Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control
| Autor: | Viola Vogel, Cristian Thom, Urs F. Greber, Matthias Eibauer, Annemarie Honegger, Ohad Medalia, Patrick Ernst, Martina Zimmermann, Andreas Plückthun, Sarah Stauffer, Anja Kipar, Markus Schmid, Birgit Dreier, Lukas Braun, Maarit Suomalainen |
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| Přispěvatelé: | University of Zurich, Plückthun, Andreas |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Receptor ErbB-2 Genetic enhancement animal diseases viruses General Physics and Astronomy Viral proteins Targeted therapies Genetic vectors Cryoelectron microscopy medicine.disease_cause Crystallography X-Ray Molecular Targeted Therapy lcsh:Science Multidisciplinary Gene Transfer Techniques Signal transducing adaptor protein Acquired immune system 10124 Institute of Molecular Life Sciences 3100 General Physics and Astronomy Cell biology ErbB Receptors Liver Female Viral protein Science Genetic Vectors 10184 Institute of Veterinary Pathology 1600 General Chemistry chemical and pharmacologic phenomena Mice Transgenic Biology General Biochemistry Genetics and Molecular Biology Article Viral vector 03 medical and health sciences Immune system 1300 General Biochemistry Genetics and Molecular Biology Cell Line Tumor 10019 Department of Biochemistry medicine Gene silencing Animals Humans Adenoviruses Human Virion General Chemistry biochemical phenomena metabolism and nutrition Xenograft Model Antitumor Assays 030104 developmental biology Cell culture 570 Life sciences biology bacteria lcsh:Q Capsid Proteins Spleen Single-Chain Antibodies |
| Zdroj: | Nature Communications, 9 Nature Communications Nature Communications, Vol 9, Iss 1, Pp 1-16 (2018) |
| ISSN: | 2041-1723 |
| Popis: | 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. Nature Communications, 9 ISSN:2041-1723 |
| Databáze: | OpenAIRE |
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