Combination therapy with gold controlled transgenes

Inventors

Wang, Benjamin • Dylla, Scott • Zeiner, Gusti

Assignees

Chimera Bioengineering Inc

Abstract

Control Devices are disclosed including RNA destabilizing elements (RDE) combined with transgenes, including Chimeric Antigen Receptors (CARs) in eukaryotic cells. These RDEs can be used to optimize expression of transgenes, e.g., 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 at desired times from the eukaryotic cell. Such CAR T-cells with transgene payloads can be combined with the administration of other molecules, e.g., other therapeutics such as anticancer therapies.

Core Innovation

The patent relates to RNA control technology for engineered eukaryotic cells, where RNA destabilizing elements regulate transgene expression kinetics. The disclosed concept uses RNA degradation elements, including AU rich elements and specific AU#/3′UTR-derived elements, coupled with ligand-controlled RNA control devices and with metabolic or glycolytic state control, including GAPDH and HuR, to control expression timing of payloads, including chimeric antigen receptor payloads.

The disclosed invention provides nucleic-acid constructs for CAR and transgenes in which payload expression is conditionally controlled using a RNA degradation element linked to the transgene. Transcribing the heterologous nucleic acid produces a transcript encoding the transgene operably linked to the RDE, thereby conditioning payload production, including cytokines and other functional molecules such as IL-12, antibodies, gene regulatory RNAs, enzymes, imaging reporters, and a kill-switch example using HSV-TK/GCV.

In the CAR T-cell context, a therapeutically effective method includes administering primary T-cells comprising an anti-TnMUC1 chimeric antigen receptor together with a heterologous nucleic acid that encodes an IL-12 transgene operably linked to an RNA degradation element that is an AU rich element. Binding of the anti-TnMUC1 chimeric antigen receptor to TnMUC1-positive prostate, triple negative breast, or pancreatic cancer activates the primary T-cell, increases the IL-12 amount from the polynucleotide, and results in killing of the cancer cells, while reducing systemic cytokine levels while maintaining localized anti-tumor activity.

Claims Coverage

The provided independent claim recites a method of treating a patient with TnMUC1-positive prostate, triple negative breast, or pancreatic cancer using primary T-cells expressing an anti-TnMUC1 CAR and a heterologous IL-12 nucleic acid whose transcript includes an RDE that is an AU rich element. The inventive coverage is centered on 3 main inventive features governing targeting, conditional IL-12 expression, and therapeutic effect.

Overall claim coverage centers on administering primary anti-TnMUC1 CAR T-cells to engage TnMUC1-positive tumors, while using an AU-rich RNA degradation element linked to a heterologous IL-12 encoding nucleic acid to condition transcriptional output, increasing IL-12 upon CAR binding and enabling killing of tumor cells.

Stated Advantages

Documented Applications