Optimized PEGylated Adenovirus Vector Reduces the Anti-vector Humoral Immune Response against Adenovirus and Induces a Therapeutic Effect against Metastatic Lung Cancer

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  • Eto Yusuke
    Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Yoshioka Yasuo
    Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University The Center for Advanced Medical Engineering and Informatics, Osaka University
  • Ishida Tatsuhiro
    Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima
  • Yao Xinglei
    Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Morishige Tomohiro
    Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Narimatsu Shogo
    Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Mizuguchi Hiroyuki
    Department of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation
  • Mukai Yohei
    Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Okada Naoki
    Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University
  • Kiwada Hiroshi
    Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima
  • Nakagawa Shinsaku
    Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University The Center for Advanced Medical Engineering and Informatics, Osaka University

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Application of adenovirus vectors (Adv) in metastatic cancer treatment is limited. We previously demonstrated that covalent conjugation of polyethleneglycol (PEG) to Adv enhances therapeutic effects and decreases toxic side-effects after systemic administration, but the level of immune response to PEGylated Adv (PEG-Ad) was not examined. Here, we examined the effect of PEGylation of Adv on the production of anti-Adv antibodies and antitumor response. We constructed a set of PEG-Ad using 5-kDa PEG, with modification rates of 30%, 45% and 90%. After systemic administration of Advs to rats, we examined the level of anti-Adv immunoglobulin (Ig)G and IgM in serum. The levels of anti-Adv IgG and anti-Adv IgM in rats treated with unmodified Adv were higher than those in control group. Rats treated with PEG-Ad that had a 90% modification rate showed lower level of anti-Adv IgG and anti-Adv IgM than those treated with unmodified Adv, whereas rats treated with PEG-Ad that had a 30% or 45% modification rate showed a similar level of anti-Adv IgG and IgM to those treated with unmodified Adv. Systemic administration of PEG-Ad that had a 90% modification rate, and expressed tumor necrosis factor-α, significantly reduced the number of metastatic colonies in the lung compared to unmodified Adv, with negligible side effects. These results suggest that systemic administration of PEG-Ad with an appropriate PEG modification rate has the potential to reduce the production of antibodies against Adv and increase the therapeutic response against metastatic cancer.

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