Engineered immune cells
AssigneeUnikum Therapeutics Aps
InventorsRasmus Otkjær BAK, Anders LAUSTSEN
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Abstract
The present invention relates to engineered immune cells expressing synthetic receptors that activate expression of a response element encoding a stimulator of interferon genes (STING) protein, and their use in methods for treating disease, in particular cancer and autoimmune, inflammatory and infectious diseases.
Claims25
An engineered immune cell that expresses on its surface a synthetic receptor comprising an extracellular antigen recognition domain that recognises an antigen on a target cell, a transmembrane domain, and an intracellular signalling domain that activates expression of a response element in the cell when the extracellular antigen recognition domain binds the target cell, wherein the response element encodes a stimulator of interferon genes (STING) protein.
The cell of any one of the preceding claims, wherein the synthetic receptor is:
- (d) a synthetic intramembrane proteolysis receptor (SNIPR), such as wherein the synthetic receptor is a synthetic RIP family receptor, optionally wherein the receptor is:
- (i) synthetic Notch receptor;
- (ii) a synthetic Robo receptor;
- or
- (iii) a synthetic RoboNotch receptor;
- (e) a Tango receptor;
- or
- (f) a modular extracellular signalling architecture (MESA) system.
The cell of any one of the preceding claims, wherein the intracellular signalling domain is a transcription factor, optionally wherein the transcription factor comprises a DNA binding domain and a transcriptional activation domain, such as wherein:
- (a) the DNA binding domain is selected from the group consisting of Gal4, Pax6, zinc fingers (ZFs), synthetic zinc fingers (synZFs), transcription activator like effectors (TALEs), TetR, HNF1 alpha, and vHNF1 beta;
- and/or
- (b) the transcription activation domain is selected from the group consisting of VP64, VP16, WWTR1, CREB3, NF-κB, p65, Rta, HSF1, and RelA;
- and/or
- (c) the intracellular signalling domain is selected from the group consisting of Gal4-VP64, Gal4-VP16, TetR-VP64, LacI-VP64, HNF1-WWTR1, HNF1-CREB3, Pax6-p65, ZF-p65, synZF-p65, and HNF1-p65.
The cell of any one of the preceding claims, wherein the extracellular antigen recognition domain is an antibody-derived domain, such as wherein the extracellular antigen recognition domain is an scFv domain.
The cell of any one of the preceding claims, wherein the STING protein comprises:
- (a) a gain-of-function mutation that causes it to be constitutively active in the absence of 2′3′-cGAMP;
- and/or
- (b) a mutation, preferably a substitution, at one or more residues corresponding to R71, S102, V147, N154, V155, G166, C206, G207, G230, H232, R238, F279, R281, R284, R293, or Q315 of SEQ ID NO:1.
The cell of any one of the preceding claims, wherein:
- (a) the cell comprises a heterologous nucleic acid encoding the synthetic receptor;
- and/or
- (b) the cell comprises a heterologous nucleic acid encoding the response element;
- and/or
- (c) the cell comprises a single heterologous nucleic acid encoding the synthetic receptor and the response element.
The cell of any one of the preceding claims, wherein the STING protein activates an immune response, such as wherein:
- (a) the immune response comprises secretion of cytokines, optionally wherein the cytokines modulate the environment of the diseased tissue, or wherein the immune response comprises recruitment or activation of immune cells, such as wherein the cytokines are pro-inflammatory cytokines, optionally wherein the cytokines comprise CXCL10, MCP-1, MCP-2, MIP-1a and/or MIP-1b;
- and/or
- (b) the immune response comprises production of type I IFN.
A method of treating a disease in a subject, comprising administering the cell of any one of the preceding claims, optionally wherein the disease is:
- (e) a cancer;
- (f) an autoimmune disease;
- (g) an inflammatory disease;
- or
- (h) an infectious disease.
The cell or method of any preceding claim, wherein the antigen is a tumour-associated antigen, such as wherein the antigen is selected from:
- (c) the group consisting of CD19, CD20, CD22, CD30, CD33, CD38, CD123, CD138, CS-1, B-cell maturation antigen (BCMA), MAGEA3, MAGEA3/A6, KRAS, CLL1, MUC-1, HER2, EpCam, GD2, GPA7, PSCA, EGFR, EGFRVIII, ROR1, mesothelin, CD33/IL3Ra, c-Met, CD37, PSMA, Glycolipid F77, GD-2, gp100, NY-ESO-1 TCR, FRalpha, CD24, CD44, CD133, CD166, CA-125, HE4, Oval, estrogen receptor, progesterone receptor, uPA, PAI-1, MICA, MICB, ULBP1, ULBP2, ULBP3, ULBP4, ULBP5 or ULBP6, or a combination thereof;
- or
- (d) the group consisting of 5T4, alphafetoprotein (AFP), B7-1 (CD80), B7-2 (CD86), BCMA, B-human chorionic gonadotropin, CA-125, carcinoembryonic antigen (CEA), carcinoembryonic antigen (CEA), CD123, CD133, CD138, CD19, CD20, CD22, CD23, CD24, CD25, CD30, CD33, CD34, CD4, CD40, CD44, CD56, CD70, CD8, CLL-1, c-Met, CMV-specific antigen, CS-1, CSPG4, CTLA-4, DLL3, disialoganglioside GD2, ductal-epithelial mucine, EBV-specific antigen, EGFR variant III (EGFRvIII), ELF2M, endoglin, ephrin B2, epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), epithelial tumour antigen, ErbB2 (HER2/neu), fibroblast associated protein (fap), FLT3, folate binding protein, GD2, GD3, glioma-associated antigen, glycosphingolipids, gp36, HBV-specific antigen, HCV-specific antigen, HER1, HER2, HER2-HER3 in combination, HERV-K, high molecular weight-melanoma associated antigen (HMW-MAA), HIV-1 envelope glycoprotein gp41, HPV-specific antigen, human telomerase reverse transcriptase, IGFI receptor, IGF-II, IL-11Ralpha, IL-13R-a2, Influenza Virus-specific antigen, CD38, insulin growth factor (IGF1)-1, intestinal carboxyl esterase, kappa chain, LAGA-1a, lambda chain, Lassa Virus-specific antigen, lectin-reactive AFP, lineage-specific or tissue specific antigen such as CD3, MAGE, MAGE-A1, major histocompatibility complex (MHC) molecule, major histocompatibility complex (MHC) molecule presenting a tumour-specific peptide epitope, M-CSF, melanoma-associated antigen, mesothelin, MN-CA IX, MUC-1, mut hsp70-2, mutated p53, mutated p53, mutated ras, neutrophil elastase, NKG2D, Nkp30, NY-ESO-1, p53, PAP, prostase, prostate specific antigen (PSA), prostate-carcinoma tumour antigen-1 (PCTA-1), prostate-specific antigen protein, STEAP1, STEAP2, PSMA, RAGE-1, ROR1, RU1, RU2 (AS), surface adhesion molecule, survivin, telomerase, TAG-72, the extra domain A (EDA) and extra domain B (EDB) of fibronectin and the A1 domain of tenascin-C (TnC Al), thyroglobulin, tumour stromal antigens, vascular endothelial growth factor receptor-2 (VEGFR2), virus-specific surface antigen such as an HIV-specific antigen, or a combination thereof.
The cell or method of any one of the preceding claims, wherein the cell has been extracted from blood or bone marrow.
A pharmaceutical composition comprising the engineered immune cell of any preceding claim and a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.