Arsenal of Nanobodies for Broad-Spectrum Countermeasures against Current and Future SARS-CoV-2 Variants of Concerns
ABSTRACT Nanobodies offer several potential advantages over mAbs for the control of SARS-CoV-2. Their ability to access cryptic epitopes conserved across SARS-CoV-2 variants of concern (VoCs) and feasibility to engineer modular, multimeric designs, make these antibody fragments ideal candidates for developing broad-spectrum therapeutics against current and continually emerging SARS-CoV-2 VoCs. Here we describe a diverse collection of 37 anti-SARS-CoV-2 spike glycoprotein nanobodies extensively characterized as both monovalent and IgG Fc-fused bivalent modalities. The panel of nanobodies were shown to have high intrinsic affinity; high thermal, thermodynamic and aerosolization stability; broad subunit/domain specificity and cross-reactivity across many VoCs; wide-ranging epitopic and mechanistic diversity; high and broad in vitro neutralization potencies; and high neutralization efficacies in hamster models of SARS-CoV-2 infection, reducing viral burden by up to six orders of magnitude to below detectable levels. In vivo protection was demonstrated with anti-RBD and previously unreported anti-NTD and anti-S2 nanobodies. This collection of nanobodies provides a therapeutic toolbox from which various cocktails or multi-paratopic formats could be built to tackle current and future SARS-CoV-2 variants and SARS-related viruses. Furthermore, the high aerosol-ability of nanobodies provides the option for effective needle-free delivery through inhalation..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
bioRxiv.org - (2021) vom: 23. Dez. Zur Gesamtaufnahme - year:2021 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Rossotti, M. A. [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| doi: |
10.1101/2021.12.20.473401 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI033268711 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI033268711 | ||
| 003 | DE-627 | ||
| 005 | 20230429090039.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 211222s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2021.12.20.473401 |2 doi | |
| 035 | |a (DE-627)XBI033268711 | ||
| 035 | |a (biorXiv)10.1101/2021.12.20.473401 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 082 | 0 | |a 570 |q DE-84 | |
| 100 | 1 | |a Rossotti, M. A. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Arsenal of Nanobodies for Broad-Spectrum Countermeasures against Current and Future SARS-CoV-2 Variants of Concerns |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a ABSTRACT Nanobodies offer several potential advantages over mAbs for the control of SARS-CoV-2. Their ability to access cryptic epitopes conserved across SARS-CoV-2 variants of concern (VoCs) and feasibility to engineer modular, multimeric designs, make these antibody fragments ideal candidates for developing broad-spectrum therapeutics against current and continually emerging SARS-CoV-2 VoCs. Here we describe a diverse collection of 37 anti-SARS-CoV-2 spike glycoprotein nanobodies extensively characterized as both monovalent and IgG Fc-fused bivalent modalities. The panel of nanobodies were shown to have high intrinsic affinity; high thermal, thermodynamic and aerosolization stability; broad subunit/domain specificity and cross-reactivity across many VoCs; wide-ranging epitopic and mechanistic diversity; high and broad in vitro neutralization potencies; and high neutralization efficacies in hamster models of SARS-CoV-2 infection, reducing viral burden by up to six orders of magnitude to below detectable levels. In vivo protection was demonstrated with anti-RBD and previously unreported anti-NTD and anti-S2 nanobodies. This collection of nanobodies provides a therapeutic toolbox from which various cocktails or multi-paratopic formats could be built to tackle current and future SARS-CoV-2 variants and SARS-related viruses. Furthermore, the high aerosol-ability of nanobodies provides the option for effective needle-free delivery through inhalation. | ||
| 700 | 1 | |a van Faassen, H. |e verfasserin |4 aut | |
| 700 | 1 | |a Tran, A. |e verfasserin |4 aut | |
| 700 | 1 | |a Sheff, J. |e verfasserin |4 aut | |
| 700 | 1 | |a Sandhu, J. K. |e verfasserin |4 aut | |
| 700 | 1 | |a Duque, D. |e verfasserin |4 aut | |
| 700 | 1 | |a Hewitt, M. |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, S. |e verfasserin |4 aut | |
| 700 | 1 | |a Bavananthasivam, R. |e verfasserin |4 aut | |
| 700 | 1 | |a Beitari, S. |e verfasserin |4 aut | |
| 700 | 1 | |a Matte, K. |e verfasserin |4 aut | |
| 700 | 1 | |a Laroche, G. |e verfasserin |4 aut | |
| 700 | 1 | |a Giguère, P. M. |e verfasserin |4 aut | |
| 700 | 1 | |a Gervais, C. |e verfasserin |4 aut | |
| 700 | 1 | |a Stuible, M. |e verfasserin |4 aut | |
| 700 | 1 | |a Guimond, J. |e verfasserin |4 aut | |
| 700 | 1 | |a Perret, S. |e verfasserin |4 aut | |
| 700 | 1 | |a Hussack, G. |e verfasserin |4 aut | |
| 700 | 1 | |a Langlois, M.-A. |e verfasserin |4 aut | |
| 700 | 1 | |a Durocher, Y. |e verfasserin |4 aut | |
| 700 | 1 | |a Tanha, J. |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2021) vom: 23. Dez. |
| 773 | 1 | 8 | |g year:2021 |g day:23 |g month:12 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2021.12.20.473401 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 912 | |a SSG-OLC-PHA | ||
| 951 | |a AR | ||
| 952 | |j 2021 |b 23 |c 12 | ||
| 953 | |2 045F |a 570 | ||