Smart CAR devices, DE CAR polypeptides, side CARs and uses thereof
Inventors
Wang, Benjamin • Zeiner, Gusti
Assignees
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Publication Number
US-10508152-B2
Publication Date
2019-12-17
Expiration Date
Abstract
The present invention relates generally to the field of RNA Control Devices and/or destabilizing elements (DE) combined with Chimeric Antigen Receptors (CARs) in eukaryotic cells. The present invention also relates to split CARs (Side-CARs) in eukaryotic cells. More specifically, the present invention relates to DEs, RNA Control Devices, and/or side-CARs combined with Chimeric Antigen Receptors to make small molecule actuatable CAR polypeptides. The present invention also relates to DE-CARs, Smart CARs (Smart=small molecule actuatable RNA trigger), Smart-DE-CARs, and/or Side-CARs for use in the treatment of disease.
Core Innovation
The invention relates to controlling expression of a chimeric antigen receptor by transcribing a polynucleotide encoding the chimeric antigen receptor together with an RNA control device comprised of a sensor element and a ribozyme element. The RNA control device is encoded by an RNA transcript that includes the sensor element and ribozyme element operably linked to a portion of the transcript encoding the chimeric antigen receptor. A promoter is operably linked to the polynucleotide encoding the RNA control device and the polynucleotide encoding the chimeric antigen receptor to drive transcription of the combined construct.
The RNA control device is exposed to a ligand for the sensor domain. Ligand binding by the sensor domain changes the activity of the ribozyme, thereby changing the expression of the chimeric antigen receptor. The chimeric antigen receptor is comprised of an extracellular element, a transmembrane element, and an intracellular element, with the transmembrane element positioned between the extracellular element and the intracellular element.
The described approach is applied to engineered eukaryotic cells, preferably human T-cells and related immune cell populations, in which the constructs can be introduced ex vivo or in vivo using viral and non-viral delivery methods. The document further describes modulating cellular activity by adding ligands for the DEs, RNA control devices comprised of sensor element and ribozyme, and/or Side-CAR, including combination or orthogonal CAR systems and ligand/anti-ligand approaches to control expression timing and associated toxicity/effector function.
Claims Coverage
The independent claim is directed to a method of controlling expression of a chimeric antigen receptor using an RNA control device with a sensor element and a ribozyme element, where ligand binding changes ribozyme activity and therefore changes CAR expression. The independent claim includes key structural features of the CAR (extracellular, transmembrane, intracellular elements) and the transcriptional organization of the RNA control device on the same transcript.
Ligand-responsive ribozyme-based RNA control of CAR expression
Transcribing a polynucleotide encoding a chimeric antigen receptor and an RNA control device comprised of a sensor element and a ribozyme element to form an RNA transcript that encodes the RNA control device operably linked to a portion of the transcript encoding the chimeric antigen receptor, and exposing the transcript to a ligand for the sensor domain so that ligand binding changes ribozyme activity to change CAR expression.
CAR architecture with extracellular, transmembrane, and intracellular elements
Configuring the chimeric antigen receptor to include an extracellular element, a transmembrane element, and an intracellular element, wherein the transmembrane element is between the extracellular element and the intracellular element.
Overall, the claim coverage centers on a ligand-activated RNA control device (sensor element and ribozyme element) that changes ribozyme activity upon ligand binding to alter chimeric antigen receptor expression, together with a CAR having extracellular, transmembrane, and intracellular elements arranged with the transmembrane element between the extracellular and intracellular elements.
Stated Advantages
Documented Applications
No documented applications found
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