TY - JOUR
T1 - Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control
AU - Schmid, Markus
AU - Ernst, Patrick
AU - Honegger, Annemarie
AU - Suomalainen, Maarit
AU - Zimmermann, Martina
AU - Braun, Lukas
AU - Stauffer, Sarah
AU - Thom, Cristian
AU - Dreier, Birgit
AU - Eibauer, Matthias
AU - Kipar, Anja
AU - Vogel, Viola
AU - Greber, Urs F.
AU - Medalia, Ohad
AU - Plückthun, Andreas
N1 - Funding Information:
This work was funded by the Schweizerische Nationalfonds (SNF) Sinergia program grant CRSII5-170929 to A.P., predoctoral fellowships from the Forschungskredit of the University of Zurich to M.Sc. and P.E., and SNF grant 310030B-160316 (to U.F.G.) and the Maxi Foundation (to O.M.) We thank the Center for Microscopy and Image Analysis at the University of Zurich (ZMB).
Funding Information:
We would like to thank Simon Hansen and Florian Kast for helpful discussions. The authors are grateful to the technical assistants at the Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, for excellent technical support. We would like to thank Céline Stutz-Ducommun and Beat Blattmann from the high-throughput crystallization center at University of Zurich and the staff from beamlines X06SA of the Swiss Light Source. We also would like to thank Achilleas Frangakis and Cristina Paulino as well as the S3IT cluster for the help with the EM structure. This work was funded by the Schweizerische Nationalfonds (SNF) Sinergia program grant CRSII5_170929 to A.P., predoctoral fellowships from the For-schungskredit of the University of Zurich to M.Sc. and P.E., and SNF grant 310030B_160316 (to U.F.G.) and the Maxi Foundation (to O.M.) We thank the Center for Microscopy and Image Analysis at the University of Zurich (ZMB).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85041354061&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-02707-6
DO - 10.1038/s41467-017-02707-6
M3 - Article
AN - SCOPUS:85041354061
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 450
ER -
