Optimized PEGylated adenovirus vector reduces the anti-vector humoral immune response against adenovirus and induces a therapeutic effect against metastatic lung cancer.
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.
Eto
Yusuke
Y
Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Yoshioka
Yasuo
Y
Ishida
Tatsuhiro
T
Yao
Xinglei
X
Morishige
Tomohiro
T
Narimatsu
Shogo
S
Mizuguchi
Hiroyuki
H
Mukai
Yohei
Y
Okada
Naoki
N
Kiwada
Hiroshi
H
Nakagawa
Shinsaku
S
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
D000914:Antibodies, Viral; D000998:Antiviral Agents; D011092:Polyethylene Glycols