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US 2024/0122979 A1Published application
Chimeric Cytokine Receptors
OwnerBrad Nelson, Megan Fuller +1inventors
InventorsBrad Nelson, Megan Fuller, Martin J. Boulanger
Life of this patent
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Abstract
Described herein are chimeric receptors comprising G-CSFR extracellular domains and the intracellular domains of various multi-subunit cytokine receptors for selective activation of cytokine signaling in cells of interest. In certain aspects, the selective activation of cytokine signaling in cells expressing the chimeric receptors described herein includes the ability to specifically stimulate adoptively transferred cells.
Claims55
A chimeric receptor, comprising:
- (a) an extracellular domain (ECD) of a G-CSFR (Granulocyte-Colony Stimulating Factor Receptor) operatively linked to a second domain;
- the second domain comprising
- (b) at least a portion of an intracellular domain (ICD) of a multi-subunit cytokine receptor selected from the group consisting of:
- IL-2R (Interleukin-2 receptor), IL-7R (Interleukin-7 receptor), IL-12R (Interleukin-12 Receptor), and IL-21R (Interleukin-21 Receptor) and, optionally, the IL-2R is selected from the group consisting of IL-2Rβ and IL-2Rγc, and, optionally, the second domain comprises at least a portion of the C-terminal region of IL-2Rβ, IL-7Rα, IL-12Rβ2 or IL-21R;
- wherein at least a portion of the ICD of the cytokine receptor comprises at least one signaling molecule binding site from an intracellular domain of a cytokine receptor, and, optionally,
- the at least one signaling molecule binding site is selected from the group consisting of:
- a STAT3 binding site of G-CSFR;
- a STAT3 binding site of gp130;
- a SHP-2 binding site of gp130;
- a SHC binding site of IL-2Rβ;
- a STAT5 binding site of IL-2Rβ;
- a STAT3 binding site of IL-2Rβ;
- a STAT1 binding site of IL-2Rβ;
- a STAT5 binding site of IL-7Rα;
- a phosphatidylinositol 3-kinase (PI3K) binding site of IL-7Rα;
- a STAT4 binding site of IL-12Rβ2;
- a STAT5 binding site of IL-12Rβ2;
- a STAT3 binding site of IL-12Rβ2;
- a STAT5 binding site of IL-21R;
- a STAT3 binding site of IL-21R;
- and a STAT1 binding site of IL-21R;
- and, optionally, the ICD comprises a Box 1 region and a Box 2 region of a protein selected from the group consisting of G-CSFR and gp130;
- and, optionally, the chimeric receptor comprises a third domain comprising at least a portion of a transmembrane domain of a protein selected from the group consisting of:
- G-CSFR, gp130 (Glycoprotein 130), and IL-2Rβ, and, optionally, the transmembrane domain is a wild-type transmembrane domain.
21 more elements
A chimeric receptor, comprising:
- an ECD of a G-CSFR operatively linked to a second domain;
- the second domain comprising:
- (i)
- (a) a transmembrane domain of gp130;
- (b) a Box 1 and a Box 2 region of gp130;
- and
- (c) a C-terminal region of IL-2Rβ;
- or
- (ii)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-2Rβ;
- or
- (iii)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-12Rβ2;
- or
- (iv)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-21R;
- or
- (v)
- (a) a transmembrane domain of IL-2Rβ+γc;
- (b) a Box 1 and a Box 2 region of IL-2Rβ+γc;
- and
- (c) a C-terminal region of IL-2Rβ+γc;
- or
- (vi)
- (a) a transmembrane domain of G-CSFR
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-7Rα.
34 more elements
A nucleic acid encoding a chimeric receptor;
- wherein the chimeric receptor comprises:
- (a) an extracellular domain (ECD) of a G-CSFR (Granulocyte-Colony Stimulating Factor Receptor) operatively linked to a second domain;
- the second domain comprising
- (b) at least a portion of an intracellular domain (ICD) of a multi-subunit cytokine receptor selected from the group consisting of:
- IL-2R (Interleukin-2 receptor), IL-7R (Interleukin-7 receptor), IL-12R (Interleukin-12 Receptor), and IL-21R (Interleukin-21 Receptor), and, optionally,
- the IL-2R is selected from the group consisting of IL-2Rβ and IL-2Rγc, and, optionally,
- the second domain comprises at least a portion of the C-terminal region of IL-2Rβ, IL-7Rα, IL-12Rβ2 or IL-21R;
- wherein
- at least a portion of the ICD of the cytokine receptor comprises at least one signaling molecule binding site from an intracellular domain of a cytokine receptor, and, optionally,
- the ICD comprises at least one signaling molecule binding site selected from the group consisting of:
- a STAT3 binding site of G-CSFR;
- a STAT3 binding site of gp130;
- a SHP-2 binding site of gp130;
- a SHC binding site of IL-2Rβ;
- a STAT5 binding site of IL-2Rβ;
- a STAT3 binding site of IL-2Rβ;
- a STAT1 binding site of IL-2Rβ;
- a STAT5 binding site of IL-7Rα;
- a phosphatidylinositol 3-kinase (PI3K) binding site of IL-7Rα;
- a STAT4 binding site of IL-12Rβ2;
- a STAT5 binding site of IL-12Rβ2;
- a STAT3 binding site of IL-12Rβ2;
- a STAT5 binding site of IL-21R;
- a STAT3 binding site of IL-21R;
- and a STAT1 binding site of IL-21R;
- and, optionally, the ICD comprises a Box 1 region and a Box 2 region of a protein selected from the group consisting of G-CSFR and gp130;
- and, optionally, the chimeric receptor comprises a third domain comprising at least a portion of a transmembrane domain of a protein selected from the group consisting of:
- G-CSFR, gp130 (Glycoprotein 130), and IL-2Rβ;
- and, optionally,
- the transmembrane domain is a wild-type transmembrane domain.
27 more elements
A nucleic acid encoding a chimeric receptor;
- wherein the chimeric receptor comprises:
- an ECD of a G-CSFR operatively linked to a second domain;
- the second domain comprising:
- (i)
- (a) a transmembrane domain of gp130;
- (b) a Box 1 and a Box 2 region of gp130;
- and
- (c) a C-terminal region of IL-2Rβ;
- or
- (ii)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-2Rβ;
- or
- (iii)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-12Rβ2;
- or
- (iv)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-21R;
- or
- (v)
- (a) a transmembrane domain of IL-2Rβ+γc;
- (b) a Box 1 and a Box 2 region of IL-2Rβ+γc;
- and
- (c) a C-terminal region of IL-2Rβ+γc;
- or
- (vi)
- (a) a transmembrane domain of G-CSFR
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-7Rα.
35 more elements
A cell comprising a nucleic acid encoding a chimeric receptor;
- wherein the chimeric receptor comprises:
- (a) an extracellular domain (ECD) of a G-CSFR (Granulocyte-Colony Stimulating Factor Receptor) operatively linked Receptor) operatively linked to a second domain;
- the second domain comprising
- (b) at least a portion of an intracellular domain (ICD) of a multi-subunit cytokine receptor selected from the group consisting of:
- IL-2R (Interleukin-2 receptor), IL-7R (Interleukin-7 receptor), IL-12R (Interleukin-12 Receptor), and IL-21R (Interleukin-21 Receptor), and, optionally,
- the IL-2R is selected from the group consisting of IL-2Rβ and IL-2Rγc, and, optionally,
- the second domain comprises at least a portion of the C-terminal region of IL-2Rβ, IL-7Rα, IL-12Rβ2 or IL-21R;
- wherein
- at least a portion of the ICD of the cytokine receptor comprises at least one signaling molecule binding site from an intracellular domain of a cytokine receptor, and, optionally,
- the ICD comprises at least one signaling molecule binding site selected from the group consisting of:
- a STAT3 binding site of G-CSFR;
- a STAT3 binding site of gp130;
- a SHP-2 binding site of gp130;
- a SHC binding site of IL-2Rβ;
- a STAT5 binding site of IL-2Rβ;
- a STAT3 binding site of IL-2Rβ;
- a STAT1 binding site of IL-2Rβ;
- a STAT5 binding site of IL-7Rα;
- a phosphatidylinositol 3-kinase (PI3K) binding site of IL-7Rα;
- a STAT4 binding site of IL-12Rβ2;
- a STAT5 binding site of IL-12Rβ2;
- a STAT3 binding site of IL-12Rβ2;
- a STAT5 binding site of IL-21R;
- a STAT3 binding site of IL-21R;
- and a STAT1 binding site of IL-21R;
- and, optionally, the ICD comprises a Box 1 region and a Box 2 region of a protein selected from the group consisting of G-CSFR and gp130;
- and, optionally, the chimeric receptor comprises a third domain comprising at least a portion of a transmembrane domain of a protein selected from the group consisting of:
- G-CSFR, gp130 (Glycoprotein 130), and IL-2Rβ, and, optionally,
- the transmembrane domain is a wild-type transmembrane domain;
- and, optionally,
- the cell is an immune cell, and, optionally,
- a T cell, and, optionally,
- a NK cell, and, optionally,
- a NKT cell, and, optionally,
- a B cell, and, optionally,
- a plasma cell, and, optionally,
- a macrophage, and, optionally,
- a dendritic cell, and, optionally,
- the cell is a stem cell, and, optionally,
- the cell is a primary cell, and, optionally,
- the cell is a human cell.
38 more elements
A cell comprising a nucleic acid encoding a chimeric receptor;
- wherein the chimeric receptor comprises:
- an ECD of a G-CSFR operatively linked to a second domain;
- the second domain comprising:
- (i)
- (a) a transmembrane domain of gp130;
- (b) a Box 1 and a Box 2 region of gp130;
- and
- (c) a C-terminal region of IL-2Rβ;
- or
- (ii)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-2Rβ;
- or
- (iii)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-12Rβ2;
- or
- (iv)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-21R;
- or
- (v)
- (a) a transmembrane domain of IL-2Rβ+γc;
- (b) a Box 1 and a Box 2 region of IL-2Rβ+γc;
- and
- (c) a C-terminal region of IL-2Rβ+γc;
- or
- (vi)
- (a) a transmembrane domain of G-CSFR
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-7Rα;
- and, optionally,
- the cell is an immune cell;
- and, optionally,
- a T cell, and, optionally,
- a NK cell, and, optionally,
- a NKT cell, and, optionally,
- a B cell, and, optionally,
- a plasma cell, and, optionally,
- a macrophage, and, optionally,
- a dendritic cell, and, optionally,
- the cell is a stem cell, and, optionally,
- the cell is a primary cell, and, optionally,
- the cell is a human cell.
48 more elements
A method of selective activation of a chimeric receptor expressed on the surface of a cell, comprising:
- contacting a chimeric receptor with a G-CSF that selectively activates the chimeric receptor;
- wherein the chimeric receptor comprises:
- (a) an extracellular domain (ECD) of a G-CSFR (Granulocyte-Colony Stimulating Factor Receptor) operatively linked to a second domain;
- the second domain comprising
- (b) at least a portion of an intracellular domain (ICD) of a multi-subunit cytokine receptor selected from the group consisting of:
- IL-2R (Interleukin-2 receptor), IL-7R (Interleukin-7 receptor), IL-12R (Interleukin-12 Receptor), and IL-21R (Interleukin-21 Receptor), and, optionally,
- the IL-2R is selected from the group consisting of IL-2Rβ and IL-2Rγc, and, optionally,
- the second domain comprises at least a portion of the C-terminal region of IL-2Rβ, IL-7Rα, IL-12Rβ2 or IL-21R;
- wherein
- at least a portion of the ICD of the cytokine receptor comprises at least one signaling molecule binding site from an intracellular domain of a cytokine receptor, and, optionally,
- the at least one signaling molecule binding site selected from the group consisting of:
- a STAT3 binding site of G-CSFR;
- a STAT3 binding site of gp130;
- a SHP-2 binding site of gp130;
- a SHC binding site of IL-2Rβ;
- a STAT5 binding site of IL-2Rβ;
- a STAT3 binding site of IL-2Rβ;
- a STAT1 binding site of IL-2Rβ;
- a STAT5 binding site of IL-7Rα;
- a phosphatidylinositol 3-kinase (PI3K) binding site of IL-7Rα;
- a STAT4 binding site of IL-12Rβ2;
- a STAT5 binding site of IL-12Rβ2;
- a STAT3 binding site of IL-12Rβ2;
- a STAT5 binding site of IL-21R;
- a STAT3 binding site of IL-21R;
- and a STAT1 binding site of IL-21R, and, optionally,
- the ICD comprises a Box 1 region and a Box 2 region of a protein selected from the group consisting of G-CSFR and gp130;
- and, optionally, the chimeric receptor comprises a third domain comprising at least a portion of a transmembrane domain of a protein selected from the group consisting of:
- G-CSFR, gp130 (Glycoprotein 130), and IL-2Rβ, and, optionally,
- the transmembrane domain is a wild-type transmembrane domain.
27 more elements
A method of selective activation of a chimeric receptor expressed on the surface of a cell, comprising:
- contacting a chimeric receptor with a G-CSF that selectively activates the chimeric receptor;
- wherein the chimeric receptor, comprises
- an ECD of a G-CSFR operatively linked to a second domain;
- the second domain comprising:
- (i)
- (a) a transmembrane domain of gp130;
- (b) a Box 1 and a Box 2 region of gp130;
- and
- (c) a C-terminal region of IL-2Rβ;
- or
- (ii)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-2Rβ;
- or
- (iii)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-12Rβ2;
- or
- (iv)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-21R;
- or
- (v)
- (a) a transmembrane domain of IL-2Rβ+γc;
- (b) a Box 1 and a Box 2 region of IL-2Rβ+γc;
- and
- (c) a C-terminal region of IL-2Rβ+γc;
- or
- (vi)
- (a) a transmembrane domain of G-CSFR
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-7Rα.
36 more elements
A method of treating a subject in need thereof, comprising:
- infusing into the subject a cell expressing a chimeric receptor and administering a cytokine that binds the chimeric receptor;
- wherein the chimeric receptor comprises:
- (a) an extracellular domain (ECD) of a G-CSFR (Granulocyte-Colony Stimulating Factor Receptor) operatively linked to a second domain;
- the second domain comprising
- (b) at least a portion of an intracellular domain (ICD) of a multi-subunit cytokine receptor selected from the group consisting of:
- IL-2R (Interleukin-2 receptor), IL-7R (Interleukin-7 receptor), IL-12R (Interleukin-12 Receptor), and IL-21R (Interleukin-21 Receptor);
- and, optionally,
- the IL-2R is selected from the group consisting of IL-2Rβ and IL-2Rγc;
- and, optionally,
- the second domain comprises at least a portion of the C-terminal region of IL-2Rβ, IL-7Rα, IL-12Rβ2 or IL-21R;
- wherein
- at least a portion of the ICD of the cytokine receptor comprises at least one signaling molecule binding site from an intracellular domain of a cytokine receptor;
- and, optionally,
- the ICD comprises at least one signaling molecule binding site selected from the group consisting of:
- a STAT3 binding site of G-CSFR;
- a STAT3 binding site of gp130;
- a SHP-2 binding site of gp130;
- a SHC binding site of IL-2Rβ;
- a STAT5 binding site of IL-2Rβ;
- a STAT3 binding site of IL-2Rβ;
- a STAT1 binding site of IL-2Rβ;
- a STAT5 binding site of IL-7Rα;
- a phosphatidylinositol 3-kinase (PI3K) binding site of IL-7Rα;
- a STAT4 binding site of IL-12Rβ2;
- a STAT5 binding site of IL-12Rβ2;
- a STAT3 binding site of IL-12Rβ2;
- a STAT5 binding site of IL-21R;
- a STAT3 binding site of IL-21R;
- and a STAT1 binding site of IL-21R;
- and, optionally, the ICD comprises a Box 1 region and a Box 2 region of a protein selected from the group consisting of G-CSFR and gp130;
- and, optionally, the chimeric receptor comprises comprising a third domain comprising at least a portion of a transmembrane domain of a protein selected from the group consisting of:
- G-CSFR, gp130 (Glycoprotein 130), and IL-2Rβ;
- and, optionally,
- the transmembrane domain is a wild-type transmembrane domain.
31 more elements
A method of treating a subject in need thereof, comprising:
- infusing into the subject a cell expressing a chimeric receptor and administering a cytokine that binds the chimeric receptor;
- wherein the chimeric receptor comprises:
- an ECD of a G-CSFR operatively linked to a second domain;
- the second domain comprising:
- (i)
- (a) a transmembrane domain of gp130;
- (b) a Box 1 and a Box 2 region of gp130;
- and
- (c) a C-terminal region of IL-2Rβ;
- or
- (ii)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-2Rβ;
- or
- (iii)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-12Rβ2;
- or
- (iv)
- (a) a transmembrane domain of G-CSFR;
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-21R;
- or
- (v)
- (a) a transmembrane domain of IL-2Rβ+γc;
- (b) a Box 1 and a Box 2 region of IL-2Rβ+γc;
- and
- (c) a C-terminal region of IL-2Rβ+γc;
- or
- (vi)
- (a) a transmembrane domain of G-CSFR
- (b) a Box 1 and a Box 2 region of G-CSFR;
- and
- (c) a C-terminal region of IL-7Rα.
36 more elements
Dependencies are inferred from the claim text.