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

• Published in: Nature communications Vol. 9; no. 1; pp. 450 - 16
• Main Authors: Schmid, Markus, Ernst, Patrick, Honegger, Annemarie, Suomalainen, Maarit, Zimmermann, Martina, Braun, Lukas, Stauffer, Sarah, Thom, Cristian, Dreier, Birgit, Eibauer, Matthias, Kipar, Anja, Vogel, Viola, Greber, Urs F., Medalia, Ohad, Plückthun, Andreas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-01-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 13/44; 14/1; 14/5; 38/77; 42/41; 631/45/535/1258/1259; 631/45/612/1256; 631/61/2300/1514; 631/67/1059/602; 64/60; 82/103; 96/35; 96/63; Adapters; Adaptive immunity; Adaptor proteins; Adenoviruses, Human - genetics; Adenoviruses, Human - pathogenicity; Animals; Avidity; Cancer; Capsid Proteins - chemistry; Capsid Proteins - genetics; Capsid Proteins - metabolism; Cell Line, Tumor; Crystallography; Crystallography, X-Ray; Electron microscopy; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; ErbB-2 protein; Female; Gene silencing; Gene therapy; Gene transfer; Gene Transfer Techniques; Genes; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Genetic Vectors - immunology; Humanities and Social Sciences; Humans; Immune clearance; Immunity; In vivo methods and tests; Liver; Liver - physiology; Liver - virology; Mice, Transgenic; Molecular Targeted Therapy - methods; multidisciplinary; Neutralization; Protein engineering; Proteins; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Science; Science (multidisciplinary); Shielding; Single-Chain Antibodies - chemistry; Single-Chain Antibodies - genetics; Single-Chain Antibodies - metabolism; Spleen - virology; Tumors; Virion - chemistry; Virion - metabolism; Virions; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02707-6

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.
Viral gene therapy can be limited by the efficacy of virion sequestration, immune responses and the silencing of genetic payloads. Here the authors engineer an advenovirus protein coat which shields the virion from the immune system while targeting cancer cells.