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OwnerNishith REDDY, Milos SIMIC +4inventors
InventorsNishith REDDY, Milos SIMIC, Wendell A. LIM, Hasna MAACHI, Matthias HEBROK, Audrey PARENT
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A method for inhibiting an immune response against a transplanted cell, tissue or organ is provided. In some embodiments, the method comprises administering an immunosuppressive cell to an individual that has received a transplant, wherein the immunosuppressive cell comprises a molecular circuit comprising the following components: (a) a binding-triggered transcriptional switch (BTTS) that recognizes a cell surface marker on a cell of the transplant; and one or any combination of (b) a nucleic acid encoding a pro-inflammatory cytokine sink, (c) a nucleic acid encoding an anti-inflammatory cytokine; (d) a nucleic acid encoding an immune inhibitory receptor, or ligand thereof; and (e) a nucleic acid encoding an ectonucleotidase, and wherein binding of the BTTS to the cell surface marker activates the protein(s) encoded by one or any combination of (b)-(e) by the immunosuppressive cell, thereby inhibiting an immune response against the transplanted organ or cell.
A method for inhibiting an immune response against a transplanted cell, tissue or organ, comprising:
The method of any prior claim, wherein the cell surface marker is a tissue- or organ-specific marker on the transplant.
The method of any prior claim, wherein the anti-inflammatory cytokine is Il-1ra, IL-4, IL-10, IL-11, IL-13, IL-35, and TGF-β, or a variant thereof.
The method of any prior claim, wherein the cytokine sink comprises at least the extracellular domain of a receptor that binds to a pro-inflammatory cytokine.
The method of any prior claim, wherein the cytokine sink is CD25.
The method of any prior claim, wherein the cytokine sink comprises at least the extracellular domain of IL-1R, IL-12R/CD25, IL-18R, TNFR1, TNFR2, IFNGR, GM-CSFR or a subunit thereof that binds to its cognate ligand.
The method of any prior claim, wherein the cytokine sink is an antibody that is tethered to the cell and binds to a pro-inflammatory cytokine.
The method of any prior claim, wherein the immune inhibitory receptor is PD1, CTLA4, BTLA, CD160, KRLG-1, 2B4, Lag-3, Tim-3, or TIGIT.
The method of any prior claim, wherein the ectonucleotidase is CD39 or CD73.
The method of any prior claim, wherein the circuit comprises components (a) and (b).
The method of any prior claim, wherein the circuit comprises components (a) and (c).
The method of any prior claim, wherein the circuit comprises components (a), (b) and (c).
The method of any prior claim, wherein binding of the BTTS to the marker activates expression of TGFβ1, CD25 and, optionally, IL-10.
The method of any prior claim, wherein the BTTS comprises:
The method of any prior claim, wherein the immunosuppressive cell is a myeloid or lymphoid cell.
The method of any prior claim, wherein the immunosuppressive cell is a T cell, a B cell, a macrophage, or a neutrophil.
The method of any prior claim, wherein the immunosuppressive cell is a CD4+ T cell.
The method of any prior claim, wherein the method comprises:
A cell therapy comprising:
Dependencies are inferred from the claim text.