Schmid, Markus, Ernst, Patrick, Honegger, Annemarie, Suomalainen, Maarit, Zimmermann, Martina, Braun, Lukas, Stauffer, Sarah, Thom, Cristian, Dreier, Birgit, Eibauer, Matthias et al (show 5 more authors)
(2018)
Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control.
NATURE COMMUNICATIONS, 9 (1).
450-.
Abstract
Most systemic viral gene therapies have been limited by sequestration and degradation of virions, innate and adaptive immunity, and silencing of therapeutic genes within the target cells. Here we engineer a high-affinity protein coat, shielding the most commonly used vector in clinical gene therapy, human adenovirus type 5. Using electron microscopy and crystallography we demonstrate a massive coverage of the virion surface through the hexon-shielding scFv fragment, trimerized to exploit the hexon symmetry and gain avidity. The shield reduces virion clearance in the liver. When the shielded particles are equipped with adaptor proteins, the virions deliver their payload genes into human cancer cells expressing HER2 or EGFR. The combination of shield and adapter also increases viral gene delivery to xenografted tumors in vivo, reduces liver off-targeting and immune neutralization. Our study highlights the power of protein engineering for viral vectors overcoming the challenges of local and systemic viral gene therapies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Liver, Spleen, Cell Line, Tumor, Animals, Mice, Transgenic, Humans, Adenoviruses, Human, Virion, Receptor, erbB-2, Capsid Proteins, Crystallography, X-Ray, Xenograft Model Antitumor Assays, Gene Transfer Techniques, Genetic Vectors, Female, Single-Chain Antibodies, Molecular Targeted Therapy, ErbB Receptors |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 07 Feb 2020 11:14 |
| Last Modified: | 19 Jan 2023 00:04 |
| DOI: | 10.1038/s41467-017-02707-6 |
| Open Access URL: | https://doi.org/10.1038/s41467-017-02707-6 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3073947 |
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