IP Library › Granted Patent US 12,528,856
Granted Patent B2
US 12,528,856 · App. 17/005,757 · Granted Jan 20, 2026

Chimeric cytokine receptors comprising TGF β binding domains

Inventors: Regina Junhui Lin (San Mateo, CA); Siler Panowski (Berkeley, CA); Thomas John Van Blarcom (Oakland, CA); Shanshan Lang (San Mateo, CA); Barbra Johnson Sasu (San Francisco, CA)
Assignee: Allogene Therapeutics, Inc.
C07K14/71A61K40/11A61K40/31A61K40/4203A61K40/4204A61K40/4214C12N5/0636C12N15/86C07K2319/03C07K2319/70C12N2740/15043
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Quick Facts
Patent No.
US 12,528,856
App. No.
17/005,757
Granted
Jan 20, 2026
Kind
B2
Abstract

Provided herein are chimeric cytokine receptors bearing a binding domain capable of binding a TGF-β ligand or a TGF-β receptor antibody. When present on chimeric antigen receptor (CAR)-bearing immune cells (CAR-T-cells), such receptors allow for increased CAR-T cell expansion, activity and persistence, constitutively and/or through engagement of a TGF-β ligand or a TGF-β receptor antibody. Also provided are methods of making and using the chimeric cytokine receptors described herein.

Claims (45)

1 . A chimeric cytokine receptor comprising:

a) a binding domain comprising an extracellular portion of a TGF-β receptor, or a TGF-β antigen binding domain;

b) a transmembrane domain;

c) an intracellular Janus Kinase (JAK)-binding domain; and

d) an intracellular recruiting domain,

wherein the transmembrane domain and the intracellular JAK-binding domain is a fragment of a variant of the full-length thrombopoietin receptor/myeloproliferative leukemia protein receptor (TPOR/MPLR) as shown in SEQ ID NO: 26, wherein the fragment is selected from the group consisting of SEQ ID NO: 30-71, 73-79, 160, and 217-234, and wherein the intracellular recruiting domain is not from TPOR/MPLR.

2 . The chimeric cytokine receptor of claim 1 , wherein the intracellular recruiting domain is a STAT-recruiting domain.

3 . The chimeric cytokine receptor of claim 2 , wherein the STAT-recruiting domain is from a receptor selected from BLNK, IL2RG, EGFR, EpoR, GHR, IFNAR1, IFNAR2, IFNAR1/2, IFNLR1, IL10R1, IL12Rb1, IL12Rb2, IL2Rb, IL2small, IL7R, IL7Ra, IL9R, IL15R, and IL21R.

4 . The chimeric cytokine receptor of claim 3 , wherein the recruiting domain comprises the STAT-recruiting domain from one or more receptors of IL7Ra, IL12Rb2, EGFR, IL21R, or IL2Rb.

5 . The chimeric cytokine receptor of claim 2 , wherein the STAT-recruiting domain comprises any one of the amino acid sequences of SEQ ID NO: 80-SEQ ID NO: 122 and SEQ ID NO: 161.

6 . The chimeric cytokine receptor of claim 2 , wherein the STAT-recruiting domain comprises SEQ ID NO: 80, SEQ ID NO: 112, SEQ ID NO: 111, SEQ ID NO: 101, SEQ ID NO: 120, SEQ ID NO: 99, or SEQ ID NO: 161.

7 . The chimeric cytokine receptor of claim 1 , wherein the chimeric cytokine receptor is a dimerized chimeric cytokine receptor comprising monomers that each comprise a) to d).

8 . The chimeric cytokine receptor of claim 1 , wherein the binding domain comprising an extracellular portion of a TGF-β receptor comprises an extracellular portion of a wild type TGF-β receptor sequence or one or more mutations to the extracellular portion of a wild type TGF-β receptor sequence.

9 . The chimeric cytokine receptor of claim 8 , wherein the binding domain comprising an extracellular portion of a TGF-β receptor comprises the extracellular portion of TGFBR2.

10 . The chimeric cytokine receptor of claim 8 , wherein the binding domain comprising an extracellular portion of a TGF-β receptor comprises the amino acid sequence of any one of SEQ ID NO: 2 to SEQ ID NO: 20 and SEQ ID NO: 159.

11 . The chimeric cytokine receptor of claim 1 , wherein the transmembrane domain and intracellular JAK-binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 37-40, 53-56, 44-45, 64 and 70.

12 . The chimeric cytokine receptor of claim 1 , wherein the chimeric cytokine receptor is inducible.

13 . The chimeric cytokine receptor of claim 12 , wherein the chimeric cytokine receptor can be induced by a TGF-β ligand or an anti-TGFβR antibody.

14 . The chimeric cytokine receptor of claim 13 , wherein the TGF-B ligand is any one of TGFβ-1, TGF-μ2, or TGF-β3.

15 . The chimeric cytokine receptor of claim 1 , wherein the chimeric cytokine receptor is constitutively active.

16 . The chimeric cytokine receptor of claim 15 , wherein the chimeric cytokine receptor is constitutively active and can be further induced or exhibits further improved activities in the presence of TGF-β or an anti-TGFβR antibody.

17 . The chimeric cytokine receptor of claim 1 , wherein the chimeric cytokine receptor is capable of inhibiting TGFβR2-mediated signal transduction and/or enhancing STAT-mediated signal transduction when expressed in a cell.

18 . The chimeric cytokine receptor of claim 17 , wherein the cell is an immune cell.

19 . A polynucleotide encoding the chimeric cytokine receptor of claim 1 .

20 . An expression vector comprising the polynucleotide of claim 19 .

21 . The expression vector of claim 20 , further comprising a polynucleotide encoding a chimeric antigen receptor (CAR).

22 . The expression vector of claim 21 , wherein the CAR binds to any one or more of the targets selected from BCMA, EGFRVIII, Flt-3, WT-1, CD20, CD23, CD30, CD38, CD70, CD33, CD133, MHC-WT1, TSPAN10, MHC-PRAME, Liv1, ADAM10, CHRNA2, LeY, NKG2D, CS1, CD44v6, ROR1, CD19, Claudin-18.2, Claudin-18A2, Claudin18 isoform 2, Delta-like protein 3 (DLL3), Drosophila Delta homolog 3, Delta3, Mucin 17, Muc3, Fibroblast Activation Protein alpha (FAP alpha), Lymphocyte antigen 6 complex locus protein God (Ly6G6D), c6orf23, G6D, MEGT1, NG25, E3 ubiquitin-protein ligase RNF43, RING finger protein 43, ErbB2, carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), CD40, disialoganglioside GD2, GD3, C-type lectin-like molecule-1 (CLL-1), ductal-epithelial mucin, gp36, TAG-72, a glycosphingolipid, glioma-associated antigen, β-human chorionic gonadotropin, alphafetoprotein (AFP), lectin- reactive AFP, thyroglobulin, RAGE-1, MN-CA IX, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxyl esterase, mut hsp70-2, M-CSF, prostase, prostase specific antigen (PSA), PAP, NY-ESO-1, LAGA-1a, p53, prostein, PSMA, survivin, telomerase, prostate-carcinoma tumor antigen-1 (PCTA-1), MAGE, ELF2M, neutrophil elastase, ephrin B2, CD22, insulin growth factor (IGF1)-1, IGF-II, IGFI receptor, mesothelin, a major histocompatibility complex (MHC) molecule presenting a tumor-specific peptide epitope, 5T4, O1, Nkp30, tumor stromal antigen, the extra domain A (EDA) of fibronectin, the extra domain B (EDB) of fibronectin, the AI domain of tenascin-C (TnC AI), fibroblast associated protein (fap), LRP6, melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP), MARTI, MUC1, LMP2, Idiotype, NY-ESO-1, Ras mutant, gp100, proteinase 3, bcr-abl, tyrosinase, hTERT, EphA2, ML-TAP, ERG, NA17, PAX3, ALK, Androgen receptor, CD3, CD4, CD8, CD24, CD25, CD34, CD79, CD116, CD117, CD135, CD123, CD138, CTLA-4, B7-1, B7-2, endoglin, a major histocompatibility complex (MHC) molecule, MUC16, PSCA, Trop2, CD171, CA9, STEAP1, and VEGFR2.

23 . An engineered immune cell comprising the vector of claim 20 .

24 . A method of preparing an engineered immune cell, the method comprising introducing the polynucleotide of claim 19 into an immune cell.

25 . The method of claim 24 , wherein the immune cell is selected from the group consisting of: T-cell, dendritic cell, killer dendritic cell, mast cell, NK-cell, macrophage, monocyte, B-cell and an immune cell derived from a stem cell.

26 . An engineered immune cell expressing the chimeric cytokine receptor of claim 1 .

27 . The engineered immune cell of claim 26 , further expressing at least one CAR.

28 . The engineered immune cell of claim 27 , wherein the CAR binds to any one or more of the targets selected from BCMA, EGFRVIII, Flt-3, WT-1, CD20, CD23, CD30, CD38, CD70, CD33, CD133, MHC-WT1, TSPAN10, MHC-PRAME, Liv1, ADAM10, CHRNA2, LeY, NKG2D, CS1, CD44v6, ROR1, CD19, Claudin-18.2, Claudin-18A2, Claudin18 isoform 2, Delta-like protein 3 (DLL3), Drosophila Delta homolog 3, Delta3, Mucin 17, Muc3, Fibroblast Activation Protein alpha (FAP alpha), Lymphocyte antigen 6 complex locus protein God (Ly6G6D), c6orf23, G6D, MEGT1, NG25, E3 ubiquitin-protein ligase RNF43, RING finger protein 43, ErbB2, carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), CD40, disialoganglioside GD2, GD3, C-type lectin-like molecule-1 (CLL-1), ductal-epithelial mucin, gp36, TAG-72, a glycosphingolipid, glioma- associated antigen, β-human chorionic gonadotropin, alphafetoprotein (AFP), lectin-reactive AFP, thyroglobulin, RAGE-1, MN-CA IX, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxyl esterase, mut hsp70-2, M-CSF, prostase, prostase specific antigen (PSA), PAP, NY-ESO-1, LAGA-1a, p53, prostein, PSMA, survivin, telomerase, prostate-carcinoma tumor antigen-1 (PCTA-1), MAGE, ELF2M, neutrophil elastase, ephrin B2, CD22, insulin growth factor (IGF1)-1, IGF-II, IGFI receptor, mesothelin, a major histocompatibility complex (MHC) molecule presenting a tumor-specific peptide epitope, 5T4, O1, Nkp30, tumor stromal antigen, the extra domain A (EDA) of fibronectin, the extra domain B (EDB) of fibronectin, the AI domain of tenascin-C (TnC AI), fibroblast associated protein (fap), LRP6, melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP), MARTI, MUC1, LMP2, Idiotype, NY-ESO-1, Ras mutant, gp100, proteinase 3, bcr-abl, tyrosinase, hTERT, EphA2, ML-TAP, ERG, NA17, PAX3, ALK, Androgen receptor, CD3, CD4, CD8, CD24, CD25, CD34, CD79, CD116, CD117, CD135, CD123, CD138, CTLA-4, B7-1, B7-2, endoglin, a major histocompatibility complex (MHC) molecule, MUC16, PSCA, Trop2, CD171, CA9, STEAP1, and VEGFR2.

29 . The engineered immune cell of claim 27 , wherein the immune cell is an allogeneic immune cell or an autologous immune cell.

30 . The engineered immune cell of claim 27 , wherein the immune cell is selected from the group consisting of: T-cell, dendritic cell, killer dendritic cell, mast cell, NK-cell, macrophage, monocyte, B-cell and an immune cell derived from a stem cell.

31 . The engineered immune cell of claim 27 , wherein the immune cell exhibits reduced TGFβR-mediated signal transduction and/or enhanced STAT-mediated signal transduction as compared to an immune cell without expressing the chimeric cytokine receptor.

32 . The engineered immune cell of claim 31 , wherein the immune cell exhibits reduced TGFβR mediated signal transduction and/or enhanced STAT-mediated signal transduction when engaged with TGF-β or an anti-TGFβR antibody.

33 . A pharmaceutical composition comprising the immune cells of claim 27 .

34 . A kit comprising the pharmaceutical composition of claim 33 .

35 . A method of treating a cancer, an autoimmune disorder, or an infection in a subject, comprising administering to the subject a therapeutically effective amount of the engineered immune cells of claim 27 .

36 . The method of claim 35 , wherein the cancer comprises a solid tumor or a liquid tumor.

37 . The method of claim 36 , wherein the tumor is TGF-β positive tumor.

38 . The method of claim 35 , wherein the subject is treated with an anti-TGFβR-antibody.

39 . A method of modulating an activity of the engineered immune cell of claim 32 , comprising contacting the immune cell with a TGF-β ligand or with an anti-TGFβR antibody.

40 . A chimeric cytokine receptor comprising the amino acid sequence selected from SEQ ID NOs: 124-151 and SEQ ID NOs: 163-216.

Continuity (3)
Provisional Application 63053322 · Jul 17, 2020
Provisional Application 62894658 · Aug 30, 2019
Related Publication 20210061881A1 · Mar 4, 2021
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