WO2021244486A1 - Signal conversion receptor and use thereof - Google Patents

Signal conversion receptor and use thereof Download PDF

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WO2021244486A1
WO2021244486A1 PCT/CN2021/097361 CN2021097361W WO2021244486A1 WO 2021244486 A1 WO2021244486 A1 WO 2021244486A1 CN 2021097361 W CN2021097361 W CN 2021097361W WO 2021244486 A1 WO2021244486 A1 WO 2021244486A1
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seq
receptor
tgf
7ralpha
intracellular region
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PCT/CN2021/097361
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French (fr)
Chinese (zh)
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金华君
王超
郭晓春
黄晨
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上海君赛生物科技有限公司
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Priority to CN202180039676.XA priority Critical patent/CN115698038A/en
Publication of WO2021244486A1 publication Critical patent/WO2021244486A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material

Definitions

  • the present invention relates to the field of biotechnology, in particular to a signal conversion receptor and its use.
  • ACT tumor adoptive cell therapy
  • the human immune system has evolved a sophisticated and complex two-way immune regulation mechanism to regulate the immune response in both positive and negative directions.
  • the positive regulatory molecules of effector T cells include CD3/TCR complex, CD28, CD134 (OX40), CD137 (4-1BB), etc.
  • negative regulatory molecules include PD-1 (PDCD1, CD279), CTLA -4 (CD152), LAG3 (CD223), TIM3 (HAVCR2), etc.
  • TEE tumor microenvironment
  • TME tumor microenvironment
  • TGF- ⁇ has an inhibitory effect on the systemic immune system and inhibits the host's immune monitoring.
  • TGF- ⁇ plays an important role in the initiation and progression of tumors.
  • TGF- ⁇ has a tumor-promoting effect, it is usually produced in large numbers in many types of tumors and is known to have carcinogenic effects, and it has a negative impact on tumor immunity and significantly inhibits tumor immune monitoring of the host.
  • TGF- ⁇ significantly and directly inhibits the cytotoxic program of cytotoxic T lymphocytes (CTL) by inhibiting the transcription of genes encoding multiple key proteins. These key proteins include at least: perforin, granzyme A, Cytotoxins such as granzyme B, Fas ligand and g interferon.
  • TGF- ⁇ also has a significant impact on the differentiation and function of CD4+ T cells.
  • CN103965361B discloses a chimeric molecular converter for T cell signaling.
  • the chimeric molecular converter includes the extracellular domain of PD1 molecule (or the fusion protein of the extracellular domain of PD1 molecule and HERIN), CD28 transmembrane domain and CD28 (or 4-1BB) Intracellular costimulatory domain.
  • Tumor infiltrating lymphocytes (TIL) expressing the T cell signal chimeric molecular converter have significantly improved proliferation and killing effects on tumor target cells.
  • CN105452287A discloses an immunosuppressive TGF- ⁇ signal converter, which is a chimera comprising the extracellular domain of TGF- ⁇ receptor and an intracellular domain from another molecule, so that TGF- ⁇ interacts with the extracellular domain. The binding of the domains causes the intracellular domains to stimulate T cell activity.
  • the present invention provides an isolated fusion protein comprising: an extracellular domain of an immunosuppressive cytokine receptor or a functional fragment or mutant that retains specific binding to an immunosuppressive cytokine; a transmembrane region or a mutant thereof; Intracellular domain of costimulatory signal molecules or functional fragments or mutants that retain the biological functions of costimulatory signal molecules to transmit costimulatory signals and activate immune cells.
  • the immunosuppressive cytokine includes tumor cell or tumor stromal cell membrane protein and tumor cell or tumor stromal cell secreted protein.
  • the tumor cell or tumor stromal cell membrane protein includes PDL1/PDL2, FasL, B7-H4, Crry and HLA-G.
  • the tumor cell or tumor stromal cell secreted protein includes IL13, IL4, TGF- ⁇ , IL6, IL8, IL-10, CCL21, IDO, and VEGF.
  • the receptors for TGF- ⁇ include TGF- ⁇ receptor 1, TGF- ⁇ receptor 2, and TGF- ⁇ receptor 3, preferably TGF- ⁇ receptor 1 and TGF- ⁇ Receptor 2.
  • the costimulatory signal molecule includes CD28, CD134 (OX40), CD137 (4-1BB), LCK, ICOS, DAP10, siglec-9, siglec-10, siglec-15, TLR1, One of TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, IL-R2, IL-4R, IL-7R, IL-10R, IL-12R, IL-15R, IL-21R, CD27, and CD40 Kind or more.
  • the transmembrane region includes CD28, CD8, CD134 (OX40), CD137 (4-1BB), LCK, ICOS, DAP10, siglec-9, siglec-10, siglec-15, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, IL-2Rbeta, IL-2Rgamma, IL-4Ralpha, IL-7Ralpha, IL-10R, IL-12R, IL-15R, IL-21R, Any one or more of the transmembrane regions of CD27 and CD40.
  • the transmembrane region is derived from the IL-7Ralpha transmembrane region or a mutant thereof.
  • the amino acid sequence of the IL-7Ralpha transmembrane region mutant is shown in any one of SEQ ID NO: 29-60.
  • the coding sequence of the IL-7Ralpha transmembrane region mutant is shown in any one of SEQ ID NO: 61-94.
  • the extracellular region of the fusion protein is the extracellular region of TGF- ⁇ receptor 1, and the transmembrane region is derived from the IL-7Ralpha transmembrane region or a mutant thereof, and the fusion protein
  • the intracellular domain of the costimulatory molecule is selected from IL-7Ralpha intracellular region, CD28 intracellular region in series 4-1BB intracellular region, CD28 intracellular region, 4-1BB intracellular region, CD28 intracellular region in series OX40 cells Intracellular region, 28-IL2RB-z (YXXQ) intracellular region, 28-DeltaIL2RB-z (YXXQ) intracellular region, IL2RB-z (YXXQ) intracellular region and DeltaIL2RB-z (YXXQ) intracellular region kind.
  • the amino acid sequence of the fusion protein is shown in any one of SEQ ID NO: 95-350.
  • the extracellular region of the fusion protein is the extracellular region of TGF- ⁇ receptor 2, and the transmembrane region is derived from the IL-7Ralpha transmembrane region or a mutant thereof, and the fusion protein
  • the intracellular domain of the costimulatory molecule is selected from IL-7Ralpha intracellular region, CD28 intracellular region in series 4-1BB intracellular region, CD28 intracellular region, 4-1BB intracellular region, CD28 intracellular region in series OX40 cells Intracellular region, 28-IL2RB-z (YXXQ) intracellular region, 28-DeltaIL2RB-z (YXXQ) intracellular region, IL2RB-z (YXXQ) intracellular region and DeltaIL2RB-z (YXXQ) intracellular region kind.
  • the amino acid sequence of the fusion protein is SEQ ID NO: 351-606, SEQ ID NO: 1647, SEQ ID NO: 1649, SEQ ID NO: 1651, SEQ ID NO: 1653, SEQ ID NO: 1655, SEQ ID NO: 1657, SEQ ID NO: 1659, SEQ ID NO: 1661, SEQ ID NO: 1663, SEQ ID NO: 1665, SEQ ID NO: 1667, SEQ ID NO: 1669, SEQ ID NO :1671, SEQ ID NO: 1673 and SEQ ID NO: 1675 are shown in any one.
  • the extracellular region of the fusion protein is the extracellular region of TGF- ⁇ receptor 3, and the transmembrane region is derived from the IL-7Ralpha transmembrane region or a mutant thereof, and the fusion protein
  • the intracellular domain of the costimulatory molecule is selected from IL-7Ralpha intracellular region, CD28 intracellular region in series 4-1BB intracellular region, CD28 intracellular region, 4-1BB intracellular region, CD28 intracellular region in series OX40 cells Intracellular region, 28-IL2RB-z (YXXQ) intracellular region, 28-DeltaIL2RB-z (YXXQ) intracellular region, IL2RB-z (YXXQ) intracellular region and DeltaIL2RB-z (YXXQ) intracellular region kind.
  • the amino acid sequence of the fusion protein is shown in any one of SEQ ID NO: 607-862.
  • the present invention also provides a polynucleotide molecule selected from: polynucleotide molecules or complementary sequences encoding the fusion protein according to any embodiment of the present invention.
  • the polynucleotide molecule is selected from SEQ ID NO: 863-1630, SEQ ID NO: 1648, SEQ ID NO: 1650, SEQ ID NO: 1652, SEQ ID NO: 1654, SEQ ID NO: 1656, SEQ ID NO: 1658, SEQ ID NO: 1660, SEQ ID NO: 1662, SEQ ID NO: 1664, SEQ ID NO: 1666, SEQ ID NO: 1668, SEQ ID NO: 1670, SEQ ID NO :1672, SEQ ID NO: 1674 and SEQ ID NO: 1676 are shown in any one of them, or the complementary sequence of any of the shown polynucleotide molecules.
  • the present invention also provides a nucleic acid construct containing the polynucleotide molecule according to any embodiment of the present invention.
  • the nucleic acid construct is a vector.
  • the vector is an expression vector; preferably a viral vector.
  • the present invention also provides a genetically engineered cell that expresses the fusion protein according to any embodiment of the present invention and/or carries the coding sequence of the fusion protein.
  • the cell is an immune cell.
  • the immune cells are T cells.
  • the cell also expresses the CAR, or carries the coding sequence of the CAR.
  • the cell also expresses an exogenous TCR, or carries a coding sequence for an exogenous TCR.
  • the present invention also provides the use of the fusion protein, polynucleotide molecule, nucleic acid construct and genetically engineered cell according to any embodiment of the present invention in the preparation of a medicine for treating or preventing cancer.
  • Figure 1 Fluorescence micrographs of TCR-T electrotransformed with TCR-EGFP fusion gene and SCR1-5 TCR-T cells cotransfected with TCR-EGFP fusion gene + TGF- ⁇ signal conversion receptor gene.
  • FIG. 1 SCR1-5 TCR-T, RIID 2 TCR-T and TCR-T on the target cell A375 effective target ratio is set to 1.5:1 in vitro killing effect diagram.
  • FIG. 3 SCR1-5 TCR-T, RIID 4 TCR-T and TCR-T on the target cell A375 effective target ratio is set to 1.5:1 in vitro killing effect diagram.
  • FIG. 4 TCR-T, SCR5 TCR-T, RIID2 TCR-T on the target cell A375 effective target ratio is set to 1:1 in vitro killing effect diagram.
  • FIG. 6 TCR-T, SCR6 TCR-T, SCR7 TCR-T, SCR8 TCR-T, SCR9 TCR-T and SCR10 TCR-T to target cell A375 cell effective target ratio is set to 1.5:1 in vitro killing activity graph.
  • Figure 7 In vitro killing activity graph of TCR-T, SCR10 TCR-T and RIID2 TCR-T to target cell A375 cells with a target ratio of 0.5:1.
  • FIG. 8 TCR-T, SCR11 TCR-T, SCR12 TCR-T, SCR13 TCR-T, SCR14 TCR-T and SCR15 TCR-T to target cell A375 cell effective target ratio is set to 1.5:1 in vitro killing activity graph.
  • Figure 9 In vitro killing activity graph of TCR-T, SCR15 TCR-T and RIID4 TCR-T to target cell A375 cells with a target ratio of 0.75:1.
  • Figure 10 Diagram of the inhibitory effect of TCR-T, RIID2 TCR-T, RIID4 TCR-T and SCR5 TCR-T on tumor growth in mice with tumor cell line A375.
  • Figure 11 A diagram of the inhibitory effect of immune effector cells expressing the TGF- ⁇ signal conversion receptor SCR5 of the present invention, such as TCR-T, on tumor proliferation in vivo.
  • the present invention provides immune cells used for adoptive cell therapy of tumors, which, after being modified, can convert inhibitory signals that inhibit the proliferation of immune cells into stimulatory signals that enhance the proliferation of immune cells.
  • the stimulatory signal further includes a stimulatory signal that enhances anti-tumor activity.
  • immune cells have well-known meanings in the art, and refer to cells involved in or related to immune responses, including lymphocytes, dendritic cells, monocytes/macrophages, granulocytes, mast cells, and the like.
  • Lymphocytes include T lymphocytes, tumor infiltrating lymphocytes, B lymphocytes, K lymphocytes and NK lymphocytes.
  • Immune cells suitable for use in the present invention especially include those commonly used for adoptive cell therapy of tumors.
  • the immune cell of the present invention expresses the signal conversion receptor of the present invention, and/or contains the coding sequence of the signal conversion receptor.
  • the signal conversion receptor of the present invention is designed to bind inhibitory molecules but transmit a positive signal rather than an inhibitory signal. That is, these cells convert the "brake” signal into an "accelerate” signal to improve the anti-tumor effect of each immune cell.
  • expression cassette refers to the complete elements required to express a gene, including promoters, gene coding sequences, and PolyA tailing signal sequences.
  • coding sequence is defined herein as the part of the nucleic acid sequence that directly determines the amino acid sequence of its protein product (for example, signal switch receptor, CAR).
  • the boundary of the coding sequence is usually determined by the ribosome binding site (for prokaryotic cells) immediately upstream of the open reading frame at the 5'end of the mRNA and the transcription termination sequence immediately downstream of the open reading frame at the 3'end of the mRNA.
  • Coding sequences can include, but are not limited to DNA, cDNA, and recombinant nucleic acid sequences.
  • costimulatory signal molecule refers to a molecule that exists on the surface of antigen-presenting cells and can bind to the receptor for costimulatory signal molecules on Th cells to generate a costimulatory signal. It can activate the second signal of immune cells, enhance the proliferation ability of immune cells and the secretion of cytokines, and prolong the survival time of activated immune cells.
  • the proliferation of lymphocytes requires not only antigen binding, but also signals from costimulatory molecules.
  • Co-stimulatory signals are transmitted to T cells mainly through the co-stimulatory molecules CD80 expressed on the surface of antigen-presenting cells, and CD86 binds to CD28 molecules on the surface of T cells.
  • B cells can receive costimulatory signals through general pathogen components such as LPS, or through complement components, or through activated antigen-specific CD40L on the surface of Th cells.
  • linker or hinge is a polypeptide fragment that connects different proteins or polypeptides, and its purpose is to keep the connected proteins or polypeptides in their respective spatial conformations, so as to maintain the function or activity of the protein or polypeptide.
  • exemplary linkers include linkers containing G and/or S, and, for example, Furin 2A peptide.
  • pharmaceutically acceptable excipients refers to carriers and/or excipients that are pharmacologically and/or physiologically compatible with the subject and the active ingredient, which are well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and includes but not limited to: pH adjusters, surfactants, adjuvants, ionic strength enhancers.
  • pH adjusting agents include, but are not limited to, phosphate buffer
  • surfactants include, but are not limited to, cationic, anionic or nonionic surfactants, such as Tween-80
  • ionic strength enhancers include, but are not limited to, sodium chloride.
  • the term "effective amount” refers to a dose that can treat, prevent, alleviate and/or alleviate the disease or condition described in the present invention in a subject.
  • disease and/or disorder refers to a physical state of the subject, which is related to the disease and/or disorder described in the present invention.
  • subject may refer to patients or other animals receiving the pharmaceutical composition of the present invention to treat, prevent, alleviate and/or alleviate the diseases or conditions of the present invention, especially mammals, such as humans, dogs, monkeys, cows , Horse, etc.
  • tumor stromal cells refers to cells in the tumor microenvironment that support the malignant proliferation, anti-apoptosis, invasion and metastasis of tumor cells, escape immune surveillance and other life activities, mainly including fibroblasts and tumor-associated macrophages (TAMs) , Regulatory T cells (Treg), undifferentiated bone marrow cells, endothelial cells, pericytes and platelets, endothelial cells, etc.
  • immunosuppressive cytokine refers to a molecule that is produced by tumor cells or tumor stromal cells, which suppresses immunity, allows tumor cells to escape the body's immune monitoring, and induces immune tolerance.
  • extracellular region refers to the segment of membrane protein located outside the cell.
  • domain refers to a region with a specific structure and independent function in a protein.
  • the number of amino acid residues in common domains is between 100 and 400, and the smallest domain has only 40 to 50 amino acid residues, a large structure The domain can exceed 400 amino acid residues.
  • the signal conversion receptor of the present invention is a polypeptide, which is a fusion protein containing an intracellular domain (also referred to as an "intracellular region") with an immunostimulatory molecule (also referred to as a "costimulatory signal molecule”)
  • the extracellular domain of the fused immunosuppressive cytokine receptor also referred to as the "extracellular domain”
  • the signal conversion receptor of the present invention includes the extracellular domain of the immunosuppressive cytokine receptor, the transmembrane domain, and the intracellular domain of a costimulatory signal molecule.
  • the signal conversion receptor of the present invention binds Th2 or immunosuppressive cytokines but induces immunostimulatory signals instead of immunosuppression, resulting in the maintenance of Th1 phenotype, proliferation and cytotoxicity characteristics.
  • the immunosuppressive cytokine may be an immunosuppressive cytokine secreted by cancer cells or surrounding tumor stroma, including tumor cell or tumor stromal cell membrane protein and tumor cell or tumor stromal cell secreted protein.
  • the tumor cell or tumor stromal cell membrane protein includes but is not limited to PDL1/PDL2 (PD-1 ligand), FasL (Fas ligand), B7-H4 (immune costimulatory protein B7-H4, also known as VTCN1), Crry ( Membrane-associated complement regulatory protein, also known as Cr11) and HLA-G (non-classical MHC class I molecules), etc.;
  • the tumor cell or tumor stromal cell secreted protein includes but is not limited to IL13, IL4, TGF- ⁇ , IL6, IL8 , IL-10, CCL21, IDO (indoleamine 2,3-dioxygenase) and VEGF.
  • the present invention relates to the use of the extracellular domain
  • the immunosuppressive cytokine receptor in the signal conversion receptor of the present invention is the TGF- ⁇ receptor.
  • the extracellular domain of the TGF- ⁇ receptor of the present invention may only include the extracellular domain of the TGF- ⁇ receptor, or may be a chimeric TGF- ⁇ receptor containing a TGF-binding fragment of the TGF- ⁇ receptor.
  • the extracellular domain of any isotype of natural TGF- ⁇ receptor can be used, including TGF- ⁇ receptor 1, TGF- ⁇ receptor 2, and TGF- ⁇ receptor 3, preferably TGF- ⁇ receptor 1 and TGF - ⁇ receptor 2.
  • the amino acid sequence and polynucleotide sequence of an exemplary TGF- ⁇ receptor 1 extracellular region may be shown in SEQ ID NOs: 1 and 2, respectively.
  • An exemplary nucleotide sequence encoding TGF- ⁇ receptor 2 includes the sequence shown in Genbank accession number NM_001024847.2 or NM_003242.5, and the Genbank accession number of its amino acid sequence is NP_001020018 or NM_003242, respectively.
  • the extracellular domain of the present invention includes amino acids 23-166 from TGF- ⁇ receptor 2, as shown in SEQ ID NO: 3, and its coding sequence is as shown in SEQ ID NO: 4.
  • the exemplary amino acid sequence and polynucleotide sequence of the extracellular region of TGF- ⁇ receptor 3 may be shown in SEQ ID NOs: 5 and 6, respectively.
  • the receptor of the immunosuppressive factor in the signal conversion receptor of the present invention is the IL13 receptor, and the extracellular domain is the extracellular domain of the IL13 receptor, or the IL13 binding containing the IL13 receptor Fragment of the chimeric IL13 receptor.
  • costimulatory signal molecules include CD28, CD134 (OX40), CD137 (4-1BB), LCK, ICOS, DAP10, siglec-9, siglec-10, siglec-15, TLR1, TLR2, TLR3, TLR4, TLR5 , TLR6, TLR7, TLR8, TLR9, IL-2R, IL-4R, IL-7R, IL-10R, IL-12R, IL-15R, IL-21R, CD27 and CD40.
  • An exemplary IL-7R may be IL-7Ralpha, and its exemplary amino acid sequence and corresponding coding sequence may be as shown in SEQ ID NOs: 7 and 8, respectively.
  • the amino acid sequence and corresponding coding sequence of an exemplary CD28 intracellular region can be shown in SEQ ID NO: 9 and 10, respectively.
  • the amino acid sequence and the corresponding coding sequence of an exemplary 4-1BB intracellular region can be shown in SEQ ID NOs: 11 and 12, respectively.
  • the amino acid sequence of the intracellular region of OX40 is shown in SEQ ID NO:1645, and its coding sequence is shown in SEQ ID NO:1646.
  • the extracellular domain of an immunosuppressive cytokine receptor is connected to the intracellular domain of a costimulatory signal molecule through a transmembrane region (transmembrane domain).
  • the transmembrane zone can be of any source.
  • Transmembrane regions suitable for use in the present invention include but are not limited to CD28, CD8, CD134 (OX40), CD137 (4-1BB), LCK, ICOS, DAP10, siglec-9, siglec-10, siglec-15, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, IL-2Rgamma, IL-2Rbeta, IL-4Ralpha, IL-7Ralpha, IL-10R, IL-12R, IL-15R, IL-21R, CD27 and CD40 Any one or more of the transmembrane region or its mutants that retain the transmembrane function.
  • the transmembrane region can be derived from the same molecule as the intracellular domain, or from a different molecule.
  • the preferred transmembrane region is derived from the IL-7Ralpha transmembrane region and its mutants.
  • the exemplary amino acid sequence of the transmembrane region of IL-7Ralpha and its coding sequence are shown in SEQ ID NOs: 27 and 28, respectively.
  • the exemplary amino acid sequence of the IL-7Ralpha transmembrane region mutant can be selected from any one of SEQ ID NO: 29-60; preferably, the encoding nucleic acid sequence thereof is selected from any one of SEQ ID NO: 61-94.
  • the "functional fragment” described herein refers to a fragment that retains the desired biological function.
  • the functional fragment of the extracellular domain described herein refers to an organism that retains the ability to bind to the corresponding immunosuppressive cytokine;
  • the functional fragment of the intracellular domain refers to an organism that retains the costimulatory signal molecule to transmit costimulatory signals and activate immune cells. Fragment of learning function.
  • the functional fragment of the extracellular domain of TGF- ⁇ receptor 2 is a functional fragment from the extracellular domain that can bind to TGF- ⁇ receptor 2.
  • the functional fragments of each extracellular domain and the functional fragments of each intracellular domain suitable for the present invention can be easily determined by those skilled in the art in combination with the existing technical means in the art.
  • mutants include mutants of each extracellular domain, transmembrane region, and intracellular domain, as long as the mutant retains the extracellular domain, transmembrane region, and intracellular domain.
  • the biological function can be.
  • mutants of the extracellular domain suitable for use in the present invention include those having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity with the extracellular domain for comparison.
  • Mutants suitable for use in the transmembrane region of the present invention include at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity to the transmembrane region for comparison Mutants; mutants suitable for the intracellular domain of the present invention include at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% sequence of the intracellular domain as a comparison Mutants of identity. Alternatively, compared with the sequence for comparison, the mutants of the present invention have one or more (such as within 20, within 15, within 10, within 8, within 5 or within 3, such as 1 -20, 1-10, etc.) Insertion, substitution or deletion of amino acid residues.
  • the present invention also includes mutants of the aforementioned signal conversion receptor, such as having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity with the signal conversion receptor Mutant. More specifically, the present invention includes having one or more (such as within 20, within 15, within 10, within 8, within 5, or within 3 within) compared with the aforementioned signal conversion receptor, such as 1-20, 1-10, etc.) Mutants with insertion, substitution or deletion of amino acid residues. Such mutants retain the biological functions of the signal conversion receptor of the present invention, including but not limited to converting an inhibitory signal that inhibits the proliferation of immune cells into a stimulating signal that enhances the proliferation of immune cells. Mutations can occur in any one, any two, or all three of the extracellular domain, transmembrane region, and intracellular domain described herein.
  • Exemplary signal conversion receptors of the present invention include, but are not limited to, the extracellular domain, transmembrane region, and intracellular domain shown in each row of Table 1 below or the extracellular domain shown in each row of Table 1 below.
  • TGF- ⁇ receptor 3 IL-4Ralpha IL-4Ralpha TGF- ⁇ receptor 3 IL-7Ralpha CD28 TGF- ⁇ receptor 3 IL-7Ralpha 4-1BB TGF- ⁇ receptor 3 IL-7Ralpha OX40 TGF- ⁇ receptor 3 IL-7Ralpha CD28+4-1BB TGF- ⁇ receptor 3 IL-7Ralpha CD28+4-1BB+CD3z TGF- ⁇ receptor 3 IL-7Ralpha IL-7Ralpha TGF- ⁇ receptor 3 IL-10R CD28 TGF- ⁇ receptor 3 IL-10R 4-1BB TGF- ⁇ receptor 3 IL-10R OX40 TGF- ⁇ receptor 3 IL-10R CD28+4-1BB TGF- ⁇ receptor 3 IL-10R CD28+4-1BB+CD3z TGF- ⁇ receptor 3 IL-10R IL-10R TGF- ⁇ receptor 3 IL-12R CD28 TGF- ⁇ receptor 3 IL-12R 4-1BB TGF- ⁇ receptor 3 IL-12R OX40 TGF- ⁇ receptor 3 IL
  • the transmembrane region sequence of the mutated activation receptor may also be included, preferably a mutant of the transmembrane region of the mutated IL-7Ralpha. Mutants in the transmembrane region of the activated receptor can better aggregate the activated receptor and further activate and amplify intracellular signals on the basis of the wild-type receptor.
  • the sequence of IL-7Ralpha transmembrane mutant 1-32 (IL-7RalphaTM mut1-32) is shown in Table 2 and Table 3:
  • Exemplary signal conversion receptors of the present invention including IL-7Ralpha transmembrane region mutants 1-32 include, but are not limited to, the signal conversion receptors shown in any row of Table 4 below:
  • TGF- ⁇ receptor 1 IL-7Ralpha TM mut8 IL-7Ralpha intracellular region SEQ ID NO: 102 SEQ ID NO: 870 TGF- ⁇ receptor 1 IL-7Ralpha TM mut9 IL-7Ralpha intracellular region SEQ ID NO: 103 SEQ ID NO: 871 TGF- ⁇ receptor 1 IL-7Ralpha TM mut10 IL-7Ralpha intracellular region SEQ ID NO: 104 SEQ ID NO: 872 TGF- ⁇ receptor 1 IL-7Ralpha TM mut11 IL-7Ralpha intracellular region SEQ ID NO: 105 SEQ ID NO: 873 TGF- ⁇ receptor 1 IL-7Ralpha TM mut12 IL-7Ralpha intracellular region SEQ ID NO: 106 SEQ ID NO: 874 TGF- ⁇ receptor 1 IL-7Ralpha TM mut13 IL-7Ralpha intracellular region SEQ ID NO: 107 SEQ ID NO: 875 TGF- ⁇ receptor 1 IL-7Ralpha TM
  • TGF- ⁇ receptor 1 IL-7Ralpha TM mut30 CD28 intracellular region SEQ ID NO: 188 SEQ ID NO: 956 TGF- ⁇ receptor 1 IL-7Ralpha TM mut31 CD28 intracellular region SEQ ID NO: 189 SEQ ID NO: 957 TGF- ⁇ receptor 1 IL-7Ralpha TM mut32 CD28 intracellular region SEQ ID NO: 190 SEQ ID NO: 958 TGF- ⁇ receptor 1 IL-7Ralpha TM mut1 CD28 intracellular region + OX40 intracellular region SEQ ID NO: 191 SEQ ID NO:959 TGF- ⁇ receptor 1 IL-7Ralpha TM mut2 CD28 intracellular region + OX40 intracellular region SEQ ID NO: 192 SEQ ID NO: 960 TGF- ⁇ receptor 1 IL-7Ralpha TM mut3 CD28 intracellular region + OX40 intracellular region SEQ ID NO: 193 SEQ ID NO: 961 TGF- ⁇ receptor 1 IL-7Ralpha TM mut4
  • TGF- ⁇ receptor 1 IL-7Ralpha TM mut9 28-IL2RB-z(YXXQ) intracellular region SEQ ID NO: 231 SEQ ID NO: 999 TGF- ⁇ receptor 1 IL-7Ralpha TM mut10 28-IL2RB-z(YXXQ) intracellular region SEQ ID NO: 232 SEQ ID NO: 1000 TGF- ⁇ receptor 1 IL-7Ralpha TM mut11 28-IL2RB-z(YXXQ) intracellular region SEQ ID NO: 233 SEQ ID NO: 1001 TGF- ⁇ receptor 1 IL-7Ralpha TM mut12 28-IL2RB-z(YXXQ) intracellular region SEQ ID NO: 234 SEQ ID NO: 1002 TGF- ⁇ receptor 1 IL-7Ralpha TM mut13 28-IL2RB-z(YXXQ) intracellular region SEQ ID NO: 235 SEQ ID NO: 1003 TGF- ⁇ receptor 1 IL-7Ralpha TM mut14 28-IL
  • TGF- ⁇ receptor 1 IL-7Ralpha TM mut31 IL2RB-z(YXXQ) intracellular region SEQ ID NO: 317 SEQ ID NO:1085 TGF- ⁇ receptor 1 IL-7Ralpha TM mut32 IL2RB-z(YXXQ) intracellular region SEQ ID NO: 318 SEQ ID NO:1086 TGF- ⁇ receptor 1 IL-7Ralpha TM mut1 DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO: 319 SEQ ID NO: 1087 TGF- ⁇ receptor 1 IL-7Ralpha TM mut2 DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO: 320 SEQ ID NO: 1088 TGF- ⁇ receptor 1 IL-7Ralpha TM mut3 DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO: 321 SEQ ID NO:1089 TGF- ⁇ receptor 1 IL-7Ralpha TM mut4 DeltaIL2RB-z(
  • TGF- ⁇ receptor 2 IL-7Ralpha TM mut32 CD28 intracellular region SEQ ID NO: 446 SEQ ID NO:1214 TGF- ⁇ receptor 2 IL-7Ralpha TM mut1 CD28 intracellular region + OX40 intracellular region SEQ ID NO: 447 SEQ ID NO: 1215 TGF- ⁇ receptor 2 IL-7Ralpha TM mut2 CD28 intracellular region + OX40 intracellular region SEQ ID NO: 448 SEQ ID NO:1216 TGF- ⁇ receptor 2 IL-7Ralpha TM mut3 CD28 intracellular region + OX40 intracellular region SEQ ID NO: 449 SEQ ID NO:1217 TGF- ⁇ receptor 2 IL-7Ralpha TM mut4 CD28 intracellular region + OX40 intracellular region SEQ ID NO: 450 SEQ ID NO:1218 TGF- ⁇ receptor 2 IL-7Ralpha TM mut5 CD28 intracellular region + OX40 intracellular region SEQ ID NO: 451 SEQ ID NO:1219 TGF-
  • the present invention also includes signal conversion receptors containing CD28 transmembrane region and 28-DeltaIL2RB-z (YXXQ) intracellular region or 28-IL2RB-z (YXXQ) intracellular region.
  • Exemplary signal conversion receptors include but are not limited to Signal conversion receptors shown in Table 5:
  • TGF- ⁇ receptor 3 CD28 28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO: 1637
  • SEQ ID NO: 1643 TGF- ⁇ receptor 3
  • IL-7Ralpha TM mut1-32 in Shochat C, etc., "Gain-of-function mutations in interleukin-7 receptor- ⁇ (IL7R) in childhood acute lymphoblastic leukemias", J Exp. Med. May 9, 2011, 208(5 ): Reported publicly in 901-8, which is incorporated into this application in its entirety by reference.
  • 28-IL2RB-z(YXXQ), 28-DeltaIL2RB-z(YXXQ), 28-IL2RB-z(YXXQ) intracellular region and 28-DeltaIL2RB-z(YXXQ) intracellular region are in Yuki Kagoya, etc., "A Novel Chimeric Antigen Receptor Containing a JAK-STAT Signaling Domain Mediates Superior Antitumor Effects", Nat Med, published in March 2018, 24(3):352-359, the full text of which is incorporated into this application by reference, which is exemplary The amino acid sequence and the corresponding coding sequence are shown in SEQ ID NO: 13 and 14, SEQ ID NO: 15 and 16, SEQ ID NO: 17 and 18, and SEQ ID NO: 19 and 20, respectively.
  • IL2RB-z (YXXQ) intracellular region exemplary amino acid sequence and coding sequence are shown in SEQ ID NO: 21 and 22, respectively
  • DeltaIL2RB-z (YXXQ) intracellular region exemplary amino acid sequence and coding sequence, respectively
  • the 28-IL2RB-z (YXXQ) intracellular region and 28-DeltaIL2RB-z (YXXQ) intracellular region do not include parts of the CD28 intracellular region, respectively.
  • the signal conversion receptor further comprises a signal peptide.
  • the signal peptide is located at the N-terminus of the signal switch receptor.
  • the signal peptide can be any conventional signal peptide capable of guiding the polypeptide out of the nucleus, including but not limited to CD8, CD4, CD28, CD137, EGFR, TGFBRI, TGFBRII, TGFBRIII and light chain signal peptides.
  • the extracellular domain described herein and the transmembrane region, and/or the transmembrane region and the intracellular domain can be connected by a linker sequence.
  • a linker sequence known in the art can be used, such as a linker sequence containing G and S, such as (GSSS) n or (GSSSS) n , where n is an integer of 1-8.
  • the signal switch receptor of the present invention may also include a signal peptide sequence.
  • the signal peptide sequence is linked to the extracellular domain.
  • Exemplary signal peptide sequences include the signal peptide of the TGF- ⁇ receptor.
  • the signal peptide of the TGF- ⁇ receptor is amino acids 1-22 of TGF- ⁇ receptor 2 (SEQ ID NO: 1631), and the coding sequence is shown in SEQ ID NO: 1632.
  • the signal conversion receptor of the present invention may also contain single-chain antibodies or natural peptide fragments that recognize and bind to tumor-specific antigens or tumor-associated antigens. After the T cells expressing the molecular converter contact tumor cells, Further enhance immune activation.
  • the tumor-specific antigen or tumor-related antigen includes CD19, CD20, CEA, GD2, FR, PSMA, gp100, CA9, CD171/L1-CAM, IL-13R ⁇ 2, MART-1, ERBB2, NY-ESO-1, MAGE Family protein, BAGE family protein, GAGE family protein, AFP, MUC1, CD22, CD23, CD30, CD33, CD44v7/8, CD70, VEGFR1, VEGFR2, IL-11R ⁇ , EGP-2, EGP-40, FBP, GD3, PSCA , FSA, PSA, TAG-72, h5T4, fetal acetylcholine receptor, LeY, EpCAM, MSLN, IGFR1, EGFR, EGFRvIII, ERBB3, ERBB4, CA125, CA15-3, CA19-9, CA72-4, CA242, CA50, CYFRA21-1, SCC, AFU, EBV-VCA, TSGF, SF, POA, ⁇ 2-
  • the immune cells of the present invention may further express CAR or contain CAR coding sequence.
  • the CAR described in the present invention may be various CARs known in the art.
  • the CAR may sequentially include a polypeptide (such as scFv) that binds to tumor cell membrane antigen, a hinge region, a transmembrane region, and an intracellular signal region.
  • a polypeptide such as scFv
  • the hinge region, transmembrane region, and intracellular signal region known in the art for constructing CAR can be used to construct the CAR of the present invention.
  • polypeptides that bind tumor cell membrane antigens can bind to membrane antigens widely expressed by tumor cells with medium affinity.
  • the polypeptides are usually inserted with antigenic epitopes, and the insertion position is selected from any one, two or three of the following three positions : The N-terminus of the polypeptide, between the polypeptide and the hinge region, and inside the polypeptide.
  • the polypeptide that binds the tumor cell membrane antigen is a natural polypeptide or an artificially synthesized polypeptide; preferably, the artificially synthesized polypeptide is
  • the chimeric antigen receptor of the present invention can be directed against one or more of the following antigens: CD19, CD20, CEA, GD2 (also known as B4GALNT1, ⁇ GAL acetyl-galactosyltransferase 1), FR (Flavin reductase) ), PSMA (prostate specific membrane antigen), PMEL premelanosome protein), CA9 (carbonic anhydrase IX), CD171/L1-CAM, IL-13RL1, MART-1 (also known as mucin-A), ERBB2, NY-ESO-1 (also known as CTAG1B, cancer/testis antigen 1B), MAGE (melanoma associated antigen E1) family protein, BAGE (B melanoma antigen family) family protein, GAGE (growth hormone releasing factor) Family protein, AFP ( ⁇ fetoprotein), MUC1 (mucin1, cell surface related), CD22, CD23, CD30, CD33, CD44v7/8, CD70
  • a single cell can express multiple CARs, including CARs that target different tumor antigens.
  • TCR T cell receptor
  • the immune cells of the present invention may further express exogenous TCR or contain coding sequences expressing exogenous TCR genes.
  • the TCR of the present invention can be various TCRs known in the art, for example, a TCR with matching HLA typing, known sequence and structure, and also known bound antigen peptide sequence.
  • the exogenous TCR described in the present invention includes an ⁇ double-strand, which can form a complete TCR complex with the double-stranded structure of ⁇ , ⁇ , and ⁇ endogenously expressed by immune effector cells such as T cells.
  • the exogenous gene encoding the exogenous TCR of the present invention includes the alpha beta double-stranded gene, the alpha chain and the beta chain coding sequence are covalently linked by a linker sequence that can be cut in vivo, such as the coding DNA sequence of the P2A, T2A or F2A sequence, It can also be covalently linked via a DNA fragment encoding an IRES sequence.
  • the gene encoding the exogenous TCR of the present invention may also include a tag protein gene expressed in fusion with the ⁇ gene, such as EGFP, RFP, YFP genes and the like.
  • the tag protein gene can be covalently linked to the ⁇ double-stranded gene through a linker sequence that can be cut in vivo, such as a 2A sequence, such as a DNA sequence encoding P2A, T2A, or F2A, or a DNA sequence encoding an IRES sequence.
  • the tag proteins, such as EGFP, RFP, YFP genes, etc. are co-expressed with TCR ⁇ double-strands, and can be used as identification indicators for detecting the expression of exogenous TCR.
  • the TCR-T of the present invention can be directed against one or more of the following antigens: CD19, CD20, CEA, GD2 (also known as B4GALNT1, ⁇ GAL acetyl-galactosyltransferase 1), FR (Flavin reductase), PSMA (prostate-specific membrane antigen), PMEL premelanosome protein), CA9 (carbonic anhydrase IX), CD171/L1-CAM, IL-13RL1, MART-1 (also known as mucin-A), ERBB2, NY-ESO-1 (also known as CTAG1B, cancer/testis antigen 1B), MAGE (melanoma associated antigen E1) family protein, BAGE (B melanoma antigen family) family protein, GAGE (growth hormone releasing factor) family protein , AFP ( ⁇ fetoprotein), MUC1 (mucin 1, cell surface related), CD22, CD23, CD30, CD33, CD44v7/8, CD70, V
  • a single cell can express multiple exogenous TCRs, including exogenous TCRs targeting different tumor antigens.
  • the present invention provides polynucleotide molecules, which encode the signal conversion receptor of the present invention.
  • the present invention also provides the complementary sequence of the coding sequence of the signal conversion receptor.
  • the polynucleotide molecule can be a recombinant nucleic acid molecule or synthetic; it can include DNA, RNA, and PNA (peptide nucleic acid) and can be a hybrid thereof.
  • the expression cassette of the signal switch receptor of the present invention which is a nucleic acid construct containing a promoter, a signal switch receptor coding sequence and a PolyA tailing signal sequence.
  • the nucleic acid construct may also contain other elements required for expression, including but not limited to enhancers and the like.
  • a vector which contains the polynucleotide molecule, expression cassette or nucleic acid construct described herein.
  • the vector can be a plasmid, cosmid, virus, and phage.
  • the vector can be a cloning vector or an expression vector.
  • the expression vector may be a transposon vector.
  • the expression vector is one or more selected from the following transposon vectors: piggybac, sleeping beauty, frog prince, Tn5 and Ty.
  • the expression vector usually also contains other elements commonly contained in the vector, such as multiple cloning sites, resistance genes, replication origin sites, and the like.
  • the recombinant expression vector uses pUC18, pUC19, pMD18-T, pMD19-T, pGM-T vector, pUC57, pMAX or pDC315 series vector as a backbone.
  • the recombinant expression vector uses pCDNA3 series vectors, pCDNA4 series vectors, pCDNA5 series vectors, pCDNA6 series vectors, pRL series vectors, pUC57 vectors, pMAX vectors or pDC315 series vectors as the backbone.
  • the present invention uses the pSN vector constructed by CN 201510638974.7.
  • the CAR of the present invention can also be expressed in the immune cells of the present invention through conventional vectors.
  • the vector can be a conventional CAR expression vector, including but not limited to the various transposon vectors and recombinant expression vectors described above.
  • the same vector encodes both the signal switch receptor of the present invention and the CAR.
  • the vector can be a bicistronic.
  • the CAR coding sequence can be set at the 5'or 3'end of the signal conversion receptor coding sequence.
  • the expression of CAR and signal switch receptor can be under the guidance of the same or different regulatory sequences.
  • each polynucleotide molecule can be prepared by conventional methods in the art, and the corresponding vector can be constructed.
  • Recombinant vectors can be constructed using methods well known to those skilled in the art, see, for example, the techniques described in Sambrook et al., Ausubel (1989) or other standard textbooks.
  • the nucleic acid molecules and vectors can be reconstituted into liposomes for delivery to target cells.
  • the vector containing the nucleic acid molecule of the present invention can be transferred to a host cell by a well-known method, which varies according to the type of the cell host. For example, calcium chloride transfection is usually used for prokaryotic cells, while calcium phosphate treatment or electrotransfection can be used for other cell hosts, see Sambrook.
  • a “host cell” refers to a eukaryotic cell, which is capable of replicating a vector and/or expressing a heterologous gene encoded by the vector.
  • the host cell can be used as the acceptor of the vector.
  • a host cell can be "transfected” or “transformed”, which refers to the process of transfection or transduction of exogenous nucleic acid into the host cell. Transformed cells include the primary target cell and its progeny.
  • the terms “engineered” and “recombinant” cells or host cells as used herein often refer to cells into which exogenous nucleic acid sequences, such as vectors, have been introduced. Therefore, recombinant cells can be distinguished from naturally occurring cells that do not contain the introduced recombinant nucleic acid.
  • host cells include cells that carry the polynucleotide molecules and/or polypeptides described herein.
  • the present invention provides a cell carrying the signal conversion receptor of the present invention and/or its coding sequence.
  • the cells of the present invention are preferably immune cells, which can be used for tumor adoptive cell therapy.
  • Such cells of the present invention are also referred to as cells modified by the signal conversion receptor of the present invention.
  • the cells of the present invention are preferably immune effector cells, including T cells, such as cytotoxic T cells (also known as TC, cytotoxic T lymphocytes, CTL, T killer cells, cytolytic T cells, CD8+ T cells or killer T cells); NK cells; NKT cells; and other immune cells that can trigger effector functions.
  • T cells such as cytotoxic T cells (also known as TC, cytotoxic T lymphocytes, CTL, T killer cells, cytolytic T cells, CD8+ T cells or killer T cells); NK cells; NKT cells; and other immune cells that can trigger effector functions.
  • the cells may be autologous cells, syngeneic cells, allogeneic cells, and even xenograft cells in some cases.
  • the nucleic acid construct/recombinant expression vector of the present invention can be transferred into the cell of interest.
  • the method of transfer is a conventional method in the field, including but not limited to: virus transduction, microinjection, particle bombardment, gene gun transformation and electroporation, etc.
  • electroporation is used to transfer the nucleic acid construct or recombinant expression vector.
  • the cells of the present invention may also have one or more other characteristics that can be used in cellular immunotherapy (such as adoptive cell therapy for tumors). Such other characteristics may be inherent to the cell or may be part of the cell after a human has been genetically manipulated.
  • the cells of the present invention may carry chimeric antigen receptors, ⁇ T cell receptors, and/or antigen-specific receptors, such as tumor-specific receptors, or coding sequences thereof.
  • composition refers to a composition for administration to an individual and encompasses a composition for cells used for immunotherapy.
  • the pharmaceutical composition of the present invention may also include a pharmaceutically acceptable carrier.
  • suitable pharmaceutical carriers include phosphate buffered saline solution, water, emulsions such as oil/water emulsions, various types of wetting agents, sterile solutions, and the like.
  • Compositions containing such carriers can be formulated by well-known conventional methods. These pharmaceutical compositions can be administered to a subject in an appropriate dose.
  • the dosage regimen can be determined by the attending physician and clinical factors. As is well known in the medical field, the dosage for any one patient depends on many factors, including the patient’s size, body surface area, age, specific compound to be administered, gender, time and route of administration, general health and simultaneous Other drugs given.
  • composition of the present invention can be administered locally or systemically.
  • the composition provided by the present invention e.g., cells expressing the signal conversion receptor of the present invention
  • the DNA encoding the construct provided by the present invention can be directly administered to the target site, for example, delivered to an internal or external target site via a gene gun or delivered to an intra-arterial site via a catheter.
  • the pharmaceutical composition is administered subcutaneously, and in a more preferred embodiment, administered intravenously.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous vehicles include water, alcohol solutions/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution or fixed oil.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present, such as antimicrobial agents, antioxidants, chelating agents, inert gases, and the like.
  • the pharmaceutical composition of the present invention may include a proteinaceous carrier, such as serum albumin or immunoglobulin, preferably of human origin.
  • the pharmaceutical composition of the present invention may also contain a biologically active agent, depending on the intended use of the pharmaceutical composition.
  • the signal conversion receptors, polynucleotide molecules, vectors, host cells and pharmaceutical compositions containing these substances of the present invention can be used to prevent, treat or alleviate cancer, especially cancers with corresponding tumor antigens expressed on the surface of cancer cells, or It is used to prepare medicines for preventing, treating or alleviating cancer.
  • Treatment includes any beneficial or desired effect on the symptoms or pathology of a disease or pathological condition, and may include one or more measurable markers of the disease or condition (e.g., cancer) under treatment There is even a small reduction in the material. Treatment may optionally include a reduction or alleviation of symptoms of the disease or disorder, or a delay in the progression of the disease or disorder. “Treatment” does not necessarily mean the complete eradication or cure of a disease or condition or its related symptoms.
  • prevention refers to a method for preventing, inhibiting, or reducing the likelihood of occurrence or recurrence of a disease or condition (e.g., cancer). It also refers to delaying the onset or recurrence of a disease or condition or delaying the onset or recurrence of symptoms of a disease or condition. "Prevention” as used herein also includes reducing the intensity, impact, symptoms, and/or burden of a disease or disorder before it occurs or recurs.
  • the present invention includes the use of standard carriers and/or gene delivery systems to administer cells, polynucleotide molecules and carriers alone or in any combination, optionally together with pharmaceutically acceptable carriers or excipients.
  • the polynucleotide molecule or vector can be stably integrated into the genome of the subject.
  • a viral vector that specifically targets certain cells or tissues and persists in the cells can be used.
  • Suitable pharmaceutical carriers and excipients are well known in the art.
  • the composition prepared according to the present invention can be used to prevent or treat or delay the above-identified diseases.
  • the present invention provides a method for preventing, treating or alleviating cancer, which includes the following steps: administering to a subject in need an effective amount of cells carrying the described and/or produced by the method of the present invention Signal conversion receptors, polynucleotide molecules and/or vectors.
  • cancer includes but is not limited to breast, prostate, lung and colon cancer or epithelial cancer, such as breast cancer, colon cancer, prostate cancer, head and neck cancer, skin cancer; genital-urinary tract cancer, such as ovarian cancer, endometrial cancer , Cervical cancer; kidney cancer, lung cancer, stomach cancer, small intestine cancer, liver cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, esophageal cancer, salivary gland cancer and thyroid cancer.
  • Administration of the composition of the present invention can be used for all stages and types of cancer, including for example minimal residual disease, early cancer, advanced cancer and/or metastatic cancer and/or difficult-to-treat cancer.
  • a cancer patient or a patient susceptible to cancer or a patient suspected of having cancer are treated as follows.
  • Cells modified as described herein can be administered to an individual and stay for an extended period of time.
  • the individual can receive one or more administrations of the cells, and the interval between administrations can be days, weeks, months, or years. In specific embodiments, multiple administrations can occur within weeks or months, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks or months .
  • genetically modified cells are encapsulated to inhibit immune recognition and are located at the tumor site.
  • these cells can be changed to recognize different target tumor antigens. For example, when the initial round includes cells carrying the signal conversion receptor of the present invention and another receptor specific for a specific antigen, receptors for different specific antigens can be used after subsequent rounds (including after tumor recurrence).
  • an effective amount of therapeutic cells is provided to an individual in need, the therapeutic cells carrying or expressing the signal conversion receptor according to any embodiment of the present invention and optionally CAR or exogenous transgenic TCR.
  • These cells can be delivered at the same time or at different times with one or more other cancer treatments.
  • These cells and other cancer therapeutics can be delivered in the same or separate formulations.
  • Cells and other cancer therapeutics can be provided to individuals with separate delivery routes.
  • the cells and/or other cancer therapeutics can be delivered by, for example, injection at the tumor site or intravenously or orally. Conventional delivery routes for such compositions are known in the art.
  • the number of cells used will depend on various conditions, such as the purpose of introduction, the lifespan of the cells, the protocol to be used, the number of administrations, the ability of the cells to multiply, and the stability of the recombinant construct.
  • the cells can be administered as needed.
  • multiple protocols can be used to adjust protocol parameters.
  • the route or number of times or timing of administration, the life span of the cells, and/or the number of cells present can be changed.
  • the number of administrations may, for example, depend at least in part on the aforementioned factors.
  • kits may include cells expressing the signal conversion receptor described in any embodiment of the present invention for cell therapy and/or generating one or more cells for cell therapy Cell reagents, the therapy contains recombinant expression vectors.
  • the kit components are provided in suitable containers.
  • kits can be packaged in an aqueous matrix or packaged in a lyophilized form.
  • the container utensils of these kits usually include at least one vial, test tube, flask, bottle, syringe or other container utensil, in which the component can be placed, and is preferably appropriately dispensed therein.
  • the kit usually also contains a second, third or other container in which other components can be placed separately.
  • various combinations of components can be included in the vial.
  • the kit of the present invention usually also contains a commercially available device containing the component in a closed and restrained form.
  • Such containers may include injection-molded or blow-molded plastic containers in which the desired vials are retained.
  • the liquid solution is an aqueous solution, and a sterile aqueous solution is particularly preferred.
  • the container appliance itself may be a syringe, pipette, and/or other such devices.
  • kits can also be provided in dry powder form.
  • the powder can be reconstituted by adding a suitable solvent. Therefore, the kit may also include a second container device containing a sterile, pharmaceutically acceptable buffer and/or other diluent.
  • the cells to be used in the cell therapy described herein are provided in a kit.
  • the cell is essentially the only component of the kit.
  • the kit may contain reagents and materials for preparing the required cells.
  • the reagents and materials include primers, nucleotides, suitable buffers or buffer reagents, salts, etc., for amplifying the desired sequence, and in some cases, the reagents include coding for any of the embodiments herein.
  • the present invention creatively connects the polypeptides, transmembrane peptides and intracellular peptides of costimulatory signal molecules that efficiently bind to tumor cell surface and/or tumor stromal cell surface immunosuppressive molecules to form a fusion protein with T signal molecule converter function
  • T cells modified by the fusion protein come into contact with the immunosuppressive molecules on the surface of tumor cells and/or tumor stromal cells, they will not be negatively affected by the immunosuppressive molecules, but instead have an immune activation effect and enhance the proliferation of T cells.
  • the ability and secretion function of cytokines can prolong the survival time of activated immune cells, thereby overcoming the side effects of tumor immunosuppressive microenvironment on the effector cells of tumor adoptive cell therapy. It effectively improves the suppression and suppression of immune effector cells on tumors both in vivo and in vitro. Killing effect.
  • the pNB vector was constructed according to the method described in Example 1 on page 15 of the Chinese Patent CN105154473B specification. According to the method described in Example 2 on page 15 of CN105154473B specification, pNB containing the expression cassette of TGF- ⁇ signal conversion receptor 2-1-TGF- ⁇ signal conversion receptor 2-15 (TGFBR2-SCR1-TGFBR2-SCR15) was constructed Carrier.
  • FIG. 1 Chinese patent application CN105452287A describes a signal transduction receptor containing the extracellular domain of TGF- ⁇ receptor 2.
  • Example 1 on page 21 of the specification describes two signal transduction receptor structures, RIID2 and RIID4, each containing TGF- ⁇ Signal conversion receptor 2 signal peptide, TGF- ⁇ signal conversion receptor 2 extracellular domain, TLR2 transmembrane region, TLR2 intracellular domain signal conversion receptor and TGF- ⁇ signal conversion receptor 2 signal peptide, TGF- ⁇ signal Switch receptor 2 extracellular region, TLR4 transmembrane region, TLR4 intracellular region.
  • the signal conversion receptors SCR-RIID2 and SCR-RIID4 including the above-mentioned elements were synthesized, neither of which contained IRES and orange fluorescent protein (mOrange) or green fluorescent protein (GFP).
  • TGFBR2-SCR1-TGFBR2-SCR15 The corresponding structures of TGFBR2-SCR1-TGFBR2-SCR15, SCR-RIID2 and SCR-RIID4 are shown in Table 6 below:
  • SEQ ID NO: 1648 SEQ ID NO: 1650, SEQ ID NO: 1652, SEQ ID NO: 1654, SEQ ID NO: 1656, SEQ ID NO: 1658, SEQ ID NO: 1660, SEQ ID NO: 1662, SEQ ID NO: 1664, SEQ ID NO: 1666, SEQ ID NO: 1668, SEQ ID NO: 1670, SEQ ID NO: 1672, SEQ ID NO: 1674, SEQ ID NO: 1676, SEQ ID NO 1678, SEQ ID NO: 1680, the above sequences were cloned into the prepared pNB vector according to the method described in Example 2 on page 15 of CN105154473B specification, respectively named pNB328-1648, pNB328-1650, pNB328- 1652, pNB328-1654, pNB328-1656, pNB328-1658, pNB328-1660, pNB328-1662, pNB328-1664, p
  • the recombinant plasmids obtained above were transformed into E. coli (DH5c), and after the sequencing was correct, the plasmids were extracted and purified using Qiagen's plasmid purification kit to obtain high-quality plasmids for each recombinant expression vector.
  • the spliced sequence is as follows SEQ ID NO: 1681 is shown. At the 3'end of SEQ ID NO: 1681, the DNA sequence encoding EGFP is connected with the DNA encoding the P2A peptide segment, and the resulting sequence is shown in SEQ ID NO: 1682. The company entrusted the company to synthesize and obtain SEQ ID NO: 1682.
  • SEQ ID NO: 1682 was cloned into the prepared pNB vector and named as pNB328-1682.
  • the PB transposase coding region and CMV promoter in the pNB vector are deleted to obtain the vector pNC without the PB transposase expression cassette.
  • SEQ ID NO: 1682 was cloned into the prepared pNC vector and named as pNC328-1682.
  • the obtained recombinant plasmid was transformed into E. coli (DH5c), after the sequencing was correct, the plasmid was extracted and purified using Qiagen's plasmid purification kit to obtain high-quality plasmids for each recombinant expression vector.
  • AIM-V medium Preliminarily add AIM-V medium to 19 wells of a 12-well plate, 2 mL per well, and then transfer it to a cell incubator at 37°C and 5% CO2 for preheating for 1 hour;
  • the cells expressing foreign genes prepared by the above methods were named TCR-T, SCR1 TCR-T, SCR2 TCR-T, SCR3 TCR-T, SCR4 TCR-T, SCR5 TCR-T, SCR6 TCR-T, SCR7 TCR -T, SCR8 TCR-T, SCR9 TCR-T, SCR10 TCR-T, SCR11 TCR-T, SCR12 TCR-T, SCR13 TCR-T, SCR14 TCR-T, SCR15 TCR-T, RIID2 TCR-T, RIID4 TCR -T and Mock TCR-T.
  • EGFP-positive cells can be regarded as NY-ESO-1 TCR gene-positive cells.
  • TCR-T EGFP-positive cells
  • EGFP positive indicates that the successful integration and expression of TCR-EGFP depends on the PB transposase from the expression encoding TGF - ⁇ signal conversion receptor gene pNB vector, so in cells co-transformed with TGF- ⁇ signal conversion receptor and TCR, EGFP-positive cells can be considered as the dual integrated expression of TGF- ⁇ signal conversion receptor and NY-ESO-1 TCR .
  • Table 8 The results are shown in Figure 1 and Table 8:
  • FIG. 1 shows the fluorescence micrographs of TCR-T electrotransformed with TCR-EGFP fusion gene and SCR1-5 TCR-T cells co-transformed with TCR-EGFP fusion gene + TGF- ⁇ signal conversion receptor gene.
  • the EGFP fluorescence brightness of TCR-T is brighter than the fluorescence brightness of SCR1-5 TCR-T.
  • TCR-T is prepared by a single plasmid.
  • the single plasmid includes both the exogenous TCR-EGFP fusion gene and PB transposase.
  • TCR-T requires two plasmids to be prepared by co-transformation, and the exogenous TCR-EGFP fusion gene and PB transposase expression cassette need to be provided by two vectors, pNC and pNB, respectively.
  • the HLA-*02:01 type melanoma cell line A375 (all purchased from the American Type Culture Collection ATCC) with positive NY-ESO-1 expression was selected as the target cells, and the real-time label-free cell function analyzer (RTCA) Test the TCR-T, SCR1 TCR-T, SCR2 TCR-T, SCR3 TCR-T, SCR4 TCR-T, SCR5 TCR-T, RIID2 TCR-T and RIID4 TCR-T cells prepared in Example 3 in vitro Killing activity, the specific steps are as follows:
  • Target cell plating The melanoma cell A375 is plated on the plate containing the detection electrode at 104 cells/50 ⁇ l per well, and placed for a few minutes. After the cells have stabilized, put them in the instrument and start step 2, culturing the cells;
  • Figure 2 and Figure 3 respectively show the killing effect of SCR1-5 TCR-T, RIID 2 TCR-T and TCR-T on target cells and SCR1-5 TCR-T, RIID 4 TCR-T and TCR-T on target cells Killing effect.
  • the effect-to-target ratio is set to 1.5:1, and the killing effect is observed for a long time.
  • Figures 2 and 3 both show that shortly after adding effector cells (24h), SCR4 TCR-T and SCR5 TCR-T have been shown to be significantly better than TCR-T, SCR1/2/3 TCR-T, Target cell killing effect of RIID2 TCR-T and RIID4 TCR-T.
  • SCR1-5 TCR-T has more effective killing effect on target cell A375.
  • the killing effect of SCR1/2/3 TCR-T is close, and SCR4 TCR-
  • the killing effect of T is better than that of SCR1/2/3 TCR-T, and the killing effect of SCR5-TCR-T is significantly better than that of SCR1-4 TCR-T and TCR-T, which is the best among several effector cells.
  • Figure 2 shows that the killing effect of RIID2 TCR-T is close to that of TCR-T, which is slightly lower than that of TCR-T;
  • Figure 3 shows that the killing effect of RIID4 TCR-T is slightly better than that of TCR-T, but lower than SCR1.
  • 2/3 TCR-T which is also significantly lower than SCR4 TCR-T and SCR5TCR-T.
  • Example 5 Specific killing effect of TCR-T expressing TGF- ⁇ signal conversion receptor SCR5 on target cells under low-efficiency targets fruit
  • Example 4 A375 was selected as the target cell, and TCR-T, SCR5 TCR-T, RIID2 TCR-T and RIID4 TCR-T were selected as effector cells, and the effective target ratio was further reduced to 1:1, and several effector cells were compared
  • the operation is the same as in Example 4.
  • the 1:1 low-efficiency target ratio long-term observation is intended to simulate the scenario of T cells killing tumors in the real environment in vivo.
  • Figure 4 shows that shortly after the effector cell addition time point (just after 40h), the killing effect of RIID2 TCR-T has been shown to be better than that of TCR-T, while the killing effect of SCR5 TCR-T is significantly better than the former two. After the killing detection time exceeds 120h, the killing effect of RIID2 TCR-T is still better than that of TCR-T, while the killing effect of SCR5 TCR-T is still better than the former two.
  • Figure 5 shows that shortly after the effector cell addition time point (just after 40h), the killing effect of RIID4 TCR-T has been shown to be better than that of TCR-T, while the killing effect of SCR5 TCR-T is significantly better than the previous two.
  • the killing detection time exceeds 120h, the killing effect of RIID4 TCR-T is still better than TCR-T, and the killing effect of SCR5 TCR-T is also better than the former two.
  • the killing effect of SCR6/7/8 TCR-T is close, and SCR9 TCR-
  • the killing effect of T and SCR10 TCR-T is better than that of SCR6/7/8 TCR-T, and the killing effect of SCR10 TCR-T is the best among several effector cells.
  • Example 4 A375 was selected as target cells, TCR-T, SCR10 TCR-T and RIID2 TCR-T were selected as effector cells, and the effective target ratio was further reduced to 0.5:1, and the killing of A375 cells by several effector cells was compared. Level, the operation is the same as in Example 4.
  • 0.5:1 Low-efficiency target ratio long-term observation is intended to simulate the scene of T cells killing tumors in the real environment in vivo.
  • Figure 7 shows that after 80 hours, the killing effect of RIID2 TCR-T has been shown to be better than that of TCR-T, while the killing effect of SCR10 TCR-T is significantly better than the former two. After the killing detection time is 140h, the killing effect of RIID2 TCR-T is still better than that of TCR-T, while the killing effect of SCR10 TCR-T is significantly better than the former two.
  • the signal conversion receptor SCR10 of the present invention can still effectively increase the killing level of effector T cells on tumor target cells.
  • Example 8 Killing effect of TCR-T expressing TGF- ⁇ signal conversion receptor SCR11-15 on target cells
  • TCR-T and SCR11-15 TCR-T prepared in Example 3 were tested for their in vitro killing activity on A375 cells, and the effective target ratio was set to 1.5:1 based on the proportion of EGFP-positive cells.
  • the specific detection steps were the same as in Example 4.
  • the result is shown in Figure 8. Soon after adding the effector cells (24h), SCR11/12/14/15 TCR-T has shown a significantly better target cell killing effect than TCR-T. After the killing time reaches 90 hours, compared with TCR-T, SCR11-15 TCR-T has more obvious killing effect on target cell A375.
  • the killing effect of SCR11/12 TCR-T is close to that of SCR13 TCR-T; SCR14 /15
  • the killing effect of TCR-T is better than that of SCR11/12 TCR-T, and the killing effect of SCR15 TCR-T is the best among several effector cells.
  • the above results indicate that the signal conversion receptor SCR11-15 of the present invention can still significantly increase the killing level of effector T cells to tumor target cells under the condition of lower effective target ratio, and this improvement effect still exists when the killing time is long.
  • Example 4 A375 was selected as target cells, TCR-T, SCR15 TCR-T and RIID4 TCR-T were selected as effector cells, and the effective target ratio was further reduced to 0.75:1, and the killing of A375 cells by several effector cells was compared. Level, the operation is the same as in Example 4. 0.75:1 low-efficiency target ratio long-term observation is intended to simulate the scene of T cells killing tumors in the real environment in vivo.
  • Figure 9 shows that shortly after the addition of effector cells, the killing effect of RIID4 TCR-T has been shown to be better than that of TCR-T, and the killing effect of SCR15 TCR-T was significantly better than the former two starting from 60 hours ago. After the killing detection time reaches 100 hours, the killing effect of RIID4 TCR-T is still better than that of TCR-T, while the killing effect of SCR15 TCR-T is significantly better than the former two.
  • the signal conversion receptor SCR15 of the present invention can still effectively increase the killing level of effector T cells on tumor target cells.
  • TGF- ⁇ signal conversion receptor enhances TCR-T cytokine secretion level
  • TGF- ⁇ 1 factor purchased from R&D SYSTEMS catalog number: 240-B-002/CF
  • TGF- ⁇ 1 factor purchased from R&D SYSTEMS catalog number: 240-B-002/CF
  • HTRF IFN- ⁇ detection kit Cisbio Human IFN gamma kit item number: 62HIFNGPET
  • Figure 10 shows that compared with the TCR-T group not treated with TGF- ⁇ 1, the secretion level of IFN- ⁇ in the TCR-T group treated with TGF- ⁇ 1 was significantly reduced, indicating that the naturally occurring TGF- ⁇ receptor on the surface of T cells The body has an inhibitory effect on T cell activation after binding to the TGF- ⁇ 1 factor.
  • the secretion level of IFN- ⁇ is no matter compared with the TCR-T group treated with TGF- ⁇ 1 or compared with the TCR-T group without TGF- ⁇ 1 treatment. There has been a significant improvement.
  • immune effector cells such as TCR-T cells
  • TCR-T cells can effectively increase the activation level of T cells when they bind to the corresponding ligands such as TGF- ⁇ 1 factor after introducing the signal conversion receptor of the present invention, and this effect can be offset. And overtake the corresponding ligand such as TGF- ⁇ 1 binding to the natural inhibitory receptor on the surface of the cell itself, the inhibitory effect on the cell.
  • TGF- ⁇ signal conversion receptor enhances the tumor suppressor level of TCR-T in vivo
  • mice with tumor cell line A375 were tested.
  • the immunodeficiency mouse NSG purchased from The Jackson Laboratory
  • the immunodeficiency mouse NSG was used for tumor formation in the A375 cell line.
  • NSG mice were reared in a standard SPF animal room for two weeks to adapt to the environment, providing 12h circadian rhythm alternate control, with an ambient temperature of 20-24°C and a humidity of 45-65%.
  • A375 cells were cultured in DMEM medium and 10% fetal bovine serum to 80-90% confluence, the cell count and survival rate were calculated.
  • each mouse was subcutaneously injected with 100 ⁇ L on the left side containing 1 ⁇ 10 7 A PBS cell suspension of live A375 cells to minimize pain in mice.
  • the cells prepared in Example 3 were used for reinfusion. After the administered cells passed through a 70 ⁇ m sieve, they were resuspended in PBS.
  • TCR-T was 44.22%, which was about 2 times the proportion of EGFP positive cells in RIID2 TCR-T, RIID4 TCR-T and SCR5 TCR-T.
  • the cells in the TCR-T group gave The dose of 1 ⁇ 10 7 cells was resuspended in 200 ⁇ L PBS, and the dose of cells in the RIID2 TCR-T, RIID4 TCR-T and SCR5 TCR-T groups was 2 ⁇ 10 7 cells, resuspended in 200 ⁇ L PBS; the control group Each was given 200 ⁇ L PBS.
  • the drug was administered via tail vein injection at the three time points D0, D1 and D2. Observe the trend of tumor size in mice over time.

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Abstract

A signal conversion receptor and a use thereof. The signal conversion receptor comprises an extracellular domain of a receptor for an immunosuppressive cytokine or a functional fragment or a mutant thereof that retains the specific binding to the immunosuppressive cytokine; a transmembrane region or a mutant thereof; and an intracellular domain of a co-stimulatory signaling molecule or a functional fragment or a mutant thereof that retains the biological function of the co-stimulatory signaling molecule for transmitting co-stimulatory signals and activating immune cells. After being in contact with molecules on the tumor cell surface and/or tumor stromal cell surface playing an immunosuppressive role, the immune cells modified by the signal conversion receptor have an immune activation effect instead of being negatively affected by immunosuppressive molecules. In this way, the proliferation ability of the immune cells and the secretion function of cell factors are enhanced, and the survival time of the activated immune cells is prolonged, thereby overcoming the side effect of the tumor immunosuppressive microenvironment on the tumor adoptive cell therapy effector cells.

Description

信号转换受体及其用途Signal conversion receptor and its use
本申请要求2020年6月1日提交的发明名称为“信号转换受体及其用途”、中国申请号为202010485006.8的发明专利申请作为优先权，其全部内容以引用的方式纳入本文。This application claims the invention patent application with the title of "Signal Transformation Receptor and Its Use" and the Chinese application number of 202010485006.8 filed on June 1, 2020 as priority, and the entire contents of which are incorporated herein by reference.
技术领域Technical field
本发明涉及生物技术领域，具体地涉及一种信号转换受体及其用途。The present invention relates to the field of biotechnology, in particular to a signal conversion receptor and its use.
背景技术Background technique
在肿瘤过继细胞治疗(ACT)中，免疫系统的稳定性至关重要。反应过低可能造成严重感染，反应过强则发生过敏反应。人体免疫系统进化出精细、复杂的双向免疫调节机制对免疫应答进行正负双向调节。在排除外来抗原异物时，激活并加强免疫应答反应；外来抗原物质排除后，可使免疫应答减弱至终止。在肿瘤ACT中，效应T细胞的正向调节分子包括CD3/TCR复合物、CD28、CD134(OX40)、CD137(4-1BB)等，负向调节分子包括PD-1(PDCD1、CD279)、CTLA-4(CD152)、LAG3(CD223)、TIM3(HAVCR2)等。然而在肿瘤微环境(TME)中，存在许多能负调控T细胞免疫应答的因素，使肿瘤细胞得以逃脱肌体免疫系统的监控与清除并不断恶性增殖、侵袭与转移。In tumor adoptive cell therapy (ACT), the stability of the immune system is critical. A reaction that is too low can cause serious infection, and a reaction that is too strong can cause an allergic reaction. The human immune system has evolved a sophisticated and complex two-way immune regulation mechanism to regulate the immune response in both positive and negative directions. When foreign antigens are eliminated, the immune response is activated and strengthened; after foreign antigens are eliminated, the immune response can be weakened to stop. In tumor ACT, the positive regulatory molecules of effector T cells include CD3/TCR complex, CD28, CD134 (OX40), CD137 (4-1BB), etc., and negative regulatory molecules include PD-1 (PDCD1, CD279), CTLA -4 (CD152), LAG3 (CD223), TIM3 (HAVCR2), etc. However, in the tumor microenvironment (TME), there are many factors that can negatively regulate the immune response of T cells, allowing tumor cells to escape the monitoring and elimination of the body's immune system and continue to malignant proliferation, invasion and metastasis.
TGF-β对全身免疫系统具有抑制作用并且抑制宿主的免疫监控。TGF-β在肿瘤的起始与进展中起到重要的作用。TGF-β具有肿瘤促进效果，其通常在多类肿瘤中大量产生并已知具有致癌作用，并且其对肿瘤免疫具有负面影响且显著抑制宿主的肿瘤免疫监控。TGF-β通过抑制编码多个关键蛋白的基因的转录显著地并直接地抑制细胞毒性T淋巴细胞(CTL)的细胞毒性程序(cytotoxic program)，这些关键蛋白至少包括：穿孔素、颗粒酶A、颗粒酶B、Fas配体和g干扰素等细胞毒素。同时，TGF-β对CD4+T细胞的分化与功能也有显著影响。TGF-β has an inhibitory effect on the systemic immune system and inhibits the host's immune monitoring. TGF-β plays an important role in the initiation and progression of tumors. TGF-β has a tumor-promoting effect, it is usually produced in large numbers in many types of tumors and is known to have carcinogenic effects, and it has a negative impact on tumor immunity and significantly inhibits tumor immune monitoring of the host. TGF-β significantly and directly inhibits the cytotoxic program of cytotoxic T lymphocytes (CTL) by inhibiting the transcription of genes encoding multiple key proteins. These key proteins include at least: perforin, granzyme A, Cytotoxins such as granzyme B, Fas ligand and g interferon. At the same time, TGF-β also has a significant impact on the differentiation and function of CD4+ T cells.
针对免疫效应细胞负调控的抑制性信号通路，在近年已经有多项报道将其相应受体的胞外区与正向共刺激信号分子的跨膜区与胞内区连接，构建得到新的融合受体，这类融合受体在免疫效应细胞中表达后起到信号转换器的功能，可将肿瘤微环境内免疫抑制信号转换为免疫激活信号，即该信号转换分子胞外多肽接收肿瘤细胞表面、肿瘤基质细胞表面或肿瘤微环境中的免疫抑制分子信号并传递到胞内，通过共刺激信号分子胞内段激活免疫细 胞的第二信号，进而增强免疫效应细胞的增殖与细胞因子分泌功能，延长活化免疫效应细胞的存活时间。CN103965361B公开了一种T细胞信号的嵌合分子转换器，该嵌合分子转换器包括PD1分子的胞外区(或PD1分子胞外区与HERIN的融合蛋白)、CD28跨膜区和CD28(或4-1BB)胞内共刺激结构域。表达该T细胞信号嵌合分子转换器的肿瘤浸润淋巴细胞(TIL)在增殖与对肿瘤靶细胞的杀伤效果上均有显著提升。CN105452287A公开了一种免疫抑制性TGF-β信号转换器，其为包括TGF-β受体胞外结构域与来自另一种分子的胞内结构域的嵌合体，使得TGF-β与该胞外结构域的结合导致胞内结构域刺激T细胞活性。Aiming at the inhibitory signal pathway under the negative regulation of immune effector cells, there have been many reports in recent years connecting the extracellular region of the corresponding receptor with the transmembrane region of the positive costimulatory signal molecule and the intracellular region to construct a new fusion Receptors, these fusion receptors function as signal converters after being expressed in immune effector cells, which can convert immunosuppressive signals in the tumor microenvironment into immune activation signals, that is, the extracellular polypeptide of the signal conversion molecule receives the tumor cell surface , The immunosuppressive molecular signal on the surface of tumor stromal cells or in the tumor microenvironment is transmitted to the cell, and the second signal of the immune cell is activated through the intracellular segment of the costimulatory signal molecule, thereby enhancing the proliferation of immune effector cells and the secretion of cytokines. Prolong the survival time of activated immune effector cells. CN103965361B discloses a chimeric molecular converter for T cell signaling. The chimeric molecular converter includes the extracellular domain of PD1 molecule (or the fusion protein of the extracellular domain of PD1 molecule and HERIN), CD28 transmembrane domain and CD28 (or 4-1BB) Intracellular costimulatory domain. Tumor infiltrating lymphocytes (TIL) expressing the T cell signal chimeric molecular converter have significantly improved proliferation and killing effects on tumor target cells. CN105452287A discloses an immunosuppressive TGF-β signal converter, which is a chimera comprising the extracellular domain of TGF-β receptor and an intracellular domain from another molecule, so that TGF-β interacts with the extracellular domain. The binding of the domains causes the intracellular domains to stimulate T cell activity.
为刺激免疫效应细胞的增殖和提升其肿瘤免疫的效果，目前仍然需要更多的包括信号转换器分子在内的手段对免疫效应细胞进行改造和激活。In order to stimulate the proliferation of immune effector cells and enhance the effect of tumor immunity, more methods including signal converter molecules are still needed to transform and activate immune effector cells.
发明内容Summary of the invention
本发明提供一种分离的融合蛋白，包含：免疫抑制细胞因子的受体的胞外结构域或其保留了特异性结合免疫抑制细胞因子的功能片段或突变体；跨膜区或其突变体；和共刺激信号分子的胞内结构域或其保留了共刺激信号分子传递共刺激信号、活化免疫细胞的生物学功能的功能片段或突变体。The present invention provides an isolated fusion protein comprising: an extracellular domain of an immunosuppressive cytokine receptor or a functional fragment or mutant that retains specific binding to an immunosuppressive cytokine; a transmembrane region or a mutant thereof; Intracellular domain of costimulatory signal molecules or functional fragments or mutants that retain the biological functions of costimulatory signal molecules to transmit costimulatory signals and activate immune cells.
在一个或多个实施方案中，所述免疫抑制细胞因子包括肿瘤细胞或肿瘤基质细胞膜蛋白和肿瘤细胞或肿瘤基质细胞分泌型蛋白。In one or more embodiments, the immunosuppressive cytokine includes tumor cell or tumor stromal cell membrane protein and tumor cell or tumor stromal cell secreted protein.
在一个或多个实施方案中，所述肿瘤细胞或肿瘤基质细胞膜蛋白包括PDL1/PDL2、FasL、B7-H4、Crry和HLA-G。In one or more embodiments, the tumor cell or tumor stromal cell membrane protein includes PDL1/PDL2, FasL, B7-H4, Crry and HLA-G.
在一个或多个实施方案中，所述肿瘤细胞或肿瘤基质细胞分泌型蛋白包括IL13、IL4、TGF-β、IL6、IL8、IL-10、CCL21、IDO和VEGF。In one or more embodiments, the tumor cell or tumor stromal cell secreted protein includes IL13, IL4, TGF-β, IL6, IL8, IL-10, CCL21, IDO, and VEGF.
在一个或多个实施方案中，所述TGF-β的受体包括TGF-β受体1、TGF-β受体2和TGF-β受体3，优选TGF-β受体1和TGF-β受体2。In one or more embodiments, the receptors for TGF-β include TGF-β receptor 1, TGF-β receptor 2, and TGF-β receptor 3, preferably TGF-β receptor 1 and TGF-β Receptor 2.
在一个或多个实施方案中，所述共刺激信号分子包括CD28、CD134(OX40)、CD137(4-1BB)、LCK、ICOS、DAP10、siglec-9、siglec-10、siglec-15、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、IL-R2、IL-4R、IL-7R、IL-10R、IL-12R、IL-15R、IL-21R、CD27和CD40中的一种或多种。In one or more embodiments, the costimulatory signal molecule includes CD28, CD134 (OX40), CD137 (4-1BB), LCK, ICOS, DAP10, siglec-9, siglec-10, siglec-15, TLR1, One of TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, IL-R2, IL-4R, IL-7R, IL-10R, IL-12R, IL-15R, IL-21R, CD27, and CD40 Kind or more.
在一个或多个实施方案中，所述跨膜区包括来自CD28、CD8、CD134(OX40)、CD137(4-1BB)、LCK、ICOS、DAP10、siglec-9、siglec-10、siglec-15、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、IL-2Rbeta、IL-2Rgamma、IL-4Ralpha、IL-7Ralpha、IL-10R、IL-12R、IL-15R、IL-21R、CD27和CD40的跨膜区中的任一种或多 种。In one or more embodiments, the transmembrane region includes CD28, CD8, CD134 (OX40), CD137 (4-1BB), LCK, ICOS, DAP10, siglec-9, siglec-10, siglec-15, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, IL-2Rbeta, IL-2Rgamma, IL-4Ralpha, IL-7Ralpha, IL-10R, IL-12R, IL-15R, IL-21R, Any one or more of the transmembrane regions of CD27 and CD40.
在一个或多个实施方案中，所述跨膜区来自IL-7Ralpha跨膜区或其突变体。In one or more embodiments, the transmembrane region is derived from the IL-7Ralpha transmembrane region or a mutant thereof.
在一个或多个实施方案中，所述IL-7Ralpha跨膜区的突变体的氨基酸序列如SEQ ID NO:29-60中任一所示。In one or more embodiments, the amino acid sequence of the IL-7Ralpha transmembrane region mutant is shown in any one of SEQ ID NO: 29-60.
在一个或多个实施方案中，所述IL-7Ralpha跨膜区的突变体的编码序列如SEQ ID NO:61-94中任一所示。In one or more embodiments, the coding sequence of the IL-7Ralpha transmembrane region mutant is shown in any one of SEQ ID NO: 61-94.
在一个或多个实施方案中，所述融合蛋白的胞外区为TGF-β受体1的胞外区，所述跨膜区来自IL-7Ralpha跨膜区或其突变体，所述融合蛋白的共刺激分子的胞内结构域为选自IL-7Ralpha胞内区、CD28胞内区串联4-1BB胞内区、CD28胞内区、4-1BB胞内区、CD28胞内区串联OX40胞内区、28-IL2RB-z(YXXQ)胞内区、28-DeltaIL2RB-z(YXXQ)胞内区、IL2RB-z(YXXQ)胞内区和DeltaIL2RB-z(YXXQ)胞内区中的任一种。In one or more embodiments, the extracellular region of the fusion protein is the extracellular region of TGF-β receptor 1, and the transmembrane region is derived from the IL-7Ralpha transmembrane region or a mutant thereof, and the fusion protein The intracellular domain of the costimulatory molecule is selected from IL-7Ralpha intracellular region, CD28 intracellular region in series 4-1BB intracellular region, CD28 intracellular region, 4-1BB intracellular region, CD28 intracellular region in series OX40 cells Intracellular region, 28-IL2RB-z (YXXQ) intracellular region, 28-DeltaIL2RB-z (YXXQ) intracellular region, IL2RB-z (YXXQ) intracellular region and DeltaIL2RB-z (YXXQ) intracellular region kind.
在一个或多个实施方案中，所述融合蛋白的氨基酸序列为SEQ ID NO:95-350中任一所示。In one or more embodiments, the amino acid sequence of the fusion protein is shown in any one of SEQ ID NO: 95-350.
在一个或多个实施方案中，所述融合蛋白的胞外区为TGF-β受体2的胞外区，所述跨膜区来自IL-7Ralpha跨膜区或其突变体，所述融合蛋白的共刺激分子的胞内结构域为选自IL-7Ralpha胞内区、CD28胞内区串联4-1BB胞内区、CD28胞内区、4-1BB胞内区、CD28胞内区串联OX40胞内区、28-IL2RB-z(YXXQ)胞内区、28-DeltaIL2RB-z(YXXQ)胞内区、IL2RB-z(YXXQ)胞内区和DeltaIL2RB-z(YXXQ)胞内区中的任一种。In one or more embodiments, the extracellular region of the fusion protein is the extracellular region of TGF-β receptor 2, and the transmembrane region is derived from the IL-7Ralpha transmembrane region or a mutant thereof, and the fusion protein The intracellular domain of the costimulatory molecule is selected from IL-7Ralpha intracellular region, CD28 intracellular region in series 4-1BB intracellular region, CD28 intracellular region, 4-1BB intracellular region, CD28 intracellular region in series OX40 cells Intracellular region, 28-IL2RB-z (YXXQ) intracellular region, 28-DeltaIL2RB-z (YXXQ) intracellular region, IL2RB-z (YXXQ) intracellular region and DeltaIL2RB-z (YXXQ) intracellular region kind.
在一个或多个实施方案中，所述融合蛋白的氨基酸序列为SEQ ID NO:351-606、SEQ ID NO:1647、SEQ ID NO:1649、SEQ ID NO:1651、SEQ ID NO:1653、SEQ ID NO:1655、SEQ ID NO:1657、SEQ ID NO:1659、SEQ ID NO:1661、SEQ ID NO:1663、SEQ ID NO:1665、SEQ ID NO:1667、SEQ ID NO:1669、SEQ ID NO:1671、SEQ ID NO:1673和SEQ ID NO:1675中任一所示。In one or more embodiments, the amino acid sequence of the fusion protein is SEQ ID NO: 351-606, SEQ ID NO: 1647, SEQ ID NO: 1649, SEQ ID NO: 1651, SEQ ID NO: 1653, SEQ ID NO: 1655, SEQ ID NO: 1657, SEQ ID NO: 1659, SEQ ID NO: 1661, SEQ ID NO: 1663, SEQ ID NO: 1665, SEQ ID NO: 1667, SEQ ID NO: 1669, SEQ ID NO :1671, SEQ ID NO: 1673 and SEQ ID NO: 1675 are shown in any one.
在一个或多个实施方案中，所述融合蛋白的胞外区为TGF-β受体3的胞外区，所述跨膜区来自IL-7Ralpha跨膜区或其突变体，所述融合蛋白的共刺激分子的胞内结构域为选自IL-7Ralpha胞内区、CD28胞内区串联4-1BB胞内区、CD28胞内区、4-1BB胞内区、CD28胞内区串联OX40胞内区、28-IL2RB-z(YXXQ)胞内区、28-DeltaIL2RB-z(YXXQ)胞内区、IL2RB-z(YXXQ)胞内区和DeltaIL2RB-z(YXXQ)胞内区中的任一种。In one or more embodiments, the extracellular region of the fusion protein is the extracellular region of TGF-β receptor 3, and the transmembrane region is derived from the IL-7Ralpha transmembrane region or a mutant thereof, and the fusion protein The intracellular domain of the costimulatory molecule is selected from IL-7Ralpha intracellular region, CD28 intracellular region in series 4-1BB intracellular region, CD28 intracellular region, 4-1BB intracellular region, CD28 intracellular region in series OX40 cells Intracellular region, 28-IL2RB-z (YXXQ) intracellular region, 28-DeltaIL2RB-z (YXXQ) intracellular region, IL2RB-z (YXXQ) intracellular region and DeltaIL2RB-z (YXXQ) intracellular region kind.
在一个或多个实施方案中，所述融合蛋白的氨基酸序列为SEQ ID NO:607-862中任一所示。In one or more embodiments, the amino acid sequence of the fusion protein is shown in any one of SEQ ID NO: 607-862.
本发明还提供一种多核苷酸分子，选自：编码本发明任一实施方案所述的融合蛋白的多核苷酸分子或互补序列。The present invention also provides a polynucleotide molecule selected from: polynucleotide molecules or complementary sequences encoding the fusion protein according to any embodiment of the present invention.
在一个或多个实施方案中，所述多核苷酸分子选自SEQ ID NO:863-1630、SEQ ID NO:1648、SEQ ID NO:1650、SEQ ID NO:1652、SEQ ID NO:1654、SEQ ID NO:1656、SEQ ID NO:1658、SEQ ID NO:1660、SEQ ID NO:1662、SEQ ID NO:1664、SEQ ID NO:1666、SEQ ID NO:1668、SEQ ID NO:1670、SEQ ID NO:1672、SEQ ID NO:1674和SEQ ID NO:1676中任一所示，或者为任一所示多核苷酸分子的互补序列。In one or more embodiments, the polynucleotide molecule is selected from SEQ ID NO: 863-1630, SEQ ID NO: 1648, SEQ ID NO: 1650, SEQ ID NO: 1652, SEQ ID NO: 1654, SEQ ID NO: 1656, SEQ ID NO: 1658, SEQ ID NO: 1660, SEQ ID NO: 1662, SEQ ID NO: 1664, SEQ ID NO: 1666, SEQ ID NO: 1668, SEQ ID NO: 1670, SEQ ID NO :1672, SEQ ID NO: 1674 and SEQ ID NO: 1676 are shown in any one of them, or the complementary sequence of any of the shown polynucleotide molecules.
本发明还提供一种核酸构建体，含有本发明任一实施方案所述的多核苷酸分子。The present invention also provides a nucleic acid construct containing the polynucleotide molecule according to any embodiment of the present invention.
在一个或多个实施方案中，所述核酸构建体为载体。In one or more embodiments, the nucleic acid construct is a vector.
在一个或多个实施方案中，所述载体为表达载体；优选为病毒载体。In one or more embodiments, the vector is an expression vector; preferably a viral vector.
本发明还提供一种基因工程化的细胞，其表达本发明任一实施方案所述的融合蛋白，和/或携带所述融合蛋白的编码序列。The present invention also provides a genetically engineered cell that expresses the fusion protein according to any embodiment of the present invention and/or carries the coding sequence of the fusion protein.
在一个或多个实施方案中，所述细胞为免疫细胞。In one or more embodiments, the cell is an immune cell.
在一个或多个实施方案中，所述免疫细胞为T细胞。In one or more embodiments, the immune cells are T cells.
在一个或多个实施方案中，所述细胞还表达CAR，或携带CAR的编码序列。In one or more embodiments, the cell also expresses the CAR, or carries the coding sequence of the CAR.
在一个或多个实施方案中，所述细胞还表达外源TCR，或携带外源TCR的编码序列。In one or more embodiments, the cell also expresses an exogenous TCR, or carries a coding sequence for an exogenous TCR.
本发明还提供本发明任一实施方案所述的融合蛋白、多核苷酸分子、核酸构建体以及基因工程化细胞在制备治疗或预防癌症用的药物中的用途。The present invention also provides the use of the fusion protein, polynucleotide molecule, nucleic acid construct and genetically engineered cell according to any embodiment of the present invention in the preparation of a medicine for treating or preventing cancer.
附图说明Description of the drawings
图1：电转了TCR-EGFP融合基因的TCR-T和共转了TCR-EGFP融合基因+TGF-β信号转换受体基因的SCR1-5 TCR-T细胞的荧光显微图。Figure 1: Fluorescence micrographs of TCR-T electrotransformed with TCR-EGFP fusion gene and SCR1-5 TCR-T cells cotransfected with TCR-EGFP fusion gene + TGF-β signal conversion receptor gene.
图2：SCR1-5 TCR-T、RIID 2 TCR-T和TCR-T对靶细胞A375效靶比设置为1.5﹕1的体外杀伤效果图。Figure 2: SCR1-5 TCR-T, RIID 2 TCR-T and TCR-T on the target cell A375 effective target ratio is set to 1.5:1 in vitro killing effect diagram.
图3：SCR1-5 TCR-T、RIID 4 TCR-T和TCR-T对靶细胞A375效靶比设置为1.5﹕1的体外杀伤效果图。Figure 3: SCR1-5 TCR-T, RIID 4 TCR-T and TCR-T on the target cell A375 effective target ratio is set to 1.5:1 in vitro killing effect diagram.
图4：TCR-T、SCR5 TCR-T、RIID2 TCR-T对靶细胞A375效靶比设置为1﹕1的体外杀伤效果图。Figure 4: TCR-T, SCR5 TCR-T, RIID2 TCR-T on the target cell A375 effective target ratio is set to 1:1 in vitro killing effect diagram.
图5：TCR-T、SCR5 TCR-T、RIID4 TCR-T对靶细胞A375效靶比设置为1﹕1的体外杀伤效果图。Figure 5: TCR-T, SCR5 TCR-T, RIID4 TCR-T on the target cell A375 effective target ratio is set to 1:1 in vitro killing effect diagram.
图6：TCR-T、SCR6 TCR-T、SCR7 TCR-T、SCR8 TCR-T、SCR9 TCR-T和SCR10 TCR-T对靶细胞A375细胞效靶比设置为1.5﹕1的体外杀伤活性图。Figure 6: TCR-T, SCR6 TCR-T, SCR7 TCR-T, SCR8 TCR-T, SCR9 TCR-T and SCR10 TCR-T to target cell A375 cell effective target ratio is set to 1.5:1 in vitro killing activity graph.
图7：TCR-T、SCR10 TCR-T和RIID2 TCR-T对靶细胞A375细胞效靶比设置为0.5﹕1的体外杀伤活性图。Figure 7: In vitro killing activity graph of TCR-T, SCR10 TCR-T and RIID2 TCR-T to target cell A375 cells with a target ratio of 0.5:1.
图8：TCR-T、SCR11 TCR-T、SCR12 TCR-T、SCR13 TCR-T、SCR14 TCR-T和SCR15 TCR-T对靶细胞A375细胞效靶比设置为1.5﹕1的体外杀伤活性图。Figure 8: TCR-T, SCR11 TCR-T, SCR12 TCR-T, SCR13 TCR-T, SCR14 TCR-T and SCR15 TCR-T to target cell A375 cell effective target ratio is set to 1.5:1 in vitro killing activity graph.
图9：TCR-T、SCR15 TCR-T和RIID4 TCR-T对靶细胞A375细胞效靶比设置为0.75﹕1的体外杀伤活性图。Figure 9: In vitro killing activity graph of TCR-T, SCR15 TCR-T and RIID4 TCR-T to target cell A375 cells with a target ratio of 0.75:1.
图10：TCR-T、RIID2 TCR-T、RIID4 TCR-T和SCR5 TCR-T对肿瘤细胞系A375小鼠体内成瘤后的肿瘤生长的抑制效果图。Figure 10: Diagram of the inhibitory effect of TCR-T, RIID2 TCR-T, RIID4 TCR-T and SCR5 TCR-T on tumor growth in mice with tumor cell line A375.
图11：表达本发明TGF-β信号转换受体SCR5的免疫效应细胞，如TCR-T，在体内对肿瘤增殖的抑制效果图。Figure 11: A diagram of the inhibitory effect of immune effector cells expressing the TGF-β signal conversion receptor SCR5 of the present invention, such as TCR-T, on tumor proliferation in vivo.
具体实施方式detailed description
应理解，在本发明范围中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成优选的技术方案。It should be understood that, within the scope of the present invention, the above technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a preferred technical solution.
本发明提供用于肿瘤过继细胞治疗的免疫细胞，其经修饰后，可将抑制免疫细胞增殖的抑制性信号转化为增强免疫细胞增殖的刺激性信号。在一些实施方案中，该刺激性信号还包括增强抗肿瘤活性的刺激性信号。The present invention provides immune cells used for adoptive cell therapy of tumors, which, after being modified, can convert inhibitory signals that inhibit the proliferation of immune cells into stimulatory signals that enhance the proliferation of immune cells. In some embodiments, the stimulatory signal further includes a stimulatory signal that enhances anti-tumor activity.
本发明中，免疫细胞具有本领域周知含义，指参与免疫应答或与免疫应答相关的细胞，包括淋巴细胞、树突状细胞、单核/巨噬细胞、粒细胞、肥大细胞等。淋巴细胞包括T淋巴细胞、肿瘤浸润淋巴细胞、B淋巴细胞、K淋巴细胞和NK淋巴细胞。适用于本发明的免疫细胞尤其包括那些通常用于肿瘤过继细胞治疗的免疫细胞。In the present invention, immune cells have well-known meanings in the art, and refer to cells involved in or related to immune responses, including lymphocytes, dendritic cells, monocytes/macrophages, granulocytes, mast cells, and the like. Lymphocytes include T lymphocytes, tumor infiltrating lymphocytes, B lymphocytes, K lymphocytes and NK lymphocytes. Immune cells suitable for use in the present invention especially include those commonly used for adoptive cell therapy of tumors.
本发明的免疫细胞表达本发明所述的信号转换受体，和/或含有所述信号转换受体的编码序列。本发明的信号转换受体设计为结合抑制性分子但传送正信号而非抑制性信号。即，这些细胞将“刹车”信号转化为“加速”信号以改善各免疫细胞的抗肿瘤作用。The immune cell of the present invention expresses the signal conversion receptor of the present invention, and/or contains the coding sequence of the signal conversion receptor. The signal conversion receptor of the present invention is designed to bind inhibitory molecules but transmit a positive signal rather than an inhibitory signal. That is, these cells convert the "brake" signal into an "accelerate" signal to improve the anti-tumor effect of each immune cell.
定义definition
本发明使用到以下术语。对于本文未具体定义的术语，其具有本领域公知含义。The following terms are used in the present invention. For terms not specifically defined herein, they have a well-known meaning in the art.
术语“表达框”是指表达一个基因所需的完整元件，包括启动子、基因编码序列、PolyA加尾信号序列。The term "expression cassette" refers to the complete elements required to express a gene, including promoters, gene coding sequences, and PolyA tailing signal sequences.
术语“编码序列”在文中定义为核酸序列中直接确定其蛋白产物(例如信号转换受体、CAR)的氨基酸序列的部分。编码序列的边界通常是由紧邻mRNA 5’端开放读码框上游的核糖体结合位点(对于原核细胞)和紧邻mRNA 3’端开放读码框下游的转录终止序列确定。编码序列可以包括，但不限于DNA、cDNA和重组核酸序列。The term "coding sequence" is defined herein as the part of the nucleic acid sequence that directly determines the amino acid sequence of its protein product (for example, signal switch receptor, CAR). The boundary of the coding sequence is usually determined by the ribosome binding site (for prokaryotic cells) immediately upstream of the open reading frame at the 5'end of the mRNA and the transcription termination sequence immediately downstream of the open reading frame at the 3'end of the mRNA. Coding sequences can include, but are not limited to DNA, cDNA, and recombinant nucleic acid sequences.
术语“共刺激信号分子”是指存在于抗原提呈细胞表面，能与Th细胞上的共刺激信号分子受体结合，产生协同刺激信号的分子。其能激活免疫细胞的第二信号，增强免疫细胞的增殖能力及细胞因子的分泌功能，延长活化免疫细胞的存活时间。淋巴细胞的增殖不仅需要抗原的结合，还需要接受共刺激分子的信号。共刺激信号传递给T细胞主要是通过表达在抗原呈递细胞表面的共刺激分子CD80，CD86与T细胞表面的CD28分子结合。B细胞接受共刺激信号可以通过一般的病原体成分例如LPS，或者通过补体成分，或者通过激活了的抗原特异性的Th细胞表面的CD40L。The term "costimulatory signal molecule" refers to a molecule that exists on the surface of antigen-presenting cells and can bind to the receptor for costimulatory signal molecules on Th cells to generate a costimulatory signal. It can activate the second signal of immune cells, enhance the proliferation ability of immune cells and the secretion of cytokines, and prolong the survival time of activated immune cells. The proliferation of lymphocytes requires not only antigen binding, but also signals from costimulatory molecules. Co-stimulatory signals are transmitted to T cells mainly through the co-stimulatory molecules CD80 expressed on the surface of antigen-presenting cells, and CD86 binds to CD28 molecules on the surface of T cells. B cells can receive costimulatory signals through general pathogen components such as LPS, or through complement components, or through activated antigen-specific CD40L on the surface of Th cells.
术语“接头”或铰链是连接不同蛋白或多肽之间的多肽片段，其目的是使所连接的蛋白或多肽保持各自的空间构象，以维持蛋白或多肽的功能或活性。示例性的接头包括含有G和/或S的接头，以及例如Furin 2A肽。The term "linker" or hinge is a polypeptide fragment that connects different proteins or polypeptides, and its purpose is to keep the connected proteins or polypeptides in their respective spatial conformations, so as to maintain the function or activity of the protein or polypeptide. Exemplary linkers include linkers containing G and/or S, and, for example, Furin 2A peptide.
术语“药学上可接受的辅料”是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂，其是本领域公知的(参见例如Remington's Pharmaceutical Sciences.Edited by Gennaro AR,19th ed.Pennsylvania:Mack Publishing Company,1995)，并且包括但不限于：pH调节剂，表面活性剂，佐剂，离子强度增强剂。例如，pH调节剂包括但不限于磷酸盐缓冲液；表面活性剂包括但不限于阳离子，阴离子或者非离子型表面活性剂，例如Tween-80；离子强度增强剂包括但不限于氯化钠。The term "pharmaceutically acceptable excipients" refers to carriers and/or excipients that are pharmacologically and/or physiologically compatible with the subject and the active ingredient, which are well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and includes but not limited to: pH adjusters, surfactants, adjuvants, ionic strength enhancers. For example, pH adjusting agents include, but are not limited to, phosphate buffer; surfactants include, but are not limited to, cationic, anionic or nonionic surfactants, such as Tween-80; and ionic strength enhancers include, but are not limited to, sodium chloride.
术语“有效量”是指可在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病或病症的剂量。The term "effective amount" refers to a dose that can treat, prevent, alleviate and/or alleviate the disease or condition described in the present invention in a subject.
术语“疾病和/或病症”是指所述受试者的一种身体状态，该身体状态与本发明所述疾病和/或病症有关。The term "disease and/or disorder" refers to a physical state of the subject, which is related to the disease and/or disorder described in the present invention.
术语“受试者”可以指患者或者其它接受本发明药物组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物，特别是哺乳动物，例如人、狗、猴、牛、马等。The term "subject" may refer to patients or other animals receiving the pharmaceutical composition of the present invention to treat, prevent, alleviate and/or alleviate the diseases or conditions of the present invention, especially mammals, such as humans, dogs, monkeys, cows , Horse, etc.
术语“肿瘤基质细胞”指肿瘤微环境内一些支撑肿瘤细胞的恶性增殖、抗凋亡、侵袭、转移，逃脱免疫监控等生命活动的细胞，主要包括成纤维细胞、肿瘤相关巨噬细胞(TAMs)、调节性T细胞(Treg)、未分化的骨髓细胞、内皮细胞、周细胞和血小板、内皮细胞等。The term "tumor stromal cells" refers to cells in the tumor microenvironment that support the malignant proliferation, anti-apoptosis, invasion and metastasis of tumor cells, escape immune surveillance and other life activities, mainly including fibroblasts and tumor-associated macrophages (TAMs) , Regulatory T cells (Treg), undifferentiated bone marrow cells, endothelial cells, pericytes and platelets, endothelial cells, etc.
术语“免疫抑制细胞因子”是指由肿瘤细胞或肿瘤基质细胞产生，起抑制免疫作用，使肿瘤细胞逃脱机体免疫监控，诱导免疫耐受的分子。例如肿瘤细胞或肿瘤基质细胞膜蛋白PDL1/PDL2(PD-1配体)、FasL(Fas配体)、B7-H4(免疫共刺激蛋白B7-H4，又称VTCN1)、Crry(膜相关补体调控蛋白，又称Cr1l)、HLA-G(非经典MHC I类分子)，以及肿瘤细胞或肿瘤基质细胞分泌型蛋白IL13、IL4、TGF-β、IL6、IL8、IL-10、CCL21、IDO(吲哚胺2,3-双加氧酶)和VEGF等。The term "immunosuppressive cytokine" refers to a molecule that is produced by tumor cells or tumor stromal cells, which suppresses immunity, allows tumor cells to escape the body's immune monitoring, and induces immune tolerance. For example, tumor cells or tumor stromal cell membrane proteins PDL1/PDL2 (PD-1 ligand), FasL (Fas ligand), B7-H4 (immune costimulatory protein B7-H4, also known as VTCN1), Crry (membrane-associated complement regulatory protein) , Also known as Cr1l), HLA-G (non-classical MHC class I molecules), and tumor cell or tumor stromal cell secreted proteins IL13, IL4, TGF-β, IL6, IL8, IL-10, CCL21, IDO (indole Amine 2,3-dioxygenase) and VEGF, etc.
术语“胞外区”指膜蛋白位于细胞外的区段。The term "extracellular region" refers to the segment of membrane protein located outside the cell.
术语“结构域”是指蛋白质中具有特异结构和独立功能的区域，常见结构域的氨基酸残基数在100～400个之间，最小的结构域只有40～50个氨基酸残基，大的结构域可超过400个氨基酸残基。The term "domain" refers to a region with a specific structure and independent function in a protein. The number of amino acid residues in common domains is between 100 and 400, and the smallest domain has only 40 to 50 amino acid residues, a large structure The domain can exceed 400 amino acid residues.
信号转换受体Signal converter receptor
本发明的信号转换受体为一种多肽，其为一种融合蛋白，包含与免疫刺激分子(也称为“共刺激信号分子”)的胞内结构域(也称为“胞内区”)融合的免疫抑制细胞因子的受体的胞外结构域(也称为“胞外区”)。更具体而言，本发明的信号转换受体包括免疫抑制细胞因子的受体的胞外结构域、跨膜区和共刺激信号分子的胞内结构域。本发明的信号转换受体结合Th2或免疫抑制性细胞因子但诱导免疫刺激信号而非免疫抑制，导致维持Th1表型、增殖和细胞毒性特征。The signal conversion receptor of the present invention is a polypeptide, which is a fusion protein containing an intracellular domain (also referred to as an "intracellular region") with an immunostimulatory molecule (also referred to as a "costimulatory signal molecule") The extracellular domain of the fused immunosuppressive cytokine receptor (also referred to as the "extracellular domain"). More specifically, the signal conversion receptor of the present invention includes the extracellular domain of the immunosuppressive cytokine receptor, the transmembrane domain, and the intracellular domain of a costimulatory signal molecule. The signal conversion receptor of the present invention binds Th2 or immunosuppressive cytokines but induces immunostimulatory signals instead of immunosuppression, resulting in the maintenance of Th1 phenotype, proliferation and cytotoxicity characteristics.
本发明中，免疫抑制细胞因子可以是由癌细胞或周围肿瘤基质分泌的免疫抑制细胞因子，包括肿瘤细胞或肿瘤基质细胞膜蛋白和肿瘤细胞或肿瘤基质细胞分泌型蛋白。所述肿瘤细胞或肿瘤基质细胞膜蛋白包括但不限于PDL1/PDL2(PD-1配体)、FasL(Fas配体)、B7-H4(免疫共刺激蛋白B7-H4，又称VTCN1)、Crry(膜相关补体调控蛋白，又称Cr1l)和HLA-G(非经典MHC I类分子)等；所述肿瘤细胞或肿瘤基质细胞分泌型蛋白包括但不限于IL13、IL4、TGF-β、IL6、IL8、IL-10、CCL21、IDO(吲哚胺2,3-双加氧酶)和VEGF等。本发明涉及使用这些免疫抑制细胞因子的受体的胞外结构域或其功能片段或保留了结合对应免疫抑制细胞因子的能力的突变体来构建本发明的信号转换受体。In the present invention, the immunosuppressive cytokine may be an immunosuppressive cytokine secreted by cancer cells or surrounding tumor stroma, including tumor cell or tumor stromal cell membrane protein and tumor cell or tumor stromal cell secreted protein. The tumor cell or tumor stromal cell membrane protein includes but is not limited to PDL1/PDL2 (PD-1 ligand), FasL (Fas ligand), B7-H4 (immune costimulatory protein B7-H4, also known as VTCN1), Crry ( Membrane-associated complement regulatory protein, also known as Cr11) and HLA-G (non-classical MHC class I molecules), etc.; the tumor cell or tumor stromal cell secreted protein includes but is not limited to IL13, IL4, TGF-β, IL6, IL8 , IL-10, CCL21, IDO (indoleamine 2,3-dioxygenase) and VEGF. The present invention relates to the use of the extracellular domains of these immunosuppressive cytokine receptors or functional fragments thereof or mutants that retain the ability to bind corresponding immunosuppressive cytokines to construct the signal conversion receptor of the present invention.
在特别优选的实施方案中，本发明信号转换受体中的免疫抑制细胞因子的受体为TGF-β受体。本发明TGF-β受体的胞外结构域可以仅包含TGF-β受体的胞外结构域，或者可以是含有TGF-β受体的TGF结合片段的嵌合TGF-β受体。可使用天然TGF-β受体的任何同种型的胞外结构域，包括TGF-β受体1、TGF-β受体2和TGF-β受体3，优选TGF-β受体1和TGF-β受体2。示例性的TGF-β受体1的胞外区的氨基酸序列和多核苷酸序列可分别如SEQ ID NO:1和2所示。示例性的编码TGF-β受体2的示例性核苷酸序列包括Genbank登陆号NM_001024847.2或NM_003242.5所示的序列，其氨基酸序列的Genbank登陆号分别为NP_001020018或NM_003242。在一些实施方式中，本发明的胞外结构域包含来自TGF-β受体2的第23-166位氨基酸，如SEQ ID NO:3所示，其编码序列如SEQ ID NO:4所示。示例性的TGF-β受体3的胞外区的氨基酸序列和多核苷酸序列可分别如SEQ ID NO:5和6所示。In a particularly preferred embodiment, the immunosuppressive cytokine receptor in the signal conversion receptor of the present invention is the TGF-β receptor. The extracellular domain of the TGF-β receptor of the present invention may only include the extracellular domain of the TGF-β receptor, or may be a chimeric TGF-β receptor containing a TGF-binding fragment of the TGF-β receptor. The extracellular domain of any isotype of natural TGF-β receptor can be used, including TGF-β receptor 1, TGF-β receptor 2, and TGF-β receptor 3, preferably TGF-β receptor 1 and TGF -β receptor 2. The amino acid sequence and polynucleotide sequence of an exemplary TGF-β receptor 1 extracellular region may be shown in SEQ ID NOs: 1 and 2, respectively. An exemplary nucleotide sequence encoding TGF-β receptor 2 includes the sequence shown in Genbank accession number NM_001024847.2 or NM_003242.5, and the Genbank accession number of its amino acid sequence is NP_001020018 or NM_003242, respectively. In some embodiments, the extracellular domain of the present invention includes amino acids 23-166 from TGF-β receptor 2, as shown in SEQ ID NO: 3, and its coding sequence is as shown in SEQ ID NO: 4. The exemplary amino acid sequence and polynucleotide sequence of the extracellular region of TGF-β receptor 3 may be shown in SEQ ID NOs: 5 and 6, respectively.
在另外一些实施方案中，本发明信号转换受体中的免疫抑制因子的受体为IL13受体，所述胞外结构域为IL13受体的胞外结构域，或含有IL13受体的IL13结合片段的嵌合IL13受体。In other embodiments, the receptor of the immunosuppressive factor in the signal conversion receptor of the present invention is the IL13 receptor, and the extracellular domain is the extracellular domain of the IL13 receptor, or the IL13 binding containing the IL13 receptor Fragment of the chimeric IL13 receptor.
本发明中，共刺激信号分子包括CD28、CD134(OX40)、CD137(4-1BB)、LCK、ICOS、DAP10、siglec-9、siglec-10、siglec-15、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、IL-2R、IL-4R、IL-7R、IL-10R、IL-12R、IL-15R、IL-21R、CD27和CD40。可使用一种或多种这些共刺激信号分子的胞内结构域(胞内区)或其功能片段或保留了共刺激信号分子传递共刺激信号、活化免疫细胞的生物学功能的突变体来构建本发明的信号转换受体。示例性的IL-7R可以是IL-7Ralpha，其示例性的氨基酸序列和相应的编码序列可分别如SEQ ID NO:7和8所示。示例性的CD28的胞内区的氨基酸序列和相应的编码序列可分别如SEQ ID NO:9和10所示。示例性的4-1BB的胞内区的氨基酸序列和相应的编码序列可分别如SEQ ID NO:11和12所示。OX40胞内区的氨基酸序列如SEQ ID NO:1645所示，其编码序列如SEQ ID NO:1646所示。In the present invention, costimulatory signal molecules include CD28, CD134 (OX40), CD137 (4-1BB), LCK, ICOS, DAP10, siglec-9, siglec-10, siglec-15, TLR1, TLR2, TLR3, TLR4, TLR5 , TLR6, TLR7, TLR8, TLR9, IL-2R, IL-4R, IL-7R, IL-10R, IL-12R, IL-15R, IL-21R, CD27 and CD40. One or more of the intracellular domains (intracellular regions) of these costimulatory signal molecules or their functional fragments or mutants that retain the biological functions of costimulatory signal molecules to transmit costimulatory signals and activate immune cells can be used to construct The signal conversion receptor of the present invention. An exemplary IL-7R may be IL-7Ralpha, and its exemplary amino acid sequence and corresponding coding sequence may be as shown in SEQ ID NOs: 7 and 8, respectively. The amino acid sequence and corresponding coding sequence of an exemplary CD28 intracellular region can be shown in SEQ ID NO: 9 and 10, respectively. The amino acid sequence and the corresponding coding sequence of an exemplary 4-1BB intracellular region can be shown in SEQ ID NOs: 11 and 12, respectively. The amino acid sequence of the intracellular region of OX40 is shown in SEQ ID NO:1645, and its coding sequence is shown in SEQ ID NO:1646.
本发明中，免疫抑制细胞因子的受体的胞外结构域通过跨膜区(跨膜结构域)与共刺激信号分子的胞内结构域连接。跨膜区可以是任意来源。适用于本发明的跨膜区包括但不限于CD28、CD8、CD134(OX40)、CD137(4-1BB)、LCK、ICOS、DAP10、siglec-9、siglec-10、siglec-15、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、IL-2Rgamma、IL-2Rbeta、IL-4Ralpha、IL-7Ralpha、IL-10R、IL-12R、IL-15R、IL-21R、CD27和CD40的跨膜区或其保留了跨膜功能的突变体中的任一种或多种。跨膜区可与胞内结构域来自相同的分子，也可来自不同的分子。本发明中，优选的跨膜区来自IL-7Ralpha跨膜区及其突变体。IL-7Ralpha跨膜区的示例性氨基酸序列及其编码序列分别如SEQ ID NO:27和28所示。IL-7Ralpha跨膜区的突变体的示例性氨基酸序列可选自SEQ ID NO:29-60中的任一条；优选地，其编码核酸序列选自SEQ ID NO:61-94中任一条。In the present invention, the extracellular domain of an immunosuppressive cytokine receptor is connected to the intracellular domain of a costimulatory signal molecule through a transmembrane region (transmembrane domain). The transmembrane zone can be of any source. Transmembrane regions suitable for use in the present invention include but are not limited to CD28, CD8, CD134 (OX40), CD137 (4-1BB), LCK, ICOS, DAP10, siglec-9, siglec-10, siglec-15, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, IL-2Rgamma, IL-2Rbeta, IL-4Ralpha, IL-7Ralpha, IL-10R, IL-12R, IL-15R, IL-21R, CD27 and CD40 Any one or more of the transmembrane region or its mutants that retain the transmembrane function. The transmembrane region can be derived from the same molecule as the intracellular domain, or from a different molecule. In the present invention, the preferred transmembrane region is derived from the IL-7Ralpha transmembrane region and its mutants. The exemplary amino acid sequence of the transmembrane region of IL-7Ralpha and its coding sequence are shown in SEQ ID NOs: 27 and 28, respectively. The exemplary amino acid sequence of the IL-7Ralpha transmembrane region mutant can be selected from any one of SEQ ID NO: 29-60; preferably, the encoding nucleic acid sequence thereof is selected from any one of SEQ ID NO: 61-94.
应理解的是，本文所述的“功能片段”指保留了所需生物学功能的片段。例如，本文所述的胞外结构域的功能片段指保留了结合对应免疫抑制细胞因子的能力；胞内结构域的功能片段指保留了该共刺激信号分子传递共刺激信号、活化免疫细胞的生物学功能的片段。举例而言，TGF-β受体2的胞外结构域的功能片段为来自该胞外结构域的能结合TGF-β受体2的功能片段。适用于本发明的各胞外结构域的功能片段以及各胞内结构域的功能片段可由本领域技术人员结合本领域现有技术手段容易确定。It should be understood that the "functional fragment" described herein refers to a fragment that retains the desired biological function. For example, the functional fragment of the extracellular domain described herein refers to an organism that retains the ability to bind to the corresponding immunosuppressive cytokine; the functional fragment of the intracellular domain refers to an organism that retains the costimulatory signal molecule to transmit costimulatory signals and activate immune cells. Fragment of learning function. For example, the functional fragment of the extracellular domain of TGF-β receptor 2 is a functional fragment from the extracellular domain that can bind to TGF-β receptor 2. The functional fragments of each extracellular domain and the functional fragments of each intracellular domain suitable for the present invention can be easily determined by those skilled in the art in combination with the existing technical means in the art.
本文所述的“突变体”包括各胞外结构域、跨膜区和胞内结构域的突变体，只要该突变体保留了所述胞外结构域、跨膜区和胞内结构域各自相应的生物学功能即可。例如，适用于本发明的胞外结构域的突变体包括与作为对比的胞外结构域具有至少80％、至少85 ％、至少90％、至少95％、至少97％或至少99％序列同一性的突变体；适用于本发明的跨膜区的突变体包括与作为对比的跨膜区具有至少80％、至少85％、至少90％、至少95％、至少97％或至少99％序列同一性的突变体；适用于本发明的胞内结构域的突变体包括与作为对比的胞内结构域具有至少80％、至少85％、至少90％、至少95％、至少97％或至少99％序列同一性的突变体。或者，与作为对比的序列相比，本发明所述的突变体具有一个或多个(如20个以内、15个以内、10个以内、8个以内、5个以内或3个以内，如1-20、1-10等)氨基酸残基插入、取代或缺失。The "mutants" described herein include mutants of each extracellular domain, transmembrane region, and intracellular domain, as long as the mutant retains the extracellular domain, transmembrane region, and intracellular domain. The biological function can be. For example, mutants of the extracellular domain suitable for use in the present invention include those having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity with the extracellular domain for comparison. Mutants suitable for use in the transmembrane region of the present invention include at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity to the transmembrane region for comparison Mutants; mutants suitable for the intracellular domain of the present invention include at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% sequence of the intracellular domain as a comparison Mutants of identity. Alternatively, compared with the sequence for comparison, the mutants of the present invention have one or more (such as within 20, within 15, within 10, within 8, within 5 or within 3, such as 1 -20, 1-10, etc.) Insertion, substitution or deletion of amino acid residues.
本发明也包括前文所述信号转换受体的突变体，如与所述信号转换受体具有至少80％、至少85％、至少90％、至少95％、至少97％或至少99％序列同一性的突变体。更具体而言，本发明包括与前文所述信号转换受体相比具有一个或多个(如20个以内、15个以内、10个以内、8个以内、5个以内或3个以内，如1-20、1-10等)氨基酸残基插入、取代或缺失的突变体。这类突变体保留了本发明所述信号转换受体的生物学功能，包括但不限于将抑制免疫细胞增殖的抑制性信号转化为增强免疫细胞增殖的刺激性信号。突变可发生在本文所述胞外结构域、跨膜区和胞内结构域中的任一个、任两个或全部三个。The present invention also includes mutants of the aforementioned signal conversion receptor, such as having at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity with the signal conversion receptor Mutant. More specifically, the present invention includes having one or more (such as within 20, within 15, within 10, within 8, within 5, or within 3 within) compared with the aforementioned signal conversion receptor, such as 1-20, 1-10, etc.) Mutants with insertion, substitution or deletion of amino acid residues. Such mutants retain the biological functions of the signal conversion receptor of the present invention, including but not limited to converting an inhibitory signal that inhibits the proliferation of immune cells into a stimulating signal that enhances the proliferation of immune cells. Mutations can occur in any one, any two, or all three of the extracellular domain, transmembrane region, and intracellular domain described herein.
本发明示例性的信号转换受体包括但不限于含有下表1每一行所示的胞外结构域、跨膜区和胞内结构域或由下表1每一行所示的胞外结构域、跨膜区和胞内结构域组成的信号转换受体：Exemplary signal conversion receptors of the present invention include, but are not limited to, the extracellular domain, transmembrane region, and intracellular domain shown in each row of Table 1 below or the extracellular domain shown in each row of Table 1 below. Signal transduction receptor composed of transmembrane region and intracellular domain:
表1Table 1
胞外结构域Extracellular domain 跨膜区Transmembrane zone 胞内结构域Intracellular domain
TGF-β受体1TGF-β receptor 1 CD28CD28 OX40OX40
TGF-β受体1TGF-β receptor 1 CD28CD28 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 CD28CD28 CD8CD8
TGF-β受体1TGF-β receptor 1 CD28CD28 OX40+4-1BBOX40+4-1BB
TGF-β受体1TGF-β receptor 1 CD28CD28 CD8+4-1BBCD8+4-1BB
TGF-β受体1TGF-β receptor 1 CD28CD28 CD8+OX40CD8+OX40
TGF-β受体1TGF-β receptor 1 CD28CD28 OX40+CD3zOX40+CD3z
TGF-β受体1TGF-β receptor 1 CD28CD28 4-1BB+CD3z4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 CD28CD28 CD8+CD3zCD8+CD3z
TGF-β受体1TGF-β receptor 1 CD28CD28 OX40+4-1BB+CD3zOX40+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 CD28CD28 CD8+4-1BB+CD3zCD8+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 CD28CD28 CD8+OX40+CD3zCD8+OX40+CD3z
TGF-β受体1TGF-β receptor 1 CD8CD8 OX40OX40
TGF-β受体1TGF-β receptor 1 CD8CD8 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 CD8CD8 CD28CD28
TGF-β受体1TGF-β receptor 1 CD8CD8 OX40+4-1BBOX40+4-1BB
TGF-β受体1TGF-β receptor 1 CD8CD8 CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 CD8CD8 CD28+OX40CD28+OX40
TGF-β受体1TGF-β receptor 1 CD8CD8 OX40+CD3zOX40+CD3z
TGF-β受体1TGF-β receptor 1 CD8CD8 4-1BB+CD3z4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 CD8CD8 CD28+CD3zCD28+CD3z
TGF-β受体1TGF-β receptor 1 CD8CD8 OX40+4-1BB+CD3zOX40+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 CD8CD8 CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 CD8CD8 CD28+OX40+CD3zCD28+OX40+CD3z
TGF-β受体1TGF-β receptor 1 4-1BB4-1BB CD28CD28
TGF-β受体1TGF-β receptor 1 4-1BB4-1BB OX40OX40
TGF-β受体1TGF-β receptor 1 4-1BB4-1BB CD28+OX40CD28+OX40
TGF-β受体1TGF-β receptor 1 IL-2RgammaIL-2Rgamma 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 IL-2RgammaIL-2Rgamma CD28CD28
TGF-β受体1TGF-β receptor 1 IL-2RgammaIL-2Rgamma OX40OX40
TGF-β受体1TGF-β receptor 1 IL-2RgammaIL-2Rgamma CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 IL-2RgammaIL-2Rgamma CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 IL-2RgammaIL-2Rgamma IL-2RgammaIL-2Rgamma
TGF-β受体1TGF-β receptor 1 IL-2RbetaIL-2Rbeta 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 IL-2RbetaIL-2Rbeta CD28CD28
TGF-β受体1TGF-β receptor 1 IL-2RbetaIL-2Rbeta OX40OX40
TGF-β受体1TGF-β receptor 1 IL-2RbetaIL-2Rbeta CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 IL-2RbetaIL-2Rbeta CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 IL-2RbetaIL-2Rbeta IL-2RbetaIL-2Rbeta
TGF-β受体1TGF-β receptor 1 IL-4RalphaIL-4Ralpha CD28CD28
TGF-β受体1TGF-β receptor 1 IL-4RalphaIL-4Ralpha 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 IL-4RalphaIL-4Ralpha OX40OX40
TGF-β受体1TGF-β receptor 1 IL-4RalphaIL-4Ralpha CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 IL-4RalphaIL-4Ralpha CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 IL-4RalphaIL-4Ralpha IL-4RalphaIL-4Ralpha
TGF-β受体1TGF-β receptor 1 IL-7RalphaIL-7Ralpha CD28CD28
TGF-β受体1TGF-β receptor 1 IL-7RalphaIL-7Ralpha 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 IL-7RalphaIL-7Ralpha OX40OX40
TGF-β受体1TGF-β receptor 1 IL-7RalphaIL-7Ralpha CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 IL-7RalphaIL-7Ralpha CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 IL-7RalphaIL-7Ralpha IL-7RalphaIL-7Ralpha
TGF-β受体1TGF-β receptor 1 IL-10RIL-10R CD28CD28
TGF-β受体1TGF-β receptor 1 IL-10RIL-10R 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 IL-10RIL-10R OX40OX40
TGF-β受体1TGF-β receptor 1 IL-10RIL-10R CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 IL-10RIL-10R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 IL-10RIL-10R IL-10RIL-10R
TGF-β受体1TGF-β receptor 1 IL-12RIL-12R CD28CD28
TGF-β受体1TGF-β receptor 1 IL-12RIL-12R 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 IL-12RIL-12R OX40OX40
TGF-β受体1TGF-β receptor 1 IL-12RIL-12R CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 IL-12RIL-12R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 IL-12RIL-12R IL-12RIL-12R
TGF-β受体1TGF-β receptor 1 IL-15RIL-15R CD28CD28
TGF-β受体1TGF-β receptor 1 IL-15RIL-15R 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 IL-15RIL-15R OX40OX40
TGF-β受体1TGF-β receptor 1 IL-15RIL-15R CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 IL-15RIL-15R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 IL-15RIL-15R IL-15RIL-15R
TGF-β受体1TGF-β receptor 1 IL-21RIL-21R CD28CD28
TGF-β受体1TGF-β receptor 1 IL-21RIL-21R 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 IL-21RIL-21R OX40OX40
TGF-β受体1TGF-β receptor 1 IL-21RIL-21R CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 IL-21RIL-21R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 IL-21RIL-21R IL-21RIL-21R
TGF-β受体1TGF-β receptor 1 CD40CD40 CD28CD28
TGF-β受体1TGF-β receptor 1 CD40CD40 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 CD40CD40 OX40OX40
TGF-β受体1TGF-β receptor 1 CD40CD40 CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 CD40CD40 CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 CD40CD40 CD40CD40
TGF-β受体1TGF-β receptor 1 DAP10DAP10 CD28CD28
TGF-β受体1TGF-β receptor 1 DAP10DAP10 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 DAP10DAP10 OX40OX40
TGF-β受体1TGF-β receptor 1 DAP10DAP10 CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 DAP10DAP10 CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 DAP10DAP10 DAP10DAP10
TGF-β受体1TGF-β receptor 1 ICOSICOS CD28CD28
TGF-β受体1TGF-β receptor 1 ICOSICOS 4-1BB4-1BB
TGF-β受体1TGF-β receptor 1 ICOSICOS OX40OX40
TGF-β受体1TGF-β receptor 1 ICOSICOS CD28+4-1BBCD28+4-1BB
TGF-β受体1TGF-β receptor 1 ICOSICOS CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体1TGF-β receptor 1 ICOSICOS ICOSICOS
TGF-β受体2TGF-β receptor 2 CD28CD28 OX40OX40
TGF-β受体2TGF-β receptor 2 CD28CD28 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 CD28CD28 CD8CD8
TGF-β受体2TGF-β receptor 2 CD28CD28 OX40+4-1BBOX40+4-1BB
TGF-β受体2TGF-β receptor 2 CD28CD28 CD8+4-1BBCD8+4-1BB
TGF-β受体2TGF-β receptor 2 CD28CD28 CD8+OX40CD8+OX40
TGF-β受体2TGF-β receptor 2 CD28CD28 OX40+CD3zOX40+CD3z
TGF-β受体2TGF-β receptor 2 CD28CD28 4-1BB+CD3z4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 CD28CD28 CD8+CD3zCD8+CD3z
TGF-β受体2TGF-β receptor 2 CD28CD28 OX40+4-1BB+CD3zOX40+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 CD28CD28 CD8+4-1BB+CD3zCD8+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 CD28CD28 CD8+OX40+CD3zCD8+OX40+CD3z
TGF-β受体2TGF-β receptor 2 CD8CD8 OX40OX40
TGF-β受体2TGF-β receptor 2 CD8CD8 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 CD8CD8 CD28CD28
TGF-β受体2TGF-β receptor 2 CD8CD8 OX40+4-1BBOX40+4-1BB
TGF-β受体2TGF-β receptor 2 CD8CD8 CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 CD8CD8 CD28+OX40CD28+OX40
TGF-β受体2TGF-β receptor 2 CD8CD8 OX40+CD3zOX40+CD3z
TGF-β受体2TGF-β receptor 2 CD8CD8 4-1BB+CD3z4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 CD8CD8 CD28+CD3zCD28+CD3z
TGF-β受体2TGF-β receptor 2 CD8CD8 OX40+4-1BB+CD3zOX40+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 CD8CD8 CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 CD8CD8 CD28+OX40+CD3zCD28+OX40+CD3z
TGF-β受体2TGF-β receptor 2 4-1BB4-1BB CD28CD28
TGF-β受体2TGF-β receptor 2 4-1BB4-1BB OX40OX40
TGF-β受体2TGF-β receptor 2 4-1BB4-1BB CD28+OX40CD28+OX40
TGF-β受体2TGF-β receptor 2 IL-2RgammaIL-2Rgamma 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 IL-2RgammaIL-2Rgamma CD28CD28
TGF-β受体2TGF-β receptor 2 IL-2RgammaIL-2Rgamma OX40OX40
TGF-β受体2TGF-β receptor 2 IL-2RgammaIL-2Rgamma CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 IL-2RgammaIL-2Rgamma CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 IL-2RgammaIL-2Rgamma IL-2RgammaIL-2Rgamma
TGF-β受体2TGF-β receptor 2 IL-2RbetaIL-2Rbeta 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 IL-2RbetaIL-2Rbeta CD28CD28
TGF-β受体2TGF-β receptor 2 IL-2RbetaIL-2Rbeta OX40OX40
TGF-β受体2TGF-β receptor 2 IL-2RbetaIL-2Rbeta CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 IL-2RbetaIL-2Rbeta CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 IL-2RbetaIL-2Rbeta IL-2RbetaIL-2Rbeta
TGF-β受体2TGF-β receptor 2 IL-4RalphaIL-4Ralpha CD28CD28
TGF-β受体2TGF-β receptor 2 IL-4RalphaIL-4Ralpha 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 IL-4RalphaIL-4Ralpha OX40OX40
TGF-β受体2TGF-β receptor 2 IL-4RalphaIL-4Ralpha CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 IL-4RalphaIL-4Ralpha CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 IL-4RalphaIL-4Ralpha IL-4RalphaIL-4Ralpha
TGF-β受体2TGF-β receptor 2 IL-7RalphaIL-7Ralpha CD28CD28
TGF-β受体2TGF-β receptor 2 IL-7RalphaIL-7Ralpha 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 IL-7RalphaIL-7Ralpha OX40OX40
TGF-β受体2TGF-β receptor 2 IL-7RalphaIL-7Ralpha CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 IL-7RalphaIL-7Ralpha CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 IL-7RalphaIL-7Ralpha IL-7RalphaIL-7Ralpha
TGF-β受体2TGF-β receptor 2 IL-10RIL-10R CD28CD28
TGF-β受体2TGF-β receptor 2 IL-10RIL-10R 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 IL-10RIL-10R OX40OX40
TGF-β受体2TGF-β receptor 2 IL-10RIL-10R CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 IL-10RIL-10R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 IL-10RIL-10R IL-10RIL-10R
TGF-β受体2TGF-β receptor 2 IL-12RIL-12R CD28CD28
TGF-β受体2TGF-β receptor 2 IL-12RIL-12R 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 IL-12RIL-12R OX40OX40
TGF-β受体2TGF-β receptor 2 IL-12RIL-12R CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 IL-12RIL-12R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 IL-12RIL-12R IL-12RIL-12R
TGF-β受体2TGF-β receptor 2 IL-15RIL-15R CD28CD28
TGF-β受体2TGF-β receptor 2 IL-15RIL-15R 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 IL-15RIL-15R OX40OX40
TGF-β受体2TGF-β receptor 2 IL-15RIL-15R CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 IL-15RIL-15R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 IL-15RIL-15R IL-15RIL-15R
TGF-β受体2TGF-β receptor 2 IL-21RIL-21R CD28CD28
TGF-β受体2TGF-β receptor 2 IL-21RIL-21R 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 IL-21RIL-21R OX40OX40
TGF-β受体2TGF-β receptor 2 IL-21RIL-21R CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 IL-21RIL-21R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 IL-21RIL-21R IL-21RIL-21R
TGF-β受体2TGF-β receptor 2 CD40CD40 CD28CD28
TGF-β受体2TGF-β receptor 2 CD40CD40 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 CD40CD40 OX40OX40
TGF-β受体2TGF-β receptor 2 CD40CD40 CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 CD40CD40 CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 CD40CD40 CD40CD40
TGF-β受体2TGF-β receptor 2 DAP10DAP10 CD28CD28
TGF-β受体2TGF-β receptor 2 DAP10DAP10 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 DAP10DAP10 OX40OX40
TGF-β受体2TGF-β receptor 2 DAP10DAP10 CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 DAP10DAP10 CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 DAP10DAP10 DAP10DAP10
TGF-β受体2TGF-β receptor 2 ICOSICOS CD28CD28
TGF-β受体2TGF-β receptor 2 ICOSICOS 4-1BB4-1BB
TGF-β受体2TGF-β receptor 2 ICOSICOS OX40OX40
TGF-β受体2TGF-β receptor 2 ICOSICOS CD28+4-1BBCD28+4-1BB
TGF-β受体2TGF-β receptor 2 ICOSICOS CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体2TGF-β receptor 2 ICOSICOS ICOSICOS
TGF-β受体3TGF-β receptor 3 CD28CD28 OX40OX40
TGF-β受体3TGF-β receptor 3 CD28CD28 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 CD28CD28 CD8CD8
TGF-β受体3TGF-β receptor 3 CD28CD28 OX40+4-1BBOX40+4-1BB
TGF-β受体3TGF-β receptor 3 CD28CD28 CD8+4-1BBCD8+4-1BB
TGF-β受体3TGF-β receptor 3 CD28CD28 CD8+OX40CD8+OX40
TGF-β受体3TGF-β receptor 3 CD28CD28 OX40+CD3zOX40+CD3z
TGF-β受体3TGF-β receptor 3 CD28CD28 4-1BB+CD3z4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 CD28CD28 CD8+CD3zCD8+CD3z
TGF-β受体3TGF-β receptor 3 CD28CD28 OX40+4-1BB+CD3zOX40+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 CD28CD28 CD8+4-1BB+CD3zCD8+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 CD28CD28 CD8+OX40+CD3zCD8+OX40+CD3z
TGF-β受体3TGF-β receptor 3 CD8CD8 OX40OX40
TGF-β受体3TGF-β receptor 3 CD8CD8 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 CD8CD8 CD28CD28
TGF-β受体3TGF-β receptor 3 CD8CD8 OX40+4-1BBOX40+4-1BB
TGF-β受体3TGF-β receptor 3 CD8CD8 CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 CD8CD8 CD28+OX40CD28+OX40
TGF-β受体3TGF-β receptor 3 CD8CD8 OX40+CD3zOX40+CD3z
TGF-β受体3TGF-β receptor 3 CD8CD8 4-1BB+CD3z4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 CD8CD8 CD28+CD3zCD28+CD3z
TGF-β受体3TGF-β receptor 3 CD8CD8 OX40+4-1BB+CD3zOX40+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 CD8CD8 CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 CD8CD8 CD28+OX40+CD3zCD28+OX40+CD3z
TGF-β受体3TGF-β receptor 3 4-1BB4-1BB CD28CD28
TGF-β受体3TGF-β receptor 3 4-1BB4-1BB OX40OX40
TGF-β受体3TGF-β receptor 3 4-1BB4-1BB CD28+OX40CD28+OX40
TGF-β受体3TGF-β receptor 3 IL-2RgammaIL-2Rgamma 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 IL-2RgammaIL-2Rgamma CD28CD28
TGF-β受体3TGF-β receptor 3 IL-2RgammaIL-2Rgamma OX40OX40
TGF-β受体3TGF-β receptor 3 IL-2RgammaIL-2Rgamma CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 IL-2RgammaIL-2Rgamma CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 IL-2RgammaIL-2Rgamma IL-2RgammaIL-2Rgamma
TGF-β受体3TGF-β receptor 3 IL-2RbetaIL-2Rbeta 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 IL-2RbetaIL-2Rbeta CD28CD28
TGF-β受体3TGF-β receptor 3 IL-2RbetaIL-2Rbeta OX40OX40
TGF-β受体3TGF-β receptor 3 IL-2RbetaIL-2Rbeta CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 IL-2RbetaIL-2Rbeta CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 IL-2RbetaIL-2Rbeta IL-2RbetaIL-2Rbeta
TGF-β受体3TGF-β receptor 3 IL-4RalphaIL-4Ralpha CD28CD28
TGF-β受体3TGF-β receptor 3 IL-4RalphaIL-4Ralpha 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 IL-4RalphaIL-4Ralpha OX40OX40
TGF-β受体3TGF-β receptor 3 IL-4RalphaIL-4Ralpha CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 IL-4RalphaIL-4Ralpha CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 IL-4RalphaIL-4Ralpha IL-4RalphaIL-4Ralpha
TGF-β受体3TGF-β receptor 3 IL-7RalphaIL-7Ralpha CD28CD28
TGF-β受体3TGF-β receptor 3 IL-7RalphaIL-7Ralpha 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 IL-7RalphaIL-7Ralpha OX40OX40
TGF-β受体3TGF-β receptor 3 IL-7RalphaIL-7Ralpha CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 IL-7RalphaIL-7Ralpha CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 IL-7RalphaIL-7Ralpha IL-7RalphaIL-7Ralpha
TGF-β受体3TGF-β receptor 3 IL-10RIL-10R CD28CD28
TGF-β受体3TGF-β receptor 3 IL-10RIL-10R 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 IL-10RIL-10R OX40OX40
TGF-β受体3TGF-β receptor 3 IL-10RIL-10R CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 IL-10RIL-10R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 IL-10RIL-10R IL-10RIL-10R
TGF-β受体3TGF-β receptor 3 IL-12RIL-12R CD28CD28
TGF-β受体3TGF-β receptor 3 IL-12RIL-12R 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 IL-12RIL-12R OX40OX40
TGF-β受体3TGF-β receptor 3 IL-12RIL-12R CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 IL-12RIL-12R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 IL-12RIL-12R IL-12RIL-12R
TGF-β受体3TGF-β receptor 3 IL-15RIL-15R CD28CD28
TGF-β受体3TGF-β receptor 3 IL-15RIL-15R 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 IL-15RIL-15R OX40OX40
TGF-β受体3TGF-β receptor 3 IL-15RIL-15R CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 IL-15RIL-15R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 IL-15RIL-15R IL-15RIL-15R
TGF-β受体3TGF-β receptor 3 IL-21RIL-21R CD28CD28
TGF-β受体3TGF-β receptor 3 IL-21RIL-21R 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 IL-21RIL-21R OX40OX40
TGF-β受体3TGF-β receptor 3 IL-21RIL-21R CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 IL-21RIL-21R CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 IL-21RIL-21R IL-21RIL-21R
TGF-β受体3TGF-β receptor 3 CD40CD40 CD28CD28
TGF-β受体3TGF-β receptor 3 CD40CD40 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 CD40CD40 OX40OX40
TGF-β受体3TGF-β receptor 3 CD40CD40 CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 CD40CD40 CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 CD40CD40 CD40CD40
TGF-β受体3TGF-β receptor 3 DAP10DAP10 CD28CD28
TGF-β受体3TGF-β receptor 3 DAP10DAP10 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 DAP10DAP10 OX40OX40
TGF-β受体3TGF-β receptor 3 DAP10DAP10 CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 DAP10DAP10 CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 DAP10DAP10 DAP10DAP10
TGF-β受体3TGF-β receptor 3 ICOSICOS CD28CD28
TGF-β受体3TGF-β receptor 3 ICOSICOS 4-1BB4-1BB
TGF-β受体3TGF-β receptor 3 ICOSICOS OX40OX40
TGF-β受体3TGF-β receptor 3 ICOSICOS CD28+4-1BBCD28+4-1BB
TGF-β受体3TGF-β receptor 3 ICOSICOS CD28+4-1BB+CD3zCD28+4-1BB+CD3z
TGF-β受体3TGF-β receptor 3 ICOSICOS ICOSICOS
本发明中，还可以包含突变的激活型受体跨膜区序列，优选地包括突变的IL-7Ralpha跨膜区的突变体。激活型受体跨膜区的突变体能够更好地使激活型受体聚集，在野生型受体的基础上进一步激活放大胞内信号。IL-7Ralpha跨膜区突变体1-32(IL-7Ralpha TM mut1-32)序列如下表2和表3所示：In the present invention, the transmembrane region sequence of the mutated activation receptor may also be included, preferably a mutant of the transmembrane region of the mutated IL-7Ralpha. Mutants in the transmembrane region of the activated receptor can better aggregate the activated receptor and further activate and amplify intracellular signals on the basis of the wild-type receptor. The sequence of IL-7Ralpha transmembrane mutant 1-32 (IL-7RalphaTM mut1-32) is shown in Table 2 and Table 3:
表2：IL-7Ralpha跨膜区突变体1-32氨基酸序列Table 2: IL-7Ralpha transmembrane region mutant 1-32 amino acid sequence
名称name 序列sequence 序列号serial number
IL-7Ralpha TM mut1IL-7Ralpha TM mut1 PILLPPCLTISILSFFSVALLVILACVLWPILLPPCLTISILSFFSVALLVILACVLW SEQ ID NO:29SEQ ID NO: 29
IL-7Ralpha TM mut2IL-7Ralpha TM mut2 PILLTISKCHILSFFSVALLVILACVLWPILLTISKCHILSFFSVALLVILACVLW SEQ ID NO:30SEQ ID NO: 30
IL-7Ralpha TM mut3IL-7Ralpha TM mut3 PIFSCGPLLTISILSFFSVALLVILACVLWPIFSCGPLLTISILSFFSVALLVILACVLW SEQ ID NO:31SEQ ID NO: 31
IL-7Ralpha TM mut4IL-7Ralpha TM mut4 PILLTCHLISILSFFSVALLVILACVLWPILLTCHLISILSFFSVALLVILACVLW SEQ ID NO:32SEQ ID NO: 32
IL-7Ralpha TM mut5IL-7Ralpha TM mut5 PILLTPPVCSVTISILSFFSVALLVILACVLWPILLTPPVCSVTISILSFFSVALLVILACVLW SEQ ID NO:33SEQ ID NO: 33
IL-7Ralpha TM mut6IL-7Ralpha TM mut6 PILLFCRKDTISILSFFSVALLVILACVLWPILLFCRKDTISILSFFSVALLVILACVLW SEQ ID NO:34SEQ ID NO: 34
IL-7Ralpha TM mut7IL-7Ralpha TM mut7 PILLRCTISILSFFSVALLVILACVLWPILLRCTISILSFFSVALLVILACVLW SEQ ID NO:35SEQ ID NO: 35
IL-7Ralpha TM mut8IL-7Ralpha TM mut8 PILPCPLTISILSFFSVALLVILACVLWPILPCPLTISILSFFSVALLVILACVLW SEQ ID NO:36SEQ ID NO: 36
IL-7Ralpha TM mut9IL-7Ralpha TM mut9 PILLMPEQDCPTISILSFFSVALLVILACVLWPILLMPEQDCPTISILSFFSVALLVILACVLW SEQ ID NO:37SEQ ID NO: 37
IL-7Ralpha TM mut10IL-7Ralpha TM mut10 PILCPPLTISILSFFSVALLVILACVLWPILCPPLTISILSFFSVALLVILACVLW SEQ ID NO:38SEQ ID NO: 38
IL-7Ralpha TM mut11IL-7Ralpha TM mut11 PILRCPSTISILSFFSVALLVILACVLWPILRCPSTISILSFFSVALLVILACVLW SEQ ID NO:39SEQ ID NO: 39
IL-7Ralpha TM mut12IL-7Ralpha TM mut12 PIFDCIGVLTISILSFFSVALLVILACVLWPIFDCIGVLTISILSFFSVALLVILACVLW SEQ ID NO:40SEQ ID NO: 40
IL-7Ralpha TM mut13IL-7Ralpha TM mut13 PILLTHRGCILSFFSVALLVILACVLWPILLTHRGCILSFFSVALLVILACVLW SEQ ID NO:41SEQ ID NO: 41
IL-7Ralpha TM mut14IL-7Ralpha TM mut14 PILPLCSAISILSFFSVALLVILACVLWPILPLCSAISILSFFSVALLVILACVLW SEQ ID NO:42SEQ ID NO: 42
IL-7Ralpha TM mut15IL-7Ralpha TM mut15 PILLTISILSFFSVGEAALLVILACVLWPILLTISILSFFSVGEAALLVILACVLW SEQ ID NO:43SEQ ID NO: 43
IL-7Ralpha TM mut16IL-7Ralpha TM mut16 PILPIYRCVLISILSFFSVALLVILACVLWPILPIYRCVLISILSFFSVALLVILACVLW SEQ ID NO:44SEQ ID NO: 44
IL-7Ralpha TM mut17IL-7Ralpha TM mut17 PIFECLTISILSFFSVALLVILACVLWPIFECLTISILSFFSVALLVILACVLW SEQ ID NO:45SEQ ID NO: 45
IL-7Ralpha TM mut18IL-7Ralpha TM mut18 PIFTCPSISILSFFSVALLVILACVLWPIFTCPSISILSFFSVALLVILACVLW SEQ ID NO:46SEQ ID NO: 46
IL-7Ralpha TM mut19IL-7Ralpha TM mut19 PILCPSPTISILSFFSVALLVILACVLWPILCPSPTISILSFFSVALLVILACVLW SEQ ID NO:47SEQ ID NO: 47
IL-7Ralpha TM mut20IL-7Ralpha TM mut20 PILLTISILSFFSVEKVLVILACVLWPILLTISILSFFSVEKVLVILACVLW SEQ ID NO:48SEQ ID NO: 48
IL-7Ralpha TM mut21IL-7Ralpha TM mut21 PILLTSHQPCILSFFSVALLVILACVLWPILLTSHQPCILSFFSVALLVILACVLW SEQ ID NO:49SEQ ID NO: 49
IL-7Ralpha TM mut22IL-7Ralpha TM mut22 PILLTISILSCSTISILSFFSVALLVILACVLWPILLTISILSCSTISILSFFSVALLVILACVLW SEQ ID NO:50SEQ ID NO: 50
IL-7Ralpha TM mut23IL-7Ralpha TM mut23 PILLTISICQSVALLVILACVLWPILLTISICQSVALLVILACVLW SEQ ID NO:51SEQ ID NO: 51
IL-7Ralpha TM mut24IL-7Ralpha TM mut24 PICGIREIISILSFFSVALLVILACVLWPICGIREIISILSFFSVALLVILACVLW SEQ ID NO:52SEQ ID NO: 52
IL-7Ralpha TM mut25IL-7Ralpha TM mut25 PILLTISILSFFSGALLVILACVLWPILLTISILSFFSGALLVILACVLW SEQ ID NO:53SEQ ID NO: 53
IL-7Ralpha TM mut26IL-7Ralpha TM mut26 PILLGCTISILSFFSVALLVILACVLWPILLGCTISILSFFSVALLVILACVLW SEQ ID NO:54SEQ ID NO: 54
IL-7Ralpha TM mut27IL-7Ralpha TM mut27 PCRPHLTISILSFFSVALLVILACVLWPCRPHLTISILSFFSVALLVILACVLW SEQ ID NO:55SEQ ID NO: 55
IL-7Ralpha TM mut28IL-7Ralpha TM mut28 PILGCITISILSFFSVALLVILACVLWPILGCITISILSFFSVALLVILACVLW SEQ ID NO:56SEQ ID NO: 56
IL-7Ralpha TM mut29IL-7Ralpha TM mut29 PILLTRPCGISILSFFSVALLVILACVLWPILLTRPCGISILSFFSVALLVILACVLW SEQ ID NO:57SEQ ID NO: 57
IL-7Ralpha TM mut30IL-7Ralpha TM mut30 PILLTLPCVTISILSFFSVALLVILACVLWPILLTLPCVTISILSFFSVALLVILACVLW SEQ ID NO:58SEQ ID NO: 58
IL-7Ralpha TM mut31IL-7Ralpha TM mut31 PICWMKLTISILSFFSVALLVILACVLWPICWMKLTISILSFFSVALLVILACVLW SEQ ID NO:59SEQ ID NO: 59
IL-7Ralpha TM mut32IL-7Ralpha TM mut32 PILLKKCTNISILSFFSVALLVILACVLWPILLKKCTNISILSFFSVALLVILACVLW SEQ ID NO:60SEQ ID NO: 60
表3：IL-7Ralpha跨膜区突变体1-32核苷酸序列Table 3: IL-7Ralpha transmembrane region mutant 1-32 nucleotide sequence
Figure PCTCN2021097361-appb-000001
Figure PCTCN2021097361-appb-000001
Figure PCTCN2021097361-appb-000002
Figure PCTCN2021097361-appb-000002
Figure PCTCN2021097361-appb-000003
Figure PCTCN2021097361-appb-000003
本发明包含IL-7Ralpha跨膜区突变体1-32的示例性信号转换受体包括但不限于下表4任一行所示的信号转换受体：Exemplary signal conversion receptors of the present invention including IL-7Ralpha transmembrane region mutants 1-32 include, but are not limited to, the signal conversion receptors shown in any row of Table 4 below:
表4Table 4
胞外区Extracellular domain 跨膜区Transmembrane zone 胞内区Intracellular region 序列号(蛋白)Serial number (protein) 序列号(核酸)Serial number (nucleic acid)
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:95SEQ ID NO: 95 SEQ ID NO:863SEQ ID NO: 863
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:96SEQ ID NO: 96 SEQ ID NO:864SEQ ID NO: 864
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:97SEQ ID NO: 97 SEQ ID NO:865SEQ ID NO: 865
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:98SEQ ID NO: 98 SEQ ID NO:866SEQ ID NO: 866
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:99SEQ ID NO: 99 SEQ ID NO:867SEQ ID NO: 867
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:100SEQ ID NO: 100 SEQ ID NO:868SEQ ID NO: 868
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:101SEQ ID NO: 101 SEQ ID NO:869SEQ ID NO: 869
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:102SEQ ID NO: 102 SEQ ID NO:870SEQ ID NO: 870
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:103SEQ ID NO: 103 SEQ ID NO:871SEQ ID NO: 871
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:104SEQ ID NO: 104 SEQ ID NO:872SEQ ID NO: 872
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:105SEQ ID NO: 105 SEQ ID NO:873SEQ ID NO: 873
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:106SEQ ID NO: 106 SEQ ID NO:874SEQ ID NO: 874
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:107SEQ ID NO: 107 SEQ ID NO:875SEQ ID NO: 875
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:108SEQ ID NO: 108 SEQ ID NO:876SEQ ID NO: 876
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:109SEQ ID NO: 109 SEQ ID NO:877SEQ ID NO: 877
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:110SEQ ID NO: 110 SEQ ID NO:878SEQ ID NO: 878
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:111SEQ ID NO: 111 SEQ ID NO:879SEQ ID NO: 879
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:112SEQ ID NO: 112 SEQ ID NO:880SEQ ID NO: 880
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:113SEQ ID NO: 113 SEQ ID NO:881SEQ ID NO: 881
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:114SEQ ID NO: 114 SEQ ID NO:882SEQ ID NO: 882
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:115SEQ ID NO: 115 SEQ ID NO:883SEQ ID NO: 883
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:116SEQ ID NO: 116 SEQ ID NO:884SEQ ID NO: 884
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:117SEQ ID NO: 117 SEQ ID NO:885SEQ ID NO: 885
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:118SEQ ID NO: 118 SEQ ID NO:886SEQ ID NO:886
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:119SEQ ID NO: 119 SEQ ID NO:887SEQ ID NO: 887
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:120SEQ ID NO: 120 SEQ ID NO:888SEQ ID NO: 888
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:121SEQ ID NO: 121 SEQ ID NO:889SEQ ID NO: 889
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:122SEQ ID NO: 122 SEQ ID NO:890SEQ ID NO: 890
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:123SEQ ID NO: 123 SEQ ID NO:891SEQ ID NO: 891
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:124SEQ ID NO: 124 SEQ ID NO:892SEQ ID NO: 892
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:125SEQ ID NO: 125 SEQ ID NO:893SEQ ID NO: 893
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:126SEQ ID NO: 126 SEQ ID NO:894SEQ ID NO: 894
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:127SEQ ID NO: 127 SEQ ID NO:895SEQ ID NO: 895
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:128SEQ ID NO: 128 SEQ ID NO:896SEQ ID NO: 896
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:129SEQ ID NO: 129 SEQ ID NO:897SEQ ID NO: 897
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:130SEQ ID NO: 130 SEQ ID NO:898SEQ ID NO: 898
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:131SEQ ID NO: 131 SEQ ID NO:899SEQ ID NO: 899
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:132SEQ ID NO: 132 SEQ ID NO:900SEQ ID NO: 900
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:133SEQ ID NO: 133 SEQ ID NO:901SEQ ID NO: 901
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:134SEQ ID NO: 134 SEQ ID NO:902SEQ ID NO: 902
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:135SEQ ID NO: 135 SEQ ID NO:903SEQ ID NO: 903
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:136SEQ ID NO: 136 SEQ ID NO:904SEQ ID NO: 904
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:137SEQ ID NO: 137 SEQ ID NO:905SEQ ID NO: 905
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:138SEQ ID NO: 138 SEQ ID NO:906SEQ ID NO: 906
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:139SEQ ID NO: 139 SEQ ID NO:907SEQ ID NO: 907
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:140SEQ ID NO: 140 SEQ ID NO:908SEQ ID NO: 908
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:141SEQ ID NO: 141 SEQ ID NO:909SEQ ID NO: 909
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:142SEQ ID NO: 142 SEQ ID NO:910SEQ ID NO: 910
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:143SEQ ID NO: 143 SEQ ID NO:911SEQ ID NO: 911
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:144SEQ ID NO: 144 SEQ ID NO:912SEQ ID NO: 912
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:145SEQ ID NO: 145 SEQ ID NO:913SEQ ID NO: 913
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:146SEQ ID NO: 146 SEQ ID NO:914SEQ ID NO: 914
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:147SEQ ID NO: 147 SEQ ID NO:915SEQ ID NO: 915
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:148SEQ ID NO: 148 SEQ ID NO:916SEQ ID NO: 916
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:149SEQ ID NO: 149 SEQ ID NO:917SEQ ID NO: 917
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:150SEQ ID NO: 150 SEQ ID NO:918SEQ ID NO: 918
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:151SEQ ID NO: 151 SEQ ID NO:919SEQ ID NO: 919
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:152SEQ ID NO: 152 SEQ ID NO:920SEQ ID NO: 920
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:153SEQ ID NO: 153 SEQ ID NO:921SEQ ID NO: 921
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:154SEQ ID NO: 154 SEQ ID NO:922SEQ ID NO: 922
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:155SEQ ID NO: 155 SEQ ID NO:923SEQ ID NO: 923
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:156SEQ ID NO: 156 SEQ ID NO:924SEQ ID NO: 924
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:157SEQ ID NO: 157 SEQ ID NO:925SEQ ID NO: 925
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:158SEQ ID NO: 158 SEQ ID NO:926SEQ ID NO: 926
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 CD28胞内区CD28 intracellular region SEQ ID NO:159SEQ ID NO: 159 SEQ ID NO:927SEQ ID NO: 927
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 CD28胞内区CD28 intracellular region SEQ ID NO:160SEQ ID NO: 160 SEQ ID NO:928SEQ ID NO: 928
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 CD28胞内区CD28 intracellular region SEQ ID NO:161SEQ ID NO: 161 SEQ ID NO:929SEQ ID NO: 929
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 CD28胞内区CD28 intracellular region SEQ ID NO:162SEQ ID NO: 162 SEQ ID NO:930SEQ ID NO: 930
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 CD28胞内区CD28 intracellular region SEQ ID NO:163SEQ ID NO: 163 SEQ ID NO:931SEQ ID NO: 931
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 CD28胞内区CD28 intracellular region SEQ ID NO:164SEQ ID NO: 164 SEQ ID NO:932SEQ ID NO: 932
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 CD28胞内区CD28 intracellular region SEQ ID NO:165SEQ ID NO: 165 SEQ ID NO:933SEQ ID NO: 933
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 CD28胞内区CD28 intracellular region SEQ ID NO:166SEQ ID NO: 166 SEQ ID NO:934SEQ ID NO: 934
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 CD28胞内区CD28 intracellular region SEQ ID NO:167SEQ ID NO: 167 SEQ ID NO:935SEQ ID NO: 935
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 CD28胞内区CD28 intracellular region SEQ ID NO:168SEQ ID NO: 168 SEQ ID NO:936SEQ ID NO: 936
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 CD28胞内区CD28 intracellular region SEQ ID NO:169SEQ ID NO: 169 SEQ ID NO:937SEQ ID NO: 937
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 CD28胞内区CD28 intracellular region SEQ ID NO:170SEQ ID NO: 170 SEQ ID NO:938SEQ ID NO: 938
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 CD28胞内区CD28 intracellular region SEQ ID NO:171SEQ ID NO: 171 SEQ ID NO:939SEQ ID NO: 939
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 CD28胞内区CD28 intracellular region SEQ ID NO:172SEQ ID NO: 172 SEQ ID NO:940SEQ ID NO: 940
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 CD28胞内区CD28 intracellular region SEQ ID NO:173SEQ ID NO: 173 SEQ ID NO:941SEQ ID NO: 941
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 CD28胞内区CD28 intracellular region SEQ ID NO:174SEQ ID NO: 174 SEQ ID NO:942SEQ ID NO: 942
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 CD28胞内区CD28 intracellular region SEQ ID NO:175SEQ ID NO: 175 SEQ ID NO:943SEQ ID NO: 943
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 CD28胞内区CD28 intracellular region SEQ ID NO:176SEQ ID NO: 176 SEQ ID NO:944SEQ ID NO: 944
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 CD28胞内区CD28 intracellular region SEQ ID NO:177SEQ ID NO: 177 SEQ ID NO:945SEQ ID NO: 945
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 CD28胞内区CD28 intracellular region SEQ ID NO:178SEQ ID NO: 178 SEQ ID NO:946SEQ ID NO: 946
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 CD28胞内区CD28 intracellular region SEQ ID NO:179SEQ ID NO: 179 SEQ ID NO:947SEQ ID NO: 947
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 CD28胞内区CD28 intracellular region SEQ ID NO:180SEQ ID NO: 180 SEQ ID NO:948SEQ ID NO: 948
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 CD28胞内区CD28 intracellular region SEQ ID NO:181SEQ ID NO: 181 SEQ ID NO:949SEQ ID NO: 949
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 CD28胞内区CD28 intracellular region SEQ ID NO:182SEQ ID NO: 182 SEQ ID NO:950SEQ ID NO: 950
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 CD28胞内区CD28 intracellular region SEQ ID NO:183SEQ ID NO: 183 SEQ ID NO:951SEQ ID NO: 951
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 CD28胞内区CD28 intracellular region SEQ ID NO:184SEQ ID NO: 184 SEQ ID NO:952SEQ ID NO: 952
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 CD28胞内区CD28 intracellular region SEQ ID NO:185SEQ ID NO: 185 SEQ ID NO:953SEQ ID NO: 953
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 CD28胞内区CD28 intracellular region SEQ ID NO:186SEQ ID NO: 186 SEQ ID NO:954SEQ ID NO: 954
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 CD28胞内区CD28 intracellular region SEQ ID NO:187SEQ ID NO: 187 SEQ ID NO:955SEQ ID NO: 955
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 CD28胞内区CD28 intracellular region SEQ ID NO:188SEQ ID NO: 188 SEQ ID NO:956SEQ ID NO: 956
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 CD28胞内区CD28 intracellular region SEQ ID NO:189SEQ ID NO: 189 SEQ ID NO:957SEQ ID NO: 957
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 CD28胞内区CD28 intracellular region SEQ ID NO:190SEQ ID NO: 190 SEQ ID NO:958SEQ ID NO: 958
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:191SEQ ID NO: 191 SEQ ID NO:959SEQ ID NO:959
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:192SEQ ID NO: 192 SEQ ID NO:960SEQ ID NO: 960
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:193SEQ ID NO: 193 SEQ ID NO:961SEQ ID NO: 961
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:194SEQ ID NO: 194 SEQ ID NO:962SEQ ID NO: 962
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:195SEQ ID NO: 195 SEQ ID NO:963SEQ ID NO: 963
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:196SEQ ID NO: 196 SEQ ID NO:964SEQ ID NO: 964
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:197SEQ ID NO: 197 SEQ ID NO:965SEQ ID NO: 965
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:198SEQ ID NO: 198 SEQ ID NO:966SEQ ID NO: 966
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:199SEQ ID NO: 199 SEQ ID NO:967SEQ ID NO: 967
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:200SEQ ID NO: 200 SEQ ID NO:968SEQ ID NO: 968
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:201SEQ ID NO: 201 SEQ ID NO:969SEQ ID NO: 969
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:202SEQ ID NO: 202 SEQ ID NO:970SEQ ID NO: 970
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:203SEQ ID NO: 203 SEQ ID NO:971SEQ ID NO: 971
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:204SEQ ID NO: 204 SEQ ID NO:972SEQ ID NO: 972
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:205SEQ ID NO: 205 SEQ ID NO:973SEQ ID NO: 973
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:206SEQ ID NO: 206 SEQ ID NO:974SEQ ID NO: 974
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:207SEQ ID NO: 207 SEQ ID NO:975SEQ ID NO: 975
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:208SEQ ID NO: 208 SEQ ID NO:976SEQ ID NO: 976
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:209SEQ ID NO: 209 SEQ ID NO:977SEQ ID NO: 977
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:210SEQ ID NO: 210 SEQ ID NO:978SEQ ID NO: 978
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:211SEQ ID NO: 211 SEQ ID NO:979SEQ ID NO: 979
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:212SEQ ID NO: 212 SEQ ID NO:980SEQ ID NO: 980
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:213SEQ ID NO: 213 SEQ ID NO:981SEQ ID NO: 981
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:214SEQ ID NO: 214 SEQ ID NO:982SEQ ID NO: 982
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:215SEQ ID NO: 215 SEQ ID NO:983SEQ ID NO: 983
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:216SEQ ID NO: 216 SEQ ID NO:984SEQ ID NO: 984
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:217SEQ ID NO: 217 SEQ ID NO:985SEQ ID NO: 985
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:218SEQ ID NO: 218 SEQ ID NO:986SEQ ID NO: 986
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:219SEQ ID NO: 219 SEQ ID NO:987SEQ ID NO: 987
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:220SEQ ID NO: 220 SEQ ID NO:988SEQ ID NO: 988
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:221SEQ ID NO: 221 SEQ ID NO:989SEQ ID NO:989
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:222SEQ ID NO: 222 SEQ ID NO:990SEQ ID NO: 990
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:223SEQ ID NO: 223 SEQ ID NO:991SEQ ID NO: 991
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:224SEQ ID NO: 224 SEQ ID NO:992SEQ ID NO: 992
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:225SEQ ID NO: 225 SEQ ID NO:993SEQ ID NO: 993
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:226SEQ ID NO: 226 SEQ ID NO:994SEQ ID NO: 994
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:227SEQ ID NO: 227 SEQ ID NO:995SEQ ID NO: 995
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:228SEQ ID NO: 228 SEQ ID NO:996SEQ ID NO: 996
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:229SEQ ID NO: 229 SEQ ID NO:997SEQ ID NO: 997
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:230SEQ ID NO: 230 SEQ ID NO:998SEQ ID NO: 998
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:231SEQ ID NO: 231 SEQ ID NO:999SEQ ID NO: 999
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:232SEQ ID NO: 232 SEQ ID NO:1000SEQ ID NO: 1000
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:233SEQ ID NO: 233 SEQ ID NO:1001SEQ ID NO: 1001
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:234SEQ ID NO: 234 SEQ ID NO:1002SEQ ID NO: 1002
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:235SEQ ID NO: 235 SEQ ID NO:1003SEQ ID NO: 1003
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:236SEQ ID NO: 236 SEQ ID NO:1004SEQ ID NO: 1004
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:237SEQ ID NO: 237 SEQ ID NO:1005SEQ ID NO: 1005
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:238SEQ ID NO: 238 SEQ ID NO:1006SEQ ID NO: 1006
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:239SEQ ID NO: 239 SEQ ID NO:1007SEQ ID NO: 1007
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:240SEQ ID NO: 240 SEQ ID NO:1008SEQ ID NO: 1008
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:241SEQ ID NO: 241 SEQ ID NO:1009SEQ ID NO: 1009
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:242SEQ ID NO: 242 SEQ ID NO:1010SEQ ID NO: 1010
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:243SEQ ID NO: 243 SEQ ID NO:1011SEQ ID NO: 1011
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:244SEQ ID NO: 244 SEQ ID NO:1012SEQ ID NO: 1012
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:245SEQ ID NO: 245 SEQ ID NO:1013SEQ ID NO: 1013
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:246SEQ ID NO: 246 SEQ ID NO:1014SEQ ID NO: 1014
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:247SEQ ID NO: 247 SEQ ID NO:1015SEQ ID NO: 1015
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:248SEQ ID NO: 248 SEQ ID NO:1016SEQ ID NO: 1016
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:249SEQ ID NO: 249 SEQ ID NO:1017SEQ ID NO: 1017
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:250SEQ ID NO: 250 SEQ ID NO:1018SEQ ID NO: 1018
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:251SEQ ID NO: 251 SEQ ID NO:1019SEQ ID NO: 1019
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:252SEQ ID NO: 252 SEQ ID NO:1020SEQ ID NO: 1020
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:253SEQ ID NO: 253 SEQ ID NO:1021SEQ ID NO: 1021
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:254SEQ ID NO: 254 SEQ ID NO:1022SEQ ID NO: 1022
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:255SEQ ID NO: 255 SEQ ID NO:1023SEQ ID NO: 1023
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:256SEQ ID NO: 256 SEQ ID NO:1024SEQ ID NO: 1024
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:257SEQ ID NO: 257 SEQ ID NO:1025SEQ ID NO: 1025
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:258SEQ ID NO: 258 SEQ ID NO:1026SEQ ID NO: 1026
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:259SEQ ID NO: 259 SEQ ID NO:1027SEQ ID NO: 1027
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:260SEQ ID NO: 260 SEQ ID NO:1028SEQ ID NO: 1028
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:261SEQ ID NO: 261 SEQ ID NO:1029SEQ ID NO: 1029
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:262SEQ ID NO: 262 SEQ ID NO:1030SEQ ID NO: 1030
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:263SEQ ID NO: 263 SEQ ID NO:1031SEQ ID NO: 1031
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:264SEQ ID NO: 264 SEQ ID NO:1032SEQ ID NO: 1032
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:265SEQ ID NO: 265 SEQ ID NO:1033SEQ ID NO: 1033
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:266SEQ ID NO: 266 SEQ ID NO:1034SEQ ID NO: 1034
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:267SEQ ID NO: 267 SEQ ID NO:1035SEQ ID NO: 1035
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:268SEQ ID NO: 268 SEQ ID NO:1036SEQ ID NO: 1036
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:269SEQ ID NO: 269 SEQ ID NO:1037SEQ ID NO: 1037
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:270SEQ ID NO: 270 SEQ ID NO:1038SEQ ID NO: 1038
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:271SEQ ID NO: 271 SEQ ID NO:1039SEQ ID NO: 1039
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:272SEQ ID NO: 272 SEQ ID NO:1040SEQ ID NO: 1040
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:273SEQ ID NO: 273 SEQ ID NO:1041SEQ ID NO: 1041
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:274SEQ ID NO: 274 SEQ ID NO:1042SEQ ID NO: 1042
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:275SEQ ID NO: 275 SEQ ID NO:1043SEQ ID NO: 1043
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:276SEQ ID NO: 276 SEQ ID NO:1044SEQ ID NO: 1044
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:277SEQ ID NO: 277 SEQ ID NO:1045SEQ ID NO: 1045
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:278SEQ ID NO: 278 SEQ ID NO:1046SEQ ID NO:1046
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:279SEQ ID NO: 279 SEQ ID NO:1047SEQ ID NO:1047
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:280SEQ ID NO: 280 SEQ ID NO:1048SEQ ID NO:1048
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:281SEQ ID NO: 281 SEQ ID NO:1049SEQ ID NO:1049
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:282SEQ ID NO: 282 SEQ ID NO:1050SEQ ID NO: 1050
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:283SEQ ID NO: 283 SEQ ID NO:1051SEQ ID NO: 1051
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:284SEQ ID NO: 284 SEQ ID NO:1052SEQ ID NO: 1052
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:285SEQ ID NO: 285 SEQ ID NO:1053SEQ ID NO: 1053
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:286SEQ ID NO: 286 SEQ ID NO:1054SEQ ID NO:1054
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:287SEQ ID NO: 287 SEQ ID NO:1055SEQ ID NO:1055
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:288SEQ ID NO: 288 SEQ ID NO:1056SEQ ID NO:1056
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:289SEQ ID NO: 289 SEQ ID NO:1057SEQ ID NO: 1057
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:290SEQ ID NO: 290 SEQ ID NO:1058SEQ ID NO:1058
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:291SEQ ID NO: 291 SEQ ID NO:1059SEQ ID NO:1059
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:292SEQ ID NO: 292 SEQ ID NO:1060SEQ ID NO: 1060
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:293SEQ ID NO: 293 SEQ ID NO:1061SEQ ID NO: 1061
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:294SEQ ID NO: 294 SEQ ID NO:1062SEQ ID NO: 1062
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:295SEQ ID NO: 295 SEQ ID NO:1063SEQ ID NO: 1063
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:296SEQ ID NO: 296 SEQ ID NO:1064SEQ ID NO: 1064
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:297SEQ ID NO: 297 SEQ ID NO:1065SEQ ID NO: 1065
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:298SEQ ID NO: 298 SEQ ID NO:1066SEQ ID NO: 1066
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:299SEQ ID NO: 299 SEQ ID NO:1067SEQ ID NO: 1067
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:300SEQ ID NO: 300 SEQ ID NO:1068SEQ ID NO:1068
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:301SEQ ID NO: 301 SEQ ID NO:1069SEQ ID NO:1069
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:302SEQ ID NO: 302 SEQ ID NO:1070SEQ ID NO: 1070
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:303SEQ ID NO: 303 SEQ ID NO:1071SEQ ID NO: 1071
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:304SEQ ID NO: 304 SEQ ID NO:1072SEQ ID NO: 1072
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:305SEQ ID NO: 305 SEQ ID NO:1073SEQ ID NO: 1073
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:306SEQ ID NO: 306 SEQ ID NO:1074SEQ ID NO:1074
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:307SEQ ID NO: 307 SEQ ID NO:1075SEQ ID NO: 1075
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:308SEQ ID NO: 308 SEQ ID NO:1076SEQ ID NO:1076
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:309SEQ ID NO: 309 SEQ ID NO:1077SEQ ID NO:1077
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:310SEQ ID NO: 310 SEQ ID NO:1078SEQ ID NO:1078
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:311SEQ ID NO: 311 SEQ ID NO:1079SEQ ID NO: 1079
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:312SEQ ID NO: 312 SEQ ID NO:1080SEQ ID NO: 1080
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:313SEQ ID NO: 313 SEQ ID NO:1081SEQ ID NO: 1081
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:314SEQ ID NO: 314 SEQ ID NO:1082SEQ ID NO: 1082
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:315SEQ ID NO: 315 SEQ ID NO:1083SEQ ID NO: 1083
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:316SEQ ID NO: 316 SEQ ID NO:1084SEQ ID NO: 1084
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:317SEQ ID NO: 317 SEQ ID NO:1085SEQ ID NO:1085
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:318SEQ ID NO: 318 SEQ ID NO:1086SEQ ID NO:1086
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:319SEQ ID NO: 319 SEQ ID NO:1087SEQ ID NO: 1087
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:320SEQ ID NO: 320 SEQ ID NO:1088SEQ ID NO: 1088
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:321SEQ ID NO: 321 SEQ ID NO:1089SEQ ID NO:1089
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:322SEQ ID NO: 322 SEQ ID NO:1090SEQ ID NO: 1090
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:323SEQ ID NO: 323 SEQ ID NO:1091SEQ ID NO: 1091
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:324SEQ ID NO: 324 SEQ ID NO:1092SEQ ID NO: 1092
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:325SEQ ID NO: 325 SEQ ID NO:1093SEQ ID NO: 1093
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:326SEQ ID NO: 326 SEQ ID NO:1094SEQ ID NO: 1094
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:327SEQ ID NO: 327 SEQ ID NO:1095SEQ ID NO: 1095
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:328SEQ ID NO: 328 SEQ ID NO:1096SEQ ID NO:1096
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:329SEQ ID NO: 329 SEQ ID NO:1097SEQ ID NO:1097
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:330SEQ ID NO: 330 SEQ ID NO:1098SEQ ID NO:1098
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:331SEQ ID NO: 331 SEQ ID NO:1099SEQ ID NO: 1099
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:332SEQ ID NO: 332 SEQ ID NO:1100SEQ ID NO: 1100
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:333SEQ ID NO: 333 SEQ ID NO:1101SEQ ID NO:1101
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:334SEQ ID NO: 334 SEQ ID NO:1102SEQ ID NO:1102
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:335SEQ ID NO: 335 SEQ ID NO:1103SEQ ID NO:1103
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:336SEQ ID NO: 336 SEQ ID NO:1104SEQ ID NO:1104
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:337SEQ ID NO: 337 SEQ ID NO:1105SEQ ID NO:1105
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:338SEQ ID NO: 338 SEQ ID NO:1106SEQ ID NO:1106
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:339SEQ ID NO: 339 SEQ ID NO:1107SEQ ID NO: 1107
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:340SEQ ID NO: 340 SEQ ID NO:1108SEQ ID NO: 1108
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:341SEQ ID NO: 341 SEQ ID NO:1109SEQ ID NO:1109
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:342SEQ ID NO: 342 SEQ ID NO:1110SEQ ID NO:1110
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:343SEQ ID NO: 343 SEQ ID NO:1111SEQ ID NO:1111
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:344SEQ ID NO: 344 SEQ ID NO:1112SEQ ID NO:1112
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:345SEQ ID NO: 345 SEQ ID NO:1113SEQ ID NO:1113
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:346SEQ ID NO: 346 SEQ ID NO:1114SEQ ID NO:1114
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:347SEQ ID NO: 347 SEQ ID NO:1115SEQ ID NO:1115
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:348SEQ ID NO: 348 SEQ ID NO:1116SEQ ID NO:1116
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:349SEQ ID NO: 349 SEQ ID NO:1117SEQ ID NO:1117
TGF-β受体1TGF-β receptor 1 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:350SEQ ID NO: 350 SEQ ID NO:1118SEQ ID NO:1118
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:351SEQ ID NO: 351 SEQ ID NO:1119SEQ ID NO:1119
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:352SEQ ID NO: 352 SEQ ID NO:1120SEQ ID NO:1120
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:353SEQ ID NO: 353 SEQ ID NO:1121SEQ ID NO:1121
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:354SEQ ID NO: 354 SEQ ID NO:1122SEQ ID NO:1122
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:355SEQ ID NO: 355 SEQ ID NO:1123SEQ ID NO:1123
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:356SEQ ID NO: 356 SEQ ID NO:1124SEQ ID NO:1124
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:357SEQ ID NO: 357 SEQ ID NO:1125SEQ ID NO:1125
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:358SEQ ID NO: 358 SEQ ID NO:1126SEQ ID NO:1126
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:359SEQ ID NO: 359 SEQ ID NO:1127SEQ ID NO: 1127
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:360SEQ ID NO: 360 SEQ ID NO:1128SEQ ID NO:1128
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:361SEQ ID NO: 361 SEQ ID NO:1129SEQ ID NO: 1129
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:362SEQ ID NO: 362 SEQ ID NO:1130SEQ ID NO:1130
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:363SEQ ID NO: 363 SEQ ID NO:1131SEQ ID NO:1131
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:364SEQ ID NO: 364 SEQ ID NO:1132SEQ ID NO:1132
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:365SEQ ID NO: 365 SEQ ID NO:1133SEQ ID NO:1133
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:366SEQ ID NO: 366 SEQ ID NO:1134SEQ ID NO: 1134
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:367SEQ ID NO: 367 SEQ ID NO:1135SEQ ID NO:1135
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:368SEQ ID NO: 368 SEQ ID NO:1136SEQ ID NO: 1136
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:369SEQ ID NO: 369 SEQ ID NO:1137SEQ ID NO: 1137
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:370SEQ ID NO: 370 SEQ ID NO:1138SEQ ID NO:1138
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:371SEQ ID NO: 371 SEQ ID NO:1139SEQ ID NO:1139
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:372SEQ ID NO: 372 SEQ ID NO:1140SEQ ID NO:1140
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:373SEQ ID NO: 373 SEQ ID NO:1141SEQ ID NO:1141
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:374SEQ ID NO: 374 SEQ ID NO:1142SEQ ID NO:1142
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:375SEQ ID NO: 375 SEQ ID NO:1143SEQ ID NO:1143
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:376SEQ ID NO: 376 SEQ ID NO:1144SEQ ID NO:1144
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:377SEQ ID NO: 377 SEQ ID NO:1145SEQ ID NO:1145
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:378SEQ ID NO: 378 SEQ ID NO:1146SEQ ID NO:1146
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:379SEQ ID NO: 379 SEQ ID NO:1147SEQ ID NO: 1147
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:380SEQ ID NO: 380 SEQ ID NO:1148SEQ ID NO: 1148
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:381SEQ ID NO: 381 SEQ ID NO:1149SEQ ID NO:1149
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:382SEQ ID NO: 382 SEQ ID NO:1150SEQ ID NO:1150
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:383SEQ ID NO: 383 SEQ ID NO:1151SEQ ID NO:1151
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:384SEQ ID NO: 384 SEQ ID NO:1152SEQ ID NO:1152
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:385SEQ ID NO: 385 SEQ ID NO:1153SEQ ID NO:1153
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:386SEQ ID NO: 386 SEQ ID NO:1154SEQ ID NO:1154
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:387SEQ ID NO: 387 SEQ ID NO:1155SEQ ID NO:1155
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:388SEQ ID NO: 388 SEQ ID NO:1156SEQ ID NO:1156
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:389SEQ ID NO: 389 SEQ ID NO:1157SEQ ID NO: 1157
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:390SEQ ID NO: 390 SEQ ID NO:1158SEQ ID NO:1158
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:391SEQ ID NO: 391 SEQ ID NO:1159SEQ ID NO:1159
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:392SEQ ID NO: 392 SEQ ID NO:1160SEQ ID NO:1160
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:393SEQ ID NO: 393 SEQ ID NO:1161SEQ ID NO:1161
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:394SEQ ID NO: 394 SEQ ID NO:1162SEQ ID NO:1162
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:395SEQ ID NO: 395 SEQ ID NO:1163SEQ ID NO: 1163
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:396SEQ ID NO: 396 SEQ ID NO:1164SEQ ID NO: 1164
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:397SEQ ID NO: 397 SEQ ID NO:1165SEQ ID NO:1165
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:398SEQ ID NO: 398 SEQ ID NO:1166SEQ ID NO:1166
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:399SEQ ID NO: 399 SEQ ID NO:1167SEQ ID NO:1167
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:400SEQ ID NO: 400 SEQ ID NO:1168SEQ ID NO:1168
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:401SEQ ID NO: 401 SEQ ID NO:1169SEQ ID NO:1169
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:402SEQ ID NO: 402 SEQ ID NO:1170SEQ ID NO:1170
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:403SEQ ID NO: 403 SEQ ID NO:1171SEQ ID NO:1171
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:404SEQ ID NO: 404 SEQ ID NO:1172SEQ ID NO:1172
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:405SEQ ID NO: 405 SEQ ID NO:1173SEQ ID NO: 1173
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:406SEQ ID NO: 406 SEQ ID NO:1174SEQ ID NO: 1174
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:407SEQ ID NO: 407 SEQ ID NO:1175SEQ ID NO:1175
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:408SEQ ID NO: 408 SEQ ID NO:1176SEQ ID NO:1176
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:409SEQ ID NO: 409 SEQ ID NO:1177SEQ ID NO: 1177
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:410SEQ ID NO: 410 SEQ ID NO:1178SEQ ID NO:1178
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:411SEQ ID NO: 411 SEQ ID NO:1179SEQ ID NO: 1179
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:412SEQ ID NO: 412 SEQ ID NO:1180SEQ ID NO:1180
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:413SEQ ID NO: 413 SEQ ID NO:1181SEQ ID NO:1181
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:414SEQ ID NO: 414 SEQ ID NO:1182SEQ ID NO:1182
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 CD28胞内区CD28 intracellular region SEQ ID NO:415SEQ ID NO: 415 SEQ ID NO:1183SEQ ID NO:1183
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 CD28胞内区CD28 intracellular region SEQ ID NO:416SEQ ID NO: 416 SEQ ID NO:1184SEQ ID NO: 1184
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 CD28胞内区CD28 intracellular region SEQ ID NO:417SEQ ID NO: 417 SEQ ID NO:1185SEQ ID NO:1185
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 CD28胞内区CD28 intracellular region SEQ ID NO:418SEQ ID NO: 418 SEQ ID NO:1186SEQ ID NO: 1186
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 CD28胞内区CD28 intracellular region SEQ ID NO:419SEQ ID NO: 419 SEQ ID NO:1187SEQ ID NO:1187
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 CD28胞内区CD28 intracellular region SEQ ID NO:420SEQ ID NO: 420 SEQ ID NO:1188SEQ ID NO:1188
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 CD28胞内区CD28 intracellular region SEQ ID NO:421SEQ ID NO: 421 SEQ ID NO:1189SEQ ID NO:1189
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 CD28胞内区CD28 intracellular region SEQ ID NO:422SEQ ID NO: 422 SEQ ID NO:1190SEQ ID NO:1190
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 CD28胞内区CD28 intracellular region SEQ ID NO:423SEQ ID NO: 423 SEQ ID NO:1191SEQ ID NO:1191
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 CD28胞内区CD28 intracellular region SEQ ID NO:424SEQ ID NO: 424 SEQ ID NO:1192SEQ ID NO:1192
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 CD28胞内区CD28 intracellular region SEQ ID NO:425SEQ ID NO: 425 SEQ ID NO:1193SEQ ID NO:1193
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 CD28胞内区CD28 intracellular region SEQ ID NO:426SEQ ID NO: 426 SEQ ID NO:1194SEQ ID NO:1194
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 CD28胞内区CD28 intracellular region SEQ ID NO:427SEQ ID NO: 427 SEQ ID NO:1195SEQ ID NO:1195
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 CD28胞内区CD28 intracellular region SEQ ID NO:428SEQ ID NO: 428 SEQ ID NO:1196SEQ ID NO:1196
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 CD28胞内区CD28 intracellular region SEQ ID NO:429SEQ ID NO: 429 SEQ ID NO:1197SEQ ID NO:1197
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 CD28胞内区CD28 intracellular region SEQ ID NO:430SEQ ID NO: 430 SEQ ID NO:1198SEQ ID NO:1198
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 CD28胞内区CD28 intracellular region SEQ ID NO:431SEQ ID NO: 431 SEQ ID NO:1199SEQ ID NO:1199
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 CD28胞内区CD28 intracellular region SEQ ID NO:432SEQ ID NO: 432 SEQ ID NO:1200SEQ ID NO: 1200
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 CD28胞内区CD28 intracellular region SEQ ID NO:433SEQ ID NO: 433 SEQ ID NO:1201SEQ ID NO: 1201
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 CD28胞内区CD28 intracellular region SEQ ID NO:434SEQ ID NO: 434 SEQ ID NO:1202SEQ ID NO:1202
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 CD28胞内区CD28 intracellular region SEQ ID NO:435SEQ ID NO: 435 SEQ ID NO:1203SEQ ID NO:1203
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 CD28胞内区CD28 intracellular region SEQ ID NO:436SEQ ID NO: 436 SEQ ID NO:1204SEQ ID NO:1204
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 CD28胞内区CD28 intracellular region SEQ ID NO:437SEQ ID NO: 437 SEQ ID NO:1205SEQ ID NO:1205
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 CD28胞内区CD28 intracellular region SEQ ID NO:438SEQ ID NO: 438 SEQ ID NO:1206SEQ ID NO:1206
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 CD28胞内区CD28 intracellular region SEQ ID NO:439SEQ ID NO: 439 SEQ ID NO:1207SEQ ID NO:1207
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 CD28胞内区CD28 intracellular region SEQ ID NO:440SEQ ID NO: 440 SEQ ID NO:1208SEQ ID NO:1208
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 CD28胞内区CD28 intracellular region SEQ ID NO:441SEQ ID NO: 441 SEQ ID NO:1209SEQ ID NO:1209
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 CD28胞内区CD28 intracellular region SEQ ID NO:442SEQ ID NO: 442 SEQ ID NO:1210SEQ ID NO: 1210
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 CD28胞内区CD28 intracellular region SEQ ID NO:443SEQ ID NO: 443 SEQ ID NO:1211SEQ ID NO: 1211
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 CD28胞内区CD28 intracellular region SEQ ID NO:444SEQ ID NO: 444 SEQ ID NO:1212SEQ ID NO: 1212
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 CD28胞内区CD28 intracellular region SEQ ID NO:445SEQ ID NO: 445 SEQ ID NO:1213SEQ ID NO:1213
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 CD28胞内区CD28 intracellular region SEQ ID NO:446SEQ ID NO: 446 SEQ ID NO:1214SEQ ID NO:1214
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:447SEQ ID NO: 447 SEQ ID NO:1215SEQ ID NO: 1215
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:448SEQ ID NO: 448 SEQ ID NO:1216SEQ ID NO:1216
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:449SEQ ID NO: 449 SEQ ID NO:1217SEQ ID NO:1217
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:450SEQ ID NO: 450 SEQ ID NO:1218SEQ ID NO:1218
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:451SEQ ID NO: 451 SEQ ID NO:1219SEQ ID NO:1219
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:452SEQ ID NO: 452 SEQ ID NO:1220SEQ ID NO:1220
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:453SEQ ID NO: 453 SEQ ID NO:1221SEQ ID NO:1221
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:454SEQ ID NO: 454 SEQ ID NO:1222SEQ ID NO:1222
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:455SEQ ID NO: 455 SEQ ID NO:1223SEQ ID NO:1223
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:456SEQ ID NO: 456 SEQ ID NO:1224SEQ ID NO:1224
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:457SEQ ID NO: 457 SEQ ID NO:1225SEQ ID NO:1225
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:458SEQ ID NO: 458 SEQ ID NO:1226SEQ ID NO:1226
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:459SEQ ID NO: 459 SEQ ID NO:1227SEQ ID NO:1227
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:460SEQ ID NO: 460 SEQ ID NO:1228SEQ ID NO:1228
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:461SEQ ID NO: 461 SEQ ID NO:1229SEQ ID NO:1229
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:462SEQ ID NO: 462 SEQ ID NO:1230SEQ ID NO:1230
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:463SEQ ID NO: 463 SEQ ID NO:1231SEQ ID NO: 1231
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:464SEQ ID NO: 464 SEQ ID NO:1232SEQ ID NO:1232
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:465SEQ ID NO: 465 SEQ ID NO:1233SEQ ID NO:1233
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:466SEQ ID NO: 466 SEQ ID NO:1234SEQ ID NO:1234
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:467SEQ ID NO: 467 SEQ ID NO:1235SEQ ID NO:1235
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:468SEQ ID NO: 468 SEQ ID NO:1236SEQ ID NO:1236
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:469SEQ ID NO: 469 SEQ ID NO:1237SEQ ID NO:1237
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:470SEQ ID NO: 470 SEQ ID NO:1238SEQ ID NO:1238
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:471SEQ ID NO: 471 SEQ ID NO:1239SEQ ID NO:1239
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:472SEQ ID NO: 472 SEQ ID NO:1240SEQ ID NO:1240
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:473SEQ ID NO: 473 SEQ ID NO:1241SEQ ID NO: 1241
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:474SEQ ID NO: 474 SEQ ID NO:1242SEQ ID NO:1242
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:475SEQ ID NO: 475 SEQ ID NO:1243SEQ ID NO:1243
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:476SEQ ID NO: 476 SEQ ID NO:1244SEQ ID NO:1244
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:477SEQ ID NO: 477 SEQ ID NO:1245SEQ ID NO:1245
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:478SEQ ID NO: 478 SEQ ID NO:1246SEQ ID NO:1246
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:479SEQ ID NO: 479 SEQ ID NO:1247SEQ ID NO:1247
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:480SEQ ID NO: 480 SEQ ID NO:1248SEQ ID NO:1248
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:481SEQ ID NO: 481 SEQ ID NO:1249SEQ ID NO:1249
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:482SEQ ID NO: 482 SEQ ID NO:1250SEQ ID NO:1250
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:483SEQ ID NO: 483 SEQ ID NO:1251SEQ ID NO: 1251
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:484SEQ ID NO: 484 SEQ ID NO:1252SEQ ID NO:1252
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:485SEQ ID NO: 485 SEQ ID NO:1253SEQ ID NO:1253
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:486SEQ ID NO: 486 SEQ ID NO:1254SEQ ID NO:1254
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:487SEQ ID NO: 487 SEQ ID NO:1255SEQ ID NO:1255
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:488SEQ ID NO: 488 SEQ ID NO:1256SEQ ID NO:1256
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:489SEQ ID NO: 489 SEQ ID NO:1257SEQ ID NO:1257
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:490SEQ ID NO: 490 SEQ ID NO:1258SEQ ID NO:1258
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:491SEQ ID NO: 491 SEQ ID NO:1259SEQ ID NO:1259
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:492SEQ ID NO: 492 SEQ ID NO:1260SEQ ID NO:1260
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:493SEQ ID NO: 493 SEQ ID NO:1261SEQ ID NO: 1261
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:494SEQ ID NO: 494 SEQ ID NO:1262SEQ ID NO:1262
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:495SEQ ID NO: 495 SEQ ID NO:1263SEQ ID NO: 1263
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:496SEQ ID NO: 496 SEQ ID NO:1264SEQ ID NO:1264
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:497SEQ ID NO: 497 SEQ ID NO:1265SEQ ID NO:1265
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:498SEQ ID NO: 498 SEQ ID NO:1266SEQ ID NO:1266
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:499SEQ ID NO: 499 SEQ ID NO:1267SEQ ID NO:1267
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:500SEQ ID NO: 500 SEQ ID NO:1268SEQ ID NO:1268
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:501SEQ ID NO: 501 SEQ ID NO:1269SEQ ID NO:1269
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:502SEQ ID NO: 502 SEQ ID NO:1270SEQ ID NO:1270
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:503SEQ ID NO: 503 SEQ ID NO:1271SEQ ID NO: 1271
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:504SEQ ID NO: 504 SEQ ID NO:1272SEQ ID NO:1272
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:505SEQ ID NO: 505 SEQ ID NO:1273SEQ ID NO:1273
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:506SEQ ID NO: 506 SEQ ID NO:1274SEQ ID NO:1274
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:507SEQ ID NO: 507 SEQ ID NO:1275SEQ ID NO:1275
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:508SEQ ID NO: 508 SEQ ID NO:1276SEQ ID NO:1276
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:509SEQ ID NO: 509 SEQ ID NO:1277SEQ ID NO:1277
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:510SEQ ID NO: 510 SEQ ID NO:1278SEQ ID NO:1278
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:511SEQ ID NO: 511 SEQ ID NO:1279SEQ ID NO:1279
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:512SEQ ID NO: 512 SEQ ID NO:1280SEQ ID NO: 1280
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:513SEQ ID NO: 513 SEQ ID NO:1281SEQ ID NO:1281
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:514SEQ ID NO: 514 SEQ ID NO:1282SEQ ID NO:1282
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:515SEQ ID NO: 515 SEQ ID NO:1283SEQ ID NO:1283
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:516SEQ ID NO: 516 SEQ ID NO:1284SEQ ID NO:1284
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:517SEQ ID NO: 517 SEQ ID NO:1285SEQ ID NO: 1285
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:518SEQ ID NO: 518 SEQ ID NO:1286SEQ ID NO:1286
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:519SEQ ID NO: 519 SEQ ID NO:1287SEQ ID NO: 1287
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:520SEQ ID NO: 520 SEQ ID NO:1288SEQ ID NO:1288
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:521SEQ ID NO: 521 SEQ ID NO:1289SEQ ID NO: 1289
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:522SEQ ID NO: 522 SEQ ID NO:1290SEQ ID NO:1290
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:523SEQ ID NO: 523 SEQ ID NO:1291SEQ ID NO:1291
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:524SEQ ID NO: 524 SEQ ID NO:1292SEQ ID NO:1292
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:525SEQ ID NO: 525 SEQ ID NO:1293SEQ ID NO: 1293
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:526SEQ ID NO: 526 SEQ ID NO:1294SEQ ID NO: 1294
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:527SEQ ID NO: 527 SEQ ID NO:1295SEQ ID NO:1295
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:528SEQ ID NO: 528 SEQ ID NO:1296SEQ ID NO:1296
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:529SEQ ID NO: 529 SEQ ID NO:1297SEQ ID NO:1297
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:530SEQ ID NO: 530 SEQ ID NO:1298SEQ ID NO:1298
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:531SEQ ID NO: 531 SEQ ID NO:1299SEQ ID NO:1299
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:532SEQ ID NO: 532 SEQ ID NO:1300SEQ ID NO: 1300
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:533SEQ ID NO: 533 SEQ ID NO:1301SEQ ID NO:1301
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:534SEQ ID NO: 534 SEQ ID NO:1302SEQ ID NO:1302
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:535SEQ ID NO: 535 SEQ ID NO:1303SEQ ID NO:1303
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:536SEQ ID NO: 536 SEQ ID NO:1304SEQ ID NO: 1304
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:537SEQ ID NO: 537 SEQ ID NO:1305SEQ ID NO:1305
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:538SEQ ID NO: 538 SEQ ID NO:1306SEQ ID NO:1306
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:539SEQ ID NO: 539 SEQ ID NO:1307SEQ ID NO: 1307
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:540SEQ ID NO: 540 SEQ ID NO:1308SEQ ID NO:1308
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:541SEQ ID NO: 541 SEQ ID NO:1309SEQ ID NO:1309
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:542SEQ ID NO: 542 SEQ ID NO:1310SEQ ID NO: 1310
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:543SEQ ID NO: 543 SEQ ID NO:1311SEQ ID NO: 1311
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:544SEQ ID NO: 544 SEQ ID NO:1312SEQ ID NO: 1312
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:545SEQ ID NO: 545 SEQ ID NO:1313SEQ ID NO: 1313
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:546SEQ ID NO: 546 SEQ ID NO:1314SEQ ID NO:1314
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:547SEQ ID NO: 547 SEQ ID NO:1315SEQ ID NO:1315
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:548SEQ ID NO: 548 SEQ ID NO:1316SEQ ID NO: 1316
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:549SEQ ID NO: 549 SEQ ID NO:1317SEQ ID NO:1317
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:550SEQ ID NO: 550 SEQ ID NO:1318SEQ ID NO:1318
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:551SEQ ID NO: 551 SEQ ID NO:1319SEQ ID NO:1319
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:552SEQ ID NO: 552 SEQ ID NO:1320SEQ ID NO:1320
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:553SEQ ID NO: 553 SEQ ID NO:1321SEQ ID NO:1321
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:554SEQ ID NO: 554 SEQ ID NO:1322SEQ ID NO:1322
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:555SEQ ID NO: 555 SEQ ID NO:1323SEQ ID NO:1323
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:556SEQ ID NO: 556 SEQ ID NO:1324SEQ ID NO: 1324
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:557SEQ ID NO: 557 SEQ ID NO:1325SEQ ID NO:1325
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:558SEQ ID NO: 558 SEQ ID NO:1326SEQ ID NO: 1326
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:559SEQ ID NO: 559 SEQ ID NO:1327SEQ ID NO: 1327
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:560SEQ ID NO: 560 SEQ ID NO:1328SEQ ID NO:1328
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:561SEQ ID NO: 561 SEQ ID NO:1329SEQ ID NO:1329
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:562SEQ ID NO: 562 SEQ ID NO:1330SEQ ID NO:1330
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:563SEQ ID NO: 563 SEQ ID NO:1331SEQ ID NO:1331
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:564SEQ ID NO: 564 SEQ ID NO:1332SEQ ID NO:1332
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:565SEQ ID NO: 565 SEQ ID NO:1333SEQ ID NO:1333
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:566SEQ ID NO: 566 SEQ ID NO:1334SEQ ID NO: 1334
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:567SEQ ID NO: 567 SEQ ID NO:1335SEQ ID NO:1335
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:568SEQ ID NO: 568 SEQ ID NO:1336SEQ ID NO:1336
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:569SEQ ID NO: 569 SEQ ID NO:1337SEQ ID NO:1337
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:570SEQ ID NO: 570 SEQ ID NO:1338SEQ ID NO:1338
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:571SEQ ID NO: 571 SEQ ID NO:1339SEQ ID NO: 1339
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:572SEQ ID NO: 572 SEQ ID NO:1340SEQ ID NO: 1340
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:573SEQ ID NO: 573 SEQ ID NO:1341SEQ ID NO: 1341
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:574SEQ ID NO: 574 SEQ ID NO:1342SEQ ID NO:1342
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:575SEQ ID NO: 575 SEQ ID NO:1343SEQ ID NO: 1343
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:576SEQ ID NO: 576 SEQ ID NO:1344SEQ ID NO:1344
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:577SEQ ID NO: 577 SEQ ID NO:1345SEQ ID NO:1345
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:578SEQ ID NO: 578 SEQ ID NO:1346SEQ ID NO:1346
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:579SEQ ID NO: 579 SEQ ID NO:1347SEQ ID NO:1347
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:580SEQ ID NO: 580 SEQ ID NO:1348SEQ ID NO:1348
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:581SEQ ID NO: 581 SEQ ID NO:1349SEQ ID NO:1349
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:582SEQ ID NO: 582 SEQ ID NO:1350SEQ ID NO:1350
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:583SEQ ID NO: 583 SEQ ID NO:1351SEQ ID NO: 1351
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:584SEQ ID NO: 584 SEQ ID NO:1352SEQ ID NO:1352
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:585SEQ ID NO: 585 SEQ ID NO:1353SEQ ID NO: 1353
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:586SEQ ID NO: 586 SEQ ID NO:1354SEQ ID NO: 1354
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:587SEQ ID NO: 587 SEQ ID NO:1355SEQ ID NO:1355
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:588SEQ ID NO: 588 SEQ ID NO:1356SEQ ID NO:1356
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:589SEQ ID NO: 589 SEQ ID NO:1357SEQ ID NO: 1357
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:590SEQ ID NO: 590 SEQ ID NO:1358SEQ ID NO:1358
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:591SEQ ID NO: 591 SEQ ID NO:1359SEQ ID NO:1359
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:592SEQ ID NO: 592 SEQ ID NO:1360SEQ ID NO:1360
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:593SEQ ID NO:593 SEQ ID NO:1361SEQ ID NO: 1361
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:594SEQ ID NO: 594 SEQ ID NO:1362SEQ ID NO: 1362
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:595SEQ ID NO: 595 SEQ ID NO:1363SEQ ID NO: 1363
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:596SEQ ID NO: 596 SEQ ID NO:1364SEQ ID NO: 1364
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:597SEQ ID NO: 597 SEQ ID NO:1365SEQ ID NO:1365
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:598SEQ ID NO: 598 SEQ ID NO:1366SEQ ID NO:1366
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:599SEQ ID NO: 599 SEQ ID NO:1367SEQ ID NO:1367
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:600SEQ ID NO: 600 SEQ ID NO:1368SEQ ID NO: 1368
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:601SEQ ID NO: 601 SEQ ID NO:1369SEQ ID NO: 1369
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:602SEQ ID NO: 602 SEQ ID NO:1370SEQ ID NO:1370
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:603SEQ ID NO: 603 SEQ ID NO:1371SEQ ID NO:1371
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:604SEQ ID NO: 604 SEQ ID NO:1372SEQ ID NO:1372
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:605SEQ ID NO: 605 SEQ ID NO:1373SEQ ID NO: 1373
TGF-β受体2TGF-β receptor 2 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:606SEQ ID NO: 606 SEQ ID NO:1374SEQ ID NO:1374
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:607SEQ ID NO: 607 SEQ ID NO:1375SEQ ID NO:1375
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:608SEQ ID NO: 608 SEQ ID NO:1376SEQ ID NO: 1376
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:609SEQ ID NO: 609 SEQ ID NO:1377SEQ ID NO: 1377
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:610SEQ ID NO: 610 SEQ ID NO:1378SEQ ID NO: 1378
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:611SEQ ID NO: 611 SEQ ID NO:1379SEQ ID NO: 1379
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:612SEQ ID NO: 612 SEQ ID NO:1380SEQ ID NO:1380
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:613SEQ ID NO: 613 SEQ ID NO:1381SEQ ID NO: 1381
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:614SEQ ID NO: 614 SEQ ID NO:1382SEQ ID NO: 1382
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:615SEQ ID NO: 615 SEQ ID NO:1383SEQ ID NO: 1383
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:616SEQ ID NO: 616 SEQ ID NO:1384SEQ ID NO: 1384
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:617SEQ ID NO: 617 SEQ ID NO:1385SEQ ID NO: 1385
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:618SEQ ID NO: 618 SEQ ID NO:1386SEQ ID NO:1386
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:619SEQ ID NO: 619 SEQ ID NO:1387SEQ ID NO:1387
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:620SEQ ID NO: 620 SEQ ID NO:1388SEQ ID NO: 1388
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:621SEQ ID NO: 621 SEQ ID NO:1389SEQ ID NO:1389
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:622SEQ ID NO: 622 SEQ ID NO:1390SEQ ID NO:1390
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:623SEQ ID NO: 623 SEQ ID NO:1391SEQ ID NO: 1391
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:624SEQ ID NO: 624 SEQ ID NO:1392SEQ ID NO: 1392
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:625SEQ ID NO: 625 SEQ ID NO:1393SEQ ID NO:1393
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:626SEQ ID NO: 626 SEQ ID NO:1394SEQ ID NO: 1394
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:627SEQ ID NO: 627 SEQ ID NO:1395SEQ ID NO:1395
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:628SEQ ID NO: 628 SEQ ID NO:1396SEQ ID NO: 1396
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:629SEQ ID NO: 629 SEQ ID NO:1397SEQ ID NO: 1397
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:630SEQ ID NO: 630 SEQ ID NO:1398SEQ ID NO:1398
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:631SEQ ID NO: 631 SEQ ID NO:1399SEQ ID NO:1399
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:632SEQ ID NO: 632 SEQ ID NO:1400SEQ ID NO: 1400
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:633SEQ ID NO: 633 SEQ ID NO:1401SEQ ID NO:1401
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:634SEQ ID NO: 634 SEQ ID NO:1402SEQ ID NO:1402
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:635SEQ ID NO: 635 SEQ ID NO:1403SEQ ID NO:1403
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:636SEQ ID NO: 636 SEQ ID NO:1404SEQ ID NO:1404
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:637SEQ ID NO: 637 SEQ ID NO:1405SEQ ID NO: 1405
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 IL-7Ralpha胞内区IL-7Ralpha intracellular region SEQ ID NO:638SEQ ID NO: 638 SEQ ID NO:1406SEQ ID NO:1406
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:639SEQ ID NO: 639 SEQ ID NO:1407SEQ ID NO: 1407
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:640SEQ ID NO: 640 SEQ ID NO:1408SEQ ID NO: 1408
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:641SEQ ID NO: 641 SEQ ID NO:1409SEQ ID NO:1409
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:642SEQ ID NO: 642 SEQ ID NO:1410SEQ ID NO: 1410
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:643SEQ ID NO: 643 SEQ ID NO:1411SEQ ID NO: 1411
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:644SEQ ID NO: 644 SEQ ID NO:1412SEQ ID NO: 1412
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:645SEQ ID NO: 645 SEQ ID NO:1413SEQ ID NO: 1413
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:646SEQ ID NO: 646 SEQ ID NO:1414SEQ ID NO: 1414
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:647SEQ ID NO: 647 SEQ ID NO:1415SEQ ID NO: 1415
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:648SEQ ID NO: 648 SEQ ID NO:1416SEQ ID NO: 1416
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:649SEQ ID NO: 649 SEQ ID NO:1417SEQ ID NO: 1417
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:650SEQ ID NO: 650 SEQ ID NO:1418SEQ ID NO:1418
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:651SEQ ID NO: 651 SEQ ID NO:1419SEQ ID NO:1419
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:652SEQ ID NO: 652 SEQ ID NO:1420SEQ ID NO: 1420
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:653SEQ ID NO: 653 SEQ ID NO:1421SEQ ID NO:1421
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:654SEQ ID NO: 654 SEQ ID NO:1422SEQ ID NO:1422
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:655SEQ ID NO: 655 SEQ ID NO:1423SEQ ID NO:1423
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:656SEQ ID NO: 656 SEQ ID NO:1424SEQ ID NO: 1424
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:657SEQ ID NO: 657 SEQ ID NO:1425SEQ ID NO:1425
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:658SEQ ID NO: 658 SEQ ID NO:1426SEQ ID NO:1426
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:659SEQ ID NO: 659 SEQ ID NO:1427SEQ ID NO: 1427
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:660SEQ ID NO: 660 SEQ ID NO:1428SEQ ID NO:1428
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:661SEQ ID NO: 661 SEQ ID NO:1429SEQ ID NO: 1429
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:662SEQ ID NO: 662 SEQ ID NO:1430SEQ ID NO:1430
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:663SEQ ID NO: 663 SEQ ID NO:1431SEQ ID NO:1431
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:664SEQ ID NO: 664 SEQ ID NO:1432SEQ ID NO:1432
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:665SEQ ID NO: 665 SEQ ID NO:1433SEQ ID NO:1433
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:666SEQ ID NO: 666 SEQ ID NO:1434SEQ ID NO:1434
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:667SEQ ID NO: 667 SEQ ID NO:1435SEQ ID NO:1435
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:668SEQ ID NO: 668 SEQ ID NO:1436SEQ ID NO:1436
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:669SEQ ID NO: 669 SEQ ID NO:1437SEQ ID NO:1437
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 CD28胞内区+4-1BB胞内区CD28 intracellular region+4-1BB intracellular region SEQ ID NO:670SEQ ID NO: 670 SEQ ID NO:1438SEQ ID NO:1438
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 CD28胞内区CD28 intracellular region SEQ ID NO:671SEQ ID NO: 671 SEQ ID NO:1439SEQ ID NO: 1439
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 CD28胞内区CD28 intracellular region SEQ ID NO:672SEQ ID NO: 672 SEQ ID NO:1440SEQ ID NO: 1440
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 CD28胞内区CD28 intracellular region SEQ ID NO:673SEQ ID NO: 673 SEQ ID NO:1441SEQ ID NO:1441
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 CD28胞内区CD28 intracellular region SEQ ID NO:674SEQ ID NO: 674 SEQ ID NO:1442SEQ ID NO:1442
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 CD28胞内区CD28 intracellular region SEQ ID NO:675SEQ ID NO: 675 SEQ ID NO:1443SEQ ID NO:1443
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 CD28胞内区CD28 intracellular region SEQ ID NO:676SEQ ID NO: 676 SEQ ID NO:1444SEQ ID NO:1444
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 CD28胞内区CD28 intracellular region SEQ ID NO:677SEQ ID NO: 677 SEQ ID NO:1445SEQ ID NO:1445
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 CD28胞内区CD28 intracellular region SEQ ID NO:678SEQ ID NO: 678 SEQ ID NO:1446SEQ ID NO: 1446
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 CD28胞内区CD28 intracellular region SEQ ID NO:679SEQ ID NO: 679 SEQ ID NO:1447SEQ ID NO: 1447
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 CD28胞内区CD28 intracellular region SEQ ID NO:680SEQ ID NO: 680 SEQ ID NO:1448SEQ ID NO: 1448
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 CD28胞内区CD28 intracellular region SEQ ID NO:681SEQ ID NO: 681 SEQ ID NO:1449SEQ ID NO:1449
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 CD28胞内区CD28 intracellular region SEQ ID NO:682SEQ ID NO: 682 SEQ ID NO:1450SEQ ID NO: 1450
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 CD28胞内区CD28 intracellular region SEQ ID NO:683SEQ ID NO: 683 SEQ ID NO:1451SEQ ID NO:1451
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 CD28胞内区CD28 intracellular region SEQ ID NO:684SEQ ID NO: 684 SEQ ID NO:1452SEQ ID NO:1452
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 CD28胞内区CD28 intracellular region SEQ ID NO:685SEQ ID NO: 685 SEQ ID NO:1453SEQ ID NO:1453
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 CD28胞内区CD28 intracellular region SEQ ID NO:686SEQ ID NO: 686 SEQ ID NO:1454SEQ ID NO:1454
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 CD28胞内区CD28 intracellular region SEQ ID NO:687SEQ ID NO: 687 SEQ ID NO:1455SEQ ID NO:1455
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 CD28胞内区CD28 intracellular region SEQ ID NO:688SEQ ID NO: 688 SEQ ID NO:1456SEQ ID NO:1456
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 CD28胞内区CD28 intracellular region SEQ ID NO:689SEQ ID NO: 689 SEQ ID NO:1457SEQ ID NO: 1457
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 CD28胞内区CD28 intracellular region SEQ ID NO:690SEQ ID NO: 690 SEQ ID NO:1458SEQ ID NO: 1458
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 CD28胞内区CD28 intracellular region SEQ ID NO:691SEQ ID NO: 691 SEQ ID NO:1459SEQ ID NO:1459
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 CD28胞内区CD28 intracellular region SEQ ID NO:692SEQ ID NO: 692 SEQ ID NO:1460SEQ ID NO:1460
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 CD28胞内区CD28 intracellular region SEQ ID NO:693SEQ ID NO: 693 SEQ ID NO:1461SEQ ID NO: 1461
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 CD28胞内区CD28 intracellular region SEQ ID NO:694SEQ ID NO: 694 SEQ ID NO:1462SEQ ID NO:1462
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 CD28胞内区CD28 intracellular region SEQ ID NO:695SEQ ID NO: 695 SEQ ID NO:1463SEQ ID NO:1463
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 CD28胞内区CD28 intracellular region SEQ ID NO:696SEQ ID NO: 696 SEQ ID NO:1464SEQ ID NO: 1464
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 CD28胞内区CD28 intracellular region SEQ ID NO:697SEQ ID NO: 697 SEQ ID NO:1465SEQ ID NO:1465
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 CD28胞内区CD28 intracellular region SEQ ID NO:698SEQ ID NO: 698 SEQ ID NO:1466SEQ ID NO:1466
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 CD28胞内区CD28 intracellular region SEQ ID NO:699SEQ ID NO: 699 SEQ ID NO:1467SEQ ID NO: 1467
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 CD28胞内区CD28 intracellular region SEQ ID NO:700SEQ ID NO: 700 SEQ ID NO:1468SEQ ID NO:1468
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 CD28胞内区CD28 intracellular region SEQ ID NO:701SEQ ID NO: 701 SEQ ID NO:1469SEQ ID NO: 1469
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 CD28胞内区CD28 intracellular region SEQ ID NO:702SEQ ID NO: 702 SEQ ID NO:1470SEQ ID NO: 1470
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:703SEQ ID NO: 703 SEQ ID NO:1471SEQ ID NO: 1471
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:704SEQ ID NO: 704 SEQ ID NO:1472SEQ ID NO:1472
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:705SEQ ID NO: 705 SEQ ID NO:1473SEQ ID NO: 1473
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:706SEQ ID NO: 706 SEQ ID NO:1474SEQ ID NO:1474
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:707SEQ ID NO: 707 SEQ ID NO:1475SEQ ID NO:1475
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:708SEQ ID NO: 708 SEQ ID NO:1476SEQ ID NO: 1476
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:709SEQ ID NO: 709 SEQ ID NO:1477SEQ ID NO: 1477
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:710SEQ ID NO: 710 SEQ ID NO:1478SEQ ID NO: 1478
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:711SEQ ID NO: 711 SEQ ID NO:1479SEQ ID NO:1479
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:712SEQ ID NO: 712 SEQ ID NO:1480SEQ ID NO:1480
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:713SEQ ID NO: 713 SEQ ID NO:1481SEQ ID NO:1481
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:714SEQ ID NO: 714 SEQ ID NO:1482SEQ ID NO: 1482
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:715SEQ ID NO: 715 SEQ ID NO:1483SEQ ID NO: 1483
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:716SEQ ID NO: 716 SEQ ID NO:1484SEQ ID NO: 1484
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:717SEQ ID NO: 717 SEQ ID NO:1485SEQ ID NO:1485
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:718SEQ ID NO: 718 SEQ ID NO:1486SEQ ID NO:1486
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:719SEQ ID NO: 719 SEQ ID NO:1487SEQ ID NO:1487
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:720SEQ ID NO: 720 SEQ ID NO:1488SEQ ID NO: 1488
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:721SEQ ID NO: 721 SEQ ID NO:1489SEQ ID NO:1489
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:722SEQ ID NO: 722 SEQ ID NO:1490SEQ ID NO: 1490
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:723SEQ ID NO: 723 SEQ ID NO:1491SEQ ID NO:1491
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:724SEQ ID NO: 724 SEQ ID NO:1492SEQ ID NO: 1492
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:725SEQ ID NO: 725 SEQ ID NO:1493SEQ ID NO:1493
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:726SEQ ID NO: 726 SEQ ID NO:1494SEQ ID NO: 1494
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:727SEQ ID NO: 727 SEQ ID NO:1495SEQ ID NO:1495
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:728SEQ ID NO: 728 SEQ ID NO:1496SEQ ID NO: 1496
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:729SEQ ID NO: 729 SEQ ID NO:1497SEQ ID NO:1497
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:730SEQ ID NO: 730 SEQ ID NO:1498SEQ ID NO:1498
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:731SEQ ID NO: 731 SEQ ID NO:1499SEQ ID NO:1499
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:732SEQ ID NO: 732 SEQ ID NO:1500SEQ ID NO: 1500
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:733SEQ ID NO: 733 SEQ ID NO:1501SEQ ID NO: 1501
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 CD28胞内区+OX40胞内区CD28 intracellular region + OX40 intracellular region SEQ ID NO:734SEQ ID NO: 734 SEQ ID NO:1502SEQ ID NO: 1502
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:735SEQ ID NO: 735 SEQ ID NO:1503SEQ ID NO:1503
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:736SEQ ID NO: 736 SEQ ID NO:1504SEQ ID NO:1504
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:737SEQ ID NO: 737 SEQ ID NO:1505SEQ ID NO:1505
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:738SEQ ID NO: 738 SEQ ID NO:1506SEQ ID NO:1506
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:739SEQ ID NO: 739 SEQ ID NO:1507SEQ ID NO:1507
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:740SEQ ID NO: 740 SEQ ID NO:1508SEQ ID NO:1508
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:741SEQ ID NO: 741 SEQ ID NO:1509SEQ ID NO:1509
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:742SEQ ID NO: 742 SEQ ID NO:1510SEQ ID NO: 1510
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:743SEQ ID NO: 743 SEQ ID NO:1511SEQ ID NO: 1511
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:744SEQ ID NO: 744 SEQ ID NO:1512SEQ ID NO:1512
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:745SEQ ID NO: 745 SEQ ID NO:1513SEQ ID NO: 1513
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:746SEQ ID NO: 746 SEQ ID NO:1514SEQ ID NO:1514
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:747SEQ ID NO: 747 SEQ ID NO:1515SEQ ID NO: 1515
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:748SEQ ID NO: 748 SEQ ID NO:1516SEQ ID NO:1516
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:749SEQ ID NO: 749 SEQ ID NO:1517SEQ ID NO:1517
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:750SEQ ID NO: 750 SEQ ID NO:1518SEQ ID NO:1518
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:751SEQ ID NO: 751 SEQ ID NO:1519SEQ ID NO:1519
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:752SEQ ID NO: 752 SEQ ID NO:1520SEQ ID NO:1520
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:753SEQ ID NO: 753 SEQ ID NO:1521SEQ ID NO:1521
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:754SEQ ID NO: 754 SEQ ID NO:1522SEQ ID NO:1522
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:755SEQ ID NO: 755 SEQ ID NO:1523SEQ ID NO:1523
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:756SEQ ID NO: 756 SEQ ID NO:1524SEQ ID NO:1524
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:757SEQ ID NO: 757 SEQ ID NO:1525SEQ ID NO:1525
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:758SEQ ID NO: 758 SEQ ID NO:1526SEQ ID NO:1526
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:759SEQ ID NO: 759 SEQ ID NO:1527SEQ ID NO:1527
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:760SEQ ID NO: 760 SEQ ID NO:1528SEQ ID NO:1528
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:761SEQ ID NO: 761 SEQ ID NO:1529SEQ ID NO:1529
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:762SEQ ID NO: 762 SEQ ID NO:1530SEQ ID NO:1530
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:763SEQ ID NO: 763 SEQ ID NO:1531SEQ ID NO:1531
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:764SEQ ID NO: 764 SEQ ID NO:1532SEQ ID NO:1532
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:765SEQ ID NO: 765 SEQ ID NO:1533SEQ ID NO:1533
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:766SEQ ID NO: 766 SEQ ID NO:1534SEQ ID NO:1534
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:767SEQ ID NO:767 SEQ ID NO:1535SEQ ID NO:1535
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:768SEQ ID NO: 768 SEQ ID NO:1536SEQ ID NO:1536
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:769SEQ ID NO: 769 SEQ ID NO:1537SEQ ID NO:1537
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:770SEQ ID NO: 770 SEQ ID NO:1538SEQ ID NO:1538
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:771SEQ ID NO: 771 SEQ ID NO:1539SEQ ID NO: 1539
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:772SEQ ID NO: 772 SEQ ID NO:1540SEQ ID NO:1540
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:773SEQ ID NO: 773 SEQ ID NO:1541SEQ ID NO:1541
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:774SEQ ID NO: 774 SEQ ID NO:1542SEQ ID NO:1542
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:775SEQ ID NO: 775 SEQ ID NO:1543SEQ ID NO:1543
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:776SEQ ID NO: 776 SEQ ID NO:1544SEQ ID NO:1544
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:777SEQ ID NO: 777 SEQ ID NO:1545SEQ ID NO:1545
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:778SEQ ID NO: 778 SEQ ID NO:1546SEQ ID NO:1546
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:779SEQ ID NO: 779 SEQ ID NO:1547SEQ ID NO: 1547
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:780SEQ ID NO: 780 SEQ ID NO:1548SEQ ID NO:1548
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:781SEQ ID NO: 781 SEQ ID NO:1549SEQ ID NO: 1549
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:782SEQ ID NO: 782 SEQ ID NO:1550SEQ ID NO:1550
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:783SEQ ID NO: 783 SEQ ID NO:1551SEQ ID NO:1551
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:784SEQ ID NO: 784 SEQ ID NO:1552SEQ ID NO:1552
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:785SEQ ID NO: 785 SEQ ID NO:1553SEQ ID NO:1553
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:786SEQ ID NO: 786 SEQ ID NO:1554SEQ ID NO:1554
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:787SEQ ID NO: 787 SEQ ID NO:1555SEQ ID NO:1555
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:788SEQ ID NO: 788 SEQ ID NO:1556SEQ ID NO: 1556
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:789SEQ ID NO: 789 SEQ ID NO:1557SEQ ID NO:1557
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:790SEQ ID NO: 790 SEQ ID NO:1558SEQ ID NO: 1558
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:791SEQ ID NO: 791 SEQ ID NO:1559SEQ ID NO:1559
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:792SEQ ID NO: 792 SEQ ID NO:1560SEQ ID NO:1560
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:793SEQ ID NO: 793 SEQ ID NO:1561SEQ ID NO:1561
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:794SEQ ID NO: 794 SEQ ID NO:1562SEQ ID NO:1562
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:795SEQ ID NO: 795 SEQ ID NO:1563SEQ ID NO: 1563
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:796SEQ ID NO: 796 SEQ ID NO:1564SEQ ID NO:1564
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:797SEQ ID NO: 797 SEQ ID NO:1565SEQ ID NO:1565
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:798SEQ ID NO: 798 SEQ ID NO:1566SEQ ID NO:1566
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:799SEQ ID NO: 799 SEQ ID NO:1567SEQ ID NO:1567
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:800SEQ ID NO: 800 SEQ ID NO:1568SEQ ID NO:1568
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:801SEQ ID NO: 801 SEQ ID NO:1569SEQ ID NO:1569
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:802SEQ ID NO: 802 SEQ ID NO:1570SEQ ID NO:1570
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:803SEQ ID NO: 803 SEQ ID NO:1571SEQ ID NO: 1571
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:804SEQ ID NO: 804 SEQ ID NO:1572SEQ ID NO: 1572
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:805SEQ ID NO: 805 SEQ ID NO:1573SEQ ID NO: 1573
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:806SEQ ID NO: 806 SEQ ID NO:1574SEQ ID NO:1574
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:807SEQ ID NO: 807 SEQ ID NO:1575SEQ ID NO:1575
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:808SEQ ID NO: 808 SEQ ID NO:1576SEQ ID NO:1576
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:809SEQ ID NO: 809 SEQ ID NO:1577SEQ ID NO: 1577
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:810SEQ ID NO: 810 SEQ ID NO:1578SEQ ID NO: 1578
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:811SEQ ID NO: 811 SEQ ID NO:1579SEQ ID NO: 1579
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:812SEQ ID NO: 812 SEQ ID NO:1580SEQ ID NO:1580
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:813SEQ ID NO: 813 SEQ ID NO:1581SEQ ID NO:1581
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:814SEQ ID NO: 814 SEQ ID NO:1582SEQ ID NO: 1582
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:815SEQ ID NO: 815 SEQ ID NO:1583SEQ ID NO:1583
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:816SEQ ID NO: 816 SEQ ID NO:1584SEQ ID NO: 1584
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:817SEQ ID NO: 817 SEQ ID NO:1585SEQ ID NO:1585
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:818SEQ ID NO: 818 SEQ ID NO:1586SEQ ID NO:1586
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:819SEQ ID NO: 819 SEQ ID NO:1587SEQ ID NO: 1587
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:820SEQ ID NO: 820 SEQ ID NO:1588SEQ ID NO:1588
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:821SEQ ID NO: 821 SEQ ID NO:1589SEQ ID NO:1589
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:822SEQ ID NO: 822 SEQ ID NO:1590SEQ ID NO:1590
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:823SEQ ID NO: 823 SEQ ID NO:1591SEQ ID NO:1591
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:824SEQ ID NO: 824 SEQ ID NO:1592SEQ ID NO:1592
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:825SEQ ID NO: 825 SEQ ID NO:1593SEQ ID NO: 1593
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:826SEQ ID NO: 826 SEQ ID NO:1594SEQ ID NO: 1594
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:827SEQ ID NO: 827 SEQ ID NO:1595SEQ ID NO:1595
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:828SEQ ID NO: 828 SEQ ID NO:1596SEQ ID NO: 1596
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:829SEQ ID NO: 829 SEQ ID NO:1597SEQ ID NO:1597
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 IL2RB-z(YXXQ)胞内区IL2RB-z(YXXQ) intracellular region SEQ ID NO:830SEQ ID NO: 830 SEQ ID NO:1598SEQ ID NO: 1598
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut1IL-7Ralpha TM mut1 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:831SEQ ID NO: 831 SEQ ID NO:1599SEQ ID NO: 1599
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut2IL-7Ralpha TM mut2 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:832SEQ ID NO: 832 SEQ ID NO:1600SEQ ID NO: 1600
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut3IL-7Ralpha TM mut3 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:833SEQ ID NO: 833 SEQ ID NO:1601SEQ ID NO:1601
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut4IL-7Ralpha TM mut4 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:834SEQ ID NO: 834 SEQ ID NO:1602SEQ ID NO:1602
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut5IL-7Ralpha TM mut5 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:835SEQ ID NO: 835 SEQ ID NO:1603SEQ ID NO:1603
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut6IL-7Ralpha TM mut6 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:836SEQ ID NO: 836 SEQ ID NO:1604SEQ ID NO: 1604
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut7IL-7Ralpha TM mut7 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:837SEQ ID NO: 837 SEQ ID NO:1605SEQ ID NO: 1605
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut8IL-7Ralpha TM mut8 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:838SEQ ID NO: 838 SEQ ID NO:1606SEQ ID NO: 1606
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut9IL-7Ralpha TM mut9 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:839SEQ ID NO: 839 SEQ ID NO:1607SEQ ID NO: 1607
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut10IL-7Ralpha TM mut10 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:840SEQ ID NO: 840 SEQ ID NO:1608SEQ ID NO: 1608
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut11IL-7Ralpha TM mut11 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:841SEQ ID NO: 841 SEQ ID NO:1609SEQ ID NO: 1609
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut12IL-7Ralpha TM mut12 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:842SEQ ID NO: 842 SEQ ID NO:1610SEQ ID NO: 1610
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut13IL-7Ralpha TM mut13 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:843SEQ ID NO: 843 SEQ ID NO:1611SEQ ID NO: 1611
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut14IL-7Ralpha TM mut14 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:844SEQ ID NO: 844 SEQ ID NO:1612SEQ ID NO: 1612
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut15IL-7Ralpha TM mut15 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:845SEQ ID NO: 845 SEQ ID NO:1613SEQ ID NO:1613
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut16IL-7Ralpha TM mut16 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:846SEQ ID NO: 846 SEQ ID NO:1614SEQ ID NO:1614
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut17IL-7Ralpha TM mut17 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:847SEQ ID NO: 847 SEQ ID NO:1615SEQ ID NO: 1615
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut18IL-7Ralpha TM mut18 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:848SEQ ID NO: 848 SEQ ID NO:1616SEQ ID NO: 1616
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut19IL-7Ralpha TM mut19 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:849SEQ ID NO: 849 SEQ ID NO:1617SEQ ID NO: 1617
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut20IL-7Ralpha TM mut20 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:850SEQ ID NO: 850 SEQ ID NO:1618SEQ ID NO:1618
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut21IL-7Ralpha TM mut21 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:851SEQ ID NO: 851 SEQ ID NO:1619SEQ ID NO: 1619
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut22IL-7Ralpha TM mut22 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:852SEQ ID NO: 852 SEQ ID NO:1620SEQ ID NO:1620
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut23IL-7Ralpha TM mut23 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:853SEQ ID NO: 853 SEQ ID NO:1621SEQ ID NO: 1621
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut24IL-7Ralpha TM mut24 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:854SEQ ID NO: 854 SEQ ID NO:1622SEQ ID NO:1622
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut25IL-7Ralpha TM mut25 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:855SEQ ID NO: 855 SEQ ID NO:1623SEQ ID NO:1623
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut26IL-7Ralpha TM mut26 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:856SEQ ID NO: 856 SEQ ID NO:1624SEQ ID NO:1624
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut27IL-7Ralpha TM mut27 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:857SEQ ID NO: 857 SEQ ID NO:1625SEQ ID NO:1625
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut28IL-7Ralpha TM mut28 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:858SEQ ID NO: 858 SEQ ID NO:1626SEQ ID NO: 1626
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut29IL-7Ralpha TM mut29 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:859SEQ ID NO: 859 SEQ ID NO:1627SEQ ID NO:1627
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut30IL-7Ralpha TM mut30 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:860SEQ ID NO: 860 SEQ ID NO:1628SEQ ID NO:1628
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut31IL-7Ralpha TM mut31 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:861SEQ ID NO: 861 SEQ ID NO:1629SEQ ID NO:1629
TGF-β受体3TGF-β receptor 3 IL-7Ralpha TM mut32IL-7Ralpha TM mut32 DeltaIL2RB-z(YXXQ)胞内区DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:862SEQ ID NO: 862 SEQ ID NO:1630SEQ ID NO:1630
本发明中还包含含有CD28跨膜区和28-DeltaIL2RB-z(YXXQ)胞内区或28-IL2RB-z(YXXQ)胞内区的信号转换受体，示例性信号转换受体包括但不限于表5所示信号转换受体：The present invention also includes signal conversion receptors containing CD28 transmembrane region and 28-DeltaIL2RB-z (YXXQ) intracellular region or 28-IL2RB-z (YXXQ) intracellular region. Exemplary signal conversion receptors include but are not limited to Signal conversion receptors shown in Table 5:
表5table 5
胞外区Extracellular domain 跨膜区Transmembrane zone 胞内区Intracellular region 序列号(蛋白)Serial number (protein) 序列号(核酸)Serial number (nucleic acid)
TGF-β受体1TGF-β receptor 1 CD28CD28 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:1633SEQ ID NO:1633 SEQ ID NO:1639SEQ ID NO: 1639
TGF-β受体1TGF-β receptor 1 CD28CD28 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:1634SEQ ID NO: 1634 SEQ ID NO:1640SEQ ID NO: 1640
TGF-β受体2TGF-β receptor 2 CD28CD28 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:1635SEQ ID NO:1635 SEQ ID NO:1641SEQ ID NO:1641
TGF-β受体2TGF-β receptor 2 CD28CD28 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:1636SEQ ID NO: 1636 SEQ ID NO:1642SEQ ID NO: 1642
TGF-β受体3TGF-β receptor 3 CD28CD28 28-DeltaIL2RB-z(YXXQ)胞内区28-DeltaIL2RB-z(YXXQ) intracellular region SEQ ID NO:1637SEQ ID NO: 1637 SEQ ID NO:1643SEQ ID NO: 1643
TGF-β受体3TGF-β receptor 3 CD28CD28 28-IL2RB-z(YXXQ)胞内区28-IL2RB-z(YXXQ) intracellular region SEQ ID NO:1638SEQ ID NO: 1638 SEQ ID NO:1644SEQ ID NO:1644
IL-7Ralpha TM mut1-32在Shochat C等，“Gain-of-function mutations in interleukin-7 receptor-α(IL7R)in childhood acute lymphoblastic leukemias”，J Exp Med.2011年5月9日，208(5):901-8中公开报道，此处通过引用将其全文纳入本申请。IL-7Ralpha TM mut1-32 in Shochat C, etc., "Gain-of-function mutations in interleukin-7 receptor-α(IL7R) in childhood acute lymphoblastic leukemias", J Exp. Med. May 9, 2011, 208(5 ): Reported publicly in 901-8, which is incorporated into this application in its entirety by reference.
28-IL2RB-z(YXXQ)、28-DeltaIL2RB-z(YXXQ)、28-IL2RB-z(YXXQ)胞内区与28-DeltaIL2RB-z(YXXQ)胞内区在Yuki Kagoya等，“A Novel Chimeric Antigen Receptor Containing a JAK-STAT Signaling Domain Mediates Superior Antitumor Effects”，Nat Med，2018年3月，24(3):352-359中公开报道，此处通过引用将其全文纳入本申请，其示例性的氨基酸序列和相应的编码序列分别如SEQ ID NO:13和14、SEQ ID NO:15和16、SEQ ID NO:17和18、以及SEQ ID NO:19和20所示。IL2RB-z(YXXQ)胞内区(示例性的氨基酸序列和编码序列分别如SEQ ID NO:21和22所示)与DeltaIL2RB-z(YXXQ)胞内区(示例性的氨基酸序列和编码序列分别如SEQ ID NO:23和24所示)分别为28-IL2RB-z(YXXQ)胞内区与28-DeltaIL2RB-z(YXXQ)胞内区不包含CD28胞内区部分的部分。28-IL2RB-z(YXXQ), 28-DeltaIL2RB-z(YXXQ), 28-IL2RB-z(YXXQ) intracellular region and 28-DeltaIL2RB-z(YXXQ) intracellular region are in Yuki Kagoya, etc., "A Novel Chimeric Antigen Receptor Containing a JAK-STAT Signaling Domain Mediates Superior Antitumor Effects", Nat Med, published in March 2018, 24(3):352-359, the full text of which is incorporated into this application by reference, which is exemplary The amino acid sequence and the corresponding coding sequence are shown in SEQ ID NO: 13 and 14, SEQ ID NO: 15 and 16, SEQ ID NO: 17 and 18, and SEQ ID NO: 19 and 20, respectively. IL2RB-z (YXXQ) intracellular region (exemplary amino acid sequence and coding sequence are shown in SEQ ID NO: 21 and 22, respectively) and DeltaIL2RB-z (YXXQ) intracellular region (exemplary amino acid sequence and coding sequence, respectively) As shown in SEQ ID NOs: 23 and 24), the 28-IL2RB-z (YXXQ) intracellular region and 28-DeltaIL2RB-z (YXXQ) intracellular region do not include parts of the CD28 intracellular region, respectively.
优选地，所述信号转换受体还包含信号肽。优选地，所述信号肽位于所述信号转换受体的N端。所述信号肽可以为本领域常规的任何能够引导多肽出核的信号肽，包括但不限于CD8、CD4、CD28、CD137、EGFR、TGFBRI、TGFBRII、TGFBRIII和轻链信号肽。Preferably, the signal conversion receptor further comprises a signal peptide. Preferably, the signal peptide is located at the N-terminus of the signal switch receptor. The signal peptide can be any conventional signal peptide capable of guiding the polypeptide out of the nucleus, including but not limited to CD8, CD4, CD28, CD137, EGFR, TGFBRI, TGFBRII, TGFBRIII and light chain signal peptides.
应理解，视需要，可在本文所述的胞外结构域与跨膜区、和/或跨膜区与胞内结构域之间可通过接头序列连接。可使用本领域周知的接头序列，如含有G和S的接头序列，如(GSSS) n或(GSSSS) n，其中，n为1-8的整数。 It should be understood that, if necessary, the extracellular domain described herein and the transmembrane region, and/or the transmembrane region and the intracellular domain can be connected by a linker sequence. A linker sequence known in the art can be used, such as a linker sequence containing G and S, such as (GSSS) n or (GSSSS) n , where n is an integer of 1-8.
在一些实施方案中，本发明的信号转换受体还可包括信号肽序列。通常，信号肽序列与胞外结构域连接。示例性的信号肽序列包括TGF-β受体的信号肽。在一些实施方案中，TGF-β受体的信号肽为TGF-β受体2的第1-22位氨基酸(SEQ ID NO:1631)，编码序列如SEQ ID NO:1632所示。In some embodiments, the signal switch receptor of the present invention may also include a signal peptide sequence. Usually, the signal peptide sequence is linked to the extracellular domain. Exemplary signal peptide sequences include the signal peptide of the TGF-β receptor. In some embodiments, the signal peptide of the TGF-β receptor is amino acids 1-22 of TGF-β receptor 2 (SEQ ID NO: 1631), and the coding sequence is shown in SEQ ID NO: 1632.
在一些实施方案中，本发明的信号转换受体还可含有识别并结合肿瘤特异性抗原或肿瘤相关抗原的单链抗体或天然肽段，使表达该分子转换器的T细胞接触肿瘤细胞后，进一步增强免疫活化作用。所述肿瘤特异性抗原或肿瘤相关抗原包括CD19、CD20、CEA、GD2、FR、PSMA、gp100、CA9、CD171/L1-CAM、IL-13Rα2、MART-1、ERBB2、NY-ESO-1、MAGE家族蛋白、BAGE家族蛋白、GAGE家族蛋白、AFP、MUC1、CD22、CD23、CD30、CD33、CD44v7/8、CD70、VEGFR1、VEGFR2、IL-11Rα、EGP-2、EGP-40、FBP、GD3、PSCA、FSA、PSA、TAG-72、h5T4、胎儿乙酰胆碱受体、LeY、EpCAM、MSLN、IGFR1、 EGFR、EGFRvIII、ERBB3、ERBB4、CA125、CA15-3、CA19-9、CA72-4、CA242、CA50、CYFRA21-1、SCC、AFU、EBV-VCA、TSGF、SF、POA、β2-MG和PROGRP。In some embodiments, the signal conversion receptor of the present invention may also contain single-chain antibodies or natural peptide fragments that recognize and bind to tumor-specific antigens or tumor-associated antigens. After the T cells expressing the molecular converter contact tumor cells, Further enhance immune activation. The tumor-specific antigen or tumor-related antigen includes CD19, CD20, CEA, GD2, FR, PSMA, gp100, CA9, CD171/L1-CAM, IL-13Rα2, MART-1, ERBB2, NY-ESO-1, MAGE Family protein, BAGE family protein, GAGE family protein, AFP, MUC1, CD22, CD23, CD30, CD33, CD44v7/8, CD70, VEGFR1, VEGFR2, IL-11Rα, EGP-2, EGP-40, FBP, GD3, PSCA , FSA, PSA, TAG-72, h5T4, fetal acetylcholine receptor, LeY, EpCAM, MSLN, IGFR1, EGFR, EGFRvIII, ERBB3, ERBB4, CA125, CA15-3, CA19-9, CA72-4, CA242, CA50, CYFRA21-1, SCC, AFU, EBV-VCA, TSGF, SF, POA, β2-MG and PROGRP.
嵌合抗原受体(CAR)Chimeric Antigen Receptor (CAR)
本发明的免疫细胞可进一步表达CAR，或含有CAR的编码序列。本发明所述的CAR可以是本领域周知的各种CAR。The immune cells of the present invention may further express CAR or contain CAR coding sequence. The CAR described in the present invention may be various CARs known in the art.
CAR可依次包含结合肿瘤细胞膜抗原的多肽(如scFv)、铰链区、跨膜区和胞内信号区。可采用本领域周知的用于构建CAR的铰链区、跨膜区和胞内信号区来构建本发明的CAR。通常，结合肿瘤细胞膜抗原的多肽能够以中等亲和力结合肿瘤细胞广泛表达的膜抗原，该多肽通常插入有抗原表位，插入的位置选自如下3个位置中的任意1个、2个或3个：所述多肽的N端、所述多肽和所述铰链区之间和所述多肽内部。所述结合肿瘤细胞膜抗原的多肽为天然多肽或人工合成多肽；优选地，人工合成多肽为单链抗体或Fab片段。The CAR may sequentially include a polypeptide (such as scFv) that binds to tumor cell membrane antigen, a hinge region, a transmembrane region, and an intracellular signal region. The hinge region, transmembrane region, and intracellular signal region known in the art for constructing CAR can be used to construct the CAR of the present invention. Generally, polypeptides that bind tumor cell membrane antigens can bind to membrane antigens widely expressed by tumor cells with medium affinity. The polypeptides are usually inserted with antigenic epitopes, and the insertion position is selected from any one, two or three of the following three positions : The N-terminus of the polypeptide, between the polypeptide and the hinge region, and inside the polypeptide. The polypeptide that binds the tumor cell membrane antigen is a natural polypeptide or an artificially synthesized polypeptide; preferably, the artificially synthesized polypeptide is a single-chain antibody or a Fab fragment.
本发明的嵌合抗原受体可针对如下抗原中的一种或多种：CD19、CD20、CEA、GD2(又称B4GALNT1，ββGAL乙酰基-氨基半乳糖基转移酶1)、FR(Flavin还原酶)、PSMA(前列腺特异性膜抗原)、PMEL前黑素小体蛋白)、CA9(碳酸酐酶IX)、CD171/L1-CAM、IL-13RL1、MART-1(又称粘蛋白-A)、ERBB2、NY-ESO-1(又称CTAG1B，癌/睾丸抗原1B)、MAGE(黑素瘤相关抗原E1)家族蛋白、BAGE(B黑素瘤抗原家族)家族蛋白、GAGE(生长激素释放因子)家族蛋白、AFP(αα胎蛋白)、MUC1(mucin1，细胞表面相关)、CD22、CD23、CD30、CD33、CD44v7/8、CD70、VEGFR1、VEGFR2、IL-11R/、EGP-2、EGP-40、FBP、GD3(又称ST8SIA1，ST8SIA1乙酰基-神经酰胺α经酰胺αA唾液酸转换酶1)、PSCA(前列腺干细胞抗原)、FSA(又称KIAA1109)、PSA(又称KLK3，激肽释放酶相关的肽酶3)、HMGA2、胎儿型乙酰胆碱受体、LeY(又称FUT3)、EpCAM、MSLN(间皮素)、IGFR1、EGFR、EGFRvIII、ERBB3、ERBB4、CA125(又称MUC16，mucin 16，细胞表面相关)、CA15-3、CA19-9、CA72-4、CA242、CA50、CYFRA21-1、SCC(又称SERPINB3)、AFU(又称FUCA1)、EBV-VCA、POA(又称VDR，维生素D(1,25-二氢维生素D3)受体)、β体)、G(ββ)、微球蛋白)和PROGRP(GRP胃泌素释放肽)。The chimeric antigen receptor of the present invention can be directed against one or more of the following antigens: CD19, CD20, CEA, GD2 (also known as B4GALNT1, ββGAL acetyl-galactosyltransferase 1), FR (Flavin reductase) ), PSMA (prostate specific membrane antigen), PMEL premelanosome protein), CA9 (carbonic anhydrase IX), CD171/L1-CAM, IL-13RL1, MART-1 (also known as mucin-A), ERBB2, NY-ESO-1 (also known as CTAG1B, cancer/testis antigen 1B), MAGE (melanoma associated antigen E1) family protein, BAGE (B melanoma antigen family) family protein, GAGE (growth hormone releasing factor) Family protein, AFP (αα fetoprotein), MUC1 (mucin1, cell surface related), CD22, CD23, CD30, CD33, CD44v7/8, CD70, VEGFR1, VEGFR2, IL-11R/, EGP-2, EGP-40, FBP, GD3 (also known as ST8SIA1, ST8SIA1 acetyl-ceramide α via amide αA sialic acid converting enzyme 1), PSCA (prostate stem cell antigen), FSA (also known as KIAA1109), PSA (also known as KLK3, kallikrein related Peptidase 3), HMGA2, fetal acetylcholine receptor, LeY (also known as FUT3), EpCAM, MSLN (mesothelin), IGFR1, EGFR, EGFRvIII, ERBB3, ERBB4, CA125 (also known as MUC16, mucin 16, cell Surface related), CA15-3, CA19-9, CA72-4, CA242, CA50, CYFRA21-1, SCC (also known as SERPINB3), AFU (also known as FUCA1), EBV-VCA, POA (also known as VDR, vitamin D (1,25-Dihydrovitamin D3) receptor), β body), G (β β), microglobulin) and PROGRP (GRP gastrin releasing peptide).
单个细胞可表达多个CAR，包括靶向不同肿瘤抗原的CAR。A single cell can express multiple CARs, including CARs that target different tumor antigens.
T细胞受体(TCR)-TT cell receptor (TCR)-T
本发明的免疫细胞可进一步表达外源TCR或含有表达外源TCR基因的编码序列。本发明所述的TCR可以是本领域所周知的各种TCR，例如是HLA分型相匹配的、序列和结构已知的且相结合的抗原肽序列也已知的TCR。The immune cells of the present invention may further express exogenous TCR or contain coding sequences expressing exogenous TCR genes. The TCR of the present invention can be various TCRs known in the art, for example, a TCR with matching HLA typing, known sequence and structure, and also known bound antigen peptide sequence.
本发明所述的外源TCR包括αβ双链，其可以与免疫效应细胞如T细胞内源表达的γε、δε和ξξ的双链结构形成完整的TCR复合物。本发明所述的编码外源TCR的外源基因包括αβ双链的基因，α链和β链编码序列通过可在体内切断的接头序列如P2A、T2A或F2A序列的编码DNA序列共价连接，也可通过编码IRES序列的DNA片段共价连接。除了编码外源TCR的αβ双链外，编码本发明所述的外源TCR的基因还可以包含与αβ基因融合表达的标签蛋白基因，如EGFP、RFP、YFP基因等。所述标签蛋白基因可以通过可在体内切断的接头序列如2A序列，如P2A、T2A或F2A的编码DNA序列或通过编码IRES序列的DNA序列与αβ双链的基因共价相连接。所述标签蛋白，如EGFP、RFP、YFP基因等与TCRαβ双链共同表达，能够作为检测外源TCR表达的鉴定指标。The exogenous TCR described in the present invention includes an αβ double-strand, which can form a complete TCR complex with the double-stranded structure of γε, δε, and ξξ endogenously expressed by immune effector cells such as T cells. The exogenous gene encoding the exogenous TCR of the present invention includes the alpha beta double-stranded gene, the alpha chain and the beta chain coding sequence are covalently linked by a linker sequence that can be cut in vivo, such as the coding DNA sequence of the P2A, T2A or F2A sequence, It can also be covalently linked via a DNA fragment encoding an IRES sequence. In addition to the αβ double-strands encoding the exogenous TCR, the gene encoding the exogenous TCR of the present invention may also include a tag protein gene expressed in fusion with the αβ gene, such as EGFP, RFP, YFP genes and the like. The tag protein gene can be covalently linked to the αβ double-stranded gene through a linker sequence that can be cut in vivo, such as a 2A sequence, such as a DNA sequence encoding P2A, T2A, or F2A, or a DNA sequence encoding an IRES sequence. The tag proteins, such as EGFP, RFP, YFP genes, etc., are co-expressed with TCRαβ double-strands, and can be used as identification indicators for detecting the expression of exogenous TCR.
本发明的TCR-T可针对如下抗原中的一种或多种：CD19、CD20、CEA、GD2(又称B4GALNT1，ββGAL乙酰基-氨基半乳糖基转移酶1)、FR(Flavin还原酶)、PSMA(前列腺特异性膜抗原)、PMEL前黑素小体蛋白)、CA9(碳酸酐酶IX)、CD171/L1-CAM、IL-13RL1、MART-1(又称粘蛋白-A)、ERBB2、NY-ESO-1(又称CTAG1B，癌/睾丸抗原1B)、MAGE(黑素瘤相关抗原E1)家族蛋白、BAGE(B黑素瘤抗原家族)家族蛋白、GAGE(生长激素释放因子)家族蛋白、AFP(αα胎蛋白)、MUC1(mucin 1，细胞表面相关)、CD22、CD23、CD30、CD33、CD44v7/8、CD70、VEGFR1、VEGFR2、IL-11R/、EGP-2、EGP-40、FBP、GD3(又称ST8SIA1，ST8SIA1乙酰基-神经酰胺α经酰胺αA唾液酸转换酶1)、PSCA(前列腺干细胞抗原)、FSA(又称KIAA1109)、PSA(又称KLK3，激肽释放酶相关的肽酶3)、HMGA2、胎儿型乙酰胆碱受体、LeY(又称FUT3)、EpCAM、MSLN(间皮素)、IGFR1、EGFR、EGFRvIII、ERBB3、ERBB4、CA125(又称MUC16，mucin 16，细胞表面相关)、CA15-3、CA19-9、CA72-4、CA242、CA50、CYFRA21-1、SCC(又称SERPINB3)、AFU(又称FUCA1)、EBV-VCA、POA(又称VDR，维生素D(1,25-二氢维生素D3)受体)、β体)、G(ββ)、微球蛋白)和PROGRP(GRP胃泌素释放肽)。The TCR-T of the present invention can be directed against one or more of the following antigens: CD19, CD20, CEA, GD2 (also known as B4GALNT1, ββGAL acetyl-galactosyltransferase 1), FR (Flavin reductase), PSMA (prostate-specific membrane antigen), PMEL premelanosome protein), CA9 (carbonic anhydrase IX), CD171/L1-CAM, IL-13RL1, MART-1 (also known as mucin-A), ERBB2, NY-ESO-1 (also known as CTAG1B, cancer/testis antigen 1B), MAGE (melanoma associated antigen E1) family protein, BAGE (B melanoma antigen family) family protein, GAGE (growth hormone releasing factor) family protein , AFP (αα fetoprotein), MUC1 (mucin 1, cell surface related), CD22, CD23, CD30, CD33, CD44v7/8, CD70, VEGFR1, VEGFR2, IL-11R/, EGP-2, EGP-40, FBP , GD3 (also known as ST8SIA1, ST8SIA1 acetyl-ceramide α via amide αA sialic acid converting enzyme 1), PSCA (prostate stem cell antigen), FSA (also known as KIAA1109), PSA (also known as KLK3, kallikrein related Peptidase 3), HMGA2, fetal acetylcholine receptor, LeY (also known as FUT3), EpCAM, MSLN (mesothelin), IGFR1, EGFR, EGFRvIII, ERBB3, ERBB4, CA125 (also known as MUC16, mucin 16, cell surface Related), CA15-3, CA19-9, CA72-4, CA242, CA50, CYFRA21-1, SCC (also known as SERPINB3), AFU (also known as FUCA1), EBV-VCA, POA (also known as VDR, vitamin D ( 1,25-dihydrovitamin D3) receptor), β body), G (β β), microglobulin) and PROGRP (GRP gastrin releasing peptide).
单个细胞可表达多个外源TCR，包括靶向不同肿瘤抗原的外源TCR。A single cell can express multiple exogenous TCRs, including exogenous TCRs targeting different tumor antigens.
多核苷酸分子Polynucleotide molecule
本发明提供多核苷酸分子，其编码本发明所述的信号转换受体。本发明也提供该信号转换受体的编码序列的互补序列。该多核苷酸分子可以是重组核酸分子，也可以是合成的；其可包含DNA、RNA以及PNA(肽核酸)并且可以是其杂合体。The present invention provides polynucleotide molecules, which encode the signal conversion receptor of the present invention. The present invention also provides the complementary sequence of the coding sequence of the signal conversion receptor. The polynucleotide molecule can be a recombinant nucleic acid molecule or synthetic; it can include DNA, RNA, and PNA (peptide nucleic acid) and can be a hybrid thereof.
还提供是本发明信号转换受体的表达框，其为一种核酸构建体即含有启动子、信号转换受体编码序列和PolyA加尾信号序列。核酸构建体中还可含有其它表达所需的原件，包括但不限于增强子等。Also provided is the expression cassette of the signal switch receptor of the present invention, which is a nucleic acid construct containing a promoter, a signal switch receptor coding sequence and a PolyA tailing signal sequence. The nucleic acid construct may also contain other elements required for expression, including but not limited to enhancers and the like.
还提供一种载体，其含有本文所述的多核苷酸分子、表达框或核酸构建体。载体可以是质粒、粘粒、病毒和噬菌体。载体可以是克隆载体，也可以是表达载体。表达载体可以是转座子载体。在某些实施方案中，表达载体为选自如下转座子载体中的一种或多种：piggybac、sleeping beauty、frog prince、Tn5和Ty。除本发明所述的多核苷酸分子外，表达载体中通常还含有载体通常所含的其它元件，例如多克隆位点、抗性基因、复制起始位点等。在某些实施方案中，所述重组表达载体采用pUC18、pUC19、pMD18-T、pMD19-T、pGM-T载体、pUC57、pMAX或pDC315系列载体作为骨架。在其它实施方案中，所述重组表达载体采用pCDNA3系列载体、pCDNA4系列载体、pCDNA5系列载体、pCDNA6系列载体、pRL系列载体、pUC57载体、pMAX载体或pDC315系列载体作为骨架。在某些实施方案中，本发明使用CN 201510638974.7构建的pSN载体。A vector is also provided, which contains the polynucleotide molecule, expression cassette or nucleic acid construct described herein. The vector can be a plasmid, cosmid, virus, and phage. The vector can be a cloning vector or an expression vector. The expression vector may be a transposon vector. In some embodiments, the expression vector is one or more selected from the following transposon vectors: piggybac, sleeping beauty, frog prince, Tn5 and Ty. In addition to the polynucleotide molecules of the present invention, the expression vector usually also contains other elements commonly contained in the vector, such as multiple cloning sites, resistance genes, replication origin sites, and the like. In some embodiments, the recombinant expression vector uses pUC18, pUC19, pMD18-T, pMD19-T, pGM-T vector, pUC57, pMAX or pDC315 series vector as a backbone. In other embodiments, the recombinant expression vector uses pCDNA3 series vectors, pCDNA4 series vectors, pCDNA5 series vectors, pCDNA6 series vectors, pRL series vectors, pUC57 vectors, pMAX vectors or pDC315 series vectors as the backbone. In some embodiments, the present invention uses the pSN vector constructed by CN 201510638974.7.
本发明的CAR也可通过常规的载体在本发明所述的免疫细胞中表达。载体可以是常规的表达CAR的载体，包括但不限于前文所述的各类转座子载体和重组表达载体。The CAR of the present invention can also be expressed in the immune cells of the present invention through conventional vectors. The vector can be a conventional CAR expression vector, including but not limited to the various transposon vectors and recombinant expression vectors described above.
在一些实施方案中，同一载体同时编码本发明的信号转换受体和CAR。该载体可以是双顺反子。CAR的编码序列可设置在信号转换受体编码序列5’或3’端。CAR和信号转换受体的表达可处于相同或不同调控序列的指导下。In some embodiments, the same vector encodes both the signal switch receptor of the present invention and the CAR. The vector can be a bicistronic. The CAR coding sequence can be set at the 5'or 3'end of the signal conversion receptor coding sequence. The expression of CAR and signal switch receptor can be under the guidance of the same or different regulatory sequences.
在多核苷酸序列已知的情况下，可采用本领域常规的方法制备得到各多核苷酸分子，并构建相应的载体。可使用本领域技术人员熟知的方法来构建重组载体，参见例如Sambrook等、Ausubel(1989)或其他标准教科书中描述的技术。替代地，可将所述核酸分子和载体重建成用于递送到靶细胞的脂质体。含有本发明的核酸分子的载体可通过熟知的方法转移至宿主细胞中，其根据细胞宿主的类型而变化。例如，氯化钙转染通常用于原核细胞，而磷酸钙处理或电转可用于其它细胞宿主，可参见Sambrook。When the polynucleotide sequence is known, each polynucleotide molecule can be prepared by conventional methods in the art, and the corresponding vector can be constructed. Recombinant vectors can be constructed using methods well known to those skilled in the art, see, for example, the techniques described in Sambrook et al., Ausubel (1989) or other standard textbooks. Alternatively, the nucleic acid molecules and vectors can be reconstituted into liposomes for delivery to target cells. The vector containing the nucleic acid molecule of the present invention can be transferred to a host cell by a well-known method, which varies according to the type of the cell host. For example, calcium chloride transfection is usually used for prokaryotic cells, while calcium phosphate treatment or electrotransfection can be used for other cell hosts, see Sambrook.
宿主细胞Host cell
本文中，在表达异源核酸序列时，“宿主细胞”是指真核细胞，其能够复制载体和/或表达由载体编码的异源基因。宿主细胞可用作载体的受主。宿主细胞可以是“转染的”或“转化的”，其指外源性核酸转染或转导到宿主细胞中的过程。转化的细胞包括原代对 象细胞及其后代。本文所用的术语“工程改造的”和“重组的”细胞或宿主细胞往往指其中已经导入外源性核酸序列，例如载体的细胞。因此，重组细胞可与不含导入的重组核酸的天然存在的细胞相区分。Herein, when expressing a heterologous nucleic acid sequence, a "host cell" refers to a eukaryotic cell, which is capable of replicating a vector and/or expressing a heterologous gene encoded by the vector. The host cell can be used as the acceptor of the vector. A host cell can be "transfected" or "transformed", which refers to the process of transfection or transduction of exogenous nucleic acid into the host cell. Transformed cells include the primary target cell and its progeny. The terms "engineered" and "recombinant" cells or host cells as used herein often refer to cells into which exogenous nucleic acid sequences, such as vectors, have been introduced. Therefore, recombinant cells can be distinguished from naturally occurring cells that do not contain the introduced recombinant nucleic acid.
本文中，宿主细胞包括携带本文所述多核苷酸分子和/或多肽的细胞。具体而言，本发明提供携带本发明所述信号转换受体和/或其编码序列的细胞。本发明的细胞优选为免疫细胞，可用于肿瘤过继细胞治疗。本发明这类细胞也称为本发明信号转换受体修饰的细胞。Herein, host cells include cells that carry the polynucleotide molecules and/or polypeptides described herein. Specifically, the present invention provides a cell carrying the signal conversion receptor of the present invention and/or its coding sequence. The cells of the present invention are preferably immune cells, which can be used for tumor adoptive cell therapy. Such cells of the present invention are also referred to as cells modified by the signal conversion receptor of the present invention.
更具体而言，本发明的细胞优选为免疫效应细胞，包括T细胞，如细胞毒性T细胞(也称为TC、细胞毒性T淋巴细胞、CTL、T杀伤细胞、溶细胞性T细胞、CD8+T细胞或杀伤T细胞)；NK细胞；NKT细胞；和能引发效应功能的其他免疫细胞。More specifically, the cells of the present invention are preferably immune effector cells, including T cells, such as cytotoxic T cells (also known as TC, cytotoxic T lymphocytes, CTL, T killer cells, cytolytic T cells, CD8+ T cells or killer T cells); NK cells; NKT cells; and other immune cells that can trigger effector functions.
本文中，相对于接受它们的个体，细胞可以是自体细胞、同系细胞、同种异体细胞，并且甚至在一些情况中可以是异种移植细胞。Herein, with respect to the individual receiving them, the cells may be autologous cells, syngeneic cells, allogeneic cells, and even xenograft cells in some cases.
可将本发明的核酸构建物/重组表达载体转入感兴趣的细胞中。转入的方法为本领域常规的方法，包括但不限于：病毒转导、显微注射、粒子轰击、基因枪转化和电转等。在某些实施方案中，采用电转将所述核酸构建物或重组表达载体。The nucleic acid construct/recombinant expression vector of the present invention can be transferred into the cell of interest. The method of transfer is a conventional method in the field, including but not limited to: virus transduction, microinjection, particle bombardment, gene gun transformation and electroporation, etc. In some embodiments, electroporation is used to transfer the nucleic acid construct or recombinant expression vector.
除携带本发明所述信号转换受体和/或其编码序列外，本发明的细胞还可具有可用于细胞免疫治疗(如肿瘤过继细胞治疗)的一种或多种其他特性。这类其他特性可以是对细胞而言固有的或可以是人进行遗传操作后细胞的一部分。例如，本发明的细胞可携带嵌合抗原受体、αβT细胞受体，和/或抗原特异性受体，例如肿瘤特异性受体，或其编码序列。In addition to carrying the signal conversion receptor of the present invention and/or its coding sequence, the cells of the present invention may also have one or more other characteristics that can be used in cellular immunotherapy (such as adoptive cell therapy for tumors). Such other characteristics may be inherent to the cell or may be part of the cell after a human has been genetically manipulated. For example, the cells of the present invention may carry chimeric antigen receptors, αβ T cell receptors, and/or antigen-specific receptors, such as tumor-specific receptors, or coding sequences thereof.
药物组合物Pharmaceutical composition
本文中，“药物组合物”指用于给予个体的组合物且涵盖用于免疫治疗的细胞的组合物。本发明的药物组合物还可包含药学上可接受的运载体。合适的药物运载体的示例是本领域已知的且包括磷酸盐缓冲盐水溶液、水、乳液，如油/水乳液、多种类型的润湿剂、无菌溶液等。可通过熟知的常规方法配制包含这类运载体的组合物。这些药物组合物可以合适剂量给予对象。Herein, "pharmaceutical composition" refers to a composition for administration to an individual and encompasses a composition for cells used for immunotherapy. The pharmaceutical composition of the present invention may also include a pharmaceutically acceptable carrier. Examples of suitable pharmaceutical carriers are known in the art and include phosphate buffered saline solution, water, emulsions such as oil/water emulsions, various types of wetting agents, sterile solutions, and the like. Compositions containing such carriers can be formulated by well-known conventional methods. These pharmaceutical compositions can be administered to a subject in an appropriate dose.
可由主治医师和临床因素确定剂量方案。如医学领域所熟知，用于任何一个患者的剂量取决于多种因素，包括患者的体型、体表面积、年龄、待给予的特定化合物、性别、给药时间和给药途径、总体健康状况和同时给予的其他药物。The dosage regimen can be determined by the attending physician and clinical factors. As is well known in the medical field, the dosage for any one patient depends on many factors, including the patient’s size, body surface area, age, specific compound to be administered, gender, time and route of administration, general health and simultaneous Other drugs given.
本发明的组合物可局部或全身性给予。在某些实施方式中，本发明提供的组合物(例如表达本发明所述的信号转换受体的细胞)可通过胃肠道外给予，例如静脉内、动脉内、鞘内、真皮下或肌内给予。在某些其他实施方式中，可直接将编码本发明提供的构建体的 DNA给予至靶位点，例如通过基因枪递送到内部或外部靶位点或通过导管递送到动脉内位点。在优选的实施方式中，皮下给予药物组合物，且在更优选的实施方式中，静脉内给予。胃肠道外给药制剂包括无菌的水性或非水性溶液、悬液和乳液。非水性溶剂的示例是丙二醇、聚乙二醇、植物油如橄榄油，和可注射有机酯如油酸乙酯。水性运载体包括水、醇溶液/水溶液、乳液或悬液，包括盐水和缓冲介质。胃肠道外载剂包括氯化钠溶液、林格右旋糖、右旋糖和氯化钠、乳酸林格溶液或固定油。静脉内载剂包括液体和营养补充剂、电解质补充剂(例如基于林格右旋糖的那些物质)等。也可存在防腐剂和其它添加剂，例如，抗微生物剂、抗氧化剂、螯合剂和惰性气体等。此外，本发明的药物组合物可包含蛋白性运载体，例如血清白蛋白或免疫球蛋白，优选人源的。除蛋白性嵌合细胞因子受体构建体或编码其的核酸分子或载体外，设想本发明的药物组合物还可包含生物活性试剂，这取决于该药物组合物的预定用途。The composition of the present invention can be administered locally or systemically. In certain embodiments, the composition provided by the present invention (e.g., cells expressing the signal conversion receptor of the present invention) can be administered parenterally, such as intravenously, intraarterially, intrathecal, subdermal or intramuscular give. In certain other embodiments, the DNA encoding the construct provided by the present invention can be directly administered to the target site, for example, delivered to an internal or external target site via a gene gun or delivered to an intra-arterial site via a catheter. In a preferred embodiment, the pharmaceutical composition is administered subcutaneously, and in a more preferred embodiment, administered intravenously. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous vehicles include water, alcohol solutions/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution or fixed oil. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present, such as antimicrobial agents, antioxidants, chelating agents, inert gases, and the like. In addition, the pharmaceutical composition of the present invention may include a proteinaceous carrier, such as serum albumin or immunoglobulin, preferably of human origin. In addition to the protein chimeric cytokine receptor construct or the nucleic acid molecule or vector encoding it, it is envisaged that the pharmaceutical composition of the present invention may also contain a biologically active agent, depending on the intended use of the pharmaceutical composition.
方法和应用Method and application
本发明所述的信号转换受体、多核苷酸分子、载体、宿主细胞以及包含这些物质的药物组合物可用于预防、治疗或缓解癌症，尤其是癌细胞表面表达有相应肿瘤抗原的癌症，或用于制备用于预防、治疗或缓解癌症的药物。The signal conversion receptors, polynucleotide molecules, vectors, host cells and pharmaceutical compositions containing these substances of the present invention can be used to prevent, treat or alleviate cancer, especially cancers with corresponding tumor antigens expressed on the surface of cancer cells, or It is used to prepare medicines for preventing, treating or alleviating cancer.
本文所用“治疗”或“处理”包括对疾病或病理状况的症状或病变的任何有益或需要的效果，并且可包括治疗中的疾病或病症(例如，癌症)的一种或多种可测量标记物的甚至很小的减少。治疗可任选地包括疾病或病症的症状的减少或缓解，或者疾病或病症进展的延迟。“治疗”不一定表示疾病或病症或其相关症状的完全根除或治愈。"Treatment" or "treatment" as used herein includes any beneficial or desired effect on the symptoms or pathology of a disease or pathological condition, and may include one or more measurable markers of the disease or condition (e.g., cancer) under treatment There is even a small reduction in the material. Treatment may optionally include a reduction or alleviation of symptoms of the disease or disorder, or a delay in the progression of the disease or disorder. "Treatment" does not necessarily mean the complete eradication or cure of a disease or condition or its related symptoms.
本文所用的“预防”表示用于预防、抑制或降低疾病或病症(例如，癌症)出现或复发的可能性的方法。其也指延迟疾病或病症的发生或复发或者延迟疾病或病症的症状的出现或复发。本文所用“预防”也包括在疾病或病症发生或复发之前降低疾病或病症的强度、影响、症状和/或负担。As used herein, "prevention" refers to a method for preventing, inhibiting, or reducing the likelihood of occurrence or recurrence of a disease or condition (e.g., cancer). It also refers to delaying the onset or recurrence of a disease or condition or delaying the onset or recurrence of symptoms of a disease or condition. "Prevention" as used herein also includes reducing the intensity, impact, symptoms, and/or burden of a disease or disorder before it occurs or recurs.
本发明包括使用标准载体和/或基因递送系统将细胞、多核苷酸分子和载体单独或以任意组合的方式给予，任选地与药学上可接受的运载体或赋形剂一同使用。在某些实施方式中，给药后，所述多核苷酸分子或载体可稳定地整合至对象的基因组中。The present invention includes the use of standard carriers and/or gene delivery systems to administer cells, polynucleotide molecules and carriers alone or in any combination, optionally together with pharmaceutically acceptable carriers or excipients. In some embodiments, after administration, the polynucleotide molecule or vector can be stably integrated into the genome of the subject.
在具体的实施方式中，可使用特异性针对某些细胞或组织且在所述细胞中持续存在的病毒载体。合适的药物运载体和赋形剂在本领域是众所周知的。根据本发明制备的组合物可而用于预防或治疗或延缓上述鉴定的疾病。In a specific embodiment, a viral vector that specifically targets certain cells or tissues and persists in the cells can be used. Suitable pharmaceutical carriers and excipients are well known in the art. The composition prepared according to the present invention can be used to prevent or treat or delay the above-identified diseases.
此外，本发明提供一种预防、治疗或缓解癌症的方法，包括以下步骤：向有此需要的对象给予有效量的细胞，所述细胞携带本发明所述和/或由本发明所述方法生成的信号转换受体、多核苷酸分子和/或载体。In addition, the present invention provides a method for preventing, treating or alleviating cancer, which includes the following steps: administering to a subject in need an effective amount of cells carrying the described and/or produced by the method of the present invention Signal conversion receptors, polynucleotide molecules and/or vectors.
本文中，癌症包括但不限于乳腺、前列腺、肺和结肠癌或上皮癌，如乳腺癌、结肠癌、前列腺癌、头颈癌、皮肤癌；生殖-泌尿道癌症，例如卵巢癌、子宫内膜癌、宫颈癌；肾癌、肺癌、胃癌、小肠癌、肝癌、胰腺癌、胆囊癌、胆管癌、食道癌、唾液腺癌和甲状腺癌等。给予本发明的组合物可用于癌症的所有阶段和类型，包括用于例如微小残留病、早期癌症、晚期癌症和/或转移性癌症和/或难以治疗的癌症。Herein, cancer includes but is not limited to breast, prostate, lung and colon cancer or epithelial cancer, such as breast cancer, colon cancer, prostate cancer, head and neck cancer, skin cancer; genital-urinary tract cancer, such as ovarian cancer, endometrial cancer , Cervical cancer; kidney cancer, lung cancer, stomach cancer, small intestine cancer, liver cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, esophageal cancer, salivary gland cancer and thyroid cancer. Administration of the composition of the present invention can be used for all stages and types of cancer, including for example minimal residual disease, early cancer, advanced cancer and/or metastatic cancer and/or difficult-to-treat cancer.
通过示例的方式，如下治疗癌症患者或易患癌症的患者或疑似患有癌症的患者。如本文所述修饰的细胞可给予个体并且停留延长的时间段。该个体可接受细胞的一次或多次给药，且给药的间隔时间可以是数天、数周、数月或数年。在具体实施方式中，多次给药可在数周或数月内发生，例如1、2、3、4、5、6、7、8、9、10、11、12或更多周或月。在一些实施方式中，遗传修饰的细胞经包封以抑制免疫识别并位于肿瘤位点。在使用本发明的细胞进行初始治疗后肿瘤复发后向个体提供细胞的情况中，可改变这些细胞使其识别不同的靶肿瘤抗原。例如，当初始轮次包括携带本发明的信号转换受体和特异性针对特定抗原的另一受体的细胞时，后续轮次后(包括肿瘤复发后)可使用针对不同特定抗原的受体。By way of example, a cancer patient or a patient susceptible to cancer or a patient suspected of having cancer are treated as follows. Cells modified as described herein can be administered to an individual and stay for an extended period of time. The individual can receive one or more administrations of the cells, and the interval between administrations can be days, weeks, months, or years. In specific embodiments, multiple administrations can occur within weeks or months, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks or months . In some embodiments, genetically modified cells are encapsulated to inhibit immune recognition and are located at the tumor site. In the case of providing cells to individuals after tumor recurrence after initial treatment using the cells of the present invention, these cells can be changed to recognize different target tumor antigens. For example, when the initial round includes cells carrying the signal conversion receptor of the present invention and another receptor specific for a specific antigen, receptors for different specific antigens can be used after subsequent rounds (including after tumor recurrence).
在一些实施方案中，向需要的个体提供有效量的治疗性细胞，所述治疗性细胞携带或表达本发明任一实施方案所述的信号转换受体和任选的CAR或外源转基因TCR。可与一种或多种其他癌症治疗同时或不同时递送这些细胞。可在同一或单独的制剂中递送这些细胞和其他癌症治疗剂。可以单独的递送途径向个体提供细胞和其他癌症治疗剂。可通过例如在肿瘤位点处注射或静脉内或口服来递送细胞和/或其他癌症治疗剂。这类组合物的常规递送途径是本领域已知的。In some embodiments, an effective amount of therapeutic cells is provided to an individual in need, the therapeutic cells carrying or expressing the signal conversion receptor according to any embodiment of the present invention and optionally CAR or exogenous transgenic TCR. These cells can be delivered at the same time or at different times with one or more other cancer treatments. These cells and other cancer therapeutics can be delivered in the same or separate formulations. Cells and other cancer therapeutics can be provided to individuals with separate delivery routes. The cells and/or other cancer therapeutics can be delivered by, for example, injection at the tumor site or intravenously or orally. Conventional delivery routes for such compositions are known in the art.
所采用的细胞数量将取决于多种情况，例如导入的目的、细胞的寿命、待使用的方案、给药的次数、细胞繁殖的能力、重组构建体的稳定性等。The number of cells used will depend on various conditions, such as the purpose of introduction, the lifespan of the cells, the protocol to be used, the number of administrations, the ability of the cells to multiply, and the stability of the recombinant construct.
可根据需要给予细胞。在某些实施方式中，可使用多种方案来调节方案参数。在具体实施方式中，给药的途径或次数或时机、细胞的寿命和/或存在的细胞数目可以发生变化。给药的次数可例如至少部分取决于上述因素。The cells can be administered as needed. In some embodiments, multiple protocols can be used to adjust protocol parameters. In specific embodiments, the route or number of times or timing of administration, the life span of the cells, and/or the number of cells present can be changed. The number of administrations may, for example, depend at least in part on the aforementioned factors.
试剂盒Reagent test kit
本文所述的任意组合物可包含于试剂盒中。在一个非限制性实施例中，可在试剂盒中包含用于细胞疗法的表达本发明任一实施方案所述的信号转换受体的细胞和/或生成用于 细胞疗法的一种或多种细胞的试剂，该疗法含有重组表达载体。以合适的容器方式提供试剂盒组分。Any of the compositions described herein can be included in a kit. In a non-limiting embodiment, the kit may include cells expressing the signal conversion receptor described in any embodiment of the present invention for cell therapy and/or generating one or more cells for cell therapy Cell reagents, the therapy contains recombinant expression vectors. The kit components are provided in suitable containers.
这些试剂盒的一些组分可包装在水性基质中或包装成冻干形式。这些试剂盒的容器用具通常包括至少一种小瓶、试管、烧瓶、瓶、注射器或其它容器用具，其中该组分可放置，并优选适当分装于其中。在试剂盒中存在超过一种组分的情况中，该试剂盒通常还含有第二、第三或其他容器，其中可分开放置其他组分。然而，可在小瓶中包含组分的各种组合。本发明的试剂盒通常还包含用于市售的封闭约束形式含有该组分的器具。此类容器可包括注塑或吹塑的塑料容器，其中保留所需小瓶。Some components of these kits can be packaged in an aqueous matrix or packaged in a lyophilized form. The container utensils of these kits usually include at least one vial, test tube, flask, bottle, syringe or other container utensil, in which the component can be placed, and is preferably appropriately dispensed therein. In the case where there is more than one component in the kit, the kit usually also contains a second, third or other container in which other components can be placed separately. However, various combinations of components can be included in the vial. The kit of the present invention usually also contains a commercially available device containing the component in a closed and restrained form. Such containers may include injection-molded or blow-molded plastic containers in which the desired vials are retained.
当在一种和/或多种液体溶液中提供试剂盒的组分时，液体溶液是水性溶液，特别优选无菌水性溶液。在一些情况中，容器用具本身可以是注射器、移液器和/或其他这类设备。When the components of the kit are provided in one and/or more liquid solutions, the liquid solution is an aqueous solution, and a sterile aqueous solution is particularly preferred. In some cases, the container appliance itself may be a syringe, pipette, and/or other such devices.
试剂盒的组也分可以干粉形式提供。当以干粉提供试剂和/或组分时，可通过加入合适的溶剂来重建粉末。因此，试剂盒还可包含含有无菌的、药学上可接受的缓冲剂和/或其他稀释剂的第二容器用具。The components of the kit can also be provided in dry powder form. When the reagents and/or components are provided as a dry powder, the powder can be reconstituted by adding a suitable solvent. Therefore, the kit may also include a second container device containing a sterile, pharmaceutically acceptable buffer and/or other diluent.
在本发明的具体实施方式中，在试剂盒中提供待用于本文所述细胞疗法的细胞。在一些实施方案中，细胞基本上是试剂盒的唯一组分。该试剂盒可包含制备所需细胞的试剂和材料。在具体实施方式中，该试剂和材料包含用于扩增所需序列的引物、核苷酸、合适的缓冲剂或缓冲试剂、盐等，并且在一些情况中，该试剂包括编码本文任一实施方案所述的信号转换受体和/或其调控元件的DNA和/或载体。In a specific embodiment of the present invention, the cells to be used in the cell therapy described herein are provided in a kit. In some embodiments, the cell is essentially the only component of the kit. The kit may contain reagents and materials for preparing the required cells. In specific embodiments, the reagents and materials include primers, nucleotides, suitable buffers or buffer reagents, salts, etc., for amplifying the desired sequence, and in some cases, the reagents include coding for any of the embodiments herein. The DNA and/or vector of the signal conversion receptor and/or its regulatory elements described in the scheme.
本发明的效果Effect of the present invention
本发明创造性地将高效结合肿瘤细胞表面和/或肿瘤基质细胞表面免疫抑制分子的多肽、跨膜区肽段和共刺激信号分子胞内肽段相连，构成具有T信号分子转换器功能的融合蛋白，经该融合蛋白修饰后的T细胞在接触肿瘤细胞表面和/或肿瘤基质细胞表面起免疫抑制作用的分子后，不受免疫抑制分子的负面影响，反而起免疫活化作用，增强T细胞的增殖能力及细胞因子的分泌功能，延长活化免疫细胞的存活时间，从而克服肿瘤免疫抑制微环境对肿瘤过继细胞治疗效应细胞的副作用，在体内和体外都有效地提升了免疫效应细胞对肿瘤的抑制和杀伤效果。The present invention creatively connects the polypeptides, transmembrane peptides and intracellular peptides of costimulatory signal molecules that efficiently bind to tumor cell surface and/or tumor stromal cell surface immunosuppressive molecules to form a fusion protein with T signal molecule converter function After the T cells modified by the fusion protein come into contact with the immunosuppressive molecules on the surface of tumor cells and/or tumor stromal cells, they will not be negatively affected by the immunosuppressive molecules, but instead have an immune activation effect and enhance the proliferation of T cells. The ability and secretion function of cytokines can prolong the survival time of activated immune cells, thereby overcoming the side effects of tumor immunosuppressive microenvironment on the effector cells of tumor adoptive cell therapy. It effectively improves the suppression and suppression of immune effector cells on tumors both in vivo and in vitro. Killing effect.
下面将结合实施例对本发明的实施方案进行详细描述。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件(例如参考J.萨姆布鲁克等著，黄 培堂等译的《分子克隆实验指南》，第三版，科学出版社)、相应的参考文献、或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The embodiments of the present invention will be described in detail below in conjunction with examples. Those skilled in the art will understand that the following embodiments are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the examples, follow the techniques or conditions described in the literature in the field (for example, refer to the "Molecular Cloning Experiment Guide" translated by J. Sambrook et al., Huang Peitang et al., third edition, Science Press), the corresponding references, or follow the product instructions. The reagents or instruments used without the manufacturer's indication are all conventional products that can be purchased commercially.
实施例1信号转换受体表达载体的构建Example 1 Construction of signal conversion receptor expression vector
按照中国专利CN105154473B说明书第15页实施例1记载的方法，构建pNB载体。按照CN105154473B说明书第15页实施例2记载的方法，构建含有TGF-β信号转换受体2-1-TGF-β信号转换受体2-15(TGFBR2-SCR1-TGFBR2-SCR15)的表达框的pNB载体。The pNB vector was constructed according to the method described in Example 1 on page 15 of the Chinese Patent CN105154473B specification. According to the method described in Example 2 on page 15 of CN105154473B specification, pNB containing the expression cassette of TGF-β signal conversion receptor 2-1-TGF-β signal conversion receptor 2-15 (TGFBR2-SCR1-TGFBR2-SCR15) was constructed Carrier.
中国专利申请CN105452287A中记载了一种包含TGF-β受体2胞外区的信号转换受体，在说明书21页实施例1记载了RIID2和RIID4两种信号转换受体结构，分别包含TGF-β信号转换受体2信号肽、TGF-β信号转换受体2胞外区、TLR2跨膜区、TLR2胞内区的信号转换受体和TGF-β信号转换受体2信号肽、TGF-β信号转换受体2胞外区、TLR4跨膜区、TLR4胞内区。根据上述记载的结构，合成包括上述元件的信号转换受体SCR-RIID2与SCR-RIID4，两者均不包含IRES与橙色荧光蛋白(mOrange)或绿色荧光蛋白(GFP)。Chinese patent application CN105452287A describes a signal transduction receptor containing the extracellular domain of TGF-β receptor 2. Example 1 on page 21 of the specification describes two signal transduction receptor structures, RIID2 and RIID4, each containing TGF-β Signal conversion receptor 2 signal peptide, TGF-β signal conversion receptor 2 extracellular domain, TLR2 transmembrane region, TLR2 intracellular domain signal conversion receptor and TGF-β signal conversion receptor 2 signal peptide, TGF-β signal Switch receptor 2 extracellular region, TLR4 transmembrane region, TLR4 intracellular region. According to the structure described above, the signal conversion receptors SCR-RIID2 and SCR-RIID4 including the above-mentioned elements were synthesized, neither of which contained IRES and orange fluorescent protein (mOrange) or green fluorescent protein (GFP).
TGFBR2-SCR1-TGFBR2-SCR15、SCR-RIID2及SCR-RIID4所对应的结构如下表6所示：The corresponding structures of TGFBR2-SCR1-TGFBR2-SCR15, SCR-RIID2 and SCR-RIID4 are shown in Table 6 below:
表6Table 6
Figure PCTCN2021097361-appb-000004
Figure PCTCN2021097361-appb-000004
Figure PCTCN2021097361-appb-000005
Figure PCTCN2021097361-appb-000005
具体地，委托公司合成获得SEQ ID NO:1648、SEQ ID NO:1650、SEQ ID NO:1652、SEQ ID NO:1654、SEQ ID NO:1656、SEQ ID NO:1658、SEQ ID NO:1660、SEQ ID NO:1662、SEQ ID NO:1664、SEQ ID NO:1666、SEQ ID NO:1668、SEQ ID NO:1670、SEQ ID NO:1672、SEQ ID NO:1674、SEQ ID NO:1676、SEQ ID NO:1678、SEQ ID NO:1680所示序列，分别将上述序列按照CN105154473B说明书第15页实施例2记载的方法克隆到制备好的pNB载体中，分别命名为pNB328-1648、pNB328-1650、pNB328-1652、pNB328-1654、pNB328-1656、pNB328-1658、pNB328-1660、pNB328-1662、pNB328-1664、pNB328-1666、pNB328-1668、pNB328-1670、pNB328-1672、pNB328-1674、pNB328-1676、pNB328-1678、pNB328-1680。Specifically, entrust the company to synthesize and obtain SEQ ID NO: 1648, SEQ ID NO: 1650, SEQ ID NO: 1652, SEQ ID NO: 1654, SEQ ID NO: 1656, SEQ ID NO: 1658, SEQ ID NO: 1660, SEQ ID NO: 1662, SEQ ID NO: 1664, SEQ ID NO: 1666, SEQ ID NO: 1668, SEQ ID NO: 1670, SEQ ID NO: 1672, SEQ ID NO: 1674, SEQ ID NO: 1676, SEQ ID NO 1678, SEQ ID NO: 1680, the above sequences were cloned into the prepared pNB vector according to the method described in Example 2 on page 15 of CN105154473B specification, respectively named pNB328-1648, pNB328-1650, pNB328- 1652, pNB328-1654, pNB328-1656, pNB328-1658, pNB328-1660, pNB328-1662, pNB328-1664, pNB328-1666, pNB328-1668, pNB328-1670, pNB328-1672, pNB328-1674, pNB328-1676, pNB328-1678, pNB328-1680.
将上述获得的重组质粒转化到E.coli(DH5c)，经测序正确后，使用Qiagen公司的质粒纯化试剂盒提取并纯化质粒，获得各重组表达载体的高品质质粒。The recombinant plasmids obtained above were transformed into E. coli (DH5c), and after the sequencing was correct, the plasmids were extracted and purified using Qiagen's plasmid purification kit to obtain high-quality plasmids for each recombinant expression vector.
实施例2 NY-ESO-1 TCR表达载体的制备Example 2 Preparation of NY-ESO-1 TCR expression vector
合成编码识别NY-ESO-1抗原肽SLLMWITQC(HLA-*02:01)的TCR的α链和β链的基因DNA序列，两者通过编码P2A肽段的DNA序列链接，所拼接成的序列如SEQ ID NO:1681所示。再在SEQ ID NO:1681的3’端通过编码P2A肽段的DNA连接编码EGFP的DNA序列，所得到的序列如SEQ ID NO:1682所示。委托公司合成获得SEQ ID NO:1682，按照CN105154473B说明书第15页实施例2记载的方法将SEQ ID NO:1682克隆到制备好的pNB载体中，命名为pNB328-1682。将pNB载体中的PB转座酶编码区和CMV启 动子进行删除，获得不含PB转座酶表达框的载体pNC。按照CN105154473B说明书第15页实施例2记载的方法将SEQ ID NO:1682克隆到制备好的pNC载体中，命名为pNC328-1682。将获得的重组质粒转化到E.coli(DH5c)，经测序正确后，使用Qiagen公司的质粒纯化试剂盒提取并纯化质粒，获得各重组表达载体的高品质质粒。Synthesize the gene DNA sequence encoding the α chain and β chain of the TCR that recognizes the NY-ESO-1 antigen peptide SLLMWITQC (HLA-*02:01). The two are linked by the DNA sequence encoding the P2A peptide. The spliced sequence is as follows SEQ ID NO: 1681 is shown. At the 3'end of SEQ ID NO: 1681, the DNA sequence encoding EGFP is connected with the DNA encoding the P2A peptide segment, and the resulting sequence is shown in SEQ ID NO: 1682. The company entrusted the company to synthesize and obtain SEQ ID NO: 1682. According to the method described in Example 2 on page 15 of the CN105154473B manual, SEQ ID NO: 1682 was cloned into the prepared pNB vector and named as pNB328-1682. The PB transposase coding region and CMV promoter in the pNB vector are deleted to obtain the vector pNC without the PB transposase expression cassette. According to the method described in Example 2 on page 15 of the CN105154473B specification, SEQ ID NO: 1682 was cloned into the prepared pNC vector and named as pNC328-1682. The obtained recombinant plasmid was transformed into E. coli (DH5c), after the sequencing was correct, the plasmid was extracted and purified using Qiagen's plasmid purification kit to obtain high-quality plasmids for each recombinant expression vector.
实施例3 TCR-T的制备Example 3 Preparation of TCR-T
人活化T细胞的制备：Preparation of human activated T cells:
用含有5μg/ml的抗CD3抗体和5μg/ml的抗CD28抗体的包被液包被六孔板室温2-4小时，吸去包被液后用生理盐水洗涤孔板1-3次，加入含2％FBS AIM-V培养基待用；人外周血PBMC(HLA-*02:01，购买自ALLCELLS)37℃水浴复苏，将PBMC贴壁培养2-4h，其中未贴壁的悬浮细胞即为初始T细胞，将悬浮细胞收集到15ml离心管中，1200rmp离心3min，弃上清，加入生理盐水，1200rmp离心3min，弃生理盐水，并重复此步骤；再将洗涤后的初始T细胞转移至盛有待用培养基的抗体包被孔中，37℃，5％CO2培养3～4天后进行后续实验。Coat the six-well plate with a coating solution containing 5μg/ml anti-CD3 antibody and 5μg/ml anti-CD28 antibody at room temperature for 2-4 hours, aspirate the coating solution and wash the well plate with saline 1-3 times, add AIM-V medium containing 2% FBS is ready for use; human peripheral blood PBMC (HLA-*02:01, purchased from ALLCELLS) is resuscitated in a 37°C water bath, and the PBMC is cultured adherently for 2-4 hours, and the non-adherent suspended cells are For the initial T cells, collect the suspended cells in a 15ml centrifuge tube, centrifuge at 1200rpm for 3min, discard the supernatant, add physiological saline, centrifuge at 1200rpm for 3min, discard the physiological saline, and repeat this step; then transfer the washed initial T cells to The antibody-coated wells containing the medium to be used are incubated at 37°C and 5% CO2 for 3 to 4 days, and then the follow-up experiment is carried out.
电转制备表达NY-ESO-1 TCR及表达NY-ESO-1 TCR+TGF-β信号转换受体的TCR-T细胞：Preparation of TCR-T cells expressing NY-ESO-1 TCR and NY-ESO-1 TCR+TGF-β signal conversion receptor by electroporation:
1)预先将AIM-V培养基加入12孔板的19个孔，每孔2mL，随后转入细胞培养箱内37℃5％CO2预热1小时；1) Preliminarily add AIM-V medium to 19 wells of a 12-well plate, 2 mL per well, and then transfer it to a cell incubator at 37°C and 5% CO2 for preheating for 1 hour;
2)按下表7进行每孔单次用量的电转液配比，总共配制19孔：2) Perform the electro-transfer solution ratio for a single amount of each hole according to Table 7, and prepare a total of 19 holes:
表7Table 7
 To 100μL Nucleocuvette TM Strip(μL) 100μL Nucleocuvette TM Strip(μL)
Nucleofector TM溶液的体积 Volume of Nucleofector TM solution 8282
电转补充溶液Electric to replenishment solution 1818
3)取获得的活化T细胞至19个EP管内，每个EP管内加入5×106个细胞，1200rpm离心5min，弃上清，随后用500μL生理盐水重悬细胞，重复离心步骤洗涤细胞沉淀；3) Take the obtained activated T cells into 19 EP tubes, add 5×106 cells to each EP tube, centrifuge at 1200 rpm for 5 min, discard the supernatant, then resuspend the cells with 500 μL of saline, and repeat the centrifugation step to wash the cell pellet;
4)向2)中配置好的电转液体系分别加入质粒pNB328-1682 6μg、pNC328-1682 3μg+pNB328-1648 3μg、pNC328-1682 3μg+pNB328-1650 3μg、pNC328-1682 3μg+pNB328-1652 3μg、pNC328-1682 3μg+pNB328-1654 3μg、pNC328-1682 3μg+pNB328-1656 3μg、pNC328-1682 3μg+pNB328-1658 3μg、pNC328-1682 3μg+pNB328-1660 3μg、pNC328-1682 3μg+pNB328-1662 3μg、pNC328-1682 3μg+pNB328-1664 3μg、pNC328-1682 3μg+pNB328-1666 3μg、pNC328-1682 3μg+pNB328-1668 3μg、pNC328-1682 3μg+pNB328-1670  3μg、pNC328-1682 3μg+pNB328-1672 3μg、pNC328-1682 3μg+pNB328-1674 3μg、pNC328-1682 3μg+pNB328-1676 3μg、pNC328-1682 3μg+pNB328-1678 3μg、pNC328-1682 3μg+pNB328-1680 3μg、pNC空载体3μg+pNB空载体3μg，随后室温静置30min以内；4) Add plasmid pNB328-1682 6μg, pNC328-1682 3μg+pNB328-1648 3μg, pNC328-1682 3μg+pNB328-1650 3μg, pNC328-1682 3μg+pNB328-1652 3μg, to the electrotransfer solution system configured in 2). pNC328-1682 3μg+pNB328-1654 3μg, pNC328-1682 3μg+pNB328-1656 3μg, pNC328-1682 3μg+pNB328-1658 3μg, pNC328-1682 3μg+pNB328-1660 3μg, pNC328-1682 3μg+pNB328-1662 pNC328-1682 3μg+pNB328-1664 3μg, pNC328-1682 3μg+pNB328-1666 3μg, pNC328-1682 3μg+pNB328-1668 3μg, pNC328-1682 3μg+pNB328-1670 3μg, pNC328-1682 3μg+pNB328-1672 pNC328-1682 3μg+pNB328-1674 3μg, pNC328-1682 3μg+pNB328-1676 3μg, pNC328-1682 3μg+pNB328-1678 3μg, pNC328-1682 3μg+pNB328-1680 3μg, pNC empty vector 3μg+pNB empty vector 3μg, Then let it stand at room temperature within 30 minutes;
5)用4)中配置好的含质粒的电转液重悬19管活化T细胞，每管100μL，小心吸取细胞重悬液转入LONZA 100μL电转杯内，将电转杯放入LONZA Nucleofector TM 2b电转槽内，启动电转程序，电转程序选择T-020； 5) Resuspend 19 tubes of activated T cells with the plasmid-containing electroporation solution prepared in 4), 100μL per tube, carefully pipette the cell resuspension into a LONZA 100μL electroporation cup, and place the electroporation cup into the LONZA Nucleofector TM 2b for electrotransduction In the slot, start the electric transfer program, and select T-020 for the electric transfer program;
6)电转完成后小心取出电转杯，吸取细胞悬液转移至EP管中，每管加入预热的AIM-V培养基200μL，随后转入1)中12孔板内含预热AIM-V培养基的孔中，37℃、5％CO2培养，培养1h后加入化合物G150(购自MedChemExpress)至终浓度为5μM，随后继续培养13天，期间根据细胞增殖情况进行传代，13天后对各电转样品的细胞数量和细胞成活率进行检测。6) After the electroporation is completed, carefully remove the electroporation cup, transfer the cell suspension to the EP tube, add 200μL of preheated AIM-V medium to each tube, and then transfer to 1) the 12-well plate containing preheated AIM-V culture Incubate at 37°C and 5% CO2. After culturing for 1 hour, add compound G150 (purchased from MedChemExpress) to a final concentration of 5μM, and then continue to incubate for 13 days, during which passage is carried out according to cell proliferation, and after 13 days, each electroporated sample The number of cells and cell survival rate are tested.
通过上述方法制备的表达外源基因的细胞分别命名为TCR-T、SCR1 TCR-T、SCR2 TCR-T、SCR3 TCR-T、SCR4 TCR-T、SCR5 TCR-T、SCR6 TCR-T、SCR7 TCR-T、SCR8 TCR-T、SCR9 TCR-T、SCR10 TCR-T、SCR11 TCR-T、SCR12 TCR-T、SCR13 TCR-T、SCR14 TCR-T、SCR15 TCR-T、RIID2 TCR-T、RIID4 TCR-T和Mock TCR-T。将获得的上述细胞上流式细胞仪(Beckman Cytoflex)检测EGFP阳性的细胞占比。对于TCR-T，EGFP阳性细胞可被视为NY-ESO-1 TCR基因表达阳性的细胞。对于共转了TGF-β信号转换受体和TCR的细胞，因为pNC载体中不包含PB转座酶表达框，EGFP阳性表明TCR-EGFP的成功整合表达所依赖的PB转座酶来自表达编码TGF-β信号转换受体基因的pNB载体，因此共转TGF-β信号转换受体和TCR的细胞中，EGFP阳性细胞可以认为是TGF-β信号转换受体和NY-ESO-1 TCR双重整合表达。结果如图1和表8所示：The cells expressing foreign genes prepared by the above methods were named TCR-T, SCR1 TCR-T, SCR2 TCR-T, SCR3 TCR-T, SCR4 TCR-T, SCR5 TCR-T, SCR6 TCR-T, SCR7 TCR -T, SCR8 TCR-T, SCR9 TCR-T, SCR10 TCR-T, SCR11 TCR-T, SCR12 TCR-T, SCR13 TCR-T, SCR14 TCR-T, SCR15 TCR-T, RIID2 TCR-T, RIID4 TCR -T and Mock TCR-T. The proportion of EGFP-positive cells detected by the flow cytometer (Beckman Cytoflex) on the obtained cells. For TCR-T, EGFP-positive cells can be regarded as NY-ESO-1 TCR gene-positive cells. For cells co-transfected with TGF-β signal conversion receptor and TCR, because the pNC vector does not contain the PB transposase expression cassette, EGFP positive indicates that the successful integration and expression of TCR-EGFP depends on the PB transposase from the expression encoding TGF -β signal conversion receptor gene pNB vector, so in cells co-transformed with TGF-β signal conversion receptor and TCR, EGFP-positive cells can be considered as the dual integrated expression of TGF-β signal conversion receptor and NY-ESO-1 TCR . The results are shown in Figure 1 and Table 8:
表8Table 8
细胞组别Cell group EGFP阳性细胞比例(％)Proportion of EGFP positive cells (%)
Mock-TCR-TMock-TCR-T 00
TCR-TTCR-T 44.2244.22
SCR1 TCR-TSCR1 TCR-T 17.0417.04
SCR2 TCR-TSCR2 TCR-T 15.1015.10
SCR3 TCR-TSCR3 TCR-T 20.6820.68
SCR4 TCR-TSCR4 TCR-T 31.6931.69
SCR5 TCR-TSCR5 TCR-T 20.8220.82
SCR6 TCR-TSCR6 TCR-T 18.8318.83
SCR7 TCR-TSCR7 TCR-T 41.1741.17
SCR8 TCR-TSCR8 TCR-T 27.1327.13
SCR9 TCR-TSCR9 TCR-T 19.4219.42
SCR10 TCR-TSCR10 TCR-T 21.3921.39
SCR11 TCR-TSCR11 TCR-T 18.0718.07
SCR12 TCR-TSCR12 TCR-T 16.6516.65
SCR13 TCR-TSCR13 TCR-T 23.7623.76
SCR14 TCR-TSCR14 TCR-T 29.5829.58
SCR15 TCR-TSCR15 TCR-T 31.2431.24
RIID2 TCR-TRIID2 TCR-T 23.3123.31
RIID4 TCR-TRIID4 TCR-T 21.7521.75
图1显示了电转了TCR-EGFP融合基因的TCR-T和共转了TCR-EGFP融合基因+TGF-β信号转换受体基因的SCR1-5 TCR-T细胞的荧光显微图。TCR-T的EGFP荧光亮度比SCR1-5 TCR-T的荧光亮度均更亮，可能原因是TCR-T通过单转质粒制备，单质粒中同时包括外源TCR-EGFP融合基因和PB转座酶表达框；而SCR1-5 TCR-T需要两个质粒共转制备，其中外源TCR-EGFP融合基因和PB转座酶表达框需要pNC和pNB两个载体分别提供。Figure 1 shows the fluorescence micrographs of TCR-T electrotransformed with TCR-EGFP fusion gene and SCR1-5 TCR-T cells co-transformed with TCR-EGFP fusion gene + TGF-β signal conversion receptor gene. The EGFP fluorescence brightness of TCR-T is brighter than the fluorescence brightness of SCR1-5 TCR-T. The possible reason is that TCR-T is prepared by a single plasmid. The single plasmid includes both the exogenous TCR-EGFP fusion gene and PB transposase. Expression cassette; while SCR1-5 TCR-T requires two plasmids to be prepared by co-transformation, and the exogenous TCR-EGFP fusion gene and PB transposase expression cassette need to be provided by two vectors, pNC and pNB, respectively.
实施例4表达TGF-β信号转换受体SCR1-5的TCR-T对靶细胞的杀伤效果Example 4 Killing effect of TCR-T expressing TGF-β signal conversion receptor SCR1-5 on target cells
选取NY-ESO-1表达阳性的HLA-*02:01型黑色素瘤细胞系A375(均购买于美国典型培养物保藏中心ATCC)作为靶细胞，应用艾森公司的实时无标记细胞功能分析仪(RTCA)检测实施例3制备得到的TCR-T、SCR1 TCR-T、SCR2 TCR-T、SCR3 TCR-T、SCR4 TCR-T、SCR5 TCR-T、RIID2 TCR-T和RIID4 TCR-T细胞的体外杀伤活性，具体步骤如下：The HLA-*02:01 type melanoma cell line A375 (all purchased from the American Type Culture Collection ATCC) with positive NY-ESO-1 expression was selected as the target cells, and the real-time label-free cell function analyzer ( RTCA) Test the TCR-T, SCR1 TCR-T, SCR2 TCR-T, SCR3 TCR-T, SCR4 TCR-T, SCR5 TCR-T, RIID2 TCR-T and RIID4 TCR-T cells prepared in Example 3 in vitro Killing activity, the specific steps are as follows:
(1)调零：每孔加入50μl DMEM或1640培养液，放入仪器中，选择step 1，调零；(1) Zero adjustment: add 50μl DMEM or 1640 culture medium to each well, put it into the instrument, select step 1, adjust zero;
(2)靶细胞铺板：黑色素瘤细胞A375按每孔104个细胞/50μl铺在含有检测电极的板 中，放置数分钟，待细胞稳定一下，再放入仪器中，开始step 2，培养细胞；(2) Target cell plating: The melanoma cell A375 is plated on the plate containing the detection electrode at 104 cells/50μl per well, and placed for a few minutes. After the cells have stabilized, put them in the instrument and start step 2, culturing the cells;
(3)加入效应细胞：靶细胞培养8-48h至细胞指数(Cell Index)到达1.0后，暂停step 2，加入效应细胞，每孔50μl，以表1中的阳性细胞比例按效靶比1.5﹕1添加效应细胞数量，开始step 3，继续共培养超过120h后，观察细胞增殖曲线。(3) Add effector cells: After the target cells are cultured for 8-48h until the Cell Index reaches 1.0, stop step 2, add effector cells, 50μl per well, and use the ratio of positive cells in Table 1 according to the effective target ratio of 1.5: 1 Add the number of effector cells, start step 3, continue to co-culture for more than 120 hours, observe the cell proliferation curve.
结果如图2和图3所示。图2和图3分别显示SCR1-5 TCR-T、RIID 2 TCR-T和TCR-T对靶细胞的杀伤效果与SCR1-5 TCR-T、RIID 4 TCR-T和TCR-T对靶细胞的杀伤效果。效靶比设置为1.5﹕1，长时间观察杀伤效果。图2与图3均显示，在刚加入效应细胞时间点(24h)后不久，SCR4 TCR-T和SCR5 TCR-T即已显示出明显优于TCR-T、SCR1/2/3 TCR-T、RIID2 TCR-T和RIID4 TCR-T的靶细胞杀伤效果。杀伤时间到120h后，SCR1-5 TCR-T与TCR-T相比，对靶细胞A375的杀伤效果均仍更加明显，其中SCR1/2/3 TCR-T三者的杀伤效果接近，SCR4 TCR-T的杀伤效果较SCR1/2/3 TCR-T更优，SCR5-TCR-T的杀伤效果则明显优于SCR1-4 TCR-T和TCR-T，为几种效应细胞中最优。图2结果显示，RIID2 TCR-T与TCR-T杀伤效果接近，略低于TCR-T的杀伤效果；图3显示，RIID4 TCR-T的杀伤效果略优于TCR-T，但低于SCR1/2/3 TCR-T，同时明显低于SCR4 TCR-T与SCR5TCR-T。上述结果表明，本发明信号转换受体SCR1-5在较低效靶比条件下仍然能够显著提升效应T细胞对肿瘤靶细胞的杀伤水平，并且这种提升效果在杀伤时间较长时仍然存在。The results are shown in Figure 2 and Figure 3. Figure 2 and Figure 3 respectively show the killing effect of SCR1-5 TCR-T, RIID 2 TCR-T and TCR-T on target cells and SCR1-5 TCR-T, RIID 4 TCR-T and TCR-T on target cells Killing effect. The effect-to-target ratio is set to 1.5:1, and the killing effect is observed for a long time. Figures 2 and 3 both show that shortly after adding effector cells (24h), SCR4 TCR-T and SCR5 TCR-T have been shown to be significantly better than TCR-T, SCR1/2/3 TCR-T, Target cell killing effect of RIID2 TCR-T and RIID4 TCR-T. After the killing time reaches 120h, compared with TCR-T, SCR1-5 TCR-T has more effective killing effect on target cell A375. Among them, the killing effect of SCR1/2/3 TCR-T is close, and SCR4 TCR- The killing effect of T is better than that of SCR1/2/3 TCR-T, and the killing effect of SCR5-TCR-T is significantly better than that of SCR1-4 TCR-T and TCR-T, which is the best among several effector cells. Figure 2 shows that the killing effect of RIID2 TCR-T is close to that of TCR-T, which is slightly lower than that of TCR-T; Figure 3 shows that the killing effect of RIID4 TCR-T is slightly better than that of TCR-T, but lower than SCR1. 2/3 TCR-T, which is also significantly lower than SCR4 TCR-T and SCR5TCR-T. The above results indicate that the signal conversion receptor SCR1-5 of the present invention can still significantly increase the killing level of effector T cells to tumor target cells under the condition of a lower effective target ratio, and this improvement effect still exists when the killing time is long.
实施例5表达TGF-β信号转换受体SCR5的TCR-T对靶细胞在低效靶下的比杀伤效Example 5 Specific killing effect of TCR-T expressing TGF-β signal conversion receptor SCR5 on target cells under low-efficiency targets 果fruit
参照实施例4，选用A375作为靶细胞，选取TCR-T、SCR5 TCR-T、RIID2 TCR-T和RIID4 TCR-T为效应细胞，将效靶比进一步降低至1﹕1，比较几种效应细胞对A375细胞的杀伤水平，操作同实施例4。1﹕1低效靶比长时间观察意在模拟体内真实环境下T细胞杀伤肿瘤的场景。Referring to Example 4, A375 was selected as the target cell, and TCR-T, SCR5 TCR-T, RIID2 TCR-T and RIID4 TCR-T were selected as effector cells, and the effective target ratio was further reduced to 1:1, and several effector cells were compared For the killing level of A375 cells, the operation is the same as in Example 4. The 1:1 low-efficiency target ratio long-term observation is intended to simulate the scenario of T cells killing tumors in the real environment in vivo.
结果如图4和图5所示。图4显示，在效应细胞加入时间点(40h刚过)后不久，RIID2 TCR-T的杀伤效果已表现出优于TCR-T，而SCR5 TCR-T的杀伤效果则显著优于前两者。在杀伤检测时长超过120h后，RIID2 TCR-T的杀伤效果仍然优于TCR-T，而SCR5 TCR-T的杀伤效果较前两者均仍更优。类似地，图5显示，在效应细胞加入时间点(40h刚过)后不久，RIID4 TCR-T的杀伤效果已表现出优于TCR-T，而SCR5 TCR-T的杀伤效果显 著优于前两者。当杀伤检测时长超过120h后，RIID4 TCR-T的杀伤效果也仍然优于TCR-T，SCR5 TCR-T的杀伤效果也均优于前两者。上述结果表明，即使在效靶比极低和杀伤时间很长的条件下，本发明信号转换受体SCR5仍然能够有效提升效应T细胞对肿瘤靶细胞的杀伤水平。The results are shown in Figure 4 and Figure 5. Figure 4 shows that shortly after the effector cell addition time point (just after 40h), the killing effect of RIID2 TCR-T has been shown to be better than that of TCR-T, while the killing effect of SCR5 TCR-T is significantly better than the former two. After the killing detection time exceeds 120h, the killing effect of RIID2 TCR-T is still better than that of TCR-T, while the killing effect of SCR5 TCR-T is still better than the former two. Similarly, Figure 5 shows that shortly after the effector cell addition time point (just after 40h), the killing effect of RIID4 TCR-T has been shown to be better than that of TCR-T, while the killing effect of SCR5 TCR-T is significantly better than the previous two. By. When the killing detection time exceeds 120h, the killing effect of RIID4 TCR-T is still better than TCR-T, and the killing effect of SCR5 TCR-T is also better than the former two. The above results indicate that even under the conditions of extremely low effect-to-target ratio and long killing time, the signal conversion receptor SCR5 of the present invention can still effectively increase the killing level of effector T cells on tumor target cells.
实施例6表达TGF-β信号转换受体SCR6-10的TCR-T对靶细胞的杀伤效果Example 6 Killing effect of TCR-T expressing TGF-β signal conversion receptor SCR6-10 on target cells
检测实施例3制备得到的TCR-T、SCR6 TCR-T、SCR7 TCR-T、SCR8 TCR-T、SCR9 TCR-T和SCR10 TCR-T对A375细胞的体外杀伤活性，按EGFP阳性细胞占比设置效靶比为1.5﹕1，具体检测步骤同实施例4。结果如图6所示。在刚加入效应细胞时间点(24h)后不久，SCR10 TCR-T即已显示出明显优于TCR-T、SCR6/7/8/9 TCR-T的靶细胞杀伤效果。杀伤时间到90h后，SCR6-10 TCR-T与TCR-T相比，对靶细胞A375的杀伤效果均仍更加明显，其中SCR6/7/8 TCR-T三者的杀伤效果接近，SCR9 TCR-T和SCR10 TCR-T的杀伤效果较SCR6/7/8 TCR-T更优，其中SCR10 TCR-T的杀伤效果为几种效应细胞中最优。上述结果表明，本发明信号转换受体SCR6-10在低效靶比条件下仍然能够显著提升效应T细胞对肿瘤靶细胞的杀伤水平，并且这种提升效果在杀伤时间较长时仍然存在。Test the in vitro killing activity of TCR-T, SCR6 TCR-T, SCR7 TCR-T, SCR8 TCR-T, SCR9 TCR-T and SCR10 TCR-T on A375 cells prepared in Example 3, set according to the proportion of EGFP-positive cells The effective target ratio is 1.5:1, and the specific detection steps are the same as in Example 4. The result is shown in Figure 6. Soon after adding the effector cell time point (24h), SCR10 TCR-T has shown a significantly better target cell killing effect than TCR-T and SCR6/7/8/9 TCR-T. After the killing time reaches 90 hours, compared with TCR-T, SCR6-10 TCR-T has more effective killing effect on target cell A375. Among them, the killing effect of SCR6/7/8 TCR-T is close, and SCR9 TCR- The killing effect of T and SCR10 TCR-T is better than that of SCR6/7/8 TCR-T, and the killing effect of SCR10 TCR-T is the best among several effector cells. The above results indicate that the signal conversion receptor SCR6-10 of the present invention can still significantly increase the killing level of effector T cells to tumor target cells under the condition of low-efficiency target ratio, and this improvement effect still exists when the killing time is long.
实施例7表达TGF-β信号转换受体SCR10的TCR-T对靶细胞在低效靶比下的杀伤Example 7 Killing target cells by TCR-T expressing TGF-β signal conversion receptor SCR10 under low-efficiency target ratio 效果Effect
参照实施例4，选用A375作为靶细胞，选取TCR-T、SCR10 TCR-T和RIID2 TCR-T为效应细胞，将效靶比进一步降低至0.5﹕1，比较几种效应细胞对A375细胞的杀伤水平，操作同实施例4。0.5﹕1低效靶比长时间观察意在模拟体内真实环境下T细胞杀伤肿瘤的场景。Referring to Example 4, A375 was selected as target cells, TCR-T, SCR10 TCR-T and RIID2 TCR-T were selected as effector cells, and the effective target ratio was further reduced to 0.5:1, and the killing of A375 cells by several effector cells was compared. Level, the operation is the same as in Example 4. 0.5:1 Low-efficiency target ratio long-term observation is intended to simulate the scene of T cells killing tumors in the real environment in vivo.
结果如图7所示。图7显示，在80h后，RIID2 TCR-T的杀伤效果已表现出优于TCR-T，而SCR10 TCR-T的杀伤效果则显著优于前两者。在杀伤检测时长到140h后，RIID2 TCR-T的杀伤效果仍然优于TCR-T，而SCR10 TCR-T的杀伤效果已明显优于前两者。上述结果表明，即使在效靶比低至0.5﹕1和杀伤时间较长的条件下，本发明信号转换受体SCR10仍然能够有效提升效应T细胞对肿瘤靶细胞的杀伤水平。The result is shown in Figure 7. Figure 7 shows that after 80 hours, the killing effect of RIID2 TCR-T has been shown to be better than that of TCR-T, while the killing effect of SCR10 TCR-T is significantly better than the former two. After the killing detection time is 140h, the killing effect of RIID2 TCR-T is still better than that of TCR-T, while the killing effect of SCR10 TCR-T is significantly better than the former two. The above results indicate that even under the condition that the effect-to-target ratio is as low as 0.5:1 and the killing time is long, the signal conversion receptor SCR10 of the present invention can still effectively increase the killing level of effector T cells on tumor target cells.
实施例8表达TGF-β信号转换受体SCR11-15的TCR-T对靶细胞的杀伤效果Example 8 Killing effect of TCR-T expressing TGF-β signal conversion receptor SCR11-15 on target cells
检测实施例3制备得到的TCR-T、SCR11-15 TCR-T对A375细胞的体外杀伤活性，按EGFP阳性细胞占比设置效靶比为1.5﹕1，具体检测步骤同实施例4。结果如图8所示。在刚加入效应细胞时间点(24h)后不久，SCR11/12/14/15 TCR-T即已显示出明显优于TCR-T的靶细胞杀伤效果。杀伤时间到90h后，SCR11-15 TCR-T与TCR-T相比，对靶细胞A375的杀伤效果均更加明显，其中SCR11/12 TCR-T的杀伤效果接近，优于SCR13 TCR-T；SCR14/15 TCR-T的杀伤效果较SCR11/12 TCR-T更优，SCR15 TCR-T的杀伤效果为几种效应细胞中最优。上述结果表明，本发明信号转换受体SCR11-15在较低效靶比条件下仍然能够显著提升效应T细胞对肿瘤靶细胞的杀伤水平，并且这种提升效果在杀伤时间较长时仍然存在。The TCR-T and SCR11-15 TCR-T prepared in Example 3 were tested for their in vitro killing activity on A375 cells, and the effective target ratio was set to 1.5:1 based on the proportion of EGFP-positive cells. The specific detection steps were the same as in Example 4. The result is shown in Figure 8. Soon after adding the effector cells (24h), SCR11/12/14/15 TCR-T has shown a significantly better target cell killing effect than TCR-T. After the killing time reaches 90 hours, compared with TCR-T, SCR11-15 TCR-T has more obvious killing effect on target cell A375. Among them, the killing effect of SCR11/12 TCR-T is close to that of SCR13 TCR-T; SCR14 /15 The killing effect of TCR-T is better than that of SCR11/12 TCR-T, and the killing effect of SCR15 TCR-T is the best among several effector cells. The above results indicate that the signal conversion receptor SCR11-15 of the present invention can still significantly increase the killing level of effector T cells to tumor target cells under the condition of lower effective target ratio, and this improvement effect still exists when the killing time is long.
实施例9表达TGF-β信号转换受体SCR15的TCR-T对靶细胞在低效靶比下的杀伤Example 9 Killing target cells by TCR-T expressing TGF-β signal conversion receptor SCR15 under low-efficiency target ratio 效果Effect
参照实施例4，选用A375作为靶细胞，选取TCR-T、SCR15 TCR-T和RIID4 TCR-T为效应细胞，将效靶比进一步降低至0.75﹕1，比较几种效应细胞对A375细胞的杀伤水平，操作同实施例4。0.75﹕1低效靶比长时间观察意在模拟体内真实环境下T细胞杀伤肿瘤的场景。Referring to Example 4, A375 was selected as target cells, TCR-T, SCR15 TCR-T and RIID4 TCR-T were selected as effector cells, and the effective target ratio was further reduced to 0.75:1, and the killing of A375 cells by several effector cells was compared. Level, the operation is the same as in Example 4. 0.75:1 low-efficiency target ratio long-term observation is intended to simulate the scene of T cells killing tumors in the real environment in vivo.
结果如图9所示。图9显示，在加入效应细胞后不久，RIID4 TCR-T的杀伤效果已表现出优于TCR-T，而从60h前开始SCR15 TCR-T的杀伤效果开始显著优于前两者。在杀伤检测时长到100h后，RIID4 TCR-T的杀伤效果仍然优于TCR-T，而SCR15 TCR-T的杀伤效果已明显优于前两者。上述结果表明，即使在效靶比低至0.75﹕1和杀伤时间较长的条件下，本发明信号转换受体SCR15仍然能够有效提升效应T细胞对肿瘤靶细胞的杀伤水平。The result is shown in Figure 9. Figure 9 shows that shortly after the addition of effector cells, the killing effect of RIID4 TCR-T has been shown to be better than that of TCR-T, and the killing effect of SCR15 TCR-T was significantly better than the former two starting from 60 hours ago. After the killing detection time reaches 100 hours, the killing effect of RIID4 TCR-T is still better than that of TCR-T, while the killing effect of SCR15 TCR-T is significantly better than the former two. The above results indicate that even under the conditions that the effect-to-target ratio is as low as 0.75:1 and the killing time is long, the signal conversion receptor SCR15 of the present invention can still effectively increase the killing level of effector T cells on tumor target cells.
实施例10：TGF-β信号转换受体提升TCR-T的细胞因子的分泌水平Example 10: TGF-β signal conversion receptor enhances TCR-T cytokine secretion level
向实施例3制得的TCR-T和SCR1-5 TCRT细胞培养体系中加入TGF-β1因子(购自R&D SYSTEMS货号：240-B-002/CF)至终浓度为2.0ng/mL，每组细胞设置3个平行样品孔，另外设置一组TCR-T不用TGF-β1因子处理。处理24小时后，用HTRF IFN-γ检测试剂盒(Cisbio Human IFN gamma kit货号：62HIFNGPET)根据说明书记载的方法检测IFN-γ分泌水平。结果如图10所示。Add TGF-β1 factor (purchased from R&D SYSTEMS catalog number: 240-B-002/CF) to the TCR-T and SCR1-5 TCRT cell culture system prepared in Example 3 to a final concentration of 2.0ng/mL, each group Three parallel sample holes are set for the cells, and another set of TCR-T is not treated with TGF-β1 factor. After 24 hours of treatment, use the HTRF IFN-γ detection kit (Cisbio Human IFN gamma kit item number: 62HIFNGPET) to detect the IFN-γ secretion level according to the method described in the manual. The result is shown in Figure 10.
图10显示，与未经TGF-β1处理的TCR-T组相比，经过TGF-β1处理的TCR-T组IFN-γ的分泌水平明显降低，表明在T细胞表面天然存在的TGF-β受体在结合TGF-β1因子后对T细胞的激活产生了抑制效果。SCR1-5 TCR-T经过TGF-β1因子处理后，IFN-γ的分泌水平无论与经过TGF-β1处理的TCR-T组相比还是与未经TGF-β1处理的TCR-T组相比都有了明显的提升。这表明免疫效应细胞，如TCR-T细胞在导入本发明的信号转换受体后，在结合相应的配体如TGF-β1因子时能够有效提升T细胞的活化水平，并且这种提升效果能够抵消并反超相应的配体如TGF-β1结合到细胞自身表面天然的抑制性受体后对细胞产生的抑制效果。Figure 10 shows that compared with the TCR-T group not treated with TGF-β1, the secretion level of IFN-γ in the TCR-T group treated with TGF-β1 was significantly reduced, indicating that the naturally occurring TGF-β receptor on the surface of T cells The body has an inhibitory effect on T cell activation after binding to the TGF-β1 factor. After SCR1-5 TCR-T is treated with TGF-β1 factor, the secretion level of IFN-γ is no matter compared with the TCR-T group treated with TGF-β1 or compared with the TCR-T group without TGF-β1 treatment. There has been a significant improvement. This indicates that immune effector cells, such as TCR-T cells, can effectively increase the activation level of T cells when they bind to the corresponding ligands such as TGF-β1 factor after introducing the signal conversion receptor of the present invention, and this effect can be offset. And overtake the corresponding ligand such as TGF-β1 binding to the natural inhibitory receptor on the surface of the cell itself, the inhibitory effect on the cell.
实施例11：TGF-β信号转换受体提升TCR-T的体内肿瘤抑制水平Example 11: TGF-β signal conversion receptor enhances the tumor suppressor level of TCR-T in vivo
在免疫缺陷小鼠模型中检测TCR-T、RIID2 TCR-T、RIID4 TCR-T和SCR5 TCR-T对肿瘤细胞系A375小鼠体内成瘤后的肿瘤生长的抑制效果。选用免疫缺陷小鼠NSG(购自The Jackson Laboratory)进行A375细胞系体内成瘤。NSG小鼠在接种肿瘤细胞前在标准SPF动物房中饲养两周适应环境，提供12h昼夜节律交替控制，环境温度为20-24℃，湿度为45-65％。A375细胞在DMEM培养基和10％胎牛血清中培养至80-90％汇合度后进行细胞计数和计算成活率，对每只小鼠异氟烷麻醉后左侧皮下注射100μL含有1×10 7A375活细胞的PBS细胞悬液以减少小鼠的疼痛感至最小程度。小鼠成瘤后将荷瘤小鼠进行随机分组，总计分为5组，n＝6，分为对照组(A375)、TCR-T组、RIID2组、RIID4组和SCR5组。使用实施例3制备的细胞进行回输。给药细胞过70μm筛后，用PBS重悬。根据表8中记录的EGFP阳性率，TCR-T为44.22％，是RIID2 TCR-T、RIID4 TCR-T和SCR5 TCR-T中EGFP阳性细胞比例的均大约2倍，TCR-T组的细胞给药量为1×10 7细胞重悬于200μL PBS，RIID2 TCR-T、RIID4 TCR-T和SCR5 TCR-T组的细胞给药量均为2×10 7细胞，重悬于200μL PBS；对照组每只给予200μL PBS。在D0、D1和D2三个时间点分别通过尾静脉注射给药。观察小鼠的肿瘤大小随时间变化趋势。 In the immunodeficiency mouse model, the inhibitory effects of TCR-T, RIID2 TCR-T, RIID4 TCR-T and SCR5 TCR-T on tumor growth in mice with tumor cell line A375 were tested. The immunodeficiency mouse NSG (purchased from The Jackson Laboratory) was used for tumor formation in the A375 cell line. Before inoculating tumor cells, NSG mice were reared in a standard SPF animal room for two weeks to adapt to the environment, providing 12h circadian rhythm alternate control, with an ambient temperature of 20-24°C and a humidity of 45-65%. After A375 cells were cultured in DMEM medium and 10% fetal bovine serum to 80-90% confluence, the cell count and survival rate were calculated. After anesthesia with isoflurane, each mouse was subcutaneously injected with 100μL on the left side containing 1×10 7 A PBS cell suspension of live A375 cells to minimize pain in mice. After tumor formation, the tumor-bearing mice were randomly divided into 5 groups, n=6, divided into control group (A375), TCR-T group, RIID2 group, RIID4 group and SCR5 group. The cells prepared in Example 3 were used for reinfusion. After the administered cells passed through a 70μm sieve, they were resuspended in PBS. According to the EGFP positive rate recorded in Table 8, TCR-T was 44.22%, which was about 2 times the proportion of EGFP positive cells in RIID2 TCR-T, RIID4 TCR-T and SCR5 TCR-T. The cells in the TCR-T group gave The dose of 1×10 7 cells was resuspended in 200 μL PBS, and the dose of cells in the RIID2 TCR-T, RIID4 TCR-T and SCR5 TCR-T groups was 2×10 7 cells, resuspended in 200 μL PBS; the control group Each was given 200μL PBS. The drug was administered via tail vein injection at the three time points D0, D1 and D2. Observe the trend of tumor size in mice over time.
结果如图11所示。与未进行细胞回输的对照组相比，TCR-T组荷瘤小鼠的肿瘤增殖变慢，RIID2组与RIID4组的肿瘤增殖与TCR-T相比进一步受到抑制，并且RIID4组的肿瘤增殖略慢于RIID2组。SCR5组的肿瘤增殖受到的抑制在几组小鼠中最为明显，肿瘤增殖速率较RIID2组和RIID4组进一步被抑制。以上结果表明，表达本发明TGF-β信号转换受体SCR5的免疫效应细胞，如TCR-T，在体内能够具有显著提升的对肿瘤增殖的 抑制效果。The result is shown in Figure 11. Compared with the control group without cell reinfusion, the tumor proliferation of the tumor-bearing mice in the TCR-T group became slower, the tumor proliferation of the RIID2 group and the RIID4 group was further inhibited compared with TCR-T, and the tumor proliferation of the RIID4 group Slightly slower than the RIID2 group. The inhibition of tumor proliferation in the SCR5 group was the most obvious among several groups of mice, and the tumor proliferation rate was further inhibited compared with the RIID2 and RIID4 groups. The above results indicate that immune effector cells expressing the TGF-β signal conversion receptor SCR5 of the present invention, such as TCR-T, can have a significantly enhanced inhibitory effect on tumor proliferation in vivo.
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员应理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。Although the specific embodiments of the present invention have been described in detail, those skilled in the art should understand. According to all the teachings that have been disclosed, various modifications and substitutions can be made to those details, and these changes are all within the protection scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (14)

  1. 一种分离的融合蛋白，包含：An isolated fusion protein containing:
    免疫抑制细胞因子的受体的胞外结构域或其保留了特异性结合免疫抑制细胞因子的功能片段或突变体；The extracellular domain of the receptor of immunosuppressive cytokine or its functional fragment or mutant that retains specific binding to immunosuppressive cytokine;
    跨膜区或其突变体；和Transmembrane region or its mutants; and
    共刺激信号分子的胞内结构域或其保留了共刺激信号分子传递共刺激信号、活化免疫细胞的生物学功能的功能片段或突变体。The intracellular domain of costimulatory signal molecules or functional fragments or mutants thereof that retain the biological functions of costimulatory signal molecules to transmit costimulatory signals and activate immune cells.
  2. 如权利要求1所述的融合蛋白，其特征在于，所述免疫抑制细胞因子包括肿瘤细胞或肿瘤基质细胞膜蛋白和肿瘤细胞或肿瘤基质细胞分泌型蛋白。The fusion protein of claim 1, wherein the immunosuppressive cytokine comprises a tumor cell or tumor stromal cell membrane protein and a tumor cell or tumor stromal cell secreted protein.
  3. 如权利要求2所述的融合蛋白，其特征在于，The fusion protein of claim 2, wherein:
    所述肿瘤细胞或肿瘤基质细胞膜蛋白包括PD-L1/PD-L2、FasL、B7-H4、Crry和HLA-G；The tumor cell or tumor stromal cell membrane protein includes PD-L1/PD-L2, FasL, B7-H4, Crry and HLA-G;
    所述肿瘤细胞或肿瘤基质细胞分泌型蛋白包括IL-13、IL-4、TGF-β、IL-6、IL-8、IL-10、CCL21、IDO和VEGF。The tumor cell or tumor stromal cell secreted protein includes IL-13, IL-4, TGF-β, IL-6, IL-8, IL-10, CCL21, IDO and VEGF.
  4. 如权利要求3所述的融合蛋白，其特征在于，所述TGF-β的受体包括TGF-β受体1、TGF-β受体2和TGF-β受体3，优选TGF-β受体1和TGF-β受体2。The fusion protein of claim 3, wherein the receptors of TGF-β include TGF-β receptor 1, TGF-β receptor 2 and TGF-β receptor 3, preferably TGF-β receptor 1 and TGF-β receptor 2.
  5. 如权利要求1-4中任一项所述的融合蛋白，其特征在于，所述共刺激信号分子包括CD28、CD134(OX40)、CD137(4-1BB)、LCK、ICOS、DAP10、siglec-9、siglec-10、siglec-15、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、IL-R2、IL-4R、IL-7R、IL-10R、IL-12R、IL-15R、IL-21R、CD27和CD40中的一种或多种。The fusion protein of any one of claims 1-4, wherein the costimulatory signal molecule comprises CD28, CD134 (OX40), CD137 (4-1BB), LCK, ICOS, DAP10, siglec-9 , Siglec-10, siglec-15, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, IL-R2, IL-4R, IL-7R, IL-10R, IL-12R, IL-15R , IL-21R, CD27 and CD40 one or more.
  6. 如权利要求1-5中任一项所述的融合蛋白，其特征在于，所述跨膜区包括来自CD28、CD8、CD134(OX40)、CD137(4-1BB)、LCK、ICOS、DAP10、siglec-9、siglec-10、siglec-15、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、IL-2Rbeta、IL-2Rgamma、IL-4Ralpha、IL-7Ralpha、IL-10R、IL-12R、IL-15R、IL-21R、CD27和CD40的跨膜区中的任一种或多种。The fusion protein according to any one of claims 1 to 5, wherein the transmembrane region includes CD28, CD8, CD134 (OX40), CD137 (4-1BB), LCK, ICOS, DAP10, siglec -9, siglec-10, siglec-15, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, IL-2Rbeta, IL-2Rgamma, IL-4Ralpha, IL-7Ralpha, IL-10R, IL Any one or more of the transmembrane regions of -12R, IL-15R, IL-21R, CD27 and CD40.
  7. 如权利要求6所述的融合蛋白，其特征在于，所述跨膜区来自IL-7Ralpha跨膜区或其突变体；The fusion protein of claim 6, wherein the transmembrane region is derived from the IL-7Ralpha transmembrane region or a mutant thereof;
    优选地，所述IL-7Ralpha跨膜区的氨基酸序列如SEQ ID NO:27所示；更优选地，所述IL-7Ralpha跨膜区的编码序列如SEQ ID NO:28所示；Preferably, the amino acid sequence of the transmembrane region of IL-7Ralpha is shown in SEQ ID NO: 27; more preferably, the coding sequence of the transmembrane region of IL-7Ralpha is shown in SEQ ID NO: 28;
    优选地，所述IL-7Ralpha跨膜区的突变体的氨基酸序列如SEQ ID NO:29-60中任一 所示；更优选地，所述IL-7Ralpha跨膜区的突变体的编码序列如SEQ ID NO:61-94中任一所示。Preferably, the amino acid sequence of the IL-7Ralpha transmembrane region mutant is as shown in any of SEQ ID NO: 29-60; more preferably, the coding sequence of the IL-7Ralpha transmembrane region mutant is as SEQ ID NO: any one of 61-94.
  8. 如权利要求7所述的融合蛋白，其特征在于，所述融合蛋白的胞外区为TGF-β受体1的胞外区，所述融合蛋白的共刺激分子的胞内结构域为选自IL-7Ralpha胞内区、CD28胞内区串联4-1BB胞内区、CD28胞内区、4-1BB胞内区、CD28胞内区串联OX40胞内区、28-IL2RB-z(YXXQ)胞内区、28-DeltaIL2RB-z(YXXQ)胞内区、IL2RB-z(YXXQ)胞内区和DeltaIL2RB-z(YXXQ)胞内区中的任一种；优选地，所述融合蛋白的氨基酸序列为SEQ ID NO:95-350中任一所示。The fusion protein of claim 7, wherein the extracellular domain of the fusion protein is the extracellular domain of TGF-β receptor 1, and the intracellular domain of the costimulatory molecule of the fusion protein is selected from IL-7Ralpha intracellular region, CD28 intracellular region series 4-1BB intracellular region, CD28 intracellular region, 4-1BB intracellular region, CD28 intracellular region series OX40 intracellular region, 28-IL2RB-z(YXXQ) cell Intracellular region, 28-DeltaIL2RB-z (YXXQ) intracellular region, IL2RB-z (YXXQ) intracellular region and DeltaIL2RB-z (YXXQ) intracellular region; preferably, the amino acid sequence of the fusion protein It is shown in any one of SEQ ID NO: 95-350.
  9. 如权利要求7所述的融合蛋白，其特征在于，所述融合蛋白的胞外区为TGF-β受体2的胞外区，所述融合蛋白的共刺激分子的胞内结构域为选自IL-7Ralpha胞内区、CD28胞内区串联4-1BB胞内区、CD28胞内区、4-1BB胞内区、CD28胞内区串联OX40胞内区、28-IL2RB-z(YXXQ)胞内区、28-DeltaIL2RB-z(YXXQ)胞内区、IL2RB-z(YXXQ)胞内区和DeltaIL2RB-z(YXXQ)胞内区中的任一种；优选地，所述融合蛋白的氨基酸序列为SEQ ID NO:351-606、SEQ ID NO:1647、SEQ ID NO:1649、SEQ ID NO:1651、SEQ ID NO:1653、SEQ ID NO:1655、SEQ ID NO:1657、SEQ ID NO:1659、SEQ ID NO:1661、SEQ ID NO:1663、SEQ ID NO:1665、SEQ ID NO:1667、SEQ ID NO:1669、SEQ ID NO:1671、SEQ ID NO:1673和SEQ ID NO:1675中任一所示。The fusion protein of claim 7, wherein the extracellular domain of the fusion protein is the extracellular domain of TGF-β receptor 2, and the intracellular domain of the costimulatory molecule of the fusion protein is selected from IL-7Ralpha intracellular region, CD28 intracellular region series 4-1BB intracellular region, CD28 intracellular region, 4-1BB intracellular region, CD28 intracellular region series OX40 intracellular region, 28-IL2RB-z(YXXQ) cell Intracellular region, 28-DeltaIL2RB-z (YXXQ) intracellular region, IL2RB-z (YXXQ) intracellular region and DeltaIL2RB-z (YXXQ) intracellular region; preferably, the amino acid sequence of the fusion protein It is SEQ ID NO: 351-606, SEQ ID NO: 1647, SEQ ID NO: 1649, SEQ ID NO: 1651, SEQ ID NO: 1653, SEQ ID NO: 1655, SEQ ID NO: 1657, SEQ ID NO: 1659 , SEQ ID NO: 1661, SEQ ID NO: 1663, SEQ ID NO: 1665, SEQ ID NO: 1667, SEQ ID NO: 1669, SEQ ID NO: 1671, SEQ ID NO: 1673, and SEQ ID NO: 1675 One shown.
  10. 如权利要求7所述的融合蛋白，其特征在于，所述融合蛋白的胞外区为TGF-β受体3的胞外区，所述融合蛋白的共刺激分子的胞内结构域为选自IL-7Ralpha胞内区、CD28胞内区串联4-1BB胞内区、CD28胞内区、4-1BB胞内区、CD28胞内区串联OX40胞内区、28-IL2RB-z(YXXQ)胞内区、28-DeltaIL2RB-z(YXXQ)胞内区、IL2RB-z(YXXQ)胞内区和DeltaIL2RB-z(YXXQ)胞内区中的任一种；优选地，所述融合蛋白的氨基酸序列为SEQ ID NO:607-862中任一所示。The fusion protein of claim 7, wherein the extracellular region of the fusion protein is the extracellular region of TGF-β receptor 3, and the intracellular domain of the costimulatory molecule of the fusion protein is selected from IL-7Ralpha intracellular region, CD28 intracellular region series 4-1BB intracellular region, CD28 intracellular region, 4-1BB intracellular region, CD28 intracellular region series OX40 intracellular region, 28-IL2RB-z(YXXQ) cell Intracellular region, 28-DeltaIL2RB-z (YXXQ) intracellular region, IL2RB-z (YXXQ) intracellular region and DeltaIL2RB-z (YXXQ) intracellular region; preferably, the amino acid sequence of the fusion protein It is shown in any one of SEQ ID NO: 607-862.
  11. 一种多核苷酸分子，选自：A polynucleotide molecule selected from:
    (1)编码权利要求1-10中任一项所述的融合蛋白的多核苷酸分子；和(1) A polynucleotide molecule encoding the fusion protein of any one of claims 1-10; and
    (2)(1)所述多核苷酸分子的互补序列；(2) The complementary sequence of the polynucleotide molecule described in (1);
    优选地，所述多核苷酸分子包括选自SEQ ID NO:863-1630、SEQ ID NO:1648、SEQ ID NO:1650、SEQ ID NO:1652、SEQ ID NO:1654、SEQ ID NO:1656、SEQ ID NO:1658、SEQ ID NO:1660、SEQ ID NO:1662、SEQ ID NO:1664、SEQ ID NO:1666、SEQ ID NO:1668、SEQ ID NO:1670、SEQ ID NO:1672、SEQ ID NO:1674和SEQ ID NO:1676中任一所示，或者为任一所示多核苷酸分子的互补序列。Preferably, the polynucleotide molecule is selected from SEQ ID NO: 863-1630, SEQ ID NO: 1648, SEQ ID NO: 1650, SEQ ID NO: 1652, SEQ ID NO: 1654, SEQ ID NO: 1656, SEQ ID NO: 1658, SEQ ID NO: 1660, SEQ ID NO: 1662, SEQ ID NO: 1664, SEQ ID NO: 1666, SEQ ID NO: 1668, SEQ ID NO: 1670, SEQ ID NO: 1672, SEQ ID No. 1674 and SEQ ID NO: 1676 are shown in any one of them, or the complementary sequence of any of the shown polynucleotide molecules.
  12. 核酸构建体，含有权利要求11所述的多核苷酸分子；优选地，所述核酸构建体 为载体，更优选为表达载体。The nucleic acid construct contains the polynucleotide molecule of claim 11; preferably, the nucleic acid construct is a vector, more preferably an expression vector.
  13. 基因工程化的细胞，其表达权利要求1-10中任一项所述的融合蛋白，和/或携带所述融合蛋白的编码序列；A genetically engineered cell that expresses the fusion protein of any one of claims 1-10, and/or carries the coding sequence of the fusion protein;
    优选地，所述细胞为免疫细胞；更优选地，为T细胞；Preferably, the cell is an immune cell; more preferably, it is a T cell;
    优选地，所述细胞还表达CAR，或携带CAR的编码序列；Preferably, the cell also expresses CAR, or carries the coding sequence of CAR;
    优选地，所述细胞还表达外源TCR，或携带外源TCR的编码序列。Preferably, the cell also expresses an exogenous TCR, or carries a coding sequence of an exogenous TCR.
  14. 权利要求1-10中任一项所述的融合蛋白、权利要求11所述的多核苷酸分子、权利要求12所述的核酸构建体以及权利要求13所述的基因工程化细胞在制备治疗或预防癌症用的药物中的用途。The fusion protein of any one of claims 1-10, the polynucleotide molecule of claim 11, the nucleic acid construct of claim 12, and the genetically engineered cell of claim 13 are used in the preparation of therapeutic or Use in medicines for cancer prevention.
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