NR4A super-repressors and methods of use thereof
Inventors
Schlabach, Michael • SOSA-ALVARADO, Brian Alexander
Assignees
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Publication Number
US-12590312-B2
Publication Date
2026-03-31
Expiration Date
Abstract
The present disclosure provides super-repressors capable of inhibiting the transcription of NR4A1, NR4A2, and NR4A3 target genes. The super-repressors can be used to enhance the effector functions of immune cells, e.g., for adoptive cell therapy. Methods of treating disorders using the modified immune cells are also provided.
Core Innovation
The disclosure describes NR4A super-repressors used with immune effector cells, particularly T cells, for adoptive cell therapy. The super-repressors are DNA-binding proteins that bind the NBRE and/or NurRE response elements but lack a transcription activation domain, thereby inhibiting NR4A1, NR4A2, and NR4A3 transcriptional activity.
The disclosed approach includes polynucleotides encoding polypeptides with a DNA-binding domain that specifically binds both the NBRE element and the NurRE element. In some embodiments, the polypeptide inhibits the activity of NR4A1, NR4A2, and NR4A3, while in other embodiments it is capable of inhibiting transcription of a gene operably associated with both the NBRE element and the NurRE element.
The disclosure further describes fusion architectures in which the DNA-binding domain is combined with optional repression-enhancing domains, including an NR4A ligand-binding domain, KRAB, NCOR1 or NCOR1 fragments, a T2A self-cleavage domain, a nuclear localization signal, a dimerization domain, transcriptional repressor/chromatin compaction domain, and linker options. The immune effector cell population may include an engineered immune receptor such as a CAR or an engineered TCR, with therapeutic use including treating cancer.
Claims Coverage
The partial content identifies two independent claims, each directed to a method of treating cancer by administering cells that encode an NR4A super-repressor polypeptide. Across the two independent claims, the core claim coverage centers on a DNA-binding domain that specifically binds both NBRE and NurRE elements, with one independent claim allowing inhibition of NR4A1/NR4A2/NR4A3 activity or transcriptional repression, and the other independent claim expressly requiring the absence of a transcription activation domain. Inventive features explicitly mentioned are consolidated below based on the independent claim language.
DNA-binding domain specific to both NBRE and NurRE elements
Administering to the subject cells comprising a polynucleotide encoding a polypeptide with a DNA-binding domain that specifically binds to both the NBRE element and the NurRE element.
Inhibition of NR4A1/NR4A2/NR4A3 activity or NurRE/NBRE-associated gene transcription
A polypeptide that inhibits the activity of NR4A1, NR4A2, and NR4A3, or a polypeptide capable of inhibiting transcription of a gene operably associated with both the NBRE element and the NurRE element.
No transcription activation domain in the super-repressor polypeptide
The polypeptide does not comprise a transcription activation domain.
The independent claims cover cancer treatment by administering cells that encode an NR4A super-repressor polypeptide. The claims require a DNA-binding domain that specifically binds both the NBRE and NurRE elements, and they describe functional inhibition of NR4A1/NR4A2/NR4A3 activity or transcription of NBRE/NurRE-associated genes, with one independent claim additionally requiring the polypeptide lacks a transcription activation domain.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating cancer in a subject in need thereof by administering an effective amount of cells comprising a polynucleotide encoding an NR4A super-repressor polypeptide.
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