Switch receptor using IL-9 signaling domain

Abstract

The present disclosure generally relates to a class of chimeric switch receptors that contain, inter alia, an endodomain of the IL-9 receptor that has been engineered to regulate transcriptional regulation in a ligand-dependent manner. The disclosure also provides compositions and methods useful for producing such receptors, nucleic acids encoding the receptors, host cells genetically engineered with the nucleic acids, and methods of regulating gene expression, regulating cellular activity, and / or treating various conditions or diseases.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 245,661, filed September 17, 2021, which is incorporated by reference in its entirety herein.

[0002] The present disclosure relates generally to synthetic cellular receptors that bind extracellular ligands and have an IL-9 endodomain. The disclosure also provides compositions and methods useful for producing such receptors, nucleic acids encoding the receptors, host cells genetically engineered with the nucleic acids, and methods for modulating gene expression, modulating cellular activity, and / or treating various conditions or diseases. [Background technology]

[0003] Manipulating cells, particularly immune cells, to differentiate, develop specialized functions, and increase in number is of great clinical interest. Many protein factors that affect their activity are known in the art, including cytokines and chemokines in particular. However, these signaling molecules also have pleiotropic effects on cells that are not targeted for manipulation, and therefore methods to selectively activate signaling in targeted cell populations are desirable. The ability to manipulate immune cells to achieve controlled behavior is of interest in the art. For example, in adoptive immunotherapy, T cells are isolated from blood, processed ex vivo, and reinfused into the patient's body. Such T cells are being developed for use in therapeutic applications, such as the treatment of cancer, infectious diseases, and autoimmune diseases.

[0004] A key challenge in cell-based therapy is to be able to engineer receptors that respond to native molecules while allowing selective manipulation of immune cells. Several groups have engineered proteins to bind and respond to modified ligands in an orthogonal manner, independent of the effects of the native protein or ligand. This technology relies on the engineering of both orthogonal cytokines and orthogonal receptors, and on the premise that the native molecule does not recognize the orthogonal receptor. One of the challenges with generating orthogonal ligand-receptor pairs is to find mutations that efficiently prevent activation by endogenous molecules without compromising the receptor's structure or its inherent ability to activate gene transcription. Alternatively, the only way to prevent negative signals delivered by molecules such as PD-1 to regulate signaling in immune cells is to subject patients to systemic treatment with antagonistic antibodies that bind to PD-1. A limitation of this approach is that systemic treatment prevents inactivation of T cells present in the tumor microenvironment and the immune system as a whole, which can lead to autoimmune or systemic inflammatory syndromes in some patients (Beck et al., 2006, J Clin Oncol 24:2283-9; Blansfield et al., 2005, J Immunother 28:593-8; Dougan et al., 2009, Annual Review of Immunology 27:83-117).

[0005] The present disclosure provides solutions to problems present in previous attempts to manipulate immune cells and potentially provide improved therapeutic methods involving cell transplantation. Summary of the Invention

[0006] The present disclosure relates generally to chimeric switch receptors that, inter alia, comprise an endodomain of the IL-9 receptor engineered to regulate transcription in a ligand-dependent manner. The activity of these switch receptors can be controlled by the presence of an extracellular ligand, allowing for spatial and temporal control of specific gene expression in mammalian cells, enabling use in regulating cellular activity or treating various health conditions, such as diseases.

[0007] In one aspect, provided herein is a recombinant nucleic acid molecule encoding a chimeric receptor that comprises an extracellular portion comprising the binding domain of an endogenous cytokine receptor, an intracellular portion comprising the endodomain of an IL-9 receptor, and a transmembrane domain connecting the extracellular and intracellular portions.

[0008] In some embodiments, the recombinant nucleic acid molecule further comprises one or more linkers.

[0009] In some embodiments, the endogenous cytokine receptor is selected from IL-2rb, IL-2ra, IL-4r, IL-7ra, IL-15ra, and IL-2Ira.

[0010] In some embodiments, the endogenous cytokine receptor comprises an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from SEQ ID NOs:1-6.

[0011] In some embodiments, the transmembrane domain is selected from the transmembrane domains of IL-9, IL-7ra, IL-2rb, and TNFR1. In some embodiments, the transmembrane domain comprises an amino acid sequence selected from SEQ ID NOs: 53-56.

[0012] In some embodiments, the chimeric receptor comprises an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from SEQ ID NOs:63-80.

[0013] Another embodiment provides a recombinant nucleic acid molecule encoding a chimeric receptor comprising an extracellular portion comprising the binding domain of an endogenous inhibitory receptor, an intracellular portion comprising the endodomain of the IL-9 receptor linked to the BOX1 / 2 common gamma chain domain, and a transmembrane domain connecting the extracellular and intracellular portions.

[0014] In some embodiments, the recombinant nucleic acid molecule further comprises one or more linkers.

[0015] In some embodiments, the endogenous inhibitory receptor is selected from TGF-beta R1, TGF-beta R2, IL-10ra, FAS, CTLA4, LAG3, TIM3, PD1, ILT2, ILT3, ILT4, ILT5, and VEGF.

[0016] In some embodiments, the endogenous inhibitory receptor comprises an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from SEQ ID NOs: 7-52.

[0017] In some embodiments, the BOX1 / 2 common gamma chain domain comprises the amino acid sequence of SEQ ID NO:58: ERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET.

[0018] In some embodiments, the transmembrane domain is selected from the transmembrane domains of IL-9, IL-7ra, IL-2rb, and TNFR1.

[0019] In some embodiments, the transmembrane domain is selected from a transmembrane domain comprising an amino acid sequence selected from SEQ ID NOs: 53-56.

[0020] In some embodiments, the chimeric receptor comprises an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from SEQ ID NOs: 81-203.

[0021] In one embodiment, the chimeric receptor comprises the amino acid sequence of SEQ ID NO:113.

[0022] In some embodiments, the recombinant nucleic acid molecule is incorporated into a vector.

[0023] In some embodiments, the recombinant nucleic acid molecule further comprises a signal sequence. In one embodiment, the signal sequence comprises the amino acid sequence MAAPALSWRLPLLILLLPLATSWASA (SEQ ID NO:62).

[0024] In some embodiments, the recombinant nucleic acid molecule further comprises a 2A linker.

[0025] In some embodiments, the recombinant nucleic acid molecule further comprises a nucleic acid sequence encoding a chimeric antigen receptor.

[0026] Another embodiment provides a recombinant nucleic acid molecule encoding a chimeric receptor comprising an extracellular portion comprising the binding domain of an endogenous inhibitory receptor linked to an agent specific for the common gamma chain, an intracellular portion comprising the endodomain of the IL-9 receptor, and a transmembrane domain connecting the extracellular and intracellular portions.

[0027] In some embodiments, the recombinant nucleic acid molecule further comprises one or more linkers.

[0028] In some embodiments, the endogenous inhibitory receptor is selected from TGF-beta R1, TGF-beta R2, IL-10ra, FAS, CTLA4, LAG3, TIM3, PD1, ILT2, ILT3, ILT4, ILT5, and VEGF.

[0029] In some embodiments, the endogenous inhibitory receptor comprises an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from SEQ ID NOs: 7-52.

[0030] In some embodiments, the transmembrane domain is selected from the transmembrane domains of IL-9, IL-7ra, IL-2rb, and TNFR1. In some embodiments, the transmembrane domain comprises an amino acid sequence selected from SEQ ID NOs: 53-56.

[0031] In some embodiments, agents specific for the common gamma chain include nanobodies, DARPins, IL-2, IL-4, IL-7, and scFVs.

[0032] Another aspect pertains to an expression vector comprising a recombinant nucleic acid molecule of the present disclosure.

[0033] Another aspect relates to a recombinant host cell comprising a recombinant nucleic acid construct or expression vector of the present disclosure. In some embodiments, the host cell is a eukaryotic cell. In some embodiments, the host cell is an animal cell. In some embodiments, the host cell is a mammalian cell. In some embodiments, the host cell is an immune cell, a neuron, an epithelial cell, an endothelial cell, or a stem cell. In some embodiments, the recombinant cell is an immune cell or a dendritic cell. In some embodiments, the immune cell is a B cell, a monocyte, a natural killer (NK) cell, a basophil, an eosinophil, a neutrophil, a dendritic cell, a macrophage, a regulatory T cell, a helper T cell (T H ), cytotoxic T cells (T CTL ), or other T cells.

[0034] Another aspect provides a composition of cells comprising a recombinant nucleic acid of the disclosure.

[0035] Another aspect provides a composition of cells comprising an expression vector of the present disclosure.

[0036] Another aspect provides a polypeptide encoded by a recombinant nucleic acid of the disclosure.

[0037] Another aspect provides compositions of one or more polypeptides encoded by one or more recombinant nucleic acids of the disclosure.

[0038] Another aspect provides a composition of cells capable of expressing a chimeric receptor encoded by a recombinant nucleic acid of the present disclosure.

[0039] Another aspect provides a composition of cells comprising a chimeric receptor comprising an amino acid sequence selected from SEQ ID NOs: 63-203.

[0040] Another aspect provides a composition of cells comprising a chimeric receptor comprising an amino acid sequence selected from SEQ ID NOs:81-203.

[0041] Another aspect relates to a method for modulating the activity of an immune cell comprising administering to the immune cell a recombinant nucleic acid of the disclosure.

[0042] In some embodiments, the immune cells are B cells, monocytes, natural killer (NK) cells, basophils, eosinophils, neutrophils, dendritic cells, macrophages, regulatory T cells, helper T cells (T H ), cytotoxic T cells (T CTL ), or other T cells. In some embodiments, the immune cell is a T cell. In some embodiments, the T cell is a CAR-T cell.

[0043] Another aspect relates to a method of treating a subject comprising administering to the subject a chimeric switch receptor expressed by a recombinant nucleic acid of the disclosure, or a cell expressing a recombinant nucleic acid of the disclosure.

[0044] In some embodiments, the subject is treated for cancer.

[0045] In some embodiments, the subject is treated for an autoimmune disease.

[0046] In some embodiments, the subject is treated for an infection.

[0047] The above summary is illustrative only and is not intended to be in any way limiting. In addition to the exemplary embodiments and features described herein, further aspects, embodiments, objects, and features of the present disclosure will become more fully apparent from the drawings, detailed description, and claims. [Brief description of the drawings]

[0048] [Figure 1]FIG. 1 shows pSTAT expression profiles in stimulated or unstimulated primary human T cells transduced with lentiviral vectors encoding the switch receptor of SEQ ID NO:63+CAR+ (IL21RECD+IL9R TM+IL9R ICD, and CAR 4D5), SEQ ID NO:66 (IL15Ra+IL9R TM+IL9R ICD), SEQ ID NO:72+CAR+ (IL4R ECD+IL9R TM+IL9R ICD, and CAR 4D5) or SEQ ID NO:153+CAR+ (IL10Ra ECD+IL9R TM+IL9R ICD, and CAR 4D5).

[0049] [Diagram 2] Figure 2 shows a real-time cytotoxicity assay (RTCA) against HER2-expressing SKOV-3 human ovarian adenocarcinoma cells using T cells co-expressing the switch receptor SEQ ID NO:63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR (4D5). Double positive T cells (SEQ ID NO:63+CAR+) were added to SKOV-3 tumor cells at an effector to target ratio of 1:8 after unstimulated ("No Stim") or pretreated with IL21 for 48 hours before being added to the plate with continued ligand stimulation ("Pretreatment+IL21"). Untransduced T cells (UTD) served as a control and were added to tumor cells with continued IL21 stimulation ("UTD+IL21").

[0050] [Diagram 3] Figure 3 shows a real-time cytotoxicity assay (RTCA) against HER2-expressing SKOV-3 human ovarian adenocarcinoma cells using T cells co-expressing the switch receptor SEQ ID NO: 72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR (4D5). Double-positive T cells (SEQ ID NO: 72+CAR+) were added to SKOV-3 tumor cells at an effector-to-target ratio of 1:8 after unstimulated ("No Stim") or pretreated with IL4 for 48 hours before being added to the plate with continued ligand stimulation ("Pretreatment+IL4"). Untransduced T cells (UTD) served as a control and were added to tumor cells with continued IL4 stimulation ("UTD+IL4").

[0051] [Figure 4] Figure 4 shows a real-time cytotoxicity assay (RTCA) against HER2-expressing KOV-3 human ovarian adenocarcinoma cells using T cells co-expressing the switch receptor SEQ ID NO: 113 (Fas ECD+IL9R TM+IL9R ICD) and CAR (4D5). The double positive T cells (SEQ ID NO: 113+CAR+) were added to SKOV-3 tumor cells at an effector to target ratio of 1:4 after unstimulated ("No Stim") or pretreated with FasL for 48 hours before being added to the plate ("Pre-treated + No Stim"). Untransduced T cells (UTD) served as a control and were added to unstimulated tumor cells ("UTD + No Stim").

[0052] [Diagram 5] Figure 5 shows that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptor SEQ ID NO: 63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR (4D5) and co-cultured with IL-21 (i) before, (ii) during, or (iii) before + during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the fold change relative to unstimulated.

[0053] [Figure 6] Figure 6 shows that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptor SEQ ID NO: 72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR (4D5) and co-cultured with IL-4 (i) before, (ii) during, or (iii) before + during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the fold change relative to unstimulated.

[0054] [Figure 7] Figure 7 shows that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptor SEQ ID NO: 72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR (4D5) and co-cultured with IL-4 (i) before, (ii) during, or (iii) before + during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows EGF concentration in pg / mL.

[0055] [Figure 8] Figures 8A-8B show that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptors SEQ ID NO:63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 8A), and SEQ ID NO:72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 8B), and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before+during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. Graph shows concentration of FGF-2 in pg / mL.

[0056] [Figure 9]Figures 9A-9B show that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptors SEQ ID NO:63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 9A), and SEQ ID NO:72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 9B), and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before+during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the concentration of GM-CSF in pg / mL.

[0057] [Figure 10] Figure 10 shows that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptor SEQ ID NO: 72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR (4D5) and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before + during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the concentration of IFNa2 in pg / mL.

[0058] [Figure 11]Figures 11A-11B show that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptors SEQ ID NO: 63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 11A), and SEQ ID NO: 72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 11B), and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before + during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the concentration of IFNg in pg / mL.

[0059] [Figure 12] Figure 12 shows that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptor SEQ ID NO: 63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR (4D5) and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before + during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the concentration of IL-10 in pg / mL.

[0060] [Figure 13]Figures 13A-13B show that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptors SEQ ID NO:63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 13A), and SEQ ID NO:72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 13B), and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before+during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the concentration of IL-1a in pg / mL.

[0061] [Figure 14] Figure 14 shows that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptor SEQ ID NO: 72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR (4D5) and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before + during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the concentration of IL-2 in pg / mL.

[0062] [Figure 15]Figures 15A-15B show that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptors SEQ ID NO:63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 15A), and SEQ ID NO:72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 15B), and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before+during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the concentration of IL-3 in pg / mL.

[0063] [Figure 16] Figures 16A-16B show that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptors SEQ ID NO:63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 16A), and SEQ ID NO:72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 16B), and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before+during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the concentration of IL-6 in pg / mL.

[0064] [Figure 17]Figures 17A-17B show that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptors SEQ ID NO:63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 17A), and SEQ ID NO:72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 17B), and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before+during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the concentration of IP-10 in pg / mL.

[0065] [Figure 18] Figures 18A-18B show that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptors SEQ ID NO:63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 18A), and SEQ ID NO:72 (IL4R ECD+IL9R TM+IL9R ICD) and CAR(4D5) (Figure 18B), and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before+during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the concentration of MIP-1a in pg / mL.

[0066] [Figure 19]Figure 19 shows that hybrid cytokine receptors induce functional activation of T cells in response to ligand stimulation. T cells were transduced with hybrid cytokine receptor SEQ ID NO: 63 (IL21R ECD+IL9R TM+IL9R ICD) and CAR (4D5) and co-cultured with the respective ligands (i) before, (ii) during, or (iii) before + during co-culture with target cells for 160 hours. Cell culture supernatants were collected and the concentration of effector cytokines was measured by Luminex assay. The graph shows the concentration of RANTES in pg / mL. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] The present disclosure generally relates to chimeric switch receptors that, inter alia, comprise an endodomain of the IL-9 receptor and a binding domain of an endogenous receptor, which are engineered to regulate transcription in a ligand-dependent manner. The activity of these switch receptors can be controlled by the presence of an extracellular ligand, allowing for spatial and temporal control of specific gene expression in mammalian cells, and can also be used to regulate cellular activity, immune system responses, or treat various health conditions, such as disease. In particular, the chimeric switch receptors (referred to as "IL-9 switch receptors"), despite containing the endodomain of the IL-9 receptor, do not require IL-9 for activation and can be tailored to be activated by ligands specific for the binding domain of the endogenous receptor, such as normally inhibitory ligands. This class of chimeric switch receptors is synthetic and recombinant, and does not occur in nature. As explained below, the chimeric switch receptors disclosed herein can be synthetic polypeptides, which can be engineered, designed, or modified to provide desired and / or improved properties, such as regulation of transcription. The disclosure also provides compositions and methods useful for producing such receptors, nucleic acids encoding the receptors, cells genetically modified with the nucleic acids, and methods for modulating the activity of cells, modulating the immune system, and / or treating various diseases.

[0068] The following detailed description is not intended to limit the scope of the exemplary alternatives and claims described in the detailed description. Other alternatives may be used, or other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects generally described herein can be arranged, substituted, combined, and designed in a variety of different configurations, all of which are expressly contemplated and made a part of this application.

[0069] definition The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a cell" includes one or more cells (including mixtures thereof). As used herein, "A and / or B" includes all of the following options: "A," "B," "A or B," and "A and B."

[0070] As used herein, the terms "administration" and "administering" refer to delivering a composition or formulation disclosed herein by a route of administration, including, but not limited to, intravenous, intraarterial, intracranial, intramuscular, intraperitoneal, subcutaneous, intramuscular, or a combination thereof. This term includes, but is not limited to, administration by a medical professional and self-administration.

[0071] "Cancer" refers to the presence of cells that have several characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Cancer cells can be aggregated into masses, such as tumors, or can exist alone in a subject. Tumors can be solid tumors, soft tissue tumors, or metastatic lesions. The term "cancer" as used herein also includes other types of non-tumor cancers. Non-limiting examples include blood cancer or hematological cancer, such as leukemia. Cancer also includes pre-cancerous and malignant cancers.

[0072] The terms "cell," "cell culture," and "cell line" refer not only to a particular subject cell or cell line, but also to the progeny or potential progeny of such a cell, cell culture, or cell line, regardless of the number of transplants or passages in culture. It should be understood that not all progeny are completely identical to the parent cell. This is because certain modifications may arise in subsequent generations due to mutations (e.g., deliberate or accidental mutations) or environmental influences (e.g., methylation or other epigenetic modifications). As a result, the progeny may not actually be identical to the parent cell, but still be within the scope of the term as used herein, so long as the progeny retains the same function as the original cell, cell culture, or cell line.

[0073] As used herein, "endogenous" refers to any material that is derived from or produced within (e.g., naturally occurring or produced in) an organism, cell, tissue, or system.

[0074] The term "percent identity" as used herein in the context of two or more nucleic acids or proteins refers to two or more sequences or subsequences that are the same, or that have a specified percentage of nucleotides or amino acids that are the same (e.g., about 60% sequence identity, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity over a specified region when compared and aligned for maximum matching over a comparison window or specified region) as measured using the BLAST or BLAST 2.0 sequence comparison algorithm with default parameters as described below, or by manual alignment and visual inspection. See, for example, the NCBI website ncbi.nlm.nih.gov / BLAST. Such sequences are said to be "substantially identical". This definition may also refer to or apply to the complement of a sequence. This definition includes sequences that have deletions and / or additions as well as sequences that have substitutions. Sequence identity can be calculated over a region at least about 20 amino acids or nucleotides in length, or over a region 10-100 amino acids or nucleotides in length, or over the entire length of a given sequence. Sequence identity can be calculated using published techniques and widely available computer programs, such as the GCS program package (Devereux et al, Nucleic Acids Res. 12:387, 1984), BLASTP, BLASTN, FASTA (Atschul et al., J Mol Biol 215:403, 1990). Sequence identity can be measured using sequence analysis software, such as the Sequence Analysis Software Package of the Genetics Computer Group at the University of Wisconsin Biotechnology Center (1710 University Avenue, Madison, Wis. 53705), using its default parameters.

[0075] As used herein, a "subject" or "individual" includes animals, such as humans (e.g., human subjects) and non-human animals. In some embodiments, a "subject" or "individual" is a patient of a physician. Thus, a subject may be a human patient, or a subject who has, is at risk of, or is suspected of having a disease (e.g., cancer) and / or one or more symptoms of a disease of interest. A subject may also be a subject who has been diagnosed at or after diagnosis as being at risk for a condition of interest. The term "non-human animal" includes all vertebrates, such as mammals, e.g., rodents, e.g., mice, non-human primates, and other mammals, such as sheep, dogs, cows, chickens, and non-mammals, such as amphibians, reptiles, and the like.

[0076] Where a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, to the nearest tenth of the lower limit, and any other stated or other intervening value in that stated range, is included in the disclosure, unless the context clearly indicates otherwise. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are included within the disclosure, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0077] All ranges disclosed herein include any and all possible subranges and combinations of subranges. Any recited range can be recognized as fully descriptive and allowing for at least equal subdivisions of the range into halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily sub-divided into a lower third, middle third, upper third, etc. As will be understood by one of ordinary skill in the art, all terms such as "up to," "at least," "greater than," "less than," etc. refer to ranges that include the recited numbers and can then be sub-divided into sub-ranges as discussed above. Finally, as will be understood by one of ordinary skill in the art, a range includes each individual member. Thus, for example, a group having 1 to 3 entities refers to a group having 1, 2, or 3 entities. Similarly, a group having 1 to 5 entities refers to a group having 1, 2, 3, 4, or 5 entities.

[0078] It is understood that certain features of the present disclosure that are described for clarity in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure that are described for brevity in the context of a single embodiment can also be provided separately or in any suitable subcombination. All combinations of the embodiments related to the present disclosure are specifically embraced by the present disclosure and are disclosed herein as if each and every combination were individually and expressly disclosed. Furthermore, all subcombinations of the various embodiments and elements thereof are specifically embraced by the present disclosure and are disclosed herein as if each and every such subcombination were individually and expressly disclosed herein.

[0079] IL-9 and common gamma chain receptor Interleukin-9 (IL-9) is a member of a group of cytokines called common gamma chain cytokines. Common gamma chain cytokines exert various functions on immune cell survival, function, and proliferation. The gamma family consists of six members, IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, all of which have unique receptors. Upon receptor binding, gamma cytokines activate various developmental pathways, including STAT1, STAT3, STAT5, MAPK, and PI3K / AKT pathways, via JAK1 and JAK3.

[0080] An important aspect of γc receptor signaling is the positive and negative regulation of pathways to enhance or suppress signaling. Several of the γc cytokines can mediate similar signaling pathways and transcriptional programs (Kovanen PE, Rosenwald A, Fu J, Hurt EM, Lam LT, Giltnane JM, et al. Analysis of Gamma C-Family Cytokine Target Genes. Identification of Dual-Specificity Phosphatase 5 (DUSP5) as a Regulator of Mitogen-Activated Protein Kinase Activity in Interleukin-2 Signaling. J Biol Chem (2003) 278(7):5205-13; Osinalde N, Sanchez-Quiles V, Akimov V, Guerra B, Blagoev B, Krachmarova I. Simultaneous Dissection and Comparison of IL-2 and IL-15 Signaling Pathways by Global Quantitative Phosphoproteomics. Proteomics (2015) 15 (2-3): 520-31), but physiological differences in cytokine signaling are due to competition between different receptors for γc (Gonnord P, Angermann BR, Sadtler K, Gombos E, Chappert P, Meier-Schellersheim M, et al. A Hierarchy of Affinities Between Cytokine Receptors and the Common Gamma Chain Leads to Pathway Cross-Talk. Sci Signal (2018) 11 (524)), variations in receptor expression on T cell subsets, biased signaling through different STAT molecules, and differential activation of MAPK and PI3K pathways (Zeng R, Spolski R, Casas E, Zhu W, Levy DE, Leonard WJ.The Molecular Basis of IL-21-Mediated Proliferation.Blood (2007)109(10):4135-42;Gadina M,Sudarshan C,Visconti R,Zhou YJ,Gu H,Neel BG,et al.The Docking Molecule Gab2 is Induced by Lymphocyte Activation and is Involved in Signaling by Interleukin-2 and Interleukin-15 But Not Other Common Gamma Chain-Using Cytokines.J Biol Chem (2000)275(35):26959-66). .

[0081] IL-9 receptor alpha (IL-9Rα), a member of the type I hematopoietin receptor superfamily, has a high affinity for IL-9 (Kd of approximately 100 pM). This 64 kDa glycoprotein has been reported to be present on a variety of hematopoietic cells, especially T cells. Like other members of the IL-2 receptor family, IL-9Rα also forms a heterotypic receptor complex with the common gamma (γc) chain. In the IL-9R heterocomplex, the IL-9Rα chain is the ligand-binding domain and the γ chain functions as the signaling subunit. The IL-9Rα subunit is characterized by four extracellular cysteines and a conserved WSXWS motif, while the intracellular domain contains a BOX1 consensus sequence and a serine-rich region. IL-9Rα exists in both membrane-bound and soluble forms, whereas the γc subunit is only observed in the membrane-bound form.

[0082] IL-9 binding to IL-9Rα results in the formation of an IL-9R heterocomplex. A characteristic of the IL-9R heterocomplex is the lack of any intracellular enzymatic activity, and therefore Janus kinase (JAK) is required to mediate receptor phosphorylation (Knoops L., Renauld JCIL-9 and its receptor: From signal transduction to tumorigenesis. Growth Factors. 2004;22:207-215). IL-9 binding to the receptor induces a conformational change in the IL-9R heterocomplex that allows JAK molecules to bind to the proline-rich BOX1 motif in the membrane-proximal region of IL-9Rα. JAK1 binds to IL-9Rα, whereas JAK3 binds to yc. Phosphorylated JAK1 and JAK3 mediate phosphorylation of receptor tyrosine residues. The phosphorylated tyrosine residues serve as docking sites for downstream Src homology 2 (SH2) domain containing signaling molecules such as signal transducer and activator of transcription (STAT) transcription factors, insulin receptor substrates (IRS), and adaptors of the mitogen-activated protein kinase (MAPK) pathway.

[0083] Compositions of the Disclosure As described in more detail below, one aspect of the present disclosure relates to a recombinant nucleic acid encoding a chimeric switch receptor comprising an extracellular portion comprising a binding domain of an endogenous cytokine receptor or an endogenous inhibitory receptor, an intracellular portion comprising an endodomain of an IL-9 receptor, and a transmembrane domain connecting the extracellular portion and the intracellular portion. Such receptors are engineered to regulate transcription in a ligand-dependent manner and have various advantages, including the ability to convert an otherwise negative signal into a positive signal in a cell. Thus, the present disclosure also encompasses switch receptors that can switch a negative signal into a positive signal to enhance an immune response. The present disclosure also encompasses receptors that can bind to endogenously or exogenously provided ligands (e.g., cytokines) and result in activation of STAT5, regardless of the cytokine, for example, via the common gamma chain and IL-9 endodomain.

[0084] As described in the Examples, certain recombinant nucleic acids encoding chimeric receptors can be tested and validated in T cells. These chimeric receptors are expected to show similar performance in mouse models and other suitable animal models or in vitro systems. The receptors disclosed herein may be engineered into various immune cell types to enhance tumor recognition and elimination, or engineered in recombinant host cells to control autoimmunity and infectious diseases. Thus, recombinant host cells and cell compositions, such as immune cells, capable of expressing one or more of the chimeric receptors disclosed herein are also within the scope of the present disclosure. In some embodiments, the cell composition expresses a chimeric receptor encoded by a recombinant nucleic acid described herein.

[0085] Switch Receptor The present invention is particularly based on recombinant nucleic acid molecules encoding chimeric receptors that contain the endodomain of the IL-9 receptor, thus creating chimeric receptors that can respond to a variety of extracellular ligands while retaining the ability to initiate intracellular signaling via the endodomain of the IL-9 receptor. Immune cells expressing these chimeric receptors can be useful in the context of regulating the activity of immune cells. In some embodiments, the ligands can be added exogenously and are not limited to being produced in cells.

[0086] As outlined above, some embodiments of the present disclosure relate to recombinant nucleic acid molecules encoding chimeric receptors that include an IL-9 receptor endodomain. In particular, the chimeric receptors, although they include an IL-9 endodomain, do not require binding of IL-9 for the receptor to function. In general, chimeric receptors are composed of an extracellular portion, an intracellular portion that includes the IL-9 receptor endodomain, and a transmembrane domain that connects the extracellular portion and the intracellular portion. In some embodiments, the extracellular portion includes a binding domain of an endogenous cytokine receptor. In some embodiments, the extracellular portion includes a binding domain of an endogenous inhibitory receptor.

[0087] In some embodiments, provided herein are recombinant nucleic acids encoding a chimeric polypeptide comprising: (a) an extracellular portion comprising a binding domain of an endogenous cytokine receptor; (b) an intracellular portion comprising an endodomain of an IL-9 receptor; and (c) a transmembrane domain connecting the extracellular and intracellular portions.

[0088] In some embodiments, provided herein are recombinant nucleic acids encoding a chimeric polypeptide comprising: (a) an extracellular portion comprising a binding domain of an endogenous inhibitory receptor; (b) an intracellular portion comprising an endodomain of the IL-9 receptor linked to the BOX1 / 2 common gamma chain domain; and (c) a transmembrane domain connecting the extracellular and intracellular portions.

[0089] In some embodiments, provided herein are recombinant nucleic acids encoding a chimeric polypeptide comprising: (a) an extracellular portion comprising a binding domain of an endogenous inhibitory receptor linked to an agent specific for the common gamma chain; (b) an intracellular portion comprising an endodomain of an IL-9 receptor; and (c) a transmembrane domain connecting the extracellular and intracellular portions.

[0090] extracellular part As outlined above, the extracellular portion of the chimeric receptor (e.g., switch receptor) in some embodiments of the present disclosure has a binding domain of an endogenous cytokine receptor or an endogenous inhibitory receptor. The binding domain of the endogenous cytokine receptor can be an extracellular portion of the endogenous cytokine receptor, or a fragment or truncation thereof that can bind to a cytokine polypeptide sequence. In some embodiments, the endogenous cytokine receptor is a member of the common gamma chain receptor family. Members of the common gamma chain receptor family are known in the art and discussed above. In some embodiments, the endogenous cytokine receptor is selected from IL-2rb, IL-2ra, IL-4r, IL-7ra, IL-15ra, and IL-21ra. As described above, IL-2rb, IL-2ra, IL-4r, IL-7ra, IL-15ra, and IL-2Ira are all part of the common gamma chain family. Thus, these receptors can recruit the common gamma chain upon ligand binding and can proceed with signal transduction through the IL-9 endodomain.

[0091] In one embodiment, the endogenous cytokine receptor comprises the amino acid sequence of IL-2rb (SEQ ID NO:1): AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWACNLILGAPDSQKLTTVDIVTLRRVLCREGVRWRVMAIQDFKPFENLRLM APISLQVVHVETHRCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDT

[0092] In one embodiment, the endogenous cytokine receptor comprises the amino acid sequence of IL-2ra (SEQ ID NO:2): ELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYMLCTGNSSHSSWDNQCQCTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCREPPP WENEATERIYHFVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGEEKPQASPEGRPESETSCLVTTTDFQIQTEMAATMETSIFTTEYQ

[0093] In one embodiment, the endogenous cytokine receptor comprises the following amino acid sequence of IL-4 (SEQ ID NO:3): MKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRLLYQLVFLLSEAHTCIPENNGGAGCVCHLLMDDVVSADNYTLDLWAGQQLLWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSNPYPPDNYLYNHLTYAVNIWSENDPADFRIYNVTYLEPSLRIAASTLKSGISYRARVRAWAQCYNTTWSEWSPSTKWHNSYREPFEQH

[0094] In one embodiment, the endogenous cytokine receptor comprises the amino acid sequence of IL-7ra (SEQ ID NO:4): ESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDPDVNITNLEFEICGALVEV KCLNFRKLQEIYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSVVYR EGANDFVVTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKLQPAAMYEIKVRSIPDHYFKGFWSEWSPSYYFRTPEINNSSGEMD

[0095] In one embodiment, the endogenous cytokine receptor comprises the amino acid sequence of IL-15ra (SEQ ID NO:5): ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPS LKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGSQLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQPPGVYPQGHSDTT

[0096] In one embodiment, the endogenous cytokine receptor comprises the following amino acid sequence of IL-21ra (SEQ ID NO:6): CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKDEATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESIKPAPPFN VTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSEELKE

[0097] In some embodiments, the extracellular portion of a chimeric polypeptide disclosed herein (e.g., an IL-9 switch receptor) has at least 80% sequence identity, e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% sequence identity, to a sequence selected from the group consisting of SEQ ID NOs: 1-6 in the sequence listing. In some embodiments, the extracellular portion comprises an amino acid sequence having at least 90% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1-6. In some embodiments, the extracellular portion comprises an amino acid sequence having at least 95% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1-6. In some embodiments, the extracellular portion comprises an amino acid sequence having about 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1-6. In some embodiments, the extracellular portion comprises an amino acid sequence having a sequence selected from the group consisting of SEQ ID NOs: 1-6, wherein one, two, three, four, or five of the amino acid residues in any one of SEQ ID NOs: 1-6 are replaced with a different amino acid residue.

[0098] In another aspect of the present invention, the extracellular portion of the chimeric receptor of the present disclosure can also include a binding domain of an endogenous inhibitory receptor. Specifically, as described above, in some embodiments, provided herein is a recombinant nucleic acid encoding a chimeric polypeptide comprising: (a) an extracellular portion comprising a binding domain of an endogenous inhibitory receptor linked to an agent specific for the common gamma chain; (b) an intracellular portion comprising an endodomain of the IL-9 receptor; and (c) a transmembrane domain connecting the extracellular portion and the intracellular portion.

[0099] As described above, the recruitment of common gamma chain is required for signal transduction via IL-9 endodomain. In some embodiments, the binding domain of the extracellular portion of the inhibitory receptor described herein cannot naturally recruit common gamma chain to induce signal transduction via IL-9 endodomain of chimeric receptor. Thus, in these embodiments, the binding domain of the endogenous inhibitory receptor is linked to an agent specific for common gamma chain. The binding domain of the inhibitory receptor is linked to an agent specific for common gamma chain, so that both components can function as intended (e.g., the binding domain can bind to a ligand, and the agent specific for common gamma chain can bind to common gamma chain).

[0100] In some embodiments, the common gamma chain specific agent comprises a nanobody, a DARPin, IL-2, IL-4, IL-7, or an agent specific for common gamma chain including an scFv.

[0101] In some embodiments, an scFv against the common gamma chain is cloned in frame with the extracellular portion of the chimeric receptor, with a suitable linker sequence inserted between these components, and binding of the common gamma chain to the scFv is sufficient to induce dimerization of the chimeric receptor.

[0102] The scFVs against the common gamma chain and their sequences are known in the art and are described in WO2017 / 021540, however the use of the scFVs against the common gamma chain in the context of a switch receptor is not disclosed therein.

[0103] The binding domain of an endogenous inhibitory receptor can be an extracellular portion of an endogenous inhibitory receptor, or a fragment or truncation thereof that can bind to a cytokine polypeptide sequence and subsequently reduce immune activity. For example, a native inhibitory receptor can reduce T cell proliferation, T cell survival, cytokine release, or immune cell lytic activity upon binding of a natural agonist.

[0104] Endogenous inhibitory receptors are known in the art and are contemplated for use in the compositions described herein (Turnis et al., "Inhibitory Receptors as Targets for Cancer Immunotherapy," Eur J Immunol 2015 45(7):1892-1905).

[0105] In some embodiments, the endogenous inhibitory receptor signals via trimerization. In some embodiments, the endogenous inhibitory receptor is a member of the TNF receptor superfamily.

[0106] In some embodiments, the endogenous inhibitory receptor signals as a functional dimer of dimers. In some embodiments, the endogenous inhibitory receptor is a member of the TGF beta superfamily of receptors. Receptors of this family include, for example, type I, type II, and type III receptors. Representative members of the type I receptor family include, but are not limited to, ACVRL1, ACVR1A, BMPR1A, ACVR1B, TGFpR1, BMPR1B, and ACVR1C. Representative members of the type II receptor family include, but are not limited to, TGFBR2, BMPR2, ACVR2A, ACVR2B, and AMHR2. TGF beta R3 is a member of the type III receptor family.

[0107] In some embodiments, the endogenous inhibitory receptor signals as a dimer. In some embodiments, the endogenous inhibitory receptor is a member of the VEGF receptor family. Receptors in this family include, for example, VEGFR1, VEGFR2, and VEGFR3.

[0108] In some embodiments, the endogenous inhibitory receptor is selected from TGF-beta R1, TGF-beta R2, IL-10ra, FAS, CTLA4, LAG3, TIM3, PD1, ILT2, ILT3, ILT4, ILT5, and VEGF. Thus, in some embodiments, the extracellular portion of the chimeric receptor of the present disclosure can be the binding domain of TGF-beta R1, TGF-beta R2, IL-10ra, FAS, CTLA4, LAG3, TIM3, PD1, ILT2, ILT3, ILT4, ILT5, and VEGF.

[0109] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of TGFBR1 (SEQ ID NO:7): LQCFCHLCTKDNFTCVTDGLCFVSVTETTDKVIHNSMCIAEIDLIPRDRPFVCAPSSKTGSVTTTYCCNQDHCNKIELPTTVKSSPGLGPVEL

[0110] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of TGFBR2 (SEQ ID NO:8): TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQE VCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQ

[0111] In one embodiment, the endogenous inhibitory receptor comprises the amino acid sequence of IL-10ra (SEQ ID NO:9): HGTELPSPPSVWFEAEFFHHILHWTPIPNQSESTCYEVALLRYGIESWNSISNCSQTLSYDLTAVTLDLYHSNGYRARVRAVDGSRHSNWTVTNTRFSVDEVTLTVGSVNLEIHNGFILGKIQLPRPKMAPANDTYESIFSHFREYEIAIRKVPGNFTFTHKKVKHENFSLLTSGEVGEFCVQVKPSVASRSNKGMWSKEECISLTRQYFTVTN

[0112] In one embodiment, the endogenous inhibitory receptor comprises the amino acid sequence of FAS (SEQ ID NO: 10): QVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKEEGSRSN

[0113] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of CTLA4 (SEQ ID NO:11): KAMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSD

[0114] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of LAG3 (SEQ ID NO: 12): LQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQR GDFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLRASDWVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDS GPWGCILTYRDGFNVSIMYNLTVLGLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGPDLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLN ATVTLAIITVTPKSFGSPGSLGKLLCEVTPVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPGAQRSGRAPGALPAGHL

[0115] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of TIM3 (SEQ ID NO: 13): SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANELRDSRLANDLRDSGATIRIG

[0116] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of PD1 (SEQ ID NO: 14): FTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITV KVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNER

[0117] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of ILT2 (SEQ ID NO: 15): GHLPKPTLWAEPGSVITQGSPVTLRCQGGQETQEYRLYREKKTALWITRIPQELVKKGQFPIPSITWEHAGRYRCYYGSDTAGRSESSDPLELVVTGAYIKPTLSAQPS PVVNSGGNVILQCDSQVAFDGFSLCKEGEDEHPQCLNSQPHARGSSRAIFSVGPVSPSRRWWYRCYAYDSNSPYEWSLPSDLLELLVLGVSKKPSLSVQPGPIVAPEETL TLQCGSDAGYNRFVLYKDGERDFLQLAGAQPQAGLSQANFTLGPVSRSYGGQYRCYGAHNLSSEWSAPSDPLDILIAGQFYDRVSLSVQPGPTVASGENVTLLCQSQGW MQTFLLTKEGAADDPWRLRSTYQSQKYQAEFPMGPVTSAHAGTYRCYGSQSSKPYLLTHPSDPLELVVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLGV

[0118] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of ILT3 (SEQ ID NO: 16): QAGPLPKPTLWAEPGSVISWGNSVTIWCQGTLEAREYRLDKEESPAPWDRQNPLEPKNKARFSIPSMTEDYAGRYRCYYRSPVGWSQPSDPLELVMTGAYSKPTLSALPSPLVTSGKSV TLLCQSRSPMDTFLLIKERAAHPLLHLRSEHGAQQHQAEFPMSPVTSVHGGTYRCFSSHGFSHYLLSHPSDPLELIVSGSLEDPRPSPTRSVSTAAGPEDQPLMPTGSVPHSGLRRHWE

[0119] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of ILT4 (SEQ ID NO: 17): QTGTIPKPTLWAEPDSVITQGSPVTLSCQGSLEAQEYRLYREKKSASWITRIRPELVKNGQFHIPSITWEHTGRYGCQYYSRARWSELSDPLVLVMTGAYPKPTLSAQPS PVVTSGGRVTLQCESQVAFGGFILCKEGEEEHPQCLNSQPHARGSSRAIFSVGPVSPNRRWSHRCYGYDLNSPYVWSSPSDLLELLVPGVSKKPSLSVQPGPVVAPGESL TLQCVSDVGYDRFVLYKEGERDLRQLPGRQPQAGLSQANFTLGPVSRSYGGQYRCYGAHNLSSECSAPSDPLDILITGQIRGTPFISVQPGPTVASGENVTLLCQSWRQF HTFLLTKAGAADAPLRLRSIHEYPKYQAEFPMSPVTSAHAGTYRCYGSLNSDPYLLSHPSEPLELVVSGPSMGSSPPPTGPISTPAGPEDQPLTPTGSDPQSGLGRHLGV

[0120] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of ILT5 (SEQ ID NO: 18): GPFPKPTLWAEPGSVISWGSPVTIWCQGSQEAQEYRLHKEGSPEPLDRNNPLEPKNKARFSIPSMTEHHAGRYRCHYYSSAGWSEPSDPLEMVMTGAYSKPTLSA LPSPVVASGGNMTLRCGSQKGYHHFVLMKEGEHQLPRTLDSQQLHSRGFQALFPVGPVTPSHRWRFTCYYYYTNTPWVWSHPSDPLEILPSGVSRKPSLLTLQGP VLAPGQSLTLQCGSDVGYNRFVLYKEGERDFLQRPGQQPQAGLSQANFTLGPVSPSNGGQYRCYGAHNLSSEWSAPSDPLNILMAGQIYDTVSLSAQPGPTVASG ENVTLLCQSWWQFDTFLLTKEGAAHPPLRLRSMYGAHKYQAEFPMSPVTSAHAGTYRCYGSYSSNPHLLSHPSEPLELVVSGHSGGSSLPPTGPPSTPGLGRYLE

[0121] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of VEGFR1 (SEQ ID NO: 19): SKLKDPELSLKGTQHIMQAGQTLHLQCRGEAAHKWSLPEMVSKESERLSITKSACGRNGKQFCSTLTLNTAQANHTGFYSCKYLAVPTSKKKETESAIYIFISDTGRPFVEMYSEIPEIIIHMTEGRELVI PCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEA TVNGHLYKTNYLTHRQTNTIIDVQISTPRPVKLLRGHTLVLNCTATTPLNTRVQMTWSYPDEKNKRASVRRRIDQSNSHANIFYSVLTIDKMQNKDKGLYTCRVRSGPSFKSVNTSVHIYDKAFITVKHRKQQVLETVAGKRSYRLSMKVKAFPSPEVVWLKDGLPATEKSARYLTRGYSLII KDVTEEDAGNYTILLSIKQSNVFKNLTATLIVNVKPQIYEKAVSSFPDPALYPLGSRQILTCTAYGIPQPTIKWFWHPCNHNHSEARCDFCSNNEESFILDADSNMGNRIESITQRMAIIEGKNKMASTLVVADSRISGIYICIASNKVGTVGRNISFYITDVPNGFHVNLEKMPTEGEDLKL SCTVNKFLYRDVTWILLRTVNNRTMHYSISKQKMAITKEHSITLNLTIMNVSLQDSGTYACRARNVYTGEEILQKKEITIRDQEAPYLLRNLSDHTVAISSSTTLDCHANGVPEPQITWFKNNHKIQQEPGIILGPGSSTLFIERVTEEDEGVYHCKATNQKGSVESSAYLTVQGTSDKSNLE

[0122] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of VEGFR2 (SEQ ID NO:20): ASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLDWLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVFCEAKIN DESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVLTIMEVSER DTGNYTVILTNPISKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAVSVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVISFHVTRGPEITLQPDMQPTEQESVSLWCTADRST FENLTWYKLGPQPLPIHVGELPTPVCKNLDTLWKLNATMFSNSTNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLTVLERVAPTITGNLENQTTSIGESIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLE

[0123] In one embodiment, the endogenous inhibitory receptor comprises the following amino acid sequence of VEGFR3 (SEQ ID NO:21): YSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWG DQDFLSNPFLVHITGNELYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTHTELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTEVIVHENPFISVEWLKGPILEATAGDELVKLPVKLAAYPPPEFQWYKDGKALSGRHSPHALVLKEVTEASTGTYTL ALWNSAAGLRRNISLELVVNVPPQIHEKEASSPSIYSRHSRQALTCTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQQDLMPQCRDWRAVTTQDAVNPIESLDTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKVGQDERLIYFYVTTIPDGFTIESKPSEELLEGQPVLLSCQADSYKYEH LRWYRLNLSTLHDAHGNPLLLDCKNVHLFATPLAASLEEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRSHDKHCHKKYLSVQALEAPRLTQNLTDLLVNVSDSLEMQCLVAGAHAPSIVWYKDERLLEEKSGVDLADSNQKLSIQRVREEDAGRYLCSVCNAKGCVNSSASVAVEGSEDKGSME

[0124] Many other receptor sequences are contemplated for use in the extracellular portion of the chimeric receptors described herein. Such sequences may be used to switch the natural biology of the receptor ligand or to provide localized stimulation of a cell population. Exemplary sequences of the extracellular portion of such receptors are shown in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3]

[0125] In some embodiments, the extracellular portion of the chimeric polypeptide disclosed herein (e.g., an IL-9 switch receptor) has at least 80% sequence identity, e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% sequence identity, to a sequence selected from the group consisting of SEQ ID NOs: 7-52 in the sequence listing. In some embodiments, the extracellular portion comprises an amino acid sequence having at least 90% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 7-52. In some embodiments, the extracellular portion comprises an amino acid sequence having at least 95% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 7-52. In some embodiments, the extracellular portion comprises an amino acid sequence having about 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 7-52. In some embodiments, the extracellular portion comprises an amino acid sequence having a sequence selected from the group consisting of SEQ ID NOs: 7-52, wherein one, two, three, four, or five of the amino acid residues in any one of SEQ ID NOs: 7-52 are replaced with a different amino acid residue.

[0126] Transmembrane domain (TMD) As outlined above, the chimeric switch receptors of the present disclosure also include a transmembrane domain that connects the extracellular and intracellular portions of the chimeric receptor.

[0127] A transmembrane domain is a region that is generally hydrophobic and crosses the cell membrane. This domain can be arranged to directly or indirectly connect or bind the extracellular portion of the chimeric switch receptor to the intracellular portion of the chimeric switch receptor. This includes, but is not limited to, recombinant fusion, covalent bond, disulfide bond, ionic bond, hydrogen bond, electrostatic bond, etc. The transmembrane domain may be a hydrophobic alpha helix that spans the cell membrane. A transmembrane domain associated with an endodomain is generally used. However, in some embodiments, the transmembrane domain of TNFR1 is used in combination with an extracellular portion from the TNF superfamily (e.g., DCR2, TNFRSF1, etc.) to stabilize the receptor structure.

[0128] The transmembrane domain can be of any length, in some embodiments the transmembrane domain comprises 1 amino acid, or 10 amino acids, or 20 amino acids, or 50 amino acids, or 60 amino acids, or 70 amino acids, or 80 amino acids, or 100 amino acids, or 120 amino acids, or 140 amino acids, or 160 amino acids, or 180 amino acids, or 200 amino acids, or 250 amino acids, or 300 amino acids, or any number therebetween.

[0129] In some embodiments, the transmembrane domain is selected from the transmembrane domains of IL-9, IL-7ra, IL-2rb, and TNFR1. Exemplary amino acid sequences of transmembrane domains for use herein are shown in Table 2. [Table 2]

[0130] In some embodiments, the transmembrane domain comprises the transmembrane domain of IL-9. In some embodiments, the transmembrane domain comprises the amino acid sequence of LIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPR (SEQ ID NO:53).

[0131] In some embodiments, the transmembrane domain comprises the transmembrane domain of TNFR1. In some embodiments, the transmembrane domain comprises the amino acid sequence of VLLPLVIFFGLCLLSLLFIGLMY (SEQ ID NO:56).

[0132] In some embodiments, the transmembrane domain comprises an amino acid sequence that exhibits at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with one or more of SEQ ID NOs: 53-56 in the sequence listing. In some embodiments, the transmembrane domain comprises an amino acid sequence that has at least 90% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 53-56. In some embodiments, the transmembrane domain comprises an amino acid sequence that has at least 95% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 53-56. In some embodiments, the transmembrane domain comprises an amino acid sequence that has about 100% sequence identity with one or more of SEQ ID NOs: 53-56. In some embodiments, the transmembrane domain comprises an amino acid sequence having a sequence selected from the group consisting of SEQ ID NOs: 53-56, in which one, two, three, four, or five of the amino acid residues in any one of SEQ ID NOs: 53-56 are replaced with different amino acid residues.

[0133] End Domain In some embodiments, the endodomain is responsible for receptor clustering / dimerization following antigen binding and initiation of signal transduction into the cell.

[0134] As outlined above, the chimeric receptor of the present disclosure comprises the endodomain of the IL-9 receptor.

[0135] In some embodiments, the amino acid sequence of the IL-9 receptor endodomain is as follows: SEQ ID NO:57: VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYL PQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF

[0136] In another embodiment, amino acid numbers 292 to 521 of IL-9Rα (NCBI REFSEQ:NP_002177.2) can be used.

[0137] Alternatively, truncated fragments of the above endodomains of the IL-9 receptor chain may also be used, for example truncated fragments consisting of up to 250 amino acids, or 50-200 amino acids or 80-150 amino acids of the ILR cytoplasmic domain.

[0138] As mentioned above, one aspect of the present disclosure relates to a recombinant nucleic acid encoding a chimeric receptor comprising (a) an extracellular portion comprising a binding domain of an endogenous inhibitory receptor, (b) an intracellular portion comprising an endodomain of an IL-9 receptor linked to a BOX1 / 2 common gamma chain domain, and (c) a transmembrane domain linking the extracellular portion and the intracellular portion. The extracellular portion comprising a binding domain of an inhibitory receptor is described above and is also useful in the chimeric receptors described below. In this category of chimeric receptors, recruitment of a common gamma chain is required for signaling through the IL-9 endodomain. In some embodiments, the binding domain of the extracellular portion of the chimeric receptor described herein is not naturally capable of recruiting a common gamma chain to induce signaling through the IL-9 endodomain of the chimeric receptor. Thus, in these embodiments, the endodomain of the IL-9 receptor may be linked to a BOX1 / 2 domain. Receptors of the common gamma chain family comprise two regions in the cytoplasmic tail, designated BOX1 and BOX2. These domains are important for the association of JAK with the receptor (see, for example, Murakami M, Narazaki M, Hibi M, Yawata H, Yasukawa K, Hamaguchi M, Taga T, Kishimoto T (1991) Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc Natl Acad Sci USA 88:11349-11353). In general, the Box1 domain contains a proline-rich amino acid residue segment, and the Box2 domain contains a hydrophobic amino acid residue segment.

[0139] In some embodiments, the chimeric receptor comprises a BOX1 / 2 domain of the following amino acid sequence of SEQ ID NO:58: ERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALG EGPGASPCNQHSPYWAPPCYTLKPET

[0140] Linker The nucleic acid encoding the chimeric receptor can further comprise a linker between any of the above portions or domains. As used herein, the term "linker" generally refers to an oligopeptide or polypeptide that functions to link one region of a nucleic acid to another region of a nucleic acid. A spacer or linker can comprise, for example, up to 300 amino acids, 0-100 amino acids, 25-50 amino acids, 10-15 amino acids.

[0141] Linkers useful in the chimeric receptors described herein include those in Table 3 below. [Table 3]

[0142] In some embodiments, the linker is a Gly Ser linker. In some embodiments, the linker comprises the amino acid sequence GGGGSGGGSGGGGS (SEQ ID NO:59).

[0143] In some embodiments, the linker is a Q-Pro linker. In some embodiments, the linker comprises the amino acid sequence QPQPQPQPQPQP (SEQ ID NO: 60).

[0144] In some embodiments, the linker is not present.

[0145] In some embodiments, the linker can be a 2A self-cleaving peptide. 2A peptides are a class of 18-22 amino acid peptides that can cause ribosomal skipping during translation of proteins in cells. In some embodiments, a linker such as a 2A peptide can be included to link a nucleic acid region encoding a chimeric receptor of the present disclosure to another nucleic acid region encoding a chimeric antigen receptor (CAR). In some embodiments, the CAR is an anti-HER2 CAR (4D5).

[0146] Signal sequence The coding sequence of the chimeric receptors disclosed herein can also include a "signal sequence" at the beginning. This sequence encodes a signal peptide at the N-terminus of the mature polypeptide that directs translocation of the polypeptide to a host cell. Translocation signal sequences are found associated with a variety of proteins native to eukaryotes and prokaryotes, and are often functional in both types of organisms.

[0147] An exemplary signal sequence that can be used in the chimeric receptors herein includes the amino acid sequence MAAPALSWRLPLLILLLPLATSWASA (SEQ ID NO:62).

[0148] nucleic acid molecule Provided herein are various nucleic acid molecules that contain nucleotide sequences encoding the chimeric receptors of the present disclosure. In some embodiments, expression cassettes and expression vectors contain these nucleic acid molecules operably linked to heterologous nucleic acid sequences, such as regulatory sequences that allow for in vivo expression of the receptor in a host cell.

[0149] The terms "nucleic acid molecule" and "polynucleotide" are used interchangeably herein and refer to both RNA and DNA molecules, including nucleic acid molecules that include cDNA, genomic DNA, synthetic DNA, and DNA or RNA molecules, including nucleic acid analogs. Nucleic acid molecules can be double-stranded or single-stranded (e.g., sense or antisense strands). Nucleic acid molecules may contain unusual or modified nucleotides. As used herein, the terms "polynucleotide sequence" and "nucleic acid sequence" refer interchangeably to the sequence of a polynucleotide molecule. The nomenclature for nucleotide bases set forth in 37 CFR § 1.822 is used herein.

[0150] Nucleic acid molecules of the present disclosure can be of any length, including, for example, about 1.5 Kb to about 50 Kb, about 5 Kb to about 40 Kb, about 5 Kb to about 30 Kb, about 5 Kb to about 20 Kb, or about 10 Kb to about 50 Kb, e.g., about 15 Kb to 30 Kb, about 20 Kb to about 50 Kb, about 20 Kb to about 40 Kb, about 5 Kb to about 25 Kb, or about 30 Kb to about 50 Kb.

[0151] In some embodiments, provided herein is a nucleic acid molecule comprising a nucleotide sequence encoding a chimeric polypeptide comprising (a) an extracellular portion comprising a binding domain of an endogenous cytokine receptor, (b) a transmembrane domain, and (c) an intracellular portion comprising the endodomain of an IL-9 receptor.

[0152] In one embodiment, the nucleic acid molecule comprises a sequence encoding a chimeric polypeptide comprising (a) a binding domain of IL-21, (b) a transmembrane domain of IL-9, and (c) an endodomain of the IL-9 receptor.

[0153] In one embodiment, the nucleic acid molecule comprises a sequence encoding a chimeric polypeptide comprising (a) a binding domain of IL-4, (b) a transmembrane domain of IL-9, and (c) an endodomain of the IL-9 receptor.

[0154] In one embodiment, the nucleic acid molecule comprises a sequence encoding a chimeric polypeptide comprising (a) the binding domain of IL-15Ra, (b) the transmembrane domain of IL-9, and (c) the endodomain of the IL-9 receptor.

[0155] In one embodiment, the nucleic acid molecule comprises a sequence encoding a chimeric polypeptide comprising (a) the binding domain of IL-10Ra, (b) the transmembrane domain of IL-9, and (c) the endodomain of the IL-9 receptor.

[0156] In some embodiments, provided herein is a nucleic acid molecule comprising a nucleotide sequence encoding a chimeric polypeptide comprising: (a) an extracellular portion comprising a binding domain of an endogenous inhibitory receptor, (b) a transmembrane domain, and (c) an intracellular portion comprising the endodomain of the IL-9 receptor linked to the BOX1 / 2 common gamma chain domain.

[0157] The orientation of the IL-9 receptor endodomain linked to the BOX1 / 2 common gamma chain domain may be varied depending on the desired structure and function. For example, the intracellular portion may comprise, from N-terminal to C-terminal, the IL-9 receptor endodomain, a linker, and the BOX1 / 2 common gamma chain domain. Alternatively, the intracellular portion may comprise, from N-terminal to C-terminal, the BOX1 / 2 common gamma chain domain, a linker, and the IL-9 receptor endodomain.

[0158] In one embodiment, the nucleic acid molecule comprises a sequence encoding a chimeric polypeptide comprising (a) a binding domain of Fas, (b) a transmembrane domain of IL-9, and (c) an endodomain of the IL-9 receptor linked to the BOX1 / 2 common gamma chain domain.

[0159] In some embodiments, provided herein is a nucleic acid molecule comprising a nucleotide sequence encoding a chimeric polypeptide comprising: (a) an extracellular portion comprising a binding domain of an endogenous inhibitory receptor linked to an agent specific for the common gamma chain, (b) a transmembrane domain, and (c) an intracellular portion comprising an endodomain of an IL-9 receptor.

[0160] The orientation of the extracellular portion comprising the binding domain of the endogenous inhibitory receptor linked to the common gamma chain specific agent may be altered depending on the desired structure and function. For example, the extracellular portion may comprise, from the N-terminus to the C-terminus, the binding domain of the endogenous inhibitory receptor, a linker, and the common gamma chain specific agent. Alternatively, the extracellular portion may comprise, from the N-terminus to the C-terminus, the agent specific for the common gamma chain, a linker, and the binding domain of the endogenous inhibitory receptor.

[0161] In some embodiments, the nucleotide sequence is incorporated into an expression cassette or expression vector. An expression cassette will generally be understood to include a construct of genetic material that includes a coding sequence and sufficient control information to direct the correct transcription and / or translation of the coding sequence in a recipient cell in vivo and / or ex vivo. In general, the expression cassette can be inserted into a vector for targeting to a desired host cell and / or subject. Thus, in some embodiments, an expression cassette of the present disclosure includes a coding sequence of a chimeric polypeptide disclosed herein, which is operably linked to any one or combination of expression control elements such as a promoter, and optionally other nucleic acid sequences that affect the transcription or translation of the coding sequence.

[0162] In some embodiments, the nucleotide sequence is incorporated into a cloning vector or an expression vector. Those skilled in the art will appreciate that the term "vector" generally refers to a recombinant polynucleotide construct designed for transmission between host cells and that can be used for the purpose of transformation, e.g., introducing heterologous DNA into a host cell. Thus, in some embodiments, the vector is a replicon, such as a plasmid, phage, or cosmid, into which another DNA segment can be inserted and the inserted segment can be replicated. In some embodiments, the expression vector can be an integrating vector. In some embodiments, the nucleotide sequence is incorporated into a cloning vector.

[0163] As described above in relation to the linker, the nucleic acid sequence encoding the chimeric receptor described herein can also encode a CAR. Each is provided on a separate expression vector, with each nucleic acid sequence operably linked to one or more expression control elements to achieve expression of the CAR and the chimeric receptor in the target cell, and the vectors are co-transfected into the target cell. Alternatively, the nucleic acid sequences encoding the CAR and the chimeric receptor may each be provided on a single vector, with each nucleic acid sequence under the control of one or more expression control elements to achieve expression of the associated nucleic acid sequence. Alternatively, both nucleic acid sequences may be placed under the control of a single promoter with intermediate or downstream control elements facilitating co-expression of the two sequences from the vector.

[0164] In some embodiments, the expression vector may be a viral vector. As will be appreciated by those skilled in the art, the term "viral vector" is used broadly to refer to either a nucleic acid molecule (e.g., a transfer plasmid) that generally contains nucleic acid elements derived from a virus that facilitate the transfer or integration of the nucleic acid molecule into the genome of a cell, or a viral particle that mediates the transfer of nucleic acid. A viral particle generally contains various viral components, and may contain host cell components in addition to the nucleic acid. The term viral vector may refer to either a virus or viral particle that can transfer a nucleic acid to a cell, or the transferred nucleic acid itself. Viral vectors and transfer plasmids contain structural and / or functional genetic elements that are primarily derived from a virus. The term "retroviral vector" refers to a viral vector or plasmid that contains structural and functional genetic elements or portions thereof that are primarily derived from a retrovirus. The term "lentiviral vector" refers to a viral vector or plasmid that contains structural and functional genetic elements or portions thereof, including LTRs, that are primarily derived from the retrovirus genus, lentivirus.

[0165] In some embodiments, provided herein are nucleic acid molecules that encode a polypeptide having an amino acid sequence that has at least about 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a chimeric receptor disclosed herein. In some embodiments, provided herein are nucleic acid molecules that encode a polypeptide having an amino acid sequence that has at least about 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 63-203 identified in the Sequence Listing.

[0166] The nucleic acid sequence encoding the chimeric receptor can be optimized for expression in a host cell of interest. For example, the GC content of the sequence can be adjusted to the average level for a given cell when calculated with reference to known genes expressed in the host cell. Methods of codon usage optimization are known in the art. The codon usage in the coding sequence of the chimeric receptor disclosed herein can be optimized to enhance expression in a host cell, and about 1%, about 5%, about 10%, about 25%, about 50%, about 75%, or up to 100% of the codons in the coding sequence are optimized for expression in a particular host cell.

[0167] Some embodiments disclosed herein relate to vectors or expression cassettes comprising recombinant nucleic acid molecules encoding the chimeric receptors disclosed herein. Expression cassettes generally contain a coding sequence and sufficient regulatory information to direct accurate transcription and / or translation of the coding sequence in a recipient cell in vivo and / or in vitro. The expression cassette may be inserted into a vector for targeting to a desired host cell and / or subject. Expression cassettes can be derived from any source and inserted into plasmids, cosmids, viruses, autonomously replicating polynucleotide molecules, phages as linear or circular single- or double-stranded DNA or RNA polynucleotide molecules capable of genomic integration or autonomous replication and comprising one or more nucleic acid sequences functionally linked, i.e., operably linked, nucleic acid molecules.

[0168] Also provided herein is a vector, plasmid, or virus that includes one or more of the nucleic acid molecules encoding the chimeric receptors disclosed herein. The nucleic acid molecule can be included within a vector that can, for example, direct expression in a cell transformed / transduced with the vector. Vectors suitable for use in eukaryotic and prokaryotic cells are known in the art and are commercially available or readily prepared by one of ordinary skill in the art. For example, Sambrook, J., & Russell, DW (2012). Molecular Cloning: A Laboratory Manual (4th ed.). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory and Sambrook, J., & Russell, DW (2001). Molecular Cloning: A Laboratory Manual (3rd ed.). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory (jointly referred to herein as “Sambrook”);Ausubel,FM(1987).Current Protocols in Molecular Biology.New York,NY:Wiley(including supplements through 2014);Bollag,DMet al.(1996).Protein Methods.New York,NY:Wiley-Liss;Huang,L.et al.(2005).Nonviral Vectors for Gene Therapy.San Diego:Academic Press;Kaplitt,MGet al.(1995).Viral Vectors:Gene Therapy and Neuroscience Applications. San Diego, CA: Academic Press; Lefkovits, I. (1997). The Immunology Methods Manual: The Comprehensive Sourcebook of Techniques. San Diego, CA: Academic Press; Doyle, A. et al.(1998). Cell and Tissue Culture: Laboratory Procedures in Biotechnology. New York, NY: Wiley; Mullis, KB, Ferre, F. & Gibbs, R. (1994). PCR: The Polymerase Chain Reaction. Boston: Birkhauser Publisher; Greenfield, EA (2014). Antibodies: A Laboratory Manual (2nd ed.). New York, NY: Cold Spring Harbor Laboratory Press; Beaucage, SLet al. (2000). Current Protocols in Nucleic Acid Chemistry. New York, NY: Wiley, (including supplements through 2014); and Makrides, SC (2003). Gene Transfer and Expression in Mammalian Cells. Amsterdam, NL: Elsevier Sciences BV, the disclosures of which are incorporated herein by reference.

[0169] DNA vectors can be introduced into eukaryotic cells by conventional transformation or transfection techniques. Suitable methods for transforming or transfecting host cells are described in Sambrook et al. (2012, supra) and other standard molecular biology laboratory manuals, such as calcium phosphate transfection, DEAE-dextran mediated transfection, transfection, microinjection, cationic lipid mediated transfection, electroporation, transduction, scrape loading, ballistic introduction, nucleoporation, hydrodynamic shock, and infection.

[0170] Viral vectors that can be used in the present disclosure include, for example, retroviral vectors, adenoviral vectors, adeno-associated viral vectors, lentiviral vectors, herpes viruses, simian virus 40 (SV40), and bovine papilloma virus vectors (see, for example, Gluzman (Ed.), Eukaryotic Viral Vectors, CSH Laboratory Press, Cold Spring Harbor, NY). For example, the chimeric receptors disclosed herein can be produced in eukaryotic hosts such as mammalian cells (e.g., COS cells, NIH3T3 cells, or HeLa cells). These cells are available from many sources, including the American Type Culture Collection (Manassas, VA). When selecting an expression system, care must be taken to ensure that the components are compatible with each other. Those of skill in the art can select and design an expression system that is suitable and functional in the engineered cells of choice. For further guidance in selecting an expression system, those of skill in the art may refer to P. Jones, "Vectors: Cloning Applications", John Wiley and Sons, New York, NY, 2009.

[0171] The nucleic acid molecules provided may include naturally occurring sequences or sequences that differ from naturally occurring sequences but encode the same polypeptide (e.g., an antibody) due to the degeneracy of the genetic code. These nucleic acid molecules are composed of RNA or DNA (e.g., genomic DNA, cDNA, or synthetic DNA produced by phosphoramidite-based synthesis), or combinations or modifications of nucleotides within these types of nucleic acids. Furthermore, the nucleic acid molecules can be double-stranded or single-stranded (e.g., either the sense or antisense strand).

[0172] Recombinant cells and cell cultures A nucleic acid of the disclosure can be introduced into a host cell, such as a human T lymphocyte, to generate a host cell comprising a recombinant nucleic acid molecule. Accordingly, some embodiments of the disclosure relate to a method for making a host cell comprising: (a) providing a cell capable of protein expression; and (b) contacting the provided cell with a recombinant nucleic acid of the disclosure.

[0173] Introduction of the nucleic acid molecules of the present disclosure into cells can be accomplished by methods known to those of skill in the art, such as, for example, viral infection, transfection, conjugation, protoplast fusion, lipofection, electroporation, nucleofection, calcium phosphate precipitation, polyethyleneimine (PEI)-mediated transfection, DEAE-dextran-mediated transfection, liposome-mediated transfection, particle gun technology, calcium phosphate precipitation, direct microinjection, nanoparticle-mediated nucleic acid delivery, and the like.

[0174] Thus, in some embodiments, the nucleic acid molecule can be delivered by viral or non-viral delivery vehicles known in the art. For example, the nucleic acid molecule can be stably integrated into the host genome, replicated episomally, or present in the recombinant cell as a minicircle expression vector for transient expression. Thus, in some embodiments, the nucleic acid molecule is maintained and replicated in the recombinant cell as an episomal unit. In some embodiments, the nucleic acid molecule is stably integrated into the genome of the recombinant cell. Stable integration can be achieved using classical random genome recombination techniques, or using more precise techniques such as guide RNA-guided CRISPR / Cas9 genome editing, DNA-guided endonuclease genome editing using NgAgo (Natronobacterium gregoryi Argonaute), or TALEN genome editing (transcription activator-like effector nuclease). In some embodiments, the nucleic acid molecule is present in the recombinant cell as a minicircle expression vector for transient expression.

[0175] Nucleic acid molecules can be encapsulated in viral capsids or lipid nanoparticles, or delivered by viral or non-viral delivery means and methods known in the art, such as electroporation. For example, introduction of nucleic acid into cells can be achieved by viral transduction. In a non-limiting example, adeno-associated virus (AAV) is engineered to deliver nucleic acid to target cells by viral transduction. Several AAV serotypes have been described, and all known serotypes are capable of infecting cells of multiple diverse tissue types. AAV can transduce a wide range of species and tissues in vivo without evidence of toxicity, and generates relatively mild innate and adaptive immune responses.

[0176] Lentivirus-derived vector systems are also useful for nucleic acid delivery and gene therapy by viral transduction. Lentivirus vectors offer several attractive properties as gene delivery vehicles, including (i) sustained gene delivery through stable vector integration into the host genome, (ii) ability to infect both dividing and non-dividing cells, (iii) broad tissue tropism, including important gene therapy and cell therapy target cell types, (iv) lack of viral protein expression after vector transduction, (v) ability to deliver complex genetic elements such as polycistronic or intron-containing sequences, (vi) potentially safe integration site profile, and (vii) a relatively simple system for vector manipulation and generation.

[0177] In some embodiments, host cells can be genetically engineered (e.g., transduced, transformed, or transfected) with, for example, a vector construct of the present application, which can be, for example, a viral vector, or a vector for homologous recombination that contains a nucleic acid sequence that is homologous to a portion of the genome of the host cell, or an expression vector for expression of a polypeptide of interest. These cells can be either untransformed cells or cells that have already been transformed with at least one nucleic acid molecule.

[0178] In some embodiments, the recombinant cell is a prokaryotic or eukaryotic cell. In some embodiments, the cell is in vivo. In some embodiments, the cell is ex vivo. In some embodiments, the cell is in vitro. In some embodiments, the recombinant cell is a prokaryotic cell comprising a recombinant nucleic acid disclosed herein. In some embodiments, the recombinant prokaryotic cell comprises a recombinant nucleic acid that is a cloning vector. In some embodiments, the recombinant cell is a eukaryotic cell. In some embodiments, the recombinant cell is an animal cell. In some embodiments, the animal cell is a mammalian cell. In some embodiments, the animal cell is a human cell. In some embodiments, the cell is a non-human primate cell. In some embodiments, the mammalian cell is an immune cell, a neuron, an epithelial cell, and an endothelial cell, or a stem cell. In some embodiments, the recombinant cell is an immune system cell, such as a lymphocyte (e.g., a T cell or a NK cell), or a dendritic cell. In some embodiments, the immune cells are B cells, monocytes, natural killer (NK) cells, basophils, eosinophils, neutrophils, dendritic cells, macrophages, regulatory T cells, helper T cells (TH), cytotoxic T cells (TCTL), or other T cells. In some embodiments, the immune system cells are T lymphocytes.

[0179] In some embodiments, the cell is a stem cell. In some embodiments, the cell is a hematopoietic stem cell. In some embodiments of the cell, the cell is a lymphocyte. In some embodiments, the cell is a precursor T cell or a T regulatory (Treg) cell. In some embodiments, the cell is a CD34+, CD8+, or CD4+ cell. In some embodiments, the cell is a CD8+ T cytotoxic lymphocyte cell selected from the group consisting of naive CD8+ T cells, central memory CD8+ T cells, effector memory CD8+ T cells, and bulk CD8+ T cells. In some embodiments of the cell, the cell is a CD4+ T helper lymphocyte cell selected from the group consisting of naive CD4+ T cells, central memory CD4+ T cells, effector memory CD4+ T cells, and bulk CD4+ T cells. In some embodiments, the cell can be obtained by leukapheresis performed on a sample obtained from a subject. In some embodiments, the subject is a human patient.

[0180] In one embodiment, the cell expressing the recombinant nucleic acid molecule described herein is a T cell modified to surface express a chimeric antigen receptor ("CAR-T" cell). As used herein, a CAR-T cell may be engineered to express the chimeric receptor of the present disclosure. CARs useful for implementing the present disclosure can be prepared according to principles well known in the art. See, for example, U.S. Patent No. 7,741,465Bl, issued June 22, 2010 to Eshhaar et al; Sadelain, et al (2013) Cancer Discovery 3(4):388-398; Jensen and Riddell (2015) Current Opinions in Immunology 33:9-15; Gross, et al. (1989) PNAS (USA) 86(24):10024-10028; Curran, et al. (2012) J Gene Med 14(6):405-15. Examples of commercially available CAR-T cell products that may be modified to incorporate the chimeric receptors of the present disclosure include axicabtagene ciloleucel (marketed as Yescarta®, available from Gilead Pharmaceuticals) and tisagenlecleucel (marketed as Kymriah®, available from Novartis).

[0181] In some embodiments, the recombinant cell further comprises a first and a second nucleic acid molecule disclosed herein, wherein the first and the second nucleic acid molecule do not have the same sequence. In some embodiments, the recombinant cell further comprises a first and a second chimeric polypeptide disclosed herein, wherein the first and the second chimeric polypeptide do not have the same sequence. In some embodiments, the first and the second chimeric polypeptide are CARs. In some embodiments, the first chimeric polypeptide regulates the expression and / or activity of the second chimeric polypeptide.

[0182] In some embodiments, the recombinant cell further comprises an expression cassette or vector encoding a protein of interest operably linked to a promoter, and expression of the protein is regulated by the transcriptional effector of the chimeric receptor. In some embodiments, the protein of interest is heterologous to the recombinant cell. In some embodiments, the heterologous protein is a protein not normally found in the cell, e.g., a protein not normally produced by the cell. In some embodiments, the expression vector encodes a copy of a protein already present in the cell. Exemplary types of proteins suitable for use in the compositions and methods disclosed herein include cytokines, cytotoxins, chemokines, immunomodulators, pro-apoptotic factors, anti-apoptotic factors, hormones, differentiation factors, de-differentiation factors, immune cell receptors, or reporters.

[0183] In another aspect, a composition of cells comprising the expression vector described herein is provided herein. A cell culture comprising at least one host cell and a culture medium disclosed herein is also contemplated. In general, the culture medium can be any suitable culture medium for culturing the cells described herein. Techniques for transforming the above-mentioned wide variety of cells and species are known in the art and described in the technical and scientific literature. Thus, a cell culture comprising at least one recombinant cell disclosed herein is also within the scope of this application. Methods and systems suitable for generating and maintaining cell cultures are known in the art.

[0184] Pharmaceutical Compositions In some embodiments, the nucleic acids, host cells, and / or polypeptides (i.e., chimeric receptors) of the present disclosure can be incorporated into compositions, including pharmaceutical compositions. Such compositions include the recombinant nucleic acids, host cells, and / or polypeptides (i.e., chimeric receptors) disclosed herein. The compositions can also include a pharma- ceutically acceptable excipient, such as a carrier.

[0185] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria or fungi. The carrier can be a solvent or dispersion medium, including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants, such as sodium dodecyl sulfate. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride, are included in the composition. Absorption of the injectable compositions can be prolonged by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0186] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.

[0187] In some embodiments, the chimeric receptors of the present disclosure can also be administered by transfection or infection using methods known in the art, including but not limited to those described in McCaffrey et al. (Nature 418:6893, 2002), Xia et al. (Nature Biotechnol. 20:1006-10, 2002), or Putnam (Am. J. Health Syst. Pharm. 53:151-60, 1996, erratum at Am. J. Health Syst. Pharm. 53:325, 1996).

[0188] As described in more detail below, in some embodiments, the host cells of the present disclosure can be formulated for administration to a subject using techniques known to those of skill in the art. For example, a formulation comprising a population of recombinant cells can include a pharma- ceutically acceptable excipient. The excipients included in the formulation have different purposes depending, for example, on the recombinant cells used and the mode of administration. Examples of commonly used excipients include, but are not limited to, saline, buffered saline, dextrose, water for injection, glycerol, ethanol, and combinations thereof, stabilizers, solubilizers and surfactants, buffers and preservatives, tonicity agents, bulking agents, and lubricants. The formulation comprising recombinant cells can be prepared and cultured in the absence of non-human components, for example, in the absence of animal serum. The formulation can include one recombinant cell population or two or more recombinant cell populations, such as two, three, four, five, six, or more.

[0189] The formulation containing the population of recombinant cells can be administered to a subject using methods and techniques known to those skilled in the art. Exemplary modes include, but are not limited to, intravenous injection. Other modes include, but are not limited to, intratumoral, intradermal, subcutaneous (SC, sq, sub-Q, Hypo), intramuscular (im), intraperitoneal (ip), intraarterial, intramedullary, intracardiac, intraarticular (joint), intrasynovial (joint fluid area), intracranial, intraspinal, and intrathecal (spinal fluid). Such administration can be performed using devices useful for parenteral injection or infusion of the formulation.

[0190] Methods of the Disclosure Methods for modulating cellular activity In one aspect, provided herein is a method for modulating the activity of an immune cell. The method comprises administering to an immune cell a recombinant nucleic acid as described herein. One of skill in the art will understand upon reading this disclosure that the disclosed methods can be performed in vivo, ex vivo, or in vitro.

[0191] Non-limiting exemplary cellular activities that can be modulated using the methods provided herein include, but are not limited to, gene expression, proliferation, apoptosis, non-apoptotic death, differentiation, dedifferentiation, migration, secretion of gene products, cell adhesion, and cytolytic activity.

[0192] In some embodiments, expression of a cellular gene product is modulated.

[0193] In some embodiments, the gene product in the cell is selected from the group consisting of a chemokine, a chemokine receptor, a chimeric antigen receptor, a cytokine, a cytokine receptor, a differentiation factor, a growth factor, a growth factor receptor, a hormone, a metabolic enzyme, a pathogen-derived protein, a proliferation inducer, a receptor, an RNA-guided nuclease, a site-specific nuclease, a T cell receptor (TCR) or a component thereof, a chimeric antigen receptor (CAR), a toxin, a toxin-derived protein, a transcription effector, a transcription activator, a transcription repressor, a translation regulator, a translation activator, a translation repressor, an activating immunoreceptor, an antibody, an apoptosis inhibitor, an apoptosis inducer, an engineered T cell receptor, an immune activator, an immune suppressor, and an inhibitory immune receptor.

[0194] When chemokine or cytokine expression is modulated, in some embodiments, cytokine and chemokine expression is modulated to increase type 1 polarization following ligand stimulation compared to a control. Exemplary cytokines and chemokines that can be modulated include, but are not limited to, FGF2, GMCSF, IFNa, IFNg, IL-10, IL-17, IL-12, IL-2, IL-3, IL-6, IP-10, MIP1a, and RANTES.

[0195] Methods for measuring cytokine and chemokine levels are known in the art. Cytokine and chemokine levels can be measured, for example, by enzyme-linked immunosorbent assay (ELISA), bead-based systems (e.g., Luminex), cytokine bead arrays (Pharmingen), array-based systems (e.g., ProteoPlex from EMD Biosciences).

[0196] In some embodiments, modulating the activity of immune cells can involve altering cell signaling events within the cell. As described herein, the endodomain of the IL-9 receptor signals through JAK1 and JAK3 to activate various developmental pathways, including STAT1, STAT3, STAT5, MAPK, and PI3K / AKT pathways. Activation of STAT family members by ligand-mediated phosphorylation is believed to provide benefits to T cell effector function, polarization, and proliferation. In some embodiments, administration of a recombinant nucleic acid encoding a chimeric switch receptor described herein induces phosphorylation of STAT1, STAT3, and / or STAT5 upon stimulation with a ligand. Methods for measuring the phosphorylation state of one or more proteins are known in the art and include, for example, Western blotting and phospho flow cytometry, as described in the Examples herein.

[0197] Cell death (e.g., apoptotic and non-apoptotic cell death) can also be modulated by the methods described herein. In some embodiments, administration of a recombinant nucleic acid encoding a chimeric switch receptor described herein can increase cell death of a target cell. By way of example, a real-time cytotoxicity assay can be used to analyze whether cells expressing a chimeric switch receptor of the present disclosure exhibit increased cytotoxicity when exposed to a ligand. In some embodiments, cells expressing a chimeric switch receptor of the present disclosure exhibit improved target cell killing when stimulated with a ligand compared to unstimulated controls.

[0198] Treatment method Administration of any of the therapeutic compositions described herein, e.g., chimeric receptors, nucleic acids, host cells, and pharmaceutical compositions, can be used to treat patients with cancer, autoimmune diseases, and related diseases, such as infectious diseases. In some embodiments, the recombinant nucleic acids, host cells, and pharmaceutical compositions described herein can be incorporated into therapeutic agents for use in methods of treating or aiding in the treatment of a subject who has, is suspected of having, or may be at high risk for developing one or more diseases.

[0199] One aspect of the present disclosure relates to a method of treating a subject comprising administering to the subject a cell expressing a chimeric switch receptor of the present disclosure or a recombinant nucleic acid of the present disclosure.

[0200] In one embodiment, the subject is treated for cancer. Cancer can be any unwanted cell proliferation (or any disease manifested by unwanted cell proliferation), neoplasm or tumor, or an increased risk of or predisposition to unwanted cell proliferation, neoplasm, or tumor. Cancer can be benign or malignant, primary or secondary (metastatic). A neoplasm or tumor can be any abnormal growth or proliferation of cells and can be located in any tissue. Exemplary tissues include adrenal gland, adrenal medulla, anus, appendix, bladder, blood, bone, bone marrow, brain, breast, cecum, central nervous system (including or excluding the brain), cerebellum, cervix, colon, duodenum, endometrium, epithelial cells (e.g., renal epithelium), gallbladder, esophagus, glial cells, heart, ileum, jejunum, kidney, lacrimal gland, larynx, liver, lung, lymph, lymph node, lymphoblasts, maxilla, mediastinum, mesentery, myometrium, nasopharynx, omentum, oral cavity, ovary, pancreas, parotid gland, peripheral nervous system, peritoneum, pleura, prostate, salivary gland, sigmoid colon, skin, small intestine, soft tissue, spleen, stomach, testis, thymus, thyroid, tongue, tonsils, trachea, uterus, vulva, and white blood cells.

[0201] The tumor to be treated may be a nervous system tumor or a non-nervous system tumor. Nervous system tumors may occur in either the central nervous system or the peripheral nervous system, for example, glioma, medulloblastoma, meningioma, neurofibroma, ependymoma, schwannoma, neurofibrosarcoma, astrocytoma, and oligodendroglioma. Non-nervous system cancers / tumors may occur from any other non-nervous tissue, examples of which include melanoma, mesothelioma, lymphoma, myeloma, leukemia, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL), hepatocellular carcinoma, epidermoid carcinoma, prostate cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, pancreatic cancer, thymic cancer, NSCLC, blood cancer, and sarcoma. In particular, the treatment of melanoma, kidney cancer (eg, renal cell carcinoma), or bladder cancer is contemplated.

[0202] In some embodiments, the cancer is an EBV or HPV positive cancer.

[0203] In one embodiment, the subject is treated for an autoimmune disease. Exemplary autoimmune diseases include Crohn's disease and multiple sclerosis.

[0204] In one embodiment, the subject is treated for infectious disease. The infectious disease may be any infectious disease or disease, such as bacterial, viral, fungal, or parasitic. In some embodiments, it may be particularly desirable to treat chronic / persistent infectious disease, for example, when the infectious disease is associated with T cell dysfunction or T cell exhaustion. It is well documented that T cell exhaustion is a state of T cell dysfunction that occurs in many chronic infectious diseases (including viral, bacterial, and parasitic) or cancer (Wherry Nature Immunology Vol.12, No.6, p492-499, June 2011).

[0205] Examples of bacterial infections that may be treated include Bacillus spp., Bordetella pertussis, Clostridium spp., Corynebacterium spp., Vibrio chloerae, Staphylococcus spp., Streptococcus spp., Escherichia coli, Klebsiella, Proteus, Yersinia, Erwinia, Salmonella, Listeria spp., Helicobacter pylori, mycobacteria (e.g., Mycobacterium tuberculosis, and Pseudomonas aeruginosa). aeruginosa. For example, the bacterial infection may be sepsis or tuberculosis. Examples of viral infections that may be treated include infections with Epstein-Barr virus, influenza virus, measles virus, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), lymphocytic choriomeningitis virus (LCMV), herpes simplex virus, and human papilloma virus.

[0206] Examples of fungal infections that may be treated include infections caused by Alternaria spp., Aspergillus spp., Candida spp., and Histoplasma spp. The fungal infection may be fungal septicemia or histoplasmosis. Examples of parasitic infections that may be treated include infections caused by Plasmodium spp. (e.g., Plasmodium falciparum, Plasmodium yoeli, Plasmodium ovale, Plasmodium vivax, or Plasmodium chabaudi chabaudi). The parasitic infection may be a disease such as malaria, leishmaniasis, and toxoplasmosis.

[0207] Administration of Recombinant Cells to a Subject In some embodiments, the methods of the present disclosure include administering to a subject in need of such treatment an effective amount or number of recombinant cells. This administering step can be accomplished using any implantation delivery method in the art. For example, the recombinant cells can be injected directly into the subject's bloodstream or can be administered to the subject in other ways.

[0208] In some embodiments, the methods disclosed herein include administering recombinant cells to a subject (this term is used interchangeably with the terms "introducing," "implanting," and "transplanting") by a method or route that results in the introduced cells being at least partially localized to a desired site such that a desired effect occurs. The recombinant cells or their differentiated progeny can be administered by any suitable route that results in delivery to a desired location in a subject, where at least a portion of the administered cells or cellular components remain viable. The survival period of the cells after administration to a subject can be as short as a few hours (e.g., 24 hours) or as long as a few days, years, or even the life of the subject, i.e., long-term engraftment.

[0209] When provided prophylactically, the recombinant cells described herein can be administered to a subject prior to the symptoms of the disease or condition being treated. Thus, in some embodiments, prophylactic administration of the recombinant cell population prevents the onset of symptoms of the disease or condition.

[0210] When provided therapeutically in some embodiments, the recombinant cells are provided at (or after) the onset of a symptom or sign of a disease or condition, e.g., at the onset of a disease or condition.

[0211] For use in the various embodiments described herein, an effective amount of the recombinant cells disclosed herein is at least 10 2 cells, at least 5 x 10 2 cells, at least 10 3 cells, at least 5 x 10 3 cells, at least 10 4 cells, at least 5 x 10 4 cells, at least 10 5 cells, at least 2 x 10 5 cells, at least 3 x 10 5 cells, at least 4 x 10 5 cells, at least 5 x 10 5 cells, at least 6 x 10 5 cells, at least 7 x 10 5 cells, at least 8 x 10 5 cells, at least 9 x 10 5 cells, at least 1 x 10 6 cells, at least 2 x 10 6 cells, at least 3 x 10 6 cells, at least 4 x 10 6 cells, at least 5 x 10 6 cells, at least 6 x 10 6 cells, at least 7 x 10 6 cells, at least 8 x 10 6 cells, at least 9 x 10 6The recombinant cells may be one or more cells, or multiples thereof. The recombinant cells may be obtained from one or more donors, or may be obtained from an autologous source. In some embodiments, the recombinant cells are expanded in culture before being administered to a subject in need thereof.

[0212] In some embodiments, a recombinant cell composition (e.g., a composition comprising a plurality of recombinant cells according to any of the cells described herein) is delivered to a subject by a method or route that results in at least partial localization of the cell composition at a desired site. The recombinant cell-containing composition can be administered by any suitable route that results in an effective treatment for the subject, e.g., administration delivers at least a portion of the delivered composition, e.g., at least 1×10 4 The cells are delivered to the desired site over a period of time. Modes of administration include injection, infusion, and drip. "Injection" includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracerebrospinal, and intrasternal injection and infusion. In some embodiments, the route is intravenous. When delivering cells, delivery by injection or drip is the standard mode of administration.

[0213] In some embodiments, the recombinant cells are administered systemically, e.g., by infusion or injection, e.g., a population of recombinant cells is administered other than directly to a target site, tissue, or organ such that it enters the subject's circulatory system and is affected by metabolic and other similar biological processes.

[0214] The efficacy of a treatment, including any of the compositions provided herein for the treatment of a disease or condition, can be determined by a skilled clinician. However, one of skill in the art will understand that a treatment is considered effective if any one or all of the signs, symptoms, or markers of the disease are improved or alleviated. Efficacy can also be measured by the absence of deterioration of the subject (e.g., the progression of the disease is stopped or at least slowed) as assessed by a reduction in the need for hospitalization or medical intervention. Methods for measuring these indicators are known to those of skill in the art and / or described herein. Treatment includes any treatment of a disease in a subject or animal (some non-limiting examples include humans or mammals), including (1) suppression of the disease, e.g., stopping or slowing the progression of symptoms, or (2) remission of the disease, e.g., causing regression of symptoms, and (3) prevention or reduction in the likelihood of the onset of symptoms.

[0215] In some embodiments of the disclosed methods, the subject is a mammal. In some embodiments, the mammal is a human.

[0216] Additional Therapies As discussed above, the recombinant cells and pharmaceutical compositions described herein can be administered in combination with one or more additional therapeutic agents, such as, for example, chemotherapeutic or anti-cancer agents or anti-cancer therapies. Administration "in combination with" one or more additional therapeutic agents includes simultaneous (concurrent) administration and sequential administration in any order. In some embodiments, the one or more additional therapeutic agents, chemotherapeutic agents, anti-cancer agents, or anti-cancer therapies are selected from the group consisting of chemotherapy, radiation therapy, immunotherapy, hormone therapy, toxin therapy, and surgery. "Chemotherapy" and "anti-cancer agents" are used interchangeably herein. Various classes of anti-cancer agents can be used. Non-limiting examples include alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, podophyllotoxins, antibodies (e.g., monoclonal or polyclonal), tyrosine kinase inhibitors (e.g., imatinib mesylate (Gleevec® or Glivec®)), hormone therapy, soluble receptors, and other anti-neoplastic agents.

[0217] Thus, in some embodiments, the disclosed therapeutic methods further include administering a second therapy to the subject. In general, the second therapy can be any therapy known in the art. Non-limiting examples of suitable therapies for use in combination with the therapeutic compositions disclosed herein include chemotherapy, radiation therapy, immunotherapy, hormone therapy, toxin therapy, and surgery. In some embodiments, the second therapy includes one or more additional therapeutic agents, such as chemotherapeutic agents or anti-cancer agents or anti-cancer therapies. In some embodiments, the first therapy and the second therapy are administered together in the same composition. In some embodiments, the first therapy and the second therapy are administered in separate compositions. In some embodiments, the first therapy and the second therapy are administered simultaneously. In some embodiments, the first therapy and the second therapy are administered sequentially. In some embodiments, the first therapy is administered before the second therapy. In some embodiments, the first therapy is administered after the second therapy. In some embodiments, the first therapy and the second therapy are administered alternately.

[0218] Systems and Kits Also provided herein are kits that include the recombinant nucleic acids, recombinant cells, or pharmaceutical compositions provided and described herein, as well as instructions for making and using the same. For example, in some embodiments, provided herein are kits that include one or more of the following: (i) a recombinant nucleic acid described herein, (ii) a recombinant cell described herein, and (iii) a pharmaceutical composition described herein. In some embodiments, the systems and / or kits of the present disclosure further include one or more syringes (including pre-filled syringes) and / or catheters (including pre-filled syringes) that are used to administer any one of the provided recombinant nucleic acids, recombinant cells, or pharmaceutical compositions to a subject. In some embodiments, the kits can include one or more additional therapeutic agents that can be administered simultaneously or sequentially with other kit components for a desired purpose, for example, to modulate the activity of cells, inhibit target cancer cells, or treat a disease in a subject in need of treatment.

[0219] Any of the above systems and kits may further comprise one or more additional reagents, which may be selected from a dilution buffer, a reconstitution solution, a wash buffer, a control reagent, a control expression vector, a negative control polypeptide, a positive control polypeptide, and a reagent for in vitro production of the chimeric receptor polypeptide.

[0220] In some embodiments, the system or kit may further include instructions for carrying out the method using the components of the kit. The instructions for carrying out the method are typically recorded on a suitable recording medium. For example, the instructions can be printed on a substrate such as paper or plastic. The instructions can be present in the kit as a package insert, on a label on the container of the kit or its components (i.e., associated with the package or subpackage), etc. The instructions can be present as an electronic storage data file present on a suitable computer-readable storage medium, such as a CD-ROM, diskette, flash drive, etc. In some cases, the actual instructions are not present in the kit, but a means is provided for obtaining the instructions from a remote source (e.g., via the Internet). An example of this embodiment is a kit that includes a web address where the instructions can be viewed and / or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions can be recorded on a suitable substrate.

[0221] No admission is made that any reference cited herein constitutes prior art. The discussion of references states what their authors assert, and the inventors reserve the right to challenge the accuracy and pertinence of the cited documents. Although many sources of information, including scientific journal articles, patent documents, and textbooks, are referenced herein, this reference is expressly not an admission that any of these documents constitute part of the common general knowledge in the art.

[0222] The general method descriptions provided herein are intended for illustrative purposes only: other alternative methods and alternatives will be apparent to those of skill in the art upon review of this disclosure, and are within the spirit and scope of this application.

[0223] Throughout this specification, various patents, patent applications, and other types of conventional materials (such as journal articles, electronic database entries, etc.) are referenced. The disclosures of all patents, patent applications, and other publications cited herein are incorporated by reference in their entireties to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. EXAMPLES

[0224] The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of molecular biology, microbiology, cell biology, biochemistry, nucleic acid chemistry, and immunology that are well known to those skilled in the art and are described in detail in the above references.

[0225] Additional embodiments are disclosed in further detail in the following examples, which are provided for illustrative purposes and are not intended to limit the scope of the disclosure or claims in any way.

[0226] Example 1 Cloning of chimeric receptors. DNA encoding the binding domains of IL-2rb, IL-2ra, IL-4r, IL-7ra, IL-15ra, IL-21ra, TGF-beta R1, TGF-beta R2, IL-10ra, FAS, CTLA4, LAG3, TIM3, PD1, ILT2, ILT3, ILT4, ILT5, VEGF, the transmembrane domains of IL-9, IL-7ra, and IL-2rb, the endodomain of the IL-9 receptor, the BOX1 / 2 common gamma chain domain, and common gamma chain specific agents are cloned in various configurations into mammalian expression vectors driven by the CMV or elongation factor (EF)-1 promoter. The vectors contain a mammalian selection cassette.

[0227] Similarly, DNA encoding the binding domains of IL-2rb, IL-2ra, IL-4r, IL-7ra, IL-15ra, IL-21ra, TGF-beta R1, TGF-beta R2, IL-10ra, FAS, CTLA4, LAG3, TIM3, PD1, ILT2, ILT3, ILT4, ILT5, VEGF, the transmembrane domains of IL-9, IL-7ra, and IL-2rb, the endodomain of the IL-9 receptor, the BOX1 / 2 common gamma chain domain, and agents specific for the common gamma chain have been cloned into lentiviral vectors in various configurations.

[0228] Example 2 Expression of lentivirus. Lentiviruses were generated as previously described in [Tiscornia G. et al. Nature Protocols 27 June 2006; doi:10.1038 / nprot.2006.37].

[0229] Example 3 Assessment of surface expression of chimeric receptors. Mammalian expression constructs encoding the chimeric receptors are transfected into 293 cells using methods well known in the art, such as Lipofection 2000 (Invitrogen) or electroporation. After 24-48 hours, cell surface expression is assessed by flow cytometry using fluorescently labeled antibodies specific for the ectodomain chimeric receptors. One example is a FITC-labeled anti-IL4R antibody against 293 cells transduced with construct 73.

[0230] Alternatively, Jurkat T cells are transduced with purified lentivirus expressing the chimeric receptor of interest at an MOI of 20. After 24-48 h, cell surface expression is assessed by flow cytometry using a fluorescently labeled antibody specific for the ectodomain chimeric receptor.

[0231] Example 4 Ligand stimulation and STAT5 activation. To analyze the ability of ligands to bind to the chimeric receptors and induce STAT5 activation, transfected 293 cells and virally transduced Jurkat T cells are stimulated with individual ligands. Briefly, after stimulation with ligands at various time points, cells are lysed and proteins are collected. The phosphorylation status of STAT5 is analyzed by Western blot using a phosphor-STAT5 specific antibody and assessed relative to a negative control containing an empty vector. The STAT5 phosphorylation status of ligand-activated cells relative to an empty vector control is also assessed by flow cytometry as described above (http: / / rhlccflow.facilities.northwestern.edu / files / 2011 / 09 / intracellular-phospho-protein-staining.pdf).

[0232] Example 5 STAT5 reporter assay. STAT5 reporter assay for activated JAK1-3 induced activity is performed in 293 cells. Cells are seeded in 48-well plates. The next day, cells are transfected by Lipofectamine 2000 (Invitrogen) with STAT5-luciferase vector and internal control plasmid along with other plasmids expressing genes of interest. After 24 hours, cells are stimulated with appropriate ligands at various time points, then lysed and internal control fluorescence and luciferase luminescence measurements are performed using a plate reader. Reporter gene activity is shown after normalization to the internal control readings.

[0233] Example 6 Ligand stimulation and cytokine expression. Jurkat T cells are transduced with purified lentivirus expressing the chimeric receptor of interest. After 24-48 h, cells are stimulated with the appropriate ligand at various time points: 0, 15, 30, 45, and 60 min. Cells are then collected to analyze the expression of IFNγ, IL-4, IL-5, IP-10, IL-2, MIP1α, MIP1β, and TNFα using intracellular flow cytometry. Culture supernatants are collected and analyzed by Luminex analysis for the expression of 30 cytokines and chemokines (Thermo Fisher) (https: / / www.thermofisher.com / order / catalog / product / LHC6003M# / LHC6003M).

[0234] Example 7 Cytotoxicity assay. The ability of the recombinant nucleic acid described herein to stimulate CTL cytotoxicity can be measured by methods known to those skilled in the art. The cytotoxicity of T cells against a given target cell can be examined using any of the methods reviewed in, for example, Zaritskaya et al. Expert Rev Vaccines (2011), 9(6):601-616 (incorporated herein by reference in its entirety). In addition, the ability of chimeric cytokine receptors to enhance the cell killing of GPC3CAR is evaluated by measuring the cell killing of cell line targets in real time by electrical impedance as described in (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC5834184 / ). GPC3 CAR (scFv-41BB-CD3ζ) expressing lentivirus is purchased from Creative Biolabs (CAR-MO158-YC) and used to transduce T cells. Briefly, T cells are isolated from the PBMC fraction of peripheral blood by negative selection. Prior to lentiviral transduction, cells are stimulated with TransAct (Miltenyi) in the presence of IL-2 for 72 hours. Cells are cultured for 48 hours and cells expressing the CAR are sorted by FACS. The CAR-positive fraction is then transduced with the chimeric cytokine receptor construct. 48 hours after transduction, cell surface expression of the chimeric cytokine receptor is assessed by flow cytometry. Cells are stimulated with the appropriate ligand for another 48 hours, washed and cultured with HEPG2 target cells on XCellegence plates (https: / / www.agilent.com / en / product / cell-analysis / real-time-cell-analysis / rtca-analyzers / xcelligence-rtca-mp-multiple-plates-741230). Transduced T cells and target cells are co-cultured for 96 hours. Target killing is measured in real time according to the manufacturer's protocol.

[0235] Example 8 Materials and Methods for Examples 9-12 Cloning of chimeric receptors. DNA encoding the binding domains of various endogenous cytokine and inhibitory receptors, the transmembrane domains of IL-9 or TNFR1, the endodomain of the IL-9 receptor, and / or the BOX1 / 2 common gamma chain domain were cloned in various configurations into pTRPE backbone lentiviral transfer plasmids. Some receptors were co-expressed with an anti-HER2 CAR (4D5) via a 2A linker sequence. The 4D5 amino acid sequence is as follows: MDFQVQIFSFLLISASVIMSRGDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGT KVEIKRTGSTSGSGKPGSGEGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDG FYAMDVWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR* (SEQ ID NO: 204)

[0236] Similarly, DNA encoding the binding domains of IL-21R, IL-15ra, IL-4ra, IL-10ra, IL-7ra, TWEAKR, CTLA4, TIM3, LAG3, PD1, DCR1, CD40, Fas, Dr4, TNFRSF1B, TGFBR2, TIGIT, and 2B4, the transmembrane domains of IL-9 and TNFR1, the endodomain of the IL-9 receptor, and the BOX1 / 2 consensus gamma chain domain were cloned into lentiviral vectors in various configurations.

[0237] Evaluation of surface expression of the chimeric receptor. Lentiviral transfer plasmids encoding the chimeric receptors were transfected into 293 cells using Lipofectamine 3000 and 500 ng of lentiviral expression plasmid. After 24 hours, cell surface expression was assessed by flow cytometry using a fluorescently labeled antibody specific for the ectodomain of the chimeric receptor. Expression of the chimeric receptor on primary human T cells was measured by transducing them with a dilution series of lentiviral supernatants and analyzed by flow cytometry after 72 hours.

[0238] Lentivirus. Lentivirus for transduction of primary human CD3+ T cells was produced in 293T cells by lipofection of transfer and packaging plasmids (Lipofectamine 3000, ThermoFisher Scientific) and purified by ultracentrifugation. T cells activated with human CD3 / CD28 Dynabeads (3:1 bead to cell ratio) in the presence of recombinant IL-7 and IL-15 were infected with lentivirus 1 day after activation, beads were removed on day 3, and expanded until day 5.

[0239] Flow cytometry. Flow cytometric detection of chimeric cytokine receptors and chimeric antigen receptors was performed by incubating lentivirally transduced primary human T cells with receptor-specific antibodies for 20 min at room temperature in the dark, followed by acquisition of at least 10,000 events on a FACSymphony A3 flow cytometer (BD Biosciences). Data were analyzed using FlowJo software (BD Biosciences). Transiently transfected 293T cells were treated similarly for detection of chimeric cytokine receptors and chimeric antigen receptors 24 h after lipofection (Lipofectamine 3000, Thermo Fisher Scientific) of 500 ng of lentiviral expression plasmids.

[0240] pSTAT detection. In phosphorylation flow experiments, transduced human T cells were stimulated by adding ligand for 30 min at 37°C and the reaction was stopped by fixing with 1.5% paraformaldehyde (PFA) for 15 min at room temperature with agitation. Cells were washed and permeabilized with ice-cold 100% methanol for 60 min on ice or stored at -80°C overnight. Cells were washed with FACS buffer and then stained with pSTAT antibody (Thermo Fisher Scientific) for 1 h at 4°C in the dark. Cells were washed and analyzed on a FACSymphony A3 flow cytometer. Data represent mean fluorescence intensity (MFI).

[0241] xCELLigence Real-Time Cell Analysis. Tumor cell killing was assessed using the xCELLigence Real-Time Cell Analysis (RTCA) Analyzer (Agilent). SKOV-3 human ovarian adenocarcinoma tumor cells were seeded at 10,000 cells per well on 96-well xCELLigence E-Plates. After 24 hours, transduced T cells that had been preincubated with ligands for the switch receptor for 48 hours or not were added in triplicate at various effector-to-target ratios with or without continued ligand stimulation. At the end of the assay, supernatants were harvested from each experimental well of the E-Plate, centrifuged to remove debris, and immediately frozen at -80°C.

[0242] Cytokine multiplex analysis. Samples were analyzed for cytokines and chemokines using the Multiplex Cytokine Assay Kit (Millipore) according to the manufacturer's protocol. Briefly, samples were diluted 1:2.5 in assay dilution buffer and loaded into Millipor multiscreen BV 96-well filter plates. Serial dilutions of cytokine standards were prepared in parallel and added to the plates. Multiplex 42-Plex cytokine beads were vortexed for 30 seconds and 25 μl was added to each well along with the culture supernatant. Samples were then incubated at 600 rpm for 2 hours at room temperature in the dark on a plate shaker. Plates were attached to a Millipore multiscreen vacuum manifold, washed twice with 50 μl of assay buffer (PBS, pH 7.4, 1% BSA, 0.05% Tween 20, 0.05% sodium azide) and each well was resuspended in 75 μl of assay buffer. 25 μl of biotinylated anti-human multicytokine reporter was added to each well. Plates were incubated at 600 rpm on a plate shaker in the dark for 1.5 hours at room temperature. Streptavidin phycoerythrin was diluted 1:12.5 in assay buffer and then 25 μl was added directly to each well. Plates were incubated at 600 rpm on a plate shaker in the dark for 30 minutes at room temperature. 25 μl of stop solution (0.2% (v / v) formaldehyde in PBS, pH 7.4) was added to each well and incubated at room temperature for 5 minutes. Plates were then attached to a vacuum manifold and each well was resuspended in 125 μL of assay buffer and shaken for 1 minute. Assay plates were transferred to a Bio-Plex Luminex 200XYP instrument for analysis. Cytokine concentrations were calculated using Bio-Plex Manager 6.2 software with a five-parameter curve-fitting algorithm applied to calculate the standard curve.

[0243] Example 9 The chimeric switch receptor is expressed on the cell surface To analyze whether the chimeric switch receptor can be correctly folded and expressed on the cell surface, 293T cells were transiently transfected with lentiviral transfer plasmids encoding the chimeric switch receptor. After 24 hours, cell surface expression was evaluated by flow cytometry. The expression levels of the various constructs are shown in Table 4 below. [Table 4]

[0244] As shown by the data in Table 4, all constructs showed some degree of cell surface expression in 293T cells. These results indicate that the constructs produced correctly folded proteins capable of endocytic trafficking and resistant to general proteolysis.

[0245] Constructs that showed cell surface expression in 293T cells were then packaged into lentivirus and titered in human primary T cells. Expression analysis of transduced primary human T cells is shown in Table 5 below. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6]

[0246] As shown in Table 5 above, lentiviruses were successfully generated for all constructs, and transduced primary human T cells showed at least some cell surface expression. Despite their general resistance to viral transduction and susceptibility to the unfolded protein response (UPR) [Lopez-Soto et al., “Cancer-induced Endoplasmic Reticulum Stress in T Cells Subverts Immunosurveillance,” Cell Metabolism 28(6):803-805(2018); Li et al., “The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities,” Front.Immunol.Volum 10,Article 3154], the constructs produced correctly folded proteins capable of endocytic trafficking and resistant to general proteolysis in primary T cells.

[0247] Example 10 Expression of chimeric switch receptors leads to phosphorylation of STAT receptors Several constructs were then tested for their ability to induce phosphorylation of STAT1, STAT3, and / or STAT5. Briefly, primary human T cells were transduced with lentiviral vectors encoding switch receptors SEQ ID NO:63+CAR+(IL21R ECD+IL9R TM+IL9R ICD and CAR 4D5), SEQ ID NO:66 (IL 15Ra+IL9R TM+IL9R ICD), SEQ ID NO:72+CAR+(IL4R ECD+IL9R TM+IL9R ICD and CAR 4D5), or SEQ ID NO:153+CAR+(IL10Ra ECD+IL9R TM+IL9R ICD and CAR 4D5). Cells transduced with SEQ ID NO:63+CAR+ were either unstimulated or stimulated with 200 ng / mL IL-21 for 30 minutes. Cells transduced with SEQ ID NO:66 were either unstimulated or stimulated with 200 ng / mL IL-15 for 30 minutes. Cells transduced with SEQ ID NO:72+CAR+ were either unstimulated or stimulated with 200 ng / mL IL-4 for 30 minutes. Cells transduced with SEQ ID NO:153+CAR+ were either unstimulated or stimulated with 200 ng / mL IL-4 for 30 minutes. The fold increase in gMFI of stimulated vs. unstimulated ligand was calculated and is shown in Figure 1.

[0248] As shown in Figure 1, all constructs induced phosphorylation of STAT1, STAT3, and STAT5 upon ligand stimulation. Activation of STAT family members by ligand-mediated phosphorylation is believed to confer advantages in T cell effector function, polarization, and proliferation.

[0249] Example 11 Primary T cells expressing chimeric switched receptors exhibit enhanced tumor cell killing A real-time cytotoxicity assay was then used to analyze whether cells expressing the chimeric switch receptors of the present disclosure exhibited increased cytotoxicity when exposed to ligand. As shown in Figures 2-4, upon ligand stimulation, cells expressing either SEQ ID NO:63+CAR+(IL21R ECD+IL9R TM+IL9R ICD and CAR 4D5) (Figure 2), SEQ ID NO:72+CAR+(IL4R ECD+IL9R TM+IL9R ICD and CAR 4D5) (Figure 3), or SEQ ID NO:113+CAR+(Fas ECD+IL9R TM+IL9R ICD and CAR 4D5) (Figure 4) exhibited increased killing of HER2-expressing SKOV-3 human ovarian adenocarcinoma cells when pretreated with ligand compared to untransduced stimulated cells. Consistent with the observed activation of STAT transcription factors following ligand stimulation, T cells transduced with the hybrid IL9R receptor exhibited improved killing over unstimulated controls. It should be noted that in the case of SEQ ID NO: 113, the presence of the natural ligand (TNFSF6) increases background killing in the assay, although addition of exogenous ligand enhances T cell killing over controls.

[0250] Example 12 Primary T cells expressing chimeric switch receptors exhibit increased cytokine and chemokine activity Culture supernatants of primary human T cells transduced with either SEQ ID NO:63+CAR+(IL21R ECD+IL9R TM+IL9R ICD and CAR 4D5) (FIG. 5) or SEQ ID NO:72+CAR+(IL4R ECD+IL9R TM+IL9R ICD and CAR 4D5) (FIG. 6) were then analyzed for the presence of cytokines and chemokines. Supernatants were taken from cells stimulated with ligand prior to the real-time cytotoxicity assay of Example 11 (first bar, "before"), cells stimulated with ligand during the real-time cytotoxicity assay of Example 11 (second bar, "after"), or cells stimulated at both time points in the real-time cytotoxicity assay of Example 11 (third bar, "both"). The percent increase relative to no stimulation was calculated and is shown in FIGS. 5 and 6. As shown in Figures 5 and 6, several cytokines and chemokines such as IFNg, FGF2, GMCSF, IL-3, IL-6, IP10, MIP1a, and RANTES showed increased production. The quantity and quality of cytokines produced after ligand stimulation (either "pre", "post", or "both") indicates a significant enhancement of T cell responses due to hybrid IL9R engagement. Furthermore, the pattern of cytokine responses indicates increased type 1 polarization after ligand stimulation compared to the control group.

[0251] Figures 7-19 show results from the same experiment, but data are presented as cytokine or chemokine concentration (pg.mL) for each experimental condition described above. Similarly, the quantity and quality of cytokines produced after ligand stimulation (either "before", "after", or "both") indicates a large enhancement of T cell responses due to hybrid IL9R engagement, and the pattern of cytokine responses indicates increased type 1 polarization after ligand stimulation compared to control groups.

[0252] Unofficial sequence listing SEQ ID NO:63 IL21r / IL9R CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKDEATSCSLHRSAHNATHATY TCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWR SDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDSSYELQ VRAGMPGSSYQGTWSEWSDPVIFQTQSEELKELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEE QEGPGTRLPGNLSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF SEQ ID NO:64 IL21r / IL9R / IL7RaTM CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKDEATSCSLHRSAHNATHATY TCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWR SDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDSSYELQ VRAGMPGSSYQGTWSEWSDPVIFQTQSEELKEPILLTISILSFFSVALLVILACVLWVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGP GTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF SEQ ID NO:65 IL21r / IL9R / IL2RbTM CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKDEATSCSLHRSAHNATHATY TCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWR SDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDSSYELQ VRAGMPGSSYQGTWSEWSDPVIFQTQSEELKE IPWLGHLLVGLSGAFGFIILVYLLI VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYL PQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF SEQ ID NO:66 IL15r-alpha / IL9R ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPS LKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGS QLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQPPGVYPQGHSDTTLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 67 IL15r-alpha / IL9R / IL7RaTM ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPS LKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGS QLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQPPGVYPQGHSDTTPILLTISILSFFSVALLVILACVLW VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 68 IL15r-alpha / IL9R / IL2RbTM ITCPPPMSVEHADIWVKSYSLYSRERYICNSGFKRKAGTSSLTECVLNKATNVAHWTTPS LKCIRDPALVHQRPAPPSTVTTAGVTPQPESLSPSGKEPAASSPSSNNTAATTAAIVPGS QLMPSKSPSTGTTEISSHESSHGTPSQTTAKNWELTASASHQPPGVYPQGHSDTT IPWLGHLLVGLSGAFGFIILVYLLI VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 69 IL7r-alpha / IL9R ESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDPDVNITNLEFEICGALVEV KCLNFRKLQEIYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSVVYR EGANDFVVTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKLQPAAM YEIKVRSIPDHYFKGFWSEWSPSYYFRTPEINNSSGEMDLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 70 IL7r-alpha / IL9R / IL7RaTM ESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDPDVNITNLEFEICGALVEV KCLNFRKLQEIYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSVVYR EGANDFVVTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKLQPAAM YEIKVRSIPDHYFKGFWSEWSPSYYFRTPEINNSSGEMD PILLTISILSFFSVALLVILACVLW VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 71 IL7r-alpha / IL9R / IL2RbTM ESGYAQNGDLEDAELDDYSFSCYSQLEVNGSQHSLTCAFEDPDVNITNLEFEICGALVEV KCLNFRKLQEIYFIETKKFLLIGKSNICVKVGEKSLTCKKIDLTTIVKPEAPFDLSVVYR EGANDFVVTFNTSHLQKKYVKVLMHDVAYRQEKDENKWTHVNLSSTKLTLLQRKLQPAAM YEIKVRSIPDHYFKGFWSEWSPSYYFRTPEINNSSGEMD IPWLGHLLVGLSGAFGFIILVYLLI VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 72 IL4r-alpha / IL9R MKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRLLYQLVFLLSEAHTCIPENNGGAGCV CHLLMDDVVSADNYTLDLWAGQQLLWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSN PYPPDNYLYNHLTYAVNIWSENDPADFRIYNVTYLEPSLRIAASTLKSGISYRARVRAWA QCYNTTWSEWSPSTKWHNSYREPFEQHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 73 IL4r-alpha / IL9R / IL7RaTM MKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRLLYQLVFLLSEAHTCIPENNGGAGCV CHLLMDDVVSADNYTLDLWAGQQLLWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSN PYPPDNYLYNHLTYAVNIWSENDPADFRIYNVTYLEPSLRIAASTLKSGISYRARVRAWA QCYNTTWSEWSPSTKWHNSYREPFEQH PILLTISILSFFSVALLVILACVLW VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 74 IL4r-alpha / IL9R / IL2RbTM MKVLQEPTCVSDYMSISTCEWKMNGPTNCSTELRLLYQLVFLLSEAHTCIPENNGGAGCV CHLLMDDVVSADNYTLDLWAGQQLLWKGSFKPSEHVKPRAPGNLTVHTNVSDTLLLTWSN PYPPDNYLYNHLTYAVNIWSENDPADFRIYNVTYLEPSLRIAASTLKSGISYRARVRAWA QCYNTTWSEWSPSTKWHNSYREPFEQH IPWLGHLLVGLSGAFGFIILVYLLI VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 75 IL2r-beta Ectodomain / IL9R AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWAC NLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAPISLQVVHVETH RCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEF QVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDTLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 76 IL2r-beta Ectodomain / IL9R / IL7RaTM AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWAC NLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAPISLQVVHVETH RCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEF QVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDT PILLTISILSFFSVALLVILACVLW VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 77 IL2r-beta Ectodomain / IL9R / IL2RbTM AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWAC NLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAPISLQVVHVETH RCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEF QVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDT IPWLGHLLVGLSGAFGFIILVYLLI VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF Sequence number 78 IL2r-alpha Ectodomain / IL9R ELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYMLCTGNSSHSSWDNQCQ CTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCREPPPWENEATERIYH FVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGEEKPQA SPEGRPESETSCLVTTTDFQIQTEMAATMETSIFTTEYQLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVAL EEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF sequence no. 79 IL2r-alpha Ectodomain / IL9R / IL7RaTM ELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYMLCTGNSSHSSWDNQCQ CTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCREPPPWENEATERIYH FVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGEEKPQA SPEGRPESETSCLVTTTDFQIQTEMAATMETSIFTTEYQ PILLTISILSFFSVALLVILACVLW VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF sequence no. 80 IL2r-alpha Ectodomain / IL9R / IL2RbTM ELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYMLCTGNSSHSSWDNQCQ CTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCREPPPWENEATERIYH FVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGEEKPQA SPEGPERSETSCLVTTTDFQIQTEMAATMETSIFTTEYQ IPWLGHLLVGLSGAFGFIILVYLLI VKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTF sequence no. 81 ILT5 / IL9R / cGC-F GPFPKPTLWAEPGSVISWGSPVTIWCQGSQEAQEYRLHKEGSPEPLDRNNPLEPKNKARF SIPSMTEHHAGRYRCHYYSSAGWSEPSDPLEMVMTGAYSKPTLSALPSPVVASGGNMTLR CGSQKGYHHFVLMKEGEHQLPRTLDSQQLHSRGFQALFPVGPVTPSHRWRFTCYYYYTNT PWVWSHPSDPLEILPSGVSRKPSLTLQGPVLAPGQSLTLQCGSDVGYNRFVLYKEGERD FLQRPGQQPQAGLSQANFTLGPVSPSNGGQYRCYGAHNLSSEWSAPSDPLNILMAGQIYD TVSLSAQPGPTVASGENVTLLCQSWWQFDTFLLTKEGAAHPPLRLRSMYGAHKYQAEFPM SPVTSAHAGTYRCYGSYSSNPHLLSHPSEPLELVVSGHSGGSSLPPTGPPSTPGLGRYLELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQED WAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCAlgCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number82 ILT5 / IL9R / cGC-S GPFPKPTLWAEPGSVISWGSPVTIWCQGSQEAQEYRLHKEGSPEPLDRNNPLEPKNKARF SIPSMTEHHAGRYRCHYYSSAGWSEPSDPLEMVMTGAYSKPTLSPVVASGGNMTLR CGSQKGYHHFVLMKEGEHQLPRTLDSQQLHSRGFQALFPVGPVTPSHRWRFTCYYYYTNT PWVWSHPSDPLEILPSGVSRKPSLLTLQGPVLAPGQSLTLQCGSDVGYNRFVLYKEGERD FLQRPGQQPQAGLSQANFTLGPVSPSNGGQYRCYGAHNLSSEWSAPSDPLNILMAGQIYD TVSLSAQPGPTVASGENVTLLCQSWWQFDTFLLTKEGAAHPPLRLRSMYGAHKYQAEFPM SPVTSAHAGTYRCYGSYSSNPHLLSHPSEPLELVVSGHSGGSSLPPTGPPSTPGLGRYLELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDVLPGTEWRVQTLAYLPQ EDWAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence no. 83 ILT3 / IL9R / cGC-F QAGPLPKPTLWAEPGSVISWGNSVTIWCQGTLEAREYRLDKEESPAPWDRQNPLEPKNKA RFSIPSMTEDYAGRYRCYYRSPVGWSQPSDPLELVMTGAYSKPTLSALPSPLVTSGKSVT LLCQSRSPMDTFLLIKERAAHPLLHLRSEHGAQQHQAEFPMSPVTSVHGGTYRCFSSHGF SHELLSHPSDPLELIVSGSLEDPRSPPTRSVSTAAGPEDQPLMPTGSVPHSGLRRHWE LIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTGRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNN YCAlgCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence no. 84 ILT3 / IL9R / cGC-S QAGPLPKPTLWAEPGSVISWGNSVTIWCQGTLEAREYRLDKEESPAPWDRQNPLEPKNKA RFSIPSMTEDYAGRYRCYYRSPVGWSQPSDPLELVMTGAYSKPTLSALPSPLVTSGKSVT LLCQSRSPMDTFLLIKERAAHPLLHLRSEHGAQQHQAEFPMSPVTSVHGGTYRCFSSHGF SHYLLSHPSDPLELIVSGSLEDPRSPPTRSVSTAAGPEDQPLMPTGSVPHSGLRRHWELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGTGRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEL DWAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence no. 85 ILT4 IL9R / cGC-F QTGTIPKPTLWAEPDSVITQGSPVTLSCQGSLEAQEYRLYREKKSASWITRIRPELVKNG QFHIPSITWEHTGRYGCQYYSRARWSELSDPLVLVMTGAYPKPTLSAQPSPVVTSGGRVT LQCESQVAFGGFILCKEGEEEHPQCLNSQPHARGSSRAIFSVGPVSPNRRRWSHRCYGYDL NSPYVWSSPSDLLELLVPGVSKKPSLSVQPGPVAPGESLTLQCVSDVGYDRFVLYKEGE RDLRQLPGRQPQAGLSQANFTLGPVSRSYGGQYRCYGAHNLSSECSAPSDPLDILITGQI RGTPFISVQPGPTVASGENVTLLCQSWRQFHTFLLTKAGAADAPLRLRSIHEYPKYQAEF PMSPVTSAHAGTYRCYGSLNSDYLLSHPSEPLELVVSGPSMGSSPPPTGPISTPAGPED QPLTPTGSDPQSGLGRHLGVLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSS SSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:86 ILT4 IL9R / cGC-S QTGTIPKPTLWAEPDSVITQGSPVTLSCQGSLEAQEYRLYREKKSASWITRIRPELVKNG QFHIPSITWEHTGRYGCQYYSRARWSELSDPLVLVMTGAYPKPTLSAQPSPVVTSGGRVT LQCESQVAFGGFILCKEGEEEHPQCLNSQPHARGSSRAIFSVGPVSPNRRWSHRCYGYDL NSPYVWSSPSDLLELLVPGVSKKPSLSVQPGPVVAPGESLTLQCVSDVGYDRFVLYKEGE RDLRQLPGRQPQAGLSQANFTLGPVSRSYGGQYRCYGAHNLSSECSAPSDPLDILITGQI RGTPFISVQPGPTVASGENVTLLCQSWRQFHTFLLTKAGAADAPLRLRSIHEYPKYQAEF PMSPVTSAHAGTYRCYGSLNSDPYLLSHPSEPLELVVSGPSMGSSPPPTGPISTPAGPED QPLTPTGSDPQSGLGRHLGVLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSR SSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence no. 87 ILT2 IL9R / cGC-F GHLPKPTLWAEPGSVITQGSPVTLRCQGGQETQEYRLYREKKTALWITRIPQELVKKGQF PIPSITWEHAGRYRCYYGSDTAGRSESSDPLELVVTGAYIKPTLSAQPSPVVNSGGNVIL QCDSQVAFDGFSLCKEGEDEHPQCLNSQPHARGSSRAIFSVGPVSPSRRWWYRCYAIDSN SPYEWSLPSDLLELLVLGVSKKPSLSVQPGPIVAPEETLTLQCGSDAGYNRFVLYKDGER DFLQLAGAQPQAGLSQANFTLGPVSRSYGGQIRCYGANHLSSEWSAPSDPLDILIAGQFY DRVSLSVQPGPTVASGENVTLLCQSQGWMQTFLLTKEGAADDPWRLRSTYQSQKYQAEFP MGPVTSAHAGTYRCYGSQSSKPYLLTHPSDPLELVVSGPSGGPSSPTTGPTSTSGPEDQP LTPTGSDPQSGLGRHLGVLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGRSSS SSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number88 ILT2 IL9R / cGC-S GHLPKPTLWAEPGSVITQGSPVTLRCQGGQETQEYRLYREKKTALWITRIPQELVKKGQF PIPSITWEHAGRYRCYYGSDTAGRSESSDPLELVVTGAYIKPTLSAQPSPVVNSGGNVIL QCDSQVAFDGFSLCKEGEDEHPQCLNSQPHARGSSRAIFSVGPVSPSRRWWYRCYAYDSN SPYEWSLPSDLLELLVLGVSKKPSLSVQPGPIVAPEETLTLQCGSDAGYNRFVLYKDGER DFLQLAGAQPQAGLSQANFTLGPVSRSYGGQYRCYGAHNLSSEWSAPSDPLDILIAGQFY DRVSLSVQPGPTVASGENVTLLCQSQGWMQTFLLTKEGAADDPWRLRSTYQSQKYQAEFP MGPVTSAHAGTYRCYGSQSSKPYLLTHPSDPLELVVSGPSGGPSSPTTGPTSTSGPEDQP LTPTGSDPQSGLGRHLGVLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRS SSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence no. 89 CTLA4 IL9R / cGC-F KAMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNEL TFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPE PCPDSDLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSN NNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 90 CTLA4 IL9R / cGC-S KAMHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNEL TFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPE PCPDSDLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGRSSSSSSS SNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 91 TIM3 / IL9R / cGC-F SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSR YWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPAPTRQ RDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANELRDSRLANDLRDSGATIRI GLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDEVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNNN NYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 92 TIM3 / IL9R / cGC-S SEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPVFECGNVVLRTDERDVNYWTSR YWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMNDEKFNLKLVIKPAKVTPAPTRQ RDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLANELRDSRLANDLRDSGATIRI GLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTGRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNN NNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:93 LAG3 / IL9R / cGC-S LQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAP GPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRA DAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLRASDWVILNCSFSRPDRPASVHW FRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWGCILTYRDGFNVSIMYNLTVLGL EPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGPDLLVTGDNGDFTLRLED VSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVTPVSGQERFVW SSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPGAQRSGRAP GALPAGHLLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSS SSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:94 LAG3 / IL9R / cGC-F LQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAP GPHPAAPSSWGPRPRRYTVLSVGPGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRA DAGEYRAAVHLRDRALSCLRLRLGQASMTASPPGSLRASDWVILNCSFSRPDRPASVHW FRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWGCILTYRDGFNVSIMYNLTVLGL EPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGPDLLVTGDNGDFTLRLED VSQAQAGTYTCHIHLQEQQLNATVTLAITVTPKSFGSPGSLGKLLCEVTPVSGQERFVW SSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPGAQRSGRAP GALPAGHLLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSS NNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 95 PD1 / IL9R / cGC-F FTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQH SSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKIN QRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLR INTTTNEIFYCTFRRLDPEENHTAELPLAHPPNERLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGP GTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGS ERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALG EGPGASPCNQHSPYWAPPCYTLKPET sequence number 96 PD1 / IL9R / cGC-S FTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQH SSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKIN QRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLR INTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAY LPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPPKGGALG EGPGASPCNQHSPYWAPPCYTLKPET sequence number 97 OPG / IL9R / cGC-F ETFPPKYLHYDEETSHQLLCDKCPPGTYLKQHCTAKWKTVCAPCPDHYYTDSWHTSDECL YCSPVCKELQYVKQECNRTHNRVCECKEGRYLEIEFCLKHRSCPPGFGVVQAGTPERNTV CKRCPDGFFSNETWORK KHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCGIDVTL CEEAFFRFAVPTKFTPNWLSVLVDNLPGTKVNAESVERIKRQHSSQEQTFQLLKLWKHQN KDQDIVKKIIQDIDLCENSVQRHIGHANLTFEQLRSLMESLPGKKVGAEDIEKTIKACKP SDQILKLLSLWRIKNGDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRFLHSFTMYKLY QKLFLEMIGNQVQSVKISCLLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSS SSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 98 OPG / IL9R / cGC-S ETFPPKYLHYDEETSHQLLCDKCPPGTYLKQHCTAKWKTVCAPCPDHYYTDSWHTSDECL YCSPVCKELQYVKQECNRTHNRVCECKEGRYLEIEFCLKHRSCPPGFGVVQAGTPERNTV CKRCPDGFFSNETWORK KHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCGIDVTL CEEAFFRFAVPTKFTPNWLSVLVDNLPGTKVNAESVERIKRQHSSQEQTFQLLKLWKHQN KDQDIVKKIIQDIDLCENSVQRHIGHANLTFEQLRSLMESLPGKKVGAEDIEKTIKACKP SDQILKLLSLWRIKNGDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRFLHSFTMYKLY QKLFLEMIGNQVQSVKISCLLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSR SSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence no. 99 TACI / IL9R / cGC-F MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQR TCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRR QRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKSADQVALVYS LIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTGRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNN YCAlgCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:100 TACI / IL9R / cGC-S MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQR TCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRR QRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKLSADQVALVYS LIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNN NNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:101 BCMA / IL9R / cGC-F MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNALIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAP TSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 102 BCMA / IL9R / cGC-S MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNALIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDW APTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 103 NGFR / IL9R / cGC-F KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTE CVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEE CPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRSTPPEGSDST APSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRP APPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 104 NGFR / IL9R / cGC-S KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTE CVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEE CPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRSTPPEGSDST APSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLT RPAPPDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 105 EDAR / IL9R / cGC-F EYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCGYGTKDEDYGCVPCPAEKFSKGGYQI CRRHKDCEGFFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTK ECVGATSGASANFPGTGSSTLSPFQHAHKELSGQGHLATALIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDVLPGATEWRVQTLAYLPQEDWAPTSLTRP APPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 106 EDAR / IL9R / cGC-S EYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCGYGTKDEDYGCVPCPAEKFSKGGYQI CRRHKDCEGFFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTK ECVGATSGASANFPGTSGSSTLSPFQHAHKELSGQGHLATALIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTR PAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:107 DCR2 (TNFRSF10D) / IL9R / cGC-F ATIPRQDEVPQQTVAPQQQRRSLKEEECPAGSHRSEYTGACNPCTEGVDYTIASNNLPSC LLCTVCKSGQTNKSSCTTTRDTVCQCEKGSFQDKNSPEMCRTCRTGCPRGMVKVSNCTPR SDIKCKNESAASSTGKTPAAEETVTTILGMLASPYHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPP DSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:108 DCR2 (TNFRSF10D) / IL9R / cGC-S ATIPRQDEVPQQTVAPQQQRRSLKEEECPAGSHRSEYTGACNPCTEGVDYTIASNNLPSC LLCTVCKSGQTNKSSCTTTRDTVCQCEKGSFQDKNSPEMCRTCRTGCPRGMVKVSNCTPR SDIKCKNESAASSTGKTPAAEETVTTILGMLASPYHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPGATEWRVQTLAYLPQEDWAPTSLTRPA PPDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 109 DCR1 (TNFRSF10C) / IL9R / cGC-F ATARQEEVPQQTVAPQQQRHSFKGEECPAGSHRSEHTGACNPCTEGVDYTNASNNEPSC FPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCSRCPSGEVQVSNCTSWD DIQCVEEFGANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTTSPGTP APAAEETMTTSPGTPAPAAEETMITSPGTPALIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDS EGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 110 DCR1 (TNFRSF10C) / IL9R / cGC-S ATARQEEVPQQTVAPQQQRHSFKGEECPAGSHRSEHTGACNPCTEGVDYTNASNNEPSC FPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCSRCPSGEVQVSNCTSWD DIQCVEEFGANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTTSPGTP APAAEETMTTSPGTPAPAAEETMITSPGTPALIPPWGWPGNTLVAVSIFFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPD SEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:111 CD40 / IL9R / cGC-F EPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQH KYCDPNGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSD TICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAP TSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 112 CD40 / IL9R / cGC-S EPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTECLPCGESEFLDTWNRETHCHQH KYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSD TICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 113 FAS / IL9R / cGC-F QVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPC QEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDP CTKCEHGIIKECTLTSNTKCKEEGSRSNLIPPWGWPGNTLVAVSIFFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEG SRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:114 FAS / IL9R / cGC-S QVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPC QEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDP CTKCEHGIIKECTLTSNTKCKEEGSRSNLIPPWGWPGNTLVAVSIFFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDS EGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:115 DR4 / IL9R / cGC-F ASGTEAAAATPSKVWGSSAGRIEPRGGGRGALPTSMGQHGPSARARAGRAPGPRPAREAS PRLRVHKTFKFVVVGVLLQVVPSSAATIKLHDQSIGTQQWEHSPLGELCPPGSHRSEHPG ACNRCTEGVGYTNASNNLFACLPCTACKSDEEERSPCTTTRNTACQCKPGTFRNDNSAEM CRKCSRGCPRGMVKVKDCTPWSDIECVHKESGNGHNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPP DSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 116 DR4 / IL9R / cGC-S ASGTEAAAATPSKVWGSSAGRIEPRGGGRGALPTSMGQHGPSARARAGRAPGPRPAREAS PRLRVHKTFKFVVVGVLLQVVPSSAATIKLHDQSIGTQQWEHSPLGELCPPGSHRSEHPG ACNRCTEGVGYTNASNNLFACLPCTACKSDEEERSPCTTTRNTACQCKPGTFRNDNSAEM CRKCSRGCPRGMVKVKDCTPWSDIECVHKESGNGHNLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPA PPDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 117 DR6 / IL9R / cGC-F QPEQKASNLIGTYRHVDRATGQVLTCDKCPAGTYVSEHCTNTSLRVCSSCPVGTFTRHEN GIEKCHDCSQPCPWPMIEKLPCAALTDRECTCPPGMFQSNATCAPHTVCPVGWGVRKKGT ETEDVRCKQCARGTFSDVPSSVMKCKAYTDCLSQNLVVIKPGTKETDNVCGTLPSFSSST SPSPGTAIFPRPPEHMETHEVPSSTYVPKGMNSTESNSSASVRPKVLSSIQEGTVPDNTSS ARGKEDVNKTLPNLQVVNHQQGPHHRHILKLLPSMEATGGEKSSTPIKGPKRGHPRQNLH KHFDINEHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSS NNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 118 DR6 / IL9R / cGC-S QPEQKASNLIGTYRHVDRATGQVLTCDKCPAGTYVSEHCTNTSLRVCSSCPVGTFTRHEN GIEKCHDCSQPCPWPMIEKLPCAALTDRECTCPPGMFQSNATCAPHTVCPVGWGVRKKGT ETEDVRCKQCARGTFSDVPSSVMKCKAYTDCLSQNLVVIKPGTKETDNVCGTLPSFSSST SPSPGTAIFPRPPEHMETHEVPSSTYVPKGMNSTESNSSASVRPKVLSSIQEGTVPDNTSS ARGKEDVNKTLPNLQVVNHQQGPHHRHILKLLPSMEATGGEKSSTPIKGPKRGHPRQNLH KHFDINEHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSS SSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:119 DR5 / IL9R / cGC-F ITQQDLAPQQRAAPQQKRSSPSEGLCPPGHHISEDGRDCISCKYGQDYSTHWNDLLFCLR CTRCDSGEVELSPCTTTRNTVCQCEEGTFREEDSPEMCRKCRTGCPRGMVKVGDCTPWSD IECVHKESGTKHSGEVPAVEETVTSSPGTPASPCSLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPP DSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:120 DR5 / IL9R / cGC-S ITQQDLAPQQRAAPQQKRSSPSEGLCPPGHHISEDGRDCISCKYGQDYSTHWNDLLFCLR CTRCDSGEVELSPCTTTRNTVCQCEEGTFREEDSPEMCRKCRTGCPRGMVKVGDCTPWSD IECVHKESGTKHSGEVPAVEETVTSSPGTPASPCSLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAP PDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 121 DR3 / IL9R / cGC-F QGGTRSPRCDCAGDFHKKIGLFCCRGCPAGHYLKAPCTEPCGNSTCLVCPQDTFLAWENH HNSECARCQACDEQASQVALENCSAVADTRCGCKPGWFVECQVSQCVSSSPFYCQPCLDC GALHRHTRLLCSRRDTDCGTCLPGFYEHGDGCVSCPTSTLGSCPERCAAVCGWRQLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAM FFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:122 DR3 / IL9R / cGC-S QGGTRSPRCDCAGDFHKKIGLFCCRGCPAGHYLKAPCTEPCGNSTCLVCPQDTFLAWENH HNSECARCQACDEQASQVALENCSAVADTRCGCKPGWFVECQVSQCVSSSPFYCQPCLDC GALHRHTRLLCSRRDTDCGTCLPGFYEHGDGCVSCPTSTLGSCPERCAAVCGWRQLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAM FFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDW APTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKA RSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:123 TNFRSF1B / IL9R / cGC-F LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDSCEDST YTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRK CRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMDAVCTS TSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAM FFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:124 TNFRSF1B / IL9R / cGC-S LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDSCEDST YTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRK CRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMDAVCTS TSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDLIPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDW APTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 125 TNFRSF1 / IL9R / cGC-F LVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTYLYNDCPPGPGQDTDCRECESGSF TASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRNKNQYRHYWSENLFQCFNCSLC LNGTVHLSCQEKQNTVCTCHAGFFLRENECVSCSNCKKSLECTKLCLPQIENVKGTEDSG TTLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTGRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNNN NYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 126 TNFRSF1 / IL9R / cGC-S LVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTYLYNDCPPGPGQDTDCRECESGSF TASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRNKNQYRHYWSENLFQCFNCSLC LNGTVHLSCQEKQNTVCTCHAGFFLRENECVSCSNCKKSLECTKLCLPQIENVKGTEDSG TTLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTGRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSN NNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 127 BMPR1B / IL9R / cGC-F KKEDGESTATPPRKPVLRCCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTSGCLG LEGSDFQCRDTPIPHQRRSIECCTERNECNKDLHPTLPPLKNRDFVDGPIHHRLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPGATEWRVQTLAYLPQEDWAP TSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 128 BMPR1B / IL9R / cGC-S KKEDGESTATPPRKPVLRCCHHHCPEDSVNNICSTDGYCFTMIEEDDSGLPVVTSGCLG LEGSDFQCRDTPIPHQRRSIECCTERNECNKDLHPTLPPLKNRDFVDGPIHHRLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDVLPGATEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 129 BMPR1A / IL9R / cGC-F QNLDSMLHGTGMKSDSDQKKSENGVTLAPEDTLPFLKCYCSGHCPDDAINNTCITNGHCF AIIEEDDQGETTLASGCMKYEGSDFQCKDSPKAQLRRTIECCRTNLCNQYLQPTLPPVVI GPFFDGSIRLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGRSSSSSSS SNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 130 BMPR1A / IL9R / cGC-S QNLDSMLHGTGMKSDSDQKKSENGVTLAPEDTLPFLKCYCSGHCPDDAINNTCITNGHCF AIIEEDDQGETTLASGCMKYEGSDFQCKDSPKAQLRRTIECCRTNLCNQYLQPTLPPVVI GPFFDGSIRLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPGATTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSS SSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 131 BMPR2 / IL9R / cGC-F SQNQERLCAFKDPYQQDLGIGESRISHENGTILCSKGSTCYGLWEKSKGDINLVKQGCWS HIGDPQECHYEECVVTTTPPSIQNGTYRFCCCSTDLCNVNFTENFPPPDTTPLSPPHSFN RDETLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNN NNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 132 BMPR2 / IL9R / cGC-S SQNQERLCAFKDPYQQDLGIGESRISHENGTILCSKGSTCYGLWEKSKGDINLVKQGCWS HIGDPQECHYEECVVTTTPPSIQNGTYRFCCCSTDLCNVNFTENFPPPDTTPLSPPHSFN RDETLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSS NNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 133 CSF3R / IL9R / cGC-F ECGHISVSAPIVHLGDPITASCIIKQNCSHLDPEPQILWRLGAELQPGGRQQRLSDGTQE SIITLPHLNHTQAFLSSCCLNWGNSLQILDQVELRAGYPPAIPHNLSCLMNLTTSSLICQW EPGPETHLPTSFTLKSFKSRGNCQTQGDSILDCVPKDGQSHCCIPRKHLLLYQNMGIWVQ AENALGTSMSPQLCLDPMDVVKLEPPMLRTMDPSPEAAPPQAGCLQLCWEPWQPGLHINQ KCELRHKPQRGEASWALVGPLPLEALQYELCGLLPTAYTLQIRCIRWPLPGHWSDWSPS LELRTTERAPTVRLDTWWRQRQLDPRTVQLFWKPVPLEEDSGRIQGYVVSWRPSGQAGAI LPLCNTTELSCTFHLPSEAQEVALVAYNSAGTSRTPVVFSESRGPALTRLHAMARDPHS LWVGWEPPNPWPQGYVIEWGLGPPSASNSNKTWRMEQNGRATGFLLKENIRPFQLYEIIV TPLYQDTMGPSQHVYAYSQEMAPSHAPELHLKHIGKTWAQLEWVPEPPELGKSPLTHYTI FWTNAQNQSFSAILNASSRGFVLHGLEPASLYHIHLMAASQAGATNSTVLTLMTLTPEGS ELHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNN NNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:134 CSF3R / IL9R / cGC-S ECGHISVSAPIVHLGDPITASCIIKQNCSHLDPEPQILWRLGAELQPGGRQQRLSDGTQE SIITLPHLNHTQAFLSCCLNWGNSLQILDQVELRAGYPPAIPHNLSCLMNLTTSSLICQW EPGPETHLPTSFTLKSFKSRGNCQTQGDSILDCVPKDGQSHCCIPRKHLLLYQNMGIWVQ AENALGTSMSPQLCLDPMDVVKLEPPMLRTMDPSPEAAPPQAGCLQLCWEPWQPGLHINQ KCELRHKPQRGEASWALVGPLPLEALQYELCGLLPATAYTLQIRCIRWPLPGHWSDWSPS LELRTTERAPTVRLDTWWRQRQLDPRTVQLFWKPVPLEEDSGRIQGYVVSWRPSGQAGAI LPLCNTTELSCTFHLPSEAQEVALVAYNSAGTSRPTVVFSESRGPALTRLHAMARDPHS LWVGWEPPNPWPQGYVIEWGLGPPSASNSNKTWRMEQNGRATGFLLKENIRPFQLYEIIV TPLYQDTMGPSQHVYAYSQEMAPSHAPEHLKHIGKTWAQLEWVPEPPELGKSPLTHYTI FWTNAQNQSFSAILNASSRGFVLHGLEPASLYHIHLMAASQAGATNSTVLTLMTLTPEGS ELHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSN NNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 135 CSF1R / IL9R / cGC-F IPVIEPSVPELVVKPGATVTLRCVGNGSVEWDGPPSPHWTLYSDGSSSILSTNNATFQNT GTYRCTEPGDPLGGSAAIHLYVKDPARPWNVLAQEVVVFEDQDALLPCLLLTDPVLEAGVS LVRVRGRPLMRHTNYSFSPWHGFTIHRAKFIQSQDYQCSALMGGRKVMSISIRLKVQKVI PGPPALTLVPAELVRIRGEAAQIVCSASSVDVNFDVFLQHNNTKLAIPQQSDFHNNRYQK VLTLNLDQVDFQHAGNYSCVASNVQGKHSTSMFFRVVESAYLNLSSEQNLIQEVTVGEGL NLKVMVEAYPGLQGFNWTYLGPFSDHQPEPCLANATTKDTYRHFTLSLPRLKPSEAGRY SFLARNPGGWRALTFELTLRYPPEVSVIWTFINGSGTLLCAASGYPQPNVTWLQCSGHTD RCDEAQVLQVWDDPYPEVLSQEPFHKVTVQSLLTVETLEHNQTYECRAHNSVGSGSWAFI PISAGAHTHPPDEFLFTPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGRSSS SSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 136 CSF1R / IL9R / cGC-S IPVIEPSVPELVVKPGATVTLRCVGNGSVEWDGPPSPHWTLYSDGSSSILSTNNATFQNT GTYRCTEPGDPLGGSAAIHLYVKDPARPWNVLAQEVVVFEDQDALLPCLLLTDPVLEAGVS LVRVRGRPLMRHTNYSFSPWHGFTIHRAKFIQSQDYQCSALMGGRKVMSISIRLKVQKVI PGPPALTLVPAELVRIRGEAAQIVCSASSVDVNFDVFLQHNNTKLAIPQQSDFHNNRYQK VLTLNLDQVDFQHAGNYSCVASNVQGKHSTSMFFRVVESAYLNLSSEQNLIQEVTVGEGL NLKVMVEAYPGLQGFNWTYLGPFSDHQPEPCLANATTKDTYRHFTLSLPRLKPSEAGRY SFLARNPGGWRALTFELTLRYPPEVSVIWTFINGSGTLLCAASGYPQPNVTWLQCSGHTD RCDEAQVLQVWDDPYPEVLSQEPFHKVTVQSLLTVETLEHNQTYECRAHNSVGSGSWAFI PISAGAHTHPPDEFLFTPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRS SSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 137 VEGF Receptor 1 / IL9R / cGC-F SKLKDPELSLKGTQHIMQAGQTLHLQCRGEAAHKWSLPEMVSKESERLSITKSACGRNGK QFCSTLTLNTAQANHTGFYSCKYLAVPTSKKKETESAIYIFISDTGRPFVEMYSEIPEII HMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLT CEATVNGHLYKTNYLTHRQTNTIIDVQISTPRPVKLLRGHTLVLNCTATTPLNTRVQMTW SYPDEKNKRASVRRRIDQSNSHANIFYSVLTIDKMQNKDKGLYTCRVRSGPSFKSVNTSV HIYDKAFITVKHRKQQVLETVAGKRSYRLSMKVKAFPSPEVVWLKDGLPATEKSARYLTR GYSLIIKDVTEEDAGNYTILLSIKQSNVFKNLTATLIVNVKPQIYEKAVSSFPDPALYPL GSRQILTCTAYGIPQPTIKWFWHPCNHNHSEARCDFCSNNEESFILDADSNMGNRIESIT QRMAIIEGKNKMASTLVVADSRISGIYICIASNKVGTVGRNISFYITDVPNGFHVNLEKM PTEGEDLKLSCTVNKFLYRDVTWILLRTVNNRTMHYSISKQKMAITKEHSITLNLTIMNV SLQDSGTYACRARNVYTGEEILQKKEITIRDQEAPYLLRNLSDHTVAISSSTTLDCHANG VPEPQITWFKNNHKIQQEPGIILGPGSSTLFIERVTEEDEGVYHCKATNQKGSVESSAYL TVQGTSDKSNLELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSS SSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 138 VEGF Receptor 1 / IL9R / cGC-S SKLKDPELSLKGTQHIMQAGQTLHLQCRGEAAHKWSLPEMVSKESERLSITKSACGRNGK QFCSTLTNLTAQANHTGFYSCKYLAVPTSKKKETESAIYIFISDTGRPFVEMYSEIPEII HMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLT CEATVNGHLYKTNYLTHRQTNTIIDVQISTPRPVKLLRGHTLVLNCTATTPLNTRVQMTW SYPDEKNKRASVRRRIDQSNSHANIFYSVLTIDKMQNKDKGLYTCRVRSGPSFKSVNTSV HIYDKAFITVKHRKQQVLETVAGKRSYRLSMKVKAFPSPEVVWLKDGPLATEKSARYLTR GYSLIIKDVTEEDAGNYTILLSIKQSNVFKNLTATLIVNVKPQIYEKAVSSFPDPALYPL GSRQILTCTAYGIPQPTIKWFWHPCNHNHSEARCDFCSNNEESFILDADSNMGNRIESIT QRMAIIEGKNKMASTLVVADSRISGIYICIASNKVGTVGRNISFYITDVPNGFHVNLEKM PTEGEDLKLSCTVNKFLYRDVTWILLRTVNNRTMHYSISKQKMAITKEHSITLNLTIMNV SLQDSGTYACRARNVYTGEEILQKKEITIRDQEAPYLLRNLSDHTVAISSSTTLDCHANG VPEPQITWFKNNHKIQQEPGIILGPGSSTLFIERVTEEDEGVYHCKATNQKGSVESSAYL TVQGTSDKSNLELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSS SSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 139 VEGF Receptor 2 / IL9R / cGC-F ASVGLPSVSLDPRLSIQKDILTIKANTTLQITCRGQRDLDWLWPNNQSGSEQRVEVTEC SDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGVVYIT ENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVF CEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFN WEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNS TFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPPEIKWYKNGIPLESNHTIKA GHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGT TQTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAVSVTNPYPCEEWRSVEDFQGGNKIEV NKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVISFHVTRGPEITLQPDM QPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPTPVCKNLDTLWKLNATMFSN STNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLTVLERVAPTITGNLENQTTS IGESIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQA CSVLGCAKVEAFFIIEGAQEKTNLELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGTGRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGS RSSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 140 VEGF Receptor 2 / IL9R / cGC-S ASVGLPSVSLDPRLSIQKDILTIKANTTLQITCRGQRDLDWLWPNNQSGSEQRVEVTEC SDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGVVYIT ENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVF CEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFN WEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNS TFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPPEIKWYKNGIPLESNHTIKA GHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGT TQTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAVSVTNPYPCEEWRSVEDFQGGNKIEV NKNQFALIEGKNKTVSTLVIQAANVSALYCCEAVNKVGRGERVISFHVTRGPEITLQPDM QPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPTPVCKNLDTLWKLNATMFSN STNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLTVLERVAPTITGNLENQTTS IGESIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQA CSVLGCAKVEAFFIIEGAQEKTNLELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEG SRSSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 141 VEGF Receptor 3 / IL9R / cGC-S YSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDC EGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPD TLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYL QCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTF DWDYPGKQAERGKWVPERRSQQTHTELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTE VIVHENPFISVEWLKGPILEATAGDELVKLPVKLAAYPPPEFQWYKDGKALSGRHSPHAL VLKEVTEASTGTYTLALWNSAAGLRRNISLELVVNVPPQIHEKEASSPSIYSRHSRQALT CTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQQDLMPQCRDWRAVTTQDAVNPIESL DTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKVGQDERLIYFYVTTIPDGFTIESKP SEELLEGQPVLLSCQADSYKYEHLRWYRLNLSTLHDAHGNPLLLDCKNVHLFATPLAASL EEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRSHDKHCHKKYLSVQALEAPRLTQNL TDLLVNVSDSLEMQCLVAGAHAPSIVWYKDERLLEEKSGVDLADSNQKLSIQRVREEDAG RYLCSVCNAKGCVNSSASVAVEGSEDKGSMELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPD SEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 142 VEGF Receptor 3 / IL9R / cGC-F YSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDC EGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPD TLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYL QCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTF DWDYPGKQAERGKWVPERRSQQTHTELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTE VIVHENPFISVEWLKGPILEATAGDELVKLPVKLAAYPPPEFQWYKDGKALSGRHSPHAL VLKEVTEASTGTYTLALWNSAAGLRRNISLELVVNVPPQIHEKEASSPSIYSRHSRQALT CTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQQDLMPQCRDWRAVTTQDAVNPIESL DTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKVGQDERLIIFYVTTIPDGFTIESKP SEELLEGQPVLLSCQADSYKYEHLRWYRLNLSLTLHDAHGNPLLLDCKNVHLFATPLAASL EEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRSHDKHCHKKYLSVQALEAPRLTQNL TDLLVNVSDSLEMQCLVAGAHAPSIVWYKDERLLEEKSGVDLADSNQKLSIQRVREEDAG RYLCSVCNAKGCVNSSASVAVEGSEDKGSMELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDS EGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 143 Activin R1A ectodomain / IL9R / cGC-F MEDEKPKVNPKLYMCVCEGLSCGNEDHCEGQQCFSSLSINDGFHVYQKGCFQVYEQGKMT CKTPPSPGQAVECCQGDWCNRNITAQLPTKGKSFPGTQNFHLELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTR PAPPDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 144 Activin R1A ectodomain / IL9R / cGC-S MEDEKPKVNPKLYMCVCEGLSCGNEDHCEGQQCFSSLSINDGFHVYQKGCFQVYEQGKMT CKTPPSPGQAVECCQGDWCNRNITAQLPTKGKSFPGTQNFHLELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLT RPAPPDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 145 Activin R1B ectodomain / IL9R / cGC-F SGPRGVQALLCACTSCLQANYTCETDGACMVSIFNLDGMEHHVRTCIPKVELVPAGKPFY CLSSEDLRNTHCCYTDYCNRIDLRVPSGHLKEPEHPSMWGPVELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTR PAPPDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 146 Activin R1B ectodomain / IL9R / cGC-S SGPRGVQALLCACTSCLQANYTCETDGACMVSIFNLDGMEHHVRTCIPKVELVPAGKPFY CLSSEDLRNTHCCYTDYCNRIDLRVPSGHLKEPEHPSMWGPVELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLT RPAPPDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 147 Activin R1C ectodomain / IL9R / cGC-F LSPGLKCVCLLCDSSNFTCQTEGACWASVMLTNGKEQVIKSCVSLPELNAQVFCHSSNNV TKTECCFTDFCNNITLHLPTASPNAPKLGPMELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDS EGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 148 Activin R1C ectodomain / IL9R / cGC-S LSPGLKCVCLLCDSSNFTCQTEGACWASVMLTNGKEQVIKSCVSLPELNAQVFCHSSNNV TKTECCFTDFCNNITLHLPTASPNAPKLGPMELIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPP DSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 149 Activin R2B ectodomain / IL9R / cGC-F SGRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCW LDDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTLLLTLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSEDVLPGATEWRVQTLAYLPQED WAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 150 Activin R2B ectodomain / IL9R / cGC-S SGRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRLHCYASWRNSSGTIELVKKGCW LDDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTLLLTLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSEDVLPGTEWRVQTLAYLPQE DWAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET Accession No. 151 Activin R2A ectodomain / IL9R / cGC-F AILGRSETQECLFFNANWEKDRTNQTGVEPCYGDKDKRRHCFATWKNISGSIEIVKQGCW LDDINCYDRTDCVEKKDSPEVYFCCCEGNMCNEKFSYFPEMEVTQPTSNPVTPKPPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET Accession No. 152 Activin R2A ectodomain / IL9R / cGC-S AILGRSETQECLFFNANWEKDRTNQTGVEPCYGDKDKRRHCFATWKNISGSIEIVKQGCW LDDINCYDRTDCVEKKDSPEVYFCCCEGMNMCNEKFSYFPEMEVTQPTSNVPTPKPPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQED WAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 153 IL10R-alpha / IL9R / cGC-F HGTELPSPPSVWFEAEFFHHILHWTPIPNQSESTCYEVALLRYGIESWNSISNCSQTLSY DLTAVTLDLYHSNGYRARVRAVDGSRHSNWTVTNTRFSVDEVTLTVGSVNLEIHNGFILG KIQLPRPKMAPANDTYESIFSHFREYEIAIRKVPGNFTFTHKKVKHENFSLLTSGEVGEF Resume SEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 154 IL10R-alpha / IL9R / cGC-S HGTELPSPPSVWFEAEFFHHILHWTPIPNQSESTCYEVALLRYGIESWNSISNCSQTLSY DLTAVTLDLYHSNGYRARVRAVDGSRHSNWTVTNTRFSVDEVTLTVGSVNLEIHNGFILG KIQLPRPKMAPANDTYESIFSHFREYEIAIRKVPGNFTFTHKKVKHENFSLLTSGEVGEF Resume PDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 155 TGFBR2 ectodomain / IL9R / cGC-F TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQE VCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDE CNDNIIFSEEYNTSNPDLLLVIFQLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSR SSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET Accession number 156 TGFBR2 ectodomain / IL9R / cGC-S TIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQE VCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDE CNDNIIFSEEYNTSNPDLLLVIFQLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET Accession number 157 TGFBR1 ectodomain / IL9R / cGC-F LQCFCHLCTKDNFTCVTDGLCFVSVTETTDKVIHNSMCIAEIDLIPRDRPFVCAPSSKTG SVTTTYCCNQDHCNKIELPTTVKSSPGLGPVELLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPD SEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 158 TGFBR1 ectodomain / IL9R / cGC-S LQCFCHLCTKDNFTCVTDGLCFVSVTETTDKVIHNSMCIAEIDLIPRDRPFVCAPSSKTG SVTTTYCCNQDHCNKIELPTTVKSSPGLGPVELLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPP DSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 159 TIGIT / IL9R / cGC-F MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSF KDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQED WAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCAlgCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 160 TIGIT / IL9R / cGC-S MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSF KDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVP SPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQ EDWAPTSLTRPAPPDSEGSRSSSSSSSNNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLS KARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:161 FCGR2B / IL9R / cGC-F TPAAPPKAVLKLEPQWINVLQEDSVTLTCRGTHSPESDSIQWFHNGNLIPHTQPSYRFK ANNNDSGEYTCQTGQTSLSDPVHLTVLSEWLVLQTPHLEFQEGETIVLRCHSWKDKPLVK VTFFQNGKSKKFSRSDPNFSIPQANHSHSGDYHCTGNIGYTLYSSKPVTITVQAPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAM FFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:162 FCGR2B / IL9R / cGC-S TPAAPPKAVLKLEPQWINVLQEDSVTLTCRGTHSPESDSIQWFHNGNLIPHTQPSYRFK ANNNDSGEYTCQTGQTSLSDPVHLTVLSEWLVLQTPHLEFQEGETIVLRCHSWKDKPLVK VTFFQNGKSKKFSRSDPNFSIPQANHSHSGDYHCTGNIGYTLYSSKPVTITVQAPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDW APTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 163 FCGR1 / IL9R / cGC-F QVDTTKAVITLQPPWVSVFQEETVTLHCEVLHLPGSSSTQWFNLGTATQTSTPSYRITSA SVNDSGEYRCQRGLSGRSDPIQLEIHRGWLLLQVSSRVFTEGEPLALRCHAWKDKLVYNV LYYRNGKAFKFFHWNSNLTILKTNISHNGTYHCSGMGKHRYTSAGISVTVKELFPAPVLN ASVTSPLLEGNLVTLSCETKLLLQRPGLQLYFSFYMGSKTLRGRNTSSEYQILTARREDS GLYWCEAATEDGNVLKRSPELELQVLGLQLPTPVWFHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAP PDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 164 FCGR1 / IL9R / cGC-S QVDTTKAVITLQPPWVSVFQEETVTLHCEVLHLPGSSSTQWFNLGTATQTSTPSYRITSA SVNDSGEYRCQRGLSGRSDPIQLEIHRGWLLLQVSSRVFTEGEPLALRCHAWKDKLVYNV LYYRNGKAFKFFHWNSNLTILKTNISHNGTYHCSGMGKHRYTSAGISVTVKELFPAPVLN ASVTSPLLEGNLVTLSCETKLLLQRPGLQLYFSFYMGSKTLRGRNTSSEYQILTARREDS GLYWCEAATEDGNVLKRSPELELQVLGLQLPTPVWFHLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPA PPDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 165 2B4 / IL9R / cCG-F CQGSADHVVSISGVPLQLQPNSIQTKVDSIAWKKLLPSQNGFHHILKWENGSLPSNTSND RFSFIVKNLSLLIKAAQQQDSGLYCLEVTSISGKVQTATFQVFVFESLLPDKVEKPRLQG QGKILDRGRCQVALSCLVSRDGNVSYAWYRGSKLIQTAGNLTYLDEEVDINGTHTYTCNV SNPVSWESHTLNLTQDCQNAHQEFRFWPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEG SRSSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 166 2B4 / IL9R / cCG-S CQGSADHVVSISGVPLQLQPNSIQTKVDSIAWKKLLPSQNGFHHILKWENGSLPSNTSND RFSFIVKNLSLLIKAAQQQDSGLYCLEVTSISGKVQTATFQVFVFESLLPDKVEKPRLQG QGKILDRGRCQVALSCLVSRDGNVSYAWYRGSKLIQTAGNLTYLDEEVDINGTHTYTCNV SNPVSWESHTLNLTQDCQNAHQEFRFWPLIPPWGWPGNTLVAVSIFFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDS EGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:167 LAIR1 / IL9R / cGC-F QEEDLPRPSISAEPGTVIPLGSHVTFVCRGPVGVQTFRLERESRSTYNDTEDVSQASPSE SEARFRIDSVSEGNAGPYRCIYYKPPKWSEQSDYLELLVKETSGGPDSPDTEPGSSAGPT QRPSDNSHNEHAPASQGLKAEHLYLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSR SSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:168 LAIR1 / IL9R / cGC-S QEEDLPRPSISAEPGTVIPLGSHVTFVCRGPVGVQTFRLERESRSTYNDTEDVSQASPSE SEARFRIDSVSEGNAGPYRCIYYKPPKWSEQSDYLELLVKETSGGPDSPDTEPGSSAGPT QRPSDNSHNEHAPASQGLKAEHLYLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEG SRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 169 CD5 / IL-9R / cGC-F RLSWYDPDFQARLTRSNSKCQGQLEVYLKDGWHMVCSQSWGRSSKQWEDPSQASKVCQRL NCGVPLSLGPFLVTYTPQSSIICYGQLGSFSNCSHSRNDMCHSLGLTCLEPQKTTPPTTR PPPTTTPEPTAPPRLQLVAQSGGQHCAGVVEFYSGSLGGTISYEAQDKTQDLENFLCNNL QCGSFLKHLPETEAGRAQDPGEPREHQPLPIQWKIQNSSCTSLEHCFRKIKPQKSGRVLA LLCSGFQPKVQSRLVGGSSICEGTVEVRQGAQWAALCDSSSARSSLRWEEVCREQQCGSV NSIRVLDAGDPTSRGLFCPHQKLSQCHELWERNSYCKKKVFVTCQDPNPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSL TRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 170 CD5 / IL-9R / cGC-S RLSWYDPDFQARLTRSNSKCQGQLEVYLKDGWHMVCSQSWGRSSKQWEDPSQASKVCQRL NCGVPLSLGPFLVTYTPQSSIICYGQLGSFSNCSHSRNDMCHSLGLTCLEPQKTTPPTTR PPPTTTPEPTAPPRLQLVAQSGGQHCAGVVEFYSGSLGGTISYEAQDKTQDLENFLCNNL QCGSFLKHLPETEAGRAQDPGEPREHQPLPIQWKIQNSSCTSLEHCFRKIKPQKSGRVLA LLCSGFQPKVQSRLVGGSSICEGTVEVRQGAQWAALCDSSSARSSLRWEEVCREQQCGSV NSIRVLDAGDPTSRGLFCPHQKLSQCHELWERNSYCKKKVFVTCQDPNPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPT SLTRPAPPDSEGRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 171 TWEAKR / IL9R / cGC-F EQAPGTAPCSRGSSWSADLDKCMDCASCRARPHSDFCLGCAAAPPAPFRLLWPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAP TSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 172 TWEAKR / IL9R / cGC-S EQAPGTAPCSRGSSWSADLDKCMDCASCRARPHSDFCLGCAAAPPAPFRLLWPLIPPWGWPGNTLVAVSIFLLLTGPTYLLFKLSPRVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWA PTSLTRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 173 TWEAKR / IL9R / cGC-F / TNFR1-TM EQAPGTAPCSRGSSWSADLDKCMDCASCRARPHSDFCLGCAAAPPAPFRLLWPVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSDVLPGATEWRVQTLAYLPQEDWAPTSLTRP APPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 174 TWEAKR / IL9R / cGC-S / TNFR1-TM EQAPGTAPCSRGSSWSADLDKCMDCASCRARPHSDFCLGCAAAPPAPFRLLWPVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLT RPAPPDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 175 OPG / IL9R / cGC-F / TNFR1-TM ETFPPKYLHYDEETSHQLLCDKCPPGTYLKQHCTAKWKTVCAPCPDHYYTDSWHTSDECL YCSPVCKELQYVKQECNRTHNRVCECKEGRYLEIEFCLKHRSCPPGFGVVQAGTPERNTV CKRCPDGFFSNETWORK KHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCGIDVTL CEEAFFRFAVPTKFTPNWLSVLVDNLPGTKVNAESVERIKRQHSSQEQTFQLLKLWKHQN KDQDIVKKIIQDIDLCENSVQRHIGHANLTFEQLRSLMESLPGKKVGAEDIEKTIKACKP SDQILKLLSLWRIKNGDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRFLHSFTMYKLY QKLFLEMIGNQVQSVKISCLVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGRSSSSSSS SNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 176 OPG / IL9R / cGC-S / TNFR1-TM ETFPPKYLHYDEETSHQLLCDKCPPGTYLKQHCTAKWKTVCAPCPDHYYTDSWHTSDECL YCSPVCKELQYVKQECNRTHNRVCECKEGRYLEIEFCLKHRSCPPGFGVVQAGTPERNTV CKRCPDGFFSNETWORK KHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCGIDVTL CEEAFFRFAVPTKFTPNWLSVLVDNLPGTKVNAESVERIKRQHSSQEQTFQLLKLWKHQN KDQDIVKKIIQDIDLCENSVQRHIGHANLTFEQLRSLMESLPGKKVGAEDIEKTIKACKP SDQILKLLSLWRIKNGDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRFLHSFTMYKLY QKLFLEMIGNQVQSVKISCLVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSS SSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:177 TACI / IL9R / cGC-F / TNFR1-TM MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQR TCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRR QRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKLSADQVALVYS VLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNNYCALG CYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:178 TACI / IL9R / cGC-S / TNFR1-TM MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQR TCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRR QRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKSADQVALVYS VLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCAL GCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 179 BCMA / IL9R / cGC-F / TNFR1-TM MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTR PAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 180 BCMA / IL9R / cGC-S / TNFR1-TM MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLT RPAPPDSEGSRSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 181 NGFR / IL9R / cGC-F / TNFR1-TM KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTE CVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEE CPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRSTPPEGSDST APSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDNVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDS EGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 182 NGFR / IL9R / cGC-S / TNFR1-TM KEACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTE CVGLQSMSAPCVEADDAVCRCAYGYYQDETTGRCEACRVCEAGSGLVFSCQDKQNTVCEE CPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAECEEIPGRWITRSTPPEGSDST APSTQEPEAPPEQDLIASTVAGVVTTVMGSSQPVVTRGTTDNVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPD SEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 183 EDAR / IL9R / cGC-F / TNFR1-TM EYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCGYGTKDEDYGCVPCPAEKFSKGGYQI CRRHKDCEGFFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTK ECVGATSGASANFPGTGSSTLSPFQHAHKELSGQGHLATAVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGTGRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSE GSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:184 EDAR / IL9R / cGC-S / TNFR1-TM EYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCGYGTKDEDYGCVPCPAEKFSKGGYQI CRRHKDCEGFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTK ECVGATSGASANFPGTSGSSTLSPFQHAHKELSGQGHLATAVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPD SEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:185 DCR2 (TNFRSF10D) / IL9R / cGC-F / TNFR1-TM ATIPRQDEVPQQTVAPQQQRRSLKEEECPAGSHRSEYTGACNPCTEGVDYTIASNNLPSC LLCTVCKSGQTNKSSCTTTRDTVCQCEKGSFQDKNSPEMCRTCRTGCPRGMVKVSNCTPR SDIKCKNESAASSTGKTPAAEETVTTILGMLASPYHVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGS RSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 186 DCR2 (TNFRSF10D) / IL9R / cGC-S / TNFR1-TM ATIPRQDEVPQQTVAPQQQRRSLKEEECPAGSHRSEYTGACNPCTEGVDYTIASNNLPSC LLCTVCKSGQTNKSSCTTTRDTVCQCEKGSFQDKNSPEMCRTCRTGCPRGMVKVSNCTPR SDIKCKNESAASSTGKTPAAEETVTTILGMLASPYHVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGTGRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEG SRSSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 187 DCR1 (TNFRSF10C) / IL9R / cGC-F / TNFR1-TM ATARQEEVPQQTVAPQQQRHSFKGEECPAGSHRSEHTGACNPCTEGVDYTNASNNEPSC FPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCSRCPSGEVQVSNCTSWD DIQCVEEFGANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTTSPGTP APAAEETMTTSPGTPAPAAEETMITSPGTPAVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSS SSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 188 DCR1 (TNFRSF10C) / IL9R / cGC-S / TNFR1-TM ATARQEEVPQQTVAPQQQRHSFKGEECPAGSHRSEHTGACNPCTEGVDYTNASNNEPSC FPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCSRCPSGEVQVSNCTSWD DIQCVEEFGANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTTSPGTP APAAEETMTTSPGTPAPAAEETMITSPGTPAVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSR SSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 189 CD40 / IL9R / cGC-F / TNFR1-TM EPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTECLPCGESEFLDTWNRETHCHQH KYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSD TICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRP APPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:190 CD40 / IL9R / cGC-S / TNFR1-TM EPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQH KYCDPNGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSD TICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLT RPAPPDSEGSRSSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:191 FAS / IL9R / cGC-F / TNFR1-TM QVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPC QEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDP CTKCEHGIIKECTLTSNTKCKEEGSRSNVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSS SSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:192 FAS / IL9R / cGC-S / TNFR1-TM QVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPC QEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDP CTKCEHGIIKECTLTSNTKCKEEGSRSNVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSS SSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:193 DR4 / IL9R / cGC-F / TNFR1-TM ASGTEAAAATPSKVWGSSAGRIEPRGGGRGALPTSMGQHGPSARARAGRAPGPRPAREAS PRLRVHKTFKFVVVGVLLQVVPSSAATIKLHDQSIGTQQWEHSPLGELCPPGSHRSEHPG ACNRCTEGVGYTNASNNLFACLPCTACKSDEEERSPCTTTRNTACQCKPGTFRNDNSAEM CRKCSRGCPRGMVKVKDCTPWSDIECVHKESGNGHNVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGTGRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGS RSSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 194 DR4 / IL9R / cGC-S / TNFR1-TM ASGTEAAAATPSKVWGSSAGRIEPRGGGRGALPTSMGQHGPSARARAGRAPGPRPAREAS PRLRVHKTFKFVVVGVLLQVVPSSAATIKLHDQSIGTQQWEHSPLGELCPPGSHRSEHPG ACNRCTEGVGYTNASNNLFACLPCTACKSDEEERSPCTTTRNTACQCKPGTFRNDNSAEM CRKCSRGCPRGMVKVKDCTPWSDIECVHKESGNGHNVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEG SRSSSSSSSSNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 195 DR6 / IL9R / cGC-S / TNFR1-TM QPEQKASNLIGTYRHVDRATGQVLTCDKCPAGTYVSEHCTNTSLRVCSSCPVGTFTRHEN GIEKCHDCSQPCPWPMIEKLPCAALTDRECTCPPGMFQSNATCAPHTVCPVGWGVRKKGT ETEDVRCKQCARGTFSDVPSSVMKCKAYTDCLSQNLVVIKPGTKETDNVCGTLPSFSSST SPSPGTAIFPRPEHMETHEPVPSSTYVPKGMNSTESNSSASVRPKVLSSIQEGTVPDNTSS ARGKEDVNKTLPNLQVVNHQQGPHHRHILKLLPSMEATGGEKSSTPIKGPKRGHPRQNLH KHFDINEHVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSSNNNN YCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:196 DR5 / IL9R / cGC-F / TNFR1-TM ITQQDLAPQQRAAPQQKRSSPSEGLCPPGHHISEDGRDCISCKYGQDYSTHWNDLLFCLR CTRCDSGEVELSPCTTTRNTVCQCEEGTFREEDSPEMCRKCRTGCPRGMVKVGDCTPWSD IECVHKESGTKHSGEVPAVEETVTSSPGTPASPCSVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEQEGPGTRLPGNLSSEDVLPAGCTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSR SSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET SEQ ID NO:197 DR5 / IL9R / cGC-S / TNFR1-TM ITQQDLAPQQRAAPQQKRSSPSEGLCPPGHHISEDGRDCISCKYGQDYSTHWNDLLFCLR CTRCDSGEVELSPCTTTRNTVCQCEEGTFREEDSPEMCRKCRTGCPRGMVKVGDCTPWSD IECVHKESGTKHSGEVPAVEETVTSSPGTPASPCSVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEG SRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 198 DR3 / IL9R / cGC-F / TNFR1-TM QGGTRSPRCDCAGDFHKKIGLFCCRGCPAGHYLKAPCTEPCGNSTCLVCPQDTFLAWENH HNSECARCQACDEQASQVALENCSAVADTRCGCKPGWFVECQVSQCVSSSPFYCQPCLDC GALHRHTRLLCSRDTDCGTCLPGFYEHDGDGCVSCPTSTLGSCPERCAAVCGWRQVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTR PAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 199 DR3 / IL9R / cGC-S / TNFR1-TM QGGTRSPRCDCAGDFHKKIGLFCCRGCPAGHYLKAPCTEPCGNSTCLVCPQDTFLAWENH HNSECARCQACDEQASQVALENCSAVADTRCGCKPGWFVECQVSQCVSSSPFYCQPCLDC GALHRHTRLLCSRDTDCGTCLPGFYEHDGDGCVSCPTSTLGSCPERCAAVCGWRQVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSL TRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRITLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence number 200 TNFRSF1B / IL9R / cGC-F / TNFR1-TM LPAQVAFTPYAPEGSTCRRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDSCEDST YTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRK CRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPPHQICNVVAIPGNASMDAVCTS TSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSLTR PAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence no. 201 TNFRSF1B / IL9R / cGC-S / TNFR1-TM LPAQVAFTPYAPEGSTCRRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDSCEDST YTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRK CRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPPHQICNVVAIPGNASMDAVCTS TSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDVLLPLVIFFGLCLLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEEGPGGTRLPGNLSSDVLPAGCTEWRVQTLAYLPQEDWAPTSL TRPAPPDSEGSRSSSSSSSNNNNYCALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRITLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence no. 202 TNFRSF1 / IL9R / cGC-F / TNFR1-TM LVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTYLYNDCPGPPGQDTDCRECESGSF TASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRNKNQYRHYWSENLFQCFNCSLC LNGTVHLSCQEKQNTVCTCHAGFFLRENECVSCSNCKKSLECTKLCPQIENVKGTEDSG TTVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCAL GCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence no. 203 TNFRSF1 / IL9R / cGC-S / TNFR1-TM LVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTYLYNDCPPGPGQDTDCRECESGSF TASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRNKNQYRHYWSENLFQCFNCSLC LNGTVHLSCQEKQNTVCTCHAGFFLRENECVSCSNCKKSLECTKLCLPQIENVKGTEDSG TTVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGACTEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNNNYCA LGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFQPQPQPQPQPERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET sequence no. 205 DR6 / IL9R / cGC-F / TNFR1-TM QPEQKASNLIGTYRHVDRATGQVLTCDKCPAGTYVSEHCTNTSLRVCSSCPVGTFTRHEN GIEKCHDCSQPCPWPMIEKLPCAALTDRECTCPPGMFQSNATCAPHTVCPVGWGVRKKGT ETEDVRCKQCARGTFSDVPSSVMKCKAYTDCLSQNLVVIKPGTKETDNVCGTLPSFSSST SPSPGTAIFPRPEHMETHEPVPSSTYVPKGMNSTESNSSASVRPKVLSSIQEGTVPDNTSS ARGKEDVNKTLPNLQVVNHQQGPHHRHILKLLPSMEATGGEKSSTPIKGPKRGHPRQNLH KHFDINEHVLLPLVIFFGLCLLSLLFIGLMYVKRIFYQNVPSPAMFFQPLYSVHNGNFQTWMGAHGAGVLLSQDCAGTPQGALEPCVQEATALLTCGPARPWKSVALEEQEGPGTRLPGNLSSEDVLPGATEWRVQTLAYLPQEDWAPTSLTRPAPPDSEGSRSSSSSSSNNNNY CALGCYGGWHLSALPGNTQSSGPIPALACGLSCDHQGLETQQGVAWVLAGHCQRPGLHEDLQGMLLPSVLSKARSWTFGGGGSGGGGSGGGGSERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPCGGALGEGPGASPCNQHSPYWAPPCYTLKPET

Claims

1. 1. A recombinant nucleic acid molecule encoding a chimeric receptor, said chimeric receptor comprising: an extracellular portion containing the binding domain of an endogenous inhibitory receptor; an intracellular portion comprising the endodomain of the IL-9 receptor linked to the BOX1 / 2 common gamma chain domain; and a transmembrane domain connecting the extracellular portion and the intracellular portion A recombinant nucleic acid molecule comprising:

2. The recombinant nucleic acid molecule of claim 1, further comprising one or more linkers.

3. 2. The recombinant nucleic acid molecule of claim 1, wherein the endogenous inhibitory receptor is selected from TGF-betaR1, TGF-betaR2, IL-10ra, FAS, CTLA4, LAG3, TIM3, PD1, ILT2, ILT3, ILT4, ILT5, and VEGF.

4. 2. The recombinant nucleic acid molecule of claim 1, wherein the endogenous inhibitory receptor comprises an amino acid sequence having at least 80% sequence identity with an amino acid sequence selected from SEQ ID NOs: 7-52.

5. 2. The recombinant nucleic acid molecule of claim 1, wherein the BOX1 / 2 common gamma chain domain comprises the amino acid sequence of SEQ ID NO: 58: ERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPET.

6. 2. The recombinant nucleic acid molecule of claim 1, wherein the transmembrane domain is selected from the transmembrane domains of IL-9, IL-7ra, IL-2rb, and TNFR1.

7. 2. The recombinant nucleic acid molecule of claim 1, wherein the transmembrane domain comprises an amino acid sequence selected from SEQ ID NOs: 53-56.

8. 2. The recombinant nucleic acid molecule of claim 1, wherein the chimeric receptor comprises an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from SEQ ID NOs: 81-203.

9. The recombinant nucleic acid molecule of claim 1 , wherein the chimeric receptor comprises the amino acid sequence of SEQ ID NO:

113.

10. The recombinant nucleic acid molecule of claim 1 , wherein the recombinant nucleic acid molecule is incorporated into a vector.

11. The recombinant nucleic acid molecule of claim 1 , further comprising a signal sequence.

12. 12. The recombinant nucleic acid molecule of claim 11, wherein the signal sequence comprises the amino acid sequence MAAPALSWRLPLLILLLPLATSWASA (SEQ ID NO: 62).

13. The recombinant nucleic acid molecule of claim 1, further comprising a 2A linker.

14. 10. The recombinant nucleic acid molecule of claim 1, further comprising a nucleic acid sequence encoding a chimeric antigen receptor.

15. 1. A recombinant nucleic acid molecule encoding a chimeric receptor, said chimeric receptor comprising: an extracellular portion comprising the binding domain of an endogenous inhibitory receptor linked to a drug specific for the common gamma chain; an intracellular portion comprising the endodomain of the IL-9 receptor; and a transmembrane domain connecting the extracellular portion and the intracellular portion A recombinant nucleic acid molecule comprising:

16. 16. The recombinant nucleic acid molecule of claim 15, further comprising one or more linkers.

17. 16. The recombinant nucleic acid molecule of claim 15, wherein the endogenous inhibitory receptor is selected from TGF-betaR1, TGF-betaR2, IL-10ra, FAS, CTLA4, LAG3, TIM3, PD1, ILT2, ILT3, ILT4, ILT5, and VEGF.

18. 16. The recombinant nucleic acid molecule of claim 15, wherein the endogenous inhibitory receptor comprises an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from SEQ ID NOs: 7-52.

19. 16. The recombinant nucleic acid molecule of claim 15, wherein the transmembrane domain is selected from the transmembrane domains of IL-9, IL-7ra, IL-2rb, and TNFR1.

20. 20. The recombinant nucleic acid molecule of claim 19, wherein the transmembrane domain comprises an amino acid sequence selected from SEQ ID NOs: 53-56.

21. 16. The recombinant nucleic acid molecule of claim 15, wherein the common gamma chain-specific agent comprises a nanobody, a DARPin, IL-2, IL-4, or an scFv.

22. An expression vector comprising a recombinant nucleic acid molecule according to any one of claims 1 to 21.

23. A recombinant host cell comprising a recombinant nucleic acid according to any one of claims 1 to 21 or an expression vector comprising a recombinant nucleic acid according to any one of claims 1 to 21.

24. 24. The recombinant cell of claim 23, wherein the recombinant cell is a eukaryotic cell.

25. 25. The recombinant cell of claim 24, wherein the eukaryotic cell is an animal cell.

26. 26. The recombinant cell of claim 25, wherein the animal cell is a mammalian cell.

27. 27. The recombinant cell of claim 26, wherein the mammalian cell is an immune cell, a neuron, an epithelial cell, an endothelial cell, or a stem cell.

28. 28. The recombinant cell of claim 27, wherein the recombinant cell is an immune cell or a dendritic cell.

29. The immune cells include B cells, monocytes, natural killer (NK) cells, basophils, eosinophils, neutrophils, dendritic cells, macrophages, regulatory T cells, helper T cells (T Ｈ ), cytotoxic T cells (T ＣＴＬ 29. The recombinant cell of claim 28, which is a T cell.

30. A composition comprising the recombinant nucleic acid of any one of claims 1 to 21.

31. A composition of cells comprising the expression vector of claim 22.

32. A polypeptide comprising a chimeric receptor encoded by a recombinant nucleic acid of any one of claims 1 to 21.

33. A composition comprising one or more polypeptides encoded by one or more recombinant nucleic acids of any one of claims 1 to 21.

34. A composition of cells capable of expressing a chimeric receptor encoded by a recombinant nucleic acid according to any one of claims 1 to 21.

35. A composition of cells comprising a chimeric receptor comprising an amino acid sequence selected from SEQ ID NOs: 81-203.

36. A method for modulating the activity of an immune cell, the method comprising administering to the immune cell a recombinant nucleic acid according to any one of claims 1 to 21.

37. 37. The method of claim 36, wherein the immune cell is a B cell, monocyte, natural killer (NK) cell, basophil, eosinophil, neutrophil, dendritic cell, macrophage, regulatory T cell, helper T cell (TH), cytotoxic T cell (TCTL), or other T cell.

38. 38. The method of claim 37, wherein the immune cell is a T cell.

39. The method of claim 38, wherein the T cells are CAR-T cells.

40. 22. A pharmaceutical composition for treating a disease in a subject, comprising a chimeric switch receptor expressed by a recombinant nucleic acid of any one of claims 1 to 21 or a cell expressing a recombinant nucleic acid of any one of claims 1 to 21.

41. 41. The pharmaceutical composition of claim 40, wherein the disease is cancer.

42. 41. The pharmaceutical composition of claim 40, wherein the disease is an autoimmune disease.

43. 41. The pharmaceutical composition of claim 40, wherein the disease is an infectious disease.

Images