Changing the adenovirus fiber for retaining gene delivery efficacy in the presence of neutralizing antibodies

• Published in: Gene therapy Vol. 15; no. 12; pp. 921 - 929
• Main Authors: Särkioja, M, Pesonen, S, Raki, M, Hakkarainen, T, Salo, J, Ahonen, M T, Kanerva, A, Hemminki, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2008; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Adenoviruses; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antibodies; Antibodies, Viral - immunology; Antigens, Viral - genetics; Antigens, Viral - immunology; Applied cell therapy and gene therapy; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer; Capsid Proteins - genetics; Carcinoma, Non-Small-Cell Lung - therapy; Care and treatment; Cell Biology; Development and progression; Explants; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Therapy; Gene transfer; Genetic aspects; Genetic Engineering; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Health aspects; Health. Pharmaceutical industry; Human Genetics; Humans; Immunology; Industrial applications and implications. Economical aspects; Infections; Intravenous administration; Lung - immunology; Lung - virology; Lung cancer; Lung Neoplasms - immunology; Lung Neoplasms - therapy; Medical sciences; Mice; Mice, Inbred ICR; Mice, Nude; Nanotechnology; original-article; Patient outcomes; Rodents; Spleen; Transduction, Genetic; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tumors; Viral antibodies; Viruses; Xenograft Model Antitumor Assays; Xenografts; United States; Finland; seroswitching; neutralizing antibody; oncolytic adenovirus; cancer; Virus; Adenoviridae; Antibody; Malignant tumor; Gene therapy; Vector; Cancer
• ISSN: 0893-133X; 0969-7128; 1740-634X; 1476-5462
• DOI: 10.1038/gt.2008.56

Prior infection has primed most adult humans for a rapid neutralizing antibody (NAb) response when re-exposed to adenovirus. NAb induction can severely limit the efficacy of systemic re-administration of adenoviral gene therapy. We hypothesized that changing the fiber knob could overcome NAb. Immune-competent mice were exposed to serotype 5 adenovirus (Ad5)(GL), Ad5/3luc1, Ad5lucRGD or Ad5pK7(GL). Mice immunized with Ad5(GL) featured reduced intravenous Ad5(GL) gene transfer to most organs, including the liver, lung and spleen. Ad5(GL) gene transfer was affected much less by exposure to capsid-modified viruses. Anti-Ad5(GL) NAb blocked intravenous Ad5(GL) gene transfer to orthotopic lung cancer xenografts, whereas capsid-modified viruses were not affected. When gene transfer to fresh cancer and normal lung explants was analyzed, we found that capsid-modified viruses allowed effective gene delivery to tumors in the presence of anti-Ad5(GL) NAb, whereas Ad5(GL) was blocked. In contrast, crossblocking by NAbs induced by different viruses affected gene delivery to normal human lung explants, suggesting the importance of non-fiber-knob-mediated infection mechanisms. We conclude that changing the adenovirus fiber knob is sufficient to allow a relative degree of escape from preexisting NAb. If confirmed in trials, this approach might improve the efficacy of re-administration of adenoviral gene therapy to humans.