Development of an adenovirus vector vaccine platform for targeting dendritic cells
| Autor: | Elena A. Kashentseva, Samuel W. Kim, David T. Curiel, S. Peter Goedegebuure, William E. Gillanders, Lijin Li, Igor P. Dmitriev, Geert Raes, Jeffrey M. Arbeit, Timothy P. Fleming, Sergey A. Kaliberov, Zhi Hong Lu, Piyush Kumar Sharma |
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| Přispěvatelé: | Department of Bio-engineering Sciences, Cellular and Molecular Immunology |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research single domain antibody dendritic cell Transgene viruses Genetic Vectors Biology medicine.disease_cause Article Virus Adenoviridae Viral vector Mice Viral Proteins 03 medical and health sciences Chimera (genetics) Adenoviral vaccine 0302 clinical medicine medicine Animals Molecular Biology Targeted Ad5 Tropism Vaccines Dendritic Cells Vaccine efficacy Virology 3. Good health 030104 developmental biology 030220 oncology & carcinogenesis Molecular Medicine Homologous recombination Single-Chain Antibodies |
| Zdroj: | Cancer gene therapy |
| DOI: | 10.1038/s41417-017-0002-1 |
| Popis: | Adenoviral (Ad) vector vaccines represent one of the most promising modern vaccine platforms, and Ad vector vaccines are currently being investigated in human clinical trials for infectious disease and cancer. Our studies have shown that specific targeting of adenovirus to dendritic cells dramatically enhanced vaccine efficacy. However, this was achieved using a molecular adapter, thereby necessitating a two component vector approach. To address the mandates of clinical translation of our strategy, we here sought to accomplish the goal of DC targeting with a single-component adenovirus vector approach. To redirect the specificity of Ad vector vaccines, we replaced the Ad fiber knob with fiber-fibritin chimeras fused to DC1.8, a single-domain antibody (sdAb) specific for murine immature DC. We engineered a fiber-fibritin-sdAb chimeric molecule using the coding sequence for DC1.8, and then replaced the native Ad5 fiber knob sequence by homologous recombination. The resulting Ad5 virus, Ad5FF1.8, expresses the chimeric fiber-fibritin sdAb chimera. Infection with Ad5FF1.8 dramatically enhances transgene expression in DC2.4 dendritic cells compared with infection with native Ad5. Ad5FF1.8 infection of bone marrow-derived DC demonstrates that Ad5FF1.8 selectively infects immature DC consistent with the known specificity of DC1.8. Thus, sdAb can be used to selectively redirect the tropism of Ad5 vector vaccines, providing the opportunity to engineer Ad vector vaccines that are specifically targeted to DC, or specific DC subsets. |
| Databáze: | OpenAIRE |
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