Journal Article

DAS181, a sialidase fusion protein, protects human airway epithelium against influenza virus infection: an in vitro pharmacodynamic analysis

Gallen B. Triana-Baltzer, Maria Babizki, Michael C. W. Chan, Adam C. N. Wong, Laura M. Aschenbrenner, Erin R. Campbell, Qi-Xiang Li, Renee W. Y. Chan, J. S. Malik Peiris, John M. Nicholls and Fang Fang

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 65, issue 2, pages 275-284
Published in print February 2010 | ISSN: 0305-7453
Published online November 2009 | e-ISSN: 1460-2091 | DOI: https://dx.doi.org/10.1093/jac/dkp421
DAS181, a sialidase fusion protein, protects human airway epithelium against influenza virus infection: an in vitro pharmacodynamic analysis

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Objectives

The influenza virus (IFV) infection models commonly used to evaluate antiviral agents (e.g. MDCK cell line and mice) are limited by physiological differences from the human respiratory tract in vivo. Here we report the pharmacodynamics of DAS181, a sialidase fusion protein that inhibits influenza infection, in the model systems of well-defined human airway epithelium (HAE) culture and ex vivo culture of fresh human bronchial tissue, both of which are close mimics of the human respiratory tract in vivo.

Methods

HAE culture and ex vivo human bronchi were used to evaluate the sialic acid removal and regeneration efficiency and IFV inhibition after various DAS181 treatment levels and regimens.

Results

DAS181 effectively desialylates HAE cultures and ex vivo bronchi tissues and therefore potently inhibits replication of different IFV strains. The treatment effect of DAS181 occurs immediately upon application to the epithelial surface and is unaffected by the respiratory mucus. In both HAE and human bronchial tissue, the inhibitory effect of DAS181 treatment lasts for at least 2 days. Approximately 80% epithelial surface desialylation and significant anti-IFV efficacy can be achieved at topical concentrations of DAS181 in the range of 5–10 µg/cm2 when applied once daily. An additional treatment or a higher loading dose of DAS181 on the first day provides significant additional treatment benefit. Comparing the effect of DAS181 versus its two analogues, DAS180 and DAS185, has confirmed that sialidase function is critical for DAS181, and the cell-binding domain (amphiregulin tag) prolongs DAS181 retention and potentiates its function.

Conclusions

These results provide valuable insights into DAS181 treatment dose and potential regimens in the clinical setting.

Keywords: HAE; ex vivo bronchi; Fludase

Journal Article.  7410 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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