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Publication Number
US-11535853-B2
Publication Date
2022-12-27
Expiration Date
Abstract
Control Devices are disclosed including RNA destabilizing elements (RDE), RNA control devices, and destabilizing elements (DE) combined with Chimeric Antigen Receptors (CARs) or other transgenes in eukaryotic cells. Multicistronic vectors are also disclosed for use in engineering host eukaryotic cells with the CARs and transgenes under the control of the control devices. These control devices can be used to optimize expression of CARs in the eukaryotic cells so that, for example, effector function is optimized. CARs and transgene payloads can also be engineered into eukaryotic cells so that the transgene payload is expressed and delivered after stimulation of the CAR on the eukaryotic cell.
Core Innovation
The invention provides a primary T-cell that includes a chimeric antigen receptor together with a heterologous nucleic acid. The heterologous nucleic acid comprises a promoter operably linked to a transgene and the transgene is operably linked to an RNA degradation element (RDE), and the heterologous nucleic acid is transcribed to make a transcript encoding the transgene operably linked to the RDE.
In the primary T-cell, the RDE binding protein binds to the AU rich element and regulates expression of the transgene. The RDE can be localized in RNA features including a 3′UTR, 5′UTR, or intron, and the RNA control device can optionally include or omit microRNA binding sites to affect dynamic range.
The invention further describes combining CAR activation with the RNA control device so that expression of effector or payload transgenes preferentially occurs upon stimulation in target sites. CAR and payload co-delivery is described using multicistronic, bicistronic, and lentiviral vector designs that incorporate RDE-regulated payload expression together with CAR-related components.
Claims Coverage
The provided independent claim is directed to a primary T-cell architecture combining a chimeric antigen receptor with an RDE-regulated transgene expression system. Two inventive features are stated, with dependent refinements mainly narrowing the CAR activation ligand and/or the transgene payload to specific named options.
Primary T-cell with CAR and AU-rich RDE-regulated transgene expression
A primary T-cell comprising a chimeric antigen receptor and a heterologous nucleic acid having a promoter operably linked to a transgene that is operably linked to a polynucleotide encoding an RNA degradation element (RDE), wherein the RDE is an AU rich element; and an RDE binding protein, wherein the heterologous nucleic acid is transcribed to make a transcript encoding the transgene operably linked to the RDE, and wherein the RDE binding protein binds to the RDE and regulates expression of the transgene.
AU-rich RNA degradation element with RDE binding protein control
The heterologous nucleic acid includes an RDE that is an AU rich element, and the RDE binding protein binds to the AU rich element and regulates expression of the transgene.
The claim coverage centers on an RDE-based regulation mechanism for transgene expression in a primary T-cell, where an AU rich RDE and an RDE binding protein regulate the transgene produced from a promoter-linked transcript.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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