title: Determinants of intracellular RNA pharmacokinetics: Implications for RNA-based immunotherapeutics.
abstract: RNAs with optimized properties are increasingly investigated as a tool to deliver the genetic information of complete antigens into professional antigen-presenting dendritic cells for HLA haplotype-independent antigen-specific vaccination against cancer. As the dose of the antigen and duration of its presentation are critical factors for generating strong and sustained antigen-specific immune responses, improvement of the immunobioavailability of RNA-based vaccines has been a recurrent subject of research. Substantial increase of the amount of antigen produced from RNA can be achieved by optimizing RNA stability and translational efficiency. Both features are determined by cis-acting elements in the RNA, namely the 5' cap, the poly(A) tail, and the sequence of the coding and non-coding regions, which interact with corresponding trans-acting factors. This article summarizes recent developments in identifying optimized RNA for expression of foreign proteins in dendritic cells, as well as their implications for immunotherapy based on antigen-encoding RNA.
authors.affiliation: Center for Translational Oncology and Immunology (TrOn), Mainz, Germany.
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Kuhn
authors.forename: Mustafa
authors.initials: M
authors.lastname: Diken
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kreiter
authors.forename: Britta
authors.initials: B
authors.lastname: Vallazza
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Türeci
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
mesh_terms: D020413:3' Untranslated Regions; D017951:Antigen Presentation / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000493:pharmacokinetics*; D003713:Dendritic Cells / Q000276:immunology; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D009369:Neoplasms / Q000628:therapy; D011061:Poly A / Q000378:metabolism; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D026723:Polyadenylation; D012313:RNA / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012315:RNA Caps / Q000276:immunology / Q000378:metabolism*; D020871:RNA Stability
chemical_list: D020413:3' Untranslated Regions; D019496:Cancer Vaccines; D039102:Poly(A)-Binding Proteins; D012315:RNA Caps; D011061:Poly A; D012313:RNA; D015252:Deoxyribonucleases, Type II Site-Specific