerNichollas E ScottAdam K WheatleyNicholas A GherardinHariprasad VenugopalDeborah CromerMiles P DavenportRaelene PickeringDale I GodfreyDamian F J PurcellStephen J KentAmy W ChungKanta SubbaraoMarc PellegriniAlisa GlukhovaWai-Hong ThamPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
Neutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas immunized with coronavirus spike and receptor-binding domains (RBD) that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2. Epitope mapping, X-ray crystallography, and cryo-electron microscopy revealed two distinct antigenic sites and showed two neutralizing nanobodies from different epitope classes bound simultaneously to the spike trimer. Nanobody-Fc fusions of the four most potent nanobodies blocked ACE2 engagement with RBD variants present in human populations and potently neutralized both wild-type SARS-CoV-2 and the N501Y D614G variant at concentrations as low as 0.1 nM. Prophylactic administration of either single nanobody-Fc or as mixtures reduced viral loads by up to 104-fold in mice infected with the N501Y D614G SARS-CoV-2 virus. These results suggest a role for nanobody-Fc fusions as prophylactic agents against SARS-CoV-2.
Keyphrases
- sars cov
- angiotensin converting enzyme
- respiratory syndrome coronavirus
- electron microscopy
- wild type
- angiotensin ii
- endothelial cells
- social media
- magnetic resonance imaging
- type diabetes
- magnetic resonance
- induced pluripotent stem cells
- computed tomography
- single cell
- gene expression
- coronavirus disease
- small molecule
- dna methylation
- high density
- dna binding