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Publication Number
US-10858660-B2
Publication Date
2020-12-08
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 describes engineered immune effector cells in which time-varying control of CAR/DE-CAR/Side-CAR activity is achieved by administering ligand(s) in regimes and leveraging protein half-life, dilution by cell proliferation, short-lived ligand, and ligand-blocking. This dynamic control tunes CAR-related expression to balance tumor killing with reduced toxicity, including reduced cytokine release syndrome (CRS) and tumor lysis syndrome (TLS), and reduced on-target/off-tumor effects.
The invention further describes RNA control device outputs using RNA degradation elements (RDEs), including AU-rich elements, with degradation dynamics influenced by receptor activation and changes in metabolic state. In this framework, the amount of polypeptide made from a transgene is increased after receptor activation and thereby changes a metabolic state of the immune cell, with depletion/turn-off behavior supported by RDE-mediated transcript degradation and receptor/antigen dynamics.
A mathematical model of effector activity as a function of CAR receptor number and binding interactions is provided, including dynamic range, effector versus inhibitory activity, and cycling on/off with receptor/antigen dynamics and defined timing on/off windows. The invention also links RDE-controlled transgene payload delivery to glycolysis state sensing, including examples involving GAPDH/RDE and IL-2/IFN-γ 3′-UTR-derived RDEs, and outlines therapeutic uses across diseases as well as diagnostic detection of aberrant RDEs.
Claims Coverage
The provided claim content centers on one independent claim directed to a primary T-cell with a receptor-linked RDE transgene whose polypeptide output is increased after receptor activation, changing a metabolic state. Dependent claims refine the encoded transgene products, receptor/target ligand context, and RDE sources such as specific 3′-UTRs.
Primary T-cell with receptor-linked RDE transgene
A primary T-cell comprising a receptor, and a heterologous nucleic acid comprising a promoter operably linked to a polynucleotide encoding a transgene operably linked to a polynucleotide encoding a RNA degradation element (RDE), wherein the RDE is an AU rich element, wherein the heterologous nucleic acid is transcribed to make a transcript encoding the transgene operably linked to the RDE, and wherein the amount of polypeptide made from the transgene is increased after the receptor activates the primary T-cell and thereby changes a metabolic state of the primary T-cell.
Claim coverage centers on receptor activation-dependent regulation of transgene polypeptide output using an AU-rich RDE in the transgene transcript, producing a change in the primary T-cell metabolic state. Dependent claims refine the encoded transgene products, receptor/target ligand context, and RDE sources such as specific 3′-UTRs.
Stated Advantages
Increased amount of polypeptide made from the transgene after receptor activates the primary T-cell.
Activation results in a change in a metabolic state of the primary T-cell.
Activation-dependent increased or timed transgene expression and payload delivery.
Balances tumor killing with reduced toxicity, including reduced CRS/TLS and reduced on-target/off-tumor effects.
Minimizes exhaustion/dysfunction of effector cells.
Documented Applications
Use of the primary T-cell for use where the solid tumor is ovarian cancer.
CAR targeting against antigen examples associated with AML and DLBCL.
Therapeutic uses across diseases are outlined, including contexts where engineered T-cells target tumor-associated ligands.
Diagnostic detection of aberrant RDEs is described.
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