Smart car devices, DE car polypeptides, side CARs and uses thereof
Inventors
Wang, Benjamin • Zeiner, Gusti
Assignees
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Publication Number
US-11530272-B2
Publication Date
2022-12-20
Expiration Date
Abstract
RNA Control Devices and/or destabilizing elements (DE) can regulate the expression of Chimeric Antigen Receptors (CARs) in eukaryotic cells. More specifically, DEs, RNA Control Devices, and/or side-CARs can be used with small molecule ligands to regulate the expression of Chimeric Antigen Receptors. These DE-CARs, Smart CARs (Smart=small molecule actuatable RNA trigger), Smart-DE-CARs, and/or Side-CARs can be used in the treatment of disease.
Core Innovation
The invention provides Smart CAR systems in eukaryotic cells, combining a chimeric antigen receptor with a ligand-actuatable RNA control device and destabilizing elements (DE, degrons). The nucleic acid includes a polynucleotide encoding a degron operably linked to a polynucleotide encoding a chimeric antigen receptor, under the control of a promoter operably linked to the nucleic acid in an isolated T-cell.
The control architecture uses a sensor element and a regulatory element, optionally including an information transmission element, to modulate CAR/DE-CAR/Smart-DE-CAR expression. The destabilizing element is configured so that expression is regulated in response to binding or actuation, and DE engineering via ligand-binding domains is described to enable tunable control of polypeptide stability or translation upon small-molecule or ligand binding.
In addition, split CARs (“Side-CARs”) are described, where CAR or DE-CAR functionality is reconstituted when two parts associate in response to a stimulus. The stimulus can be a small molecule, antibody crosslinking, or physical stimuli like light, and modulation via GPI cleavage is described. Regulatory factor coupling is also described, including DE- and/or RNA-controlled expression of lymphocyte expansion molecules and cytokines for therapeutic use.
Claims Coverage
The provided independent claims include two inventive claim concepts, both centered on promoter-controlled, nucleic-acid encoded linkage of a degron to a chimeric antigen receptor in an isolated T-cell.
Promoter-linked degron operably linked to a CAR in an isolated T-cell
An isolated T-cell comprising a promoter operably linked to a nucleic acid, wherein the nucleic acid comprises a polynucleotide encoding a degron operably linked to a polynucleotide encoding a chimeric antigen receptor.
Promoter-linked degron operably linked to a CAR in an isolated cytotoxic T-cell
An isolated cytotoxic T-cell comprising a promoter operably linked to a nucleic acid, wherein the nucleic acid comprises a polynucleotide encoding a degron operably linked to a polynucleotide encoding a chimeric antigen receptor.
Across both independent claims, the core inventive architecture is the same: a promoter operably linked to a nucleic acid encoding a degron that is operably linked to a polynucleotide encoding a chimeric antigen receptor, implemented in an isolated T-cell or an isolated cytotoxic T-cell.
Stated Advantages
Manages CAR-related toxicity, including cytokine release (CRS/TLS) and issues associated with CAR activity such as on-tumor off-tumor.
Enables CAR-activity modulation via ligand-controlled DE/RNA control and Side-CAR mechanisms.
Documented Applications
Therapeutic use through adoptive transfer of modified T-cells expressing Smart CAR/DE-CAR/Smart-DE-CAR/Side CAR.
Use of CAR-expression detection as part of evaluating CAR expression.
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