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US 2025/0082679 A1Published application
Method of Targeting Cells and Associated Compositions
AssigneeThunder Biotech Inc.
InventorsKim Leslie O'Neill, Michelle Townsend
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AssigneeThunder Biotech Inc.
InventorsKim Leslie O'Neill, Michelle Townsend
Estimating the term…
Described herein is a delivery system that targets leukocytes and in some embodiments monocytes to deliver nucleic acid encoding a chimeric antigen receptor. Additionally, described herein is a method of using a delivery system to transduce leukocytes and in some embodiments monocytes to deliver nucleic acid encoding a chimeric antigen receptor. The delivery system may also function to activate the target cell by providing a ligand to the chimeric antigen receptor. Furthermore, described herein is a delivery system that also include a nucleic acid inhibitor that decreases the expression of a protein that forms a part of the pathway that degrades the chimeric receptor. In embodiments, the binding of a ligand to the extracellular domain of the chimeric receptor activates the intracellular portion of the chimeric receptor. Activation of the intracellular portion of the chimeric receptor may polarize the macrophage into an M1 or M2 macrophage.
A nucleic acid delivery system, comprising:
The nucleic acid delivery system of any one of the preceding claims, wherein the cell is a leukocyte.
The nucleic acid delivery system of any one of the preceding claims, wherein the leukocyte is a macrophage or dendritic cell.
The nucleic acid delivery system of any one of the preceding claims, wherein the cell is in vivo.
The nucleic acid delivery system of any one of the preceding claims, wherein the cell is a macrophage is expressing the chimeric receptor.
The nucleic acid delivery system of any one of the preceding claims, wherein the nucleic acid is an RNA.
The nucleic acid delivery system of any one of the preceding claims, wherein activation of the cytoplasmic portion of the chimeric receptor polarizes the macrophage or dendritic cell to an M1 macrophage.
The nucleic acid delivery system of any one of the preceding claims, wherein activation of the cytoplasmic portion of the chimeric receptor polarizes the macrophage or dendritic cell to an M2 macrophage.
The nucleic acid delivery system of any one of the preceding claims, wherein the extracellular domain is an antibody.
The nucleic acid delivery system of any one of the preceding claims, wherein the protein is RFN216 or Rab7b.
The nucleic acid delivery system of any one of the preceding claims, wherein the nucleic acid inhibitor is an shRNA that is not integrated into the genome.
The nucleic acid delivery system of any one of the preceding claims, wherein the binding of a ligand to the extracellular domain of the chimeric receptor initiates downstream signaling in the cytoplasmic portion.
The nucleic acid delivery system of any one of the preceding claims, wherein the cytoplasmic portion of the chimeric receptor comprises a cytoplasmic domain from a toll-like receptor, myeloid differentiation primary response protein (MYD88), toll-like receptor 3 (TLR3), toll-like receptor 4 (TLR4), toll-like receptor 7 (TLR7), toll-like receptor 8 (TLR8), toll-like receptor 9 (TLR9), myelin and lymphocyte protein (MAL), interleukin-1 receptor associated kinase 1 (IRAK1), low affinity immunoglobulin gamma Fc region receptor III-A (FCGR3A), low affinity immunoglobulin gamma Fc region receptor II-a (FCGR2A), and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G).
The nucleic acid delivery system of any one of the preceding claims, wherein the ligand is selected from the group consisting of Thymidine Kinase (TK1), Hypoxanthine-Guanine Phosphoribosyltransferase (HPRT), Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1), Mucin-16 (MUC-16), Epidermal Growth Factor Receptor vIII (EGFRvIII), Mesothelin, Human Epidermal Growth Factor Receptor 2 (HER2), Carcinoembryonic Antigen (CEA), B-Cell Maturation Antigen (BCMA), Glypican 3 (GPC3), Fibroblast Activation Protein (FAP), Erythropoietin-Producing Hepatocellular Carcinoma A2 (EphA2), Natural Killer Group 2D (NKG2D) ligands, Disialoganglioside 2 (GD2), B7-H3, PSCA, PSMA, CD19, CD20, CD30, CD33, CD123, CD133, CD138, and CD171.
The nucleic acid delivery system of any one of the preceding claims, wherein the extracellular domain of the chimeric receptor is an antibody or fragment thereof specific for a ligand selected from the group consisting of Thymidine Kinase (TK1), Hypoxanthine-Guanine Phosphoribosyltransferase (HPRT), Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1), Mucin-16 (MUC-16), Epidermal Growth Factor Receptor vIII (EGFRvIII), Mesothelin, Human Epidermal Growth Factor Receptor 2 (HER2), Carcinoembryonic Antigen (CEA), B-Cell Maturation Antigen (BCMA), Glypican 3 (GPC3), Fibroblast Activation Protein (FAP), Erythropoietin-Producing Hepatocellular Carcinoma A2 (EphA2), Natural Killer Group 2D (NKG2D) ligands, Disialoganglioside 2 (GD2), CD19, CD20, CD30, CD33, CD123, CD133, CD138, and CD171.
The nucleic acid delivery system of any one of the preceding claims, wherein the antibody or fragment thereof is a single-chain variable fragment (scFv) or a single-domain antibody (sdAb).
The nucleic acid delivery system of any one of the preceding claims, wherein the chimeric receptor further comprises a hinge between the transmembrane domain and the extracellular domain.
The nucleic acid delivery system of any one of the preceding claims, wherein the targeting agent is protein based.
The nucleic acid delivery system of any one of the preceding claims, wherein the targeting agent is lipid based.
The nucleic acid delivery system of any one of the preceding claims, wherein activation of the cytoplasmic portion of the chimeric receptor polarizes the macrophage.
The nucleic acid delivery system of any one of the preceding claims, wherein the nucleic acid comprises a promoter operably linked to the polynucleotide.
The nucleic acid delivery system of any one of the preceding claims, wherein the promoter is selected from the group consisting of CD68 promoter (for example CD68/150(r)), EF1α, CMV, lysM, csflr, CD11c, SRA, and CDF11b.
The nucleic acid delivery system of any one of the preceding claims, wherein the delivery vector is a liposome.
The nucleic acid delivery system of any one of the preceding claims, wherein the delivery vector is a lipid nanoparticle.
The nucleic acid delivery system of any one of the preceding claims, wherein the targeting agent is a macrophage ligand.
The nucleic acid delivery system of any one of the preceding claims, wherein the macrophage ligand is selected from the group consisting of toll-like receptor, GM-CSF, CD14, CD16, CD64, CD115, CD192, CX2CR1, CD226, CD284, CD155, or any combination thereof comprises anyone of CD3, CD4, CD8, CD23, or CD28.
A delivery system for a chimeric antigen receptor, the system comprising:
A method of producing a polarized macrophage in a subject, the method comprising:
The method according to claim 97, wherein the activating agent and the targeting agent are the same.
A method of producing a polarized tumor associated macrophage (TAM) in a subject, the method comprising:
A method of altering a tumor in a subject, the method comprising:
A method of treating a cancer in a subject, the method comprising:
Dependencies are inferred from the claim text.