CHIMERIC TRANSCRIPTION FACTOR VARIANTS WITH AUGMENTED SENSITIVITY TO DRUG LIGAND INDUCTION OF TRANSGENE EXPRESSION IN MAMMALIAN CELLS

    公开(公告)号:US20200181624A1

    公开(公告)日:2020-06-11

    申请号:US16467015

    申请日:2017-12-11

    摘要: Provided herein is a system for inducible expression of a chimeric antigen receptor in cells, such as mammalian cells. The system comprises: a) a first nucleic acid comprising a first promoter inducible by a drug, wherein the first nucleic acid is operably linked to a first polynucleotide that encodes a chimeric antigen receptor, which comprises a ligand binding domain that is specific for a ligand selected from the group consisting of a tumor specific molecule, a viral specific molecule, and any other selected molecule expressed on a target cell population, wherein the ligand elicits recognition, modulation, inhibition, and/or elimination by a lymphocyte, a second polynucleotide, which encodes a spacer or an optimized polypeptide spacer, a third polynucleotide, which encodes a transmembrane domain and a fourth polynucleotide, which encodes an intracellular signaling domain and b) a second nucleic acid comprising a second promoter that is operably linked to a nucleic acid encoding a transcriptional activator for the first promoter inducible by drug, wherein the system is inducible by an amount of the drug that is less than a comparable system utilizing a wild type HEA3 chimeric transcription factor, or the system has an enhanced transcriptional expression at a given concentration of the drug compared to a wild type HEA3. Methods of making such cells and methods of treatment using these cells are also provided.