Therapeutic cell systems and methods for treating cancer and infectious diseases
AssigneeRubius Therapeutics, Inc.
InventorsThomas Joseph Wickham, Sivan Elloul
Life of this patent
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Abstract
The present disclosure relates to erythroid cells that have been engineered to include, e.g., at the surface of the cell, one or more exogenous stimulatory polypeptides, wherein the exogenous stimulatory polypeptides presented are sufficient to stimulate an immune killer cell. The engineered enucleated cells of the present disclosure are useful in methods of activating NK cells and/or CD8+T-cells in a subject in need thereof, such as subjects having cancer or an infectious disease, and in particular cancers or infectious diseases characterized by downregulation of MHC Class I presentation.
Claims30
An enucleated erythroid cell engineered to stimulate an immune killer cell, wherein the enucleated erythroid cell comprises:
- a first exogenous stimulatory polypeptide, wherein the first exogenous stimulatory polypeptide is a fusion polypeptide comprising a heterologous transmembrane domain from a polypeptide selected from the group consisting of:
- glycophorin A, glycophorin B, cluster of differentiation (CD) 147, CD44, CD58, intercellular adhesion molecule 4, basal cell adhesion molecule, complement receptor 1, CD99, erythroblast membrane-associated protein (ERMAP), junctional adhesion molecule A, neuroplastin, amphoterin-induced protein 2, Down Syndrome cell adhesion molecule-like 1, small integral membrane protein 1, transferrin receptor, Fas ligand, and Kell;
- and
- a second exogenous stimulatory polypeptide,
- wherein the first and second exogenous stimulatory polypeptides are sufficient to stimulate the immune killer cell.
An engineered enucleated erythroid cell comprising a first exogenous stimulatory polypeptide, wherein the first exogenous stimulatory polypeptide is a fusion polypeptide comprising (i) an interleukin-15 (IL-15) polypeptide, or a fragment thereof, (ii) an extracellular portion of an interleukin-15 receptor alpha (IL-15RA) polypeptide, or a fragment thereof, and (iii) a heterologous transmembrane domain from a polypeptide selected from the group consisting of:
- glycophorin A, glycophorin B, CD147, CD44, CD58, intercellular adhesion molecule 4, basal cell adhesion molecule, complement receptor 1, CD99, ERMAP, junctional adhesion molecule A, neuroplastin, amphoterin-induced protein 2, Down Syndrome cell adhesion molecule-like 1, small integral membrane protein 1, transferrin receptor, Fas ligand, and Kell.
An engineered enucleated erythroid cell comprising at least a first exogenous stimulatory polypeptide comprising a fusion polypeptide comprising (i) a polypeptide selected from the group consisting of:
- MICA, MICB, and IGF-1, and (ii) a heterologous transmembrane domain from a polypeptide selected from the group consisting of:
- glycophorin A, glycophorin B, CD147, CD44, CD58, intercellular adhesion molecule 4, basal cell adhesion molecule, complement receptor 1, CD99, ERMAP, junctional adhesion molecule A, neuroplastin, amphoterin-induced protein 2, Down Syndrome cell adhesion molecule-like 1, small integral membrane protein 1, transferrin receptor, Fas ligand, and Kell.
An engineered enucleated erythroid cell, comprising:
- i. a first exogenous stimulatory polypeptide, wherein the first exogenous stimulatory polypeptide is a fusion polypeptide comprising an IL-15/IL15RA fusion comprising an IL-15 polypeptide, or a fragment thereof, linked to the extracellular portion of an IL-15RA polypeptide, or a fragment thereof, by a linker;
- and
- ii. a second exogenous stimulatory polypeptide, wherein the second exogenous stimulatory polypeptide comprises 4-1BBL, or a functional fragment thereof;
- wherein one or both of the first exogenous stimulatory polypeptide and the second exogenous stimulatory polypeptide comprise a heterologous transmembrane domain from a polypeptide selected from the group consisting of:
- glycophorin A, glycophorin B, CD147, CD44, CD58, intercellular adhesion molecule 4, basal cell adhesion molecule, complement receptor 1, CD99, ERMAP, junctional adhesion molecule A, neuroplastin, amphoterin-induced protein 2, Down Syndrome cell adhesion molecule-like 1, small integral membrane protein 1, transferrin receptor, Fas ligand, and Kell.
An engineered enucleated erythroid cell, comprising:
- i. a first exogenous stimulatory polypeptide, wherein the first exogenous stimulatory polypeptide comprises 4-1BBL, or a fragment thereof;
- and
- ii. a second exogenous stimulatory polypeptide, wherein the second exogenous stimulatory polypeptide comprises IL-12, or a fragment thereof,
- wherein one or both of the first exogenous stimulatory polypeptide and the second exogenous stimulatory polypeptide is a fusion polypeptide further comprising a heterologous transmembrane domain from a polypeptide selected from the group consisting of:
- glycophorin A, glycophorin B, CD147, CD44, CD58, intercellular adhesion molecule 4, basal cell adhesion molecule, complement receptor 1, CD99, ERMAP, junctional adhesion molecule A, neuroplastin, amphoterin-induced protein 2, Down Syndrome cell adhesion molecule-like 1, small integral membrane protein 1, transferrin receptor, Fas ligand, and Kell.
Dependencies are inferred from the claim text.