CN115704010A - Engineered immune cells and uses thereof - Google Patents
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- CN115704010A CN115704010A CN202110917589.1A CN202110917589A CN115704010A CN 115704010 A CN115704010 A CN 115704010A CN 202110917589 A CN202110917589 A CN 202110917589A CN 115704010 A CN115704010 A CN 115704010A
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Abstract
The present invention relates to an engineered immune cell that expresses (i) a cell surface molecule that specifically recognizes an antigen, and (ii) exogenous CCL2. The invention also provides the use of the engineered immune cells in the treatment of cancer, infection or autoimmune disease. Compared with the traditional engineered immune cell, the engineered immune cell has obviously improved tumor killing activity.
Description
Technical Field
The present invention is in the field of immunotherapy. More specifically, the invention relates to an engineered immune cell that expresses a cell surface molecule that specifically recognizes an antigen and an exogenous CCL2 gene. More preferably, the cell surface molecule specifically recognizing an antigen is a chimeric antigen receptor.
Background
In recent years, adoptive cell therapy, an emerging immunotherapy, has shown great advantages in the field of tumor therapy. Such therapies typically require that cells be first engineered, for example by gene editing and/or transduction techniques, to carry exogenous proteins such as chimeric antigen receptors, recombinant T cell receptors, etc., and then expanded in vitro and returned to the patient. Currently, these therapies have shown good efficacy against hematological tumors, but their efficacy has not been satisfactory for solid tumors, one of the reasons being the inability to effectively transport the engineered cells to the tumor site (i.e., the immunosuppressive tumor microenvironment).
Lymphocytes are generally directed to home to a target site by sensing chemokines secreted by other cells through chemokine receptors. Although the number of chemokines and their receptors is large, generally only a limited number of chemokine receptors are expressed per lymphocyte. Thus, when certain tumor cells secrete a chemokine in large amounts and lymphocytes (e.g., engineered CAR-T cells) do not express a receptor that is paired with the chemokine, the lymphocyte cannot be effectively transported to the tumor microenvironment, thereby affecting the therapeutic efficacy.
Thus, there remains a need for improved cell therapies to alter the immunosuppressive microenvironment, while recruiting other immune effector cells to the tumor site, enhancing the anti-tumor effect.
Disclosure of Invention
In a first aspect, the invention provides a novel engineered immune cell that expresses a cell surface molecule that specifically recognizes an antigen and exogenous CCL2.
In one embodiment, the engineered immune cells of the invention further express exogenous IL7.
In one embodiment, the cell surface molecule that specifically recognizes an antigen is a chimeric antigen receptor or a T cell receptor, preferably a chimeric antigen receptor.
In one embodiment, the cell surface molecule that specifically recognizes an antigen is a chimeric antigen receptor comprising an antigen binding region, a transmembrane domain, and an intracellular signaling domain comprising a co-stimulatory domain and/or a primary signaling domain. Wherein the antigen-antigen binding region may be selected from IgG, fab ', F (ab ') 2, fd ', fv, scFv, sdFv, linear antibody, single domain antibody, nanobody, diabody, anticalin and DARPIN. Preferably, the antigen-antigen binding region is selected from the group consisting of scFv, fab, single domain antibody and nanobody.
In one embodiment, the cell surface molecule that specifically recognizes an antigen binds to one or more targets selected from the group consisting of: <xnotran> CD2, CD3, CD4, CD5, CD7, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD30, CD33, CD37, CD38, CD40, CD40 3245 zxft 3245 44, CD46, CD47, CD52, CD54, CD56, CD70, CD73, CD80, CD97, CD123, CD126, CD138, CD171, CD 179a, DR4, DR5, TAC, TEM1/CD248, VEGF, GUCY2 3732 zxft 3732 40, EGP-2, EGP-4, CD133, IFNAR1, DLL3, kappa , TIM3, TSHR, CD19, BAFF-3963 zxft 3963-1, EGFRvIII, tEGFR, GD2, GD3, BCMA, tn , PSMA, ROR1, FLT3, FAP, TAG72, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, IL-llRa, IL-22Ra, IL-2, , PSCA, PRSS21, VEGFR2, lewisY, PDGFR- β, SSEA-4, AFP, folate α, erbB2 (Her 2/neu), erbB3, erbB4, MUC1, MUC16, EGFR, CS1, NCAM, claudin18.2, c-Met, prostase, PAP, ELF2M, ephrin B2, IGF-I , CAIX, LMP2, gpl00, bcr-abl, , ephA2, fucosyl GMl, sLe, GM3, TGS5, HMWMAA, o- -GD2, folate β, TEM7 4325 zxft 4325 6, GPRC5 3536 zxft 3536 61, ALK, , PLAC1, globoH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6 3926 zxft 3926 51E2, TARP, WT1, NY-ESO-1, LAGE-la, MAGE-A1, MAGE-A3, MAGE-A6, , HPV E6, E7, ETV6-AML, 17, XAGE1, tie 2, MAD-CT-1, MAD-CT-2, fos 1, p53, p53 , PSA, , PCTA-l/Galectin 8, melanA/MARTl, ras , hTERT, , ML-IAP, </xnotran> TMPRSS2 ETS fusion gene, NA17, PAX3, androgen receptor, progesterone receptor, cyclin Bl, MYCN, rhoC, TRP-2, CYP1B 1, BORIS, SART3, PAX5, OY-TES 1, LCK, AKAP-4, SSX2, RAGE-1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxylesterase, mut hsp70-2, CD79a, CD79B, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, IGLL1, PD1, PDL2, TGF β, APRIL, NKG2D, NKG D ligand, and/or a biotinylated molecule specific for antigen, biotinylated molecule, molecule expressed by HIV, HBV, HCV and/or other pathogens; and/or a neoepitope or neoantigen.
In one embodiment, the transmembrane domain is selected from the transmembrane domains of the following proteins: TCR α chain, TCR β chain, TCR γ chain, TCR δ chain, CD3 ζ subunit, CD3 ∈ subunit, CD3 γ subunit, CD3 δ subunit, CD45, CD4, CD5, CD8 α, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, and CD154. Preferably, the transmembrane domain is selected from the transmembrane domains of CD8 α, CD4, CD28 and CD 278.
In one embodiment, the primary signaling domain is an intracellular region of a protein selected from the group consisting of: fcR γ, fcR β, CD3 γ, CD3 δ, CD3 ∈, CD3 ζ, CD22, CD79a, CD79b, and CD66d. Preferably, the primary signaling domain comprises a CD3 ζ intracellular region.
In one embodiment, the co-stimulatory domain comprises one or more intracellular regions of a protein selected from the group consisting of: TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, CARD11, CD2, CD7, CD8, CD18, CD27, CD28, CD30, CD40, CD54, CD83, CD134 (OX 40), CD137 (4-1 BB), CD270 (HVEM), CD272 (BTLA), CD276 (B7-H3), CD278 (ICOS), CD357 (GITR), DAP10, DAP12, LAT, NKG2C, SLP, PD-1, LIGHT, TRIM, ZAP70 and combinations thereof. Preferably, the co-stimulatory domain is selected from the intracellular domains of CD27, CD28, CD134, CD137, DAP10, DAP12 or CD278 or a combination thereof.
In one embodiment, the immune cell is selected from a T cell, a macrophage, a dendritic cell, a monocyte, an NK cell, or an NKT cell. Preferably, the T cell is a CD4+ CD8+ T cell, a CD4+ helper T cell, a CD8+ T cell, a CD4-CD8-T cell, a tumor infiltrating cell, a memory T cell, a naive T cell, a gamma delta T cell or an alpha beta T cell.
In one embodiment, the expression or activity of exogenous CCL2 and/or IL7 is constitutive expression. In another embodiment, the expression or activity of exogenous CCL2 and/or IL7 is conditional expression. For example, conditional expression can be achieved by operably linking an exogenous gene to an inducible, repressible, or tissue-specific promoter.
In one embodiment, CCL2 and/or IL7 can be operably linked to a localization domain that can localize the expression of an exogenous gene of the invention to a specific cellular location, e.g., a cell membrane. In one embodiment, an exogenous gene of the invention, such as CCL2 and/or IL7, is operably linked to a transmembrane domain, thereby anchoring expression at the surface of an engineered immune cell.
In a second aspect, the invention provides a nucleic acid molecule comprising a nucleic acid sequence encoding a cell surface molecule specifically recognizing an antigen and a nucleic acid sequence encoding CCL2. In one embodiment, the nucleic acid molecule further comprises a nucleic acid sequence encoding IL7. Preferably, the cell surface molecule specifically recognizing an antigen is a chimeric antigen receptor or a T cell receptor, more preferably a chimeric antigen receptor. Preferably, the nucleic acid is DNA or RNA.
The invention also provides a vector comprising the nucleic acid molecule described above. In particular, the vector is selected from the group consisting of plasmids, retroviruses, lentiviruses, adenoviruses, vaccinia viruses, rous Sarcoma Viruses (RSV), polyoma viruses, and adeno-associated viruses (AAV). In some embodiments, the vector further comprises elements such as an origin of autonomous replication in an immune cell, a selectable marker, a restriction enzyme cleavage site, a promoter, a poly A tail (polyA), a 3'UTR, a 5' UTR, an enhancer, a terminator, an insulator, an operator, a selectable marker, a reporter gene, a targeting sequence, and/or a protein purification tag. In a specific embodiment, the vector is an in vitro transcription vector.
In one embodiment, the invention also provides a pharmaceutical composition comprising an engineered immune cell, nucleic acid molecule or vector of the invention, and one or more pharmaceutically acceptable excipients.
In a third aspect, the invention also provides a method of treating a subject having cancer, an infection or an autoimmune disease, comprising administering to the subject an effective amount of an immune cell, a nucleic acid molecule, a vector or a pharmaceutical composition according to the invention.
In one embodiment, the cancer is a solid tumor or a hematological tumor. More specifically, the cancer is selected from: brain glioma, blastoma, sarcoma, leukemia, basal cell carcinoma, cancer of the biliary tract, cancer of the bladder, bone, brain and CNS cancers, breast cancer, peritoneal cancer, cervical cancer, choriocarcinoma, colon and rectal cancer, cancer of connective tissue, cancer of the digestive system, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, gastric cancer, glioblastoma (GBM), liver cancer, hepatoma, intraepithelial tumors, kidney cancer, larynx cancer, liver tumor, lung cancer, lymphoma, melanoma, myeloma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, rectal cancer, cancer of the respiratory system, salivary gland carcinoma, skin cancer, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, uterine or endometrial cancer, ovarian cancer, pancreatic cancer, cancer of the bladder, cancer of the bone, cancer of the brain and CNS, cancer of the breast, peritoneum, cervical cancer, choriocarcinoma, hepatoma, intraepithelial tumors, lymphoma, melanoma, myeloma, neuroblastoma, and neuroblastoma malignant tumors of the urinary system, vulvar and other carcinomas and sarcomas, as well as B-cell lymphomas, B-lymphoblastic lymphomas (B-LBL), mantle cell lymphomas, AIDS-related lymphomas, and Waldenstrom's macroglobulinemia, chronic Lymphocytic Leukemia (CLL), acute Lymphocytic Leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia (T-ALL), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell tumors, burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic Myelogenous Leukemia (CML), malignant lymphoproliferative disorders, MALT lymphoma, hairy cell leukemia, marginal zone lymphoma, multiple myeloma, myelodysplasia, plasmacytic lymphoma, and marginal zone lymphoma, pre-leukemic, plasmacytoid dendritic cell tumors, and post-transplant lymphoproliferative disorders (PTLD).
In one embodiment, the infection includes, but is not limited to, infections caused by viruses, bacteria, fungi, and parasites.
In one embodiment, the autoimmune disease includes, but is not limited to, type I diabetes, celiac disease, graves 'disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, addison's disease, sjogren's syndrome, hashimoto's thyroiditis, myasthenia gravis, vasculitis, pernicious anemia, and systemic lupus erythematosus, among others.
Drawings
FIG. 1: CAR expression levels of CAR-T cells determined by flow cytometry.
FIG. 2: expression level of IL7 by CAR-T cells determined by ELISA.
FIG. 3: expression level of CCL2 of CAR-T cells determined by ELISA.
FIG. 4 is a schematic view of: IFN- γ release levels after co-culture of CAR-T cells with target and non-target cells, respectively.
FIG. 5: weight change profile of mice after treatment of mouse pancreatic cancer with CAR-T cells.
FIG. 6: tumor growth curves in mice after treatment of mouse pancreatic cancer with CAR-T cells.
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Cell surface molecules that specifically recognize antigens
In a first aspect, the invention provides a novel engineered immune cell expressing a cell surface molecule that specifically recognizes an antigen and exogenous CCL2.
As used herein, the term "cell surface molecule that specifically recognizes an antigen" refers to a molecule expressed on the surface of a cell that is capable of specifically binding to a target molecule (e.g., an antigen). Such surface molecules typically comprise an antigen-binding region capable of specifically binding to an antigen, a transmembrane domain that anchors the surface molecule to the cell surface, and an intracellular domain responsible for signaling. Examples of common such surface molecules include, for example, T cell receptors or chimeric antigen receptors.
As used herein, the term "T cell receptor" or "TCR" refers to a membrane protein complex that responds to antigen presentation and participates in T cell activation. Stimulation of TCRs is triggered by Major Histocompatibility Complex (MHC) molecules on antigen presenting cells that present antigenic peptides to T cells and bind to the TCR complex to induce a series of intracellular signaling. TCRs are composed of six peptide chains that form heterodimers, which are generally classified into α β type and γ δ type. Each peptide chain includes a constant region and a variable region, wherein the variable region is responsible for binding to specific antigens and MHC molecules. The variable region of the TCR may comprise or be operably linked to an antigen-binding region, wherein the antigen-binding region is defined as follows.
As used herein, the term "chimeric antigen receptor" or "CAR" refers to an artificially constructed hybrid polypeptide generally comprising an antigen binding region (e.g., an antigen-binding portion of an antibody), a transmembrane domain, and an intracellular signaling domain (comprising a costimulatory domain and/or a primary signaling domain), each linked by a linker. CARs are able to redirect the specificity and reactivity of T cells and other immune cells to a selected target in a non-MHC-restricted manner using the antigen binding properties of monoclonal antibodies. non-MHC-restricted antigen recognition gives CAR cells the ability to recognize antigens independent of antigen processing, thus bypassing the major mechanism of tumor escape. Furthermore, when expressed in T cells, the CAR advantageously does not dimerize with the alpha and beta chains of the endogenous T Cell Receptor (TCR).
As used herein, "antigen binding region" refers to any structure or functional variant thereof that can bind to an antigen. The antigen binding region can be an antibody structure including, but not limited to, monoclonal antibodies, polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, murine antibodies, chimeric antibodies and functional fragments thereof. For example, antigen binding regions include, but are not limited to, igG, fab ', F (ab ') 2, fd ', fv, scFv, sdFv, linear antibody, single domain antibody, nanobody, diabody, anticalin, DARPIN, and the like, preferably selected from Fab, scFv, sdAb, and nanobody. In the present invention, the antigen binding region may be monovalent or bivalent, and may be a monospecific, bispecific or multispecific antibody. In another embodiment, the antigen binding region may also be a specific binding polypeptide or receptor structure for a particular protein, such as PD1, PDL2, TGF β, APRIL and NKG2D.
The term "functional variant" or "functional fragment" refers to a variant that substantially comprises the amino acid sequence of a parent, but contains at least one amino acid modification (i.e., substitution, deletion, or insertion) as compared to the parent amino acid sequence, provided that the variant retains the biological activity of the parent amino acid sequence. In one embodiment, the amino acid modification is preferably a conservative modification.
As used herein, the term "conservative modification" refers to an amino acid modification that does not significantly affect or alter the binding characteristics of an antibody or antibody fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into the chimeric antigen receptors of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are those in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β -branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine tryptophan, histidine). Conservative modifications may be selected, for example, based on similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved.
Thus, a "functional variant" or "functional fragment" has at least 75%, preferably at least 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to a parent amino acid sequence and retains the biological activity, e.g., binding activity, of the parent amino acid.
As used herein, the term "sequence identity" refers to the degree to which two (nucleotide or amino acid) sequences have the same residue at the same position in an alignment, and is typically expressed as a percentage. Preferably, identity is determined over the entire length of the sequences being compared. Thus, two copies of an identical sequence have 100% identity. One skilled in the art will recognize that several algorithms can be used to determine sequence identity using standard parameters, such as Blast (Altschul et al (1997) Nucleic Acids Res.25: 3389-3402), blast2 (Altschul et al (1990) J.mol.biol.215: 403-410), smith-Waterman (Smith et al (1981) J.mol.biol.147: 195-197), and ClustalW.
The choice of antigen-binding region depends on the cell surface marker on the target cell to be identified that is associated with a particular disease state, e.g., a tumor-specific antigen or a tumor-associated antigen. Thus, in one embodiment, the antigen binding region of the invention binds to one or more targets selected from the group consisting of: <xnotran> CD2, CD3, CD4, CD5, CD7, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD30, CD33, CD37, CD38, CD40, CD40 3245 zxft 3245 44, CD46, CD47, CD52, CD54, CD56, CD70, CD73, CD80, CD97, CD123, CD126, CD138, CD171, CD 179a, DR4, DR5, TAC, TEM1/CD248, VEGF, GUCY2 3732 zxft 3732 40, EGP-2, EGP-4, CD133, IFNAR1, DLL3, kappa , TIM3, TSHR, CD19, BAFF-3963 zxft 3963-1, EGFRvIII, tEGFR, GD2, GD3, BCMA, tn , PSMA, ROR1, FLT3, FAP, TAG72, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, IL-llRa, IL-22Ra, IL-2, , PSCA, PRSS21, VEGFR2, lewisY, PDGFR- β, SSEA-4, AFP, folate α, erbB2 (Her 2/neu), erbB3, erbB4, MUC1, MUC16, EGFR, CS1, NCAM, claudin18.2, c-Met, prostase, PAP, ELF2M, ephrin B2, IGF-I , CAIX, LMP2, gpl00, bcr-abl, , ephA2, fucosyl GMl, sLe, GM3, TGS5, HMWMAA, o- -GD2, folate β, TEM7 4325 zxft 4325 6, GPRC5 3536 zxft 3536 61, ALK, , PLAC1, globoH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6 3926 zxft 3926 51E2, TARP, WT1, NY-ESO-1, LAGE-la, MAGE-A1, MAGE-A3, MAGE-A6, , HPV E6, E7, ETV6-AML, 17, XAGE1, tie 2, MAD-CT-1, MAD-CT-2, fos 1, p53, p53 , PSA, , PCTA-l/Galectin 8, melanA/MARTl, ras , hTERT, , ML-IAP, </xnotran> TMPRSS2 ETS fusion gene, NA17, PAX3, androgen receptor, progesterone receptor, cyclin Bl, MYCN, rhoC, TRP-2, CYP1B 1, BORIS, SART3, PAX5, OY-TES 1, LCK, AKAP-4, SSX2, RAGE-1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxylesterase, mut hsp70-2, CD79a, CD79B, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST, EMR2, LY75, GPC3, FCRL5, IGLL1, PD1, PDL2, TGF β, APRIL, NKG2D, NKG D ligand, and/or a biotinylated molecule specific for antigen, biotinylated molecule, molecule expressed by HIV, HBV, HCV and/or other pathogens; and/or a neoepitope or neoantigen. Depending on the antigen to be targeted, the CAR of the invention may be designed to include an antigen binding region specific for that antigen. Preferably, the target is selected from the group consisting of CD7, CD19, CD20, CD22, CD30, CD33, CD38, CD123, CD138, CD171, MUC1, AFP, folate receptor alpha, CEA, PSCA, PSMA, her2, EGFR, IL13Ra2, GD2, NKG2D, claudin18.2, ROR1, EGFRvIII, CS1, BCMA, GPRC5D, mesothelin, and any combination thereof. For example, if CD19 is the antigen to be targeted, CD19 antibodies may be used as the antigen binding region of the invention. In one embodiment, the antigen binding region is a CD19 targeting antibody having the same CDRs as the antibody set forth in SEQ ID NO. 1 or 2.
As used herein, the term "transmembrane domain" refers to a polypeptide structure that enables a chimeric antigen receptor to be expressed on the surface of an immune cell (e.g., a lymphocyte, NK cell, or NKT cell) and to direct the cellular response of the immune cell against a target cell. The transmembrane domain may be natural or synthetic, and may be derived from any membrane-bound or transmembrane protein. The transmembrane domain is capable of signaling when the chimeric antigen receptor binds to a target antigen. Transmembrane domains particularly suitable for use in the present invention may be derived from, for example, TCR α chain, TCR β chain, TCR γ chain, TCR δ chain, CD3 ζ subunit, CD3 epsilon subunit, CD3 γ subunit, CD3 δ subunit, CD45, CD4, CD5, CD8 α, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, CD154 and functional fragments thereof. Alternatively, the transmembrane domain may be synthetic and may contain predominantly hydrophobic residues such as leucine and valine. Preferably, the transmembrane domain is derived from CD28 having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO. 3; or from CD8 alpha, which has at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity with the amino acid sequence shown in SEQ ID NO. 4 or 5.
In one embodiment, the chimeric antigen receptor of the present invention may further comprise a hinge region located between the antigen binding region and the transmembrane domain. As used herein, the term "hinge region" generally refers to any oligopeptide or polypeptide that functions to connect a transmembrane domain to an antigen binding region. In particular, the hinge region serves to provide greater flexibility and accessibility to the antigen binding region. The hinge region may comprise up to 300 amino acids, preferably 10 to 100 amino acids and most preferably 25 to 50 amino acids. The hinge region may be derived in whole or in part from a native molecule, such as in whole or in part from the extracellular region of CD8, fc γ RIII α receptor, igG4, igG1, CD4 or CD28, or in whole or in part from an antibody constant region. Alternatively, the hinge region may be a synthetic sequence corresponding to a naturally occurring hinge sequence, or may be a fully synthetic hinge sequence. In preferred embodiments, the hinge region comprises a CD28 hinge having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 15; or comprises a CD8 a hinge having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity to the amino acid sequence as set forth in SEQ ID NO 16 or 17; or an IgG4 hinge having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity to the amino acid sequence depicted in SEQ ID NO 18.
As used herein, the term "intracellular signaling domain" refers to a portion of a protein that transduces effector function signals and directs a cell to a specified function, which comprises a costimulatory domain and/or a primary signaling domain. The intracellular signaling domain is responsible for intracellular signaling after the antigen binding region binds the antigen, resulting in activation of the immune cell and immune response. In other words, the intracellular signaling domain is responsible for activating at least one of the normal effector functions of the immune cell in which the CAR is expressed. For example, the effector function of a T cell may be cytolytic activity or helper activity, including secretion of cytokines.
In one embodiment, the chimeric antigen receptor of the invention comprises a primary signaling domain, which may be the cytoplasmic sequences of the T cell receptor and co-receptor that work together to trigger primary signaling after antigen receptor binding, as well as any derivatives or variants of these sequences and any synthetic sequences with the same or similar function. The primary signaling domain may comprise a number of Immunoreceptor Tyrosine-based Activation Motifs (ITAMs). Non-limiting examples of primary signaling domains of the invention include, but are not limited to, those derived from FcR γ, fcR β, CD3 γ, CD3 δ, CD3 ε, CD3 ζ, CD22, CD79a, CD79b, and CD66d. In a preferred embodiment, the primary signalling domain of a CAR of the invention may comprise a CD3 ζ intracellular region having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 9, 10 or 11.
In one embodiment, the chimeric antigen receptor of the present invention comprises one or more co-stimulatory domains. The co-stimulatory domain may be an intracellular functional signaling domain from a co-stimulatory molecule, which comprises the entire intracellular portion of the co-stimulatory molecule, or a functional fragment thereof. "costimulatory molecule" refers to a cognate binding partner that specifically binds to a costimulatory ligand on a T cell, thereby mediating a costimulatory response (e.g., proliferation) of the T cell. Costimulatory molecules include, but are not limited to, MHC class 1 molecules, BTLA, and Toll ligand receptors. Non-limiting examples of co-stimulatory domains of the invention include, but are not limited to, intracellular regions derived from: TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, CARD11, CD2, CD7, CD8, CD18, CD27, CD28, CD30, CD40, CD54, CD83, CD134 (OX 40), CD137 (4-1 BB), CD270 (HVEM), CD272 (BTLA), CD276 (B7-H3), CD278 (ICOS), CD357 (GITR), DAP10, DAP12, LAT, NKG2C, SLP, PD-1, LIGHT, TRIM and ZAP70. Preferably, the co-stimulatory domain of the CAR of the invention is from 4-1BB, CD28, CD27, OX40, ICOS, DAP10, DAP12 or a combination thereof. In one embodiment, the CAR of the invention comprises a CD28 co-stimulatory domain having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 6; and/or comprises a 4-1BB co-stimulatory domain having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity to the amino acid sequence depicted in SEQ ID NO 7 or 8.
In one embodiment, the CAR of the invention may further comprise a signal peptide such that when it is expressed in a cell, for example a T cell, the nascent protein is directed to the endoplasmic reticulum and subsequently to the cell surface. The core of the signal peptide may contain a long hydrophobic amino acid segment that has a tendency to form a single alpha-helix. At the end of the signal peptide there is usually a stretch of amino acids which is recognized and cleaved by the signal peptidase. The signal peptidase may cleave during translocation or after completion to produce a free signal peptide and a mature protein. The free signal peptide is then digested by a specific protease. Signal peptides useful in the present invention are well known to those skilled in the art, such as those derived from B2M, CD α, igG1, GM-CSFR α, and the like. In one embodiment, the signal peptide useful in the present invention is a B2M signal peptide having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO. 12; or a CD8 alpha signal peptide having at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO 13 or 14.
In one embodiment, the CAR of the invention may further comprise a switch structure to regulate the time of expression of the CAR. For example, the switch structure may be in the form of a dimerization domain that causes a conformational change upon binding to its corresponding ligand, exposing the extracellular binding domain to allow binding to the targeted antigen, thereby activating the signaling pathway. Alternatively, a switch domain may be used to connect the binding domain and the signaling domain, respectively, such that the binding domain and the signaling domain are connected together via a dimer only when the switch domains are bound to each other (e.g., in the presence of an inducing compound), thereby activating the signaling pathway. The switch structure may also be in the form of a masking peptide. The masking peptide can mask the extracellular binding domain from binding to the targeted antigen, and when the masking peptide is cleaved, e.g., by a protease, the extracellular binding domain can be exposed, rendering it a "normal" CAR structure. Various switch configurations known to those skilled in the art may be used with the present invention.
In one embodiment, the CAR of the invention may also comprise a suicide gene, i.e. such that it expresses a cell death signal that can be induced by foreign substances, to eliminate CAR cells when needed (e.g. when severe toxic side effects are produced). For example, the suicide gene may be in the form of an inserted epitope, such as a CD20 epitope, RQR8, etc., and when desired, the CAR cells can be eliminated by adding antibodies or agents that target these epitopes. The suicide gene may also be herpes simplex virus thymidine kinase (HSV-TK), which causes cell death induced by treatment with ganciclovir. The suicide gene can also be iCaspase-9, and the iCaspase-9 can be induced to dimerize by chemical induction drugs such as AP1903, AP20187 and the like, so that downstream Caspase3 molecules are activated, and apoptosis is caused. Various suicide genes known to those skilled in the art can be used in the present invention.
Exogenous gene
In addition to cell surface molecules that specifically recognize antigens, the engineered immune cells of the invention also express exogenous CCL2.
Chemotactic cytokines are divided into four subfamilies of CXC, CC, XC and CX3C according to the arrangement of cysteine at the amino terminal, and CCL2 is one of the members of the CC subfamily. CCL2 has chemotactic activity for monocytes and basophils and is one of the key chemokines that regulate monocyte/macrophage migration and infiltration. CCL2 plays an important role in the progression of a variety of diseases, such as cancer (e.g., breast, colorectal, prostate, melanoma, gastric, and ovarian cancer, etc.), bone remodeling and bone-related tumors, autoimmune diseases, neurological diseases, bacterial and viral infections.
In one embodiment, CCL2 used in the invention is substantially identical to SEQ ID NO:25 or 27, or the coding sequence of CCL2 has at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:24 or 26, has at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity.
In a preferred embodiment, the engineered immune cells of the invention further express IL7. In one embodiment, the IL7 used in the present invention is substantially identical to SEQ ID NO:21 or 23, or the coding sequence for IL7 has at least 70%, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:22 or 24, preferably at least 80%, more preferably at least 90%, 95%, 97% or 99% or 100% sequence identity.
The expression of exogenous genes in the present invention, such as CCL2 and/or IL7, may be constitutive expression or conditional expression.
In one embodiment, the expression of exogenous CCL2 and/or IL7 is a conditional expression. For example, the exogenous gene of the present invention may be operably linked to an inducible, repressible or tissue-specific promoter, as desired, to regulate the expression level of the introduced exogenous gene at a particular time or in a particular tissue, cell type. In one embodiment, the promoter is an inducible promoter, i.e., a promoter that initiates transcription only in the presence of a particular environmental condition, developmental condition, or inducer. Such environmental conditions include, for example, tumor acidic microenvironments, tumor hypoxic microenvironments, and the like. Such inducers include, for example, tetracycline or analogs thereof including, for example, chlortetracycline, oxytetracycline, demethylclocycline, methacycline, doxycycline and minocycline. Inducible promoters include, for example, lac operator sequences, tetracycline operator sequences, galactose operator sequences, or doxycycline operator sequences, among others. In another embodiment, the promoter is a repressible promoter, i.e., expression of the foreign gene in the cell is inhibited or not expressed in the presence of a repressor specific for the repressible promoter. Repressible promoters include, for example, lac repressible elements or tetracycline repressible elements. Inducible/repressible expression systems well known to those skilled in the art can be used in the present invention, including but not limited to the Tet-on system, tet-off system, cre/loxP system, and the like.
In one embodiment, CCL2 and/or IL7 may be operably linked to a localization domain that can localize the exogenous gene of the invention for expression at a specific cellular location, such as a cell membrane or the like. Localization domains include, but are not limited to, nuclear localization signals, leader peptides, transmembrane domains, and the like. In one embodiment, the exogenous genes CCL2 and/or IL7 of the invention are operably linked to a transmembrane domain, thereby anchoring expression at the surface of an engineered immune cell.
In one embodiment, the exogenous gene of the invention, e.g., CCL2 and/or IL7 protein, can be wild-type or a fusion protein or mutant with specific properties (e.g., resistance to proteolysis).
Nucleic acids and vectors
The invention also provides a nucleic acid molecule comprising a nucleic acid sequence encoding a cell surface molecule that specifically recognizes an antigen and a nucleic acid sequence encoding CCL2. In one embodiment, the nucleic acid molecule further comprises a nucleic acid sequence encoding IL7.
In one embodiment, the cell surface molecule specifically recognizing an antigen is a T cell receptor or a chimeric antigen receptor, preferably a chimeric antigen receptor. The definition of chimeric antigen receptor is as described above.
As used herein, the term "nucleic acid molecule" includes sequences of ribonucleotides and deoxyribonucleotides, such as modified or unmodified RNA or DNA, each in linear or circular form, in single-and/or double-stranded form, or mixtures thereof (including hybrid molecules). Thus, nucleic acids according to the invention include DNA (such as dsDNA, ssDNA, cDNA), RNA (such as dsRNA, ssRNA, mRNA, ivtRNA), combinations or derivatives thereof (such as PNA). Preferably, the nucleic acid is DNA or RNA, more preferably mRNA.
The invention also provides a vector comprising a nucleic acid according to the invention. Wherein the nucleic acid sequence encoding a cell surface molecule specifically recognizing an antigen, the nucleic acid sequence encoding CCL2 and optionally the nucleic acid sequence encoding IL7 may be located in one or more vectors.
As used herein, the term "vector" is a vector nucleic acid molecule used as a vehicle for transferring (foreign) genetic material into a host cell where it can, for example, be replicated and/or expressed.
Vectors generally include targeting vectors and expression vectors. A "targeting vector" is a medium through which an isolated nucleic acid is delivered to the interior of a cell, for example, by homologous recombination or by using a hybrid recombinase that targets sequences at specific sites. An "expression vector" is a vector for the transcription of heterologous nucleic acid sequences (such as those encoding the chimeric antigen receptor polypeptides of the invention) in a suitable host cell and the translation of their mRNA. Suitable carriers for use in the present invention are known in the art and many are commercially available. In one embodiment, the vectors of the invention include, but are not limited to, plasmids, viruses (e.g., retroviruses, lentiviruses, adenoviruses, vaccinia viruses, rous sarcoma viruses (RSV, polyoma viruses and adeno-associated viruses (AAV), etc.), bacteriophages, phagemids, cosmids, and artificial chromosomes (including BAC and YACs). The vectors themselves are typically nucleotide sequences, typically DNA sequences comprising inserts (transgenes) and larger sequences that serve as a "backbone" for the vector.
Engineered immune cells
The invention also provides an engineered immune cell comprising a nucleic acid or vector of the invention. In other words, the engineered immune cells of the invention express a cell surface molecule that specifically recognizes an antigen and an exogenous CCL2 gene, and optionally an exogenous IL7 gene.
As used herein, the term "immune cell" refers to any cell of the immune system that has one or more effector functions (e.g., cytotoxic cell killing activity, secretion of cytokines, induction of ADCC and/or CDC). For example, the immune cells may be T cells, macrophages, dendritic cells, monocytes, NK cells and/or NKT cells, or immune cells obtained from stem cell sources such as cellular umbilical cord blood. Preferably, the immune cell is a T cell. The T cell may be any T cell, such as an in vitro cultured T cell, e.g., a primary T cell, or a T cell from an in vitro cultured T cell line, e.g., jurkat, supT1, etc., or a T cell obtained from a subject. Examples of subjects include humans, dogs, cats, mice, rats, and transgenic species thereof. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumors. T cells may also be concentrated or purified. The T cells may be at any developmental stage, including, but not limited to, CD4+ CD8+ T cells, CD4+ helper T cells (e.g., th1 and Th2 cells), CD8+ T cells (e.g., cytotoxic T cells), CD4-CD8-T cells, tumor infiltrating cells, memory T cells, naive T cells, γ δ -T cells, α β -T cells, and the like. In a preferred embodiment, the immune cell is a human T cell. T cells can be obtained from the blood of a subject using a variety of techniques known to those skilled in the art, such as Ficoll isolation.
In one embodiment, the immune cell of the invention further comprises at least one inactivated gene selected from the group consisting of: CD52, GR, TCR alpha, TCR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD247 zeta, HLA-I, HLA-II, B2M, immune checkpoint genes such as PD1, CTLA-4, LAG3 and TIM3. More particularly, at least the TCR component (including TCR α, TCR β genes) or the CD3 component (including CD3 γ, CD3 δ, CD3 ε, CD247 ζ) in the immune cell is inactivated. This inactivation renders the TCR-CD3 complex non-functional in the cell. This strategy is particularly useful for avoiding graft versus host disease (GvHD). Methods of inactivating a gene are known in the art, for example, by mediating DNA cleavage by meganucleases, zinc finger nucleases, TALEN nucleases or Cas enzymes in CRISPR systems.
Pharmaceutical composition
The invention also provides a pharmaceutical composition comprising the engineered immune cell, nucleic acid molecule or vector of the invention as an active agent, and one or more pharmaceutically acceptable excipients. Thus, the invention also encompasses the use of said nucleic acid molecule, vector or engineered immune cell for the preparation of a pharmaceutical composition or medicament.
As used herein, the term "pharmaceutically acceptable excipient" refers to carriers and/or excipients that are pharmacologically and/or physiologically compatible with the subject and active ingredient (i.e., capable of eliciting a desired therapeutic effect without causing any undesirable local or systemic effects) and are well known in the art (see, e.g., remington's pharmaceutical sciences. Edited by Gennaro AR,19th ed. Pennsylvania mack Publishing company, 1995). Examples of pharmaceutically acceptable excipients include, but are not limited to, fillers, binders, disintegrants, coatings, adsorbents, anti-adherents, glidants, antioxidants, flavoring agents, colorants, sweeteners, solvents, co-solvents, buffers, chelating agents, surfactants, diluents, wetting agents, preservatives, emulsifiers, coating agents, isotonic agents, absorption delaying agents, stabilizers, and tonicity adjusting agents. The selection of suitable excipients to prepare the desired pharmaceutical compositions of the present invention is known to those skilled in the art. Exemplary excipients for use in the pharmaceutical compositions of the present invention include saline, buffered saline, dextrose, and water. In general, the choice of suitable excipients depends, inter alia, on the active agent used, the disease to be treated and the desired dosage form of the pharmaceutical composition.
The pharmaceutical composition according to the present invention may be suitable for administration by various routes. Typically, administration is accomplished parenterally. Methods of parenteral delivery include topical, intraarterial, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, intrauterine, intravaginal, sublingual or intranasal administration.
The pharmaceutical compositions according to the invention can also be prepared in various forms, such as solid, liquid, gaseous or lyophilized forms, in particular in the form of ointments, creams, transdermal patches, gels, powders, tablets, solutions, aerosols, granules, pills, suspensions, emulsions, capsules, syrups, elixirs, extracts, tinctures or extracts of fluid extracts, or in a form which is particularly suitable for the desired method of administration. Processes known in the art for the manufacture of medicaments may comprise, for example, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions comprising immune cells such as described herein are typically provided in solution form and preferably comprise a pharmaceutically acceptable buffer.
The pharmaceutical compositions according to the invention may also be administered in combination with one or more other agents suitable for the treatment and/or prevention of the diseases to be treated. Preferred examples of the pharmaceutical agents suitable for combination include known anticancer drugs such as cisplatin, maytansine derivatives, rebeccin (rachelmycin), calicheamicin (calicheamicin), docetaxel, etoposide, gemcitabine, ifosfamide, irinotecan, melphalan, mitoxantrone, sorfimer porphyrin sodium II (sorfimer sodium phosphate II), temozolomide, topotecan, glucuronic acid trimetrexate (trimetrenate glucoside), oritavastin E (auristatin E), vincristine and adriamycin; peptide cytotoxins such as ricin, diphtheria toxin, pseudomonas bacterial exotoxin A, DNA enzyme, and rnase; radionuclides such as iodine 131, rhenium 186, indium 111, iridium 90, bismuth 210 and 213, actinium 225, and astatine 213; prodrugs, such as antibody-directed enzyme prodrugs; immunostimulants such as platelet factor 4, melanoma growth stimulating protein, and the like; antibodies or fragments thereof, such as anti-CD 3 antibodies or fragments thereof, complement activators, heterologous protein domains, homologous protein domains, viral/bacterial protein domains, and viral/bacterial peptides. In addition, the pharmaceutical compositions of the present invention may also be used in combination with one or more other therapeutic methods, such as chemotherapy, radiation therapy.
Therapeutic applications
The invention also provides a method of treating a subject having cancer, an infection or an autoimmune disease, comprising administering to the subject an effective amount of an immune cell or a pharmaceutical composition according to the invention. Thus, the invention also encompasses the use of said engineered immune cells in the preparation of a medicament for the treatment of cancer, infection or autoimmune disease.
In one embodiment, the method of treatment comprises administering to a subject an effective amount of an immune cell and/or pharmaceutical composition of the invention.
In one embodiment, the immune cell is an autologous or allogeneic cell, preferably a T cell, macrophage, dendritic cell, monocyte, NK cell and/or NKT cell, more preferably a T cell, NK cell or NKT cell.
As used herein, the term "autologous" means that any material derived from an individual will be reintroduced into the same individual at a later time. As used herein, the term "allogeneic" refers to any material derived from a different animal or patient of the same species as the individual into which the material is introduced. When the genes at one or more loci are different, two or more individuals are considered allogeneic to each other. In some cases, genetic differences in allogenic material from individuals of the same species may be sufficient for antigen interactions to occur.
As used herein, the term "subject" is a mammal. The mammal may be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects representing animal models of cancer. Preferably, the subject is a human.
In one embodiment, the cancer is a cancer associated with expression of a target to which an antigen binding region binds. For example, the cancer includes, but is not limited to: <xnotran> , , , , , , , , CNS , , , , , , , , , , , , ( ), (GBM), , , , , , , ( , , ), ( ), , , , ( , , ), , , , , , , , , , , , , , , , , B ( / (NHL), (SL) NHL, / NHL, NHL, NHL, NHL, NHL, NHL), B (B-LBL), , AIDS , Waldenstrom , (CLL), </xnotran> Acute Lymphocytic Leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia (T-ALL), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell tumor, burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic Myelogenous Leukemia (CML), malignant lymphoproliferative disease, MALT lymphoma, hairy cell leukemia, marginal zone lymphoma, multiple myeloma, myelodysplasia, plasmacytic lymphoma, pre-leukemic, plasmacytoid dendritic cell tumor, and post-transplant lymphoproliferative disorder (PTLD); and other diseases associated with target expression. Preferably, the diseases that can be treated with the engineered immune cells or the pharmaceutical compositions of the invention are selected from: leukemia, lymphoma, multiple myeloma, brain glioma, pancreatic cancer, gastric cancer, and the like.
In one embodiment, the infection includes, but is not limited to, infections caused by viruses, bacteria, fungi, and parasites.
In one embodiment, the autoimmune disease includes, but is not limited to, type I diabetes, celiac disease, graves 'disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, addison's disease, sjogren's syndrome, hashimoto's thyroiditis, myasthenia gravis, vasculitis, pernicious anemia, and systemic lupus erythematosus, among others.
In one embodiment, the method further comprises administering to the subject one or more additional chemotherapeutic agents, biologies, drugs or treatments. In this embodiment, the chemotherapeutic agent, biological agent, drug or treatment is selected from the group consisting of radiation therapy, surgery, antibody agents and/or small molecules and any combination thereof.
The invention will be described in detail below with reference to the accompanying drawings and examples. It should be noted that the drawings and their embodiments of the present invention are for illustrative purposes only and are not to be construed as limiting the invention. The embodiments and features of the embodiments in the present application may be combined with each other without contradiction.
Detailed Description
Example 1 preparation of CAR-T cells
1.1 construction of retroviral plasmids
MSCV-mCD19-CAR plasmid was constructed comprising the coding sequences for CD19-scFv (SEQ ID NO: 2), CD8 a hinge region (SEQ ID NO: 17), CD8 a transmembrane region (SEQ ID NO: 5), 41BB costimulatory domain (SEQ ID NO: 7) and CD3 ζ intracellular region (SEQ ID NO: 11).
MSCV-mCD19-CAR-IL7 plasmid was constructed which further comprises the coding sequences for T2A (SEQ ID NO: 19) and IL7 (SEQ ID NO: 23) on the basis of the MSCV-mCD19-CAR plasmid.
MSCV-mCD19-CAR-CCL2 plasmid is constructed, which further comprises the coding sequence of T2A (SEQ ID NO: 19) and CCL2 (SEQ ID NO: 25) on the basis of MSCV-mCD19-CAR plasmid.
1.2. Preparation of retrovirus
In T175 flasks at 30X 10 6 Density of Individual cells/flask 293T cells were seeded in 30ml DMEM medium containing 10% foetal calf serum at 37 ℃ 5% 2 The cells were cultured overnight in an incubator for virus packaging.
To a sterile tube, 3ml of Opti-MEM (Gibco, cat # 31985-070), 45. Mu.g of the prepared retroviral plasmid and 15. Mu.g of the packaging vector pCL-Eco (Shanghai cereal noon Biotech Co., ltd., cat # P3029) were added. Then 120. Mu. l X-treme GENE HP DNA transfection reagent (Roche, cat # 06366236001) was added, mixed immediately and incubated at room temperature for 15min. The plasmid/vector/transfection reagent mixture was then added dropwise to a pre-prepared culture flask for 293T cells5% CO at 37 ℃ 2 Incubated under conditions overnight. The culture was collected 72 hours after transfection, and centrifuged (2000 g,4 ℃,10 minutes) to obtain a retrovirus supernatant.
1.3 preparation of CAR-T cells
T lymphocytes were isolated from mouse spleen and CTS with DynaBeads CD3/CD28 TM (Gibco, cat # 40203D) activates T cells, then CO at 37 ℃ and 5% 2 The culture was performed for 1 day.
At a rate of 3X 10 per hole 6 Density of individual cells/mL activated T cells were seeded into 24-well plates previously coated overnight with RetroNectin, then 500 μ L of retroviral supernatant was added and complete medium was supplemented to 2mL.
The 24-well plate was placed in a centrifuge for centrifugal infection and centrifuged at 2000g for 2h at 32 ℃. Then, the 24-well plate was immediately placed in a CO2 incubator at 37 ℃ for static culture. The next day, the fresh medium was changed and the cell density was adjusted to 1X 10 6 Individual cells/mL. Three days after infection, cells were collected for subsequent analysis. The collected cells are mCD19-CAR cells, mCD19-CAR + CCL2 cells and mCD19-CAR + IL7+ CCL2 cells.
Example 2 detection of expression of CAR-T cells
2.1 expression levels of cell surface CAR
2X 10 of the product prepared in example 1 were taken out 5 CAR-T cells treated with Goat Anti-Rat IgG (H)&L) Biotin (BioVision, cat # 6910-250) as a primary antibody and APC Streptavidin (BD Pharmingen, cat # 554067) as a secondary antibody, the expression level of CAR on CAR T cells was examined by flow cytometry, and the results are shown in FIG. 1. It can be seen that the CAR positive efficiency in mCD19-CAR cells, mCD19-CAR + CCL2 cells and mCD19-CAR + IL7+ CCL2 cells was greater than 60% compared to untreated NT cells, indicating that these cells all efficiently expressed CAR.
2.2Expression level of IL7
The supernatant of CAR-T cells was collected and the level of IL7 secretion in the cells was determined using the Mouse IL-7DuoSet ELISA kit (R & D Systems, cat # DY 407) according to the manufacturer's recommendations and the results are shown in FIG. 2. It can be seen that mCD19-CAR + IL7+ CCL2 cells can efficiently express IL7.
2.3Expression level of CCL2
The supernatant of CAR-T cells was collected and the level of CCL2 secretion in the cells was determined using the Mouse CCL2 DuoSet ELISA kit (R & D Systems, cat # DY 479) according to the manufacturer's recommendations and the results are shown in FIG. 3. It can be seen that both mCD19-CAR + CCL2 cells and mCD19-CAR + IL7+ CCL2 cells efficiently expressed CCL2.
Example 3 detection of IFN- γ secretion levels in CAR-T cells
In 96-hole round bottom plate with 2X 10 5 NT cells, CD19-CAR cells, mCD19-CAR + CCL2 cells and mCD19-CAR + IL7+ CCL2 cells were added at a concentration of 100. Mu.l per cell, respectively. Then 1X 10 in each well 4 Panc02-mCD19 target cells (Panc 02 cells expressing mCD 19) or Panc02 non-target cells were added at a concentration of 100. Mu.l per cell, respectively. After incubation at 37 ℃ for 24h, culture supernatants were collected. According to the manufacturer's recommendations, use the Mouse IFN-gamma DuoSet ELISA kit (R)&D, cat No. DY 485) the expression level of IFN-. Gamma.in the culture supernatant was determined.
The results of the detection are shown in FIG. 4. It can be seen that no IFN- γ release was detected in non-target cells Panc02, but only significantly elevated IFN- γ levels were detected after co-culture with target cells Panc02-CD19, and that the NT cells did not express IFN- γ, indicating that the killing of CAR-T cells in this example is specific. In addition, the level of IFN-gamma of the mCD19-CAR + CCL2 cell is obviously higher than that of the CD19-CAR cell, and the additional expression of the CCL2 gene can obviously improve the killing activity of the CAR-T cell. In addition, the level of IFN- γ in CAR-T cells expressing the IL7+ CCL2 combination was also significantly higher than in CAR-T cells expressing CCL2 alone, indicating that the addition of IL7 can further increase the killing activity of CAR-T cells.
Example 4 validation of tumor-inhibiting Effect of CAR-T cells
5X 10 subcutaneous inoculations were made to the left forelimb axilla of healthy C57BL/6 mice 5 And the Panc02-mCD19 pancreatic cancer cells. Mice vaccinated with pancreatic cancer cells were randomly divided into 4 groups of 5 mice each. When the tumor volume grows to 100mm 3 In time, 5X 10 injections were given via tail vein to each group of mice 6 Individual NT cells, mCD19-CAR + CCL2 cells or mCD19-CAR + IL7+ CCL2 cells. Mice were monitored for changes in body weight and tumor volume until the end of the experiment.
The body weight changes of the mice are shown in fig. 5. As can be seen, the body weight of mice in each group was not significantly different from that of the control group after administration of CAR-T cells, and the tumor in the mice did not exceed 1500mm in the observation period 3 The mice were lively and had normal hair color, indicating that CAR-T cells administered did not have significant toxic side effects on the mice.
Changes in tumor volume in mice are shown in figure 6. It can be seen that the anti-tumor effect of the mCD19-CAR + CCL2 cells is better than that of the conventional CAR-T cells, and the fact that the additionally expressed CCL2 can generate a synergistic effect with the CAR-T cells and enhance the anti-tumor effect of the CAR-T cells is shown. Furthermore, the inventors have unexpectedly found that further expression of IL7 can significantly increase the promoting effect of CCL2 on CAR-T cells, thereby more significantly inhibiting tumor growth.
The above results indicate that co-expressing CCL2 or its combination with IL7 is effective in enhancing the inhibitory effect of CAR-expressing engineered immune cells on tumor cells.
It should be noted that the above-mentioned embodiments are merely preferred examples of the present invention, and the present invention is not limited thereto. It will be understood by those skilled in the art that any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Sequence listing
<110> Nanjing Beijing Heng Biotechnology Ltd
<120> engineered immune cells and uses thereof
<130> BHCN44
<160> 27
<170> SIPOSequenceListing 1.0
<210> 1
<211> 242
<212> PRT
<213> Artificial Sequence(Artificial Sequence)
<220>
<223> CD19 scFv
<400> 1
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu
115 120 125
Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys
130 135 140
Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg
145 150 155 160
Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser
165 170 175
Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile
180 185 190
Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln
195 200 205
Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly
210 215 220
Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
225 230 235 240
Ser Ser
<210> 2
<211> 238
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mCD19 scFv
<400> 2
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Thr Ser Leu Gly
1 5 10 15
Glu Thr Val Thr Ile Gln Cys Gln Ala Ser Glu Asp Ile Tyr Ser Gly
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Asp Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Thr Ser Met Gln Thr
65 70 75 80
Glu Asp Glu Gly Val Tyr Phe Cys Gln Gln Gly Leu Thr Tyr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln
115 120 125
Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val Lys Leu Ser Cys
130 135 140
Lys Val Ser Gly Asp Thr Ile Thr Phe Tyr Tyr Met His Phe Val Lys
145 150 155 160
Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Glu
165 170 175
Asp Glu Ser Thr Lys Tyr Ser Glu Lys Phe Lys Asn Lys Ala Thr Leu
180 185 190
Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr Leu Lys Leu Ser Ser Leu
195 200 205
Thr Ser Glu Asp Thr Ala Thr Tyr Phe Cys Ile Tyr Gly Gly Tyr Tyr
210 215 220
Phe Asp Tyr Trp Gly Gln Gly Val Met Val Thr Val Ser Ser
225 230 235
<210> 3
<211> 27
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD28 transmembrane domain
<400> 3
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val
20 25
<210> 4
<211> 25
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD8 alpha transmembrane domain
<400> 4
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys Lys
20 25
<210> 5
<211> 21
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mCD8 a transmembrane domain
<400> 5
Ile Trp Ala Pro Leu Ala Gly Ile Cys Val Ala Leu Leu Leu Ser Leu
1 5 10 15
Ile Ile Thr Leu Ile
20
<210> 6
<211> 41
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD28 Co-stimulatory Domain
<400> 6
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 7
<211> 40
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> 4-1BB Co-stimulatory Domain
<400> 7
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
1 5 10 15
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
20 25 30
Glu Glu Glu Glu Gly Gly Cys Glu
35 40
<210> 8
<211> 42
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> m4-1BB Co-stimulatory Domain
<400> 8
Arg Lys Lys Phe Pro His Ile Phe Lys Gln Pro Phe Lys Lys Thr Thr
1 5 10 15
Gly Ala Ala Gln Glu Glu Asp Ala Cys Ser Cys Arg Cys Pro Gln Glu
20 25 30
Glu Glu Gly Gly Gly Gly Gly Tyr Glu Leu
35 40
<210> 9
<211> 114
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> intracellular domain of CD3 ζ
<400> 9
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1 5 10 15
Gly Gln Asn Gln Leu Phe Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Phe Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
50 55 60
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
65 70 75 80
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Phe Gln Gly Leu Ser
85 90 95
Thr Ala Thr Lys Asp Thr Phe Asp Ala Leu His Met Gln Ala Leu Pro
100 105 110
Pro Arg
<210> 10
<211> 113
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> intracellular domain of CD3 ζ
<400> 10
Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln
1 5 10 15
Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu
20 25 30
Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly
35 40 45
Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 11
<211> 109
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mCD3 ζ intracellular domain
<400> 11
Ser Arg Ser Ala Glu Thr Ala Ala Asn Leu Gln Asp Pro Asn Gln Leu
1 5 10 15
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Glu
20 25 30
Lys Lys Arg Ala Arg Asp Pro Glu Met Gly Gly Lys Gln Gln Arg Arg
35 40 45
Arg Asn Pro Gln Glu Gly Val Tyr Asn Ala Leu Gln Lys Asp Lys Met
50 55 60
Ala Glu Ala Tyr Ser Glu Ile Gly Thr Lys Gly Glu Arg Arg Arg Gly
65 70 75 80
Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp
85 90 95
Thr Tyr Asp Ala Leu His Met Gln Thr Leu Ala Pro Arg
100 105
<210> 12
<211> 20
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> B2M Signal peptide
<400> 12
Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser
1 5 10 15
Gly Leu Glu Ala
20
<210> 13
<211> 21
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD8 alpha signal peptide
<400> 13
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 14
<211> 24
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mCD8 alpha signal peptide
<400> 14
Met Ala Ser Pro Leu Thr Arg Phe Leu Ser Leu Asn Leu Leu Leu Leu
1 5 10 15
Gly Glu Ser Ile Ile Leu Gly Ser
20
<210> 15
<211> 39
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD28 hinge region
<400> 15
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
1 5 10 15
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu
20 25 30
Phe Pro Gly Pro Ser Lys Pro
35
<210> 16
<211> 45
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> CD8 alpha hinge region
<400> 16
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 17
<211> 45
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mCD8 α hinge region
<400> 17
Thr Thr Thr Lys Pro Val Leu Arg Thr Pro Ser Pro Val His Pro Thr
1 5 10 15
Gly Thr Ser Gln Pro Gln Arg Pro Glu Asp Cys Arg Pro Arg Gly Ser
20 25 30
Val Lys Gly Thr Gly Leu Asp Phe Ala Cys Asp Ile Tyr
35 40 45
<210> 18
<211> 12
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> IgG4 hinge region
<400> 18
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 19
<211> 18
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> T2A
<400> 19
Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro
1 5 10 15
Gly Pro
<210> 20
<211> 402
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> hIL-7
<400> 20
atgttccatg tttcttttag gtatatcttt ggacttcctc ccctgatcct tgttctgttg 60
ccagtagcat catctgattg tgatattgaa ggtaaagatg gcaaacaata tgagagtgtt 120
ctaatggtca gcatcgatca attattggac agcatgaaag aaattggtag caattgcctg 180
aataatgaat ttaacttttt taaaagacat atctgtgatg ctaataaggt taaaggaaga 240
aaaccagctg ccctgggtga agcccaacca acaaagagtt tggaagaaaa taaatcttta 300
aaggaacaga aaaaactgaa tgacttgtgt ttcctaaaga gactattaca agagataaaa 360
acttgttgga ataaaatttt gatgggcact aaagaacact ga 402
<210> 21
<211> 133
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> hIL-7
<400> 21
Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Leu Pro Pro Leu Ile
1 5 10 15
Leu Val Leu Leu Pro Val Ala Ser Ser Asp Cys Asp Ile Glu Gly Lys
20 25 30
Asp Gly Lys Gln Tyr Glu Ser Val Leu Met Val Ser Ile Asp Gln Leu
35 40 45
Leu Asp Ser Met Lys Glu Ile Gly Ser Asn Cys Leu Asn Asn Glu Phe
50 55 60
Asn Phe Phe Lys Arg His Ile Cys Asp Ala Asn Lys Val Lys Gly Arg
65 70 75 80
Lys Pro Ala Ala Leu Gly Glu Ala Gln Pro Thr Lys Ser Leu Glu Glu
85 90 95
Asn Lys Ser Leu Lys Glu Gln Lys Lys Leu Asn Asp Leu Cys Phe Leu
100 105 110
Lys Arg Leu Leu Gln Glu Ile Lys Thr Cys Trp Asn Lys Ile Leu Met
115 120 125
Gly Thr Lys Glu His
130
<210> 22
<211> 465
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mIL-7
<400> 22
atgttccatg tttcttttag atatatcttt ggaattcctc cactgatcct tgttctgctg 60
cctgtcacat catctgagtg ccacattaaa gacaaagaag gtaaagcata tgagagtgta 120
ctgatgatca gcatcgatga attggacaaa atgacaggaa ctgatagtaa ttgcccgaat 180
aatgaaccaa acttttttag aaaacatgta tgtgatgata caaaggaagc tgcttttcta 240
aatcgtgctg ctcgcaagtt gaagcaattt cttaaaatga atatcagtga agaattcaat 300
gtccacttac taacagtatc acaaggcaca caaacactgg tgaactgcac aagtaaggaa 360
gaaaaaaacg taaaggaaca gaaaaagaat gatgcatgtt tcctaaagag actactgaga 420
gaaataaaaa cttgttggaa taaaattttg aagggcagta tataa 465
<210> 23
<211> 154
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mIL-7
<400> 23
Met Phe His Val Ser Phe Arg Tyr Ile Phe Gly Ile Pro Pro Leu Ile
1 5 10 15
Leu Val Leu Leu Pro Val Thr Ser Ser Glu Cys His Ile Lys Asp Lys
20 25 30
Glu Gly Lys Ala Tyr Glu Ser Val Leu Met Ile Ser Ile Asp Glu Leu
35 40 45
Asp Lys Met Thr Gly Thr Asp Ser Asn Cys Pro Asn Asn Glu Pro Asn
50 55 60
Phe Phe Arg Lys His Val Cys Asp Asp Thr Lys Glu Ala Ala Phe Leu
65 70 75 80
Asn Arg Ala Ala Arg Lys Leu Lys Gln Phe Leu Lys Met Asn Ile Ser
85 90 95
Glu Glu Phe Asn Val His Leu Leu Thr Val Ser Gln Gly Thr Gln Thr
100 105 110
Leu Val Asn Cys Thr Ser Lys Glu Glu Lys Asn Val Lys Glu Gln Lys
115 120 125
Lys Asn Asp Ala Cys Phe Leu Lys Arg Leu Leu Arg Glu Ile Lys Thr
130 135 140
Cys Trp Asn Lys Ile Leu Lys Gly Ser Ile
145 150
<210> 24
<211> 447
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mCCL2
<400> 24
atgcaggtcc ctgtcatgct tctgggcctg ctgttcacag ttgccggctg gagcatccac 60
gtgttggctc agccagatgc agttaacgcc ccactcacct gctgctactc attcaccagc 120
aagatgatcc caatgagtag gctggagagc tacaagagga tcaccagcag caggtgtccc 180
aaagaagctg tagtttttgt caccaagctc aagagagagg tctgtgctga ccccaagaag 240
gaatgggtcc agacatacat taaaaacctg gatcggaacc aaatgagatc agaacctaca 300
actttattta aaactgcatc tgccctaagg tcttcagcac ctttgaatgt gaagttgacc 360
cgtaaatctg aagctaatgc atccactacc ttttccacaa ccacctcaag cacttctgta 420
ggagtgacca gtgtgacagt gaactag 447
<210> 25
<211> 148
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mCCL2
<400> 25
Met Gln Val Pro Val Met Leu Leu Gly Leu Leu Phe Thr Val Ala Gly
1 5 10 15
Trp Ser Ile His Val Leu Ala Gln Pro Asp Ala Val Asn Ala Pro Leu
20 25 30
Thr Cys Cys Tyr Ser Phe Thr Ser Lys Met Ile Pro Met Ser Arg Leu
35 40 45
Glu Ser Tyr Lys Arg Ile Thr Ser Ser Arg Cys Pro Lys Glu Ala Val
50 55 60
Val Phe Val Thr Lys Leu Lys Arg Glu Val Cys Ala Asp Pro Lys Lys
65 70 75 80
Glu Trp Val Gln Thr Tyr Ile Lys Asn Leu Asp Arg Asn Gln Met Arg
85 90 95
Ser Glu Pro Thr Thr Leu Phe Lys Thr Ala Ser Ala Leu Arg Ser Ser
100 105 110
Ala Pro Leu Asn Val Lys Leu Thr Arg Lys Ser Glu Ala Asn Ala Ser
115 120 125
Thr Thr Phe Ser Thr Thr Thr Ser Ser Thr Ser Val Gly Val Thr Ser
130 135 140
Val Thr Val Asn
145
<210> 26
<211> 300
<212> DNA
<213> Artificial sequence(Artificial Sequence)
<220>
<223> hCCL2
<400> 26
atgaaagtct ctgccgccct tctgtgcctg ctgctcatag cagccacctt cattccccaa 60
gggctcgctc agccagatgc aatcaatgcc ccagtcacct gctgctataa cttcaccaat 120
aggaagatct cagtgcagag gctcgcgagc tatagaagaa tcaccagcag caagtgtccc 180
aaagaagctg tgatcttcaa gaccattgtg gccaaggaga tctgtgctga ccccaagcag 240
aagtgggttc aggattccat ggaccacctg gacaagcaaa cccaaactcc gaagacttga 300
<210> 27
<211> 99
<212> PRT
<213> Artificial sequence(Artificial Sequence)
<220>
<223> mCCL2
<400> 27
Met Lys Val Ser Ala Ala Leu Leu Cys Leu Leu Leu Ile Ala Ala Thr
1 5 10 15
Phe Ile Pro Gln Gly Leu Ala Gln Pro Asp Ala Ile Asn Ala Pro Val
20 25 30
Thr Cys Cys Tyr Asn Phe Thr Asn Arg Lys Ile Ser Val Gln Arg Leu
35 40 45
Ala Ser Tyr Arg Arg Ile Thr Ser Ser Lys Cys Pro Lys Glu Ala Val
50 55 60
Ile Phe Lys Thr Ile Val Ala Lys Glu Ile Cys Ala Asp Pro Lys Gln
65 70 75 80
Lys Trp Val Gln Asp Ser Met Asp His Leu Asp Lys Gln Thr Gln Thr
85 90 95
Pro Lys Thr
Claims (22)
1. An engineered immune cell that expresses a cell surface molecule that specifically recognizes an antigen and exogenous CCL2.
2. The engineered immune cell of claim 1, wherein the engineered immune cell further expresses exogenous IL7.
3. The engineered immune cell of claim 1, wherein the CCL2 is identical to the amino acid sequence of SEQ ID NO:25 or 27, or a coding sequence thereof which shares at least 90% identity with the amino acid sequence set forth in SEQ ID NO:24 or 26 have at least 90% identity.
4. The engineered immune cell of claim 2, wherein the IL7 is identical to the amino acid sequence of SEQ ID NO:21 or 23, or a coding sequence thereof which shares at least 90% identity with the amino acid sequence set forth in SEQ ID NO:22 or 24 have at least 90% identity.
5. The engineered immune cell of any one of claims 1-4, wherein the cell surface molecule that specifically recognizes an antigen is a chimeric antigen receptor or a T cell receptor.
6. The engineered immune cell of claim 5, wherein the chimeric antigen receptor comprises an antigen binding region, a transmembrane domain, and an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain.
7. The engineered immune cell of claim 6, wherein the antigen binding region is selected from the group consisting of IgG, fab ', F (ab ') 2, fd ', fv, scFv, sdFv, linear antibody, single domain antibody, nanobody, diabody, anticalin, and DARPIN antigen.
8. The engineered immune cell of claim 7, wherein the antigen-antigen binding region binds to one or more targets selected from the group consisting of: CD2, CD3, CD4, CD5, CD7, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD30, CD33, CD37, CD38, CD40L, CD, CD46, CD47, CD52, CD54, CD56, CD70, CD73, CD80, CD97, CD123, CD126, CD138, CD171, CD 179a, DR4, DR5, TAC, TEM1/CD248, VEGF, GUCY2C, EGP, EGP-2, EGP-4, CD133, CD15, CD23, CD52, CD80, CD37, CD38, CD40, CD138, CD 179a, DR4, DR5, TAC, TEM1/CD248, VEGF, GUCY2C, EGP, EGP-2, EGP-4, CD133 IFNAR1, DLL3, kappa light chain, TIM3, TSHR, CD19, BAFF-R, CLL-1, EGFRvIII, tEGFR, GD2, GD3, BCMA, tn antigen, PSMA, ROR1, FLT3, FAP, TAG72, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, IL-llRa, IL-22Ra, IL-2, mesothelin, PSCA, PRSS21, VEGFR2, lewisY, PDGFR-beta, SSEA-4, AFP, folate receptor alpha, erbB2 (Her 2/neu), erbB3, erbB4 MUC1, MUC16, EGFR, CS1, NCAM, claudin18.2, c-Met, prostase, PAP, ELF2M, ephrin B2, IGF-I receptor, CAIX, LMP2, gpl00, bcr-abl, tyrosinase, ephA2, fucosyl, sLe, GM3, TGS5, HMWMAA, o-acetyl-GD 2, folate receptor beta, TEM7R, CLDN, GPRC5D, CXORF, ALK, polysialic acid, PLAC1, globoh, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, NY-BR-1, and UPK2 GPR20, LY6K, OR E2, TARP, WT1, NY-ESO-1, LAGE-la, MAGE-A1, MAGE-A3, MAGE-A6, legumain, HPV E6, E7, ETV6-AML, sperm protein 17, XAGE1, tie 2, MAD-CT-1, MAD-CT-2, fos-associated antigen 1, p53 mutant, PSA, survivin and telomerase, PCTA-l/Galectin 8, melanA/MARTl, ras mutant, hTERT, sarcoma translocation breakpoint, ML-IAP, hTAP, hTAR, and hTAR, TMPRSS2 ETS fusion gene, NA17, PAX3, androgen receptor, progesterone receptor, cyclin Bl, MYCN, rhoC, TRP-2, CYP1B 1, BORIS, SART3, PAX5, OY-TES 1, LCK, AKAP-4, SSX2, RAGE-1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxylesterase, mut hsp70-2, CD79a, CD79B, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST, EMR2, LY75, GPC3, FCRL5, IGLL1, PD1, PDL2, TGF β, APRIL, NKG2D, NKG D ligand, and/or a biotinylated molecule specific for antigen, biotinylated molecule, molecule expressed by HIV, HBV, HCV and/or other pathogens; and/or a neoepitope or neoantigen.
9. The engineered immune cell of claim 6, wherein the transmembrane domain is selected from the transmembrane domains of: TCR α chain, TCR β chain, TCR γ chain, TCR δ chain, CD3 ζ subunit, CD3 ∈ subunit, CD3 γ subunit, CD3 δ subunit, CD45, CD4, CD5, CD8 α, CD9, CD16, CD22, CD33, CD28, CD37, CD64, CD80, CD86, CD134, CD137, and CD154.
10. The engineered immune cell of any one of claims 6-10, wherein the primary signaling domain is selected from the intracellular regions of: fcR γ, fcR β, CD3 γ, CD3 δ, CD3 ∈, CD3 ζ, CD22, CD79a, CD79b, and CD66d.
11. The engineered immune cell of claim 6, wherein the co-stimulatory domain comprises one or more intracellular regions of a protein selected from the group consisting of: TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, CARD11, CD2, CD7, CD8, CD18, CD27, CD28, CD30, CD40, CD54, CD83, CD134 (OX 40), CD137 (4-1 BB), CD270 (HVEM), CD272 (BTLA), CD276 (B7-H3), CD278 (ICOS), CD357 (GITR), DAP10, DAP12, LAT, NKG2C, SLP, PD-1, LIGHT, TRIM, ZAP70 and combinations thereof.
12. The engineered immune cell of any one of claims 1-11, wherein the immune cell is selected from a T cell, a macrophage, a dendritic cell, a monocyte, an NK cell, or an NKT cell.
13. The engineered immune cell of claim 12, wherein the T cell is a CD4+ CD8+ T cell, a CD4+ helper T cell, a CD8+ T cell, a CD4-CD8-T cell, a tumor infiltrating cell, a memory T cell, a naive T cell, a γ δ -T cell, or an α β -T cell.
14. The engineered immune cell of any one of claims 1-13, wherein the expression of CCL2 and/or IL7 is conditional expression or constitutive expression.
15. The engineered immune cell of any one of claims 1-14, wherein the CCL2 and/or IL7 is operably linked to a localization domain.
16. A nucleic acid molecule comprising a nucleic acid sequence encoding a cell surface molecule that specifically recognizes an antigen and a nucleic acid sequence encoding CCL2.
17. The nucleic acid molecule of claim 16, wherein the cell surface molecule that specifically recognizes an antigen is a chimeric antigen receptor.
18. The nucleic acid molecule of claim 16, wherein the nucleic acid molecule further comprises a nucleic acid sequence encoding IL7.
19. A vector comprising the nucleic acid molecule of any one of claims 16-18.
20. The vector of claim 18, wherein the vector is selected from the group consisting of a plasmid, a retrovirus, a lentivirus, an adenovirus, a vaccinia virus, a Rous Sarcoma Virus (RSV), a polyoma virus, and an adeno-associated virus (AAV).
21. A pharmaceutical composition comprising an engineered immune cell according to any one of claims 1-15, a nucleic acid molecule according to any one of claims 16-18 or a vector according to any one of claims 19-20, and one or more pharmaceutically acceptable excipients.
22. A method of treating a subject having cancer, an infection, or an autoimmune disease, comprising administering to the subject the engineered immune cell of any one of claims 1-15 or the pharmaceutical composition of claim 21.
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