title: Optimized PEGylated adenovirus vector reduces the anti-vector humoral immune response against adenovirus and induces a therapeutic effect against metastatic lung cancer.
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-alpha, 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.
authors.affiliation: Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Eto
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.forename: Xinglei
authors.initials: X
authors.lastname: Yao
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morishige
authors.forename: Shogo
authors.initials: S
authors.lastname: Narimatsu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mukai
authors.forename: Naoki
authors.initials: N
authors.lastname: Okada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Nakagawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D011092:Polyethylene Glycols