Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control

Markus Schmid, Patrick Ernst, Annemarie Honegger, Maarit Suomalainen, Martina Zimmermann, Lukas Braun, Sarah Stauffer, Cristian Thom, Birgit Dreier, Matthias Eibauer, Anja Kipar, Viola Vogel, Urs F. Greber, Ohad Medalia and Andreas Plückthun ()
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Markus Schmid: University of Zurich
Patrick Ernst: University of Zurich
Annemarie Honegger: University of Zurich
Maarit Suomalainen: University of Zurich
Martina Zimmermann: University of Zurich
Lukas Braun: ETH Zurich
Sarah Stauffer: University of Zurich
Cristian Thom: University of Zurich
Birgit Dreier: University of Zurich
Matthias Eibauer: University of Zurich
Anja Kipar: University of Zurich
Viola Vogel: ETH Zurich
Urs F. Greber: University of Zurich
Ohad Medalia: University of Zurich
Andreas Plückthun: University of Zurich

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02707-6

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