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AssigneeFlagship Pioneering Innovations VI, LLC
InventorsDouglas Ewen Cameron, Bradley Joseph Kubick, Christa Elyse Osuna, Nicolas Cordero, Edwin Xavier Arauz Diaz, Syandan Chakraborty, Pratibha Singh, Lee John Flaherty, Alok Das Mohapatra
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Compositions comprising donor cells, acceptor cells, and methods involving the same are described herein. In some embodiments, the donor cell comprises a T cell receptor (TCR) and a cargo, and the acceptor cell comprises an MHC. In some embodiments, the TCR facilitates transfer of the cargo to the acceptor cell. In some embodiments, the donor cell comprises a chimeric antigen receptor (CAR) and a cargo, and the acceptor cell comprises an antigen bound by the CAR. In some embodiments, the CAR facilitates transfer of the cargo to the acceptor cell.
A method of modifying an acceptor cell, the method comprising:
A method of modifying an acceptor cell, the method comprising:
A method of modifying an acceptor cell, the method comprising:
A method of delivering a cargo molecule to an acceptor cell, the method comprising:
A method of modulating a biological function of a target tissue or an acceptor cell in a subject, the method comprising:
A method of making a modified cell, the method comprising:
The method of any of the preceding claims, wherein the donor cell is a T cell.
The method of any of the preceding claims, wherein the donor cell is a natural killer cell (NK cell).
A composition comprising a plurality of acceptor cells, the plurality of acceptor cells comprising:
A composition comprising a plurality of acceptor cells, the plurality of acceptor cells comprising:
The method or composition of any of the preceding claims, wherein the membrane-associated agent comprises a TCR alpha molecule and a TCR beta molecule.
The method or composition of any of the preceding claims, wherein the membrane-associated agent comprises a TCR gamma molecule and/or a TCR delta molecule.
The method or composition of any of the preceding claims, wherein the membrane-associated agent comprises a CD3 zeta molecule, or a functional fragment or variant thereof.
The method or composition of any of the preceding claims, wherein the membrane-associated moiety comprises the transmembrane domains of the TCR alpha molecule, the TCR beta molecule, the TCR gamma molecule, the TCR delta molecule, and/or the CD3 zeta molecule.
The method or composition of any of the preceding claims, wherein the first docking moiety comprises the extracellular domain of the TCR alpha molecule and/or the TCR beta molecule.
The method or composition of any of the preceding claims, wherein the first docking moiety comprises the extracellular domain of the TCR gamma molecule and/or the TCR delta molecule.
The method or composition of any of the preceding claims, wherein the intracellular moiety comprises the intracellular domain of the TCR alpha molecule, the TCR beta molecule, the TCR gamma molecule, the TCR delta molecule, and/or the CD3 zeta molecule.
The method or composition of any of the preceding claims, wherein the donor cell is an activated immune cell (e.g., an activated T cell).
The method or composition of any of the preceding claims, wherein the donor cell expresses greater levels of the TCR, or the functional fragment or variant thereof, relative to a comparable donor cell that is not activated (e.g., wherein the donor cell comprises at least 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% more copies of the TCR, or the functional fragment or variant thereof, relative to a comparable donor cell that is not activated, and/or wherein the donor cell comprises at least 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 copies of the TCR, or the functional fragment or variant thereof.
The method or composition of any of the preceding claims, wherein the membrane associated agent comprises a complex, the complex comprising:
The method or composition of any of the preceding claims, wherein the intracellular moiety binds the cargo molecule.
The method or composition of any of the preceding claims, wherein the cargo molecule is associated with (e.g., covalently or non-covalently attached to, or specifically binds to a molecule bound to) the membrane-associated agent (e.g., at the intracellular moiety or the membrane-associated moiety).
The method or composition of any of the preceding claims, wherein the cargo molecule comprises a polypeptide (e.g., a CRISPR enzyme, e.g., a Cas9).
The method or composition of any of the preceding claims, wherein the cargo molecule comprises a nucleic acid molecule (e.g., a DNA molecule or an RNA molecule, e.g., an mRNA, miRNA, or circRNA);
The method or composition of any of the preceding claims, wherein the acceptor cell is comprised in a subject (e.g., a mammalian subject, e.g., a human subject).
The method or composition of any of the preceding claims, wherein the membrane-associated agent is endogenous to the donor cell.
The method or composition of any of the preceding claims, wherein the membrane-associated agent is exogenous to the donor cell.
The method or composition of any of the preceding claims, wherein the membrane-associated agent or intracellular moiety comprises a protease cleavage site recognized by a protease that is not expressed in the plurality of donor cells.
A method of modifying an acceptor cell, the method comprising:
A method of delivering a cargo molecule to an acceptor cell, the method comprising:
A method of modulating a biological function of a target tissue or an acceptor cell in a subject, the method comprising:
A method of making a modified cell, the method comprising:
The method of any of the preceding claims, wherein the donor cell is a T cell or an NK cell.
The composition comprising a plurality of acceptor cells of claim 51, which is a composition according to any of claims 53-60.
A composition comprising a plurality of acceptor cells, the plurality of acceptor cells comprising:
A composition comprising a plurality of acceptor cells, the plurality of acceptor cells comprising:
A composition comprising a plurality of donor cells, the plurality of donor cells comprising:
A composition comprising a plurality of donor cells, the plurality of donor cells comprising:
The method or composition of any of the preceding claims, wherein the cargo molecule is exogenous to the donor cell.
The method of composition of any of the preceding claims, wherein the cargo molecule is endogenous to the donor cell.
The method or composition of any of the preceding claims, wherein the cargo molecule is exogenous to the acceptor cell.
The method or composition of any of the preceding claims, wherein the cargo molecule is endogenous to the acceptor cell.
The method or composition of any of the preceding claims, wherein the CAR comprises an extracellular domain comprising the first docking moiety.
The method or composition of any of the preceding claims, wherein the first docking moiety comprises an antibody molecule and the second docking moiety comprises an epitope recognized by the antibody molecule.
The method or composition of any of the preceding claims, wherein the first docking moiety comprises an avidin (e.g., a monomeric avidin, e.g., an mSA2, or a functional fragment or variant thereof) bound to a biotinylated antibody molecule, wherein the biotinylated antibody molecule recognizes an epitope comprised by the second docking moiety.
The method or composition of any of the preceding claims, wherein the intracellular moiety of the membrane-associated agent comprises a CD3 zeta cytoplasmic domain, or a functional fragment or variant thereof;
The method or composition of any of the preceding claims, wherein the membrane associated agent comprises a fusion protein comprising:
The method or composition of any of the preceding claims, wherein the intracellular moiety binds the cargo molecule, e.g., covalently or noncovalently.
The method or composition of any of the preceding claims, wherein the membrane-associated moiety comprises a transmembrane domain, e.g., the transmembrane domain of CD28, CD8, or a TCR CD3 zeta molecule.
The method or composition of any of the preceding claims, wherein the donor cell is an activated immune cell (e.g., an activated T cell).
The method or composition of any of the preceding claims, wherein the donor cell expresses greater levels of the CAR relative to a comparable donor cell that is not activated (e.g., wherein the donor cell comprises at least 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% more copies of the CAR, relative to a comparable donor cell that is not activated, and/or wherein the donor cell comprises at least 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 copies of the CAR.
The method or composition of any of the preceding claims, wherein the cargo molecule is associated with (e.g., covalently or non-covalently attached to, or specifically binds to a molecule bound to) the membrane-associated agent (e.g., at the intracellular moiety or the membrane-associated moiety).
The method or composition of any of the preceding claims, wherein the cargo molecule comprises a polypeptide (e.g., a CRISPR enzyme, e.g., a Cas9).
The method or composition of any of the preceding claims, wherein the cargo molecule comprises a nucleic acid molecule (e.g., a DNA molecule or an RNA molecule, e.g., an mRNA, miRNA, or circRNA);
The method or composition of any of the preceding claims, wherein the acceptor cell is comprised in a subject (e.g., a mammalian subject, e.g., a human subject).
The method or composition of any of the preceding claims, wherein the membrane-associated agent or intracellular moiety comprises a protease cleavage site recognized by a protease that is not expressed in the plurality of donor cells.
The composition or method of any of the preceding claims, wherein the acceptor cell is not a cancer cell.
The composition or method of any of the preceding claims, wherein the acceptor cell is in a subject that does not have cancer.
The composition or method of any of the preceding claims, wherein the acceptor cell is ex vivo and is from subject that does not have cancer.
Dependencies are inferred from the claim text.