Transport of Designed Ankyrin Repeat Proteins through reconstituted human bronchial epithelia and protection against SARS-CoV-2
-
Published:2023-04-04
Issue:1
Volume:13
Page:
-
ISSN:2045-2322
-
Container-title:Scientific Reports
-
language:en
-
Short-container-title:Sci Rep
Author:
Künzi Lisa,Ryter Sarah,Cornelius Andreas,Leni Zaira,Baumlin Nathalie,Salathe Matthias,Walser Marcel,Engler Olivier,Geiser Marianne
Abstract
AbstractClinical studies have proven antiviral effectiveness of treatment with a Designed Ankyrin Repeat Protein (DARPin) specific against the spike protein of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). More information on transport mechanisms and efficiency to the site of action is desirable. Transepithelial migration through air–liquid interface (ALI) cultures of reconstituted human bronchial epithelia (HBE) was assessed by Enzyme-Linked Immunosorbent Assays and Confocal Laser Scanning Microscopy for different DARPin designs in comparison to a monoclonal antibody. Antiviral efficacy against authentic SARS-CoV-2, applied apically on HBE, was investigated based on viral titers and genome equivalents, after administration of therapeutic candidates on the basal side. Transepithelial translocation of all DARPin candidates and the monoclonal antibody was efficient and dose dependent. Small DARPins and the antibody migrated more efficiently than larger molecules, indicating different transport mechanisms involved.
Microscopic analyses support this, demonstrating passive paracellular transport of smaller DARPins and transcellular migration of the larger molecules. All therapeutic candidates applied to the basal side of HBE conferred effective protection against SARS-CoV-2 infection. In summary, we have shown that DARPins specific against SARS-CoV-2 translocate across intact airway epithelia and confer effective protection against infection and viral replication.
Funder
Molecular Partners AG, 8952 Zürich-Schlieren, Switzerland
Publisher
Springer Science and Business Media LLC
Subject
Multidisciplinary
Reference32 articles.
1. WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int.
2. Ritchie, H. et al. Coronavirus Pandemic (COVID-19). Coronavirus (COVID-19) Vaccinations https://ourworldindata.org/covid-vaccinations (2020).
3. Hall, V. et al. Protection against SARS-CoV-2 after Covid-19 vaccination and previous infection. N. Engl. J. Med. 386, 1207–1220 (2022).
4. Rothenberger, S. et al. The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants. Nat. Biotechnol. https://doi.org/10.1038/s41587-022-01382-3 (2022).
5. Novartis. Novartis and Molecular Partners announce start of EMPATHY clinical trial for ensovibep for the treatment of COVID-19. https://www.novartis.com/news/media-releases/novartis-and-molecular-partners-announce-start-empathy-clinical-trial-ensovibep-treatment-covid-19 (2021).
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献