Chimeric cytokine receptor polypeptides and uses thereof

Abstract

The present disclosure provides chimeric proteins capable of activating immune signaling and nucleic acid sequences and expression vectors encoding the proteins, cells expressing the proteins, and methods of using the same.

Description

Attorney Docket No. WAP-008WOCHIMERIC CYTOKINE RECEPTOR POLYPEPTIDES AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application No. 63 / 761,562, filed February 21, 2025; United States Provisional Patent Application No. 63 / 773,373, filed March 17, 2025; United States Provisional Patent Application No. 63 / 809,059, filed May 20, 2025; and United States Provisional Patent Application No, 63 / 883,382, filed September 17, 2025, the disclosures of each of which are hereby incorporated by reference in their entireties for all purposes.BACKGROUND

[0002] Designing synthetic constructs for use in cell therapy is of major importance to improve efficacy and safety of cell therapy applications. However, immune cell therapies can be limited by the necessity for in vivo expansion following infusion and by their lack of cytotoxicity or an altered cellular state. For example, to achieve robust expansion, T cells require three signals: antigen-stimulation, co-stimulation, and cytokine-induced stimulation. Activation of CARs is sufficient to induce the first two signals, but cannot recapitulate cytokine signaling. Cytokine signaling is also associated with modulating the differentiation state of T cells, resulting in altered cytotoxicity and long-term functionality, among other changes to the T cells. Furthermore, the tumor microenvironment is often immunosuppressive and devoid of pro-inflammatory cytokines. Therefore, additional strategies are needed to improve the efficacy of cell therapies.SUMMARY

[0003] Disclosed herein, in various embodiments, is a chimeric protein comprising: (i) a cytokine polypeptide, or a functional fragment thereof, operably linked to (ii) a cell-surface receptor polypeptide, wherein the cell-surface receptor polypeptide comprises: (a) an extracellular ligand -binding domain capable of binding the cytokine polypeptide; (b) a transmembrane domain; and (c) an IL-9 receptor (IL-9R) intracellular effector domain. In some embodiments, binding of the cytokine polypeptide to the ligand binding domain induces the IL-9R effector domain to activate downstream signaling.

[0004] In some embodiments, (a) the cytokine polypeptide is IL-9, or a functional fragment thereof, and the ligand binding domain is an IL-9R extracellular domain, or a ligand-binding fragment thereof; (b) the cytokine polypeptide is IL-2, or a functional fragment thereof, andAttorney Docket No. WAP-008WOthe ligand binding domain is an IL-2R extracellular domain, or a ligand-binding fragment thereof; (c) the cytokine polypeptide is IL-4, or a functional fragment thereof, and the ligand binding domain is an IL-4RA extracellular domain, or a ligand-binding fragment thereof; (d) the cytokine polypeptide is IL-7, or a functional fragment thereof, and the ligand binding domain is an IL-7R extracellular domain, or a ligand-binding fragment thereof; (e) the cytokine polypeptide is IL- 15, or a functional fragment thereof, and the ligand binding domain is an IL-15R extracellular domain, or a ligand-binding fragment thereof; or (f) the cytokine polypeptide is IL-21, or a functional fragment thereof, and the ligand binding domain is an IL-21R extracellular domain, or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide is IL-9 or a functional fragment thereof and the ligand binding domain is an IL-9R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the cytokine polypeptide is IL-2 or a functional fragment thereof and the ligand binding domain is an IL-2R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8 or 106. In some embodiments, the cytokine polypeptide is IL-4 or a functional fragment thereof and the ligand binding domain is an IL-4RA extracellular domain or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 111. In some embodiments, the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 112 or 113. In some embodiments, the cytokine polypeptide is IL-7 or a functional fragment thereof and the ligand binding domain is an IL-7R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino7Attorney Docket No. WAP-008WOacid sequence of SEQ ID NO: 4. In some embodiments, the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9 or 107. In some embodiments, the cytokine polypeptide is IL- 15 or a functional fragment thereof and the ligand binding domain is an IL-15R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10 or 108. In some embodiments, the cytokine polypeptide is IL-21 or a functional fragment thereof and the ligand binding domain is an IL-21R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 6. In some embodiments, the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 11 or 109.

[0005] In some embodiments, the cytokine polypeptide or functional fragment is operably linked to the cell-surface receptor poly peptide by a linker peptide. In some embodiments, the linker comprises an amino acid sequence selected from tire group consisting of SEQ ID NOs: 22-27. In some embodiments, the linker comprises the amino acid sequence of SEQ ID NO: 22.

[0006] Also disclosed herein, in various embodiments, is a chimeric protein comprising: (a) an extracellular domain comprising a truncated cytokine receptor extracellular domain poly peptide; (b) a transmembrane domain; and (c) an IL-9R intracellular effector domain, wherein the chimeric protein does not consist of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the truncated cytokine receptor extracellular domain is a truncated extracellular domain of IL-9R, IL-2RB, IL-7R, or IL-21R. lire chimeric protein of claim 23 or 24, wherein the truncated cytokine receptor extracellular domain is a truncated IL-9R extracellular domain. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-54.Attorney Docket No. WAP-008WO

[0007] In some embodiments, the truncated cytokine receptor extracellular domain is a truncated IL-2RB extracellular domain. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 58-60. In some embodiments, the truncated cytokine receptor extracellular domain is a truncated IL-7R extracellular domain. In some embodiments, truncated IL-7R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 55-57. In some embodiments, the truncated cytokine receptor extracellular domain is a truncated IL-21R extracellular domain, in some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 62-64. In some embodiments, the truncated cytokine receptor extracellular domain and transmembrane domain are from the same cytokine receptor. In some embodiments, the truncated cytokine receptor extracellular domain and transmembrane domain are from different cytokine receptors.

[0008] In some embodiments, the transmembrane domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 12-17 and 90. In some embodiments, the chimeric protein further comprises an additional polypeptide located between the transmembrane domain and the IL-9R intracellular effector domain. In some embodiments, the additional polypeptide is from the same cytokine receptor as the transmembrane domain. In some embodiments, the additional polypeptide is from a different cytokine receptor as the transmembrane domain. In some embodiments, the additional polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 96-98. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 12.

[0009] In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the IL-9R intracellular effector domain is a truncated IL-9R intracellular effector domain. In some embodiments, the truncated IL-9R intracellular effector domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%Attorney Docket No. WAP-008WOidentical to the amino acid sequence of SEQ ID NO: 35. In some embodiments, the chimeric protein further comprises a signal peptide at the N-terminus. In some embodiments, the signal peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19.

[0010] Also disclosed herein, in various embodiments, is a chimeric protein comprising an amino acid sequence at least 80%, at least 85%. at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 28-33, 36-45, 70-88, 101, and 114-142.

[0011] Also disclosed herein, in various embodiments, is a chimeric protein comprising the amino acid sequence of SEQ ID NO: 28.

[0012] Also disclosed herein, in various embodiments, is a chimeric protein comprising the amino acid sequence of SEQ ID NO: 142.

[0013] Also disclosed herein, in various embodiments, is a chimeric protein comprising: (a) an extracellular domain comprising a transforming growth factor beta receptor (TGFBR) extracellular domain polypeptide; (b) a transmembrane domain; and (c) a cytokine receptor intracellular effector domain. In some embodiments, tire TGFBR extracellular domain polypeptide is a TGFBR2 extracellular domain polypeptide. In some embodiments, the TGFBR2 extracellular domain polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 65. In some embodiments, the extracellular domain further comprises a extracellular domain polypeptide of a cytokine receptor located between the TGFBR extracellular domain polypeptide and the transmembrane domain. In some embodiments, the extracellular domain polypeptide of a cytokine is a truncated cytokine receptor extracellular domain. In some embodiments, the truncated cytokine receptor extracellular domain is a truncated extracellular domain of IL-9R, IL-2RB, IL-7R, or IL- 15RA.

[0014] In some embodiments, the truncated cytokine receptor extracellular domain is a truncated IL-9R extracellular domain. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 51-54. In some embodiments, the truncated cytokineAttorney Docket No. WAP-008WOreceptor extracellular domain is a truncated IL-2RB extracellular domain. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 58-60. In some embodiments, the truncated cytokine receptor extracellular domain is a truncated IL-7R extracellular domain. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 55-57. In some embodiments, the truncated cytokine receptor extracellular domain is a truncated IL-15RA extracellular domain. In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 61,

[0015] In some embodiments, the transmembrane domain is a transmembrane domain of IL-4RA, IL-9R, IL-2RB, IL-7R, or IL-15RA. In some embodiments, the transmembrane domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 12-17 and 90. In some embodiments, the chimeric protein further comprises an additional polypeptide located between the transmembrane domain and the cytokine receptor intracellular effector domain. In some embodiments, the additional polypeptide is from the same cytokine receptor as the transmembrane domain. In some embodiments, the additional polypeptide is from a different cytokine receptor as the transmembrane domain. In some embodiments, the additional polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 96-98.

[0016] In some embodiments, the intracellular effector domain is an intracellular domain of a cytokine receptor or a functional fragment thereof. In some embodiments, the intracellular effector domain is an intracellular domain of IL-9R, IL-2RB, IL-7R, or IL-I5RA. In some embodiments, the intracellular effector domain is an IL-9R intracellular domain or functional fragment thereof. In some embodiments, the IL-9R intracellular domain or functional fragment thereof comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 35, and 89. In some embodiments, the intracellular effector domain is an 1L-2RB intracellular domain or functional fragment thereof. In some embodiments, the IL-2RB intracellular domain or functional fragment thereof compri ses anAttorney Docket No. WAP-008WOamino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the intracellular effector domain is an IL-15RA intracellular domain or functional fragment thereof, in some embodiments, the IL-15RA intracellular domain or functional fragment thereof comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NOs: 68. In some embodiments, the truncated extracellular domain polypeptide, the transmembrane domain, and the intracellular effector domain are from the same cytokine receptor.

[0017] Also disclosed herein, in various embodiments, is a nucleic acid encoding the chimeric protein disclosed herein.

[0018] Also disclosed herein, in various embodiments, is an expression vector comprising the nucleic acid disclosed herein. In some embodiments, the vector is a viral vector. In some embodiments, the vector is an integrating viral vector, a non-integrating viral vector, a lentiviral vector, a retroviral vector, an AAV vector, an adenoviral vector, a Sendai viral vector, a Measles viral vector, a Foamy viral vector, or an HSV vector. In some embodiments, the vector is a non-viral vector. In some embodiments, whewherein the vector further comprises a nucleic acid sequence encoding a protein of interest. In some embodiments, wherein the protein of interest is a synthetic immune receptor. In some embodiments, the synthetic immune receptor is a chimeric antigen receptor (CAR), a T cell receptor (TCR), a T Cell Receptor Fusion Construct (TRuC), an adapter CAR, a universal / modular CAR system, a T cell antigen coupler (TAC) receptor, an HLA-independent T cell (HIT) receptor, or a logic-gated version of any of the aforementioned receptors. In some embodiments, the protein of interest is a secreted protein. In some embodiments, tire secreted protein is an antibody fragment or a bispecific T cell engager (BiTE). in some embodiments, the nucleic acid sequence encoding the chimeric protein and the nucleic acid sequence encoding the protein of interest are present in a single open reading frame. In some embodiments, the nucleic acid sequence encoding the chimeric protein and the nucleic acid sequence encoding the protein of interest are separated by a ribosomal skip site or an internal ribosome entry site (IRES). In some embodiments, the ribosomal skip site is a T2A sequence, a P2A sequence, an E2A sequence, or an F2A sequence. In some embodiments, the vector further comprises a nucleic acid sequence encoding an shRNA or an miRNA.

[0019] In some embodiments, the vector further comprises a nucleic acid sequence encoding a secreted chemokine. In some embodiments, the secreted chemokine is CCL21 orAttorney Docket No. WAP-008WOCCL19. In some embodiments, the secreted chemokine is CCL21. In some embodiments, the secreted chemokine comprises the amino acid sequence of SEQ ID NO: 47 or SEQ ID NO: 49. In some embodiments, the secreted chemokine is CCL19. In some embodiments, the secreted chemokine comprises the amino acid sequence of SEQ ID NO: 91 or SEQ ID NO: 93. In some embodiments, the nucleic acid sequence encoding the chimeric protein, the nucleic acid sequence encoding the protein of interest, and the nucleic acid sequence encoding the secreted chemokine are present in a single open reading frame or under control of a single promoter. In some embodiments, the nucleic acid sequence encoding the chimeric protein, the nucleic acid sequence encoding the protein of interest, and the nucleic acid sequence encoding the secreted chemokine are each separated by a ribosomal skip site or an internal ribosome entry site (IRES). In some embodiments, each ribosomal skip site is independently a T2A sequence, a P2A sequence, an E2A sequence, or an F2A sequence. In some embodiments, the nucleic acid sequence encoding the chimeric protein, the nucleic acid sequence encoding the protein of interest, and the nucleic acid sequence encoding the secreted chemokine are present in different open reading frames or are under the control of different promoters.

[0020] Also disclosed herein, in various embodiments, is a system comprising: (a) the expression vector disclosed herein; and (b) a second expression vector comprising a nucleic acid sequence of interest. In some embodiments, the nucleic acid sequence of interest encodes a protein of interest. In some embodiments, the protein of interest is a synthetic immune receptor. In some embodiments, the synthetic immune receptor is a chimeric antigen receptor (CAR), a T cell receptor (TCR), a T Cell Receptor Fusion Construct (TRuC), an adapter CAR, a universal / modular CAR system, a T cell antigen coupler (TAC) receptor, an HLA-independent T cell (HIT) receptor, or a logic-gated version of any of the aforementioned receptors. In some embodiments, the protein of interest is a secreted protein. In some embodiments, the secreted protein is an antibody fragment or a bispecific T cell engager (BiTE). In some embodiments, the nucleic acid sequence of interest encodes an shRNA or an miRNA.

[0021] Also disclosed herein, in various embodiments, is an expression vector comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 48, 94, and 102-105.Attorney Docket No. WAP-008WO

[0022] Also disclosed herein, in various embodiments, is a system comprising: (a) the expression vector disclosed herein; and (b) a second expression vector comprising a nucleic acid sequence encoding a secreted chemokine.

[0023] Also disclosed herein, in various embodiments, is a system comprising: (a) an expression vector comprising the nucleic acid sequence encoding the chimeric protein disclosed herein; (b) a second expression vector comprising a nucleic acid sequence of interest; and (c) a third expression vector encoding a secreted chemokine.

[0024] Also disclosed herein, in various embodiments, is a system comprising: (a) an expression vector comprising the nucleic acid sequence encoding the chimeric protein disclosed herein; and (b) a second expression vector comprising a nucleic acid sequence of interest and a nucleic acid sequence encoding a secreted chemokine. In some embodiments, the nucleic acid sequence of interest and the nucleic acid sequence encoding the secreted chemokine are each separated by a ribosomal skip site or an internal ribosome entry site (IRES). In some embodiments, the ribosomal skip site is a T2A sequence, a P2A sequence, an E2A sequence, or an F2A sequence.

[0025] Also disclosed herein, in various embodiments, is a system comprising: (a) an expression vector comprising the nucleic acid sequence encoding the chimeric protein disclosed herein and a nucleic acid sequence encoding a secreted chemokine; and (b) a second expression vector comprising a nucleic acid sequence of interest. In some embodiments, the nucleic acid sequence encoding the chimeric protein disclosed herein and the nucleic acid sequence encoding the secreted chemokine are each separated by a ribosomal skip site or an internal ribosome entry site (IRES). In some embodiments, the ribosomal skip site is a T2A sequence, a P2A sequence, an E2A sequence, or an F2A sequence.

[0026] Also disclosed herein, in various embodiments, is a system comprising: (a) an expression vector comprising the nucleic acid sequence encoding the chimeric protein disclosed herein and a nucleic acid sequence of interest; and (b) a second expression vector comprising a nucleic acid sequence encoding a secreted chemokine. In some embodiments, the nucleic acid sequence encoding the chimeric protein disclosed herein and the nucleic acid sequence of interest are each separated by a ribosomal skip site or an internal ribosome entry site (IRES). In some embodiments, the ribosomal skip site is a T2A sequence, a P2A sequence, an E2A sequence, or an F2A sequence.Attorney Docket No. WAP-008WO

[0027] In some embodiments, the nucleic acid sequence of interest encodes a protein of interest. In some embodiments, the protein of interest is a synthetic immune receptor. In some embodiments, tire synthetic immune receptor is a chimeric antigen receptor (CAR), a T cell receptor (TCR), a T Cell Receptor Fusion Construct (TRuC), an adapter CAR, a universal / modular CAR system, a T cell antigen coupler (TAC) receptor, an HLA-independent T cell (HIT) receptor, or a logic-gated version of any of the aforementioned receptors. In some embodiments, the protein of interest is a secreted protein. In some embodiments, the secreted protein is an antibody fragment or a bispecific T cell engager (BiTE). In some embodiments, the nucleic acid sequence of interest encodes an shRNA or an miRNA. In some embodiments, the secreted chemokine is CCL21 or CCL19. In some embodiments, the secreted chemokine is CCL21. In some embodiments, the secreted chemokine comprises the amino acid sequence of SEQ ID NO: 47 or SEQ ID NO: 49. In some embodiments, the secreted chemokine is CCL19. In some embodiments, the secreted chemokine comprises the amino acid sequence of SEQ ID NO: 91 or SEQ ID NO: 93.

[0028] Also disclosed herein, in various embodiments, is an isolated cell comprising: (a) the chimeric protein disclosed herein; (b) the nucleic acid disclosed herein; (c) the expression vector disclosed herein; and / or the system disclosed herein. In some embodiments, the isolated cell further comprises a protein of interest. In some embodiments, the protein of interest is a synthetic immune receptor. In some embodiments, the synthetic immune receptor is a chimeric antigen receptor (CAR) or a T cell receptor (TCR), a T Cell Receptor Fusion Construct (TRuC), an adapter CAR, a universal / modular CAR system, a T cell antigen coupler (TAC) receptor, an HLA-independent T cell receptor (HIT), or a logic-gated version of any of the aforementioned receptors. In some embodiments, the synthetic immune receptor is a CAR. In some embodiments, the chimeric protein and the protein of interes t are expressed from a single mRNA molecule. In some embodiments, the chimeric protein and the protein of interest are expressed from separate mRNA molecules.

[0029] In some embodiments, the isolated cell further comprises a chemokine that can be secreted. In some embodiments, the secreted chemokine is CCL21 or CCL19. In some embodiments, the chemokine is CCL21, In some embodiments, the secreted chemokine comprises the amino acid sequence of SEQ ID NO: 47 or SEQ ID NO: 49. In some embodiments, the secreted chemokine is CCL19. In some embodiments, the secreted chemokine comprises the amino acid sequence of SEQ ID NO: 91 or SEQ ID NO: 93. In some embodiments, the chimeric protein and the secreted chemokine are expressed from aAttorney Docket No. WAP-008WOsingle mRNA molecule. In some embodiments, the chimeric protein and the secreted chemokine are expressed from separate mRNA molecules. In some embodiments, the cell comprises a protein of interest and the chimeric protein, the protein of interest, and the secreted chemokine are expressed from a single mRNA molecule. In some embodiments, the cell comprises a protein of interest and the chimeric protein, the protein of interest, and the secreted chemokine are expressed from separate mRNA molecules. In some embodiments, the cell comprises a protein of interest and the chimeric protein is expressed from a first mRNA molecule and the protein of interest and the secreted chemokine are expressed from a second mRNA molecule. In some embodiments, the cell comprises a protein of interest and the protein of interest is expressed from a first mRNA molecule and the chimeric protein and the secreted chemokine are expressed from a second mRNA molecule, in some embodiments, the cell comprises a protein of interest and the secreted chemokine is expressed from a first mRNA molecule and the chimeric protein and the protein of interest are expressed from a second mRNA molecule.

[0030] In some embodiments, the isolated cell is an immune cell. In some embodiments, the immune cell is a peripheral blood mononuclear cell (PBMC), a T cell, an NK cell, a macrophage, a tumor infiltrating lymphocyte, a monocyte, a dendritic cell, a neutrophil, a tumor-reactive lymphocyte, or a circulating tumor-reactive lymphocyte. In some embodiments, the isolated cell is a T cell. In some embodiments, the T cell is a cytotoxic T cell, a TH1 cell, a TH2 cell, a TH9 cell, a TH17 cell, a TFH cell, a TC1 cell, a TC2 cell, a TC9 cell, a TC17 cell, a TC22 cell, an NK-T cell, a γδ T cell, a naïve T cell, a TSCM cell, a TEM cell, a TEMRA cell, or a TRM cell. In some embodiments, the isolated cell is a human cell. In some embodiments, the isolated cell is a mouse cell.

[0031] Also disclosed herein, in various embodiments, is a pharmaceutical composition comprising: (a) the chimeric protein disclosed herein; (b) the nucleic acid disclosed herein; (c) the expression vector disclosed herein; (d) the system disclosed herein; and / or (e) the isolated cell disclosed herein; and a pharmaceutically acceptable excipient or carrier.

[0032] Also disclosed herein, in various embodiments, is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering an effective amount of the nucleic acid disclosed herein, the expression vector disclosed herein, the system disclosed herein, the isolated cell disclosed herein, or the pharmaceutical composition disclosed herein to the subject, thereby treating the disease or disorder. In someAttorney Docket No. WAP-008WOembodiments, tlie disease is a cancer, an infectious disease, an autoimmune disease, or an inflammatory disease.|0033] Also disclosed herein, in various embodiments is a use of one or more of: (a) the chimeric protein disclosed herein; (b) the nucleic acid disclosed herein; (c) the expression vector disclosed herein; (d) the system disclosed herein; (e) the isolated cell disclosed herein; and (f) the pharmaceutical composition disclosed herein in the manufacture of a medicament.

[0034] Also disclosed herein, in various embodiments is a method of engineering a cell to express the chimeric protein disclosed herein, the method comprising: (a) introducing into the cell the nucleic acid disclosed herein, the expression vector disclosed herein, or the system of disclosed herein; and (b) incubating the cell under conditions sufficient for expression of the chimeric protein. In some embodiments, the nucleic acid, expression vector, or system is introduced into the cell by viral transduction. In some embodiments, the viral transduction is performed using an integrating viral vector or a non-integrating viral vector, in some embodiments, the viral transduction is lentiviral transduction, retroviral transduction, AAV transduction, adenoviral transduction, Sendai virus transduction, Measles virus transduction. Foamy virus transduction, or HSV transduction. In some embodiments, the nucleic acid, expression vector, or system is introduced into the cell non-virally. In some embodiments, the nucleic acid, expression vector, or system is introduced into the cell using a lipid nanoparticle, lipid-based nanoparticle, polymeric nanoparticle, liposome, dendrimer, cellpenetrating peptide, extracellular vesicle, electroporation, sonoporation, microinjection, hydrodynamic delivery, or a transposon system. In some embodiments, the nucleic acid, expression vector, or system is introduced into the cell ex vivo. In some embodiments, the nucleic acid, expression vector, or system is introduced into the cell in vivo. In some embodiments, herein the cell is an immune cell. In some embodiments, tlie immune cell is a peripheral blood mononuclear cell (PBMC), a T cell, an NK cell, a macrophage, a tumor infiltrating lymphocyte, or a monocyte, a dendritic cell, a neutrophil, a tumor-reactive lymphocyte, or a circulating tumor-reactive lymphocyte. In some embodiments, the cell is a T cell. In some embodiments, the T cell is a cytotoxic T cell, a TH1 cell, a TH2 cell, a TH9 cell, a TH17 cell, a TFH cell, a TC1 cell, a TC2 cell, a TC9 cell, a TC17 cell, a TC22 cell, an NK-T cell, a γδ T cell, a naïve T cell, a TSCM cell, a TEM cell, a TEMRA cell, or a TRM cell.BRIEF DESCRIPTION OF THE DRAWINGSAttorney Docket No. WAP-008WO

[0035] These and other features, aspects, and advantages of the present invention will become better understood with regard to the follow ing description, and accompanying drawings, where:

[0036] FIGs. 1A-1C depict schematics of an exemplary chimeric protein that can be expressed in mammalian immune cells to improve their function through IL-9 (Interleukin-9) signaling. FIG. 1 A depicts mature IL-9 and mature IL-9R expressed as a single polypeptide connected through a linker peptide (IL9-IL9R chimeric protein). FIG. IB depicts a schematic of an exemplary expression system including a protein of interest (e.g., a CAR) and an 1L9-IL9R chimeric protein co-delivered and co-expressed by separating the two polypeptides with a ribosomal skip site (e.g., P2A or T2A). FIG. 1C depicts a schematic of an exemplary expression system including a protein of interest (e.g., a CAR) and an 1L9-IL9R chimeric protein delivered or expressed from independent nucleic acids,

[0037] FIG. 2 depicts a schematic of spatial biology -enabled pooled in vivo screen of more than 100 different CAR T designs.

[0038] FIG. 3 depicts a graph of the relative expansion of T cells expressing three different designs from the pooled in vivo screen. The three designs shown in the graph are (1) tire “BaseCAR”; (2) the BaseCAR co-expressed with a published IL15-IL15RA chimeric protein chimeric protein; and (3) the BaseCAR co-expressed with the novel IL9-IL9R chimeric protein depicted in FIG. 1A.

[0039] FIG. 4 depicts a graph of the relative Granzyme B protein levels in T cells expressing three different designs from the pooled in vivo screen. The three designs include the (1) “BaseCAR”, (2) the BaseCAR co-expressed IL15-IL15RA, and (3) the BaseCAR coexpressed with the novel IL9-IL9R chimeric protein depicted in FIG. 1A. Tire bar graph and error bars show the mean and SEM of each design, respectively.

[0040] FIG. 5 depicts a graph of the relative TOX protein levels in T cells expressing three different designs from the pooled in vivo screen. Tire three designs include the (I) “BaseCAR”, (2) the BaseCAR co-expressed IL15-IL15RA, and (3) the BaseCAR co¬ expressed with the novel IL9-IL9R chimeric protein depicted in FIG. 1A. The bar graph and error bars show the mean and SEM of each design, respectively.

[0041] FIGs. 6A and 6B depict the results of a murine in vivo study of T cells expressing BaseCAR and an IL9-IL9R chimeric protein. FIG. 6A is a depicts a graph of tumor volume plotted against days post-T cell injection, Data points and error bars represent the mean andAttorney Docket No. WAP-008WOSEM of each group. FIG. 6B is a graph depicting the progression-free survival (PFS) between group, assessed based on tumors reaching twice their initial volume from the time of treatment.

[0042] FIGs.7A-7D depict schematics of exemplary expression systems. FIG. 7A depicts a schematic of an exemplary’ expression system including (i) a protein of interest (e.g., a CAR), (ii) an IL9-IL9R chimeric protein, and (iii) a CCL21 protein co-delivered and co-expressed by separating the three polypeptides with a ribosomal skip site (e.g., P2A or T2A). FIG. 7B depicts a schematic of an exemplary expression system including (i) a protein of interest (e.g., a CAR) delivered or expressed from a first nucleic acids, (ii) an IL9-IL9R chimeric protein, and (iii) a CCL21 protein co-delivered and co-expressed from a second nucleic acid by separating the two polypeptides with a ribosomal skip site (e.g., P2A or T2A). FIG. 7C depicts a schematic of an exemplary' expression system including (i) a protein of interest (e.g., a CAR), (ii) an IL9-IL9R chimeric protein, and (iii) a CCL21 protein delivered or expressed from independent nucleic acids. FIG. 7D depicts a schematic of an exemplary expression sy stem including an IL9-IL9R chimeric protein, and a CCL21 protein delivered or expressed from independent nucleic acids,

[0043] FIG. 8 is a depicts a graph of tumor volume plotted against days post-T cell injection from a murine in vivo study' of mice injected with (1) mock-transduced T cells; (2) T cells co-expressing the BaseCAR and a mock armor (EGFRt); (3) T cells co-expressing the BaseCAR and the 1L9-1L9R chimeric protein; and (4) T cells co-expressing the BaseCAR, the 1L9-IL9R chimeric protein, and CCL21.

[0044] FIGs. 9A-9D depict exemplary' expression systems encoding a protein of interest (e.g., a CAR) and a chimeric protein. FIG. 9 A depicts a schematic of an exemplary expression system including (i) a protein of interest (e.g., a CAR) and (ii) a chimeric protein including a signal peptide, a truncated cytokine receptor (e.g., IL-9R) extracellular domain, a transmembrane domain and an IL-9R intracellular effector domain co-delivered and coexpressed by separating the two polypeptides with a ribosomal skip site (e.g., P2A or T2A). FIG. 9B depicts a schematic of an exemplary expression system including (i) a protein of interest (e.g., a CAR) and (ii) a chimeric protein including a signal peptide, a truncated cytokine receptor (e.g., IL-9R) extracellular domain, a transmembrane domain, and an IL-9R intracellular effector domain co-delivered or expressed from independent nucleic acids. FIG.9C depicts a schematic of an exemplary expression system including (i) a protein of interest (e.g., a CAR) and (ii) a chimeric protein including a TGFBR2 extracellular domain, aAttorney Docket No. WAP-008WOtransmembrane domain and an IL-9R intracellular effector domain co-delivered and coexpressed by separating the two polypeptides with a ribosomal skip site (e.g., P2A or T2A). FIG. 9D depicts a schematic of an exemplary expression system including (i) a protein of interest (e.g., a CAR) and (ii) a chimeric protein including a TGFBR2 extracellular domain, a transmembrane domain and an IL-9R intracellular effector domain co-delivered or expressed from independent nucleic acids.

[0045] FIGs. 10A and 10B depicts results from a spatial pooled screen of T cells expressing a CLDN 18.2 CAR (BaseCAR) and a chimeric polypeptide having the indicated amino acid sequence, FIG. 10A depicts a graph of the relative Granzyme B protein levels in CAR T cells expressing different designs from the pooled in vivo screen. The amount of granzyme B in the BaseCAR + EGFRt (control armor) is set to 0. The armored CAR designs with positive values have more Granzyme B on average than cells expressing the BaseCAR + EGFRt. FIG. 10B is a plot of the relative amount of Granzyme B / TOX protein levels in CAR T cells expressing the different designs from the pooled in vivo screen. The ratio of granzyme B / TOX protein levels in the BaseCAR + EGFRt (control armor) is set to 0.Expression of the armors with positive values results in CAR T cells having a higher ratio of Granzyme B / TOX than cells expressing the BaseCAR + EGFRt.

[0046] FIGs. 11A, 11 B, and 11C depict results from an in vivo anti-tumor efficacy study of NSG mice implanted with xenograft tumors that were treated with human CAR T cells expressing the indicated proteins. The graphs depict tumor volume plotted against days post CAR T cell injection. All graphs depict results from the same experiment. For each group of mice, the data points and error bars represent the mean tumor volume and SEM, respectively.

[0047] FIG. 12 depicts a graph showing the proliferation of human CAR T cells expressing the indicated proteins or control untransduced T cells in response to AsPC-l-CLDN18.2 target cancer cells. The horizontal axis is time and the vertical axis is total cell counts. The data points and error bars represent the mean total cell count and SEM, respectively.

[0048] FIGs. 13A and 13B depict results of an Incucyte cytotoxicity assay measuring the effectiveness of T cells transduced to express BaseCAR and the indicated chimeric polypeptide or control untransduced T cells to kill target-antigen expressing cells. FIG. 13A depicts results following the first co-culture of the transduced T cells and target cells. FIG.13B depicts results following the third co-culture of the transduced T cells and target cells.Attorney Docket No. WAP-008WOThe horizontal axes shows time and the vertical axes shows the Cytotoxicity Index. The data points and error bars represent the mean Cytotoxicity Index and SEM, respectively.|0049] FIGs. 14A and 14B depict results of an Incucyte cytotoxicity assay measuring the effectiveness of T cells transduced to express BaseCAR and the indicated chimeric polypeptide or control untransduced T cells to kill target-antigen expressing cells, FIG. 14A depicts results following the first co-culture of the transduced T cells and target cells. FIG.14B depicts results following the second co-culture of the transduced T cells and target cells. The horizontal axes shows time and the vertical axes shows the Cytotoxicity Index. The data points and error bars represent the mean Cytotoxicity Index and SEM, respectively.

[0050] FIG. 15 depicts a graph showing tumor burden (in Relative Fluorescence Units: RFU) plotted against days post lentiviral injection from a murine in vivo study in NSG-DKO mice that have been humanized with human PBMCs. In this experiment, the constructs are delivered to T cells by injecting the mice with a lentivirus encoding the BaseCAR and indicated chimeric protein, with the lentivirus being specifically engineered to recognize T cells. For each group of mice, the data points and error bars represent the mean tumor volume and SEM, respectively.DETAILED DESCRIPTION OF THE INVENTION

[0051] The present disclosure generally relates to chimeric proteins (e.g., “armors”) comprising (i) an extracellular domain; (b) a transmembrane domain; and (c) a cytokine receptor intracellular effector domain. In some embodiments, the present disclosure provides a chimeric protein comprising: (i) a cytokine polypeptide or a functional fragment thereof operably linked to (ii) a cell-surface receptor polypeptide, wherein the cell-surface receptor polypeptide comprises: (a) an extracellular ligand-binding domain capable of binding the cytokine polypeptide; (b) a transmembrane domain; and (c) an IL-9 receptor (IL-9R) intracellular effector domain capable of activating downstream signaling. In some embodiments, binding of the cytokine polypeptide to the ligand binding domain induces the IL-9R effector domain to activate the downstream signaling. This structure keeps the cytokine and its cognate receptor in close proximity, enabling tire cytokine to bind to the extracellular domain of its cognate receptor, which results in signaling through an 1L-9R intracellular domain. In some embodiments, binding of the extracellular ligand-binding domain by a cytokine polypeptide in the same protein induces the IL-9R effector domain to activate downstream signaling (cis activation). In some embodiments, binding of theAttorney Docket No. WAP-008WOextracellular ligand-binding domain by a cytokine polypeptide in a different protein induces the IL-9R effector domain to activate downstream signaling (trans activation).|0052] In some embodiments, the present disclosure provides chimeric protein comprising: (a) a extracellular domain comprising a truncated cytokine receptor extracellular domain polypeptide; (b) a transmembrane domain; and (c) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein does not comprise the amino acid sequence of an endogenous full-length IL-9R. In some embodiments, the chimeric protein does not comprise the amino acid sequence of SEQ ID NO: 1. In some embodiments, the chimeric protein does not consist of the amino acid sequence of SEQ ID NO: 1, This structure may allow ligandindependent activation of the chimeric protein, which results in signaling through an IL-9R intracellular domain.

[0053] In some embodiments, the present disclosure provides chimeric protein comprising: (a) an extracellular domain comprising a transforming growth factor beta receptor (TGFBR) extracellular domain polypeptide; (b) a transmembrane domain; and (c) a cytokine receptor intracellular effector domain. In some embodiments, the chimeric protein does not comprise the amino acid sequence of SEQ ID NO: 1. In some embodiments, the extracellular domain further comprises an extracellular domain polypeptide of a cytokine receptor. This structure may both alleviate TGF-p-mediated suppression of immune cells expressing the chimeric protein and may either enhance activity of the chimeric protein upon binding to TGF-, which results in signaling through a cytokine receptor intracellular domain, or may allow ligand-independent activation of tire chimeric protein to result in signaling through a cytokine receptor intracellular domain.

[0054] Cell therapies (e.g., CAR-expressing immune cells can be limited by the necessity for in vivo expansion following infusion and by their lack of cytotoxicity or an altered cellular state. For example, to achieve robust expansion, T cells require three signals: antigen¬ stimulation, co-stimulation, and cytokine-induced stimulation. Activation of CARs is generally sufficient to induce the first two signals, but cannot recapitulate cytokine signaling. Furthermore, the tumor microenvironment is often immunosuppressive and devoid of pro-inflammatory cytokines. Cytokine signaling is also associated with modulating the differentiation state of T cells, resulting in altered cytotoxicity and long-term functionality, among other changes to the T cells. Chimeric proteins of the present disclosure can thus be used to stimulate robust in vivo expansion and enhance desirable properties (e.g., increased survival, persistence, and potency) of cell therapies as described herein.Attorney Docket No. WAP-008WODefinitions

[0055] Terms used in the claims and specification are defined as set forth below unless otherwise specified.

[0056] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0057] As used herein, the term “gene” refers to the basic unit of heredity, consisting of a segment of DNA arranged along a chromosome, which codes for a specific protein or segment of protein. A gene typically includes a promoter, a 5' untranslated region, one or more coding sequences (exons), optionally introns, and a 3' untranslated region. The gene may further comprise a terminator, enhancers and / or silencers.

[0058] The term “sufficient amount” means an amount sufficient to produce a desired effect, e.g, an amount sufficient to modulate immune signaling in a cell.

[0059] The term “therapeutically effective amount” is an amount that is effective to ameliorate a symptom of a disease.

[0060] As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0061] The term “composition” refers to a mixture that contains, e.g., a chimeric protein or engineered cell contemplated herein. In some embodiments, the composition may contain additional components, such as adjuvants, stabilizers, excipients, and the like. The term “composition” or “pharmaceutical composition” refers to a preparation which is in such form as to pennit the biological activity of an active ingredient contained therein to be effective in treating a subject, and which contains no additional components which are unacceptably toxic to the subject in the amounts provided in the pharmaceutical composition.

[0062] The term “ameliorating” refers to any therapeutically beneficial result in the treatment of a disease state, e.g., a cancer disease state, lessening in the severity or progression, remission, or cure thereof.

[0063] As used herein, the term “effective amount” refers to the amount of a compound (e.g., a chimeric protein described herein, cells described herein) sufficient to effect beneficial or desired results. An effective amount can be administered in one or moreAttorney Docket No. WAP-008WOadministrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.|0064] As used herein the term “expression cassette” is a polynucleotide construct, generated recombinantly or synthetically, comprising regulatory sequences operably linked to a selected polynucleotide to facilitate expression of the selected polynucleotide in a host cell. For example, tire regulatory sequences can facilitate transcription of the selected polynucleotide in a host cell, or transcription and translation of the selected polynucleotide in a host cell. An expression cassette can, for example, be integrated in the genome of a host cell or be present in an expression vector.

[0065] As used, the term “encoding” refers to a sequence of nucleotides which codes for a protein or polypeptide of interest or non-protein coding sequences. The nucleic acid sequence may be either a molecule of DNA or RNA. In preferred embodiments, the molecule is a DNA molecule. In other preferred embodiments, the molecule is a RNA molecule. When present as a RNA molecule, it will comprise sequences w hich direct the ribosomes of the host cell to start translation (e.g, a start codon, ATG) and direct the ribosomes to end translation (e.g., a stop codon). Between the start codon and stop codon is an open reading frame (ORF). Such terms are known to one of ordinary skill in the art. Non-protein coding sequences include, but are not limited to, short hairpin RNA (shRNA), small interfering RNA (siRNA), double stranded RNA (dsRNA), or antisense oligonucleotides.

[0066] The term percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., BLASTP and BLASTN or other algorithms available to persons of skill in the art) or by visual inspection. Depending on the application, the percent “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared.

[0067] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary’, and sequence algorithm program parameters are designated. The sequenceAttorney Docket No. WAP-008WOcomparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.|0068] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis,), or by visual inspection (see generally Ausubel et al,, infra),

[0069] One example of an algorithm that is suitable for determining percent sequence identity’ and sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol. 215:403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information(www.ncbi.nlm.nih.gov / ).

[0070] As used herein, the term “operably linked” or “operatively linked” refers to the binding of a nucleic acid sequence to a single nucleic acid fragment such that one function is affected by the other. For example, if a promoter is capable of affecting the expression of a coding sequence or functional RNA (z.e., the coding sequence or functional RNA is under transcriptional control by the promoter), the promoter is operably linked thereto. Coding sequences can be operably linked to control sequences in both sense and antisense orientation.

[0071] As used herein, the term “promoter” refers to a nucleotide sequence (e.g., DNA sequence) capable of controlling the expression of a coding sequence or functional RNA. The promoter sequence consists of proximal and more dis tal upstream elements, the latter elements often referred to as enhancers. A promoter can be derived from natural genes in its entirety’, can be composed of different elements from different promoters found in nature, and / or may comprise synthetic DNA segments, A promoter, as contemplated herein, can be endogenous to the cell of interest or exogenous to the cell of in terest. It is appreciated by those skilled in the art that different promoters can induce gene expression in different tissue or cell types, or at different developmental stages, or in response to different environmental conditions. As is known in the art, a promoter can be selected according to the strength of the promoter and / or the conditions under which the promoter is active, e.g., constitutiveAttorney Docket No. WAP-008WOpromoter, strong promoter, weak promoter, inducible / repressible promoter, tissue specific or developmentally regulated promoters, cell cycle -dependent promoters, and the like.|0072] A promoter can be an inducible promoter (e.g., a heat shock promoter, tetracycline (tet)-regulated promoter, steroid-regulated promoter, metal-regulated promoter, or estrogen receptor-regulated promoter). In some embodiments, an inducible promoter comprises one or more inducible response elements (e.g., a tet-responsive element, a hypoxia-responsive element, a cAMP -responsive element, a serum-responsive element, or an estrogen-responsive element) operably linked to a basal promoter element. The promoter can be a constitutive promoter (e.g., CMV promoter, UBC promoter). In some embodiments, the promoter can be a spatially restricted and / or temporally restricted promoter (e.g., a tissue specific promoter, a cell type specific promoter, etc.). See for example US Publication 2018 / 0127786, the disclosure of which is herein incorporated by reference in its entirety.

[0073] As used herein, the term “transgene” refers to a polynucleotide that has been transferred naturally, or by any of a number of genetic engineering techniques from one organism to another. It is optionally translated into a polypeptide. It is optionally translated into a recombinant protein. A “recombinant protein” is a protein encoded by a gene - recombinant DNA - that has been cloned in a system that supports expression of the gene and translation of messenger RNA (see expression system). The recombinant protein can be a therapeutic agent, e.g., a protein that treats a disease or disorder disclosed herein. As used, transgene can refer to a polynucleotide that encodes a polypeptide.

[0074] The terms “vector” and “plasmid” are used interchangeably and as used herein refer to polynucleotide vehicles useful to introduce genetic material into a cell. Vectors can be linear or circular. V ectors can integrate into a target genome of a host cell, replicate independently in a host cell, or be present but not replicate in a host cell. Vectors can comprise, for example, an origin of replication, a multicloning site, and / or a selectable marker. An expression vector typically comprises an expression cassette. Vectors and plasmids include, but are not limited to, integrating vectors, prokaryotic plasmids, eukaryotic plasmids, plant synthetic chromosomes, episomes, cosmids, artificial chromosomes, and RNAs including mRNAs.

[0075] lire term “in vivo" refers to processes that occur in a living organism.

[0076] The term “in situ’’ refers to processes that occur in a living cell growing separate from a living organism, e.g., growing in tissue culture.Attorney Docket No. WAP-008WO

[0077] As used herein, the term “ex vivo” generally includes experiments or measurements made in or on living tissue, preferably in an artificial environment outside the organism, preferably with minimal differences from natural conditions.

[0078] As used herein, the term “exogenous” refers to a molecule or activity that has been introduced into a host cell and is not native to that cell. The molecule can be introduced, for example, by introduction of the encoding nucleic acid into host genetic material, such as by integration into a host chromosome, or as non-chromosomal genetic material, such as a plasmid. Thus, the term, when used in connection with expression of an encoding nucleic acid, refers to the introduction of the encoding nucleic acid into a cell in an expressible form. The term “endogenous” refers to a molecule or activity that is present in a host cell under natural, unedited conditions. Similarly, the term, when used in connection with expression of the encoding nucleic acid, refers to expression of the encoding nucleic acid that is contained within the cell and not introduced exogenously.

[0079] The term “heterologous” refers to a nucleic acid or polypeptide sequence or domain which is not native to a flanking sequence, e.g., wherein the heterologous sequence is not found in nature coupled to the nucleic acid or polypeptide sequences occurring at one or both ends.

[0080] The term “homologous” refers to a nucleic acid or polypeptide sequence or domain which is native to a flanking sequence, e.g., wherein the homologous sequence is found in nature coupled to the nucleic acid or polypeptide sequences occurring at one or both ends.

[0081] The terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0082] The term “mammal” as used herein includes both humans and non-humans and include but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.

[0083] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable.

[0084] The terms “protein,” “polypeptide,” and “peptide” are used herein interchangeably.Attorney Docket No. WAP-008WO

[0085] The terms ‘"reduce” and "‘inhibit” refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0086] As used herein, the term “subject” refers to a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, pigs and sheep. In certain embodiments, the subject is a human. In some embodiments the subject has a disease or condition that can be treated with an engineered cell provided herein or population thereof. In some aspects, the disease or condition is a cancer.Chimeric Proteins

[0087] In various embodiments, a chimeric protein (e.g., an armor) provided herein provides interleukin signaling. In some embodiments, a chimeric protein provides sustained interleukin signaling. In some embodiments, a chimeric protein provides ligand -dependent interleukin signaling. In some embodiments, the ligand-dependent interleukin signaling is induced by a non-endogenous ligand to the cytokine receptor intracellular effector domain. In various embodiments, a chimeric protein provided herein provides sustained interleukin (IL)-9 / IL-9R signaling. A “chimeric protein” of the present disclosure can also be referred to as a “fusion protein.” Interleukins (e.g., IL-9) activate receptors that signal through Signal Transducer and Activator of Transcription (S TAT) transcription factors (e.g., STAT1, STAT3 and STAT.5). Once activated, interleukin receptors can dimerize with the common gamma chain (IL2RG) and bind janus-associated kinases (JAKs) to induce JAK cross¬ phosphorylation and downstream “JAK / STAT” signaling. IL-9 (Uniprot Accession No.: Pl 5248) acts as a regulator of various hematopoietic cells, stimulating cell proliferation and preventing apoptosis. IL-9 is a pleiotropic cytokine and can affect many types of immune cells, many of which can be used as cell therapies. Increasing IL-9 signaling in cell therapies may be beneficial for their potential therapeutic function, for example in increasing proliferation, increasing cytolytic function, decreasing their exhaustion, and altering their differentiation state. IL-9R (also known as CD129) (Uniprot Accession No.: Q01113) is a cytokine receptor that complexes with IL2RG upon binding to IL-9 to activate JAK / STAT signaling. The endogenous sequence of mature IL-9R is set forth in SEQ ID NO: 1.SVTGEGQGPRSRTFTCLTNNILRIDCHWSAPELGQGSSPWLLFTSNQAPGGT HKCILRGSECTWLPPEAVLVPSDNFTITFHHCMSGREQVSLVDPEYLPRRH VKLDPPSDLQSNISSGHCILTWSISPALEPMTTLLSYELAFKKQEEAWEQAQ HRDH I VGVTWL I LEAFELDPGFI HEARLRVQMATLEDDWEEERYTGQWSEWAttorney Docket No. WAP-008WOSQPVCFQAPQRQGPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRI FYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCV QEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQT LAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSA LPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGML LPSVLSKARSWTF(SEQ ID NO: 1)Extracellular DomainCytokine Polypeptide and Ligand-Binding Domains

[0088] In various embodiments, the chimeric proteins disclosed herein comprise a cytokine polypeptide. In various embodiments, the chimeric proteins disclosed herein comprise an extracellular ligand-binding domain capable of binding the cytokine polypeptide. A cytokine polypeptide can function in the chimeric polypeptide to bind the extracellular ligand-binding domain, which then can induce activation of the IL-9R intracellular effector domain. In some embodiments, the extracellular ligand-binding domain is an extracellular domain of a receptor of the cytokine polypeptide. An extracellular ligand-binding domain can function in the chimeric poly peptide to bind the cytokine polypeptide and then induce activation of the IL-9R intracellular domain,

[0089] In some embodiments, cytokine polypeptides useful in the chimeric proteins disclosed herein can be members of the interleukin (IL) family of cytokines. In some embodiments, extracellular ligand-binding domains useful in the chimeric proteins disclosed herein can be interleukin receptors. In some embodiments, the cytokine polypeptide is a mature polypeptide (z.e., does not comprise its native signal peptide). In some embodiments, the cytokine polypeptide is a functional fragment of a cytokine (z.e., is capable of binding and activating its cognate receptor. In some embodiments, the cytokine polypeptide comprises a mutated or variant amino acid sequence relative to a “wild-type” cytokine.

[0090] In some embodiments, the cytokine polypeptide is selected from the group consisting of IL-9, IL-2, IL-4, IL-7, IL- 15, and IL-21. In some embodiments, the cytokine polypeptide is selected from the group consisting of mature IL-9, mature IL-2, mature IL-4, mature IL-7, mature IL- 15, and mature IL-21. Exemplary' cytokine polypeptide sequences useful in a chimeric protein disclosed herein are provided in Table 1. In some embodiments, the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, atAttorney Docket No. WAP-008WOleast 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 2-6.Table 1: Exemplary Cytokine Polypeptide SequencesDescription SequenceMature IL-9 QGCPTLAGILDINFLINKMQEDPASKCHCSANVTSCLCLGIPSDNCTRPC FSERLSQMTNTTMQTRYPLIFSRVKKSVEVLKNNKCPYFSCEQPCNQTTA GNALTFLKSLLEIFQKEKMRGMRGKI (SEQ ID NO: 2) Mature IL-2 APTS S STKKTQLQLEHLLLDLQM I LNG I NNYKNPKLTRMLTFKF YM PKKA TELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSE TTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 3) Mature IL-4 HKCDITLQEIIKTLNSLTEQKTLCTELTVTDIFAASKNTTEKETFCRAAT VLRQFYSHHEKDTRCLGATAQQFHRHKQLIRFLKRLDRNLWGLAGLNSCP VKEANQSTLENFLERLKTIMREKYSKCSS (SEQ ID NO: 111) Mature IL-7 DCD I EGKDGKQYES VLMVS I DQLLDSMKE I GSNCLNNEFNFFKRHI CDAN KEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGTTILLNCTGQVKGRK PAALGEAQPTKSLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTK EH (SEQ ID NO: 4)Mature IL- 15 NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVI SLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFL QSFVHIVQMFINTS (SEQ ID NO: 5)Mature IL-21 QGQDRHM I RMRQLI DI VDQLKNYVNDLVPE FLPAPEDVETNCEWSAFS OF QKAQLKSANTGNNERIINVSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYE KKPPKEFLERFKSLLQKMIHQHLSSRTHGSEDS (SEQ ID NO: 6)

[0091] In some embodiments, the cytokine polypeptide is an IL-9 polypeptide or a functional fragment thereof. In some embodiments, the IL-9 polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-9 polypeptide comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-9 polypeptide comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 2, In some embodiments, the IL-9 polypeptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-9 polypeptide comprises an amino acid sequence at least 95% identical to tire amino acid sequence of SEQ ID NO: 2, In some embodiments, the IL-9 polypeptide comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-9 polypeptide comprises the amino acid sequence of SEQ ID NO: 2.Attorney Docket No. WAP-008WO

[0092] In some embodiments, the cytokine polypeptide is an IL-2 polypeptide or a functional fragment thereof. IL-2 (UniProt Accession No.: P60568) is a pro-inflammatory cytokine that, inter alia, promotes the proliferation of immune cells, e.g., natural killer (NK) cells and T-cell. In some embodiments, the IL-2 polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the IL-2 polypeptide comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the IL-2 polypeptide comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the IL-2 polypeptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the IL-2 polypeptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the IL-2 polypeptide comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the IL-2 polypeptide comprises the amino acid sequence of SEQ ID NO: 3.

[0093] In some embodiments, the cytokine polypeptide is an IL-4 polypeptide or a functional fragment thereof. IL-4 (UniProt Accession No.: P05112) is a pro-inflammatory' cytokine that, inter alia, promotes tlie activity of B cells, lymphocytes, monocytes, and macrophages. In some embodiments, the IL-4 polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 111. In some embodiments, the IL-4 polypeptide comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 111. In some embodiments, the IL-4 polypeptide comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 111. In some embodiments, the IL -4 polypeptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 111. In some embodiments, the IL-4 polypeptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 111. In some embodiments, the IL-4 polypeptide comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 111. In some embodiments, the IL-4 polypeptide comprises the amino acid sequence of SEQ ID NO: 111.

[0094] In some embodiments, the cytokine polypeptide is an IL-7 polypeptide or a functional fragment thereof. IL-7 (UniProt Accession No.: P13232) is a pro-inflammatory' cytokine that, inter alia, promotes the development, proliferation, and survi val of variousAttorney Docket No. WAP-008WOimmune cells, e.g., NK cells and T cells. In some embodiments, the IL-7 polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, the IL-7 polypeptide comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, the IL-7 polypeptide comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, the IL-7 polypeptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, the IL-7 polypeptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, the IL-7 polypeptide comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 4. in some embodiments, the IL-7 polypeptide comprises the amino acid sequence of SEQ ID NO: 4.

[0095] In some embodiments, the cytokine polypeptide is an IL- 15 polypeptide or a functional fragment thereof. IL-15 (UniProt Accession No.: P40933) is a pro-inflammatory cytokine that, inter alia, promotes the proliferation of immune cells, e.g., NK cells, T cells, and B cells. In some embodiments, the IL- 15 polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the IL- 15 polypeptide comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the IL-15 polypeptide comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the IL- 15 polypeptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the IL-15 polypeptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the IL- 15 polypeptide comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the IL-15 polypeptide comprises the amino acid sequence of SEQ ID NO: 5.

[0096] In some embodiments, the cytokine polypeptide is an IL-21 polypeptide or a functional fragment thereof, IL-21 (UniProt Accession No.: Q9HBE4) is an immunoregulatory cytokine that promotes proliferation, maturation, and maintenance of immune cells. In some embodiments, the IL-21 polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 6, In some embodiments, the IL-21Attorney Docket No. WAP-008WOpolypeptide comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 6. In some embodiments, the IL-21 polypeptide comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 6. In some embodiments, the IL-21 polypeptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 6. In some embodiments, the IL-21 polypeptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 6. In some embodiments, tire IL-21 polypeptide comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 6. In some embodiments, the IL-21 polypeptide comprises the amino acid sequence of SEQ ID NO: 6.

[0097] In some embodiments, the extracellular ligand-binding domain is selected from the group consisting of an IL-9R extracellular domain, an IL-2R extracellular domain, an IL-7R extracellular domain, an IL-15R extracellular domain, and an IL-21R extracellular domain. In some embodiments, the extracellular ligand binding domain further comprises an IL-9R juxtamembrane sequence. In some embodiments, the IL-9R juxtamembrane sequence is a portion of an IL-9R extracellular domain. In some embodiments, the IL-9R juxtamembrane sequence comprises the amino acid sequence of QRQGPLIPPWGWP (SEQ ID NO: 34). In some embodiments, the extracellular ligand binding domain further comprises an IL-15RA juxtamembrane sequence. In some embodiments, the extracellular ligand binding domain further comprises an IL-15RA juxtamembrane sequence where the extracellular ligandbinding domain and / or the transmembrane domain is from IL15RA. In some embodiments, the IL- 15 RA juxtamembrane sequence is a portion of an IL-15RA extracellular domain. In some embodiments, the IL- 15RA juxtamembrane sequence comprises the ammo acid sequence of PGVYPQGHSDTT (SEQ ID NO: 110).

[0098] Exemplary extracellular ligand-binding domain polypeptide sequences useful in a chimeric protein disclosed herein are provided in Table 2. In some embodiments, the extracellular ligand-binding domain polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 7-11.Table 2: Exemplary Ligand-Binding Domain Polypeptide SequencesDescription SequenceIL-9R extracellular domain SVTGEGQGPRSRTFTCLTNNILRIDCHWSAPELGQGSSPWLLFTSNQAPGGTHKCILRGSECTWLPPEAVLVPSDNFTITFHHAttorney Docket No. WAP-008WOCMSGREQVSLVDPEYLPRRHVKLDPPSDLQSNISSGHCILTW SIS PALE PMTTLLS YELAFKKQEEAWEQAQHRDH I VGVTWL I LEAFELDPGFIHEARLRVQMATLEDDWEEERYTGQWSEWSQ PVCFQAPQRQGPLIPPWGWP (SEQ ID NO: 7)IL-2RB extracellular domain AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRR RWNQTCELL PVS QAS WACNL I LGAPDS QKLTTVD I VTLRVLC+ IL9-R juxtamembrane REGVRWRVMAIQDFKPFENLRLMAPISLQWHVETHRCNISW sequence E I SQASHYFERHLE FEARTLS PGHTWEEAPLLTLKQKQEWI C LETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAAQ RQGPLIPPWGWP (SEQ ID NO: 8)IL-2RB extracellular domain AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRR RWNQTCELL PVS QAS WACNL I LGAPDS QKLTTVD I VTLRVLC REGVRWRVMAIQDFKPFENLRLMAPISLQWHVETHRCNISW E I SQASHYFERHLE FEARTLS PGHTWEEAPLLTLKQKQEWI C LETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAA(SEQ ID NO: 106)IL-4RA extracellular domain MKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRLLYQLVFL LSEAHTC I PENNGGAGCVCHLLMDDWSADNYTLDLWAGQQL+ IL9-R juxtamembrane LWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSNPYPPDN sequence YLYNHLTYAVNIWSENDPADFRIYNVTYLEPSLRIAASTLKS GISYRARVRAWAQCYNTTWSEWSPSTKWHNSYREPFEQHQRQ GPLIPPWGWP (SEQ ID NO: 112)IL-4RA extracellular domain MKVLQEPTCVSDYMS I STCEWKMNGPTNCSTELRLLYQLVFL LSEAHTC I PENNGGAGCVCHLLMDDWSADNYTLDLWAGQQL LWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSNPYPPDN YLYNHLTYAVNIWSENDPADFRI YNVTYLEPSLRIAASTLKS G I S YRARVRAWAQCYNTTWSEWS PSTKWHNS YRE PFEQH(SEQ ID NO: 113)IL-7RA extracellular domain ESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDP DVN I TNLE FE I CGALVEVKCLNFRKLQE I Y F I ETKKFLL I GK+ IL9-R juxtamembrane SNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSWYREGANDF sequence WTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKL TLLQRKLQPAAMYEIKVRSIPDHYFKGFWSEWSPSYYFRTPE INNSSQRQGPLI PPWGWP (SEQ ID NO: 9)IL-7RA extracellular domain ESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDP DVN I TNLE FE I CGALVEVKCLNFRKLQE I Y F I ETKKFLL I GK SNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSWYREGANDF WTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKL TLLQRKLQPAAMYEIKVRSIPDHYFKGFWSEWSPSYYFRTPE INNSS (SEQ ID NO: 107)IL-15RA extracellular domain I TCPPPMSVEHAD I WVKS YSL YS RERY I CNSG FKRKAGTS S L TECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTTAG+ IL9-R juxtamembrane VTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGSQLMPSK sequence SPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQPQRQGP LIPPWGWP (SEQ ID NO: 10)Attorney Docket No. WAP-008WOIL-15RA extracellular domain ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSL TECVLNKATNVAHWTTPSLKCIRDPALVHQRPAPPSTVTTAG VTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGSQLMPSK SPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQP (SEQ ID NO: 108)IL-21R extracellular domain CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKDE ATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITDQSG+ IL9-R juxtamembrane NYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWRSDYEDP sequence AFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLP LEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSQR QGPLIPPWGWP (SEQ ID NO: 11)IL-21R extracellular domain CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKDE ATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITDQSG NYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWRSDYEDP AFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLP LEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQS(SEQ ID NO: 109)

[0099] In some embodiments, the extracellular ligand-binding domain comprises an IL-9R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the IL-9R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the IL-9R extracellular domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the IL-9R extracellular domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the IL-9R extracellular domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 7, In some embodiments, the IL-9R extracellular domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the IL-9R extracellular domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the IL-9R extracellular domain comprises the amino acid sequence of SEQ ID NO: 7.

[0100] In some embodiments, the extracellular ligand-binding domain comprises an IL-2R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the IL-2R extracellular domain is an IL-2RB extracellular domain. IL-2RB (also known as CD 122) (Uniprot Accession No.: Pl 4784) is a cytokine receptor that forms heterotrimeric complex upon binding to IL-2 to activate downstream signaling. In some embodiments, the IL-2RAttorney Docket No. WAP-008WOextracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the IL-2R extracellular domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 8. in some embodiments, the IL-2R extracellular domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 8, In some embodiments, the IL-2R extracellular domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the IL-2R extracellular domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the IL-2R extracellular domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 8. in some embodiments, the IL-2R extracellular domain comprises the amino acid sequence of SEQ ID NO: 8, In some embodiments, the IL-2R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 106. In some embodiments, the IL-2R extracellular domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 106. In some embodiments, the IL-2R extracellular domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 106. In some embodiments, the IL-2R extracellular domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 106. In some embodiments, the IL-2R extracellular domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 106. In some embodiments, the IL-2R extracellular domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 106. In some embodiments, the IL-2R extracellular domain comprises the amino acid sequence of SEQ ID NO: 106.

[0101] In some embodiments, the extracellular ligand-binding domain comprises an IL-4R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the IL-4R extracellular domain is an IL-4RA extracellular domain. IL-4RA (also known as CD 124) (Uniprot Accession No.: P24394) is a cytokine receptor that complexes with IL2RG upon binding to IL-4 to activate JAK / STAT signaling. In some embodiments, the IL-4R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 112. In some embodiments, the IL-4R extracellular domain comprises an amino acidAttorney Docket No. WAP-008WOsequence at least 80% identical to the amino acid sequence of SEQ ID NO: 112. In some embodiments, the IL-4R extracellular domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 112. In some embodiments, the IL-4R extracellular domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 112. In some embodiments, the IL-4R extracellular domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 112. In some embodiments, the IL-4R extracellular domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 112. In some embodiments, the IL-4R extracellular domain comprises tire amino acid sequence of SEQ ID NO: 112. In some embodiments, the IL-4R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 113. In some embodiments, tire IL-4R extracellular domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 113. In some embodiments, the IL-4R extracellular domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 113. In some embodiments, the IL-4R extracellular domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 113, In some embodiments, the IL-4R extracellular domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 113. In some embodiments, tire IL-4R extracellular domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 113. In some embodiments, the IL-4R extracellular domain comprises the amino acid sequence of SEQ ID NO: 113.

[0102] In some embodiments, the extracellular ligand-binding domain compri ses an IL-7R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the IL-7R extracellular domain is an IL-7RA extracellular domain. IL-7RA (also known as CD 127) (Uniprot Accession No.: P16871) is a cytokine receptor that complexes with IL2RG upon binding to IL-7 to activate JAK / STAT signaling. In some embodiments, the IL-7R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the IL-7R extracellular domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the IL-7R extracellular domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the IL-7RAttorney Docket No. WAP-008WOextracellular domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the IL-7R extracellular domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the IL-7R extracellular domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 9. In some embodiments, the IL-7R extracellular domain comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the IL-7R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 107. In some embodiments, the IL-7R extracellular domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 107. In some embodiments, the IL-7R extracellular domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 107. In some embodiments, the IL-7R extracellular domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 107. In some embodiments, the IL-7R extracellular domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 107. In some embodiments, the IL-7R extracellular domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 107. In some embodiments, the IL-7R extracellular domain comprises the amino acid sequence of SEQ ID NO: 107.

[0103] In some embodiments, the extracellular ligand-binding domain comprises an IL-15R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the IL-15R extracellular domain is an IL-15RA extracellular domain. IL-15RA (also known as CD215) (Uniprot Accession No,: QI 3261) is a cytokine receptor that complexes with IL2RG upon binding to IL-15 to activate JAK / STAT signaling. In some embodiments, the IL-15R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-15R extracellular domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-15R extracellular domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-15R extracellular domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-15R extracellular domain comprises an amino acid sequence at least 95% identical to the amino acid sequenceAttorney Docket No. WAP-008WOof SEQ ID NO: 10. In some embodiments, the IL-15R extracellular domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-15R extracellular domain comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-15R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 108. In some embodiments, the IL-15R extracellular domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 108. In some embodiments, the 1L-15R extracellular domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 108. In some embodiments, the IL-15R extracellular domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 108. In some embodiments, the IL-15R extracellular domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 108, In some embodiments, the IL-15R extracellular domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 108. In some embodiments, the IL- 15R extracellular domain comprises the amino acid sequence of SEQ ID NO: 108.

[0104] In some embodiments, the extracellular ligand-binding domain comprises an IL-21R extracellular domain or a ligand-binding fragment thereof. IL-21R (also known as CD360) (Uniprot Accession No.: Q9HBE5) is a cytokine receptor that complexes with IL2RG upon binding to IL-21 to activate JAK / STAT signaling. In some embodiments, the IL-21R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the IL-21R extracellular domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the 1L-21R extracellular domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the IL-21R extracellular domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the 1L-21R extracellular domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 11, In some embodiments, the IL-21 R extracellular domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 11. In some embodiments, the IL-21R extracellular domain comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the IL-21R extracellular domain comprises an aminoAttorney Docket No. WAP-008WOacid sequence at least 80%, at least 85%. at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 109. In some embodiments, the IL-21R extracellular domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 109. In some embodiments, the IL-21R extracellular domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 109. In some embodiments, the IL-21R extracellular domain comprises an amino acid sequence at least 90% identical to tire amino acid sequence of SEQ ID NO: 109. In some embodiments, the IL-21R extracellular domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 109. In some embodiments, the IL-21R extracellular domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 109. In some embodiments, the IL-21R extracellular domain comprises the amino acid sequence of SEQ ID NO: 109.

[0105] In some embodiments, a cytokine polypeptide is paired with an extracellular domain of its cognate receptor. In some embodiments, the cytokine polypeptide is IL-9 or a functional fragment thereof and the ligand binding domain is an IL-9R extracellular domain or a ligand-binding fragment thereof, the cytokine polypeptide is IL-2 or a functional fragment thereof and the ligand binding domain is an IL-2R extracellular domain or a ligand¬ binding fragment thereof, the cytokine polypeptide is IL-4 or a functional fragment thereof and the ligand binding domain is an IL-4R extracellular domain or a ligand-binding fragment thereof, the cytokine polypeptide is IL-7 or a functional fragment thereof and the ligand binding domain is an IL-7R extracellular domain or a ligand-binding fragment thereof, the cytokine polypeptide is IL-15 or a functional fragment thereof and the ligand binding domain is an IL-15R extracellular domain or a ligand-binding fragment thereof; or the cytokine polypeptide is IL-21 or a functional fragment thereof and the ligand binding domain is an IL-21R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide is IL-9 or a functional fragment thereof and the ligand binding domain is an IL-9R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide is IL-2 or a functional fragment thereof and the ligand binding domain is an IL-2R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide is IL-4 or a functional fragment thereof and the ligand binding domain is an IL-4R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide is IL-7 or a functional fragment thereof and the ligand binding domain is an IL-7R extracellular domain or a ligand-binding fragmentAttorney Docket No. WAP-008WOthereof. In some embodiments, the cytokine polypeptide is IL- 15 or a functional fragment thereof and the ligand binding domain is an IL-15R extracellular domain or a ligand-binding fragment thereof. In some embodiments, the cytokine polypeptide is IL-21 or a functional fragment thereof and the ligand binding domain is an IL-21R extracellular domain or a ligand-binding fragment thereof.Modified Extracellular Domains|0106] In various embodiments, the extracellular domain of the chimeric protein comprises a truncation or deletion of a cytokine receptor extracellular domain polypeptide. The truncation can be an N-terminal deletion or a C-terminal deletion. Without being bound to any particular theory, a truncated cytokine extracellular domain can function in tire chimeric polypeptide to promote sustained signaling by allowing ligand-independent dimerization of the chimeric polypeptide with, for example, the common gamma chain receptor (IL2RG). Additionally, a more compact design may allow improved expression compared to larger proteins. In some embodiments, the truncated cytokine receptor extracellular domain is a truncated extracellular domain of IL-9R, IL-2RB, IL-7R, IL-15RA, or IL-21R. In some embodiments, the truncated extracellular domain comprises an ammo acid sequence as set forth in Table 3. The sequences in Table 3 are non-limiting and other truncations can be utilized by removing 1, 2, or 3 amino acids from the N- or C -terminus of the amino acid sequences set forth in Table 3.Table 3: Truncated Cytokine Receptor Extracellular Domain Polypeptides Description SequenceTruncated IL-9R PPWGWP (SEQ ID NO: 51 )extracellular domain (6 aa)Truncated IL-9R GPLI PPWGWP (SEQ ID NO: 52)extracellular domain (10 aa)Truncated IL-9R QPVCFQAPQRQGPLI PPWGWP (SEQ ID NO: 53) extracellular domain (21 aa)Truncated IL-9R GQWSEWSQPVCFQAPQRQGPLI PPWGWP (SEQ ID NO: extracellular domain (28 aa) 54)(WSxWS)Attorney Docket No. WAP-008WOTruncated IL-7R GEMD (SEQ ID NO: 55)extracellular domain (4 aa)Truncated IL-7R PSYYFRTPEINNSSGEMD (SEQ ID NO: 56) extracellular domain (18 aa)Truncated IL-7R GFWSEWSPSYYFRTPEINNSSGEMD (SEQ ID NO: 57) extracellular domain (25 aa)(WSxWS)Truncated IL-2RB GEFTTWSPWSQPLAFRTKPAALGKDT (SEQ ID NO: 58) extracellular domain (26 aa)(WSxWS)Truncated IL-2RB QPLAFRTKPAALGKDT (SEQ ID NO: 59) extracellular domain (16 aa)Truncated IL-2RB GKDT (SEQ ID NO: 60)extracellular domain (4 aa)Truncated IL-15RA TAKNWELTASASHQPPGVYPQGHSDTT (SEQ ID NO: extracellular domain (27 aa) 61)Truncated IL -21 R PGSSYQGTWSEWSDPVI FQTQSEELKE (SEQ ID NO: extracellular domain (27 aa) 62)(WSxWS)Truncated IL-21R DPVI FQTQSEELKE (SEQ ID NO: 63)extracellular domain (14 aa)Truncated IL-21R SEELKE (SEQ ID NO: 64)extracellular domain (6 aa)

[0107] In some embodiments, the truncated cytokine receptor extracellular domain is a truncated IL-9R extracellular domain. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 60%, at least 80%, or 100% identical to SEQ ID NO: 51. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 60% identical to SEQ ID NO: 51. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence atAttorney Docket No. WAP-008WOleast 80% identical to SEQ ID NO: 51. In some embodiments, the truncated IL-9R extracellular domain comprises the amino acid sequence of SEQ ID NO: 51.|0108] In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 52, In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 52. in some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 52, In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 52. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 52. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 52. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence of SEQ ID NO: 52,|0109] In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 53, In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 53. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 53. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 53, In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 53. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 53. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence of SEQ ID NO: 53.

[0110] In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 54. In some embodiments, theAttorney Docket No. WAP-008WOtruncated IL-9R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 54. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 54. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 54, In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 54. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 54. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence of SEQ ID NO: 54.

[0111] In some embodiments, the truncated cytokine receptor extracellular domain is a truncated IL-7R extracellular domain. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 50%, at least 75%, or 100% identical to SEQ ID NO: 55. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 50% identical to SEQ ID NO: 55. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 75% identical to SEQ ID NO: 55. In some embodiments, the truncated IL-7R extracellular domain comprises the amino acid sequence of SEQ ID NO: 55.

[0112] In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 56. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 56. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 56. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 56. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 56. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 56. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence of SEQ ID NO: 56.Attorney Docket No. WAP-008WO

[0113] In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 57. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 57. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 57. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 57. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 57. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 57. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence of SEQ ID NO: 57.

[0114] In some embodiments, the truncated cytokine receptor extracellular domain is a truncated IL-2RB extracellular domain. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 58. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 58. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 58. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 58. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 58. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 58. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence of SEQ ID NO: 58.

[0115] In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 59. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 80%Attorney Docket No. WAP-008WOidentical to an amino acid sequence of SEQ ID NO: 59. in some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 59. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 59. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 59. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 59. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence of SEQ ID NO: 59.

[0116] In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 50%, at least 75%, or 100% identical to SEQ ID NO: 60, In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 50% identical to SEQ ID NO: 60. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 75% identical to SEQ ID NO: 60. In some embodiments, the truncated IL-2RB extracellular domain comprises the amino acid sequence of SEQ ID NO: 60.

[0117] In some embodiments, the truncated cytokine receptor extracellular domain is a truncated IL-15RA extracellular domain. In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 61, In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 61. In some embodiments, the truncated 1L-15RA extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 61, In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 61. In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 61. In some embodiments, the truncated IL-1 RA extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 61. In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence of SEQ ID NO: 61.Attorney Docket No. WAP-008WO

[0118] In some embodiments, the truncated cytokine receptor extracellular domain is a truncated IL-21R extracellular domain. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 62. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 62, In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 62. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 62. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 62. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 62. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence of SEQ ID NO: 62.

[0119] In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 63. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 63. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 63. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 63. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 63. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 63. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence of SEQ ID NO: 63.

[0120] In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 64%, at least 80%, or 100% identical to SEQ ID NO: 64. In some embodiments, the truncated IL-21R extracellular domain comprises an amino acid sequence at least 64% identical to SEQ ID NO: 64, In some embodiments, the truncated IL-Attorney Docket No. WAP-008WO21R extracellular domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 64. In some embodiments, the truncated IL-21R extracellular domain comprises the amino acid sequence of SEQ ID NO: 64.TGFBR Extracellular Domains

[0121] In various embodiments, the chimeric protein comprises an extracellular domain of a transforming growth factor beta (TGF-β) receptor (TGFBR). Transforming growth factor beta (TGF-β) is a multifunctional cytokine family that can inhibit the function of T cells within the tumor microenvironment. This family includes TGF-β1, TGF-β2, and TGF-β3, and these cytokines bind to TGF-β receptors that include TGFBR1 and TGFBR2. Without being bound to any particular theory, signaling through these receptors can exert poten t immunosuppressive effects on multiple immune cell types, including T cells. TGF-P levels are frequently increased in the microenvironment of many different tumor types, and, thus, heavily contributes to the immunosuppressive nature of many solid tumors. Use of a TGFBR extracellular domain in the chimeric polypeptide disclosed herein can function to prevent TGF-β-mediated inhibition of immune cells expressing the receptors and may instead promote activity of the immune cells by TGF-β-mediated activation of the chimeric protein. In some embodiments, the chimeric protein comprises a TGFBR extracellular domain. In some embodiments, the chimeric protein comprises (i) a TGFBR extracellular domain and (ii) a truncated cytokine receptor extracellular domain, a transmembrane domain, and an intracellular effector domain. In some embodiments, the truncated cytokine receptor extracellular domain and transmembrane domain are from the same cytokine receptor. In some embodiments, the truncated cytokine receptor extracellular domain and transmembrane domain are from different cytokine receptors.

[0122] In some embodiments, the TGFBR extracellular domain is all or a portion of the TGFBR2 extracellular domain. In some embodiments, the TGFBR2 extracellular domain comprises the amino acid sequence as set forth in SEQ ID NO: 65.MGRGLLRGLWPLH I VLWTR I AS TI P PHVQKS VNNDM I VTDNNGAVKF PQLCK FCDVRFSTCDNQKSCMSNCS I TS I CEKPQEVCVAVWRKNDENI TLETVCHDP KLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTS NPDLLLVI FQ ( SEQ ID NO: 65)

[0123] In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%Attorney Docket No. WAP-008WOidentical to an amino acid sequence of SEQ ID NO: 65. in some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 65. In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 65. In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 65, In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 65. In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 65. In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence of SEQ ID NO: 65.

[0124] In some embodiments, the TGFBR2 extracellular domain does not comprise its endogenous signal peptide. In some embodiments, the extracellular domain does not comprise the contiguous sequence of MGRGLLRGLWPLHIVLWTRIAS (SEQ ID NO: 95). In some embodiments, the TGFBR2 extracellular domain amino acid sequence lacking the signal peptide comprises the amino acid sequence as set forth in SEQ ID NO: 66.TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSIT S I CEKPQEVCVAVWRKNDEN I TLETVCHD PKL PYHD F I LEDAAS PKC IMKEK KKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQ (SEQ ID NO:66)

[0125] In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 66. In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 66. In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 66. In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 66. In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 66. In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 66. In some embodiments, the TGFBR2 extracellular domain comprises an amino acid sequence of SEQ ID NO: 66.Attorney Docket No. WAP-008WO

[0126] In some embodiments, the chimeric protein comprises an extracellular domain comprising a TGFBR extracellular domain and a truncated cytokine receptor extracellular domain. In some embodiments, the chimeric protein comprises an extracellular domain comprising a TGFBR2 extracellular domain and a truncated cytokine receptor extracellular domain. In some embodiments, the truncated cytokine receptor extracellular domain is a truncated extracellular domain of IL-9R, IL-2RB, IL-7R, or IL-15RA.

[0127] In some embodiments, the chimeric protein comprises an extracellular domain comprising a TGFBR2 extracellular domain and a truncated IL-9R extracellular domain. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 54. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 54. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 54. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 54. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 54. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 54. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence of SEQ ID NO: 54.

[0128] In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 53, In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 53. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 53, In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 53. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 53. In some embodiments, the truncated IL-9R extracellular domainAttorney Docket No. WAP-008WOcomprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 53. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence of SEQ ID NO: 53.

[0129] In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 52. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 52. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 52. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 52, In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 52. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 52. In some embodiments, the truncated IL-9R extracellular domain comprises an amino acid sequence of SEQ ID NO: 52.

[0130] In some embodiments, the chimeric protein comprises an extracellular domain comprising a TGFBR2 extracellular domain and a truncated IL-7R extracellular domain. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 57. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 57. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 57. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 57. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 57. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence of SEQ ID NO: 57.

[0131] In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 56. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acidAttorney Docket No. WAP-008WOsequence at least 85% identical to an amino acid sequence of SEQ ID NO: 56. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 96% identical to an amino acid sequence of SEQ ID NO: 56. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 56. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 56. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence of SEQ ID NO: 56.

[0132] In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 50%, at least 75%, or 100% identical to SEQ ID NO: 55. In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 50% identical to SEQ ID NO: 55, In some embodiments, the truncated IL-7R extracellular domain comprises an amino acid sequence at least 75% identical to SEQ ID NO: 55. In some embodiments, the truncated IL-7R extracellular domain comprises the amino acid sequence of SEQ ID NO: 55.

[0133] In some embodiments, the chimeric protein comprises an extracellular domain comprising a TGFBR2 extracellular domain and a truncated IL-15RA extracellular domain. In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence of SEQ ID NO: 61. In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 61. In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 61. In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 61. In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 61. In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 61. In some embodiments, the truncated IL-15RA extracellular domain comprises an amino acid sequence of SEQ ID NO: 61.

[0134] In some embodiments, the chimeric protein comprises an extracellular domain comprising a TGFBR2 extracellular domain and a truncated IL-2RB extracellular domain. InAttorney Docket No. WAP-008WOsome embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 80% identical to an amino acid sequence of SEQ ID NO: 59. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 85% identical to an amino acid sequence of SEQ ID NO: 59. in some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 59. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 59. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence at least 99% identical to an amino acid sequence of SEQ ID NO: 59. In some embodiments, the truncated IL-2RB extracellular domain comprises an amino acid sequence of SEQ ID NO: 59.Transmembrane Domains

[0135] In various embodiments, the cell-surface receptor polypeptide of the chimeric protein comprises a transmembrane domain linking the extracellular ligand-binding domain and the IL-9R intracellular effector domain. A transmembrane domain useful in the chimeric proteins disclosed herein can also function to promote activation of the chimeric protein. In some embodiments, the transmembrane domain is a transmembrane domain of an interleukin receptor. Interleukin receptor transmembrane domains can function by enhancing heterodimerization of IL2RB upon binding of the receptor to the cytokine.

[0136] In some embodiments, the transmembrane domain is selected from the group consisting of an IL-9R transmembrane domain, an IL-2R transmembrane domain, an IL-4RA transmembrane domain, an IL-7R transmembrane domain, an IL- 15R transmembrane domain, and an IL-21R transmembrane domain. Exemplary transmembrane domain polypeptide sequences useful in a chimeric protein disclosed herein are provided in Table 4. In some embodiments, the transmembrane domain polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 12-17 and 90. In some embodiments, the chimeric protein further comprises an additional polypeptide located between the transmembrane domain and the cytokine receptor intracellular effector domain. In some embodiments, the additional polypeptide is from the same cytokine receptor as the transmembrane domain. In some embodiments, the additional polypeptide is from a different cytokine receptor as the transmembrane domain.Attorney Docket No. WAP-008WOTable 4: Exemplary Transmembrane Domain Polypeptide SequencesDescription SequenceIL-9R transmembrane domain GNTLVAVSIFLLLTGPTYLLF (SEQ ID NO: 12) IL-2RB transmembrane domain I PWLGHLLVGLSGAFGFI ILVYLLI (SEQ ID NO: 13) IL-4RA transmembrane domain LLLGVSVSCIVILAVCLLCYVSIT (SEQ ID NO: 14) IL-7RA transmembrane domain PILLTISILSFFSVALLVILACVLW (SEQ ID NO: 15) IL-15RA transmembrane domain VAISTSTVLLCGLSAVSLLACYL (SEQ ID NO: 16) IL-21 R transmembrane domain GWNPHLLLLLLLVIVFIPAFW (SEQ ID NO: 17) TGFBR2 transmembrane domain VTGISLLPPLGVAISVIIIFY (SEQ ID NO: 90)|0137] In some embodiments, the transmembrane domain is an IL-9R transmembrane domain. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 12. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 12,

[0138] In some embodiments, the transmembrane domain is an IL-2R transmembrane domain. In some embodiments, the IL-2R transmembrane domain is an IL-2RB transmembrane domain. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80% identical to the aminoAttorney Docket No. WAP-008WOacid sequence of SEQ ID NO: 13. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 13. In some embodiments, a chimeric protein comprising an IL-2RB transmembrane domain further comprises an additional polypeptide located between the transmembrane domain and the intracellular effector domain. In some embodiments, the additional polypeptide is from the IL-2RB intracellular domain. In some embodiments, the additional polypeptide comprises the amino acid sequence of NCRN (SEQ ID NO: 96).

[0139] In some embodiments, the transmembrane domain is an IL-4R transmembrane domain. In some embodiments, the IL-4R transmembrane domain is an IL-4RA transmembrane domain. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 14, In some embodiments, the transmembrane domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 14. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 14.

[0140] In some embodiments, the transmembrane domain is an IL-7R transmembrane domain. In some embodiments, the IL-7R transmembrane domain is an IL-7RA transmembrane domain. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, orAttorney Docket No. WAP-008WO100% identical to the amino acid sequence of SEQ ID NO: 15. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 15. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 15. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 15. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 15. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 15. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, a chimeric protein comprising an IL-7R transmembrane domain further comprises an additional polypeptide located between the transmembrane domain and the intracellular effector domain. In some embodiments, the additional polypeptide is from the IL-7R intracellular domain. In some embodiments, the additional polypeptide comprises the amino acid sequence of KKRI (SEQ ID NO: 97).

[0141] In some embodiments, the transmembrane domain is an IL- 15R transmembrane domain. In some embodiments, the IL- 15R transmembrane domain is an IL-15RA transmembrane domain. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 16. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 16, In some embodiments, the transmembrane domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 16. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 16. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 16. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 16, In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 16.

[0142] In some embodiments, the transmembrane domain is an IL-21R transmembrane domain. In some embodiments, the transmembrane domain comprises an amino acidAttorney Docket No. WAP-008WOsequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 17. in some embodiments, the transmembrane domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 17, In some embodiments, the transmembrane domain comprises an ammo acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 17. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 17. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 17. in some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments, a chimeric protein comprising an IL-21R transmembrane domain further comprises an additional polypeptide located between the transmembrane domain and the intracellular effector domain. In some embodiments, the additional polypeptide is from the IL-21R intracellular domain. In some embodiments, the additional polypeptide comprises the amino acid sequence of SLKT (SEQ ID NO: 98).

[0143] In some embodiments, the transmembrane domain is an TGFBR2 transmembrane domain. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 90. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 90, In some embodiments, the transmembrane domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 90. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 90. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 90. In some embodiments, the transmembrane domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 90, In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 90. In some embodiments, a chimeric protein comprising a TGFBR2 transmembrane domain further comprises an additional polypeptide located between the transmembrane domain and the intracellular effectorAttorney Docket No. WAP-008WOdomain. In some embodiments, the additional polypeptide is from the TGFBR2 intracellular domain. In some embodiments, the additional polypeptide comprises the amino acid sequence of CYRVNRQ (SEQ ID NO: 99).Intracellular Effector Domain

[0144] In various embodiments, the chimeric proteins provided for herein comprise an intracellular effector domain of a cytokine receptor. In various embodiments, the chimeric proteins disclosed herein comprise an IL-9R intracellular effector domain. Upon binding of IL-9 to IL-9R and subsequent recruitment of IL2RG, the IL-9R intracellular effector domain can promote the cross-phosphorylation of JAK1 and JAK3, resulting in downstream activation of STAT1, STAT3, and STAT5. Exemplary cytokine receptor intracellular effector domain polypeptide sequences useful in a chimeric protein disclosed herein are provided in Table 5. In some embodiments, the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence set forth in any one of SEQ ID NOs: 18 or 35.Table 5: Exemplary Intracellular Effector Domain SequencesDescription SequenceIL-9R Intracellular Effector KLS PRVKRI FYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAG VLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEdomain QEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTS LTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPG NTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLH EDLQGMLLPSVLSKARSWTF (SEQ ID NO: 18) Truncated IL-9R Intracellular KLS PRVKRI FYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAG VLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEEffector domain QEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTS LTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPG NTQSS (SEQ ID NO: 35)N -terminally truncated IL-9R KRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQD CAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTIntracellular Effector domain RLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAP PDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSG PIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGM LLPSVLSKARSWTF (SEQ ID NO: 89)IL-2RB Intracellular Effector NCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSP FPS SS FS PGGLAPE I S PLEVLERDKVTQLLLQQDKVPEPASLdomain SSNHSLTSCFTNQGYFFFHLPDALEIEACQVYFTYDPYSEED PDEGVAGAPTGSSPQPLQPLSGEDDAYCTFPSRDDLLLFSPS LLGGPSPPSTAPGGSGAGEERMPPSLQERVPRDWDPQPLGPPTPGVPDLVDFQPPPELVLREAGEEVPDAGPREGVSFPWSRPPAttorney Docket No. WAP-008WOGQGEFRALNARLPLNTDAYLSLQELQGQDPTHLV (SEQ ID NO: 67)IL-I5RA Intracellular KSRQTPPLASVEMEAMEALPVTWGTSSRDEDLENCSHHL (SEQ ID NO: 68)Effector domain|0145] In some embodiments, the intracellular effector domain is capable of activating downstream signaling (e.g., signaling through JAK1 / JAK3 and / or STAT1 / STAT3 / STAT5).

[0146] In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the IL-9R intracellular effector domain comprises the amino acid sequence of SEQ ID NO: 18.

[0147] In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 35. In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 35. In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 35. In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 35. In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 35. In some embodiments, the IL-9R intracellular effector domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 35. In someAttorney Docket No. WAP-008WOembodiments, the IL-9R intracellular effector domain comprises the amino acid sequence of SEQ ID NO: 35.10148] In some embodiments, the IL-9R intracellular effector domain comprises one or more mutations relative to the wild-type sequence. In some embodiments, the one or more mutations are selected from the group consisting of a Q I 15T amino acid substitution, an amino acid substitution at Y405 (e.g., a Y405F amino acid substitution), aP407A amino acid substitution, a Q409R amino acid substitution, and a repeat (e.g., a 2x repeat, a 3x repeat, a 4x repeat, or a 5 repeat) of amino acids 386 to 424 of the wild type sequence (GSEHVLPAGCLELEGQPSAYLPQEDWAPLGSARPPPPDS (SEQ ID NO: 46).

[0149] In various embodiments, the chimeric proteins disclosed herein comprise an IL-2RB intracellular effector domain. In some embodiments, the IL-2RB intracellular effector domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the IL-2RB intracellular effector domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the IL-2RB intracellular effector domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the IL-2RB intracellular effector domain comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the IL-2RB intracellular effector domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the IL-2RB intracellular effector domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 67. In some embodiments, the IL-2RB intracellular effector domain comprises the amino acid sequence of SEQ ID NO: 67.

[0150] In various embodiments, the chimeric proteins disclosed herein comprise an IL-15RA intracellular effector domain. In some embodiments, the IL-15RA intracellular effector domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 68. In some embodiments, the IL-15RA intracellular effector domain comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 68. In some embodiments, the IL-15RA intracellular effector domain comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 68. In some embodiments, the IL-15RA intracellular effector domain comprises an amino acid sequence at least 90% identical to theAttorney Docket No. WAP-008WOamino acid sequence of SEQ ID NO: 68. In some embodiments, the IL-15RA intracellular effector domain comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 68. In some embodiments, the IL-15RA intracellular effector domain comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 68. In some embodiments, the IL-15RA intracellular effector domain comprises the amino acid sequence of SEQ ID NO: 68.Signal Peptides

[0151] In various embodiments, a chimeric protein disclosed herein further comprises a signal peptide at its N-terminus. Signal peptides can induce the cellular protein synthesis and trafficking machinery to localize a protein to the cell membrane or to secretory vesicles. Different signal peptides can yield variant levels of membrane localization of expressed cell¬ surface proteins. Selection of specific signal peptides can therefore allow rheostat tuning of chimeric protein surface localization based on desired levels of downstream signaling. For example, for proteins that are expressed with low efficiency, a signal peptide yielding highly efficient membrane localization can be selected to improve overall activation of downstream signaling. In another example, for proteins that are toxic at high levels, a signal peptide yielding reduced efficiency of membrane can be selected to reduce the toxic effects of the protein.

[0152] In some embodiments, the signal peptide is an IgE signal peptide, an IL-9 signal peptide, and a CD8a signal peptide. Exemplary signal peptide sequences useful in a chimeric protein disclosed herein are provided in Table 6. In some embodiments the signal peptide comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19-21.Table 6: Exemplary Signal Peptide SequencesDescription SequenceIgE signal peptide MDWTWILFLVAAATRVHS (SEQ ID NO: 19)IL-9 signal peptide MLLAMVLTSALLLCSVAG (SEQ ID NO: 20)CD8a signal peptide MALPVTALLLPLALLLHAARP (SEQ ID NO: 21) TGFBR2 signal peptide MGRGLLRGLWPLHIVLWTRIAS (SEQ ID NO: 69)

[0153] In some embodiments, the signal peptide is an IgE signal peptide. In some embodiments, the signal peptide comprises an amino acid sequence at least 80%, at leastAttorney Docket No. WAP-008WO85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the signal peptide comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the signal peptide comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the signal peptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the signal peptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the signal peptide comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19. Additionally, as provided herein, certain embodiments or examples are illustrated with fusion (chimeric proteins) with an IgE signal peptide, The use of an IgE signal peptide is a non-limiting example and as provided herein, the signal peptide can be replaced with any suitable signal peptide, such as, but not limited to those illustrated in Table 6.

[0154] In some embodiments, the signal peptide is an IL-9 signal peptide. In some embodiments, the signal peptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the signal peptide comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the signal peptide comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the signal peptide comprises an amino acid sequence at least 90% identical to the ammo acid sequence of SEQ ID NO: 20. In some embodiments, the signal peptide comprises an amino acid sequence at least 95 % identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the signal peptide comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20.

[0155] In some embodiments, the signal peptide is an CD8a signal peptide. In some embodiments, the signal peptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 21. In some embodiments, the signal peptide comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 21. In someAttorney Docket No. WAP-008WOembodiments, the signal peptide comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 21. In some embodiments, the signal peptide comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 21. In some embodiments, the signal peptide comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 21. In some embodiments, the signal peptide comprises an ammo acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21.

[0156] In some embodiments, the signal peptide is an TGFBR2 signal peptide. In some embodiments, the signal peptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 69. In some embodiments, the signal peptide comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 69. In some embodiments, the signal peptide comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 69. In some embodiments, the signal peptide comprises an amino acid sequence at least 90% identical to the ammo acid sequence of SEQ ID NO: 69. In some embodiments, the signal peptide comprises an amino acid sequence at least 95 % identical to the amino acid sequence of SEQ ID NO: 69. In some embodiments, the signal peptide comprises an ammo acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 69. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 69.Linker Domain

[0157] In various embodiments, a chimeric protein comprises a linker domain operably linking the cytokine polypeptide to the extracellular ligand-binding domain. A linker domain useful in a chimeric protein disclosed herein can be flexible to allow efficient binding of the cytokine polypeptide to the extracellular ligand-binding domain. In some embodiments, the linker is a protease -cleavable linker. The length and sequence of the linker domain can be adjusted to adjust binding of the cytokine polypeptide to the extracellular ligand-binding domain. In some embodiments the linker domain is a 26mer linker, a Whitlow 218 linker, a (G4S)5 linker, a (G4S)3 linker, a (G4S)2 linker, or a G4S linker. Exemplary linker domain sequences useful in a chimeric protein disclosed herein are provided in Table 7. In some embodiments the linker domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 22-27. In certain embodiments provided herein, the fusion polypeptides, whichAttorney Docket No. WAP-008WOcan also be referred to as a chimeric protein, or other analogous name, are illustrated with the 26mer linker (SEQ ID NO: 22). This linker can be swapped or replaced with any suitable peptide linker, such as, but not limited to, those provided for in Table 7.Table 7: Exemplary Linker Domain SequencesDescription Sequence26mer linker SGGGSGGGGSGGGGSGGGGSGGGSLQ (SEQ ID NO: 22) Whitlow 218 linker GSTSGSGKPGSGEGSTKG (SEQ ID NO: 23)(G4S)5 linker GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 24) (G4S)3 linker GGGGSGGGGSGGGGS (SEQ ID NO: 25) (G4S)2 linker GGGGSGGGGS (SEQ ID NO: 26) G4S linker GGGGS (SEQ ID NO: 27)|0158] In some embodiments the linker domain is a 26mer linker. In some embodiments the linker domain comprises the amino acid sequence of SEQ ID NO: 22. In some embodiments the linker domain is a Whitlow 218 linker. In some embodiments the linker domain comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments the linker domain is a (G4S)5 linker. In some embodiments the linker domain comprises the amino acid sequence of SEQ ID NO: 24. In some embodiments the linker domain is a (G4S)3 linker. In some embodiments the linker domain comprises the amino acid sequence of SEQ ID NO: 25. In some embodiments the linker domain is a (G4S)2 linker. In some embodiments the linker domain comprises the amino acid sequence of SEQ ID NO: 26. In some embodiments the linker domain is a G4S linker. In some embodiments the linker domain comprises the amino acid sequence of SEQ ID NO: 27.Exemplary Chimeric Proteins

[0159] Exemplary chimeric protein sequences are provided in Table 8. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from SEQ ID NOs: 28-33 and 36-45.Attorney Docket No. WAP-008WOTable 8: Exemplary Chimeric Protein SequencesDescription SequenceIL-9-linker-IL-9R QGCPTLAG I LDINFL INKMQEDPASKCHCSANVTS CLCLG IPS DNCTR PCFSERLS QMTNTTMQTR Y PL I FS RVKKS VE VLKNNKC PYFSCEQPCNQTTAGNALTFLKSLLEIFQKEKMRGMRGKISGG GSGGGGSGGGGSGGGGSGGGSLQSVTGEGQGPRSRTFTCLTNN I LR I DCHWSAPELGQGS S PWLLFTSNQAPGGTHKC I LRGSECT WLPPEAVLVPSDNFTITFHHCMSGREQVSLVDPEYLPRRHVK LDPPSDLQSNISSGHCILTWSISPALEPMTTLLSYELAFKKQE E AWEQAQHRDH I VGVTWLI LEAFELD PGF I HEARLRVQMATLE DDWEEERYTGQWSEWSQPVCFQAPQRQGPLIPPWGWPGNTLV AVS I FLLLTGPTYLLFKLSPRVKRI FYQNVPSPAMFFQPLYSV HNGNFQTWMGAHGAGVLLS QDCAGTPQGALE PCVQEATALLTC GPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQT LAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALG CYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWV LAGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 28)IL-9-linker-IL-9R plus MDWTW ILFLVAAATRVHSQGCPTLAG I LD INFL INKMQEDPAS KCHCSANVTSCLCLGIPSDNCTRPCFSERLSQMTNTTMQTRYPsignal peptide L I F S RVKKS VE VLKNNKC P Y FS CE Q P CNQTTAGNALT FLKS LL E I FQKEKMRGMRGKI SGGGSGGGGSGGGGSGGGGSGGGSLQS V TGEGQGPRSRTFTCLTNNILRIDCHWSAPELGQGSSPWLLFTS NQAPGGTHKCILRGSECTWLPPEAVLVPSDNFTITFHHCMSG REQVSLVDPEYLPRRHVKLDPPSDLQSNISSGHCILTWSISPA LEPMTTLLSYELAFKKQEEAWEQAQHRDHIVGVTWLILEAFEL DPGFIHEARLRVQMATLEDDWEEERYTGQWSEWSQPVCFQAP QRQGPLIPPWGWPGNTLVAVSI FLLLTGPTYLLFKLSPRVKRI FYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGT PQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGN LSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGS RSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALAC GLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSK ARSWTF (SEQ ID NO: 29)IL2 linker 1L2RB- APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFK FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDL I ECD IL-9R-TM-plus-IL- SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSII9R ICD STLTSGGGSGGGGSGGGGSGGGGSGGGSLQAVNGTSQFTCFYN SRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQA SWACNLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFK PFENLRLMAPISLQWHVETHRCNISWEISQASHYFERHLEFE ARTLS PGHTWEE APLLTLKQKQEW I CLETLTPDTQ YE FQVRVK PLQGEFTTWSPWSQPLAFRTKPAAQRQGPLIPPWGWPGNTLVA VSI FLLLTGPTYLLFKLSPRVKRI FYQNVPSPAMFFQPLYSVH NGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCG PARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCAttorney Docket No. WAP-008WOYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVL AGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 30) IL2 linker IL2RB- MDWTW I LFLVAAATRVHS APTS S S TKKTQLQLEHLLLDLQM I L NGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEE ECD lL-9R-TM-plus-IL- VLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADET 9R ICD plus IgE signal ATIVEFLNRWITFCQSIISTLTSGGGSGGGGSGGGGSGGGGSG GGS LQAVNGTSQ FTC FYNS RAN I S CVWSQDGALQDTS CQVHAWpeptide PDRRRWNQTCELLPVSQASWACNLILGAPDSQKLTTVDIVTLR VLCREGVRWRWAIQDFKPFENLRLMAPISLQWHVETHRCNI SWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWI CLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAAQ RQGPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIF YQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTP QGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNL SSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSR S S S S S S S SNNNNYCALGCYGGWHLS ALPGNTQS SG P I PALACG LSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKA RSWTF (SEQ ID NO: 36)IL4-linker-IL4R ECD-IL- HKCDITLQEIIKTLNSLTEQKTLCTELTVTDIFAASKNTTEKE TFCRAATVLRQFYSHHEKDTRCLGATAQQFHRHKQLIRFLKRL9R_TM-IL-9R_ICDDRNLWGLAGLNSCPVKEANQSTLENFLERLKTIMREKYSKCSS SGGGSGGGGSGGGGSGGGGSGGGSLQMKVLQEPTCVSDYMSIS TCEWKMNGPTNCSTELRLLYQLVFLLSEAHTCIPENNGGAGCV CHLLMDDWSADNYTLDLWAGQQLLWKGSFKPSEHVKPRAPGN LTVHTNVSDTLLLTWSNPYPPDNYLYNHLTYAVNIWSENDPAD FR I YNVTYLE PS LR I AASTLKSG I S YRARVRAWAQCYNTTWS E WSPSTKWHNSYREPFEQHQRQGPLIPPWGWPGNTLVAVSIFLL LTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQT WMGAHGAGVLLS QDCAGTPQGALE PCVQE ATALLTCG PAR PWK SVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQE DWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHL SALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQR PGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 114) IL4-linker-lL4R ECD-IL- MDWTWILFLVAAATRVHSHKCDITLQEIIKTLNSLTEQKTLCT ELTVTDIFAASKNTTEKETFCRAATVLRQFYSHHEKDTRCLGA9R TM-IL-9R ICD plus TAQQFHRHKQLIRFLKRLDRNLWGLAGLNSCPVKEANQSTLEN IgE signal peptide FLERLKTIMREKYSKCSSSGGGSGGGGSGGGGSGGGGSGGGSL QMKVLQEPTCVSDYMS I STCEWKMNGPTNCSTELRLLYQLVFL LSEAHTCIPENNGGAGCVCHLLMDDWSADNYTLDLWAGQQLL WKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSNPYPPDNYL YNHLTYAVNI WSENDPADFRIYNVTYLEPSLRI AASTLKSG! S YRARVRAWAQCYNTTWSEWSPSTKWHNSYREPFEQHQRQGPLI PPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEP CVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVL PAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPI PALACGLSCDHQAttorney Docket No. WAP-008WOGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF(SEQ ID NO: 115)IL7-linker-IL7RA_ECD-IL- DCDIEGKDGKQYESVLMVSIDQLLDSMKEIGSNCLNNEENFFK RHICDANKEGMFLFRAARKLRQFLKMNSTGDFDLHLLKVSEGT9R TM-IL-9R 1CD TILLNCTGQVKGRKPAALGEAQPTKSLEENKSLKEQKKLNDLC FLKRLLQEIKTCWNKILMGTKEHSGGGSGGGGSGGGGSGGGGS GGGSLQESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTC AFEDPDVNITNLEFE I CGALVEVKCLNFRKLQEI YFIETKKFL LIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSWYREGA NDFWTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSST KLTLLQRKLQPAAMYEIKVRSIPDHYFKGFWSEWSPSYYFRTP E INNS SQRQGPL I PPWGWPGNTLVAVS I FLLLTGPTYLLFKLS PRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLS QDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPG TRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAP PDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGP IPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLL PSVLSKARSWTF (SEQ ID NO: 31)IL7-linker-IL7RA_ECD-IL- MDWTW ILFLVAAATRVHSDCDI EGKDGKQYESVLMVS I DQLLD SMKE I GSNCLNNE FNFFKRH I CDANKEGM FL FRAARKLRQ FLK9R TM-IL-9R ICD plus MNS TGDFDLHLLKVS EGTT I LLNCTGQVKGRKPAALGEAQ PTK IgE signal peptide SLEENKSLKEQKKLNDLCFLKRLLQEIKTCWNKILMGTKEHSG GGSGGGGSGGGGSGGGGSGGGSLQESGYAQNGDLEDAELDDYS FS C YS QLE VNGS QHS LTCAFED PDVN I TNLE FE I CGALVE VKC LNFRKLQE I Y F I ETKKFLL I GKSN I CVKVGEKS LTCKKI DLTT IVKPEAPFDLSWYREGANDFWTFNTSHLQKKYVKVLMHDVA YRQEKDENKWTHVNLSSTKLTLLQRKLQPAAMYEIKVRSIPDH YFKGFWSEWSPSYYFRTPEINNSSQRQGPLIPPWGWPGNTLVA VSI FLLLTGPTYLLFKLSPRVKRI FYQNVPSPAMFFQPLYSVH NGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCG PARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTL AYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGC YGGWHLS ALPGNTQS SG P I PALACGLS CDHQGLETQQGVAWVL AGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 37) IL15-linker-lL15RA ECD- NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCF LLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCK IL-9R TM-IL-9R ICD ECEELEEKNIKEFLQSFVHIVQMFINTSSGGGSGGGGSGGGGS GGGGSGGGSLQITCPPPMSVEHADIWVKSYSLYSRERYICNSG FKRKAGTS SLTECVLNKATNVAHWTTPSLKC I RDPALVHQRPA PPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVP GSQLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASH QPQRQGPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVK RIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCA GTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLP GNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALAttorney Docket No. WAP-008WOACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVL SKARSWTF (SEQ ID NO: 32)IL 15 -linker-IL 15RA ECD- MDWTW I LFLVAAATRVHSNWVNVI SDLKKIEDL I QSMHI DATL YTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLII IL-9R TM-IL-9R ICD plus LANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFI IgE signal peptide NTSSGGGSGGGGSGGGGSGGGGSGGGSLQITCPPPMSVEHADI WVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWT TPSLKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPA ASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSHG TPSQTTAKNWELTASASHQPQRQGPLI PPWGWPGNTLVAVS I F LLLTG PTYLL FKLS PRVKR I FYQNVPS PAMFFQ PL YS VHNGNF QTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARP WKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLP QEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGW HLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHC QRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 38) IL21 -linker-IL2 IRA ECD- QGQDRHMIRMRQLIDIVDQLKNYVNDLVPEFLPAPEDVETNCE WS AFS CFQKAQLKS ANTGNNER 11 NVS I KKLKRKP PS TNAGRR IL-9R TM-IL-9R ICD QKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQHLSSRTHG SEDSSGGGSGGGGSGGGGSGGGGSGGGSLQCPDLVCYTDYLQT VICILEMWNLHPSTLTLTWQDQYEELKDEATSCSLHRSAHNAT HATYTCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESI KPAPPFNVTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQYR NRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDSSYELQVRAGP MPGSSYQGTWSEWSDPVI FQTQSQRQGPLI PPWGWPGNTLVAV S I FLLLTGPTYLLFKLSPRVKRI FYQNVPSPAMFFQPLYSVHN GNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGP ARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLA YLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCY GGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLA GHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 33) IL21 -linker-IL2 IRA ECD- MDWTW ILFLVAAATRVHSQGQDRHMI RMRQL I DI VDQLKNYVN DLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIIN IL-9R TM-IL-9R ICD plus VSIKKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERF IgE signal peptide KSLLQKMIHQHLSSRTHGSEDSSGGGSGGGGSGGGGSGGGGSG GGSLQCPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEE LKDEATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITD QSGNYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWRSDYE D PAFYMLKGKLQ YELQYRNRGD PWAVS PRRKL I SVDSRSVSLL PLEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSQR QGPLI PPWGWPGNTLVAVS I FLLLTG PTYLL FKLS PRVKRI FY QNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQ GALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLS SEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRS S S S S S S SNNNNYCALGC YGGWHLS AL PGNTQS SGP I PALACGL SCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKAR SWTF (SEQ ID NO: 39)Attorney Docket No. WAP-008WOIL9_261inker_IL9R-ECD- MDWTWILFLVAAATRVHSQGCPTLAGILDINFLINKMQEDPAS KCHCSANVTSCLCLGIPSDNCTRPCFSERLSQMTNTTMQTRYP IL2Rb-TM IL9R ICD plus L I F S RVKKS VEVLKNNKCP YFS CE Q P CNQTTAGNALT FLKS LL IgE signal peptide E I FQKEKMRGMRGKI SGGGSGGGGSGGGGSGGGGSGGGSLQSV TGEGQGPRSRTFTCLTNNILRIDCHWSAPELGQGSSPWLLFTS NQAPGGTHKCILRGSECTWLPPEAVLVPSDNFTITFHHCMSG REQVSLVDPEYLPRRHVKLDPPSDLQSNISSGHCILTWSISPA LEPMTTLLSYELAFKKQEEAWEQAQHRDHIVGVTWLILEAFEL DPGFIHEARLRVQMATLEDDWEEERYTGQWSEWSQPVCFQAP QRQGPL I P PWGW P I PWLGHLLVGLSGAFG F I I LVYLL I KLS PR VKR I F YQNVP S PAM F FQ PL YS VHNGN FQTWMGAHG AG VLL S QD CAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTR LPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPD S EG S RS S S S S S S SNNNN YCALG C YGGWHLS ALPGNTQS SG P I P ALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPS VLSKARSWTF (SEQ ID NO: 40)IL9 _261inker IL9R-ECD- QGCPTLAG I LDINFL INKMQEDPASKCHCSANVTS CLCLG IPS DNCTRPCFSERLSQMTNTTMQTRYPLIFSRVKKSVEVLKNNKC IE2Rb-TM_IL9R_ICD PYFSCEQPCNQTTAGNALTFLKSLLE I FQKEKMRGMRGKI SGG GSGGGGSGGGGSGGGGSGGGSLQSVTGEGQGPRSRTFTCLTNN I LR I DCHWS APELGQGS S PWLL FTSNQAPGGTHKC I LRGS ECT WLPPEAVLVPSDNFTITFHHCMSGREQVSLVDPEYLPRRHVK LDPPSDLQSNISSGHCILTWSISPALEPMTTLLSYELAFKKQE E AWEQAQHRDH I VGVTWLI LEAFELD PGF I HEARLRVQMATLE DDWEEERYTGQWSEWSQPVCFQAPQRQGPLI PPWGWPI PWLG HLLVGLSGAFGFI ILVYLLIKLSPRVKRI F YQNVP SP AM FFQP LYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATA LLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEW RVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNY CALGC YGGWHLS ALPGNTQS SG P I PALACGLS CDHQGLETQQG VAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 116)IL9 261inker IL9R-ECD- MDWTWILFLVAAATRVHSQGCPTLAGILDINFLINKMQEDPAS KCHCSANVTSCLCLGIPSDNCTRPCFSERLSQMTNTTMQTRYP IL4RA-TM IL9R ICD plus L I F S R VKKS VE VLKNNKC P Y FS CE Q P CNQTTAGNALT FLKS LL IgE signal peptide E I FQKEKMRGMRGKI SGGGSGGGGSGGGGSGGGGSGGGSLQSV TGEGQGPRSRTFTCLTNNI LRI DCHWSAPELGQGS S PWLLFTS NQAPGGTHKCILRGSECTWLPPEAVLVPSDNFTITFHHCMSG REQVSLVDPEYLPRRHVKLDPPSDLQSNISSGHCILTWSISPA LEPMTTLLSYELAFKKQEEAWEQAQHRDHIVGVTWLILEAFEL DPGFIHEARLRVQMATLEDDWEEERYTGQWSEWSQPVCFQAP QRQGPLIPPWGWPLLLGVSVSCIVILAVCLLCYVSITKLSPRV KRI FYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDC AGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRL PGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDS EGS RS S S S S S S SNNNNY CALGC YGGWHLS AL PGNTQS SGP I PA LACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSV LSKARSWTF (SEQ ID NO: 41)Attorney Docket No. WAP-008WOIL9_261inker_IL9R-ECD- QGCPTLAG I LDINFL INKMQEDPASKCHCSANVTS CLCLG IPS DNCTRPCFSERLSQMTNTTMQTRYPLIFSRVKKSVEVLKNNKC IL4RA-TM IL9R ICD PYFSCEQPCNQTTAGNALTFLKSLLE I FQKEKMRGMRGKI SGG GSGGGGSGGGGSGGGGSGGGSLQSVTGEGQGPRSRTFTCLTNN I LR I DCHWSAPELGQGS S PWLLFTSNQAPGGTHKC I LRGSECT WLPPEAVLVPSDNFTITFHHCMSGREQVSLVDPEYLPRRHVK LDPPSDLQSNISSGHCILTWSISPALEPMTTLLSYELAFKKQE EAWEQAQHRDHIVGVTWLILEAFELDPGFIHEARLRVQMATLE DDWEEERYTGQWSEWSQPVCFQAPQRQGPLIPPWGWPLLLGV SVSCIVILAVCLLCYVSITKLSPRVKRIFYQNVPSPAMFFQPL YSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATAL LTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWR VQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYC ALGCYGGWHLSALPGNTQS SGP I PALACGLS CDHQGLETQQGV AWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 117)IL9 _261inker IL9R-ECD- MDWTWILFLVAAATRVHSQGCPTLAGILDINFLINKMQEDPAS KCHCSANVTSCLCLGIPSDNCTRPCFSERLSQMTNTTMQTRYP IL7RA-TM IL9R ICD plus L I F S RVKKS VEVLKNNKCP YFS CE Q P CNQTTAGNALT FLKS LL IgE signal peptide E I FQKEKMRGMRGKI SGGGSGGGGSGGGGSGGGGSGGGSLQS V TGEGQGPRSRTFTCLTNNILRIDCHWSAPELGQGSSPWLLFTS NQAPGGTHKCILRGSECTWLPPEAVLVPSDNFTITFHHCMSG REQVSLVDPEYLPRRHVKLDPPSDLQSNISSGHCILTWSISPA LEPMTTLLSYELAFKKQEEAWEQAQHRDHIVGVTWLILEAFEL DPGFIHEARLRVQMATLEDDWEEERYTGQWSEWSQPVCFQAP QRQGPLIPPWGWPPILLTISILSFFSVALLVILACVLWKLSPR VKR I F YQNVP S P AM F FQ PL YS VHNGN FQTWMGAHG AG VLL S QD CAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTR LPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPD SEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIP ALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPS VLSKARSWTF (SEQ ID NO: 42)IL9 261inker IL9R-ECD- QGCPTLAGILDINFLINKMQEDPASKCHCSANVTSCLCLGIPS DNCTRPCFSERLS QMTNTTMQTR Y PL I FS RVKKS VEVLKNNKC IL7RA-TM IL9R ICD PYFSCEQPCNQTTAGNALTFLKSLLE I FQKEKMRGMRGKI SGG GSGGGGSGGGGSGGGGSGGGSLQSVTGEGQGPRSRTFTCLTNN I LR I DCHWSAPELGQGS S PWLL FTSNQAPGGTHKC I LRGS ECT WLPPEAVLVPSDNFTITFHHCMSGREQVSLVDPEYLPRRHVK LDPPSDLQSNISSGHCILTWSISPALEPMTTLLSYELAFKKQE EAWEQAQHRDHIVGVTWLILEAFELDPGFIHEARLRVQMATLE DDWEEERYTGQWSEWSQPVCFQAPQRQGPLIPPWGWPPILLT I S I LS FFS VALLVI LACVLWKLS PRVKRI FYQNVPS PAMFFQP LYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATA LLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEW RVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNY CALGCYGGWHLS ALPGNTQS SG P I PALACGLS CDHQGLETQQG VAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 118)Attorney Docket No. WAP-008WOIL9_261inker_IL9R-ECD- MDWTWILFLVAAATRVHSQGCPTLAGILDINFLINKMQEDPAS KCHCSANVTSCLCLGIPSDNCTRPCFSERLSQMTNTTMQTRYP IL15RA-TM IL9R ICD L I F S RVKKS VEVLKNNKCP YFS CE Q P CNQTTAGNALT FLKS LL plus IgE signal peptide E I FQKEKMRGMRGKI SGGGSGGGGSGGGGSGGGGSGGGSLQSV TGEGQGPRSRTFTCLTNNILRIDCHWSAPELGQGSSPWLLFTS NQAPGGTHKCILRGSECTWLPPEAVLVPSDNFTITFHHCMSG REQVSLVDPEYLPRRHVKLDPPSDLQSNISSGHCILTWSISPA LEPMTTLLSYELAFKKQEEAWEQAQHRDHIVGVTWLILEAFEL DPGFIHEARLRVQMATLEDDWEEERYTGQWSEWSQPVCFQAP QRQGPLIPPWGWPVAISTSTVLLCGLSAVSLLACYLKLSPRVK RIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCA GTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLP GNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSE G S R S S S S S S S SNNNN YCALGC YGGWHLS AL PGNTQ S S G P I PAL ACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVL SKARSWTF (SEQ ID NO: 43)IL9 _261inker IL9R-ECD- QGCPTLAG I LDINFL INKMQEDPASKCHCSANVTS CLCLG IPS DNCTRPCFSERLSQMTNTTMQTRYPLIFSRVKKSVEVLKNNKC IL15RA-TM IL9R ICD PYFSCEQPCNQTTAGNALTFLKSLLE I FQKEKMRGMRGKI SGG GSGGGGSGGGGSGGGGSGGGSLQSVTGEGQGPRSRTFTCLTNN I LR I DCHWS APELGQGS S PWLL FTSNQAPGGTHKC I LRGS ECT WLPPEAVLVPSDNFTITFHHCMSGREQVSLVDPEYLPRRHVK LDPPSDLQSNISSGHCILTWSISPALEPMTTLLSYELAFKKQE E AWEQAQHRDH I VGVTWLI LEAFELD PGF I HEARLRVQMATLE DDWEEERYTGQWSEWSQPVCFQAPQRQGPLIPPWGWPVAIST STVLLCGLSAVSLLACYLKLSPRVKRIFYQNVPSPAMFFQPLY SVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALL TCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRV QTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCA LGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVA WVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 119)IL9~261inkerJL9R-ECD- MDWTWILFLVAAATRVHSQGCPTLAGILDINFLINKMQEDPAS KCHCSANVTSCLCLGIPSDNCTRPCFSERLSQMTNTTMQTRYP IL21R-TM IL9R ICD plus L I F S R VKKS VE VLKNNKC P Y FS CE Q P CNQTTAGNALT FLKS LL IgE signal peptide E I FQKEKMRGMRGKI SGGGSGGGGSGGGGSGGGGSGGGSLQSV TGEGQG PRSRTFTCLTNNI LRI DCHWSAPELGQGS S PWLLFTS NQAPGGTHKCILRGSECTWLPPEAVLVPSDNFTITFHHCMSG REQVSLVDPEYLPRRHVKLDPPSDLQSNISSGHCILTWSISPA LEPMTTLLSYELAFKKQEEAWEQAQHRDHIVGVTWLILEAFEL DPGFIHEARLRVQMATLEDDWEEERYTGQWSEWSQPVCFQAP QRQGPLIPPWGWPGWNPHLLLLLLLVIVFIPAFWKLSPRVKRI FYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGT PQGALE PCVQEATALLTCG PAR PWKS VALEEEQEG PGTRL PGN LSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGS RSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALAC GLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSK ARSWTF (SEQ ID NO: 44)Attorney Docket No. WAP-008WOIL9 261inker_IL9R-ECD- QGCPTLAG I LDINFL INKMQEDPASKCHCSANVTS CLCLG IPS DNCTRPCFSERLSQMTNTTMQTRYPLIFSRVKKSVEVLKNNKC IL21R-TM IL9R ICD PYFSCEQPCNQTTAGNALTFLKSLLE I FQKEKMRGMRGKI SGG GSGGGGSGGGGSGGGGSGGGSLQSVTGEGQGPRSRTFTCLTNN I LR I DCHWSAPELGQGS S PWLLFTSNQAPGGTHKC I LRGSECT WLPPEAVLVPSDNFTITFHHCMSGREQVSLVDPEYLPRRHVK LDPPSDLQSNISSGHCILTWSISPALEPMTTLLSYELAFKKQE EAWEQAQHRDHIVGVTWLILEAFELDPGFIHEARLRVQMATLE DDWEEERYTGQWSEWSQPVCFQAPQRQGPLIPPWGWPGWNPH LLLLLLLVIVFIPAFWKLSPRVKRIFYQNVPSPAMFFQPLYSV HNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTC GPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQT LAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALG CYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWV LAGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 120)IL9 _261inker_IL9R- MDWTWILFLVAAATRVHSQGCPTLAGILDINFLINKMQEDPAS KCHCSANVTSCLCLGIPSDNCTRPCFSERLSQMTNTTMQTRYPtruncated lCD plus IgE L I F S RVKKS VEVLKNNKCP YFS CE Q P CNQTTAGNALT FLKS LL signal peptide E I FQKEKMRGMRGKI SGGGSGGGGSGGGGSGGGGSGGGSLQS V TGEGQGPRSRTFTCLTNNILRIDCHWSAPELGQGSSPWLLFTS NQAPGGTHKCILRGSECTWLPPEAVLVPSDNFTITFHHCMSG REQVSLVDPEYLPRRHVKLDPPSDLQSNISSGHCILTWSISPA LEPMTTLLSYELAFKKQEEAWEQAQHRDHIVGVTWLILEAFEL DPGFIHEARLRVQMATLEDDWEEERYTGQWSEWSQPVCFQAP QRQGPL I P PWGW PGNTLVAVS I FLLLTGPTYLL FKLS PRVKR I FYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGT PQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGN LSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGS RSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS (SEQ ID NO: 45)IL9_261inker_IL9R- QGCPTLAG I LDINFL INKMQEDPASKCHCSANVTS CLCLG IPS DNCTRPCFSERLS QMTNTTMQTR Y PL I FS RVKKS VEVLKNNKCtruncated lCD PYFSCEQPCNQTTAGNALTFLKSLLE I FQKEKMRGMRGKI SGG GSGGGGSGGGGSGGGGSGGGSLQSVTGEGQGPRSRTFTCLTNN I LR I DCHWSAPELGQGS S PWLLFTSNQAPGGTHKC I LRGSECT WLPPEAVLVPSDNFTITFHHCMSGREQVSLVDPEYLPRRHVK LDPPSDLQSNISSGHCILTWSISPALEPMTTLLSYELAFKKQE E AWEQAQHRDH I VGVTWL I LEAFELD PGF I HEARLRVQMATLE DDWEEERYTGQWSEWSQPVCFQAPQRQGPLIPPWGWPGNTLV AVS I FLLLTGPTYLL FKLS PRVKR I FYQNVPSPAMFFQPLYSV HNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTC GPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQT LAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALG CYGGWHLSALPGNTQSS (SEQ ID NO: 121)Attorney Docket No. WAP-008WOIgE(sp)_IL9R-6aa-TMD- MDWTWILFLVAAATRVHSPPWGWPGNTLVAVSIFLLLTGPTYL L FKLS PRVKR I F YQNVPS PAMFFQ PL YSVHNGNFQTWMGAHGA ICD GVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEE QEG PGTRL PGNLS SEDVLPAGCTE WRVQTLAYL PQEDWAPTS L TRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNT QSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDL QGMLLPSVLSKARSWTF (SEQ ID NO: 70)IL9R-6aa-TMD-ICD PPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEP CVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVL PAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSS SSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQ GLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF(SEQ ID NO: 122)IgE(sp) IL7R-4aa-TMD- MDWTW ILFLVAAATRVHSGEMDPI LLTI S ILSFFSVALLVILA CVLWKKRI PRVKRI FYQNVPSPAMFFQPLYSVHNGNFQTWMGA4aa_IL9R-ICD HGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVAL EEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAP TSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALP GNTQS SGP I PALACGLS CDHQGLETQQGVAWVLAGHCQRPGLH EDLQGMLLPSVLSKARSWTF (SEQ ID NO: 71)IL7R-4aa-TMD-4aa_IL9R- GEMDP I LLTI S I LS F FS VALLVI LACVLWKKR I PRVKR I F YQN VPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGA ICD LEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSE DVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSS S S S S SNNNNYCALGCYGGWHLS AL PGNTQS SGP I PALACGLS C DHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSW TF (SEQ ID NO: 123)IgE(sp)_IL9R- MDWTWILFLVAAATRVHSGQWSEWSQPVCFQAPQRQGPLIPPW GWPGNTLVAVSI FLLLTGPTYLLFKLSPRVKRI FYQNVPSPAM27aa(WSxWS)-TMD-ICD F FQ PL YS VHNGN FQTWMGAHGAGVLL S QD CAGT PQGALE P CVQ EATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAG CTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSN NNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLE TQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF(SEQ ID NO: 72)IL9R-27aa(WSxWS)-TMD- GQWSEWSQPVCFQAPQRQGPLI PPWGWPGNTLVAVSI FLLLTG PTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMG ICD AHG AG VLL S QDCAGT PQGALE P CVQEATALLTCG PAR PWKSVA LEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSAL PGNTQS SG P I PALACGLS CDHQGLETQQGVAWVLAGHCQR PGL HEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 124)Attorney Docket No. WAP-008WOIgE(sp)_IL7R- MDWTWILFLVAAATRVHSGFWSEWSPSYYFRTPEINNSSGEMD P I LLTI SILS FFSVALLVI LACVLWKKRI PRVKRI FYQNVPS P25aa(WSxWS)-TMD- AMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPC 4aa_IL9R-ICD VQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLP AGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSS SNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQG LETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF(SEQ ID NO: 73)IL7R-25aa(WSxWS)-TMD- GFWSEWSPSYYFRTPEINNSSGEMDPILLTISILSFFSVALLV ILACVLWKKRIPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTW4aa_IL9R-ICD MGAHG AGVLL S QDCAGT PQGALE P CVQE ATALLTCG PAR P WKS VALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQED WAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLS ALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRP GLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 125) IgE(sp)JL2RB- MDWTWILFLVAAATRVHSGEFTTWSPWSQPLAFRTKPAALGKD TI PWLGHLLVGLSGAFGFI ILVYLLINCRNPRVKRI FYQNVPS26aa(WSxWS)-TMD- PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEP 4aa IL9R-ICD CVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVL PAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSS S SNNNNYCALGC YGGWHLS ALPGNTQSSG P I PALACGLS CDHQ GLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF(SEQ ID NO: 74)IL2RB-26aa(WSxWS)- GE FTTWS PWS QPLAFRTKPAALGKDT I PWLGHLLVGLSGAFG F I ILVYLLINCRNPRVKRI FYQNVPSPAMFFQPLYSVHNGNFQT TMD-4aa IL9R-ICD WMGAHGAGVLLS QDCAGTPQGALE PCVQE ATALLTCG PAR PWK SVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQE DWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHL SALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQR PGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 126) IgE(sp)_IL2RB- 16aa-TMD- MDWTWILFLVAAATRVHSQPLAFRTKPAALGKDTIPWLGHLLV GLSGAFGFI ILVYLLINCRNPRVKRI FYQNVPS PAMFFQPLYS4aa IL9R-ICD VHNGN FQTWMGAHGAGVLL S QD CAGT PQG ALE P CVQE ATALLT CGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQ TLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCAL GCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAW VLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 75)IL2RB-16aa-TMD- QPLAFRTKPAALGKDTI PWLGHLLVGLSGAFGFI I LVYLL INC RNPRVKRI FYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVL4aa 1L9R-ICD LSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEG PGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRP APPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS G P I PALACGLS CDHQGLETQQGVAWVLAGHCQR PGLHEDLQGM LLPSVLSKARSWTF (SEQ ID NO: 127)Attorney Docket No. WAP-008WOIgE(sp)_IL2RB-4aa-TMD- MDWTWILFLVAAATRVHSGKDTIPWLGHLLVGLSGAFGFIILV YLLINCRNPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGA4aa 1L9R-ICD HGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVAL EEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAP TSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALP GNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLH EDLQGMLLPSVLSKARSWTF (SEQ ID NO: 76)IL2RB-4aa-TMD- GKDTI PWLGHLLVGLSGAFGFI ILVYLLINCRNPRVKRI FYQN VPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGA4aa_IL9R-ICD LEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSE DVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSS S S S S SNNNNYCALGC YGGWHLS AL PGNTQS SGP I PALACGLS C DHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSW TF (SEQ ID NO: 128)IgE(sp)JL21R- MDWTWILFLVAAATRVHSPGSSYQGTWSEWSDPVIFQTQSEEL KEGWNPHLLLLLLLVI VFI PAFWSLKTPRVKRI FYQNVPS PAM27aa(WSxWS)-TMD- F FQ PL YS VHNGN FQTWMGAHGAGVLL S QD CAGT PQGALE P CVQ 4aa IL9R-ICD EATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAG CTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSN NNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLE TQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF(SEQ ID NO: 77)IL21R-27aa(WSxWS)- PGSSYQGTWSEWSDPVIFQTQSEELKEGWNPHLLLLLLLVIVF I PAFWSLKTPRVKRI FYQNVPS PAMFFQPLYSVHNGNFQTWMG TMD-4aa IL9R-ICD AHG AG VLL S QDC AGT PQGALE P CVQE ATALLTCG PAR PWKS VA LEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSAL PGNTQS SG P I PALACGLS CDHQGLETQQGVAWVLAGHCQR PGL HEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 129) IgE(sp) IL21 R- 14aa-TMD- MDWTWILFLVAAATRVHSDPVIFQTQSEELKEGWNPHLLLLLL LVI VFI PAFWSLKTPRVKRI FYQNVPSPAMFFQ PL YSVHNGNF4aa IL9R-ICD QTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARP WKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLP QEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGW HLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHC QRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 78) IL21R-14aa-TMD- DPVI FQTQSEELKEGWNPHLLLLLLLVI VFI PAFWSLKTPRVK RI FYQNVPSPAMFFQ PLYSVHNGNFQTWMGAHGAGVLLSQDCA4aa IL9R-ICD GTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLP GNLSSEDVLPAGCTEWRVQTLAYLPQEDW APTSLTRPAPPDSE GSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPAL ACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVL SKARSWTF (SEQ ID NO: 130)Attorney Docket No. WAP-008WOIgE(sp) JL21 R-6aa-TMD- MDWTWILFLVAAATRVHSSEELKEGWNPHLLLLLLLVIVFIPA FWSLKTPRVKRI FYQNVPS PAMFFQPLYSVHNGNFQTWMGAHG4aa 1L9R-ICD AGVLLS QD CAGT PQG ALE P CVQEATALLTCG PAR P WKS VALE E EQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTS LTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGN TQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHED LQGMLLPSVLSKARSWTF (SEQ ID NO: 79)IL21R-6aa-TMD- SEELKEGWNPHLLLLLLLVIVFI PAFWSLKTPRVKRI FYQNVP SPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALE4aa_lL9R-ICD PCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDV LPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSS SSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDH QGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF(SEQ ID NO: 131)TGFbR2-ECD JL9R- MGRGLLRGLWPLHIVLWTRIASTI PPHVQKS VNNDMI VTDNNG AVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVA WSxWS-TM-plus-ICD VWRKNDEN I TLETVCHD PKLPYHD F I LEDAAS PKC IMKEKKKP GETFFMCSCSSDECNDNI I FSEEYNTSNPDLLLVI FQGQWSEW SQPVCFQAPQRQGPLI PPWGWPGNTLVAVS I FLLLTGPTYLLF KLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGV LLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQE G PGTRLPGNLS S EDVLPAGCTE WRVQTLAYL PQEDWAPTS LTR PAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQS SGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQG MLLPSVLSKARSWTF (SEQ ID NO: 80)TGFbR2-ECD_IL9R- TIP PHVQKS VNNDM I VTDNNGAVKFPQLCKFCDVR FS TCDNQK S CMSNCS I TS I CEKPQEVCVAVWRKNDENI TLETVCHDPKLPY WSxWS-TM-plus-lCD (no HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSE signal peptide) EYNTSNPDLLLVI FQGQWSEWSQPVCFQAPQRQGPLI PPWGWP GNTLVAVS I FLLLTGPTYLLFKLS PRVKRI FYQNVPS PAMFFQ PLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEAT ALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTE WRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNN YCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQ GVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 132)TGFbR2-ECD IL9R-21 aa- MGRGLLRGLW PLH I VLWTR IAS TI PPHVQKS VNNDM I VTDNNG AVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVA TM-plus-ICD VWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKP GETFFMCSCSSDECNDNI I FSEEYNTSNPDLLLVI FQQPVCFQ APQRQGPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVK RIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCA GTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLP GNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEG S R S S S S S S S SNNNN YCALGC YGGWHLS AL PGNTQ S S G P I PALAttorney Docket No. WAP-008WOACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVL SKARSWTF (SEQ ID NO: 81)TGFbR2-ECD IL9R-21 aa- TIP PHVQKS VNNDM I VTDNNGAVKFPQLCKFCDVR FS TCDNQK S CMSNCS I TS I CEKPQEVCVAVWRKNDENI TLETVCHDPKLPY TM-plus-ICD (no signal HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSE peptide) EYNTSNPDLLLVI FQQPVCFQAPQRQGPLI PPWGWPGNTLVAV S I FLLLTGPTYLLFKLSPRVKRI FYQNVPSPAMFFQPLYSVHN GNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGP ARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLA YLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCY GGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLA GHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 133) TGFbR2 -ECD IL9R- 1 Oaa- MGRGLLRGLW PLH I VLWTR I AS TI PPHVQKS VNNDM I VTDNNG AVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVA TM-plus-ICD VWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKP GETFFMCSCSSDECNDNI I FSEEYNTSNPDLLLVI FQGPLI PP WGWPGNTLVAVS I FLLLTGPTYLLFKLSPRVKRI FYQNVPSPA MFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCV QEATALLTCG PARPWKS VALEEEQEG PGTRL PGNLS S EDVLPA GCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSS NNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGL ETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF(SEQ ID NO: 82)TGFbR2-ECD_IL9R- 1 Oaa- TIP PHVQKS VNNDM I VTDNNGAVKFPQLCKFCDVR FS TCDNQK S CMSNCS I TS I CEKPQEVCVAVWRKNDENI TLETVCHDPKLPY TM-plus-ICD (no signal HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSE peptide) EYNTSNPDLLLVI FQGPLI PPWGWPGNTLVAVS I FLLLTGPTY LLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHG AGVLL S QD CAGT PQG ALE P CVQEATALLTCG PAR P WKS VALE E EQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTS LTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGN TQS SG P I PALACGLS CDHQGLETQQGVAWVLAGHCQR PGLHED LQGMLLPSVLSKARSWTF (SEQ ID NO: 134)TGFbR2-ECD JL7R- MGRGLLRGLW PLH I VLWTR IAS TI PPHVQKS VNNDM I VTDNNG AVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVA WSxWS-TM-4aa_IL9R- VWRKNDEN I TLE TVCHD PKLPYHD F I LEDAAS PKC I MKEKKKP ICD GETFFMCSCSSDECNDNI I FSEEYNTSNPDLLLVI FQGFWSEW SPSYYFRTPEINNSSGEMDPILLTISILSFFSVALLVILACVL WKKRI PRVKRI FYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGA GVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEE QEG PGTRL PGNLS SEDVLPAGCTE WRVQTLAYL PQEDWAPTS L TRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNT QSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDL QGMLLPSVLSKARSWTF (SEQ ID NO: 83)Attorney Docket No. WAP-008WOTGFbR2-ECD IL7R- TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQK S CMSNCS I TS I CEKPQEVCVAVWRKNDENI TLETVCHDPKLPY WSxWS-TM-4aa IL9R- HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSE ICD (no signal peptide) EYNTSNPDLLLVIFQGFWSEWSPSYYFRTPEINNSSGEMDPIL LTI S I LS FFS VALLVI LACVLWKKR I PRVKR I F YQNVPS PAM F FQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQE ATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGC TEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNN NNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLET QQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 135)TGFbR2 -ECD IL7R- 18aa- MGRGLLRGLW PLH I VLWTR I AS TI PPHVQKSVNNDM I VTDNNG AVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVA TM-4aa IL9R-ICD VWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKP GETFFMCSCSSDECNDNI I FSEEYNTSNPDLLLVI FQPSYYFR TPEINNSSGEMDPILLTISILSFFSVALLVILACVLWKKRIPR VKR I F YQNVP S P AM F FQ PL YS VHNGN FQTWMGAHG AG VLL S QD CAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTR LPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPD SEGSRSSSSSSS SNNNN YCALG C YGG WHL SAL PGNTQS SG P I P ALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPS VLSKARSWTF (SEQ ID NO: 84)TGFbR2-ECD_IL7R- 18aa- TIP PHVQKS VNNDM I VTDNNGAVKFPQLCKFCDVR FS TCDNQK S CMSNCS I TS I CEKPQEVCVAVWRKNDENI TLETVCHDPKLPY TM-4aa IL9R-ICD (no HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSE signal peptide) EYNTSNPDLLLVIFQPSYYFRTPEINNSSGEMDPILLTISILS FFSVALLVILACVLWKKRI PRVKRI FYQNVPSPAMFFQPLYSV HNGNFQTWMGAHGAGVLLS QDCAGTPQGALE PCVQEATALLTC GPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQT LAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALG CYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWV LAGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 136)TGFbR2-ECD IL7R-4aa- MGRGLLRGLW PLH I VLWTR IAS TI PPHVQKSVNNDM I VTDNNG AVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVA TM-4aa IL9R-ICD VWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKP GETFFMCSCSSDECNDNI I FSEEYNTSNPDLLLVI FQGEMDPI LLT I S I LS FFS VALLVI LACVLWKKR I PRVKR I FYQNVPS PAM F FQ PL YS VHNGN FQTWMGAHGAGVLL S QD CAGT PQGALE P CVQ EATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAG CTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSN NNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLE TQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF(SEQ ID NO: 85)Attorney Docket No. WAP-008WOTGFbR2-ECD IL7R-4aa- TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQK S CMSNCS I TS I CEKPQEVCVAVWRKNDENI TLETVCHDPKLPY TM-4aa IL9R-ICD (no HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSE signal peptide) EYNTSNPDLLLVIFQGEMDPILLTISILSFFSVALLVILACVL WKKRI PRVKRI FYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGA GVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEE QEG PGTRL PGNLS SEDVLPAGCTE WRVQTLAYL PQEDWAPTS L TRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNT QSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDL QGMLLPSVLSKARSWTF (SEQ ID NO: 137)TGFbR2-ECD IL 15RA- MGRGLLRGLW PLH I VLWTR I AS TI PPHVQKS VNNDM I VTDNNG AVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVA TM-plus ICD VWRKNDEN I TLE TVCHD PKLPYHD F I LEDAAS PKC I MKEKKKP GETFFMCSCSSDECNDNI I FSEEYNTSNPDLLLVI FQTAKNWE LTASASHQPPGVYPQGHSDTTVAISTSTVLLCGLSAVSLLACY LKSRQTPPLASVEMEAMEALPVTWGTSSRDEDLENCSHHL(SEQ ID NO: 86)TGFbR2-ECD IL 15RA- TIP PHVQKS VNNDM I VTDNNGAVKFPQLCKFCDVRFS TCDNQK S CMSNCS I TS I CEKPQEVCVAVWRKNDENI TLETVCHDPKLPY TM-plus_ICD (no signal HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSE peptide) EYNTSNPDLLLVIFQTAKNWELTASASHQPPGVYPQGHSDTTV AISTSTVLLCGLSAVSLLACYLKSRQTPPLASVEMEAMEALPV TWGTSSRDEDLENCSHHL (SEQ ID NO: 138)TGFbR2-ECD_IL2RB- MGRGLLRGLW PLH I VLWTR IAS TI PPHVQKS VNNDM I VTDNNG AVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVA18aa-TM-plus-ICD VWRKNDEN I TLE TVCHD PKLPYHD F I LEDAAS PKC I MKEKKKP GETFFMCSCSSDECNDNI I FSEEYNTSNPDLLLVI FQQPLAFR TKPAALGKDT I PWLGHLLVGLSGAFG F 11 LVYLL I NCRNTGPW LKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPG GLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCF TNQGY FFFHL PDALE I E ACQVY FTYD PYS EEDPDEGVAGAPTG SSPQPLQPLSGEDDAYCTFPSRDDLLLFSPSLLGGPSPPSTAP GGSGAGEERMPPSLQERVPRDWDPQPLGPPTPGVPDLVDFQPP PELVLREAGEEVPDAGPREGVSFPWSRPPGQGEFRALNARLPL NTDAYLSLQELQGQDPTHLV (SEQ ID NO: 87) TGFbR2-ECD IL2RB- TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQK S CMSNCS I TS I CEKPQEVCVAVWRKNDENI TLETVCHDPKLPY18aa-TM-plus-ICD (no HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSE signal peptide) EYNTSNPDLLLVI FQQPLAFRTKPAALGKDTI PWLGHLLVGLS GAFGFIILVYLLINCRNTGPWLKKVLKCNTPDPSKFFSQLSSE HGGDVQKWLS SPFPSSSFS PGGLAPE I S PLE VLERDKVTQLLL QQDKVPEPASLSSNHSLTSCFTNQGYFFFHLPDALEIEACQVY FTYDPYSEEDPDEGVAGAPTGSSPQPLQPLSGEDDAYCTFPSR DDLLLFSPSLLGGPSPPSTAPGGSGAGEERMPPSLQERVPRDWDPQPLGPPTPGVPDLVDFQPPPELVLREAGEEVPDAGPREGVSAttorney Docket No. WAP-008WOFPWSRPPGQGEFRALNARLPLNTDAYLSLQELQGQDPTHLV(SEQ ID NO: 139)TGFbR2-ECD-TM- MGRGLLRGLW PLHI VLWTR I ASTI PPHVQKS VNNDM I VTDNNG AVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVA7aaICD IL9R-ICD VWRKNDEN I TLE TVCHD PKLPYHD F I LEDAAS PKC I MKEKKKP GETFFMCSCSSDECNDNI I FSEEYNTSNPDLLLVI FQVTGISL LPPLGVAI SVI I I FYCYRVNRQVKRI FYQNVPS PAMFFQPLYS VHNGN FQTWMGAHGAGVLL S QD CAGT PQG ALE P CVQE ATALLT CGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQ TLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCAL GCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAW VLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 88)TGFbR2-ECD-TM- TIP PHVQKSVNNDM I VTDNNGAVKFPQLCKFCDVR FS TCDNQK S CMSNCS I TS I CEKPQEVCVAVWRKNDENI TLETVCHDPKLPY7aaICD IL9R-ICD (no HDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSE signal peptide) EYNTSNPDLLLVI FQVTGI SLLPPLGVAI SVI I I FYCYRVNRQ VKR I F YQNVP S PAM F FQ PL YS VHNGN FQTWMGAHGAGVLL S QD CAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTR LPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPD SEGSRSSSSSSS SNNNN YCALG C YGGWHLS ALPGNTQS SG P I P ALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPS VLSKARSWTF (SEQ ID NO: 140)IgE(sp) IL 15_261inker IL 1 MDWTW I LFLVAAATRVHSNWVNVI SDLKKI EDL I QSMHI DATL YTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLII5RA-ECD-TM IL9R-ICD LANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFI NTSSGGGSGGGGSGGGGSGGGGSGGGSLQITCPPPMSVEHADI WVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWT TPSLKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPA ASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSHG TPSQTTAKNWELTASASHQPPGVYPQGHSDTTVAISTSV LLC GLSAVSLLACYLKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGN FQTWMGAHGAGVLLS QDCAGTPQGALE PCVQEATALLTCG PAR PWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYL PQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGG WHLSALPGNTQS SGP I PALACGLS CDHQGLETQQGVAWVLAGH CQRPGLHEDLQGMLLPSVLSKARSWTF (SEQ ID NO: 100) IL15 261inker IL15RA- NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCF LLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCK ECD-TM IL9R-ICD ECEELEEKNIKEFLQSFVHIVQMFINTSSGGGSGGGGSGGGGS GGGGSGGGSLQITCPPPMSVEHADIWVKSYSLYSRERYICNSG FKRKAGTS SLTECVLNKATNVAHWTTPSLKC I RDPALVHQRPA PPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVP GSQLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASH QPPGVYPQGHSDTTVAI STSTVLLCGLSAVSLLACYLKLS PRV KRI FYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLAttorney Docket No. WAP-008WOPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDS EGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPA LACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSV LSKARSWTF (SEQ ID NO: 141)IgE( sp) IL9 _261inker IL9R MDWTWILFLVAAATRVHSQGCPTLAGILDINFLINKMQEDPAS KCHCSANVTSCLCLGIPSDNCTRPCFSERLSQMTNTTMQTRYP-ECD IL4R-TMD IL9R- L I F S R VKKS VE VLKNNKC P Y FS CE Q P CNQTTAGNALT FLKS LL truncated-ICD E I FQKEKMRGMRGKI SGGGSGGGGSGGGGSGGGGSGGGSLQS V TGEGQGPRSRTFTCLTNNILRIDCHWSAPELGQGSSPWLLFTS NQAPGGTHKCILRGSECTWLPPEAVLVPSDNFTITFHHCMSG REQVSLVDPEYLPRRHVKLDPPSDLQSNISSGHCILTWSISPA LEPMTTLLSYELAFKKQEEAWEQAQHRDHIVGVTWLILEAFEL DPGFIHEARLRVQMATLEDDWEEERYTGQWSEWSQPVCFQAP QRQGPLIPPWGWPLLLGVSVSCIVILAVCLLCYVSITKLSPRV KRI FYQNVPS PAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDC AGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRL PGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDS EGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSS (SEQ ID NO: 101)IL9 _261inker_IL9R- QGCPTLAG I LDINFL INKMQEDPASKCHCSANVTS CLCLG IPS DNCTRPCFSERLSQMTNTTMQTRYPLIFSRVKKSVEVLKNNKC ECD IL4R-TMD IL9R- PYFSCEQPCNQTTAGNALTFLKSLLE I FQKEKMRGMRGKI SGG truncated-ICD GSGGGGSGGGGSGGGGSGGGSLQSVTGEGQGPRSRTFTCLTNN I LR I DCHWS APELGQGS S PWLL FTSNQAPGGTHKC I LRGS ECT WLPPEAVLVPSDNFTITFHHCMSGREQVSLVDPEYLPRRHVK LDPPSDLQSNISSGHCILTWSISPALEPMTTLLSYELAFKKQE E AWEQAQHRDH I VGVTWLI LEAFELD PGF I HEARLRVQMATLE DDWEEERYTGQWSEWSQPVCFQAPQRQGPLIPPWGWPLLLGV S VS C I VI LAVCLLCYVS I TKLS PRVKR I F YQ NVP S PAMFFQPL YSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATAL LTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWR VQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYC ALGCYGGWHLSALPGNTQSS (SEQ ID NO: 142)

[0160] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL-9 polypeptide, (b) a 26mer linker, (c) an IL-9R extracellular ligand¬ binding domain, (d) an IL-9R transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%. at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, theAttorney Docket No. WAP-008WOchimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 28.

[0161] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL-9 polypeptide, (c) a 26mer linker, (d) an IL-9R extracellular ligand-binding domain, (e) an IL-9R transmembrane domain, and (f) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 29. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 29. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to tire amino acid sequence of SEQ ID NO: 29. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 29. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 29, In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 29. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 29.

[0162] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL-2 polypeptide, (b) a 26mer linker, (c) an IL-2R extracellular ligand¬ binding domain, (d) an IL-9R transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 30. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 30. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 30. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 30. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 30. In someAttorney Docket No. WAP-008WOembodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 30. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 30.

[0163] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL-4 polypeptide, (b) a 26mer linker, (c) an IL-4RA extracellular ligandbinding domain, (d) an IL-9R transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 114. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 114. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the ammo acid sequence of SEQ ID NO: 114. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 114. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 114. In some embodiments, the chimeric protein comprises an ammo acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 114. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 114.

[0164] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL-7 polypeptide, (b) a 26mer linker, (c) an IL-7R extracellular ligand¬ binding domain, (d) an IL-9R transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an ammo acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 31. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 31. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 31. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90 % identical to the amino acid sequence of SEQ ID NO: 31. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 31. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99?4 identical to the amino acid sequence of SEQ ID NO: 31. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 31.Attorney Docket No. WAP-008WO

[0165] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL- 15 polypeptide, (b) a 26mer linker, (c) an IL-15R extracellular ligandbinding domain, (d) an IL-9R transmembrane domain, and (e) an IL-9R intracellular effector domain, in some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 32. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 32. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 32. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 32. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 32. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 32. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 32.

[0166] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL-21 polypeptide, (b) a 26mer linker, (c) an IL-21R extracellular ligandbinding domain, (d) an 1L-9R transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 33. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 33. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 33. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 33. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 33. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 33. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 33,

[0167] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL-2 polypeptide, (c) a 26mer linker, (d) an IL-2RB extracellular ligand-binding domain, (e) an IL-9R transmembrane domain, and (f) an IL-9RAttorney Docket No. WAP-008WOintracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 36. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 36. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 36. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 36. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 36. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 36. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 36.

[0168] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL -4 polypeptide, (c) a 26mer linker, (d) an IL-4RA extracellular ligand-binding domain, (e) an IL-9R transmembrane domain, and (f) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 115. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 115. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 115. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 115. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 115. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 115. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 115.

[0169] In some embodiments, a chimeric protein comprises, from N-terminus to C- terminus, (a) an IgE signal peptide, (b) an IL-7 polypeptide, (c) a 26mer linker, (d) an IL-7RA extracellular ligand-binding domain, (e) an IL-9R transmembrane domain, and (f) an IL- 9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 37, In some embodiments, theAttorney Docket No. WAP-008WOchimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 37. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 37. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 37. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 37. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 37. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 37.

[0170] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL- 15 polypeptide, (c) a 26mer linker, (d) an IL-15RA extracellular ligand -binding domain, (e) an IL-9R transmembrane domain, and (f) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%. at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 38. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 38. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 38. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 38. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 38. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 38. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 38.

[0171] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL-21 polypeptide, (c) a 26mer linker, (d) an IL-21R extracellular ligand-binding domain, (e) an IL-9R transmembrane domain, and (f) an IL- 9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 39. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 39. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 39. In someAttorney Docket No. WAP-008WOembodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 39. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 39. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 39. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 39.

[0172] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL-9 polypeptide, (c) a 26mer linker, (d) an IL-9R extracellular ligand-binding domain, (e) an IL-2RB transmembrane domain, and (f) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 40. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 40. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to tire amino acid sequence of SEQ ID NO: 40. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 40. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 40, In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 40. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 40.

[0173] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL-9 polypeptide, (b) a 26mer linker, (c) an IL-9R extracellular ligand¬ binding domain, (d) an IL-2RB transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 116. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 116. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 116. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 116. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQAttorney Docket No. WAP-008WOID NO: 116. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 116. In some embodiments, the chimeric protein comprises tire amino acid sequence of SEQ ID NO: 116.

[0174] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL-9 polypeptide, (c) a 26mer linker, (d) an IL-9R extracellular ligand-binding domain, (e) an IL-4RA transmembrane domain, and (f) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 41. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 41.

[0175] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL-9 polypeptide, (b) a 26mer linker, (c) an IL-9R extracellular ligand¬ binding domain, (d) an IL-4RA transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 117. in some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 117. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 117. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 117. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 117. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 117. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 117.Attorney Docket No. WAP-008WO

[0176] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL-9 polypeptide, (c) a 26mer linker, (d) an IL-9R extracellular ligand-binding domain, (e) an IL-7RA transmembrane domain, and (f) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 42. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 42. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 42. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 42. in some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 42, In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 42. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 42.

[0177] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL-9 polypeptide, (b) a 26mer linker, (c) an IL-9R extracellular ligand¬ binding domain, (d) an IL-7RA transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 118. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 118. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 118. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 118. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 118. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 118. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 118.

[0178] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL-9 polypeptide, (c) a 26mer linker, (d) an IL-9R extracellular ligand-binding domain, (e) an IL-L5RA transmembrane domain, and (f) an IL-Attorney Docket No. WAP-008WO9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 43. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 43.

[0179] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL-9 polypeptide, (b) a 26mer linker, (c) an IL-9R extracellular ligand¬ binding domain, (d) an IL-15RA transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 119. in some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 119. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 119. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 119. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 119. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 119. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 119.

[0180] In some embodiments, a chimeric protein comprises, from N-terminus to C- terminus, (a) an IgE signal peptide, (b) an IL-9 polypeptide, (c) a 26mer linker, (d) an IL-9R extracellular ligand-binding domain, (e) an IL-21R transmembrane domain, and (f) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the chimericAttorney Docket No. WAP-008WOprotein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 44. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 44.

[0181] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL-9 polypeptide, (b) a 26mer linker, (c) an IL-9R extracellular ligand¬ binding domain, (d) an IL-21R transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 120. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 120. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 120. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 120. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 120. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 120. In some embodiments, the chimeric protein comprises tire amino acid sequence of SEQ ID NO: 120.

[0182] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL-9 polypeptide, (c) a 26mer linker, (d) an IL-9R extracellular ligand-binding domain, (e) an IL-9R transmembrane domain, and (f) a truncated IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 45. In someAttorney Docket No. WAP-008WOembodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 45. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 45.

[0183] In some embodiments, a chimeric protein comprises, from N-terminus to C- terminus, (a) an IL-9 polypeptide, (b) a 26mer linker, (c) an IL-9R extracellular ligand¬ binding domain, (d) an IL-9R transmembrane domain, and (e) a truncated IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 121, In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 121. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 121. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 121. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 121. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 121. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 121.

[0184] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) a truncated IL-9R extracellular domain (6 aa), (c) an 1L-9R transmembrane domain, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to tire amino acid sequence of SEQ ID NO: 70. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments, theAttorney Docket No. WAP-008WOchimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 70.

[0185] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) a truncated IL-9R extracellular domain (6 aa), (c) an IL-9R transmembrane domain, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 122. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 122. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 122. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 122. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 122. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 122. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 122.

[0186] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) a truncated IL-7R extracellular domain (4 aa), (c) an IL-7R transmembrane domain, (d) an amino acid sequence of SEQ ID NO: 97; and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 71. in some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 71. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 71. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 71. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 71. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 71. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 71.Attorney Docket No. WAP-008WO

[0187] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a truncated IL-7R extracellular domain (4 aa), (b) an IL-7R transmembrane domain, (c) an amino acid sequence of SEQ ID NO: 97; and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 123, In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 123. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 123. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 123. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 123. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 123. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 123.

[0188] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) a truncated IL-9R extracellular domain (27 aa) (WSxWS), (c) an IL-9R transmembrane domain, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 72. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 72. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85 % identical to the amino acid sequence of SEQ ID NO: 72. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 72. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 72. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 72. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 72,

[0189] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a truncated IL-9R extracellular domain (27 aa) (WSxWS), (b) an IL-9R transmembrane domain, and (c) an IL-9R intracellular effector domain. In someAttorney Docket No. WAP-008WOembodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to tire amino acid sequence of SEQ ID NO: 124. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 124. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 124. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 124. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 124. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 124. in some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 124.

[0190] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) a truncated IL-7R extracellular domain (25 aa) (WSxWS), (c) an IL-7R transmembrane domain, (d) an amino acid sequence of SEQ ID NO: 97, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 73.

[0191] In some embodiments, a chimeric protein comprises, from N-terminus to C- terminus, (a) a truncated IL-7R extracellular domain (25 aa) (WSxWS), (b) an IL-7R transmembrane domain, (c) an amino acid sequence of SEQ ID NO: 97, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 125, In some embodiments, the chimericAttorney Docket No. WAP-008WOprotein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 125. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 125. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 125. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 125. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 125. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 125.

[0192] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) a truncated IL-2RB extracellular domain (26 aa) (WSxWS), (c) an IL-2RB transmembrane domain, (d) an amino acid sequence of SEQ ID NO: 96, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 74. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 74. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 74, In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 74. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 74. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 74. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 74.

[0193] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a truncated IL-2RB extracellular domain (26 aa) (WSxWS), (b) an IL-2RB transmembrane domain, (c) an amino acid sequence of SEQ ID NO: 96, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 126. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 126. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 126. In someAttorney Docket No. WAP-008WOembodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 126. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 126. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 126. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 126.

[0194] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) a truncated IL-2RB extracellular domain (16 aa), (c) an IL-2RB transmembrane domain, (d) an amino acid sequence of SEQ ID NO: 96, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 75, In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 75. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 75. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 75. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 75, In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 75. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 75.

[0195] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a truncated IL-2RB extracellular domain (16 aa), (b) an IL-2RB transmembrane domain, (c) an amino acid sequence of SEQ ID NO: 96, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 127. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 127. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 127. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 127. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQAttorney Docket No. WAP-008WOID NO: 127. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 127. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 127.

[0196] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) a truncated IE-2RB extracellular domain (4 aa), (c) an IL-2RB transmembrane domain, (d) an amino acid sequence of SEQ ID NO: 96, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 76. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 76. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 76. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 76. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 76. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 76. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 76.

[0197] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a truncated IL-2RB extracellular domain (4 aa), (b) an IL-2RB transmembrane domain, (c) an amino acid sequence of SEQ ID NO: 96, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 128. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 128. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 128. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 128. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 128. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 128. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 128.Attorney Docket No. WAP-008WO

[0198] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) a truncated IL-21R extracellular domain (27 aa) (WSxWS), (c) an IL-21 R transmembrane domain, (d) an amino acid sequence of SEQ ID NO: 98, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 77, In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 77. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 77. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 77. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 77. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 77. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 77.

[0199] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a truncated IL-21 R extracellular domain (27 aa) (WSxWS), (b) an IL-21R transmembrane domain, (c) an amino acid sequence of SEQ ID NO: 98, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 129. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 129. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 129. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 129. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 129. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 129. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 129.

[0200] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) a truncated IL-21R extracellular domain (14 aa), (c) an IL-21 R transmembrane domain, (d) an amino acid sequence of SEQ ID NO: 98, and (e) anAttorney Docket No. WAP-008WOIL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 78. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 78. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 78. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 78. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 78. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 78. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 78.

[0201] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a truncated IL-21R extracellular domain (14 aa), (b) an IL-21R transmembrane domain, (c) an amino acid sequence of SEQ ID NO: 98, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 130. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 130. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 130. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 130. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 130. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 130. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 130.

[0202] In some embodiments, a chimeric protein comprises, from N-terminus to C-temiinus, (a) an IgE signal peptide, (b) a truncated IL-21R extracellular domain (6 aa), (c) an IL-21R transmembrane domain, (d) an amino acid sequence of SEQ ID NO: 98, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 79, In some embodiments, theAttorney Docket No. WAP-008WOchimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 79. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 79. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 79. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 79. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 79. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 79.

[0203] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a truncated IL-21R extracellular domain (6 aa), (b) an IL-21R transmembrane domain, (c) an amino acid sequence of SEQ ID NO: 98, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 131. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 131. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 131. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 131. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 131. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 131. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 131.

[0204] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 signal peptide, (b) a TGFBR2 extracellular domain, (c) a truncated IL-9R extracellular domain (28 aa) (WSxWS), (d) an IL-9R transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 80. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 80. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 80. In someAttorney Docket No. WAP-008WOembodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 80. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 80. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 80. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 80.

[0205] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 extracellular domain, (b) a truncated IL-9R extracellular domain (28 aa) (WSxWS), (c) an IL-9R transmembrane domain, and (d) an IL-9R intracellular effector domain, in some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 132. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 132. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 132. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 132. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 132. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 132. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 132.

[0206] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 signal peptide, (b) a TGFBR2 extracellular domain, (c) a truncated 1L-9R extracellular domain (21 aa), (d) an IL-9R transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 81. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 81, In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 81. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 81. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQAttorney Docket No. WAP-008WOID NO: 81. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 81. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 81.

[0207] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 extracellular domain, (b) a truncated IL-9R extracellular domain (21 aa), (c) an IL-9R transmembrane domain, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 133. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 133. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 133, In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 133. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 133. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 133. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 133.

[0208] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 signal peptide, (b) a TGFBR2 extracellular domain, (c) a truncated IL-9R extracellular domain (10 aa), (d) an IL-9R transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 82. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 82. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 82. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 82. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 82. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 82. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 82.Attorney Docket No. WAP-008WO

[0209] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 extracellular domain, (b) a truncated IL-9R extracellular domain (10 aa), (c) an IL-9R transmembrane domain, and (d) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 134, In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 134. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 134. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 134. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 134. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 134. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 134.

[0210] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 signal peptide, (b) a TGFBR2 extracellular domain, (c) a truncated IL-7R extracellular domain (25 aa) (WSxWS), (d) an IL-7R transmembrane domain, (e) an amino acid sequence of SEQ ID NO: 97, and (f) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 83. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 83. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 83. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 83. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 83. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 83. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 83.

[0211] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 extracellular domain, (b) a truncated IL-7R extracellular domain (25Attorney Docket No. WAP-008WOaa) (WSxWS), (c) an IL-7R transmembrane domain, (d) an amino acid sequence of SEQ ID NO: 97, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 135. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 135, In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 135. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 135. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 135. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 135. In some embodiments, the chimeric protein comprises the amino acid sequence ofSEQ ID NO: 135.

[0212] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 signal peptide, (b) a TGFBR2 extracellular domain, (c) a truncated IL-7R extracellular domain (18 aa), (d) an IL-7R transmembrane domain, (e) an amino acid sequence of SEQ ID NO: 97, and (f) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 84. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 84. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 84. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 84. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 84. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 84. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 84,

[0213] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 extracellular domain, (b) a truncated IL-7R extracellular domain (18 aa), (c) an IL- 7R transmembrane domain, (d) an amino acid sequence of SEQ ID NO: 97, andAttorney Docket No. WAP-008WO(e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95 % identical to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 136.

[0214] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 signal peptide, (b) a TGFBR2 extracellular domain, (c) a truncated IL-7R extracellular domain (4 aa), (d) an IL-7R transmembrane domain, (e) an amino acid sequence of SEQ ID NO: 97, and (f) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 85. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 85. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the ammo acid sequence of SEQ ID NO: 85. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 85. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 85. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 85. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 85.

[0215] In some embodiments, a chimeric protein comprises, from N-terminus to C- terminus, (a) a TGFBR2 extracellular domain, (b) a truncated IL-7R extracellular domain (4 aa), (c) an IL-7R transmembrane domain, (d) an amino acid sequence of SEQ ID NO: 97, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric proteinAttorney Docket No. WAP-008WOcomprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 137. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 137. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 137. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 137. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 137. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 137. in some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 137.

[0216] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 signal peptide, (b) a TGFBR2 extracellular domain, (c) a truncated IL-15RA extracellular domain, (d) an IL-15RA transmembrane domain, and (e) an IL-15RA intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 86. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 86. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 86. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the ammo acid sequence of SEQ ID NO: 86. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 86. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 86. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 86.

[0217] In some embodiments, a chimeric protein comprises, from N-terminus to C- terminus, (a) a TGFBR2 extracellular domain, (b) a truncated IL-15RA extracellular domain, (c) an IL-15RA transmembrane domain, and (d) an IL-15RA intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 138, In some embodiments, the chimeric protein comprises anAttorney Docket No. WAP-008WOamino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 138.

[0218] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 signal peptide, (b) a TGFBR2 extracellular domain, (c) a truncated IL-2RB extracellular domain (18 aa), (d) an IL-2RB transmembrane domain, and (e) an IL-2RB intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%. at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 87. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the ammo acid sequence of SEQ ID NO: 87. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 87. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 87. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 87. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 87. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 87.

[0219] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 extracellular domain, (b) a truncated IL-2RB extracellular domain (18 aa), (c) an IL-2RB transmembrane domain, and (d) an IL-2RB intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 139. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 139. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the ammo acid sequence of SEQ ID NO: 139. In some embodiments,Attorney Docket No. WAP-008WOthe chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 139. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 139. in some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 139. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 139.

[0220] In some embodiments, a chimeric protein comprises, from N-terminus to C- terminus, (a) a TGFBR2 signal peptide, (b) a TGFBR2 extracellular domain, (c) a TGFBR2 transmembrane domain, and (d) an N-terminally truncated IL-9R effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 88. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 88. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 88. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the ammo acid sequence of SEQ ID NO: 88. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 88. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 88. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 88.

[0221] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) a TGFBR2 extracellular domain, (b) a TGFBR2 transmembrane domain, and (c) an N-terminally truncated IL-9R effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 140. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to tire amino acid sequence of SEQ ID NO: 140. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the ammo acid sequence of SEQ ID NO: 140. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 140. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 140, In some embodiments, the chimeric protein comprises anAttorney Docket No. WAP-008WOamino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 140. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 140.

[0222] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL-15 polypeptide, (c) a 26mer linker, (d) an IL-15RA extracellular ligand-binding domain, (e) an IL-15RA transmembrane domain, and (f) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 100. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 100. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the ammo acid sequence of SEQ ID NO: 100. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 100. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 100. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 100. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 100.

[0223] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IL-15 polypeptide, (b) a 26mer linker, (c) an IL-15RA extracellular ligand-binding domain, (d) an IL-15RA transmembrane domain, and (e) an IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 141. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 141. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 141. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the ammo acid sequence of SEQ ID NO: 141. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 141. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 141. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 141.Attorney Docket No. WAP-008WO

[0224] In some embodiments, a chimeric protein comprises, from N-terminus to C-terminus, (a) an IgE signal peptide, (b) an IL-9 polypeptide, (c) a 26mer linker, (d) an IL-9R extracellular ligand-binding domain, (e) an IL-4RA transmembrane domain, and (f) a truncated IL-9R intracellular effector domain. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 101, In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 101. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 101. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 101. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 101, In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 101. In some embodiments, the chimeric protein comprises the amino acid sequence of SEQ ID NO: 101.

[0225] In some embodiments, a chimeric protein comprises, from N-terminus to C- terminus, (a) an IL-9 polypeptide, (b) a 26mer linker, (c) an IL-9R extracellular ligandbinding domain, (d) an IL-4RA transmembrane domain, and (e) a truncated IL-9R intracellular effector domain. In some embodiments, tire chimeric protein comprises an amino acid sequence at least 80%, at least 85%. at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 142. In some embodiments, the chimeric protein comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 142. In some embodiments, the chimeric protein comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 142. In some embodiments, the chimeric protein comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 142. In some embodiments, the chimeric protein comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 142. In some embodiments, the chimeric protein comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 142. In some embodiments, the chimeric protein comprises tire amino acid sequence of SEQ ID NO: 142.Attorney Docket No. WAP-008WONucleic Acids, Expression Vectors, and Expression Systems

[0226] In various embodiments, the present disclosure provides nucleic acids encoding the chimeric protein provided herein. In some embodiments, the nucleic acids are recombinant nucleic acids.

[0227] In various embodiments, the present disclosure provides expression vectors comprising a nucleic acid sequence encoding a chimeric protein provided herein. In some embodiments, the expression vector is a viral vector. In some embodiments, the viral vector is a lentiviral vector, a retroviral vector, or an adenoviral vector. In some embodiments, the viral vector is a lentiviral vector. In some embodiments, the viral vector is a retroviral vector. In some embodiments, the viral vector is an adenoviral vector. In some embodiments, the expression vector is a non-viral vector. In some embodiments, the expression vector is a polynucleotide sequence encapsulated in an LNP. In some embodiments, the expression vector is a polynucleotide sequence combined with an exosome, micelle or other extracellular vesicle. In some embodiments, tire expression vector is a polymeric or inorganic nanoparticle complexed with a polynucleotide.

[0228] In some embodiments, the expression vector further comprises a nucleic acid sequence encoding a protein of interest. In some embodiments, the protein of interest is a synthetic immune receptor. In some embodiments, the synthetic immune receptor is a chimeric antigen receptor (CAR), a T cell receptor (TCR), a T Cell Receptor Fusion Construct (TRuC), an adapter CAR, a universal / modular CAR system, a T cell antigen coupler (TAC) receptor, or a logic-gated version of any of the aforementioned receptors. In some embodiments, the nucleic acid sequence encoding the chimeric protein and the nucleic acid sequence encoding the protein of interest are present in a single open reading frame. In some embodiments, the nucleic acid sequence encoding the chimeric protein and the nucleic acid sequence encoding the protein of interest are separated by a ribosomal skip site. In some embodiments the ribosomal skip site is a T2A sequence, a P2A sequence, an E2A sequence, or an F2A sequence. In some embodiments the nucleic acid sequence encoding the chimeric protein and the nucleic acid sequence encoding the protein of interest are encoded on two separate polynucleotide molecules. In some embodiments, the protein of interest is a secreted protein. In some embodiments, the secreted protein is an antibody fragment or a bispecific T cell engager (BiTE). In some embodiments, the expression vector further comprises a nucleic acid sequence encoding an shRN A or an miRNA.Attorney Docket No. WAP-008WO

[0229] In various embodiments, the expression vector further comprises a nucleic acid sequence encoding a secreted chemokine (e.g., a chemokine that when expressed in a ceil can be secreted from the cell comprising the nucleic acid sequence encoding the chemokine). In some embodiments, the secreted chemokine is CCL21 or CCL19.

[0230] In some embodiments, the secreted chemokine is CCL21. CCL21 (C-C motif chemokine 21; Uniprot Accesion No. 000585) is a chemokine that can signal to other cells that express its receptors (e.g., CCR7 and CXCR3). These receptors are expressed by a variety of immune cells, and binding of CCL21 to these receptors can facilitate cellular migration. T cells can express CCR7 to vary ing degrees, thus potentially enabling chemokine signaling between T cells that also secrete high levels of CCL21. The amino acid sequence of CCL21 is:MAQSLALSLLILVLAFGI PRTQGSDGGAQDCCLKYSQRKI PAKWRSYRKQE PS LGCS I PAI L FL PRKRS QAELCAD PKELWVQQLMQHLDKTPS PQKPAQGCR KDRGASKTGKKGKGSKGCKRTERSQTPKGP (SEQ ID NO: 47)

[0231] In some embodiments, the secreted chemokine comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, tlie secreted chemokine comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 85 % identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the secreted chemokine comprises the amino acid sequence of SEQ ID NO: 47.

[0232] As provided for herein, SEQ ID NO: 47 contains a signal peptide sequence of CCL21 that can be cleaved when CCL21 is expressed and secreted. The signal peptide sequence of MAQSLALSLLILVLAFGIPRTQG (SEQ ID NO: 50) can be used or a different signal peptide sequence can be used to express CCL21.Attorney Docket No. WAP-008WO

[0233] Thus, in some embodiments, CCL21 is processed before being secreted. The processing can remove the -terminal signal peptide sequence. Accordingly, in some embodiments, the secreted chemokine can comprise the amino acid sequence of:SDGGAQDCCLKYSQRKIPAKWRSYRKQEPSLGCSIPAILFLPRKRSQAELC ADPKELWVQQLMQHLDKTPSPQKPAQGCRKDRGASKTGKKGKGSKGCKRTER SQTPKGP (SEQ ID NO: 49)

[0234] In some embodiments, the secreted chemokine comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 49, In some embodiments, the secreted chemokine comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the secreted chemokine comprises the amino acid sequence of SEQ ID NO: 49,

[0235] In some embodiments, the secreted chemokine is CCL19. CCL19 (C-C motif chemokine 19; Uniprot Accesion No, Q99731) is a chemokine that can signal to other cells that express its receptors (e.g., CCR7 and ACKR4). Binding of CCL19 to these receptors can facilitate lymphocyte recirculation, homing, and chemotaxis. In some embodiments, the amino acid sequence of CCL19 is:MALLLALSLLVLWTSPAPTLSGTNDAEDCCLSVTQKPIPGYIVRNFHYLLIK DGCRVPAWFTTLRGRQLCAPPDQPWVERIIQRLQRTSAKMKRRSS (SEQ ID NO: 91)

[0236] In some embodiments, the secreted chemokine comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 91. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 80% identical to the amino acid sequence of SEQ ID NO: 91. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 91, In some embodiments, the secreted chemokine comprises an amino acid sequence at least 90% identical to the aminoAttorney Docket No. WAP-008WOacid sequence of SEQ ID NO: 91. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 91. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO: 91. In some embodiments, the secreted chemokine comprises the amino acid sequence of SEQ ID NO: 91.

[0237] In some embodiments, the CCL19 protein that is expressed or after being processed does not comprise a signal peptide. For example, as provided for herein, the amino acid sequence of SEQ ID NO: 91 comprises a signal peptide sequence of CCL19 that can be cleaved when CCL19 is expressed and secreted. The signal peptide sequence of MALLLALSLLVLWTSPAPTLS (SEQ ID NO: 92) can be used or a different signal peptide sequence can be used to express CCL19. Accordingly, in some embodiments, the protein does not comprise the contiguous sequence of MALLLALSLLVLWTSPAPTLS (SEQ ID NO: 92).

[0238] Thus, in some embodiments, CCL19 is processed before being secreted. The processing can remove the N-terminal signal peptide sequence. Accordingly, in some embodiments, the secreted chemokine can comprise the amino acid sequence of:GTNDAEDCCLSVTQKPIPGYIVRNFHYLLIKDGCRVPAWFTTLRGRQLCAPPDQPWVERIIQRLQRTSAKMKRRSS (SEQ ID NO: 93)

[0239] In some embodiments, the secreted chemokine comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 93. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 80% identical to the ammo acid sequence of SEQ ID NO: 93. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO: 93. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 93, In some embodiments, the secreted chemokine comprises an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 93. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 99% identical to the ammo acid sequence of SEQ ID NO: 93. In some embodiments, the secreted chemokine comprises the amino acid sequence of SEQ ID NO: 93.

[0240] In various embodiments, the present disclosure provides systems comprising (a) an expression vector comprising a nucleic acid sequence encoding a chimeric protein providedAttorney Docket No. WAP-008WOherein and (b) a second expression vector comprising a nucleic acid sequence of interest. In various embodiments, the present disclosure provides a system comprising a first expression vector encoding a nucleic acid sequence encoding a chimeric protein provided herein, and a second expression vector comprising a nucleic acid sequence encoding a secreted chemokine. In various embodiments, the present disclosure provides a system comprising (a) a first expression vector encoding a nucleic acid sequence encoding a chimeric protein provided herein, (b) a second expression vector comprising a nucleic acid sequence of interest, and (c) a third expression vector comprising a nucleic acid sequence encoding a secreted chemokine. In some embodiments, the secreted chemokine is CCL21. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 47 or SEQ ID NO: 49. In some embodiments, the secreted chemokine is CCL19. In some embodiments, the secreted chemokine comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 91 or SEQ ID NO: 93. In some embodiments, the nucleic acid sequence of interest encodes a protein of interest. In some embodiments, the protein of interest is a synthetic immune receptor. In some embodiments, the synthetic immune receptor is a chimeric antigen receptor (CAR), a T cell receptor (TCR), a T Cell Receptor Fusion Construct (TRuC), an adapter CAR, a universal / modular CAR system, a T cell antigen coupler (TAC) receptor, an HLA-independent T cell (HIT) receptor, or a logic-gated version of any of the aforementioned receptors. In some embodiments, the protein of interest is a secreted protein. In some embodiments, wherein the secreted protein is an antibody fragment or a bispecific T cell engager (BiTE). In some embodiments, the nucleic acid sequence of interest encodes an shRNA or an miRNA. FIGs. 9A-9D detail exemplary constructs for expression of a protein of interest and a chimeric protein.Isolated Cells

[0241] In various embodiments, the present disclosure also provides an isolated cell expressing a chimeric protein disclosed herein. In various embodiments, the present disclosure also provides isolated cell comprising nucleic acid encoding a chimeric protein disclosed herein (i.e., an engineered cell). In some embodiments, the engineered cells used in the present disclosure are human cell lines grown in vitro (e.g., deliberately immortalized cell lines, cancer cell lines, etc.). In some embodiments, the isolated cell is a human cell. In someAttorney Docket No. WAP-008WOembodiments, the isolated cell is a mouse cell. In some embodiments, the isolated cell is present in a mixed population of cells.|0242] In some embodiments, the isolated cell is a hematopoietic cell. “Hematopoietic cell” refers to a cell derived from a hematopoietic stem cell. The hematopoietic cell may be obtained or provided by isolation from an organism, system, organ, or tissue (e.g., blood, ora fraction thereof). Alternatively, an hematopoietic stem cell can be isolated and the hematopoietic cell obtained or provided by differentiating the stem cell. Hematopoietic cells include cells with limited potential to differentiate into further cell types. Such hematopoietic cells include, but are not limited to, multipotent progenitor cells, lineage-restricted progenitor cells, common myeloid progenitor cells, granulocyte-macrophage progenitor cells, or megakaryocyte-erythroid progenitor cells. Hematopoietic cells include cells of the lymphoid and myeloid lineages, such as lymphocytes, erythrocytes, granulocytes, monocytes, and thrombocytes. In some embodiments, a cell is a blood mononuclear cells (PBMC) or a peripheral blood leukocytes (PBL).

[0243] In some embodiments, the isolated cell is an immune cell, “Immune cell” is inclusive of all cell types that can give rise to immune cells, including hematopoietic cells such hematopoietic stem cells, pluripotent stem cells, and induced pluripotent stem cells (iPSCs). In some embodiments, the immune cell is a B cell, macrophage, a natural killer (NK) cell, an induced pluripotent stem cell (iPSC), a human pluripotent stem cell (HSPC), a T cell, a T cell progenitor cell, a dendritic cell a neutrophil, a tumor-reactive lymphocyte, or a circulating tumor-reactive lymphocyte. In some embodiments, the cell is an innate immune cell.

[0244] In some embodiments, the isolated cell is a T cell. A “T cell” is a cell that has completed maturation in the thymus and identifies certain foreign antigens in the body. T cells include the major leukocyte types that have various roles in the immune system, including actuation and deactivation of other immune cells. The T cell can be any T cell such as a cultured T cell, e. g., a primary T cell, or a T cell derived from a cultured T cell line, e. g., a Jurkat, SupTl, etc,, or a T cell obtained from a mammal. T cells include, but are not limited to, naive T cells, stimulated T cells, primary T cells (e.g., uncultured), cultured T cells, immortalized T cells, helper T cells, cytotoxic T cells, memory T cells, regulatory T cells, natural killer T cells, combinations thereof, or sub-populations thereof. The T cell can be a CD3+cell. T cells can be CD4+, CD8+, or CD4+and CD8+. The T cell can be any type of T cell, CD4+CD8+double positive T cells, CD4+helper T cells (e.g., TH 1 and TH2 cells), CD8+Attorney Docket No. WAP-008WOT cells (e.g., cytotoxic T cells), tumor infiltrating lymphocytes (TIL), memory T cells, naive T cells, regulatory T cells, y5 T cells, etc. It can be any T cell at any stage of development. Additional types of helper T cells include TH3 (Treg) cells, TH17 cells, TH9 cells, or TFH cells. Additional types of memory T cells include cells such as central memory T cells (TCM cells), stem cell memory T cells (TSCM cells), effector memory T cells (TEM cells and TEMRA cells), and resident memory’ cells (TRM cells). A T cell can also refer to a genetically’ modified T cell, such as a T cell that has been modified to express a T cell receptor (TCR) or a chimeric antigen receptor (CAR). T cells can also be differentiated from stem cells or progenitor cells.

[0245] In some embodiments, the isolated cell is a CD4+T cell, A “CD4” T cell” is a T cell that express CD4 on its surface and is associated with a cellular immune response. CD4’ T cells are characterized by a post-stimulation secretion profile that can include secretion of cytokines such as IFN-y, TNF-a, IL-2, IL-4 and IL-10. " CD4” is a 55 kDa glycoprotein originally defined as a differentiation antigen on T lymphocytes, but was also found on other cells including monocytes / macrophages. The CD4 antigen is a member of the immunoglobulin superfamily and has been implicated as an associative recognition element in MHC (major histocompatibility complex) class II restricted immune responses. On T lymphocytes, the CD4 antigen defines a helper / inducer subset.

[0246] In some embodiments, the isolated cell is a CD8+T cell. ACCD8+T cell” is a T cell that express CD8 on its surface, is MHC class I restricted, and functions as a cytotoxic T cell. The “CD8” molecule is a differentiation antigen present on thymocytes, as well as on cytotoxic and suppressor T lymphocytes. The CD8 antigen is a member of the immunoglobulin superfamily and is an associative recognition element in MHC class I restriction interactions.

[0247] In some embodiments, the T cell is a natural killer T (“NK-T”) cell. Natural killer T cells represent a subset of T lymphocytes with unique properties. NK-T cells are different from functionally differentiated conventional a[3 T cells in that they share properties of both natural killer cells and T cells are can rapidly produce both TH 1 -type and Tn2-type responses upon stimulation with their ligands (innate immunity). The activation of NK-T cells can lead either to suppression or stimulation of immune responses. For example, tire production of THI cytokines is thought to promote cellular immunity with antitumor, antiviral / antibacterial, and adjuvant activities, whereas TH2 cytokine production is thought to subdue autoimmune diseases and promote antibody production. Many of these cells recognize the non-polymorphic CD Id molecule, an antigen-presenting molecule that binds self- and foreignAttorney Docket No. WAP-008WOlipids and glycolipids. The TCR of the NK-T cells are able to recognize glycolipid antigens presented (chaperoned) by a CD Id molecule. A major response of NK-T cells is rapid secretion of cytokines, including IL-4, IFN-y and IL-10 after stimulation and thus influence diverse immune responses and pathogenic processes.

[0248] In some embodiments, the T cell is a gamma delta (y5) T cell. A small subset express a TCR made from gamma and delta chains, as opposed to the alpha and beta chains expressed by most T cells. In general, y5-T cells have several functions, including killing tumor cells and pathogen-infected cells. Stimulation through their unique TCRs composed of two glycoprotein chains, y and 5, improves the capacity for cellular cytotoxicity, cytokine secretion and other effector functions. The TCRs of y5-T cells have unique specificities, and the cells themselves occur in high clonal frequencies, thus allowing rapid innate-like responses to tumors and pathogens.

[0249] In some embodiments, the immune cell is a natural-killer (NK) cell. NK cells are a sub-population of lymphocytes, involved in non-conventional immunity. Characteristics and biological properties of NK cells include the expression of surface antigens including CD 16, CD56, and / or CD57; the absence of the alpha / beta or gamma / delta TCR complex on the cell surface; the ability to bind to and kill cells that fail to express ‘"self” MHC / HLA antigens by the activation of specific cytolytic enzymes; the ability to kill tumor cells or other diseased cells that express a NK activating receptor-ligand; the ability to release cytokines that stimulate or inhibit the immune response; and the ability to undergo multiple rounds of cell division and produce daughter cells with similar biologic properties as the parent cell. Within the context of this invention “active” NK cells designate biologically active NK cells, more particularly NK cells having the capacity of lysing target cells. For instance, an “active” NK cell is able to kill cells that express an NK activating receptor-ligand and fail to express “self ” MHC / HLA antigens (KIR-incompatible cells).

[0250] In some embodiments, the isolated cell is a macrophage. “Macroph...

Claims

Attorney Docket No. WAP-008WOWHAT IS CLAIMED IS:

1. A chimeric protein comprising: (i) a cytokine polypeptide, or a functional fragment thereof, operably linked to (ii) a cell-surface receptor polypeptide, wherein the cell-surface receptor polypeptide comprises:(a) an extracellular ligand-binding domain capable of binding the cytokine polypeptide;(b) a transmembrane domain; and(c) an IL-9 receptor (IL-9R) intracellular effector domain.

2. The chimeric protein of claim 1, wherein binding of the cytokine polypeptide to the ligand binding domain induces the IL-9R effector domain to activate downstream signaling.

3. The chimeric protein of claim 1 or 2, wherein:(a) the cytokine polypeptide is IL-9, or a functional fragment thereof, and the ligand binding domain is an IL-9R extracellular domain, or a ligand-binding fragment thereof;(b) the cytokine polypeptide is IL-2, or a functional fragment thereof, and the ligand binding domain is an IL-2R extracellular domain, or a ligand-binding fragment thereof;(c) the cytokine polypeptide is IL-4, or a functional fragment thereof, and the ligand binding domain is an IL-4RA extracellular domain, or a ligand-binding fragment thereof;(d) the cytokine polypeptide is IL-7, or a functional fragment thereof, and the ligand binding domain is an IL-7R extracellular domain, or a ligand-binding fragment thereof;(e) the cytokine polypeptide is IL- 15, or a functional fragment thereof, and the ligand binding domain is an IL-15R extracellular domain, or a ligand-binding fragment thereof; or(f) the cytokine polypeptide is IL-21, or a functional fragment thereof, and the ligand binding domain is an IL-21R extracellular domain, or a ligand-binding fragment thereof.

4. The chimeric protein of any one of claims 1-3, wherein:Attorney Docket No. WAP-008WO(a) the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2, optionally wherein the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7;(b) wherein the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3, optionally wherein the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8 or 106;(c) the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 111, optionally wherein the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 112 or 113;(d) the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 4, optionally wherein the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9 or 107;(e) the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5, optionally wherein the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence or SEQ ID NO: 10 or 108; orAttorney Docket No. WAP-008WO(f) the cytokine polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 6, optionally wherein the ligand binding domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 11 or 109.

5. The chimeric protein of any one of claims 1-4, wherein the cytokine polypeptide or functional fragment is operably linked to the cell-surface receptor polypeptide by a linker peptide, optionally wherein the linker comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-27.

6. The chimeric protein of any one of claims 1-5, wherein the transmembrane domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 12-17 and 90.

7. The chimeric protein of any one of claims 1-6, wherein the chimeric protein further comprises an additional polypeptide located between the transmembrane domain and the IL-9R intracellular effector domain.

8. The chimeric protein of claim 7, wherein the additional polypeptide is from the same cytokine receptor or a different cytokine receptor as the transmembrane domain., optionally wherein the additional polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 96-98.

9. The chimeric protein of any one of claims 1-8, wherein the IL-9R intracellular effector domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18.

10. The chimeric protein of any one of claims 1-9, wherein the IL-9R intracellular effector domain is a truncated IL-9R intracellular effector domain, optionally wherein the truncated IL-9R intracellular effector domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 35.Attorney Docket No. WAP-008WO11. The chimeric protein of any one of claims 1-10, wherein the chimeric protein further comprises a signal peptide at the N-terminus.

12. The chimeric protein of claim 11, wherein the signal peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-21,13. A chimeric protein comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 28-33, 36-45, 70-88, 101, 114- 142.

14. A chimeric protein comprising the amino acid sequence of SEQ ID NO: 28.

15. A nucleic acid encoding the chimeric protein of any one of claims 1-14.

16. An expression vector comprising the nucleic acid of claim 15.

17. The expression vector of claim 16, wherein the vector is a viral vector, optionally wherein the vector is an integrating viral vector, a non-integrating viral vector, a lentiviral vector, a retroviral vector, an AAV vector, an adenoviral vector, a Sendai viral vector, a Measles viral vector, a Foamy viral vector, or an HSV vector.

18. The expression vector of claim 16, wherein the vector is a non-viral vector.

19. The expression vector of any one of claims 16-18, wherein the vector further comprises a nucleic acid sequence encoding a protein of interest, optionally wherein the protein of interest is a synthetic immune receptor, optionally wherein the synthetic immune receptor is a chimeric antigen receptor (CAR), a T cell receptor (TCR), a T Cell Receptor Fusion Construct (TRuC), an adapter CAR, a universal / modular CAR system, a T cell antigen coupler (TAC) receptor, an HLA-independent T cell (HIT) receptor, or a logic-gated version of any of the aforementioned receptors.

20. The expression vector of any one of claims 16-19, wherein the nucleic acid sequence encoding the chimeric protein and the nucleic acid sequence encoding the protein of interest are present in a single open reading frame or under control of a single promoter.Attorney Docket No. WAP-008WO21. The expression vector of claim 20, wherein the nucleic acid sequence encoding the chimeric protein and the nucleic acid sequence encoding the protein of interest are separated by a ribosomal skip site or an internal ribosome entry site (IRES), optionally wherein the ribosomal skip site is a T2A sequence, a P2A sequence, an E2A sequence, or an F2A sequence.

22. The expression vector of any one of claims 16-19, wherein the nucleic acid sequence encoding the chimeric protein and the nucleic acid sequence encoding the protein of interest are present in different open reading frames or are under control of different promoters.

23. The expression vector of any one of claims 16-22, whewherein the vector further comprises a nucleic acid sequence encoding a secreted chemokine.

24. Tire expression vector of claim 23, wherein the secreted chemokine is CCL21 or CCL19.

25. The expression vector of claim 23 or 24, wherein the secreted chemokine comprises the ammo acid sequence of SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 91, or SEQ ID NO: 93,26. The expression vector of any one of claims 23-25, wherein the nucleic acid sequence encoding the chimeric protein, the nucleic acid sequence encoding the protein of interest, and the nucleic acid sequence encoding the secreted chemokine are present in a single open reading frame.

27. The expression vector of any one of claims 23-26, wherein the nucleic acid sequence encoding the chimeric protein, the nucleic acid sequence encoding the protein of interest, and the nucleic acid sequence encoding the secreted chemokine are each separated by a ribosomal skip site or an internal ribosome entry site (IRES), optionally wherein each ribosomal skip site is independently a T2A sequence, a P2A sequence, an E2A sequence, or an F2A sequence.

28. An expression vector comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at leastAttorney Docket No. WAP-008WO95%, at least 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 48, 94, and 102-105.

29. A system comprising:(a) (i) the expression vector of any one of claims 16-28, and (ii) a second expression vector comprising a nucleic acid sequence of interest;(b) (i) the expression vector of any one of claims 16-28 and (ii) a second expression vector comprising a nucleic acid sequence encoding a secreted chemokine;(c) (i) an expression vector comprising the nucleic acid sequence of claim 15, (ii) a second expression vector comprising a nucleic acid sequence of interest, and (iii) a third expression vector comprising a nucleic acid sequence encoding a secreted chemokine;(d) (i) an expression vector comprising the nucleic acid sequence of claim 15, and (ii) a second expression vector comprising a nucleic acid sequence of interest and a nucleic acid sequence encoding a secreted chemokine;(e) (i) an expression vector comprising the nucleic acid sequence of claim 15 and a nucleic acid sequence encoding a secreted chemokine, and (ii) a second expression vector comprising a nucleic acid sequence of interest; or(f) (i) an expression vector comprising the nucleic acid sequence of claim 15 and a nucleic acid sequence of interest, and (ii) a second expression vector comprising a nucleic acid sequence encoding a secreted chemokine.

30. The system of claim 29, wherein the nucleic acid sequence of interest encodes a protein of interest.

31. The system of claim 30, wherein the protein of interest is: (a) a synthetic immune receptor, optionally wherein the synthetic immune receptor is a chimeric antigen receptor (CAR), a T cell receptor (TCR), a T Cell Receptor Fusion Construct (TRuC), an adapter CAR, a universal / modular CAR system, a T cell antigen coupler (TAC) receptor, an HLA-independent T cell (HIT) receptor, or a logic-gated version of any of tire aforementioned receptors; or (b) a secreted protein, optionally wherein the secreted protein is an antibody fragment or a bispecific T cell engager (BiTE).Attorney Docket No. WAP-008WO32. The system of claim 29, wherein the nucleic acid sequence of interest encodes an shRNA or an miRNA.

33. The system of any one of claims 29-32, wherein: (a) the nucleic acid sequence of interest and the nucleic acid sequence encoding the secreted chemokine; (b) the nucleic acid sequence encoding the chimeric protein and the nucleic acid sequence encoding the secreted chemokine, or (c) the nucleic acid sequence encoding the chimeric protein and the nucleic acid sequence of interest are each separated by a ribosomal skip site or an internal ribosome entry site (IRES), optionally wherein the ribosomal skip site is a T2A sequence, a P2A sequence, an E2A sequence, or an F2A sequence.

34. The system of any one of claims 29-33, wherein the secreted chemokine is CCL21 or CCL19.

35. The system of any one of claims 29-34, wherein the secreted chemokine comprises the amino acid sequence of SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 91, or SEQ ID NO: 93.

36. An isolated cell comprising:(a) the chimeric protein of any one of claims 1-14;(b) the nucleic acid of claim 15;(c) the expression vector of any one of claims 16-28; and / or(d) the system of any one of claims 29-35.

37. The isolated cell of claim 36, wherein the isolated cell is an immune cell, optionally wherein the immune cell is a peripheral blood mononuclear cell (PBMC), a T cell, an NK cell, a macrophage, a tumor infiltrating lymphocyte, a monocyte, a dendritic cell, a neutrophil, a tumor-reactive lymphocyte, or a circulating tumor-reactive lymphocyte.

38. The isolated cell of claim 37, wherein the isolated cell is a T cell, optionally wherein the T cell is a cytotoxic T cell, a Ti-il cell, a Tn2 cell, a TH9 cell, a TH17 cell, a TFH cell, a Tel cell, a Tc2 cell, a Tc9 cell, a TcI7 cell, a Tc22 cell, an NK-T cell, a yo T cell, a naive T cell, a TSCM cell, a TEM cell, a I’EMRA cell, or a TRM cell.Attorney Docket No. WAP-008WO39. The isolated cell of any one of claims 36-38, wherein the isolated cell is a human cell or a mouse cell.

40. A pharmaceutical composition comprising:(a) the chimeric protein of any one of claims 1-14;(b) the nucleic acid of claim 15;(c) the expression vector of any one of claims 16-28;(d) the system of any one of claims 29-35; and / or(e) the isolated cell of any one of claims 36-39; anda pharmaceutically acceptable excipient or carrier.

41. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering an effective amount of the nucleic acid of claim 15, the expression vector of any one of claims 16-28, the system of any one of claims 29-35, the isolated cell of any one of claims 36-39, or the phar aceutical composition of claim 40 to the subject, thereby treating the disease or disorder.

42. The method of claim 41, wherein the disease is a cancer, an infectious disease, an autoimmune disease, or an inflammatory disease.

43. Use of one or more of:(a) the chimeric protein of any one of claims 1-14;(b) the nucleic acid of claim 15;(c) the expression vector of any one of claims 16-28;(d) the system of any one of claims 29-35;(e) the isolated cell of any one of claims 36-39; and(f) the pharmaceutical composition of claim 40,in the manufacture of a medicament.

44. A method of engineering a cell to express the chimeric protein of any one of claims 1- 14, tire method comprising:(a) introducing into the cell the nucleic acid of claim 1, the expression vector of any one of claims 16-28, or the system of any one of claims 29-35; and (b) incubating the cell under conditions sufficient for expression of the chimeric protein.Attorney Docket No. WAP-008WO45. The method of claim 44, wherein the nucleic acid, expression vector, or system is introduced into the cell by viral transduction.

46. The method of claim 45, wherein the viral transduction is performed using an integrating viral vector or a non-integrating viral vector.

47. The method of claim 45, wherein the viral transduction is performed using lentiviral transduction, retroviral transduction, AAV transduction, adenoviral transduction, Sendai viral transduction, Measles viral transduction, Foamy viral transduction, or HSV transduction.

48. The method of claim 44, wherein the nucleic acid, expression vector, or system is introduced into the cell non-virally, optionally wherein the nucleic acid, expression vector, or system is introduced into the cell using a lipid nanoparticle, lipid-based nanoparticle, polymeric nanoparticle, liposome, dendrimer, cell-penetrating peptide, extracellular vesicle, electroporation, sonoporation, microinjection, hydrodynamic delivery', or a transposon system.

49. The method of any one of claims 44-48, wherein the nucleic acid, expression vector, or system is introduced into the cell ex vivo or in vivo.

50. The method of any one of claims 44-49, wherein the cell is an immune cell, optionally wherein the immune cell is a peripheral blood mononuclear cell (PBMC), a T cell, an NK cell, a macrophage, a tumor infiltrating lymphocyte, a monocyte, a dendritic cell, a neutrophil, a tumor-reactive lymphocyte, or a circulating tumor-reactive lymphocyte.

1. The method of claim 50, wherein the cell is a T cell, optionally 'herein the T cell is a cytotoxic T cell, a Ti-il cell, a TH2 cell, a Tn9 cell, a THI 7 cell, a TFH cell, a Tel cell, a Tc2 cell, a Tc9 cell, a Tcl7 cell, a Tc22 cell, an NK-T cell, a yo T cell, a naive T cell, a TSCM cell, a T cell, a TEMRA cell, or a TRM cell.

Images