Lentiviral vectors containing an MHC class I promoter
Inventors
Bauche, Cecile • SARRY, Emeline
Assignees
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Publication Number
US-8951535-B2
Publication Date
2015-02-10
Expiration Date
Abstract
The present invention relates to the insertion of a promoter sequence from an MHC class I gene promoter into a lentiviral vector in order to direct the transcription of a transgene, which preferably encodes an immunogenic polypeptide to be expressed in a mammalian cell host, preferably APC (DCs). The invention encompasses these vectors, methods of making the vectors, and methods of using them, including medicinal uses.
Core Innovation
The invention relates to lentiviral vectors that comprise a transgene sequence encoding an immunogenic polypeptide, where the transgene sequence is under transcriptional control of an MHC class I promoter. The disclosed MHC class I promoter includes HLA-A2, HLA-B7, HLA-Cw5, HLA-E, and HLA-F promoter options, and excludes β2-microglobulin (β2m) promoter approaches.
By placing expression under MHC class I promoter control, the specification aims to improve safety and immunogenicity through transcriptional control rather than relying on viral enhancer-driven expression. The problem being solved is that conventional lentiviral expression elements and enhancer configurations present safety and immunogenicity limitations, including enhancer-related effects associated with viral components such as LTR enhancer/promoter regions.
The disclosure further asserts that MHCI promoter-driven transgene expression provides higher dendritic cell (DC)-focused expression and unexpectedly superior in vivo antigen-specific CD8+ CTL responses compared with control promoters such as CMV, EF1α, UBC, and MHC class II/β2m promoter systems. The disclosed vector and particle designs include cPPT/CTS and an LTR sequence that is deleted for the promoter and enhancer of U3, described as part of a self-inactivating lentiviral design.
Claims Coverage
Two independent claims are identified: clm-00001 and clm-00016. Across these independent claims, the core claim coverage is the combination of an immunogenic polypeptide transgene under MHC class I promoter transcriptional control, and a lentiviral vector particle architecture with cPPT/CTS and an LTR with U3 promoter/enhancer deleted.
MHC class I promoter-controlled immunogenic polypeptide transgene lentiviral vector
A lentiviral vector comprising a transgene sequence encoding an immunogenic polypeptide, wherein the transgene sequence is under the transcriptional control of a MHC class I promoter.
cPPT/CTS with U3 promoter/enhancer deleted LTR and MHC class I promoter-controlled transgene
A lentiviral vector particle comprising at least the following sequence elements: a cPPT/CTS polynucleotide sequence; an LTR sequence that is deleted for the promoter and enhancer of U3; and a transgene sequence under control of an MHC class I promoter.
The independent claims collectively define an immunogenic transgene expression system in lentiviral vectors where transgene transcription is controlled by an MHC class I promoter, and where the particle includes cPPT/CTS and a self-inactivating LTR configuration via U3 promoter/enhancer deletion.
Stated Advantages
Improved safety, stated as part of the rationale for replacing viral enhancers by using MHCI promoter-controlled expression.
Higher dendritic cell (DC)-focused expression.
Unexpectedly superior in vivo antigen-specific CD8+ CTL responses compared with control promoter systems (e.g., CMV, EF1α, UBC, and MHC class II/β2m promoters).
Reduced enhancer proximity effects, stated as a safety rationale linked to the vector design with LTR U3 promoter/enhancer deletion.
Documented Applications
Vaccination / immunogenic composition uses described for inducing a T-cell response, including antigen-specific CD8+ CTL responses.
In vivo immunization use described using HIV antigen-driven lentivectors and measurement of antigen-specific T-cell responses using ELISPOT in C57BL/6 mice.
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