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Publication Number
US-11572566-B2
Publication Date
2023-02-07
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 comprising a chimeric antigen receptor and a heterologous nucleic acid. The heterologous nucleic acid includes a promoter operably linked to a polynucleotide encoding a transgene that is operably linked to a RNA degradation element, and the RNA degradation element is an AU rich element. The heterologous nucleic acid is transcribed to make a transcript encoding the transgene operably linked to the RNA degradation element.
The primary T-cell is configured so that the amount of polypeptide made from the transgene is increased after the chimeric antigen receptor activates the primary T-cell. This activation changes a metabolic state of the primary T-cell, so transgene expression is linked to receptor activation and to a metabolic-state change.
The disclosed approach situates this AU rich element RNA degradation control within CAR, DE-CAR, and Side-CAR and RNA control device concepts to modulate CAR, DE-CAR, and/or Side-CAR polypeptide levels over a treatment course. The framework further indicates time-regulated dosing and control strategies to reduce initial toxicity such as tumor lysis syndrome and cytokine release syndrome, and to increase killing later as tumor antigen decreases.
Claims Coverage
The independent claim is directed to an engineered primary T-cell with CAR-driven, metabolic-state-associated upregulation of a transgene polypeptide controlled by an AU rich element RNA degradation element, producing a transcript linking the transgene to the RNA degradation element. The inventive features are the CAR-triggered increase in transgene polypeptide amount via metabolic-state change, and the use of an AU rich element as the RNA degradation element on the transcript.
CAR-activated metabolic-state increase of transgene polypeptide
A primary T-cell comprising a chimeric antigen receptor and a heterologous nucleic acid such that the amount of polypeptide made from the transgene is increased after the chimeric antigen receptor activates the primary T-cell, thereby changing a metabolic state of the primary T-cell.
AU rich element RNA degradation element operably linked to a transgene
A heterologous nucleic acid in which a promoter is operably linked to a polynucleotide encoding a transgene operably linked to a RNA degradation element, where the RNA degradation element is an AU rich element; the heterologous nucleic acid is transcribed to make a transcript encoding the transgene operably linked to the RNA degradation element.
Overall, the independent claim coverage centers on coupling CAR activation to an increase in transgene polypeptide amount through a metabolic-state change, while post-transcriptional regulation is provided by an AU rich element RNA degradation element operably linked to the transgene.
Stated Advantages
Increased amount of polypeptide made from the transgene after chimeric antigen receptor activates the primary T-cell.
Changing metabolic state of the primary T-cell to increase transgene polypeptide output after CAR activation.
Reduces initial toxicity described as tumor lysis syndrome (TLS) and cytokine release syndrome (CRS).
Increases killing later as tumor antigen decreases.
Documented Applications
Therapeutic modulation of CAR, DE-CAR, and/or Side-CAR polypeptide levels on immune cells (including T cells and NK cells) over a treatment course, with toxicity mitigation (TLS/CRS) and later increased killing as tumor antigen decreases.
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