tetano
Editor, Senior Moderator
Antiviral Res
. 2023 Dec 6:105778.
doi: 10.1016/j.antiviral.2023.105778. Online ahead of print. Nanobodies to multiple spike variants and inhalation of nanobody-containing aerosols neutralize SARS-CoV-2 in cell culture and hamsters
Metin Aksu[SUP] 1 [/SUP], Priya Kumar[SUP] 2 [/SUP], Thomas Güttler[SUP] 3 [/SUP], Waltraud Taxer[SUP] 1 [/SUP], Kathrin Gregor[SUP] 1 [/SUP], Bianka Mußil[SUP] 1 [/SUP], Oleh Rymarenko[SUP] 1 [/SUP], Kim M Stegmann[SUP] 2 [/SUP], Antje Dickmanns[SUP] 2 [/SUP], Sabrina Gerber[SUP] 2 [/SUP], Wencke Reineking[SUP] 4 [/SUP], Claudia Schulz[SUP] 5 [/SUP], Timo Henneck[SUP] 6 [/SUP], Ahmed Mohamed[SUP] 6 [/SUP], Gerhard Pohlmann[SUP] 7 [/SUP], Mehmet Ramazanoglu[SUP] 7 [/SUP], Kemal Mese[SUP] 8 [/SUP], Uwe Groß[SUP] 8 [/SUP], Tamar Ben-Yedidia[SUP] 9 [/SUP], Oded Ovadia[SUP] 9 [/SUP], Dalit Weinstein Fischer[SUP] 9 [/SUP], Merav Kamensky[SUP] 9 [/SUP], Amir Reichman[SUP] 9 [/SUP], Wolfgang Baumgärtner[SUP] 4 [/SUP], Maren von Köckritz-Blickwede[SUP] 6 [/SUP], Matthias Dobbelstein[SUP] 10 [/SUP], Dirk Görlich[SUP] 11 [/SUP]
Affiliations
The ongoing threat of COVID-19 has highlighted the need for effective prophylaxis and convenient therapies, especially for outpatient settings. We have previously developed highly potent single-domain (VHH) antibodies, also known as nanobodies, that target the Receptor Binding Domain (RBD) of the SARS-CoV-2 Spike protein and neutralize the Wuhan strain of the virus. In this study, we present a new generation of anti-RBD nanobodies with superior properties. The primary representative of this group, Re32D03, neutralizes Alpha to Delta as well as Omicron BA.2.75; other members neutralize, in addition, Omicron BA.1, BA.2, BA.4/5, and XBB.1. Crystal structures of RBD-nanobody complexes reveal how ACE2-binding is blocked and also explain the nanobodies' tolerance to immune escape mutations. Through the cryo-EM structure of the Ma16B06-BA.1 Spike complex, we demonstrated how a single nanobody molecule can neutralize a trimeric spike. We also describe a method for large-scale production of these nanobodies in Pichia pastoris, and for formulating them into aerosols. Exposing hamsters to these aerosols, before or even 24 h after infection with SARS-CoV-2, significantly reduced virus load, weight loss and pathogenicity. These results show the potential of aerosolized nanobodies for prophylaxis and therapy of coronavirus infections.
Keywords: Aerosol; Animal model; COVID-19; Hamster; Inhalation; Nanobodies; Protein structure; Receptor binding domain; SARS-CoV-2; Spike; VHH antibodies; Variants of concern.
. 2023 Dec 6:105778.
doi: 10.1016/j.antiviral.2023.105778. Online ahead of print. Nanobodies to multiple spike variants and inhalation of nanobody-containing aerosols neutralize SARS-CoV-2 in cell culture and hamsters
Metin Aksu[SUP] 1 [/SUP], Priya Kumar[SUP] 2 [/SUP], Thomas Güttler[SUP] 3 [/SUP], Waltraud Taxer[SUP] 1 [/SUP], Kathrin Gregor[SUP] 1 [/SUP], Bianka Mußil[SUP] 1 [/SUP], Oleh Rymarenko[SUP] 1 [/SUP], Kim M Stegmann[SUP] 2 [/SUP], Antje Dickmanns[SUP] 2 [/SUP], Sabrina Gerber[SUP] 2 [/SUP], Wencke Reineking[SUP] 4 [/SUP], Claudia Schulz[SUP] 5 [/SUP], Timo Henneck[SUP] 6 [/SUP], Ahmed Mohamed[SUP] 6 [/SUP], Gerhard Pohlmann[SUP] 7 [/SUP], Mehmet Ramazanoglu[SUP] 7 [/SUP], Kemal Mese[SUP] 8 [/SUP], Uwe Groß[SUP] 8 [/SUP], Tamar Ben-Yedidia[SUP] 9 [/SUP], Oded Ovadia[SUP] 9 [/SUP], Dalit Weinstein Fischer[SUP] 9 [/SUP], Merav Kamensky[SUP] 9 [/SUP], Amir Reichman[SUP] 9 [/SUP], Wolfgang Baumgärtner[SUP] 4 [/SUP], Maren von Köckritz-Blickwede[SUP] 6 [/SUP], Matthias Dobbelstein[SUP] 10 [/SUP], Dirk Görlich[SUP] 11 [/SUP]
Affiliations
- PMID: 38065245
- DOI: 10.1016/j.antiviral.2023.105778
The ongoing threat of COVID-19 has highlighted the need for effective prophylaxis and convenient therapies, especially for outpatient settings. We have previously developed highly potent single-domain (VHH) antibodies, also known as nanobodies, that target the Receptor Binding Domain (RBD) of the SARS-CoV-2 Spike protein and neutralize the Wuhan strain of the virus. In this study, we present a new generation of anti-RBD nanobodies with superior properties. The primary representative of this group, Re32D03, neutralizes Alpha to Delta as well as Omicron BA.2.75; other members neutralize, in addition, Omicron BA.1, BA.2, BA.4/5, and XBB.1. Crystal structures of RBD-nanobody complexes reveal how ACE2-binding is blocked and also explain the nanobodies' tolerance to immune escape mutations. Through the cryo-EM structure of the Ma16B06-BA.1 Spike complex, we demonstrated how a single nanobody molecule can neutralize a trimeric spike. We also describe a method for large-scale production of these nanobodies in Pichia pastoris, and for formulating them into aerosols. Exposing hamsters to these aerosols, before or even 24 h after infection with SARS-CoV-2, significantly reduced virus load, weight loss and pathogenicity. These results show the potential of aerosolized nanobodies for prophylaxis and therapy of coronavirus infections.
Keywords: Aerosol; Animal model; COVID-19; Hamster; Inhalation; Nanobodies; Protein structure; Receptor binding domain; SARS-CoV-2; Spike; VHH antibodies; Variants of concern.