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

Nat Commun. 2018 Jan 31;9(1):450. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviruses, Human / genetics*
  • Adenoviruses, Human / pathogenicity
  • Animals
  • Capsid Proteins / chemistry
  • Capsid Proteins / genetics
  • Capsid Proteins / metabolism
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Gene Transfer Techniques
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics*
  • Genetic Vectors / immunology*
  • Humans
  • Liver / physiology*
  • Liver / virology
  • Mice, Transgenic
  • Molecular Targeted Therapy / methods
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Single-Chain Antibodies / chemistry
  • Single-Chain Antibodies / genetics
  • Single-Chain Antibodies / metabolism
  • Spleen / virology
  • Virion / chemistry
  • Virion / metabolism
  • Xenograft Model Antitumor Assays


  • Capsid Proteins
  • Single-Chain Antibodies
  • hexon capsid protein, Adenovirus
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2