Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
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Optimized PEGylated Adenovirus Vector Reduces the Anti-vector Humoral Immune Response against Adenovirus and Induces a Therapeutic Effect against Metastatic Lung Cancer
Yusuke Eto, Yasuo Yoshioka, Tatsuhiro Ishida, Xinglei Yao, Tomohiro Morishige, Shogo Narimatsu, Hiroyuki Mizuguchi, Yohei Mukai, Naoki Okada, Hiroshi Kiwada, Shinsaku Nakagawa
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Keywords: adenovirus vector, gene therapy, polyethylene glycol, neutralizing antibody, metastasis
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2010 Volume 33 Issue 9 Pages 1540-1544

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Abstract

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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© 2010 The Pharmaceutical Society of Japan
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