CHIMERIC ANTIGEN RECEPTORS (CARs), COMPOSITIONS AND METHODS OF USE THEREOF

Abstract

This invention relates to compositions and methods related to chimeric antigen receptor (CAR) peptides, and related methods. In one embodiment, the invention relates to engineered cells having chimeric antigen receptor peptides targeting at least two targets. In another embodiment, the invention relates to engineered cells having a chimeric antigen receptor peptide and an enhancer moiety.

Description

Prior Art

[0001] T cells, a type of lymphocyte, play a key role in cell-mediated immunity. They are distinguished from other lymphocytes, such as B cells and natural killer cells (NK cells), by the presence of the T cell receptor (TCR) on their cell surface. T helper cells, also known as CD4+ T or CD4 T cells, express the CD4 glycoprotein on their surface. Helper T cells are activated when exposed to peptide antigens presented by MHC (major histocompatibility complex) class II molecules. Once activated, these cells proliferate rapidly and secrete cytokines that regulate immune responses. Cytotoxic T cells, also known as CD8+ T cells or CD8 T cells, express the CD8 glycoprotein on their cell surface. CD8+ T cells are activated when exposed to peptide antigens presented by MHC class I molecules. Memory T cells, a subset of T cells, persist for a long time and respond to their cognate antigen, thereby providing the immune system with "memory" of past infections and / or tumor cells. T cells can be genetically engineered to produce specific receptors on their surface, called chimeric antigen receptors (CARs). CARs are proteins that allow T cells to recognize specific proteins (antigens) on tumor cells. These engineered CAR T cells are then grown in the laboratory until their number reaches billions. The expanded CAR T cell population is then infused into the patient. To date, clinical trials have demonstrated the tremendous promise of chimeric antigen receptor (CAR) T cells in hematologic malignancies resistant to standard chemotherapy. Most notably, CD19-specific CAR (CD19CAR) T cell therapy has demonstrated remarkable results, including long-term remissions in B-cell malignancies (Kochenderfer, Wilson et al. 2010, Kalos, Levine et al. 2011, Porter, Levine et al. 2011, Davila, Riviere et al. 2013, Grupp, Frey et al. 2013, Grupp, Kalos et al. 2013, Kalos, Nazimuddin et al. 2013, Kochenderfer, Dudley et al. 2013, Kochenderfer, Dudley et al. 2013, Lee, Shah et al. 2013, Park, Riviere et al. 2013, Maude, Frey et al. 2014). Despite the success of CAR therapy in B-cell leukemias and lymphomas, its application in T-cell malignancies has not yet been established. Given that T-cell malignancies are associated with significantly worse outcomes compared to B-cell malignancies (Abramson, Feldman et al. 2014), CAR therapy has the potential to further address significant clinical needs in this setting. To date, current research has focused on CAR T cells demonstrating efficacy in various B-cell malignancies. Although initial remission rates of approximately 90% are common in B-ALL using CD19 CARs, the majority relapse within a year. Relapses can be attributed, at least in part, to antigen escape. Therefore, more effective CAR T cell therapies to prevent relapse are urgently needed. Target discovery and selection are the initial steps, as no general rules exist to ensure or guide effective CAR design. Several obstacles hinder the wider application of CAR therapeutics. The most common challenges are: (1) selection of antigen targets and chimeric antigen receptors; (2) CAR design; and (3) tumor heterogeneity, particularly differences in tumor antigen surface expression. Targeting a single antigen carries the risk of immune escape, which can be addressed by targeting multiple desired antigens. Most CAR chimeric antigen receptors are scFvs derived from monoclonal antibodies, and some of these monoclonal antibodies have been used in clinical trials or for disease treatment. However, their efficacy is limited, highlighting the need for alternative and more potent targeting approaches, such as CARs. scFvs are the most commonly used chimeric antigen receptors for CARs. However, CAR binding affinity and the location of the recognized epitope on the antigen can affect function. Furthermore, the amount of surface CAR expression on T cells or NK cells is influenced by the appropriate leader sequence and promoter. Furthermore, overexpressed CAR protein can be toxic to cells. Therefore, there remains a need for improved chimeric antigen receptor-based therapies that can achieve more effective, safe, and efficient targeting of T cell-associated malignancies. Summary of the Invention

[0002] In one embodiment, the present invention provides an engineered cell having a first chimeric antigen receptor polypeptide comprising a first antigen recognition domain, a first signal peptide, a first hinge region, a first transmembrane domain, a first costimulatory domain, and a first signaling domain; and a second chimeric antigen receptor polypeptide comprising a second antigen recognition domain, a second signal peptide, a second hinge region, a second transmembrane domain, a second costimulatory domain, and a second signaling domain; wherein the first antigen recognition domain and the second antigen recognition domain are different. In another embodiment, the present invention provides an engineered polypeptide comprising a chimeric antigen receptor and an enhancer. In another embodiment, the present invention provides an engineered polypeptide comprising a chimeric antigen receptor polypeptide and an enhancer. In another embodiment, the present invention provides an engineered chimeric antigen receptor polypeptide comprising: a signal peptide, a CD45 antigen recognition domain, a hinge region, a transmembrane domain, at least one costimulatory domain, and a signaling domain. In another embodiment, the present invention provides a polynucleotide encoding the aforementioned polypeptide. In another embodiment, the present invention provides an engineered cell having the above-mentioned engineered polypeptide or polynucleotide. In another embodiment, the present invention provides a method for reducing the number of target cells, comprising the steps of (i.) contacting the target cells with an effective amount of cells engineered to have at least one chimeric antigen receptor polypeptide, wherein the engineered cells have multiple chimeric antigen receptor polypeptides, each chimeric antigen receptor polypeptide being independent; and (ii.) optionally analyzing the cells for reduction in number. The target cells comprise at least one cell surface antigen selected from the group consisting of interleukin 6 receptor, NY-ESO-1, alpha-fetoprotein (AFP), glypican-3 (GPC3), BAFF-R, BCMA, TACI, LeY, CD5, CD13, CD14, CD15 CD19, CD20, CD22, CD33, CD41, CD45, CD61, CD64, CD68, CD117, CD123, CD138, CD267, CD269, CD38, Flt3 receptor, and CS1. In another embodiment, the present invention provides methods for treating B-cell lymphoma, T-cell lymphoma, multiple myeloma, chronic myeloid leukemia, B-cell acute lymphoblastic leukemia (B-ALL), and cell proliferative diseases by administering any of the above-described engineered cells to a patient in need thereof. Simple diagram description

[0003] Figure 1. Schematic diagram of a cCAR construct (hereinafter, "multiple CARs or composite CARs"). Multiple or composite CARs target multiple antigens (e.g., cell type 1, cell type 2, or the same cell type). Multiple or cCAR T cell immunotherapy comprises individual component CARs that contain different or identical antigen recognition domains, hinge regions, transmembrane domains, multiple costimulatory domains, and intracellular signaling domains. Figure 2A. Schematic diagram of the cCAR-T construct. The construct comprises an SFFV promoter driving expression of multiple modular CAR units linked by a P2A peptide. Following linker cleavage, the cCAR cleaves and engages when the target expresses CD33 and / or CD123. As a novel cCAR construct, the activation domain of the construct may include (but is not limited to) the 4-1BB region on the CD33 CAR segment and the CD28 region on the CD123 CAR. Figure 2B. Western blot depicting the expression of transduced CD33CD123 cCAR-T cells. This figure depicts the expression of two different CAR proteins, CD33 CAR and CD123 CAR. cCAR-T cells expressing CD33 and CD123 CAR produce two distinct and consistently intense protein bands upon linker cleavage. Green fluorescent protein (GFP) is included as a negative control. FIG2C . Flow cytometry showing transduction efficacy. The upper panel shows the lentiviral titer of CD33CD123 cCAR (also known as CD33CD123-2G-CAR) tested on 293FT HEK (human embryonic kidney) cells to verify maximum transduction efficacy before use in UCB (umbilical cord blood) and PB (peripheral blood) T cells. The lower panel shows CD33CD123 cCAR (also known as CD33CD123-2G-CAR) T cells transduced with a lentiviral vector containing the CD33CD123 cCAR construct and GFP-transduced cells as a control. The percentage indicated by the yellow ring is a surrogate for transduction efficacy. Figure 3. Schematic diagram showing the method for generating highly potent composite CAR (cCAR). Figure 4. Co-culture assay showing CD33+CD123-2G CAR-T cells (cCAR) incubated with the promyelocytic leukemia cell line HL60. Comparison of cCAR-T cells (lower panel) with control GFP-transduced T cells (upper panel). Killing efficacy was measured by the CD33+ cell population (encircled in yellow) remaining after approximately 24 hours of incubation. Figure 5. Co-culture analysis of cCAR-T cells incubated with the myeloid leukemia cell line KG-1a, which express approximately 100% CD33 and approximately 50-80% CD123. Comparison of cCAR-T cells (lower panel) with control GFP-transduced T cells (upper panel). Killing efficacy was measured by the CD33+ cell population remaining after approximately 24 hours of incubation. Figure 6. Co-culture assay showing cCAR-T cells incubated with an AML patient sample (herein referred to as AML-9). Patient cells included a mixed population of cells, such as leukemic cells, monocytes, and other blast cell types. CD33 served as a marker for CAR-T activity, along with CD34 (a specific marker for leukemic cells). The CAR-T image (right) was compared with control GFP-transduced T cells (center). Killing efficacy was measured by the CD33+ / CD34+ cell population that remained after at least 24 hours of incubation. Figure 7. Co-culture assay showing cCAR-T cells incubated with a B-ALL patient sample (herein referred to as Sp-BM-B6). Patient cells included a mixed population of leukemic cells, monocytes, and other blast cell types. CD34 serves as a specific marker for leukemic cells. The CAR-T image (right) is compared with control GFP-transduced T cells (center). Killing efficacy was measured by the CD34+ cell population that remained after at least 24 hours of incubation. Figure 8. CD33CD123 cCAR expression in NK-92 cells. CD33CD123 cCAR expression was detected using goat anti-mouse F(ab)2 antibody. Figure 9. Co-culture assay of cCAR NK-92 cells incubated with HL-60 cells. Comparison of cCAR NK-92 cells with GFP-transduced NK-92 cells. Killing efficacy was measured by the CD33+ cell population remaining after approximately 24 hours of incubation. Figure 10. Co-culture assay showing cCAR NK-92 cells incubated with KG1a. Comparison of cCAR NK cell patterns with GFP-transduced NK-92 cells. Killing efficacy was measured by the CD33+ cell population remaining after approximately 24 hours of incubation. Figure 11. Dose response of CD33CD123 cCAR (CAR-CD33 / 123) NK-92 cells with HL-60 or KG1a. Killing efficacy was measured by the CD33+ cell population remaining after approximately 24 hours of incubation. Figure 12. Comparison of CD33CD123 cCAR NK-92 cell-killing capacity in two KG11 cell populations compared to controls. The assay was performed at varying ratios of CAR-CD33 / 123 (CD33CD123 cCAR NK-92 cells) and target cells (kG1a). Killing efficacy was measured by the presence of CD33+CD123+ or CD33+CD123- cell populations after approximately 24 hours of incubation. Figure 13. Schematic diagram of cCAR. The construct comprises an SFFV promoter driving expression of multiple modular CAR units connected by a linker. Upon cleavage of the linker, the cCAR cleaves and engages when the target expresses a combination of target antigens (CD19 and / or CD20 and / or CD22 and / or CD38). Multiple cCARs utilize the same or different costimulatory domains, such as (but not limited to) 4-1BB (also labeled 4-BB) and / or CD28. Figure 14A-C. Flowchart of the BCMA-CS1 cCAR construct (BC1cCAR). (A) The construct consists of an SFFV promoter driving expression of two modular CAR units linked by a P2A peptide. When this P2A peptide is cleaved, the cCAR cleaves and engages when the target expresses BCMA and / or CS1. Both unit CARs utilize the same costimulatory domain, 4-1BB. (B) Flow cytometric analysis of BC1cCAR expression on T cells expressing the vector (left) and a BC1cCAR displaying 15.3% positivity for F(ab)2 (right, highlighted by a square). Gated against an isotype control. (C) Basic functional validation of BC1cCAR-T cells was performed by co-culturing K562 cells transduced with BCMA cDNA (BCMA-K562) (obtained from Kochenderfer, NIH). The bar graph shows the lysis of the BCMA-K562 cell line versus control T cells and the lysis of wild-type K562 (wt-K562) versus control. Figure 14D. BCMA-CS1-2G constructs, each unit using two different costimulatory domains (4-1BB or CD28). The construct includes an SFFV promoter driving expression of two modular CAR units linked by a P2A peptide. Upon cleavage of this P2A peptide, the cCAR cleaves and engages targets expressing BCMA and / or CS1. The two unit CARs use different costimulatory domains, namely 4-1BB or CD28. Flow cytometric analysis of BC1 cCAR expression on T cells expressing vector (left) and BC1 cCAR (right, highlighted by squares), which exhibited rare F(ab)2 positive cells. Gated against an isotype control. Figure 14E. Protein expression of BC1cCAR and BCMA-CS1-2G in HEK-293FT cells. HEK-293FT cells were transfected with lentiviral plasmids expressing GFP (lane 1), BC1cCAR (lane 2), and CD269-CS1-2G (lane 3) for 48 hours. The supernatant and cells were removed after transfection. Cells were lysed with mouse anti-human CD3z antibody for Western blotting and probe analysis. Figures 15A-15B. MM1S cell line co-culture. Co-culture was performed for 24 hours, harvested, and analyzed by flow cytometry. Target MM1S cells (myeloma cells) were labeled with Cytotracker (CMTMR) dye to distinguish them from effector T cells. Populations were gated using anti-BCMA (CD269) and anti-CS1 (CD319) antibodies. Figure 15A: Flow cytometry plot of co-culture. Figure 15B: Right: Graphical summary of lysis versus E:T ratio. Figures 16A-16B. RPMI-8226 cell line co-culture. Co-culture was performed for 24 hours, harvested, and analyzed by flow cytometry. Target RPMI-8226 cells were labeled with Cytotracker (CMTMR) dye to distinguish them from effector T cells. Populations were gated using anti-BCMA (CD269) and anti-CS1 (CD319) antibodies. Figure 16A: Flow cytometry plot of co-culture. Figure 16B: Graphical summary of lysis versus E:T ratio. Figures 17A-17B. Co-culture of U266 cells. Co-culture was performed for 24 hours, harvested, and analyzed by flow cytometry. Target U266 cells were labeled with Cytotracker (CMTMR) dye to distinguish them from effector T cells. Populations were gated using anti-BCMA (CD269) and anti-CS1 (CD319) antibodies. Left: Flow cytometric plot of co-culture; Right: Graphical summary of lysis versus E:T ratio. Figures 18A-18B. Co-culture of MM10-G primary patient samples and comparative lysis rates. Co-cultures were performed for 24 hours, harvested, and analyzed by flow cytometry. Target MM10-G cells were labeled with Cytotracker (CMTMR) dye to distinguish them from effector T cells. Populations were gated using anti-BCMA (CD269) and anti-CS1 (CD319) antibodies. Notably, gated displays revealed distinct BCMA+ and CS1+ populations of MM10-G. Figure 18A: Flow cytometry plot of co-cultures. Figure 18B: Graphical summary of lysis versus E:T ratio. Figures 19A-19B. Co-culture of MM7-G primary patient samples and comparative lysis rates. Co-cultures were performed for 24 hours, harvested, and analyzed by flow cytometry. Target MM7-G cells were labeled with Cytotracker (CMTMR) dye to distinguish them from effector T cells. Populations were gated using anti-BCMA (CD269) and anti-CS1 (CD319) antibodies. Figure 19A: Flow cytometry plot of co-cultures. Figure 19B: Graphical summary of lysis versus E:T ratio. Figures 20A-20B. Co-culture of MM11-G primary patient samples and comparative lysis rates. Co-cultures were performed at 24 hours, harvested, and analyzed by flow cytometry. Target MM11-G cells were labeled with Cytotracker (CMTMR) dye to distinguish them from effector T cells. Populations were gated using anti-BCMA (CD269) and anti-CS1 (CD319) antibodies. Figure 20A: Flow cytometry plot of co-cultures. Figure 20B: Graphical summary of lysis versus E:T ratio. Figure 21. CD269 CS1-BBCAR NK cells exhibit in vivo anti-leukemic effects. NSG mice were sublethally irradiated and injected intravenously with luciferase-expressing MM.1S multiple myeloma cells the following day to induce measurable tumor formation. Three days later, mice were injected intravenously with 8×10 6 CD269-CS1-BBCAR NK cells or vector-control NK cells. On days 3, 6, and 8, mice were subcutaneously injected with RediJect D-Luciferin and underwent IVIS imaging. The mean light intensity measured in mice injected with CD269-CS1-BBCAR NK cells was compared with that in mice injected with vector-control NK cells. FIG. 22 . The survival percentage of mice was measured and compared between the two groups based on the study from FIG. 21 . Figure 23. CRISPR / Cas9 interference system. Expression of sgRNA and Cas9 puromycin is driven by the U6 and SFFV promoters, respectively. Cas9 is linked to the puromycin resistance gene via an E2A autocleavage sequence. FIG24 . Schematic diagram providing an example of the steps for generating CAR T or NK cells targeting hematological malignancies. Figure 25. Generation and cell sorting of stable CD45-blocking gene-expressing NK-92 cells using the CRISPR / Cas9 lentiviral system. Flow cytometric analysis indicates the amount of CD45 expression on the NK-92 cell surface (left panel). After sgCD45B CRISPR transduction into NK-92 cells, the transduced cells were cultured for several weeks in medium containing puromycin. CD45-negative NK-92 cells were detected using a CD45 antibody and sorted. The purity of stable NK45i-92 (CD45-blocking gene-expressing) NK-92 cells was determined by flow cytometric analysis (right panel). This data confirms the successful generation and harvest of NK45i-92 cells. Figure 26. Cell growth curves of wild-type, GFP-transduced NK-92, or NK 45i-92 NK cells. To assess the cell proliferation effect of CD45 knockdown gene expression (KD) in NK-92 cells, the number of NK-92 (●), GFP-transduced NK-92 (■), and NK 45i-92 (▲) cells was counted 48 and 96 hours after plating in 24-well plates. IL-2 was added at the 48-hour time point (n=3 independent experiments performed in duplicate). Data are mean ± SD. These data indicate that knockdown gene expression of the CD45 receptor on NK-92 cells exhibits similar cell growth curves compared to untransduced NK-92 or GFP-transduced NK-92 cells. Figures 27A-27B. Co-culture assay using CCRF-CEM (target: T) and GFP NK-92 or GFP NK 45i-92 cells (effector: E) at a 5:1 (E:T) ratio. 16-hour incubation. (A) Flow cytometry analysis of co-cultures of CCRF-CEM alone (blue dots in the left panel), CCRF-CEM and control GFP-transduced NK-92 cells (center panel), or GFP NK 45i-92 cells (right panel). Blue dots in all panels indicate residual target CCRF-CEM cells, and red dots show effector cells from the co-culture assay. Total incubation time was 16 hours, and the effector T cell:target cell ratio was 5:1. All experiments were performed in duplicate. (B) Bar graph showing the percentage of cell lysis of GFP-transduced NK-92 cells compared to control GFP-transduced NK-92 cells in a co-culture assay with CCRF-CEM. These data demonstrate that blocking CD45 expression in NK-92 cells does not significantly affect the killing activity against CCRF-CEM cells compared to GFP-control NK-92 cells in an in vitro co-culture assay. Blue dots are located in the upper left panel. Figures 28A-28B. Co-culture assays using CCRF-CEM (target: T) and GFP NK-92, CD5CAR NK-92, or CD5CAR NK 45i-92 cells (effector: E). 5:1 (E:T) ratio. 16-hour incubation. (A) From right to left, flow cytometry analysis of CCRF-CEM alone (left panel), co-culture with CCRF-CEM and control GFP NK-92 cells (center left panel), CD5CAR NK-92 cells (center right panel), and CD5CAR NK 45i-92 cells (right panel). Blue dots in all panels indicate residual target CCRF-CEM cells, and red dots show effector cells from the co-culture assay. The total incubation time was 16 hours, and the effector T cell:target cell ratio was 5:1. All experiments were performed in duplicate. (B) Bar graph indicating the percentage of cell lysis by CD5CAR NK-92 cells or CD5CAR NK 45i-92 cells compared to control GFP NK92 cells in a co-culture assay with CCRF-CEM. Data are mean + SD. Compared to control GFP NK-92 cells, both CD5CAR NK cells and CD5CAR NK 45i-92 cells exhibited approximately 100% cell killing activity against CD5-positive CCRF-CEM. These data demonstrate that CD5CAR NK cells and CD5CAR NK 45i-92 cells can effectively lyse CD5-expressing CCRF-CEM cells compared to GFP control NK-92 cells in an in vitro co-culture assay and provide evidence that blocking CD45 gene expression does not affect cell function in NK-92 cells with respect to killing activity. The blue spot is located in the upper left portion of the first two figures, starting from the left. Figures 29A-29B. Organization and expression of CD45CAR constructs. (A) Schematic diagram of the CD45CAR lentiviral vector. The CD45CAR construct is a modular signaling domain containing: a leader sequence, an anti-CD45 scFv, a hinge domain (H), a transmembrane domain (TM), two costimulatory domains (CD28 and 4-1BB) that define the construct as a third-generation CAR, and the intracellular signaling domain CD3ζ. (B) HEK-293FT cells were transfected with lentiviral plasmids expressing GFP (lane 1) and CD45CAR (lane 2). 48 hours after transfection, the supernatant and cells were removed. Cells were lysed with mouse anti-human CD3ζ antibody for Western blotting and probe. Figures 30A-30B. CD45CAR was transduced into NK45i-92 cells and cell sorting of the CD45CAR-transduced cells was performed. Following lentiviral transduction of CD45CAR into NK45i-92 cells, the expression of CD45CAR on NK45i-92 cells (blue circle in the center panel) was determined by flow cytometry analysis compared to NK45i-92 cells (left panel). NK45i-92 cells expressing CD45CAR were sorted and the expression of CD45 on the cell surface was determined by flow cytometry analysis (right panel). Approximately 87% CD45CAR expression on the cell surface was detected by flow cytometry analysis. Figure 31A-31B. Co-culture assay with CCRF-CEM (target: T) and GFP NK-92 or CD45CAR NK 45i-92 cells (effector: E). 5:1 (E:T) ratio. 16-hour incubation. (A) Flow cytometry analysis of co-cultures with CCRF-CEM and control GFP-transduced NK-92 cells (left panel) or CD45CAR NK 45i-92 cells (right panel). Blue dots in all panels indicate residual target CCRF-CEM cells and red dots show effector NK-92 cells from the co-culture assay. The total incubation time was 16 hours and the ratio of effector T cells: target cells was 5:1. All experiments were performed in duplicate. (B) Bar graph indicating the percentage of cytolysis of CD45CAR NK 45i-92 cells compared to control GFP NK92 cells in a co-culture assay with CCRF-CEM. Data are mean ± SD. Compared to control GFP NK-92 cells, CD45CAR NK 45i-92 cells demonstrated approximately 70% cytolysis against CCRF-CEM cells. These data demonstrate that CD45CAR NK 45i-92 cells effectively lyse CCRF-CEM cells expressing CD45 compared to GFP control NK-92 cells in an in vitro co-culture assay. Figures 32A-32C. Co-culture assays with Jurkat cells (target: T) and GFP control or CD45CAR NK 45i-92 cells (effector: E). 5:1 or 2:1 (E:T) ratios. 6-hour incubation. (A) Flow cytometric analysis of Jurkat cells after staining with CMTMR cell tracker dye. These data demonstrate that Jurkat cells are CD45-positive (left panel) and mostly CD56-negative (right panel). (B) Flow cytometric analysis of co-culture assays with Jurkat cells (target: T) and control or CD45CAR NK 45i-92 cells (effector: E). Co-culture assays were performed at 5:1 or 2:1 (E:T) ratios. The left panel shows co-cultures with control GFP or CD45CAR / CD45KD NK-92 cells at a 5:1 (E:T) ratio, and the right panel shows co-cultures with control GFP or CD45CAR NK 45i-92 cells at a 2:1 (E:T) ratio. Blue dots in the panels indicate residual target Jurkat cells, and red dots represent effector cells from the co-culture assay. The total incubation time was 6 hours. All experiments were performed in duplicate. (C) Bar graphs show the percentage of cytolysis of CD45CAR NK 45i-92 cells compared to control GFP NK92 cells at a 5:1 or 2:1 (E:T) ratio. Data are mean ± SD. Under both conditions, CD45CAR NK 45i-92 cells demonstrated approximately 60% cytolysis against Jurkat cells compared to control GFP NK-92 cells. These data demonstrate that CD45CAR NK 45i-92 cells effectively lyse Jurkat cells expressing CD45 on their cell surface compared to GFP control NK-92 cells in an in vitro co-culture assay. Figures 33A-33C. Co-culture assays using GFP-NK-92 cells (target: T) and untransduced NK-92 cells or CD45CAR NK 45i-92 cells (effector: E). 5:1 or 2:1 (E:T) ratios. 6 hours of incubation. (A) Flow cytometric analysis using GFP-control NK-92 cells. These data demonstrate that GFP-control NK-92 cells are approximately 99% GFP-positive (green dots). (B) Flow cytometric analysis of co-culture assays with GFP-control NK-92 cells (target: T) and untransduced or CD45CAR NK 45i-92 cells (effector: E). Co-culture assays were performed at 5:1 or 2:1 (E:T) ratios. The left panel shows co-cultures with untransduced or CD45CAR NK 45i-92 cells at a 5:1 (E:T) ratio, and the right panel shows co-cultures with untransduced or CD45CAR NK 45i-92 cells at a 2:1 (E:T) ratio. Green dots in the graph indicate residual target GFP NK-92 cells, and red dots represent effector cells from the co-culture assay. Incubation time was 6 hours. All experiments were performed in duplicate. (C) Bar graph showing the percentage of cytolysis of GFP NK-92 cells by CD45CAR NK 45i-92 cells compared to untransduced NK-92 cells at a 5:1 or 2:1 (E:T) ratio. Data are mean ± SD. Compared to untransduced NK-92 cells, CD45CAR NK 45i-92 cells showed approximately 20% cell lysis at a 2:1 (E:T) ratio and approximately 55% cell lysis at a 5:1 (E:T) ratio against GFP NK-92 cells. This data demonstrates that CD45CAR NK 45i-92 cells effectively lyse GFP NK-92 cells expressing CD45 on their cell surface compared to untransduced NK-92 cells in an in vitro co-culture assay. Green dots are located in the upper right portion of each graph. Figures 33D-E. CD45b-BB or CD45b-28 was transduced into NK45i-92 cells, and the CD45b-BB or CD45b-28-transduced NK45i-92 cells were sorted. (D) Following lentiviral transduction of CD45b-BB or CD45b-28 into NK45i-92 cells, the surface expression of the CD45b-BB CAR or CD45b-28 CAR on NK45i-92 cells (blue circles in the middle panel) was determined by flow cytometry analysis compared to NK45i-92 cells (left panel). (E) NK45i-92 cells expressing the CD45b-BB or CD45b-28 CAR were sorted by flow cytometry analysis. Flow cytometry analysis detected approximately 74% CD45b-BB CAR or 82% CD45b-28 CAR expression on the cell surface. FIG33F-G . Co-culture analysis with REH cells (target: T) and GFP NK-92 cells, CD45CAR NK 45i-92 cells, CD45b-BB NK 45i-92 cells, or CD45b-28 NK 45i-92 cells (effector: E). 5:1 (E:T) ratio. 20-hour incubation. (F) Flow cytometric analysis of co-cultures with REH cells alone (left panel), REH cells and control GFP-transduced NK-92 cells (second panel from the left), CD45CAR NK 45i-92 cells (center panel), CD45b-BB NK 45i-92 cells (fourth panel from the left), or CD45b-28 NK 45i-92 cells (right panel). Blue dots in all figures indicate residual target REH cells, and red dots show effector GFP or CAR-NK-92 cells from the co-culture assay. REH is a B acute lymphoblastoid cell line. The total incubation time was 20 hours, and the effector NK-cell:target cell ratio was 5:1. All experiments were performed in duplicate. (G) Bar graph showing the percentage of cytolysis of CD45CAR NK 45i-92 cells, CD45b-BB NK 45i-92 cells, or CD45b-28 NK45i-92 cells compared to control GFP NK92 cells in a co-culture assay using REH cells. Data are mean ± SD. Compared to control GFP NK-92 cells, CD45CAR NK 45i-92 cells showed approximately 76% cytolysis, CD45b-BB NK 45i-92 cells showed approximately 79% cytolysis, and CD45b-28 NK 45i-92 cells showed 100% cytolysis against REH cells. These data indicate that all three CD45CARs effectively lyse REH cells. Figures 34A-34B. Schematic diagrams illustrating the constructs and their expression in T or NK cells. (A) A CAR (third generation) and sushi / IL-15 combination is assembled on a expression vector and expressed via an SFFV promoter. The CAR with sushi / IL-15 is linked to a P2A cleavage sequence. The sushi / IL-15 portion consists of an IL-2 signal peptide fused to the sushi domain and linked to IL-5 via a 26-amino acid polyproline linker. (B) The CAR and sushi / IL-15 are presented on a T or NK cell. Figures 35A-35B. CD4IL15RA-CAR expression. (A) HEK-293FT cells were transfected with lentiviral plasmids expressing GFP (lane 1), CD4IL15RA CAR (lane 2), and a positive control CD4 CAR (lane 3). 48 hours after transfection, the supernatant was removed, and cells were also removed for Western blotting using a mouse anti-human CD3z antibody. (B) HEK-293 cells were transduced with viral supernatant expressing GFP (left) or CD4IL15RA-CAR (right) from transfected HEK-293FT cells. After a 3-day incubation period, cells were harvested, stained with goat anti-mouse F(Ab')2, and analyzed by flow cytometry. Figure 36. Transduction of NK cells with CD4IL15RACAR. NK-92 cells were transduced with GFP (left) or CD4IL15RACAR (right) viral supernatant from transfected HEK-293FT cells. A second transduction was performed 24 hours after the first transduction. 24 hours after the second transduction, cells were harvested, washed, and transferred to tissue culture plates with fresh culture medium and IL-2. After a three-day incubation period, cells were harvested and stained with goat anti-mouse F(Ab')2 antibody or goat IgG (control) at 1:250 for 30 minutes. Cells were washed and stained with streptavidin-PE conjugate at 1:500, washed, suspended in 2% formalin, and analyzed by flow cytometry. Figure 37. T cells transduced with CD4IL15RA-CAR. Western blot on the left. HEK-293FT cells were transfected with lentiviral plasmids expressing GFP (lane 1) and CD4IL15RA-CAR (lane 2). 48 hours after transfection, the supernatant was removed, and cells were harvested for Western blot analysis using mouse anti-human CD3ζ antibodies. CD4IL15RA-CAR expression on the right. Activated T cells from umbilical cord blood buffy coats were transduced with viral supernatant from transfected HEK-293FT cells expressing GFP (left) or CD4IL15RA-CAR (right). A second transduction was performed 24 hours after the first transduction. 24 hours after the second transduction, cells were harvested, washed, and transferred to tissue culture plates with fresh culture medium and IL-2. After a 3-day incubation period, cells were harvested and stained with goat anti-mouse F(Ab')2 or an isotype control for 30 minutes. Transduced with GFP (left) or CD4IL15RA (right). Cells were washed and stained with streptavidin-PE conjugate at 1:250, washed, suspended in 2% formalin and analyzed by flow cytometry. Figures 38A-38B. CD4CAR NK-92 cells and CD4IL15RA CAR NK-92 cells eliminate KARPAS 299 T leukemia cells in co-culture. NK-92 cells transduced with GFP control (top right), CD4CAR (bottom left), or CD4IL15RA (bottom right) lentiviral supernatant were incubated with KARPAS 299 cells at a 5:1 ratio. After 4 hours of co-culture, cells were stained with mouse anti-human CD4 (APC) and CD3 (PerCp) antibodies and analyzed by flow cytometry (N=2). The upper left panel shows labeled Karpas 299 cells alone. The percentage of target cells lysed is shown in the figure. Figure 39. CD4CAR NK-92 cells and CD4IL15RA CAR NK-92 cells eliminate CD4-expressing MOLT4 T leukemia cells in co-culture. NK-92 cells transduced with lentiviral supernatant containing a GFP control (left), CD4CAR (center), or CD4IL15RA (second from the right) were incubated with MOLT4 cells at an effector:target ratio of 1:1 or 2:1. After overnight co-culture, cells were stained with mouse anti-human CD4 (APC) and CD56 (PerCp) antibodies and analyzed by flow cytometry (N=2). The upper right panel shows labeled MOLT4 cells alone. The percentage of target cells lysed is shown in the figure. Figure 40. CD4IL15RACAR T cells exhibit more potent in vivo anti-leukemic effects than CD4CAR. NSG mice were sublethally irradiated and injected intravenously (in the tail vein) with luciferase-expressing MOLM13 cells the following day to induce measurable tumor formation. Three days later, mice were injected intravenously with a course of 8×10⁶ CD4CAR, CD4IL15RACAR T cells, or vector control T cells. On days 3, 6, 9, and 11, mice were subcutaneously injected with RediJect D-Luciferin and imaged using IVIS. Figure 41. Percent tumor reduction in mice was measured and compared between three groups based on the study from Figure 40. The mean light intensity measured in mice injected with CD4CAR and CD4IL15RACAR T cells was compared to that in mice injected with vehicle control T cells and correlated with the remaining tumor burden. In each group consisting of two injections, the CD4CAR T cells are on the left and the CD4IL15RA CAR T cells are on the right. Figure 42. HEK 293 cells were transduced with EF1-GFP or SFFV-GFP viral supernatant using the indicated volumes in DMEM with 10% FBS in 6-well tissue culture plates. The medium was changed the following morning. Forty-eight hours later, transduced cells were visualized using GFP on an EVOS fluorescence microscope at 10×. FIG43 . Using volumes from previous figures, HEK 293 cells transduced with EF1-GFP or SFFV-GFP viral supernatants were trypsinized, suspended in formalin, and subjected to flow cytometry analysis using the FITC channel to determine the percentage of GFP+ cells. 44A-44B . Activated cord blood buffy coat T cells transduced with EF1-GFP or SFFV-GFP viral supernatant in the presence or absence of viral supernatant were trypsinized, suspended in formalin, and subjected to flow cytometry analysis using the FITC channel to determine the percentage of GFP+ cells on days 7, 14, 21, and 28 after transduction. (A) Percentage of GFP+ T cells in cells transduced with a small or large amount of supernatant. (B) The percentage of GFP+ T cells transduced with a large amount of EF1-GFP supernatant compared to the percentage of GFP+ T cells transduced with a small amount of SFFV-GFP supernatant (using 50 µL of SFFV-GFP and 1 mL of EF1-GFP supernatant). (N = 2). Figure 45. Ligand-receptor interactions in malignant plasma cells. APRIL ligand binds to TAC1 or BCMA. BAFF ligand binds to TAC1, BCMA, or BAFF-R. Implementation Method

[0004] Cross-reference to related applications This application is an International PCT application, which claims priority to U.S. Provisional Application Nos. 62 / 184,321, filed on June 25, 2015; 62 / 235,840, filed on October 1, 2015; and 62 / 244,435, filed on October 21, 2015, all of which are incorporated herein by reference in their entirety. The present invention provides chimeric antigen receptor (CAR) compositions, and methods of making and using the same. Chimeric antigen receptor (CAR) polypeptides include a signal peptide, an antigen recognition domain, a hinge region, a transmembrane domain, at least one costimulatory domain, and a signaling domain. First-generation CARs include CD3z as an intracellular signaling domain, while second-generation CARs include at least one single costimulatory domain derived from a variety of proteins. Examples of costimulatory domains include, but are not limited to, CD28, CD2, 4-1BB (CD137, also known as "4-BB"), and OX-40 (CD124). Third-generation CARs include two costimulatory domains, such as, but not limited to, CD28, 4-1BB, CD134 (OX-40), CD2, and / or CD137 (4-1BB). As used herein, the terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds having amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit on the maximum number of amino acids that can comprise a protein or peptide sequence. Polypeptides include any peptide or protein having two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains (also commonly referred to in the art as peptides, oligopeptides, and oligomers, for example) and long chains (of which there are many types). "Polypeptide" specifically includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, polypeptide variants, modified polypeptides, derivatives, analogs, and fusion proteins. Polypeptides include naturally occurring peptides, recombinant peptides, synthetic peptides, or combinations thereof. "Signal peptide" includes peptide sequences that direct the delivery and localization of a peptide and any linked polypeptides within a cell, for example, to a cell organelle (such as the endoplasmic reticulum) and / or the cell surface. A signal peptide is a peptide of any secretory or transmembrane protein that directs the disclosed polypeptide to the cell membrane and cell surface and provides for the correct localization of the polypeptide of the present invention. Specifically, the signal peptide of the present invention directs the polypeptide of the present invention to the cell membrane, wherein the extracellular portion of the polypeptide is displayed on the cell surface, the transmembrane portion spans the plasma membrane, and the active domain is located in the cytoplasm or in the interior of the cell. In one embodiment, the signal peptide is cleaved after passing through the endoplasmic reticulum (ER), i.e., is a cleavable signal peptide. In one embodiment, the signal peptide is a type I, II, III, or IV human protein. In one embodiment, the signal peptide comprises an immunoglobulin heavy chain signal peptide. An "antigen recognition domain" includes a polypeptide that is selective for or targets: a target antigen, receptor, peptide ligand, or protein ligand; or a target polypeptide. The antigen recognition domain can be obtained from any of a wide variety of extracellular domains or secreted proteins associated with ligand binding and / or signal transduction. The antigen recognition domain may include a portion of an Ig heavy chain linked to a portion of an Ig light chain, forming a variable single-chain fragment (scFv) that specifically binds to the target antigen. The antibody may be a monoclonal or polyclonal antibody or may have any type of specific binding to the target antigen. In another embodiment, the antigen recognition domain may be a receptor or a ligand. In specific embodiments, the target antigen is specific for a specific disease condition and the disease condition may be of any type, as long as it has a cell surface antigen that can be recognized by at least one of the chimeric receptor constructs present in the composite CAR framework. In specific embodiments, the chimeric receptor can be used for any cancer in which specific monoclonal or polyclonal antibodies exist or are capable of producing specific monoclonal or polyclonal antibodies. In particular, cancers such as neuroblastoma, small cell lung cancer, melanoma, ovarian cancer, renal cell carcinoma, colon cancer, Hodgkin's lymphoma, and childhood acute lymphoblastic leukemia have antigens specific for the chimeric receptor. The target-specific antigen recognition domain preferably includes an antigen-binding domain derived from an antibody directed against the target antigen, or a peptide that binds to the target antigen, or a peptide or protein that binds to an antibody that binds to the target antigen, or a peptide or protein ligand that binds to a receptor on the target (including but not limited to growth factors, cytokines, or hormones), or a domain derived from a receptor that binds to a peptide or protein ligand on the target (including but not limited to growth factor receptors, cytokine receptors, or hormone receptors). In one embodiment, the antigen recognition domain comprises the binding portion or variable region of a single or multiple antibodies that are selective for the target. In another embodiment, the antigen recognition domain comprises a camelid single-domain antibody, or a portion thereof. In one embodiment, a camelid single-domain antibody comprises a heavy chain antibody, or VHH antibody, found in camels. VHH antibodies from camelids (e.g., camels, dromedaries, llamas, and alpacas) refer to variable fragments of camelid single-chain antibodies (see Nguyen et al., 2001; Muyldermans, 2001), and also include isolated, recombinant, or synthetic camelid VHH antibodies. In another embodiment, the antigen recognition domain comprises a ligand that binds to its cognate receptor. For example, APRIL is a ligand that binds to the TAC1 receptor or the BCMA receptor. According to the invention disclosed herein, the antigen recognition domain comprises APRIL, or a fragment thereof. As another example, BAFF is a ligand that binds to the BAFF-R receptor or the BCMA receptor. According to the invention disclosed herein, the antigen recognition domain comprises BAFF, or a fragment thereof. In another embodiment, the antigen recognition domain is humanized. It is understood that the antigen recognition domain can include some variability in its sequence and still be selective for the targets disclosed herein. Thus, it is contemplated that polypeptides of the antigen recognition domain can have at least 95%, at least 90%, at least 80%, or at least 70% identity to the antigen recognition domain polypeptides disclosed herein and still be selective for the targets described herein and fall within the scope of the present invention. Targets include interleukin-6 receptor, NY-ESO-1, alpha-fetoprotein (AFP), glypican-3 (GPC3), BCMA, BAFF-R, TACI, LeY, CD5, CD13, CD14, CD15 CD19, CD20, CD22, CD33, CD41, CD61, CD64, CD68, CD117, CD123, CD138, CD267, CD269, CD38, Flt3 receptor, CS1, CD45, ROR1, PSMA, MAGE A3, glycolipids, glypican 3, F77, GD-2, WT1, CEA, HER-2 / neu, MAGE-3, MAGE-4, MAGE-5, MAGE-6, alpha-fetoprotein, CA 19-9, CA 72-4, NY-ESO, FAP, ErbB, c-Met, MART-1, CD30, EGFRvIII, immunoglobulins kappa and lambda, CD38, CD52, CD3, CD4, CD8, CD5, CD7, CD2, and CD138. In another embodiment, the target includes any portion of interleukin 6 receptor, NY-ESO-1, alpha-fetoprotein (AFP), glypican-3 (GPC3), BCMA, BAFF-R, TACI, LeY, CD5, CD13, CD14, CD15 CD19, CD20, CD22, CD33, CD41, CD61, CD64, CD68, CD117, CD123, CD138, CD267, CD269, CD38, Flt3 receptor, CS1, CD45, TACI, ROR1, PSMA, MAGE A3, glycolipids, glypican 3, F77, GD-2, WT1, CEA, HER-2 / neu, MAGE-3, MAGE-4, MAGE-5, MAGE-6, alpha-fetoprotein, CA 19-9, CA 72-4, NY-ESO, FAP, ErbB, c-Met, MART-1, CD30, EGFRvIII, immunoglobulins kappa and lambda, CD38, CD52, CD3, CD4, CD8, CD5, CD7, CD2, and CD138. In one embodiment, the targets include surface-exposed portions of interleukin 6 receptor, NY-ESO-1, alpha-fetoprotein (AFP), glypican-3 (GPC3), BCMA, BAFF-R, TACI, LeY, CD5, CD13, CD14, CD15 CD19, CD20, CD22, CD33, CD41, CD61, CD64, CD68, CD117, CD123, CD138, CD267, CD269, CD38, Flt3 receptor, CS1, CD45, TACI, ROR1, PSMA, MAGE A3, glycolipids, glypican 3, F77, GD-2, WT1, CEA, HER-2 / neu, MAGE-3, MAGE-4, MAGE-5, MAGE-6, alpha-fetoprotein, CA 19-9, CA 72-4, NY-ESO, FAP, ErbB, c-Met, MART-1, CD30, EGFRvIII, immunoglobulin kappa and lambda, CD38, CD52, CD3, CD4, CD8, CD5, CD7, CD2, and CD138 polypeptides. In another embodiment, the target antigen comprises a viral or fungal antigen, such as E6 and E7 from human papillomavirus (HPV), or EBV (Epstein-Barr virus) antigens; a portion thereof; or a surface-exposed region thereof. In one embodiment, the TACI antigen recognition domain comprises SEQ ID NO:24. In one embodiment, the BCMA antigen recognition domain comprises SEQ ID NO:25. In one embodiment, the CS1 antigen recognition domain comprises SEQ ID NO:26. In one embodiment, the BAFF-R antigen recognition domain comprises SEQ ID NO:27. In one embodiment, the CD33 antigen recognition domain comprises SEQ ID NO:28. In one embodiment, the CD123 antigen recognition domain comprises SEQ ID NO:29. In one embodiment, the CD19 antigen recognition domain comprises SEQ ID NO:30. In one embodiment, the CD20 antigen recognition domain comprises SEQ ID NO: 31. In another embodiment, the CD20 antigen recognition domain comprises SEQ ID NO: 32. In one embodiment, the CD22 antigen recognition domain comprises SEQ ID NO:33. In one embodiment, the CD45 antigen recognition domain comprises SEQ ID NO:34. The hinge region is a sequence positioned between, for example, a chimeric antigen receptor and at least one co-stimulatory domain and a signaling domain, including but not limited to. Hinge sequences can be obtained, including, for example, any suitable sequence from any genus, including human or a portion thereof. Such hinge regions are known in the art. In one embodiment, the hinge region comprises the hinge region of a human protein, including CD-8α, CD28, 4-1BB, OX40, CD3-ζ, T cell receptor α or β chain, CD3ζ chain, CD28, CD3ε, CD45, CD4, CD5, CD8, CD8a, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, ICOS, CD154, functional derivatives thereof, and combinations thereof. In one embodiment, the hinge region comprises a CD8 alpha hinge region. In some embodiments, the hinge region comprises one selected from, but not limited to, immunoglobulins (eg, IgG1, IgG2, IgG3, IgG4, and IgD). The transmembrane domain comprises a hydrophobic polypeptide that spans the cell membrane. Specifically, the transmembrane domain spans from one side of the cell membrane (outside the cell) to the other side of the cell membrane (inside the cell or cytoplasm). The transmembrane domain may be in the form of an α-helix or a β-barrel, or a combination thereof. The transmembrane domain may include heterologous isoforms having multiple transmembrane segments, each in the form of an α-helix, a β-sheet, or a combination thereof. In one embodiment, a transmembrane domain that is naturally associated with a domain in the CAR is used. In another embodiment, the transmembrane domain is selected or modified by amino acid substitution to prevent such domain from binding to the transmembrane domain of the same or different surface membrane proteins, thereby minimizing interactions with other members of the receptor complex. For example, transmembrane domains include transmembrane domains of T cell receptor α or β chains, CD3 zeta chain, CD28, CD3 epsilon, CD45, CD4, CD5, CD7, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD68, CD134, CD137, ICOS, CD41, CD154, functional derivatives thereof, and combinations thereof. In one embodiment, the transmembrane domain is artificially designed such that greater than 25%, greater than 50%, or greater than 75% of the amino acid residues in the domain are hydrophobic residues, such as leucine and valine. In one embodiment, a triplet of phenylalanine, tryptophan, and valine is found at each end of the synthetic transmembrane domain. In one embodiment, the transmembrane domain is a CD8 transmembrane domain. In another embodiment, the transmembrane domain is a CD28 transmembrane domain. Such transmembrane domains are known in the art. Signaling domains and co-stimulatory domains include polypeptides that can provide for activation of immune cells to stimulate or activate at least some aspect of immune cell signaling pathways. In one embodiment, the signaling domain comprises a polypeptide comprising a functional signaling domain of CD3ζ, common FcRγ (FCER1G), FcγRlla, FcRβ (Fcε Rib), CD3γ, CD3δ, CD3ε, CD79a, CD79b, DNAX-activating protein 10 (DAP10), DNAX-activating protein 12 (DAP12), active fragments thereof, functional derivatives thereof, and combinations thereof. Such signaling domains are known in the art. In one embodiment, the CAR polypeptide further comprises one or more costimulatory domains. In one embodiment, the costimulatory domain is a functional signaling domain from a protein comprising: OX40; CD27; CD28; CD30; CD40; PD-1; CD2; CD7; CD258; Natural Killer Group 2 Member C (NKG2C); Natural Killer Group 2 Member D (NKG2D), B7-H3; a ligand that binds to at least one of CD83, ICAM-1, LFA-1 (CD11a / CD18), ICOS, and 4-1BB (CD137); CDS; ICAM-1; LFA-1 (CD1a / CD18); CD40; CD27; CD7; B7-H3; NKG2C; PD-1; ICOS; active fragments thereof; functional derivatives thereof; and combinations thereof. As used herein, at least one co-stimulatory domain and a signaling domain may be collectively referred to as an intracellular domain. As used herein, a hinge region and an antigen recognition domain may be collectively referred to as an extracellular domain. The present invention also provides a polynucleotide encoding the above chimeric antigen receptor polypeptide. As used herein, the term "polynucleotide" is defined as a chain of nucleotides. Polynucleotides include DNA and RNA. Furthermore, nucleic acids are polymers of nucleotides. Therefore, as used herein, nucleic acid and polynucleotide are interchangeable. Those skilled in the art will recognize that nucleic acids are polynucleotides, which can be hydrolyzed into monomeric "nucleotides." Monomeric nucleotides can be hydrolyzed into nucleosides. As used herein, polynucleotides include, but are not limited to, all nucleic acid sequences obtained by any means available in the art, including, but not limited to, recombinant means (i.e., cloning nucleic acid sequences from recombinant libraries or cellular genomes using conventional cloning techniques), polymerase chain reaction (PCR), and similar means, as well as by synthesis. CAR-encoding polynucleotides can be readily prepared from the amino acid sequence of a given CAR using any conventional method. Regarding the amino acid sequence of each domain, the base sequence encoding the amino acid sequence can be obtained from the aforementioned NCBI RefSeq ID or GenBenk accession number, and the nucleic acids of the present invention can be prepared using standard molecular biology and / or chemical procedures. For example, based on the base sequence, polynucleotides can be synthesized, and the polynucleotides of the present invention can be prepared by assembling DNA fragments obtained from a cDNA library using polymerase chain reaction (PCR). In one embodiment, a polynucleotide disclosed herein is part of a gene, or an expression or selection cassette. The polynucleotides described above can be cloned into a vector. A "vector" is a composition of matter that includes an isolated polynucleotide and can be used to deliver the isolated polynucleotide into a cell. Numerous vectors are known in the art, including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphoteric compounds, plasmids, phagemids, cosmids, and viruses. Viruses include bacteriophages and phage derivatives. Thus, the term "vector" includes autonomously replicating plasmids or viruses. The term should also be construed to include non-plasmids and non-viral compounds that facilitate nucleic acid transfer into cells, such as polylysine compounds, liposomes, and the like. Examples of viral vectors include, but are not limited to, adenoviral vectors, adeno-associated viral vectors, retroviral vectors, lentiviral vectors, and the like. In one embodiment, vectors include cloning vectors, expression vectors, replication vectors, probe production vectors, integration vectors, and sequencing vectors. In one embodiment, the vector is a viral vector. In one embodiment, the viral vector is a retroviral vector or a lentiviral vector. In one embodiment, the engineered cells are virally transduced to express the polynucleotide sequence. Numerous viral-based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a suitable platform for gene delivery systems. The selected gene can be inserted into a vector and encapsulated into retroviral particles using techniques known in the art. The recombinant virus can then be isolated and delivered into the patient's cells in vivo or ex vivo. Numerous retroviral systems are known in the art. In some embodiments, adenoviral vectors are used. Numerous adenoviral vectors are known in the art. In one embodiment, a lentiviral vector is used. Viral vector technology is well known in the art and is described, for example, in Sambrook et al. (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York) and other virology and molecular biology manuals. Viruses suitable for use as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. Typically, suitable vectors contain an origin of replication functional in at least one organism, a promoter sequence, suitable restriction endonuclease sites, and one or more selectable markers (e.g., WO 01 / 96584; WO 01 / 29058; and U.S. Pat. No. 6,326,193). Lentiviral vectors are well-known for their ability to efficiently transfer genes into human T cells, but expression of vector-encoded genes depends on the internal promoter driving their expression. A strong promoter is particularly important for third- and fourth-generation CARs with additional costimulatory domains or genes encoding proliferative cytokines, as increased CAR body size does not guarantee equivalent expression. A variety of promoters exist with varying strengths and cell type specificities. Gene therapy using CAR T cells relies on the ability of T cells to adequately express the CAR body and maintain expression for extended periods of time. The EF-1α promoter is often used for CAR expression. The present invention relates to expression vectors containing strong promoters for high gene expression in T cells or NK cells. In other embodiments, the inventors disclose strong promoters suitable for high CAR expression in T cells or NK cells. In specific embodiments, the strong promoter is associated with the SFFV promoter, which is selectively introduced into the expression vector to achieve high expression and long-term maintenance of expression in T cells or NK cells. The genes expressed are preferentially CARs, T cell co-stimulators, and cytokines used in immunotherapy. One example of a suitable promoter is the pre-early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high expression of any operably linked polynucleotide sequence. Another example of a suitable promoter is elongated growth factor-1a (EF-1a). However, other constitutive promoter sequences may also be used, including but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, avian leukosis virus promoter, Epstein-Barr virus pre-early promoter, Rous sarcoma virus promoter, and human gene promoters such as but not limited to the actin promoter, myosin promoter, hemoglobin promoter, and creatine kinase promoter. Furthermore, the present invention should not be limited to the use of constitutive promoters, but also encompasses inducible promoters as part of the present invention. The use of an inducible promoter provides a molecular switch that can turn on the expression of the polynucleotide sequence to which it is operably linked when such expression is desired, or turn off expression when such expression is not desired. Examples of inducible promoters include, but are not limited to, the metallothionein promoter, the glucocorticoid promoter, the progesterone promoter, and the tetracycline promoter. Expression of chimeric antigen receptor polynucleotides can be achieved using, for example, expression vectors, including but not limited to, at least one of the SFFV (splenic focus forming virus) (e.g., SEQ ID NO: 23) or human elongation factor 11α (EF) promoter, the CAG (chicken β-actin promoter with CMV enhancer) promoter, or the human elongation factor 1α (EF) promoter. Examples of less potent / lower expression promoters include, but are not limited to, the simian virus 40 (SV40) early promoter, the cytomegalovirus (CMV) pre-early promoter, the ubiquitin C (UBC) promoter, and the phosphoglycerate kinase 1 (PGK) promoter, or portions thereof. Inducible expression of chimeric antigen receptors can be achieved using, for example, tetracycline-responsive promoters, including but not limited to, TRE3GV (Tet response element, including all generations and preferably generation 3), the inducible promoter (Clontech Laboratories, Mountain View, CA), or portions or combinations thereof. In a preferred embodiment, the promoter is the SFFV promoter or a derivative thereof. It has been unexpectedly found that the SFFV promoter provides stronger expression and a greater degree of persistence in cells transduced according to the present invention. "Expression vector" means a vector comprising a recombinant polynucleotide comprising an expression control sequence operably linked to a nucleotide sequence to be expressed. The expression vector comprises sufficient cis-acting elements for expression; other elements for expression may be supplied by the host cell or in an in vitro expression system. Expression vectors include all expression vectors known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes), and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide. The expression vector may be a bicistronic or polycistronic expression vector. A bicistronic or polycistronic expression vector may comprise (1) multiple promoters fused to each open reading frame; (2) splicing signals inserted between genes; a fusion of genes whose expression is driven by a single promoter; (3) a proteolytic cleavage site inserted between genes (self-cleaving peptide); and (iv) an internal ribosome entry site (IRES) inserted between genes. In one embodiment, the present invention provides cells engineered with at least one chimeric antigen receptor polypeptide or polynucleotide. "Engineered cells" means any cell of any organism that has been modified, transformed, or manipulated by the addition or modification of genes, DNA or RNA sequences, or proteins or polypeptides. The isolated cells, host cells, and genetically engineered cells of the present invention include isolated immune cells, such as NK cells and T cells, that contain DNA or RNA sequences encoding chimeric antigen receptors or chimeric antigen receptor complexes and express chimeric receptors on their cell surfaces. Isolated host cells and engineered cells can be used, for example, to enhance NK cell activity or T lymphocyte activity, treat cancer, and treat infectious diseases. In one embodiment, the engineered cells include immunoregulatory cells. These cells include T cells, such as CD4 T cells (helper T cells), CD8 T cells (cytotoxic T cells, CTLs), and memory T cells or memory stem cell T cells. In another embodiment, the T cells include natural killer T cells (NK T cells). In one embodiment, the engineered cells include natural killer cells. Natural killer cells are well known in the art. In one embodiment, natural killer cells include cell lines such as NK-92 cells. Other examples of NK cell lines include NKG, YT, NK-YS, HANK-1, YTS cells, and NKL cells. NK cells mediate anti-tumor effects without the risk of GvHD and are short-lived compared to T cells. Therefore, NK cells will be exhausted soon after destroying cancer cells, reducing the need for inducible suicide genes on the CAR construct to ablate the modified cells. According to the present invention, it was unexpectedly discovered that NK cells provide readily obtainable cells that are engineered to contain and express the chimeric antigen receptor polypeptides disclosed herein. Allogeneic or autologous NK cells induce rapid immune responses but disappear from circulation relatively quickly due to their limited lifespan. Therefore, the applicants unexpectedly discovered that the use of CAR cell-based therapies can reduce the problem of persistent side effects. The present invention includes methods for producing cCARs. In some embodiments, cCARs are produced using T cells. In other embodiments, cCARs are produced using native NK cells isolated from peripheral blood or umbilical cord blood and NK-92 cells, allowing them to be administered "off-the-shelf" to any mammal suffering from a disease or cancer. According to one aspect of the present invention, NK cells can be expanded and transfected with a CAR polynucleotide according to the present invention. NK cells can be derived from umbilical cord blood, peripheral blood, iPS cells, and embryonic stem cells. According to one aspect of the present invention, NK-92 cells can be expanded and transfected with a CAR. NK-92 is a continuously growing cell line that possesses the properties and characteristics of natural killer (NK) cells (Arai, Meagher et al. 2008). The NK-92 cell line is IL-2 dependent and has been demonstrated to be safe (Arai, Meagher et al. 2008) and viable. NK-92 cells expressing a CAR can be expanded in serum-free medium with or without co-culture of feeder cells. Pure populations of NK-92 cells carrying the relevant CAR can be obtained by sorting. In one embodiment, the engineered cells include allogeneic T cells obtained from a donor that have been modified to not activate the components of the TCR (T cell receptor) involved in MHC recognition. Thus, the TCR-deficient T cells will not cause graft-versus-host disease (GVHD). In some embodiments, the engineered cells can be modified to prevent the expression of cell surface antigens. For example, the engineered cells can be genetically modified to delete the native CD45 gene to prevent its expression and cell surface presentation. In some embodiments, the engineered cells include an inducible suicide gene ("safety switch") or a combination of safety switches, which can be assembled on a vector such as, but not limited to, a retroviral vector, a lentiviral vector, an adenoviral vector, or a plasmid. The introduction of a "safety switch" can significantly enhance the safety profile and limit on-target or off-tumor toxicity of the composite CAR. The "safety switch" can be an inducible suicide gene such as, but not limited to, caspase-9, thymidine kinase, cytosine deaminase (CD), or cytochrome P450. Other safety switches used to eliminate undesirable modified T cells involve the expression of CD20 or CD19 or a truncated epidermal growth factor receptor in T cells. All possible safety switches are contemplated and implemented in the present invention. In some embodiments, a suicide gene is integrated into the genome of the engineered cell. In one embodiment, the present invention provides engineered cells having a CD45 chimeric antigen receptor polynucleotide. In one embodiment, the CD45 CAR polypeptide comprises SEQ ID NO: 13 and the corresponding polynucleotide sequence SEQ ID NO: 14. In another embodiment, the CD45 CAR polypeptide comprises SEQ ID NO: 15 and the corresponding polynucleotide sequence SEQ ID NO: 16. In another embodiment, the CD45 CAR polypeptide comprises SEQ ID NO: 17 and the corresponding polynucleotide sequence SEQ ID NO: 18. [Multiple] [CAR] [unit] [] The present invention provides engineered cells with at least two different CAR polypeptides. As used herein, composite CAR (cCAR) or multiple CARs refers to cells engineered with at least two different chimeric antigen receptor polypeptides. As used herein, "different chimeric antigen receptor polypeptides" have unique antigen recognition domains, signal peptides, hinge regions, transmembrane domains, at least one costimulatory domain, and signaling domains. Thus, two unique chimeric antigen receptor polypeptides will have different antigen recognition domains. The signal peptide, hinge region, transmembrane domain, at least one costimulatory domain, and signaling domain may be the same or different between two different chimeric antigen receptor polypeptides. As used herein, a chimeric antigen receptor (CAR) unit refers to different chimeric antigen receptor polypeptides or polynucleotides encoding different chimeric antigen receptor polypeptides. As used herein, a unique antigen recognition domain is an antigen recognition domain that is specific for or targets a single target or a single antigenic determinant of a target. In some embodiments, the composite CAR targets the same antigen. For example, the cCAR targets different antigenic determinants or portions of a single antigen. In some embodiments, each of the CAR units in the composite CAR targets a different antigen specific for the same or different disease conditions or side effects caused by the disease condition. In some embodiments, the composite CAR targets two different antigens. Generating composite CARs carrying different CAR units can be extremely challenging: (1) CAR-CAR interactions can have adverse effects, and appropriate CAR design is key to counteract these effects; (2) Composite CARs in a single construct can increase the length of the expression cassette, which can lead to reduced viral titer and protein expression; (3) Appropriate designs are required to include multiple CAR host elements, especially strategies to express multiple CARs in a single vector; (4) Strong promoters are particularly important for composite CARs carrying other CAR units; (5) The hinge region in the CAR needs to be designed so that hinge region interactions between the CAR units are preferably avoided; and (6) Two or more CAR units expressed in cells can cause toxic effects (CAR-CAR interactions). Applicants herein provide novel and unexpected CAR compositions and methods that can address these obstacles. In one embodiment, the present invention provides engineered cells with multiple CAR units. This allows a single engineered cell to target multiple antigens. Simultaneous targeting of multiple surface markers or antigens by multiple CAR units can prevent the selection of resistant clones and reduce tumor recurrence. Multiple CAR T cell immunotherapies for any malignant disease, in which each individual component CAR comprises multiple domains and activation sites, have not yet been developed. In one aspect of the present invention, the cCAR comprises a plurality of CAR units. In some embodiments, the cCAR comprises at least two CAR units. In another embodiment, the cCAR comprises at least three CAR units. In another embodiment, the cCAR comprises at least four CAR units. In one embodiment, the present invention provides engineered cells having at least two different chimeric antigen receptor polypeptides, each having a different antigen recognition domain. In a preferred embodiment, the engineered cells with at least two different chimeric antigen receptor polypeptides are primary NK cells isolated from peripheral blood or umbilical cord blood and NK-92 cells, making them "off-the-shelf" for administration to any mammal suffering from a disease or cancer. In one embodiment, the engineered cell comprises (i.) a first chimeric antigen receptor polypeptide comprising a first antigen recognition domain, a first signal peptide, a first hinge region, a first transmembrane domain, a first costimulatory domain, and a first signaling domain; and (ii.) a second chimeric antigen receptor polypeptide comprising a second antigen recognition domain, a second signal peptide, a second hinge region, a second transmembrane domain, a second costimulatory domain, and a second signaling domain. The first antigen recognition domain and the second antigen recognition domain are different. In a preferred embodiment, each engineered CAR unit polynucleotide has a different nucleotide sequence to prevent homologous recombination. In one embodiment, the target of the first antigen recognition domain is selected from the group consisting of interleukin 6 receptor, NY-ESO-1, alpha-fetoprotein (AFP), glypican-3 (GPC3), BAFF-R, BCMA, TACI, LeY, CD5, CD13, CD14, CD15 CD19, CD20, CD22, CD33, CD41, CD61, CD64, CD68, CD117, CD123, CD138, CD267, CD269, CD38, Flt3 receptor and CS1; and the target of the second recognition domain is selected from the group consisting of interleukin 6 receptor, NY-ESO-1, alpha-fetoprotein (AFP), glypican-3 (GPC3), BAFF-R, BCMA, TACI, LeY, CD5, CD13, CD14, CD15 CD19, CD20, CD22, CD33, CD41, CD61, CD64, CD68, CD117, CD123, CD138, CD267, CD269, CD38, Flt3 receptor and CS1. In one embodiment, the engineered cell comprises a first chimeric antigen receptor polypeptide having a CD19 antigen recognition domain and a second chimeric antigen receptor polypeptide having a CD20 recognition domain. In one embodiment, the engineered cell comprises the polypeptide of SEQ ID NO: 3 and the corresponding polynucleotide of SEQ ID NO: 4. In one embodiment, the engineered cell comprises a first chimeric antigen receptor polypeptide having a CD19 antigen recognition domain and a second chimeric antigen receptor polypeptide having a CD22 recognition domain. In one embodiment, the engineered cell comprises the polypeptide of SEQ ID NO: 5 and the corresponding polynucleotide of SEQ ID NO: 6. In one embodiment, the engineered cell comprises a first chimeric antigen receptor polypeptide having a CD19 antigen recognition domain and a second chimeric antigen receptor polypeptide having a CD123 recognition domain. In one embodiment, the engineered cell comprises a polypeptide of SEQ ID NO: 7 and a corresponding polynucleotide of SEQ ID NO: 8. In one embodiment, the engineered cell comprises a first chimeric antigen receptor polypeptide having a CD33 antigen recognition domain and a second chimeric antigen receptor polypeptide having a CD123 antigen recognition domain. In one embodiment, the engineered cell comprises the polypeptide of SEQ ID NO: 9 and the corresponding polynucleotide of SEQ ID NO: 10. In another embodiment, the engineered cell comprises the polypeptide of SEQ ID NO: 11 and the corresponding polynucleotide of SEQ ID NO: 12. In one embodiment, the engineered cells include a first chimeric antigen receptor polypeptide having a BAFF-R antigen recognition domain and a second chimeric antigen receptor polypeptide having a CS1 antigen recognition domain. In one embodiment, the engineered cells comprise a first chimeric antigen receptor polypeptide having a CD269 antigen recognition domain and a second chimeric antigen receptor polypeptide having a CS1 recognition domain. In one embodiment, the engineered cells comprise a polypeptide comprising SEQ ID NO: 19 and the corresponding polynucleotide SEQ ID NO: 20. In one embodiment, the engineered cells comprise a polypeptide comprising SEQ ID NO: 21 and the corresponding polynucleotide SEQ ID NO: 22. In one embodiment, the engineered cells include a first chimeric antigen receptor polypeptide having a CD33 antigen recognition domain and a second chimeric antigen receptor polypeptide having a CD123 recognition domain. In one embodiment, each CAR unit comprises the same or different hinge regions. In another embodiment, each CAR unit comprises the same or different transmembrane regions. In another embodiment, each CAR unit comprises the same or different intracellular domains. In one embodiment, each CAR unit comprises a CD3 zeta chain signaling domain. In one embodiment, each different CAR unit includes a different costimulatory domain to prevent interaction. For example, the first chimeric antigen receptor polypeptide includes a 4-BB costimulatory domain; and the second chimeric antigen receptor polypeptide includes a CD28 costimulatory domain. In another embodiment, the hinge region is designed to exclude amino acids that may cause undesirable intramolecular or intermolecular interactions. For example, the hinge region can be designed to exclude or minimize cysteine ​​residues to prevent disulfide bond formation. In another embodiment, the hinge region can be designed to exclude or minimize hydrophobic residues to prevent undesirable hydrophobic interactions. Composite CARs can kill independently or in combination. Multiple or composite CARs contain the same or different hinge regions, the same or different transmembrane regions, the same or different costimulatory regions, and the same or different intracellular domains. The hinge regions are preferably selected to avoid overlapping sites. The composite CARs of the present invention can target the same or different tumor populations in T or NK cells. For example, the first CAR can target a large tumor population and then, or the second CAR can eradicate cancer or leukemia stem cells to prevent cancer recurrence. According to the present invention, it was unexpectedly discovered that multiple CARs targeting different or the same tumor population in T or NK cells can counteract tumor factors in cancer cells that can cause resistance to CAR killing activity, thereby resulting in downregulation of target antigens on the cancer cell surface. It was also unexpectedly discovered that this can lead to cancer cells "evading" CAR therapy, a phenomenon known as "antigen escape," and tumor heterogeneity, whereby different tumor cells can display different surface antigen expression profiles. [have] [CAR] [Cells engineered with polypeptides and enhancers] [] In another embodiment, the present invention provides engineered cells having at least one chimeric antigen receptor polypeptide and an enhancer. In one embodiment, the present invention provides cells engineered with at least two different chimeric antigen receptor polypeptides and enhancers. As used herein, enhancers include biomolecules that promote or enhance the activity of cells engineered with chimeric antigen receptor polypeptides. Enhancers include cytokines. In another embodiment, enhancers include IL-2, IL-7, IL-12, IL-15, IL-21, PD-1, PD-L1, CSF1R, CTAL-4, TIM-3, and TGFRβ, their receptors, and functional fragments thereof. Enhancers can be expressed by the engineered cells described herein and displayed on the surface of the engineered cells, or they can be secreted by the engineered cells into the surrounding extracellular space. Methods of surface presentation and secretion are well known in the art. For example, enhancers can be fusion proteins with peptides that provide for surface presentation or secretion into the extracellular space. The effects of enhancers can be supplemented by other factors, such as enhancer receptors and functional fragments thereof. Other factors can be co-expressed with enhancers in the form of fusion proteins or expressed as separate peptides and secreted into the extracellular space. In one embodiment, the enhancer is IL-15. In this case, the additional factor is the IL-15 receptor, and functional fragments thereof. Functional fragments include the IL-15 receptor, IL-15RA, and the sushi domain of IL-15RA. Examples of suitable domains include SEQ ID NO: 35. According to the present invention, any chimeric antigen receptor polypeptide disclosed herein comprises human interleukin-15 having the human interleukin-2 signal peptide of SEQ ID NO: 36. Interleukin (IL)-15 and its specific receptor chain, IL-15Rα (IL-15-RA), play important functional roles in a variety of effector cells, including NK and CD8 T cells. CD8+ T cells can be modified to express autocrine growth factors, including but not limited to IL-2, IL-7, IL21, or IL-15, to maintain survival after in vivo transfer. Without wishing to be bound by theory, it is believed that IL-15 can overcome CD4 deficiency to induce naive and recall memory CD8 T cells. Overexpression of IL-15-RA or an IL-15 IL-RA fusion on CD8 T cells significantly enhances their survival and proliferation in vitro and in vivo. In some embodiments, a CD4 CAR or any CAR may include expression of any one or more of the following: IL-15, IL15RA, and IL-15 / IL-15R or IL-15-RA / IL-15, or a portion or combination thereof, to enhance CAR T or NK cell survival or proliferation and improve the expansion of memory CAR CD8+ T cells. The present invention relates to engineered cells having a CAR and any one or more of IL-15, IL15RA, and IL-15 / IL-15R or IL15-RA / IL-15 as described herein, or a portion or combination thereof, to enhance the survival or persistence or proliferation of CAR T or NK for treating cancer in a patient. In one embodiment, the engineered cells include CD4 chimeric antigen receptor polypeptide and IL-15RA (SEQ ID NO: 1), and the corresponding polynucleotides (SEQ ID NO: 2). [Methods for Producing Engineered Cells] [] Any of the polynucleotides disclosed herein can be introduced into the engineered cells by any method known in the art. In one embodiment, the CAR polynucleotide is delivered to the engineered cells by any viral vector as disclosed herein. In one embodiment, to achieve an enhanced safety profile or therapeutic index, any of the engineered cells disclosed herein are engineered to be biodegradable versions or derivatives modified with transient RNA, or a combination thereof. The RNA-modified CARs of the present invention can be electroporated into T cells or NK cells. Expression of the composite CAR can gradually wane over several days. In some embodiments of the present invention, any of the engineered cells disclosed herein can be constructed in a transposon system (also known as "Sleeping Beauty"), which integrates CAR DNA into the host genome without a viral vector. [Generate multiple [CAR] [Methods of engineering cells] [] In another embodiment, the present invention provides a method of making an engineered cell having at least two CAR units. In some embodiments, bicistronic or polycistronic expression vectors are used to express multiple CAR units in T or NK cells. There are several strategies that can be used to construct bicistronic or polycistronic vectors, including (but not limited to) (1) multiple promoters fused to the open reading frame of the CAR; (2) inserting splicing signals between the CAR units; expressing fusions of CARs driven by a single promoter; (3) inserting a proteolytic cleavage site between the CAR units (self-cleaving peptides); and (iv) inserting an internal ribosome entry site (IRES). In a preferred embodiment, multiple CAR units are expressed in a single open reading frame (ORF), thereby generating a single polypeptide having multiple CAR units. In this embodiment, an amino acid sequence or linker containing an efficient cleavage site is placed between each CAR unit. As used herein, high cleavage efficacy is defined as greater than 50%, greater than 70%, greater than 80%, or greater than 90% cleavage of translated protein. Cleavage efficacy can be measured by Western blot analysis, as described by Kim 2011. Furthermore, in a preferred embodiment, equal amounts of cleavage products are present, as shown by Western blot analysis. Examples of efficient cleavage sites include porcine teschovirus-1 2A (P2A), FMDV 2A (referred to herein as F2A); equine rhinitis virus (ERAV) 2A (E2A); and those aasigna virus 2A (T2A), cytoplasmic polyhedrosis virus 2A (BmCPV2A), and flachie virus 2A (BmIFV2A), or combinations thereof. In a preferred embodiment, the efficient cleavage site is P2A. High-efficiency cleavage sites are described in Kim JH, Lee SR, Li LH, Park HJ, Park JH, Lee KY, et al. (2011) High Cleavage Efficiency of a 2A Peptide Derived from Porcine Teschovirus-1 in Human Cell Lines, Zebrafish and Mice. PLoS ONE 6(4): e18556, the contents of which are incorporated herein by reference. In embodiments where multiple CAR units are expressed in a single open reading frame (ORF), expression is controlled by a strong promoter. Examples of strong promoters include the SFFV promoter, and its derivatives. [have] [CAR] [Cells engineered with polypeptides and enhancers] [] In another embodiment, the present invention provides a method for producing an engineered cell expressing at least one CAR unit and an enhancer. In some embodiments, a bicistronic or polycistronic expression vector is used to express at least one CAR unit and enhancer in T or NK cells. There are several strategies that can be used to construct bicistronic or polycistronic vectors, including (but not limited to) (1) multiple promoters fused to the open reading frame of the CAR; (2) inserting splicing signals between the CAR units; expressing a fusion of CARs driven by a single promoter; (3) inserting a proteolytic cleavage site between the CAR units (self-cleaving peptide); and (iv) inserting an internal ribosome entry site (IRES). In a preferred embodiment, at least one CAR unit and enhancer are expressed in a single open reading frame (ORF), thereby generating a single polypeptide comprising at least one CAR unit and enhancer. In this embodiment, an amino acid sequence or linker containing a high-efficiency cleavage site is placed between each CAR unit and between the CAR unit and the enhancer. In this embodiment, the ORF is controlled by a strong promoter. Examples of strong promoters include the SFFV promoter and its derivatives. Furthermore, in a preferred embodiment, equal amounts of cleavage products are present, as shown by Western blot analysis. [Therapeutic Methods Using the Compositions Disclosed Herein] [] In another embodiment, the present invention provides methods for targeting CD45 for regulatory purposes prior to allogeneic transplantation in cancer treatment. CD45, also known as leukocyte common antigen (LCA), is a tyrosine phosphatase expressed on nearly all hematopoietic cells, excluding red blood cells and platelets. Most hematologic malignancies express CD45. For example, 85% to 90% of acute lymphoblastic and myeloid leukemias express CD45. CD45 is not found on non-hematopoietic cells. Furthermore, CD45 is expressed on malignant cells and leukocytes at a high average copy number of approximately 200,000 molecules per cell. CD45 presents an ideal target for a variety of hematologic malignancies. However, CAR T and NK cells also express CD45. In the absence of endogenous CD45 and inactivated, CAR T or NK cells harboring a CAR targeting CD45 can induce suicide. The association of CD45 with the TCR complex is essential for regulating T cell activation in response to antigen. The inability of CD45-deficient T cells to present antigen is attributed to reduced signaling through the T cell receptor (TCR). The TCR is a cell surface receptor that plays an important role in T cell activation in response to antigen presentation. The TCR is typically composed of two chains, α and β, which associate with the transducer unit CD3 to form the T cell receptor complex presented on the cell surface. The unexpected discovery of a key mechanism by which multiple CARs (composite CARs, cCARs) used against cancer cells to resist CAR activity is the downregulation or uneven expression of target antigens on the cancer cell surface. This mechanism allows cancer cells to "evade" CAR therapy, a phenomenon known as "antigen escape." The present invention exploits this mechanism by identifying combinations of two or more antigens that can rapidly eliminate tumors. The present invention provides methods for simultaneously targeting multiple antigens using cCARs, which results in improved tumor control by minimizing the possibility of tumor selection based on loss or downregulation of target antigens. The disclosed invention includes composite (multiple or composite) cCARs in T or NK cells targeting different or identical surface antigens presented in tumor cells. The composite chimeric antigen receptor of the present invention comprises at least a plurality of chimeric receptor constructs connected by a linker and targets the same or different antigens. For example, each CAR construct in the composite CAR (cCAR) construct includes an antigen recognition domain, an extracellular domain, a transmembrane domain and / or a cytoplasmic domain. The extracellular domain and the transmembrane domain can be derived from any desired source of such domains. Multiple CAR constructs are connected by a linker. The expression of the composite CAR construct is driven by a promoter. The linker can be a portion of a peptide or protein that self-cleaves (also known as a self-cleaving peptide) after producing a protein or peptide. In one embodiment, the composite CAR of the present invention targets myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Myelodysplastic syndrome (MDS) remains an incurable hematopoietic stem cell malignancy, most commonly occurring in the elderly, with approximately 14,000 new cases reported annually in the United States. Approximately 30-40% of MDS cases progress to AML. The incidence of MDS continues to increase with aging. Despite extensive research on MDS and AML, no satisfactory treatment has been developed. The compositions and methods of the present invention can be used to generate populations of T lymphocytes or NK cells that deliver primary and costimulatory signals for immunotherapy in the treatment of cancer, particularly lung cancer, melanoma, breast cancer, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, brain cancer, sarcoma, leukemia, and lymphoma. Immunotherapeutics often rely on the use of immune effector cells and molecules to target and destroy cancer cells. Effectors can be lymphocytes that carry surface molecules that interact directly or indirectly with tumor cell targets. Various effector cells include cytotoxic T cells, NK cells, and NK-92 cells. The compositions and methods described herein can be used in combination with other types of cancer therapies, such as chemotherapy, surgery, radiation, and gene therapy. The compositions and methods described herein can also be used for other disease conditions that rely on an immune response, such as inflammatory, immune, and infectious diseases. In some embodiments, the composite CAR of the present invention can serve as a bridge to bone marrow transplantation by achieving complete remission in patients with minimal residual disease who no longer respond to chemotherapy. In other embodiments, the composite CAR eliminates leukemia cells and then rescues bone marrow stem cells to support leukopenia. In some embodiments, the composite CARs of the present invention can counteract a key mechanism cancer cells use to resist CAR activity by downregulating target antigens. In another embodiment, the composite CARs of the present invention can also counteract the heterogeneity of cancer cells, which poses a significant challenge in conventional CAR T / NK cell therapy. In another embodiment, the disclosed composite CARs are designed so that one CAR targets large tumor populations and the other eradicates cancer or leukemia stem cells to prevent cancer recurrence. In one embodiment, the present invention provides a method for destroying cells bearing the CD33 antigen or the CD123 antigen, or by contacting such cells with engineered cells containing at least one of a chimeric antigen receptor polypeptide bearing a CD33 antigen recognition domain and a chimeric antigen receptor polypeptide bearing a CD23 antigen recognition domain. The engineered cells may be T or NK cells. Cells expressing at least one of the CD33 and CD123 antigens include acute myeloid leukemia, precursor acute lymphoblastic leukemia, chronic myeloproliferative neoplasm, chronic myeloid leukemia, myelodysplastic syndrome, blastic plasmacytoid dendritic neoplasm (BPDCN), Hodgkin's lymphoma, mastocytosis, and hairy cell leukemia cells. In another embodiment, the present invention provides a method for providing a spinal cord suppression conditioning regimen for hematopoietic stem cell transplantation. In this embodiment, T or NK cells engineered to have CD33 and CD123 cells are administered to a patient in need thereof. In other embodiments, the present invention provides a method for eradicating or killing leukemia stem cells (LSCs) or host leukemia cells that express CD123 or CD33 or both. In this embodiment, T or NK cells engineered to have both CD33 and CD123 cells are administered to a patient in need. In other embodiments, the composite CAR in T or NK cells can be used to eradicate or kill CD34+CD38- leukemia stem cells or bulk leukemia cells expressing CD123 or CD33 or both. In some embodiments, the composite CAR targets cells expressing CD19 or CD20 antigens, or both. In another embodiment, the composite CAR targets cells expressing CD19 or CD22 antigens, or both. The targeted cells may be cancer cells, such as, but not limited to, B-cell lymphomas or leukemias. In other embodiments, the target antigens may include, but are not limited to, at least one of the following: ROR1, PSMA, MAGE A3, glycolipids, glypican 3, F77, GD-2, WT1, CEA, HER-2 / neu, MAGE-3, MAGE-4, MAGE-5, MAGE-6, α-fetoprotein, CA 19-9, CA 72-4, NY-ESO, FAP, ErbB, c-Met, MART-1, CD30, EGFRvIII, immunoglobulins kappa and lambda, CD38, CD52, CD3, CD4, CD8, CD5, CD7, CD2, and CD138. Target antigens may also include viral or fungal antigens, such as E6 and E7 from human papillomavirus (HPV) or EBV (Epstein-Barr virus) antigens. In some embodiments, the composite CAR targets cells expressing CD19 or CD123 antigens or both. The targeted cells are cancer cells, such as (but not limited to) B cell lymphoma or leukemia. In other embodiments, the composite CAR targets cells expressing CS1 and / or B cell maturation antigen (BCMA), or both. In another embodiment, the target cell is a malignant plasma cell, such as, but not limited to, a multiple myeloma cell. In some embodiments, the composite CAR targets cells expressing multiple antigens, including but not limited to CS1, BCMA, CD267, BAFF-R, CD38, CD138, CD52, CD19, CD20, interleukin 6 receptor, and NY-ESO-1. In another embodiment, the target cell is a malignant plasma cell, such as, but not limited to, a multiple myeloma cell. In some embodiments, the composite CAR targets cells expressing multiple antigens, including but not limited to alpha-fetoprotein (AFP) and glypican-3 (GPC3). In another embodiment, the target cells are hepatocellular carcinoma, fibrolamellar carcinoma, hepatoblastoma, undifferentiated embryonal sarcoma and interstitial cell hamartoma of the liver, lung squamous cell carcinoma, testicular non-seminomatous germ cell tumor, liposarcoma, ovarian and extragonadal yolk sac tumor, ovarian choriocarcinoma, teratoma, ovarian clear cell carcinoma, and placental site trophoblastic tumor. According to the present invention, T or NK cells containing composite CARs targeting different or the same antigens can counteract tumor escape while being able to target tumor cells at the same time. T or NK host cells comprising the composite CAR disclosed herein are embodied in the present invention. The nucleotide and polypeptide constructs, sequences, host cells, and vectors of the composite CAR are considered part of the present invention and are embodied herein. In some embodiments, the composite CAR is administered in combination with any chemotherapy agent currently under investigation or commercially available. In some embodiments, the composite CAR is administered as a first-line treatment for diseases including, but not limited to, hematological malignancies, cancers, non-hematological tumors, inflammatory diseases, and infectious diseases such as HIV and HTLV. In one embodiment, T cells expressing the composite CAR are co-administered with NK cells expressing the same or a different composite CAR as an adaptive immunotherapy. The composite CAR NK cells provide rapid, innate activity against the target cell, while the composite T cells provide relatively long-lasting adaptive immune activity. In one embodiment, cells expressing the composite CAR are administered as a bridge to bone marrow stem cell transplantation in a mammal, such as a patient who is resistant to chemotherapy and is not a suitable candidate for bone marrow stem cell transplantation. In some embodiments, the composite CAR co-expresses a transgene in the target tumor lesion and releases the transgene product (such as IL-12) and further modulates the tumor microenvironment. In one embodiment, cells expressing the composite CAR are administered to a mammal whose bone marrow has been myeloid-ablated as part of treatment of the disease. In a specific embodiment, the cells expressing the composite CAR administered to a mammal (e.g., a human) can be T cells or NK cells. The present invention includes methods of treating a mammal suffering from a disorder or disease by administering the composite CAR. The target cells can be, for example, cancer cells, or cells affected by any other disease condition, such as infectious diseases, inflammation, and autoimmune disorders. The present invention is intended to include the use of fragments, mutants, or variants (e.g., modified forms) of composite CARs or antigens that retain the ability to induce stimulation and proliferation of T / NK cells. "Forms of the protein" is intended to mean proteins that share significant homology with at least one CAR or antigen and are capable of stimulating and proliferating T / NK cells. As used herein, the term "biologically active" or "biologically active form of a protein" is intended to include forms of the protein or variant that are capable of achieving anti-tumor activity in cells. The compositions and methods of the present invention can be used to generate T / NK cell populations capable of delivering primary and costimulatory signals for immunotherapy for the treatment of cancer, particularly lung cancer, melanoma, breast cancer, prostate cancer, colon cancer, renal cell carcinoma, ovarian cancer, neuroblastoma, rhabdomyosarcoma, leukemia, and lymphoma. The compositions and methods described herein can be used in combination with other types of cancer therapies, such as chemotherapy, surgery, radiation, and gene therapy. In some embodiments, the present invention discloses a method for depleting B cells, immature B cells, memory B cells, plasmablasts, long-lived plasma cells, or plasma cells in patients with autoimmune diseases by administering CAR or composite CAR T cells or NK cells to the patient. The cells targeted by the CAR are B or plasma cells expressing one or both of the antigen, BCMA, TACI, and BAFF-R. Autoimmune diseases include systemic scleroderma, multiple sclerosis, psoriasis, dermatitis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), systemic lupus erythematosus, vasculitis, rheumatoid arthritis, Sjögren's syndrome, polymyositis, granulomatosis and vasculitis, Addison's disease, antigen-antibody complex-mediated diseases, and anti-glomerular basement membrane disease. A variety of extracellular markers are currently being investigated as tumor-associated antigens and, therefore, as potential targets for CAR T / NK cell therapy. However, in addition to off-target toxicity, the expression of these antigens on healthy tissues, leading to on-target, off-tumor adverse events, remains a major safety concern. Furthermore, a major limitation of CAR T / NK cell therapy is the potential selection of antigen-escape variants when targeting molecules that are not essential for tumorigenesis. Consequently, malignant cells that maintain minimal or no expression of the target antigen can evade CAR T / NK cells, even with high-affinity effects. According to the present invention, natural killer (NK) cells represent an alternative cytotoxic effector for CAR-driven killing. Unlike T cells, NK cells do not require prior activation and constitutively exhibit cytolytic function. The further expression of cCAR in NK cells enables NK cells to effectively kill cancer cells, particularly those resistant to NK cell therapy. Furthermore, NK cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD). Studies have shown abnormal overexpression of CD123 on CD34+CD38- AML cells, whereas their normal bone marrow counterparts, CD34+CD38-, do not express CD123 (Jordan, Upchurch et al. 2000). This CD123+, CD34+CD38- population is considered LSC because these cells are able to initiate and maintain the leukemic process in immunodeficient mice. The number of CD34+ / CD38- / CD123+ LSCs can be used to predict clinical outcomes in AML patients. CD34+ / CD38- / CD123+ cells (greater than 15% in AML patients) are associated with incomplete remission and an unfavorable cytogenetic profile. Furthermore, the presence of more than 1% CD34+ / CD38- / CD123+ cells can also have a negative impact on disease-free and overall survival. Currently, therapies for MDS and AML focus on leukemic blasts, as they represent the majority of patients' problems. Importantly, leukemic stem cells (LSCs) are significantly different from other leukemic cells ("blasts") and constitute a rare subpopulation. While killing blasts can provide short-term remissions, if not destroyed, LSCs will invariably regrow, causing relapse in patients. LSCs must be destroyed to achieve a lasting cure for MDS. Unfortunately, standard drug regimens are ineffective against MDS or AML LSCs. Therefore, it is important to develop new therapies that can specifically target both leukemic stem cell populations and the larger leukemic population. The composite CARs disclosed in this invention target these populations and are implemented herein. According to the present invention, it was unexpectedly discovered that NK cells provide a readily available product that can be used as an allogeneic therapeutic product. Therefore, according to the present invention, and as required by the current state of the art, there is a need for patient-specific cCAR cell therapy. The applicants of the present invention have discovered a novel immunotherapy method that allows for effective CAR cell-based therapy without the need to isolate a patient's lymphocytes or tumor-infiltrating lymphocytes. Allogeneic or autologous NK cells are expected to induce rapid immune responses, but due to their limited lifespan, they disappear from circulation relatively quickly. Therefore, the applicants unexpectedly discovered that the use of cCAR cell-based therapies can reduce the problem of persistent side effects. According to one aspect of the present invention, NK cells can be expanded and transfected with the cCAR according to the present invention. NK cells can be derived from umbilical cord blood, peripheral blood, iPS cells, and embryonic stem cells. According to one aspect of the present invention, NK-92 cells can be expanded and transfected with cCAR. NK-92 is a continuously growing cell line that possesses the properties and characteristics of natural killer (NK) cells. The NK-92 cell line is IL-2 dependent and has been demonstrated to be safe and viable. NK-92 cells expressing cCAR can be expanded in serum-free medium with or without co-culture of feeder cells. Pure populations of NK-92 cells carrying the relevant cCAR can be obtained by sorting. Identification of suitable surface target antigens is a prerequisite for generating CAR T / NK cells in adaptive immunotherapy. In one aspect of the present invention, the CD123 antigen is one of the targets of cCAR therapy. CD123 (the alpha chain of the interleukin-3 receptor) is overexpressed in a variety of hematologic malignancies, including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), hairy cell leukemia, and blastic plasmacytoid dendritic neoplasm. CD123 is absent or minimally expressed on normal hematopoietic stem cells. More importantly, CD123 is expressed on a subset of leukemic cells associated with leukemic stem cells (LSCs), the elimination of which is essential to prevent disease refractoryness and relapse. In one aspect of the present invention, the CD33 antigen is one of the targets of cCAR therapy. CD33 is a transmembrane receptor expressed on 90% of malignant cells in acute myeloid leukemia. Therefore, according to the present invention, CD123 and CD33 target antigens are particularly attractive from a safety perspective. According to the present invention, a composite CD33CD123 CAR can be highly effective in the therapeutic treatment of chronic myeloid leukemia (CML) patients. In chronic myeloid leukemia (CML), there is a rare cell subset that is CD34+CD38-. This population is believed to include LSCs. Increased LSC numbers are associated with disease progression. Small molecule Bcr-Abl tyrosine kinase inhibitors (TKIs) have been shown to significantly improve the overall survival of patients with CP-CML. However, LSCs are believed to be resistant to TKI therapy. Novel therapies targeting CML-resistant LSCs are urgently needed for the treatment of CML, and these novel therapies are implemented in the form of the composite CD33CD123 CAR disclosed in the present invention. CD123 expression is high in the CD34+CD38- population. According to the present invention, a composite CD33CD123 CAR is highly effective in the therapeutic treatment of this population. In one embodiment of the present invention, leukemia cells expressing CD123 and CD33 in cCAR are used as therapeutic treatment. CD33 is expressed on myeloid cells, myeloid leukemic blasts, and mature monocytes, but not on normal multipotent hematopoietic stem cells (Griffin, Linch et al. 1984). CD33 is widely expressed on leukemia cells in CML, myeloproliferative neoplasms, and MDS. Because a significant number of patients with acute myeloid leukemia (AML) are refractory to standard chemotherapy regimens or experience disease relapse following treatment (Burnett 2012), research into CAR T cell immunotherapy for AML has the potential to address a significant clinical need. In the majority of these patients, leukemic cells express both CD123 and CD33, providing broad clinical applicability for the composite CD33CD123 CARs disclosed herein. Therefore, the present invention discloses novel multi-cCAR T / NK cell constructs comprising multiple CARs targeting multiple leukemia-associated antigens, thereby counteracting antigen escape mechanisms and targeting leukemic cells, including leukemic stem cells, through the synergistic effects of costimulatory domain activation, thereby providing a more potent, safe, and effective therapy. The present invention also discloses a composite CAR construct that exhibits enhanced anti-tumor activity against cells that co-express a target antigen while maintaining sensitivity against tumor cells expressing only one antigen. Furthermore, each CAR in the composite CAR construct includes one or two costimulatory domains and potently kills a specific target in the presence of the target. In preclinical studies of dual-specific, counter-signaling CARs targeting solid tumors (including breast and epithelial ovarian cancer), the CD3ζ intracellular signaling domain was separated from the costimulatory domain from a second-generation CAR. In other words, one CAR contained a first-generation CAR without any costimulatory domains, and the other lacked the CD3ζ intracellular domain. Therefore, the presence of two target antigens is required for T cell activation and potent killing. This has been proposed as a way to reduce the potential for off-tumor toxicity caused by healthy tissue expression of one of the two target antigens, increasing target specificity at the expense of sensitivity. In one embodiment, the composite CAR is a composite CD123CD19 CAR. It has been demonstrated that over 90% of B-ALL in a subset of populations express CD123. Similar to AML and MDS, a rare LSC population is believed to exist in B-ALL. Therefore, targeting leukemic stem cells and large leukemic populations according to the present invention can be applied to B-ALL. According to the present invention, the CD123 and CD19 surface antigens expressed in B-ALL can be targeted, as CD19 is abundantly expressed in different stages of the B cell lymphoid population. Multiple myeloma (MM) is the second most common hematologic malignancy in the United States and is caused by clonal plasma cells that accumulate in the bone marrow or extramedullary sites. MM is an incurable disease with a median survival of approximately 4.5 years (Kumar, Rajkumar, et al. 2008). Anti-myeloma CARs have been investigated in preclinical studies, and CAR targets include CD38, CS1, B-cell maturation antigen (BCMA), and CD38. However, malignant plasma cells often exhibit heterogeneity in surface antigen expression (Ruiz-Arguelles and San Miguel 1994), making them difficult to target with CARs. Malignant plasma cells also express low levels of CD19. Myeloma stem cells have previously been shown to express several B cell markers, including CD19. Targeting this population could be effective in the treatment of myeloma in combination with standard and other myeloma CAR therapies. Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal expansion of plasma cells. Despite significant therapeutic advances, myeloma remains an incurable disease; therefore, novel treatments are urgently needed. CS1 (also known as CD319 or SLAMF7) is a protein encoded by the SLAMF7 gene. Surface antigen CS1 is a stable marker for normal plasma cells and myeloma cells (malignant plasma cells). Tumor necrosis factor receptor superfamily, member 17 (TNFRSF17), also known as B-cell maturation antigen (BCMA) or CD269, is almost exclusively expressed in plasma cells and terminally ill plasma cells. Its absence in other tissues suggests its potential as a target for CAR T or NK cells. Malignant plasma cells display variable degrees of antigenic heterogeneity for CD269 and CS1. Single CAR unit products targeting CD269 or CS1 can target the majority of cells in the primary tumor, eliciting an initial, stable antitumor response. Subsequently, a small number of residual, untargeted cells expand and cause disease relapse. Although multiple myeloma is particularly heterogeneous, this phenomenon certainly applies to other leukemias or tumors. Current clinical trials at the NIH using BCMA CAR T cells have shown promising results, with complete responses in some multiple myeloma patients. However, these patients relapsed after 17 weeks, which has been attributed to antigen escape. Antigen escape has also been observed with CD19 CAR and NY-ESO1 CAR T cell therapies. Therefore, there is a pressing need for more effective CAR T cell therapies to prevent relapse. In one aspect of the present invention, BCMA and CS1 are targets of BCMACS1 CAR therapy. In some embodiments, the composite CAR targets cells expressing BCMA or CS1 antigens, or both. The target cell may be a cancer cell, such as, but not limited to, a lymphoma, leukemia, or plasma cell neoplasm. In other embodiments, the plasma cell neoplasm is selected from plasma cell leukemia, multiple myeloma, plasmacytoma, heavy chain disease, amyloidosis, Waldenstrom's macroglobulinemia, heavy chain disease, solitary plasmacytoma of bone, monoclonal globulinemia of undetermined significance (MGUS), and smoldering multiple myeloma. BAFF (B-cell activating factor) and APRIL (proliferation-inducing ligand) are two TNF homologs that specifically bind to TACI (also known as TNFRSF1 3B or CD267) and BCMA with high affinity. BAFF (also known as BLyS) binds to BAFF-R and is functionally involved in promoting B cell survival and late-stage proliferation. BAFF has been implicated in several autoimmune disorders. APRIL plays an important role in promoting antibody class switching. BAFF and APRIL have been shown to be growth and survival factors for malignant plasma cells. Ligand-receptor interactions in malignant plasma cells are described below: In some embodiments, the composite CAR targets cells expressing the TACI or CS1 antigen, or both. In another embodiment, the composite CAR targets cells expressing the TACI or CS1 antigen, or both. The target cell may be a cancer cell, such as (but not limited to) a lymphoma, leukemia, or plasma cell neoplasm. In other embodiments, the plasma cell neoplasm is selected from plasma cell leukemia, multiple myeloma, plasmacytoma, heavy chain disease, amyloidosis, Waldenstrom's macroglobulinemia, heavy chain disease, solitary plasmacytoma of bone, monoclonal globulinemia of undetermined significance (MGUS), and smoldering multiple myeloma. The target cell may also be one or two or more different cell types, including B cells, immature B cells, naive B cells, centroblasts, centrocytes, memory B cells, plasmablasts, long-lived plasma cells, and plasma cells. These cells are associated with autoimmune diseases, including systemic scleroderma, multiple sclerosis, psoriasis, dermatitis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), systemic lupus erythematosus, vasculitis, rheumatoid arthritis, Sjögren's syndrome, polymyositis, granulomatosis and vasculitis, Addison's disease, antigen-antibody complex-mediated diseases, and anti-glomerular basement membrane disease. In some embodiments, the composite CAR targets cells expressing BAFF-R or CS1 antigens, or both. In another embodiment, the composite CAR targets cells expressing BAFF-R or CS1 antigens, or both. The target cell may be a cancer cell, such as (but not limited to) a lymphoma, or a leukemia, or a plasma cell neoplasm. In other embodiments, the plasma cell neoplasm is selected from plasma cell leukemia, multiple myeloma, plasmacytoma, heavy chain disease, amyloidosis, Waldenstrom's macroglobulinemia, heavy chain disease, solitary plasmacytoma of bone, monoclonal globulinemia of undetermined significance (MGUS), and smoldering multiple myeloma. In some embodiments, the composite CAR (cCAR) targets cells expressing one, two, or all of the BAFF-R, BCMA, TACI, and CS1 antigens. In some embodiments, the CAR unit in cCAR may include: 1) scFv against BAFF-R, BCMA, TACI and CS1; 2) hinge region; 3) costimulatory domain and intracellular signaling domain. In some embodiments, the CAR unit in cCAR may include: 1) a BCMA or TACI or BAFF-R binding domain, or an APRIL binding domain; 2) a hinge region; 3) a costimulatory domain and an intracellular signaling domain. In another embodiment, the BCMA, TAC1, or BAFF-R binding domain may be the entire APRIL and BAFF molecules or a portion thereof. In some embodiments, the CAR unit in cCAR may include: 1) scFv against BCMA or CS1; 2) hinge region; 3) costimulatory domain and intracellular signaling domain. In other embodiments, the cCAR may comprise one or two or more CAR units. Each CAR unit may have the same or different hinge regions and costimulatory domains. In other embodiments, the target antigen may include, but is not limited to, at least one of the following: ROR1, PSMA, MAGE A3, glycolipids, glypican 3, F77, GD-2, WT1, CEA, HER-2 / neu, MAGE-3, MAGE-4, MAGE-5, MAGE-6, α-fetoprotein, CA 19-9, CA 72-4, NY-ESO, FAP, ErbB, c-Met, MART-1, CD30, EGFRvIII, immunoglobulins kappa and lambda, CD38, CD52, CD3, CD4, CD8, CD5, CD7, CD2, and CD 138. Target antigens may also include viral or fungal antigens, such as E6 and E7 from human papillomavirus (HPV) or EBV (Epstein-Barr virus) antigens. In some embodiments, the cCAR targets cells expressing CD19 or CD20 antigens, or both. In another embodiment, the cCAR targets cells expressing CD19 or CD22 antigens, or both. The target cells are cancer cells, such as B-cell lymphomas or leukemias. Acute graft-versus-host disease (GVHD) remains the most significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. During the effector phase of GVHD, the T cell receptor (TCR), a heterodimer of α and β chains, is expressed on the surface of T cells. The TCR recognizes certain antigens on HLA molecules on host cells, enhances T cell proliferation, and releases cytotoxic agents that damage host cells. TCR genes are effective in preventing potential graft-versus-host reactions. Inactivation of the TCR can prevent TCR recognition of alloantigens and, consequently, GVHD. The effects of CD45 on NK cells differ significantly from those on T cells. NK cells from CD45-deficient mice exhibit normal cytotoxic activity against the prototypical tumor cell line, Yac-1. Furthermore, CD45-deficient NK cells proliferate normally and respond to IL-15 and IL-21. Therefore, disruption or deletion of CD45 does not affect NK cell killing or proliferation. The present invention includes methods for permanently deleting CD45 in T or NK cells, followed by the stable introduction of a CD45-specific CAR. Thus, the engineered T cells exhibit the desired properties of redirecting specificity toward CD45 without inducing suicide or a reaction to antigen presentation. In another embodiment, the engineered T cells may have utility as an off-the-shelf therapy for treating malignancies or other diseases. The present invention relates to a method in which T cells are engineered to allow proliferation despite reduced or absent TCR signaling through inactivation or deletion of endogenous CD45. Reduced or absent TCR signaling can result in protection against GVHD. In another embodiment, T cells with reduced or absent TCR signaling through inactivation of CD45 can be used as an "off-the-shelf" therapeutic product. The present invention includes a method for modifying T or NK cells, comprising: (a) modifying T or NK cells by inactivating CD45; (b) expanding these modified cells; (c) sorting modified T or NK cells that do not express CD45; and (d) introducing CD45 CAR. In one embodiment, the CD45CAR gene encodes a chimeric antigen receptor (CAR), wherein the CAR comprises at least one of an antigen recognition domain, a hinge region, a transmembrane domain, and a T cell activation domain, and the antigen recognition domain redirects the cell to the CD45 surface antigen presented on the cell. The antigen recognition domain comprises a monoclonal antibody or polyclonal antibodies against the CD45 antigen. The antigen recognition domain comprises the binding portion or variable region of the monoclonal or polyclonal antibodies. In some embodiments, modified T cells are obtained from an allogeneic donor and used as an "off-the-shelf product." Targeting CD45 using CAR T or NK cells can induce suicide because T and NK cells express this surface antigen. To overcome this drawback, the present inventors proposed using an engineered CRISPR / Cas9 system, zinc finger nucleases (ZFNs), TALE nucleases (TALENs), and meganucleases to inactivate the CD45 gene. CD45 loss in T or NK cells is further induced by CAR targeting tumors expressing CD45. The present invention includes methods for eliminating or reducing abnormal or malignant cells in the bone marrow, blood, and organs. In some embodiments, malignant cells expressing CD45 are present in patients with acute leukemia, chronic leukemia, B- and T-cell lymphomas, myeloid leukemia, acute lymphoblastic lymphoma or leukemia, primary effusion lymphoma, reticulohistiocytoma, transient myeloproliferative disorder of Down's syndrome, lymphocyte-dominant Hodgkin's lymphoma, myeloid leukemia or sarcoma, dendritic cell tumor, histiocytic sarcoma, giant cell tumor of the tendon sheath, interdigitating dendritic cell sarcoma, post-transplant lymphoproliferative disorder, and the like. In some embodiments, CD45CAR cells can be used to create space in the bone marrow for bone marrow stem cell transplantation by removing hematopoietic cells while removing leukemia / lymphoma cells or immune cells that can cause transplant rejection. In another embodiment, CD45CAR cells can be used to pre-treat patients before they undergo a bone marrow transplant to receive stem cells. In another embodiment, CD45CAR can be used as a spinal cord suppression conditioning regimen for hematopoietic stem cell transplantation. In some embodiments, CD45CAR cells are used to treat or prevent residual disease after stem cell transplantation and / or chemotherapy. In some embodiments, the CD45CAR is part of an expression gene or cassette. In a preferred embodiment, in addition to the CD45CAR, the expression gene or cassette may include an accessory gene or tag, or a portion thereof. The accessory gene may be an inducible suicide gene, or a portion thereof, including, but not limited to, caspase 9, thymidine kinase, cytosine deaminase (CD), or cytochrome P450. "Suicide gene" ablation methods can improve the safety of gene therapy and kill cells only when triggered by specific compounds or molecules. In some embodiments, the suicide gene is inducible and activated using a specific chemical inducer of dimerization (CID). In some embodiments, the safety switch may include an additional tag, which is a c-myc tag, CD20, CD52 (Campath), a truncated EGFR gene (EGFRt), or a portion or combination thereof. The additional tag can be used as a non-immune gene selection tool or for tracking markers. In some embodiments, the safety switch may comprise a 24-residue peptide corresponding to residues 254-277 (NSELLSLINDMPITNDQKKLMSNN) of the RSV F glycoprotein A2 strain. In some embodiments, the safety switch may comprise an amino acid sequence of TNFα bound by a single anti-TNFα drug. The administration of any of the engineered cells described herein may be supplemented with the co-administration of a CAR enhancer. Examples of CAR enhancers include immunomodulatory drugs that enhance CAR activity, such as, but not limited to, agents targeting immune checkpoint pathways, inhibitors of colony stimulating factor-1 receptor (CSF1R) for better therapeutic outcomes. Agents targeting immune checkpoint pathways include small molecules, proteins, or antibodies that bind to inhibitory immune receptors CTLA-4, PD-1, and PD-L1 and cause CTLA-4 and PD-1 / PD-L1 blocking. As used herein, enhancers include enhancers as described above. As used herein, "patient" includes mammals. Reference herein to mammals can be any mammal. As used herein, the term "mammal" refers to any mammal, including, but not limited to, mammals of the order Rodentia (such as mice and hamsters) and mammals of the order Logomorpha (such as rabbits). Mammals can be from the order Carnivora, including Felines (cats) and Canines (dogs). Mammals can be from the order Artiodactyla, including Bovines (cows) and Swines (pigs), or Perssodactyla, including Equines (horses). Mammals can be primates, Ceboids, Simoids (monkeys), or Anthropoids (humans and apes). Mammals are preferably humans. Patients include individuals. In certain embodiments, the patient is a human aged 0 to 6 months, 6 to 12 months, 1 to 5 years, 5 to 10 years, 5 to 12 years, 10 to 15 years, 15 to 20 years, 13 to 19 years, 20 to 25 years, 25 to 30 years, 20 to 65 years, 30 to 35 years, 35 to 40 years, 40 to 45 years, 45 to 50 years, 50 to 55 years, 55 to 60 years, 60 to 65 years, 65 to 70 years, 70 to 75 years, 75 to 80 years, 80 to 85 years, 85 to 90 years, 90 to 95 years, or 95 to 100 years. As used herein, the terms "effective amount" and "therapeutically effective amount" of engineered cells mean an amount of engineered cells sufficient to provide a desired therapeutic or physiological effect or outcome. Such effects or outcomes include reduction or amelioration of symptoms of a cellular disorder. Undesirable effects, such as side effects, sometimes occur along with desired therapeutic effects; therefore, a physician balances potential benefits against potential risks when determining an appropriate "effective amount." The precise amount required will vary from patient to patient, depending on the patient's species, age, and general health, the mode of administration, and similar factors. Therefore, it may not be possible to specify an exact "effective amount." However, an appropriate "effective amount" in any individual case can be determined by one of ordinary skill using only routine experimentation. Generally, the engineered cells are administered in an amount and under conditions sufficient to reduce the proliferation of the target cells. Following administration of a delivery system for treating, inhibiting, or preventing cancer, the efficacy of the therapeutic engineered cells can be assessed using a variety of methods familiar to those skilled in the art. For example, one of ordinary skill in the art would understand that by observing that the therapeutic engineered cells reduce the cancer cell burden or prevent further increases in cancer cell burden, the therapeutic engineered cells delivered in combination with a chemical adjuvant can effectively treat or inhibit cancer in a patient. Cancer cell burden can be measured by methods known in the art, such as using polymerase chain reaction assays to detect the presence of certain cancer cell nucleic acids or identifying certain cancer cell markers in blood, using, for example, antibody assays to detect the presence of markers in a sample (such as, but not limited to, blood) from an individual or patient, or by measuring the level of circulating cancer cell antibodies in a patient. Throughout this specification, quantities are defined by ranges and by lower and upper limits within the ranges. Each lower limit can be combined with each upper limit to define a range. The lower and upper limits should each be considered a separate element. Throughout this specification, references to "one embodiment" or "an example" mean that a particular feature, structure, or characteristic described in connection with that embodiment or example is included in at least one embodiment of the present invention. Thus, multiple appearances of the phrase "in one embodiment" or "an example" throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features, structures, or characteristics may be combined in any suitable combinations and / or subcombinations in one or more embodiments or examples. Furthermore, it should be understood that the drawings provided herewith are for illustrative purposes only and are not necessarily drawn to scale. As used herein, the terms "comprises," "comprising," "includes," "has," "having," or any other variations thereof are intended to cover a non-exclusive inclusion. For example, a process, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, article, or apparatus. Furthermore, unless expressly stated to the contrary, "or" refers to an inclusive "or" and not an exclusive "or". For example, condition A or condition B is satisfied by any of the following: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); and both A and B are true (or exist). Furthermore, any examples or illustrations provided herein should not be construed as restricting, limiting, or implying definitions of any term used therein. Rather, such examples or illustrations are considered to describe one specific embodiment and are illustrative only. Those of ordinary skill in the art will understand that any term used with such examples or illustrations encompasses other embodiments that may or may not be provided with them or elsewhere in the specification, and all such embodiments are intended to be included within the scope of such term or terms. Language designating such non-limiting examples and illustrations includes, but is not limited to, "for example," "for instance," and "in one embodiment." In this specification, various parameter groups containing multiple members are described. Within a parameter group, each member can be combined with any one or more other members to form additional subgroups. For example, if the group members are a, b, c, d, and e, then additional subgroups specifically contemplated include any one, two, three, or four of these members, e.g., a and c; a, d, and e; b, c, d, and e; etc. As used herein, an XXXX antigen recognition domain is a polypeptide that is selective for XXXX. Therefore, XXXX is the target. For example, a CD38 antigen recognition domain is a polypeptide that is specific for CD38. As used herein, CDXCAR refers to a chimeric antigen receptor with a CDX antigen recognition domain. The present invention may be better understood with reference to the examples set forth below. The following examples are provided to provide a person of ordinary skill in the art with a complete disclosure and description of how to make and evaluate the compounds, compositions, articles, devices and / or methods claimed herein, and are intended to be illustrative only and are not intended to limit the present invention. [Example] [] [Generate compound] [CAR (cCAR)] [] The architecture of CD33CD123 cCAR follows the schematic diagram in Figure 1A. It includes an SFFV (spleen focus forming virus) promoter that drives the expression of a functional composite CAR (cCAR) with two different CAR units. Antigen receptor orientation, anti-CD33 and anti-CD123 scFv (single-chain variable fragment) nucleotide sequences. Due to the efficient mechanism of self-cleavage kinetics for the bicistronic gene construct, a P2A peptide derived from a small RNA virus is used. The self-cleavage P2A peptide is used to connect the two independent units in CAR, CD33CAR and CD123CAR together during expression. The advantages of this method over the internal ribosome entry site (IRES) commonly used in the literature include its smaller size and high cleavage efficacy between the two upstream and downstream unit proteins of the 2A peptide. In addition, when using IRES, the use of a self-cleavage P2A peptide can avoid the problem of expression differences between genes before and after IRES. The first modular unit, the CD33CAR, includes the CD33 scFv domain, the CD8a hinge region, the CD8a transmembrane domain, the 4-BB costimulatory domain, and the intracellular domain of the CD3ζ chain. The second modular CAR, the CD123CAR, shares the same hinge, transmembrane, and intracellular signaling domains as the CD33CAR, but has a different scFv and costimulatory domain. The CD33 CAR recognizes its corresponding antigen, and the CD123 CAR binds to its corresponding antigen. The hinge region is designed to avoid disulfide interaction sequences. Different costimulatory domains, 4-BB and CD28, are used. The CD33CD123 complex CAR is then cloned into lentiviral vectors. [Producing efficient compounding] [CAR (cCAR)] [] Composite CAR lentivirus was produced by transfecting HEK-293 FT cells with Lipofectamine 2000 according to the manufacturer's instructions, but due to the larger size of the insert, twice the vector DNA was used to increase titer, as shown in Figure 2. After approximately 12-16 hours of incubation, the lipofectamine-containing medium was removed and replaced with DMEM containing 10% FBS, 20 mM HEPES, 1 mM sodium pyruvate, and 1 mM sodium butyrate. After approximately 24 hours, the supernatant was collected and refrigerated, and replaced with fresh medium. After approximately 24 hours, the supernatant was collected, combined with the previous supernatant, and filtered through a 0.45 µM filter. The supernatant was aliquoted, flash-frozen with liquid nitrogen, and stored at -80°C. HEK-293 FT cells were harvested, stored frozen, and lysed for subsequent electrophoresis and Western blotting. Peripheral blood (PB) or human umbilical cord blood (CB) buffy coat cells were activated for two days with anti-CD3 antibodies and IL-2. The cCAR lentiviral supernatant was spin-coated onto a multiwell plate coated with recombinant human fibrin fragments. Activated T cells were transduced with the lentiviral supernatant at a low concentration of approximately 0.3 × 10 6 cells / mL in multiple wells to increase transduction efficiency (Figure 2). After the first overnight transduction, cells were added directly to a second virus-coated dish for a second transduction without washing, unless they appeared unhealthy. Following the second overnight transduction, cells were washed, combined, and cultured in tissue culture-treated dishes. CAR T cells were expanded for up to approximately 5 days before co-culture killing analysis. After approximately 3 days of incubation, cells were incubated with biotin-conjugated goat anti-mouse F(ab')2 or goat IgG (isotype) antibodies, washed, and then incubated with streptavidin-PE and conjugated anti-human CD3. After washing and suspension in 2% formalin, cells were analyzed by flow cytometry to determine the percent transduction efficacy. [CD33CD123 cCAR] [Representation] [] Transfected CD33CD123 cCAR HEK293T cells underwent Western blot analysis to confirm the composite construct. Immunoblot analysis with anti-CD3ζ monoclonal antibodies showed bands of the predicted size of the composite CAR CD3ζ fusion protein (Figure 1B). Importantly, as expected, two different bands of similar intensity were observed on the blots with successful high cleavage of the signaling P2A peptide. As expected, no CD3ζ expression was found for the GFP control vector. The surface expression of scFv was also tested on HEK 293 cells (Figure 1C) and naive T cells (Figure 1C). The transduction efficacy of the composite CD33CD23 CAR lentivirus was tested in HEK293 cells and analyzed by flow cytometry (Beckman Coulter) (Figure 1C). Flow cytometry showed that approximately 67% of HEK cells expressed the CD33CD123 CAR. Human peripheral blood (PB) is commonly used for autologous T cell therapy. Human PB buffy coat cells were activated with anti-CD3 antibodies and IL-2 and transduced with either a CD4 CAR or a control (GFP) lentivirus. After transduction, flow cytometric analysis showed that approximately 22% of T cells expressed the CD33CD123 CAR (Figure 1C). [result] [] [Derived from umbilical cord blood] [(UCB)] [and peripheral blood] [(PB)] [Of] [CD33CD123 cCAR T] [Cell Specificity] [Kill performance] [CD33] [Of] [Tumor cells] [] CD33CD123 cCAR T cells or GFP T cells (control) were incubated with target cells in approximately 1-2 mL of T cell culture medium at a ratio ranging from 0.5:1 to 50:1, preferably approximately 2:1, 5:1, 10:1, 20:1, or 50:1, at approximately 100,000, 200,000, 500,000, approximately 1 million, or 2 million effector cells to approximately 50,000, 100,000, or 200,000 target cells, respectively, for approximately 24 hours in the absence of IL-2. The target cells were leukemia cell lines and leukemia cells from leukemia patients. After approximately 24 hours of co-culture, the cells were stained with mouse anti-human CD33, CD123, CD34, and CD3 antibodies. CD33CD123 cCAR T cells expressing both CD33 CAR and CD123 CAR were generated and tested for anti-leukemic activity using HL60 and KG-1a cell lines. The HL60 cell line is a promyelocytic leukemia cell line highly enriched for CD33. Approximately 100% of its cell population is CD33+, with a small subset (<10%) being dim CD123+. This cell line was tested in culture to determine the efficacy of the CD33CD123 CAR, with an emphasis on targeting leukemic cells expressing CD33. Furthermore, due to the strong CD33 expression in HL60 cells, the CD33CD123 cCAR effect could be significant. Indeed, over a 24-hour co-culture period at various effector:target cell ratios, the CD33CD123 cCAR exhibited significant leukemic cell-killing properties (Figure 3). CB-derived CD33CD123 CAR T cells were first tested for their ability to kill HL60 cells. After approximately 24 hours of incubation and at low effector:target (E:T) ratios ranging from approximately 0.5:1 to 50:1, preferably 1:1 to approximately 5:1, and more preferably approximately 2:1 to 4:1, CD33CD123 CAR cells eliminated approximately 55% of CD33-expressing HL60 cells compared to a GFP control. At a ratio of approximately 5:1, killing was enhanced to approximately 82%. The CD33CD123 CAR, derived from peripheral blood mononuclear cells (PBMCs), was co-cultured with the myeloid leukemia cell line KG1a. KG1a also modestly expressed approximately 100% CD33, compared to HL60 and 50-80% CD123. Therefore, KG1a represents a relatively dual-target cell population, doubly positive for the antigen targeted by the CD33CD123 CAR. Using approximately 24 hours of incubation and low effector:target (E:T) ratios ranging from approximately 0.5:1 to 50:1, the CD33CD123 CAR exhibited modest anti-leukemic activity of approximately 26% even at a low E:T ratio of approximately 2:1. Increasing the E:T ratio to 10:1 resulted in approximately 62% killing of KG1a cells compared to a GFP control (Figure 4), indicating that CD33 marker intensity can be an indicator of killing efficacy, with HL60 strongly expressing and utilizing more CAR activity than KG1a. These experiments provide evidence for the functionality of a fully CD33CD123 CAR against its cognate antigen-presenting cell population. Another composite CAR, the CD33CD123-BB cCAR, has been generated. This composite CAR comprises two independent CAR units, CD33 and CD123. The first CAR contains a scFv that binds to CD33, while the second CAR has a different scFv that recognizes CD123. Both CARs contain the same hinge region, transmembrane, costimulatory, and intracellular domains. A CD33CD123-BB cCAR lentivirus was generated and tested for its killing ability in KG-1a cells. As shown in Figure 5, substantial killing was observed at a ratio of approximately 10:1, but the intensity was less pronounced than with the CD33CD123 cCAR. [CD33CD123 cCAR] [With targeted performance] [CD33] [and] [ / ] [or] [CD123] [Of] [Activity of Patient Samples] [] In addition to cell line experiments, studies were conducted on patient samples to test the functionality of each individual CAR unit. The efficacy of the CD33CD123 cCAR was tested using the aggressive acute myeloid leukemia (AML) cell line, AML-9. Due to the heterogeneity of the patient cell population, which includes multiple cell types in the AML-9 sample, leukemic blasts were gated using CD34 and CD33 because they are positive for both markers. At a certain CAR T cell:target cell ratio, depletion of this CD33+CD34+ population of leukemic cells was observed to be 48% higher than that of the GFP control (Figure 6). Leukemic cells that are CD123-positive and CD33-negative were also tested. For this purpose, a human B-cell acute lymphoblastic leukemia (B-ALL) sample, Sp-BM-B6, was selected. All leukemic blasts in this sample were CD34+CD33-, and over approximately 50% were positive for CD123. Compared to a GFP control, CD33CD123 cCAR T cells achieved approximately 86% depletion of the CD34+ leukemic cell population (Figure 7). Based on studies in cell lines and human samples, our data clearly demonstrate that the composite CD33CD123 CAR can target leukemic cells expressing either CD33 or CD123, or both. [CD33CD123 cCAR NK] [Cell Targeting Performance] [CD33] [or] [CD23] [or leukemia cells of both] [] Natural killer (NK) cells are CD56+ and CD3- and are similar to CD8+ T cells in their ability to effectively kill infected and tumor cells. Unlike CD8+ T cells, NK cells initiate cytotoxicity against tumors without the need for activation to kill cells. NK cells are safer than effector cells because they avoid the potentially fatal complications of cytokine storms. However, the use of CD33, CD123, or both CAR-expressing NK cells to kill leukemias has not been explored. [produce] [CD33CD123 cCAR NK] [cell] [] NK-92 cells were transduced with CD33CD123 CAR lentiviral supernatant on two consecutive overnight cycles, alternating between transductions using culture plates coated with recombinant human fibrin fragments and virus-coated plates. The transduced cells were expanded for 3 or 4 days and then analyzed by flow cytometry for CAR expression. Cells were harvested and incubated with goat anti-mouse F(Ab')2 at approximately 1:250 for approximately 30 minutes. The cells were washed, suspended, and stained with streptavidin-PE for approximately 30 minutes. The cells were washed, suspended in 2% formalin, and analyzed by flow cytometry. NK-92 cells expressing the CD33CD123 cCAR were then labeled as described above and sorted on a FACSAria, where the top 0.2% of cells expressing F(Ab')2 were collected and cultured. Subsequent labeling of the sorted and expanded cells revealed that approximately 89% of NK-92 cells were positive for anti-mouse F(Ab')2 (Figure 8). [CD33CD123 cCAR NK] [Cells effectively dissolve or eliminate leukemia cells] First, we tested the functionality of CD33CD123 cCAR NK-92 cells by evaluating their ability to kill HL-60 cancer cell lines in co-culture. While nearly all HL-60 cells highly express CD33, CD123 expression in this cell line is weak at less than 10%. Therefore, the killing ability of the CD33CD123 cCAR likely depends on the cCAR's ability to accurately target CD33. CD33CD123 cCAR NK-92 cells were co-cultured with HL-60 cells in IL-2-free NK cell culture medium for approximately 24 hours. Following incubation, the CD33CD123 cCAR NK-92 cells were labeled and compared to a non-CAR control, GFP NK-92 cells. Significant killing of HL-60 cells by CD33CD123 cCAR NK-92 cells was observed compared to the control GFP NK-92 cells. Furthermore, the killing ability of CD33CD123 cCAR NK-92 cells was dose-dependent, with a ratio of approximately 100% at approximately 10:1 compared to the control (Figures 9 and 11). A second co-culture experiment was conducted using KG1a cells and a myeloid leukemia cell line. KG1a cells expressed CD33 on all cells, but at an intermediate level compared to HL-60 cells. CD123 antigen was expressed in approximately 50-80% of KG1a cells. The experimental design was similar to the first experiment in the HL-60 killing assay, with the same incubation time, effector:cancer cell ratio, and GFP NK-92 cell control. The results showed that CD33CD123 cCAR NK-92 cells significantly killed KG1a cells in a dose-dependent manner compared to the GFP NK-92 cell control. At an effector:target ratio of 10:1, CD33CD123 cCAR NK-92 cells killed approximately 85% of KG1a cells compared to the GFP control (Figures 10 and 11). Analysis of KG1a cells revealed two distinct populations: CD33+CD123- and CD33+CD123-. Figure 11 shows the dose-dependent increase in cell killing observed in both populations. Surprisingly, the double-positive population demonstrated higher effective killing at each increasing ratio, suggesting a possible synergistic effect of the two modular CARs for CD33 and CD123 (Figure 12). [produce] [CD19CD20] [、] [CD19CD22] [、] [CD19CD138 cCAR] [] Three cCARs have been generated using a similar strategy to the CD33CD123 cCAR described above ( FIG. 13 ). [Generate includes] [BCMA CS1 cCAR] [and] [BCMA CD19 cCAR] [Of] [For the treatment of multiple myeloma] [cCAR] [] Preclinical studies of cCARs have been conducted targeting surface antigens, including CD38, CS1, CD138, B-cell maturation antigen (BCMA), and CD38. CD19 CARs have also shown some efficacy in Phase I clinical trials for the treatment of multiple myeloma. However, given the heterogeneity of surface antigen presentation common among malignant plasma cells (Ruiz-Arguelles and San Miguel 1994), a single target is unlikely to be sufficient to eliminate this disease. BCMA CS1 cCARs, BCMA CD19 cCARs, BCMA CD38 cCARs, and BCMA CD138 cCARs have been developed, and the experimental designs are similar to those described above for the CD33CD123 cCARs. [Generate includes] [BCMA CS1 cCAR (BC1cCAR)] [Of] [For the treatment of multiple myeloma] [cCAR] [] [Generation and characterization] [BCMA-CS1 cCAR (BC1cCAR)] [Structure] [] The modular design of BC1cCAR consists of an anti-CD269 (BCMA, B cell maturation antigen) single-chain variable fragment (scFv) region fused to anti-CD319 (CS1) via a self-cleaving P2A peptide, a CD8-derived hinge (H) and transmembrane (TM) region, and a tandem 4-1BB coactivation domain connected to the CD3ζ signaling domain ( FIG. 14A ). A strong spleen focus-forming viral promoter (SFFV) and a CD8 leader sequence are used for efficient expression of BC1cCAR) CAR molecules on the T cell surface. Both unit CARs use the same costimulatory domain 4-1BB. Transfected BC1cCAR HEK293T cells underwent Western blot analysis to confirm the composite construct. Immunoblotting with anti-CD3ζ monoclonal antibodies displayed bands of the predicted size of the composite CAR CD3ζ fusion protein ( FIG. 14E ). Importantly, as expected, two distinct bands of similar intensity were observed on the blots with successful high cleavage of the signaling P2A peptide. As expected, no CD3ζ expression was observed with the GFP control vector. [produce] [BC1cCAR (cCAR)T] [cell] [] After 2 days of activation, T cells isolated from umbilical cord blood (UCB) buffy coat were transduced with BC1cCAR lentivirus. Both CARs use the same costimulatory domain, 4-1BB. The transduction efficacy of BC1cCAR was determined to be approximately 15%, as determined by flow cytometry ( FIG. 14B ). BC1cCAR T cells were first tested on a CML (chronic myeloid leukemia) cell line that is negative for the myeloma markers BCMA and CS1. As expected, there was no lysis caused by control T cells or BC1cCAR T cells against wild-type K562 ( FIG. 14C ). BCMA-K562 (Kochenderfer, NIH) are K562 cells transduced with BCMA expressing cDNA to express BCMA in >80% of the cell population. BC1cCAR T cells were co-cultured with this cell line at E:T ratios of 2:1 and 5:1 and showed over 30% lysis (undetectable) compared to the control ( FIG. 14C ). These results are compatible with other cultures performed on other CAR cell lines transduced with antigens, such as CS1 CAR T cells. However, when BCMA-CS1-2G (cCAR) was used with different costimulatory domains, using either 4-BB or CD28 for each cell, rare surface CAR expression was detected, suggesting that appropriate costimulatory domain selection may be important for ensuring surface CAR expression on T cells (Figure 14D). Although protein was detected by Western blotting in HEK cells (Figure 14E), we were unable to detect surface expression in activated T cells transduced with CD269-CS1-2G lentiviral supernatant. This may be attributed to an inability to export the expressed protein to the cell membrane. In the future, we may need to optimize the sequence of this construct to allow for greater cell surface expression. [BC1cCAR T] [Cell Specificity] [Dissolve] [BCMA, + , ] [and] [CS1, + , ] [Cell line] [] To evaluate the cytotoxicity of BC1cCAR T cells, we performed co-culture assays with the myeloma cell lines MM1S (BMCA +CS1+), RPMI-8226 (BCMA +CS1-), and U266 (BCMA +CS1-dim). The ability of BC1cCAR T cells to lyse target cells was quantified by flow cytometry, and target cells were stained with Cytotracker dye (CMTMR). Within 24 hours of co-culture, BC1cCAR demonstrated near-complete lysis of MM1S cells, with over 90% target cell depletion at an E:T ratio of 2:1 and over 95% at an E:T ratio of 5:1 (Figure 15). In RPMI-8226 cells, BC1cCAR lysed over 70% of BCMA+ target cells at an E:T ratio of 2:1 and over 75% at an E:T ratio of 5:1 (Figure 16). In a 24-hour co-culture with U266 target cells, BC1cCAR lysed 80% of BCMA + U266 cells at an E:T ratio of 2:1, reaching saturation ( FIG. 17 ). [Native] [In patient myeloma samples] [BC1cCAR T] [Cell-specific targeting] [BCMA, + , ] [and] [CS1, + , ] [group] [] Flow cytometric analysis of MM10-G patient samples revealed distinct and consistent subsets of BCMA+ and CS1+ populations (Figure 18). MM7-G samples displayed a fully BCMA+CS1+ phenotype, while MM11-G exhibited a contaminated BCMAdimCS1dim phenotype, likely due to its nature as a bone marrow aspirate. After 24 hours, BC1 cCAR T cells demonstrated robust depletion of MM7-G primary patient samples, with over 75% lysis at an E:T ratio of 5:1, increasing to over 85% at 10:1 (Figure 19). For MM11-G (Figure 20), BC1 cCAR T cells were able to lyse over 45% of the BCMA+CS1+ population at an E:T ratio of 10:1. BC1cCAR demonstrated targeting and specific cytolytic capacity by significantly eliminating both BCMA+CS1+ and BCMA-CS1+ population subsets in MM10-G co-culture within 24 hours. At an E:T ratio of 2:1, BC1cCAR T cells eliminated over 60% of the BCMA+CS1+ population and 70% of the isolated CS1+ population. At an E:T ratio of 5:1, elimination of the isolated CS1+ population increased to 80% ( FIG18 ). [BC1cCAR T] [cell] [Showing significant control and reduction of tumors in vivo] [ , , ] To evaluate the in vivo anti-tumor activity of BC1cCAR T cells, we studied a xenogeneic mouse model using NSG mice that were sublethally irradiated and intravenously injected with luciferase-expressing MM.1S cells (a multiple myeloma cell line) to induce measurable leukemogenesis. Three days after tumor cell injection, mice were intravenously injected with a single dose of 8×10 BC1cCAR T cells or vector control cells. On days 3, 6, and 8, mice were subcutaneously injected with RediJect D-Luciferin (Perkin Elmer) and underwent IVIS imaging to measure tumor burden (Figure 21). The mean light intensity measured in mice injected with BC1cCAR T cells was compared with that in mice injected with the vector control to determine the percentage of tumor cells in treated versus control mice (Figures 21 and 22). Unpaired T-test analysis showed a highly significant difference between the two groups on day 8 (P = 0.0001), with the group injected with BC1cCAR T cells having lower light intensity and, therefore, lower tumor burden compared to the control group (p < 0.0001). On day 1 and every other day thereafter, tumor size area was measured and the average tumor size between the two groups was compared (Figure 21). In summary, these in vivo data indicate that CD269-CS1-BBCAR T cells significantly reduced tumor burden in MM.1S-injected NSG mice when compared to vector control NK control cells. [CD45 CAR] [therapy] [] Three pairs of sgRNAs were designed using CHOPCHOP to target relevant genes. Gene-specific sgRNAs were then cloned into a lentiviral vector expressing human Cas9 and a puromycin resistance gene linked to an E2A self-cleaving linker (Lenti U6-sgRNA-SFFV-Cas9-puro-wpre). The U6-sgRNA cassette preceded the Cas9 element. Expression of the sgRNA and Cas9 puro was driven by the U6 promoter and SFFV, respectively (Figure 23). The following gene-specific sgRNA sequences were used and constructed. In a non-limiting embodiment of the present invention, exemplary gene-specific sgRNAs have been designed and constructed as described below: CD45 sgRNA construct: Lenti-U6-sgCD45a-SFFV-Cas9-puro GTGGTGTGAGTAGGTAA Lenti-U6-sgCD45b-SFFV-Cas9-puroGAGTTTTGCATTGGCGG Lenti-U6-sgCD45c-SFFV-Cas9-puroGAGGGTGGTTGTCAATG [picture]

[24] demonstrated the steps for generating CD45 CAR T or NK cells targeting hematological malignancies. [CRISPR / Cas] [Nuclease Targeting] [NK] [On the cell] [CD45] [] NK-92 cells were transduced using a lentivirus with gene-specific sgRNA. The reduction of CD45 expression on NK-92 cells was determined by flow cytometry analysis. The CD45 negative population of NK-92 cells was sorted and amplified (Figure 25). CD45CAR NK cells were generated using sorted and amplified CD45 negative NK-92 cells. The obtained CD45CAR NK cells were used to test their ability to kill CD45+ cells. [exist] [CRISPR / Cas] [After nuclease targeting] [,] [through] [CD45] [Inactive] [NK-92] [cell] [(NK , 45i , -92) ] Functional Characterization. We demonstrated that after CD45 CRISPR / Cas9 nuclease inactivation, NK45i-92 cells grew similarly to wild-type NK-92 cells (Figure 26). CD45 inactivation did not significantly affect NK-92 cell proliferation. Furthermore, we confirmed that when co-cultured with CCRF leukemia cells, the lytic capacity of NK45i-92 cells was compatible with wild-type NK-92 (Figure 27). To demonstrate that CD45-inactivated NK-92 is compatible with CAR lysis, NK 45i-92 cells and wild-type NK-92 were transduced with lentivirus expressing either CD5 CAR or GFP. The resulting CD5 CAR NK 45i-92 cells and GFP NK 45i-92 were sorted by FACS and compared for their ability to kill target cells. When co-cultured with CCRF-CEM cells, CD5 CAR NK 45i-92 cells demonstrated robust killing of CD5 target leukemia cells at E:T ratios of 2:1 and 5:1. Similar in vitro CCRF-CEM cell depletion efficacy was observed between our CD5 CAR NK 45i-92 and CD5 CAR NK-92 cells ( FIG. 28 ). This suggests that reduced CD45 expression does not diminish the anti-tumor activity of CAR NK cells. [produce] [CD45CAR] [Structure] [] We then investigated the CD45CAR response to the CD45 antigen in leukemic cells, specifically NK 45i-92 cells. We generated a CD45CAR. The CD45CAR consists of an anti-CD45 single-chain variable fragment (scFv) region, a CD8-derived hinge (H) and transmembrane (TM) region, and tandem CD28 and 4-1BB coactivation domains linked to a CD3ζ signaling domain (Figure 29A). A strong spleen focus-forming viral promoter (SFFV) and a CD8 leader sequence were used. The CD45CAR protein was characterized by Western blotting of HEK293-FT cells transfected with the CD45CAR lentiviral plasmid using appropriate vector controls. Furthermore, immunoblotting with an anti-CD3ζ monoclonal antibody revealed a band of the predicted size for the CD45CAR protein, whereas no band was observed in the vector control (Figure 29B). [CD45CAR NK , 45i , -92 NK ] [cell] [] After enrichment of NK 45i-92 cells by fluorescence-activated cell sorting (FACS), the CD45CAR NK-92 transduction efficacy was determined to be 87%, as determined by flow cytometry after sorting (Figure 30). After FACS collection of NK 45i-92 cells, CD45CAR expression remained stable for at least 10 passages. [CD45CAR NK , 45i , -92 ] [Cell-specific lysis] [CD45+] [Leukemia cells] [] To evaluate the anti-leukemic activity of CD45CAR NK 45i-92, we performed co-culture assays using T-ALL cell lines, CCRF-CEM, and Jurkat, as well as NK cell lines and NK-92 cells, all of which express CD45 (Figures 31, 32, and 33). We demonstrated that CD45CAR NK 45i-92 cells consistently demonstrated robust lysis of leukemic cells. After 6 hours of incubation at low target cell efficiency (E:T ratio 5:1), CD45CAR NK 45i-92 cells effectively lysed over 60% of CCRF-CEM cells (Figure 31). After 6 hours of co-culture, CD45CAR NK 45i-92 cells were also able to eliminate approximately 60% of Jurkat cells at E:T ratios of 2:1 or 5:1 (Figure 32). After 6 hours of co-culture, CD45CAR NK 45i-92 cells effectively lysed 20% of CD45-positive NK-92 cells at an E:T ratio of 2:1, with nearly 60% lysis at an E:T ratio of 5:1 ( Figures 33A-33C ). To further analyze the CD45 target in hematologic malignancies, we generated two additional CARs: CD45-28 and CD45-BB. NK45i-92 cells were transduced with lentivirus expressing the CD45-28 or CD45-BB CARs. The CD45-28 and CD45-BB CARs contain novel anti-CD45 scFvs, which differ from the aforementioned CD45 CARs. The CD45-28 CAR utilizes the CD28 costimulatory domain, while the CD45-BB CAR has a 4-BB costimulatory domain. These CARs utilize a CD8-derived hinge (H) and transmembrane (TM) region, along with the CD3ζ signaling domain. The CD45 CARs demonstrated robust lysis of the B acute lymphoblastoid cell line REH. CD45 CAR NK45i-92 cells lysed approximately 76% of REH cells. Compared to control GFP NK-92 cells, CD45b-BB CAR NK45i-92 cells and CD45b-28 CAR NK45i-92 cells displayed approximately 79% and 100% REH cytolysis, respectively ( Figures 33D-G ). CD45b-28 CAR NK45i-92 cells exhibited the highest REH cytolytic capacity. [IL15] [and its receptor enhancement] [CAR T] [and] [NK] [Cellular Function] [] Recent studies have shown that T cell persistence correlates well with the efficacy of CAR T cell therapy. Current trials demonstrate that potent and sustained antitumor activity can be achieved with the infusion of only a few CAR T cells, suggesting that the quality, rather than the quantity, of the infused product is more important in promoting antitumor activity. Interleukin (IL)-15 is a cytokine that promotes lymphocyte development and hemostasis. Increased levels of IL-15 can promote T cell proliferation and enhance T cell effector responses. Data from recent studies confirm that IL-15 is important for the generation and maintenance of memory CD8 T cells, a key factor associated with antitumor activity. IL-15 binds to the IL-15 receptor α chain (also known as IL15RA or RA), promoting IL-15-mediated actions such as T cell survival, proliferation, and the generation of memory T cells. IL-15RA binds to a βγ complex in the surface of T cells and IL15 signals by binding to this IL-15RA / βγ complex on the cell surface of T cells and other types of cells. Current data show that IL-15 transfection alone does not significantly affect T cell function, but IL-15 / 1IL-15RA enables T cells to survive and proliferate spontaneously. The efficacy of administered IL-15 alone can be limited by the availability of free IL-15RA and its short half-life. Administration of a soluble IL-15 / RA complex greatly enhances the half-life and bioavailability of IL-15 in vivo. Consequently, treatment of mice with this complex, rather than IL-15 alone, leads to the stable proliferation and maintenance of memory CD8 T cells and NK cells. Recent studies have shown that a portion of the extracellular region of IL-15RA, called the sushi domain, is required for its binding to IL-15 (WEI et al., J. Immunol., Vol. 167(1), pp. 277-282, 2001). IL-15 / RA fusion proteins or IL-15 / sushi fusion proteins containing a linker are more potent than either IL-15 or soluble IL-15RA alone. The combination of IL-15 / RA or IL-15 / sushi maximizes IL-15 activity. However, it is unclear whether designs combining CAR and IL-15 / RA or IL15 / sushi in the same construct can maintain their desired biological properties in T or NK cells, as the insert sequence length can affect transfection efficiency and gene expression. The present invention provides engineered cells that have CAR and IL15 / RA or IL15 / sushi in a single construct. In some embodiments, the present invention includes methods for generating higher viral titers and using stronger promoters to drive CAR and IL15 / RA or IL-15 / sushi. In some embodiments, the present invention provides engineered cells having: (1) a CAR targeting an antigen, including but not limited to CD4, CD2, CD3, CD7, CD5, CD45, CD20, CD19, CD33, CD123, CS1, and B cell maturation antigen (BCMA); and (2) IL-15; (3) IL15RA (RA) or sushi. In other embodiments, the CAR comprises a chimeric antigen receptor, one or more of the co-stimulatory intracellular domains, such as CD28, CD2, 4-1BB, and OX40, and the intracellular domain of the CD3 zeta chain. In other embodiments, the strong promoter may be (but not limited to) SFFV, CAR, IL-15 / RA, or sushi, and an inducible suicide gene ("safety switch"), or may be assembled in combination on a vector, such as a lentiviral vector, an adenoviral vector, a retroviral vector, or a plasmid. The introduction of a "safety switch" can significantly increase the safety profile and limit the on-target or off-tumor toxicity of the CAR. [Representation] [CD4IL15RA-CAR] [] A CD4IL15RA-CAR has been generated and contains a third-generation CD4 CAR linked to IL15RA ( FIG. 34 ). The CAR (third generation), sushi / IL-15 combination was assembled on a expression vector and driven by an SFFV promoter ( FIG. 34 ). The CAR with sushi / IL-15 was linked to a P2A cleavage sequence. The sushi / IL-15 portion consisted of an IL-2 signal peptide fused to the sushi domain and linked to IL-5 via a 26-amino acid polyproline linker ( FIG. 34 ). To validate the CD4IL15RA construct, HEK293FT cells were transfected with either GFP (control) or CD4IL15RA lentiviral plasmids. Approximately 60 hours after transfection, HEK-293FT cells and supernatants were harvested. Cells were lysed in RIPA buffer containing a protease inhibitor cocktail and subjected to electrophoresis. The gel was transferred to an Immobilon FL blot membrane, blocked, and probed with a mouse anti-human CD3z antibody at 1:500. After washing, the membrane was probed with a goat anti-mouse HRP conjugate, washed, and exposed to film after treatment with HyGlo HRP substrate. The CD4IL15RA-CAR was successfully expressed in HEK 293 cells (lane 2, Figure 35a, as indicated by the recombinant IL-15 protein in lane 3 (arrow)). The CD4IL15RA-CAR lentiviral supernatant was further tested by transduction of fresh HEK-293 cells (Figure 35a). HEK-293 cells were transduced with GFP or CD4IL15RA-CAR viral supernatant from transfected HEK-293FT cells. Polybrene was added to 4 μL / mL. After 16 hours, the medium was replaced with medium without viral supernatant or polybrene. Three days after transduction, cells were harvested and stained with goat anti-mouse F(ab')2 antibody at 1:250 for 30 minutes. Cells were washed and stained with streptavidin-PE conjugate at 1:500, washed, suspended in 2% formalin, and analyzed by flow cytometry. Figure 34b shows that HEK-293 cells transduced with the CD4IL15RA-CAR lentivirus were 80% positive for F(ab')2-PE (circles, Figure 35b), while cells transduced with the GFP control lentivirus showed minimal F(ab')2-PE expression (Figure 35b, left). [produce] [CD4IL15RA-CAR NK] [cell] [] NK-92 cells were transduced with CD4IL15RA-CAR lentiviral supernatant. After 5 days of incubation, cells were harvested and incubated with goat anti-mouse F(ab')2 at a 1:250 ratio for 30 minutes. The cells were washed, suspended, and stained with streptavidin-PE for 30 minutes. The cells were washed, suspended in 2% formalin, and analyzed by flow cytometry, resulting in approximately 70% of the transduced cells expressing the CD4IL15RA-CAR (circles, Figure 36). Additional experimental testing of the CD4IL15RA-CAR will include in vitro and in vivo leukemia / lymphoma killing assays, as well as comparison of target killing and proliferation rates of CD4CAR-transduced cells. The present inventors also generated the CD19IL15RA-CAR using the same strategy as described above. [produce] [CD4IL15RA-CAR T] [cell] Human umbilical cord buffy coat cells were transduced with CD4IL15RA-CAR lentiviral supernatant. After 5 days of incubation, cells were harvested and incubated with goat anti-mouse F(Ab')2 at a 1:250 ratio for 30 minutes. Cells were washed, suspended, and stained with streptavidin-PE for 30 minutes. Cells were washed, suspended in 2% formalin, and analyzed by flow cytometry, resulting in 63% of transduced cells expressing the CD4IL15RA-CAR (circles, Figure 37). Additional experimental testing of the CD4IL15RA-CAR will include in vitro and in vivo leukemia / lymphoma killing assays, as well as comparison of target killing and proliferation rates of cells transduced with the CD4CAR. [By] [CD4IL15RACAR NK] [Cell with the following] [CD4] [Positive cell lines were co-cultured to test their relative [CD4CAR NK] [In vitro anti-leukemia activity of cells] [:] [Karpas 299] [and] [MOLT4] [] The Karpas 299 cell line was derived from a patient with polymorphic large T-cell lymphoma. The CD4-expressing MOLT4 cell line was generated from the peripheral blood of a 19-year-old patient with acute lymphoblastic leukemia (T-ALL). During a 4-hour co-culture experiment, CD4IL15RA CAR NK cells demonstrated significant killing of Karpas 299 cells (95%) at an effector:target ratio of 5:1, even at a higher ratio than CD4CAR NK cells (82%, Figure 38). Similarly, when co-cultured with MOLT4 cells at a 1:1 ratio, CD4IL15RA CAR NK cells lysed target cells at a higher ratio (84% to 65%) than CD4CAR NK cells in an overnight assay (Figure 39). These results demonstrate that CD4IL15 CAR NK cells can eliminate tumor cells at least as effectively as CD4CAR NK cells. [CD4CAR] [and] [CD4IL15RA CAR T] [cell] [Presentation ratio] [CD4CAR] [Even] [Potent anti-tumor activity in vivo] [] To evaluate the in vivo antitumor activity of CD4CAR and CD4IL15RACAR T cells and determine the potential enhanced persistence of CD4IL15RA CAR T cells relative to CD4CAR T cells, we investigated a xenogeneic mouse model using NSG mice that were sublethally irradiated and intravenously injected with luciferase-expressing MOLM13 cells (an acute myeloid leukemia cell line (M5) that is 100% CD4) to induce measurable tumor formation. Three days after tumor cell injection, six mice were each intravenously injected with 8×106 CD4CAR, CD4IL15RACAR T cells, or vector control T cells. On days 3, 6, 9, and 11, mice were subcutaneously injected with RediJect D-Luciferin (Perkin Elmer) and underwent IVIS imaging to measure tumor burden (Figure 40). On day 6, mice treated with CD4CAR T cells had a 52% reduction in tumor burden relative to controls, while mice treated with CD4IL15RACAR T cells had a 74% reduction in tumor burden (Figure 41). On day 11, in both of these groups, almost all tumor cells were lysed. On day 9, unpaired T test analysis showed a highly significant difference between the control and both groups (P = 0.0045), with lower light intensity and therefore lower tumor burden in the CD4CAR and CD4IL15RACAR T cell-treated groups compared to the control. Promoter testing using a GFP reporter HEK293FT cells were transfected with lentiviral plasmids expressing GFP under the SFFV, EF1, or CAG promoters. Approximately 60 hours after transfection, supernatants were collected from each sample. Relative viral titers were determined by first transducing HEK293 cells with supernatants from each of the three promoters. HEK-293 cells were transduced with GFP viral supernatants from each of the three transfected HEK-293FT cells. Polybrene was added to a concentration of 4 μL / mL. After 16 hours, the medium was replaced with medium without viral supernatant or polybrene. Three days after transduction, cells were harvested, washed, suspended in 2% formalin, and analyzed by flow cytometry for GFP expression (FITC). GFP expression was observed in all samples, but was highest in cells transduced with the virus produced using the SFFV promoter. Activated human umbilical cord buffy coat cells were transduced with GFP lentiviral supernatants from various promoters (quantities based on HEK293 transduction efficacy results). After 5 days of incubation, cells were harvested, washed, suspended in 2% formalin, and analyzed by flow cytometry for GFP expression. 43% of cells expressed GFP at high levels (>10³), while cells transduced with viruses using the EF1 (15%) and CAG (3%) promoters showed significantly lower GFP expression. Five days later, cells analyzed in the same manner showed nearly identical percentages (46%, 15%, and 3%, respectively; Figure 23). These results demonstrate that the SFFV promoter elicits stronger expression than the EF1 or CAG promoters, and that expression remains elevated for at least 10 days after transduction. Additional experimental testing will include longer incubation times of transduced cells beyond the 10-day window. Provided are methods for producing a CAR gene comprising a T antigen recognition portion (at least one of CD4, CD8, CD3, CD5, CD7, and CD2, or a portion or combination thereof), a hinge region, and at least one of a T cell activation domain. Methods are provided for producing multiple CAR (cCAR) units targeting antigens, including at least one of CD33, CD123, CD19, CD20, CD22, CD269, CS1, CD38, CD52, ROR1, PSMA, CD138, and GPC3, or a portion or combination of a hinge region and a T cell activation domain. All references cited and / or disclosed herein are incorporated herein by reference in their entirety. Methods provided also include: 1) generating CAR T or NK cells that target leukemias and lymphomas expressing CD45 and avoid suicide; 2) generating "armored" CAR T or NK cells that are designed to overcome the suppressive tumor microenvironment and exhibit enhanced anti-tumor activity and long-term persistence. The present invention is not limited to the embodiments described and illustrated above and is capable of variation and modification within the scope of the appended claims. Throughout this specification, various publications, including patents, published applications, technical papers, and academic papers, are cited. Each of the cited publications is incorporated herein by reference in its entirety and for all purposes. Throughout this specification and claims, various terms related to aspects of the present invention are used. Unless otherwise indicated, such terms shall have their ordinary meanings in the art. Other specifically defined terms are to be interpreted in a manner consistent with the definitions provided herein. [Functional titer of viral vector particles in the supernatant] [ , (,] The % GFP cells as determined by flow cytometry allows for regulation of viral titer, as higher titer viruses infiltrate more cells, resulting in a higher % GFP cell population. [] To determine the functional titer of viral vector particles in each supernatant, HEK 293 cells were transduced with EF1-GFP or SFFV-GFP viral supernatants at 30 μL (low), 125 μL (medium), or 500 μL (high) per well in 12-well tissue culture-treated plates. The following morning, the medium was replaced with DMEM supplemented with 10% FBS. The transduced cells were then trypsinized, washed, suspended in formalin, and subjected to flow cytometry. The percentage of GFP+ cells under each condition was determined by flow cytometry using the FITC channel (Figure 43). In each case, the percentage of GFP+ cells in cells transduced with SFFV-GFP was higher than in cells transduced with the corresponding volume of EF1-GFP viral supernatant (50% vs. 18% (low), 80% vs. 40% (medium), and 82% vs. 70% (high)). From this, we determined that the titer of the EF1 promoter virus using the highest volume was similar to that of the SFFV promoter virus using the lowest volume, and the relative promoter concentrations will be compared in the following transduction experiments. Transduced cells were also observed using GFP at 20× on an EVOS fluorescence microscope under identical exposure conditions for each well (Figure 42). Cells transduced with SFFV-GFP viral supernatant were significantly brighter than those transduced with EF1-GFP. Furthermore, comparing images of the EF1 promoter at high viral loads with images of the SFFV promoter at low viral loads revealed similar fluorescence intensities. This suggests that the SFFV promoter is a stronger driver of gene expression. [Native] [T] [cell] [Comparison of Surface Expression and Persistence of Different Promoters] [(] % of T cell transduced GFP cells as determined by flow cytometry shows expected differences in GFP cell population as expected from previous experiments with HEK293 cells) [] To determine promoter transduction efficacy and surface expression persistence in naive T cells, activated umbilical cord blood buffy coat T cells were transduced with 50 µL of SFFV-GFP or 1 mL of EF1-GFP viral supernatant in 12-well tissue culture-treated plates pre-coated with recombinant human fibrin fragments (Clontech). After two overnight transductions, cells were cultured in T cell culture medium with 300 IU / mL IL-2 (Peprotech) and maintained at a cell count of 1.0-4.0 × 10⁶ cells / mL. On days 7, 14, 21, and 28 after transduction, cells were washed, suspended in formalin, and analyzed by flow cytometry using the FITC channel to determine the percentage of GFP+ cells. Compared to T cells transduced with EF1-GFP, T cells transduced with SFFV-GFP consistently exhibited a higher percentage of GFP+ cells (Figure 44A), even though the percentage of total GFP+ cells decreased during this period. Another comparison showed that between day 7 and day 28, the percentage of T cells transduced with a higher amount (1 mL) of EF1-GFP supernatant actually decreased from over 60% to less than 40% relative to the percentage of GFP+ cells transduced with a lower amount (50 μL, or 20-fold lower) of SFFV-GFP (Figure 44B). This suggests that transduction using the SFFV promoter results in greater persistence of the transduced cells. [Targeted Performance] [BCMA] [or] [TACI] [or] [BAFF-R CAR] [At least one of the antigens] [BCMA] [or] [TACI] [or] [BAFF-R CAR NK] [Cell or] [T] [cell] [] To evaluate the cytotoxicity of CARs targeting at least one of BCMA, TACI, or BAFF-R on NK or T cells, co-culture assays were performed with cell lines or primary human cells expressing at least one of these. The ability of these CAR NK or T cells to lyse target cells was quantified by flow cytometry, and the target cells were stained with Cytotracker dye (CMTMR). Lysis was observed over a 24-hour culture period. BAFF or APRIL CAR NK or T cells targeting cells expressing at least one of BCMA or TACI or BAFF-R antigens. The chimeric antigen receptor in CAR is a ligand for BCMA, TACI, or BAFF-R. To evaluate the cytotoxicity of CARs targeting at least one of BCMA, TACI, or BAFF-R in NK or T cells, co-culture assays were performed with cell lines or human primary cells expressing at least one of these. The ability of these CAR NK or T cells to lyse target cells was quantified by flow cytometry, and the target cells were stained with Cytotracker dye (CMTMR). Lysis was observed over a 24-hour culture period. References Arai, S., R. Meagher, M. Swearingen, H. Myint, E. Rich, J. Martinson and H. Klingemann (2008). "Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial." [Cytotherapy]

[10] (6): 625-632. Boissel, L., M. Betancur-Boissel, W. Lu, D. S. Krause, R. A. Van Etten, W. S. Wels and H. Klingemann (2013). "Retargeting NK-92 cells by means of CD19- and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity." [Oncoimmunology] [2](10): e26527. Burnett, A. K. (2012). "Treatment of acute myeloid leukemia: are we making progress?" [Hematology-American Society Hematology Education Program]: 1-6. Chu, J., Y. Deng, D. M. Benson, S. He, T. Hughes, J. Zhang, Y. Peng, H. Mao, L. Yi, K. Ghoshal, X. He, S. M. Devine, X. Zhang, M. A. Caligiuri, C. C. Hofmeister and J. Yu (2014). "CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma." [Leukemia]

[28] (4): 917-927. Corbin, A. S., A. Agarwal, M. Loriaux, J. Cortes, M. W. Deininger and B. J. Druker (2011). "Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity." [J Clin Invest]

[0121] (1): 396-409. Dinndorf, P. A., R. G. Andrews, D. Benjamin, D. Ridgway, L. Wolff and I. D. Bernstein (1986). "Expression of normal myeloid-associated antigens by acute leukemia cells." [Blood]

[67] (4): 1048-1053. Djokic, M., E. Bjorklund, E. Blennow, J. Mazur, S. Soderhall and A. Porwit (2009). "Overexpression of CD123 correlates with the hyperdiploid genotype in acute lymphoblastic leukemia." [Haematologica]

[94] (7): 1016-1019. Ehninger, A., M. Kramer, C. Rollig, C. Thiede, M. Bornhauser, M. von Bonin, M. Wermke, A. Feldmann, M. Bachmann, G. Ehninger and U. Oelschlagel (2014). "Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia." [Blood Cancer J] [4]: e218. Firor, A. E., A. Jares and Y. Ma (2015). "From humble beginnings to success in the clinic: Chimeric antigen receptor-modified T-cells and implications for immunotherapy." [Exp Biol Med (Maywood)]. Garfall, A. L., M. V. Maus, W. T. Hwang, S. F. Lacey, Y. D. Mahnke, J. J. Melenhorst, Z. Zheng, D. T. Vogl, A. D. Cohen, B. M. Weiss, K. Dengel, N. D. Kerr, A. Bagg, B. L. Levine, C. H. June and E. A. Stadtmauer (2015). "Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma." [N Engl J Med]

[0373] (11): 1040-1047. Ghosh, N. and W. Matsui (2009). "Cancer stem cells in multiple myeloma." [Cancer Lett]

[0277] (1): 1-7. Griffin, J. D., D. Linch, K. Sabbath, P. Larcom and S. F. Schlossman (1984). "A monoclonal antibody reactive with normal and leukemic human myeloid progenitor cells." [Leuk Res] [8](4): 521-534. Jilani, I., E. Estey, Y. Huh, Y. Joe, T. Manshouri, M. Yared, F. Giles, H. Kantarjian, J. Cortes, D. Thomas, M. Keating, E. Freireich and M. Albitar (2002). "Differences in CD33 intensity between various myeloid neoplasms." [Am J Clin Pathol]

[0118] (4): 560-566. Jordan, C. T., D. Upchurch, S. J. Szilvassy, M. L. Guzman, D. S. Howard, A. L. Pettigrew, T. Meyerrose, R. Rossi, B. Grimes, D. A. Rizzieri, S. M. Luger and G. L. Phillips (2000). "The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells." [Leukemia]

[14] (10): 1777-1784. Klingemann, H. (2014). "Are natural killer cells superior CAR drivers?" [Oncoimmunology] [3]: e28147. Kumar, S. K., S. V. Rajkumar, A. Dispenzieri, M. Q. Lacy, S. R. Hayman, F. K. Buadi, S. R. Zeldenrust, D. Dingli, S. J. Russell, J. A. Lust, P. R. Greipp, R. A. Kyle and M. A. Gertz (2008). "Improved survival in multiple myeloma and the impact of novel therapies." [Blood]

[0111] (5): 2516-2520. Lang, S., N. L. Vujanovic, B. Wollenberg and T. L. Whiteside (1998). "Absence of B7.1-CD28 / CTLA-4-mediated co-stimulation in human NK cells." [Eur J Immunol]

[28] (3): 780-786. Lanitis, E., M. Poussin, A. W. Klattenhoff, D. Song, R. Sandaltzopoulos, C. H. June and D. J. Powell, Jr. (2013). "Chimeric antigen receptor T Cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo." [Cancer Immunol Res] [1](1): 43-53. Loke, J., J. N. Khan, J. S. Wilson, C. Craddock and K. Wheatley (2015). "Mylotarg has potent anti-leukaemic effect: a systematic review and meta-analysis of anti-CD33 antibody treatment in acute myeloid leukaemia." [Annals of Hematology]

[94] (3): 361-373. Maus, M. V., J. A. Fraietta, B. L. Levine, M. Kalos, Y. Zhao and C. H. June (2014). "Adoptive immunotherapy for cancer or viruses." [Annu Rev Immunol]

[32] : 189-225. Olson, J. A., D. B. Leveson-Gower, S. Gill, J. Baker, A. Beilhack and R. S. Negrin (2010). "NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects." [Blood]

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[69] (7): 684-690. Testa, U., E. Pelosi and A. Frankel (2014). "CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies." [Biomark Res] [2](1): 4. Vergez, F., A. S. Green, J. Tamburini, J. E. Sarry, B. Gaillard, P. Cornillet-Lefebvre, M. Pannetier, A. Neyret, N. Chapuis, N. Ifrah, F. Dreyfus, S. Manenti, C. Demur, E. Delabesse, C. Lacombe, P. Mayeux, D. Bouscary, C. Recher and V. Bardet (2011). "High levels of CD34+CD38low / -CD123+ blasts are predictive of an adverse outcome in acute myeloid leukemia: a Groupe Ouest-Est des Leucemies Aigues et Maladies du Sang (GOELAMS) study." [Haematologica]

[96] (12): 1792-1798. Wilkie, S., M. C. van Schalkwyk, S. Hobbs, D. M. Davies, S. J. van der Stegen, A. C. Pereira, S. E. Burbridge, C. Box, S. A. Eccles and J. Maher (2012). "Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling." [J Clin Immunol]

[32] (5): 1059-1070.

[0005] [] none

[0006] <![CDATA[ <110> iCell Gene Therapeutics LLC <![CDATA[ <120> Chimeric Antigen Receptors (CARs), Compositions, and Methods of Use]]> <![CDATA[ <130> TW105120100]]> <![CDATA[ <150> US 62 / 184,321 <![CDATA[ <151> June 25, 2015 <![CDATA[ <150> US 62 / 235,840 <![CDATA[ <151> 2015-10-01 <![CDATA[ <150> US 62 / 244,435 <![CDATA[ <151> October 21, 2015 <![CDATA[ <160> 36 ]]> <![CDATA[ <170> PatentIn version 3.5]]> <![CDATA[ <210> 1]]> <![CDATA[ <211> 830]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> artificial sequence]]> <![CDATA[ <220> ]]> <![CDATA[ <223> composite sequence]]> <![CDATA[ <400> 1]]> 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 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu 20 25 30 Ala Val Ser Leu Gly Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gln 35 40 45 Ser Leu Leu Tyr Ser Thr Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln 50 55 60 Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr 65 70 75 80 Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr 85 90 95 Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Val Ala Val 100 105 110 Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Arg Thr Phe Gly Gly Gly Thr 115 120 125 Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 130 135 140 Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Val Val 145 150 155 160 Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr 165 170 175 Phe Thr Ser Tyr Val Ile His Trp Val Arg Gln Lys Pro Gly Gln Gly 180 185 190 Leu Asp Trp Ile Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Asp Tyr 195 200 205 Asp Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ser Asp Thr Ser Thr 210 215 220 Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala 225 230 235 240 Val Tyr Tyr Cys Ala Arg Glu Lys Asp Asn Tyr Ala Thr Gly Ala Trp 245 250 255 Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr 260 265 270 Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln 275 280 285 Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala 290 295 300 Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala 305 310 315 320 Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr 325 330 335 Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met 340 345 350 Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro 355 360 365 Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg 370 375 380 Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln 385 390 395 400 Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu 405 410 415 Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala 420 425 430 Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu 435 440 445 Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp 450 455 460 Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly 465 470 475 480 Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 485 490 495 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu 500 505 510 Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 515 520 525 Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu 530 535 540 Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Tyr Arg 545 550 555 560 Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu Val Thr Asn 565 570 575 Ser Gly Ile His Val Phe Ile Leu Gly Cys Phe Ser Ala Gly Leu Pro 580 585 590 Lys Thr Glu Ala Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile 595 600 605 Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu 610 615 620 Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu 625 630 635 640 Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His 645 650 655 Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser 660 665 670 Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu 675 680 685 Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln 690 695 700 Met Phe Ile Asn Thr Ser Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser 705 710 715 720 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Leu Gln 725 730 735 Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala Leu 740 745 750 Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr Cys 755 760 765 Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser Tyr 770 775 780 Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg 785 790 795 800 Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala Thr 805 810 815 Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg 820 825 830 <![CDATA[<210> 2]]> <![CDATA[<211> 2509]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial sequence]]><000!1205> [[ID=!28]]<![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 2]]> gcgatcgcat ggccttacca gtgaccgcct tgctcctgcc gctggccttg ctgctccacg 60 ccgccaggcc ggacatcgtg atgacccaaa gccccgacag cctggccgtg agcctgggcg 120 agagggtgac catgaactgc aaaagcagcc agtccctgct gtactccacc aaccagaaga 180 It should be noted that there seems to be an "!" in the "<000!1205> " and "<![CDATA[<220>]]> " which might be a formatting error in the original. If it's a real error, it should be corrected before translation for a more accurate result.actacctggc ttggtatcaa cagaagcccg gacagagccc caagctgctg atctattggg 240 ccagcactag ggaaagcggc gtgcccgata ggttcagcgg cagcgggagc ggcacagact 300 tcactctgac cattagcagc gtgcaggctg aggatgtggc cgtctactac tgccagcagt 360 actacagcta caggaccttt gggggcggaa ctaagctgga gatcaaggga ggggggggat 420 ccgggggagg aggctccggc ggaggcggaa gccaagtgca actgcagcag agcggcccag 480 aggtggtcaa acctggggca agcgtgaaga tgagctgcaa ggctagcggc tataccttca 540 ccagctatgt gatccactgg gtgaggcaga aaccaggaca gggcctggac tggatcggct 600 acatcaaccc ctacaatgac ggcaccgatt atgacgaaaa attcaagggg aaggccaccc 660 tgaccagcga caccagcaca agcaccgcct acatggagct gtccagcctg aggtccgagg 720 acaccgccgt gtattactgt gccagggaga aggacaatta cgccaccggc gcttggttcg 780 cctactgggg ccagggcaca ctggtgacag tgagcagcac cacgacgcca gcgccgcgac 840 caccaacacc ggcgcccacc atcgcgtcgc agcccctgtc cctgcgccca gaggcgtgcc 900 ggccagcggc ggggggcgca gtgcacacga gggggctgga cttcgcctgt gatatctaca 960 tctgggcgcc cttggccggg acttgtgggg tccttctcct gtcactggtt atcacccttt 1020 actgcaggag taagaggagc aggctcctgc acagtgacta catgaacatg actccccgcc 1080 gccccgggcc cacccgcaag cattaccagc cctatgcccc accacgcgac ttcgcagcct 1140 atcgctccaa acggggcaga aagaaactcc tgtatatatt caaacaacca tttatgagac 1200 cattcaaac tactcaagag gaagatggct gtagctgccg atttccagaa gaagaagaag 1260 1320 gccagaacca gctctataac gagctcaatc taggacgaag agaggatac gatgttttgg 1380 acaagagacg tggccgggac cctgagatgg ggggaaagcc gcagagaagg aagaaccctc 1440 1500 ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag ggtctcagta 1560 cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct cgcggaagcg 1620 gagccaccaa cttcagccctg ctgaagcagg ccggcgacgt ggaggagaac cccggcccca 1680 tgtacagaat gcagctgctg agctgcatcg ccctgagcct gccctgtg accacagcg 1740 gcatccacgt gttcatcctg gggctgcttca gcgccggcct gcccagacc gaggccact 1800 gggtgaacgt gatcagcgac ctgaagaga tcgaggacct gatccagagc atgcacatcg 1860 acgccaccct gtacaccgag agcgacgtgc acccaccg caggtgacc gccatgaagt 1920 gcttcctgct ggagctgcag gtgatcagcc tggagcgg cgacgccagc atccacgaca 1980 ccgtggagaa cctgatcatc ctggccaaca acagcctgag cagcaacggc aacgtgaccg 2040 agagcggctg caggagtgc gaggagctgg aggagaa catchaggag ttcctgcaga 2100 gcttcgtgca catcgtgcag atgttcatca acaccagctc cggcggcggc tccggcggcg 2160 gcggctccgg cggcggcggc tccggcggcg gcggctccgg cggcggctcc ctgcaggccc 2220 ccagaagagc cagaggctgc agaaccctgg gcctgcccgc cctgctgctg ctgctgctgc 2280 tgagaccccc cgccaccaga ggcatcacct gcccccccc catgagcgtg gagcacgccg 2340 acatctgggt gaagagctac agcctgtaca gcagagagag atacatctgc aacagcggct 2400 tcaagagaaa ggccggcacc agcagcctga ccgagtgcgt gctgaacaag gccaccaacg 2460 tggcccactg gaccaccccc agcctgaagt gcatcagata agtttaaac 2509 <![CDATA[ <210> 3]]> <![CDATA[ <211> 995]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> artificial sequence]]> <![CDATA[ <220> ]]> <![CDATA[ <223> composite sequence]]> <![CDATA[ <400> 3]]> 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 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu 20 25 30 Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln 35 40 45 Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr 50 55 60 Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro 65 70 75 80 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile 85 90 95 Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly 100 105 110 Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 130 135 140 Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser 145 150 155 160 Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly 165 170 175 Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly 180 185 190 Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser 195 200 205 Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys 210 215 220 Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys 225 230 235 240 His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly 245 250 255 Thr Ser Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro 260 265 270 Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu 275 280 285 Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp 290 295 300 Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly 305 310 315 320 Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg 325 330 335 Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln 340 345 350 Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu 355 360 365 Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala 370 375 380 Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu 385 390 395 400 Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp 405 410 415 Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly 420 425 430 Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 435 440 445 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu 450 455 460 Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 465 470 475 480 Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu 485 490 495 Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu 500 505 510 Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala 515 520 525 Arg Pro Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser 530 535 540 Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Ser Val Ser 545 550 555 560 Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp 565 570 575 Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser 580 585 590 Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu 595 600 605 Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro 610 615 620 Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly 625 630 635 640 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln 645 650 655 Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser 660 665 670 Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val 675 680 685 Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro 690 695 700 Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr 705 710 715 720 Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser 725 730 735 Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr 740 745 750 Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val 755 760 765 Thr Val Ser Ala Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala 770 775 780 Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg 785 790 795 800 Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys 805 810 815 Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu 820 825 830 Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu 835 840 845 Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr 850 855 860 Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr 865 870 875 880 Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln 885 890 895 Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu 900 905 910 Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly 915 920 925 Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu 930 935 940 Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys 945 950 955 960 Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu 965 970 975 Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu 980 985 990 Pro Pro Arg 995 <![CDATA[<210> 4]]> <![CDATA[<211> 3004]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 4]]> gcgatcgcat ggccttacca gtgaccgcct tgctcctgcc gctggccttg ctgctccacg 60 ccgccaggcc ggacatccag atgacacaga ctacatcctc cctgtctgcc tctctgggag 120<00> acagagtcac catcagttgc agggcaagtc aggacattag taaatattta aattggtatc 180 agcagaaacc agatggaact gttaaactcc tgatctacca tacatcaaga ttacactcag 240 gagtcccatc aaggttcagt ggcagtgggt ctggaacaga ttattctctc accattagca 300 acctggagca agaagatatt gccacttact tttgccaaca gggtaatacg cttccgtaca 360 cgttcggagg ggggaccaag ctggagatca caggtggcgg tggctcgggc ggtggtgggt 420 cgggtggcgg cggatctgag gtgaaactgc aggagtcagg acctggcctg gtggcgccct 480 cacagagcct gtccgtcaca tgcactgtct caggggtctc attacccgac tatggtgtaa 540 gctggattcg ccagcctcca cgaaagggtc tggagtggct gggagtaata tggggtagtg 600 aaaccacata ctataattca gctctcaaat ccagactgac catcatcaag gacaactcca 660 agagccaagt tttcttaaaa atgaacagtc tgcaaactga tgacacagcc atttactact 720 gtgccaaaca ttattactac ggtggtagct atgctatgga ctactggggc caaggaacct 780 cagtcaccgt ctcctcaacc acgacgccag cgccgcgacc accaacaccg gcgcccacca 840 tcgcgtcgca gcccctgtcc ctgcgcccag aggcgtgccg gccagcggcg gggggcgcag 900 tgcacacgag gggggctggac ttcgcctgtg atatctacat ctgggcgccc ttggccggga 960 cttgtggggt ccttctcctg tcactggtta tcacccttta ctgcaaacgg ggcaagaaga 1020 aactcctgta tatattcaaa caaccattta tgagaccagt acaaactact caagaggaag 1080 atgggcttag ctgccgattt ccagaagaag aagaaggagg atgtgaactg agagtgaagt 1140 tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc tataacgagc 1200 tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc cgggaccctg 1260 agatgggggg aaagccgcag agaaggaaga accctcagga aggcctgtac aatgaactgc 1320 agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag cgccggaggg 1380 gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac acctacgacg 1440 cccttcacat gcaggccctg ccccctcgcg gaagcggagc caccaacttc agcctgctga 1500 agcaggccgg cgacgtggag gagaaccccg gccccatggc cttaccagtg accgccttgc 1560 tcctgccgct ggccttgctg ctccacgccg ccaggccgca gatcgtgctg agccagagcc 1620 ctgccatcct gtccgcaagc ccaggcgaga aggtgaccat gacctgtagg gccagcagct 1680 ccgtgagcta catccactgg tttcagcaga agcctggaag cagccctaag ccctggatct 1740 acgccacaag caatctggct agcggcgtgc ccgtgaggtt cagcggcagc gggagcggga ccagctacag cctgactatc agcagggtgg aggccgagga cgccgccaca tactactgcc aacagtggac ctccaaccca cccaccttttg gaggagggac aaaactggag atcaaagggg gcggagggtc cggaggcggc ggagcgggg gaggggag ccaggtccaa ctgcaacagc ccggagcaga actggtcaaa ccggcgcca gcgtgaagat gagctgcaag gccagcgggt acaccttcac ttcctataac atgcactggg tgaagcagac cccaggaagg ggcctggagt ggatcggggc aatctatccc ggcaacggcg acacaagcta caaccagaag ttcaagggga aagccactct gaccgccgac aagtccagct ccaccgccta catgcagctg agctccctga ccagcgagga cagcgccgtg tactattgcg ccagaagcac ttattacgga ggggactggt 2280 acttcaacgt gtggggggca gggaccaccg tgaccgtgtc cgccaccacg acgccagcgc 2340 cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg cgcccagagg 2400 cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc gcctgtgata 2460 tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca ctggttatca 2520 ccctttactg caggagtaag aggagcaggc tcctgcacag tgactacatg aacatgactc 2580 cccgccgccc cgggcccacc cgcaagcatt accagcccta tgccccacca cgcgacttcg 2640 cagcctatcg ctccagagtg aagttcagca ggagcgcaga cgcccccgcg taccagcagg 2700 gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac gatgttttgg 2760 acaagagacg tggccgggac cctgagatgg ggggaaagcc gcagagaagg aagaaccctc 2820 aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac agtgagattg 2880 <![CDATA[<210> 5]]> ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag ggtctcagta 2940 cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct cgctaagttt 3000 aaac 3004 <![CDATA[<210> 5]]> <![CDATA[<211> 1001]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic Sequence]]> <![CDATA[ <400> 5]]> Asp Arg Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu 1 5 10 15 Leu Leu His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Thr Thr Ser 20 25 30 Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala 35 40 45 Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp 50 55 60 Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly 65 70 75 80 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu 85 90 95 Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln 100 105 110 Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu 115 120 125 Ile Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser 145 150 155 160 Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp 165 170 175 Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp 180 185 190 Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu 195 200 205 Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe 210 215 220 Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys 225 230 235 240 Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly 245 250 255 Gln Gly Thr Ser Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg 260 265 270 Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg 275 280 285 Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly 290 295 300 Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr 305 310 315 320 Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg 325 330 335 Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro 340 345 350 Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu 355 360 365 Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala 370 375 380 Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu 385 390 395 400 Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly 405 410 415 Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu 420 425 430 Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser 435 440 445 Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly 450 455 460 Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu 465 470 475 480 His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser 485 490 495 Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala 500 505 510 Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala 515 520 525 Ala Arg Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala 530 535 540 Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile 545 550 555 560 Val His Ser Val Gly Asn Thr Phe Leu Glu Trp Tyr Gln Gln Lys Pro 565 570 575 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 580 585 590 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 595 600 605 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 610 615 620 Phe Gln Gly Ser Gln Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val 625 630 635 640 Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 645 650 655 Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro 660 665 670 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Glu Phe Ser 675 680 685 Arg Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu 690 695 700 Trp Val Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Ser Gly 705 710 715 720 Lys Phe Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr 725 730 735 Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 740 745 750 Tyr Cys Ala Arg Asp Gly Ser Ser Trp Asp Trp Tyr Phe Asp Val Trp 755 760 765 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro 770 775 780 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 785 790 795 800 Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 805 810 815 Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly 820 825 830 Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys 835 840 845 Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg 850 855 860 Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro 865 870 875 880 Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser 885 890 895 Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu 900 905 910 Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg 915 920 925 Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln 930 935 940 Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr 945 950 955 960 Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp 965 970 975 Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala 980 985 990 Leu His Met Gln Ala Leu Pro Pro Arg 995 1000 <![CDATA[<210> 6]]> <![CDATA[<211> 3016]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic Sequence]]> <![CDATA[<400> 6]]> gcgatcgcat ggccttacca gtgaccgcct tgctcctgcc gctggccttg ctgctccacg 60 ccgccaggcc ggacatccag atgacacaga ctacatcctc cctgtctgcc tctctgggag 120 acagagtcac catcagttgc agggcaagtc aggacattag taaatattta aattggtatc 180 agcagaaacc agatggaact gttaaactcc tgatctacca tacatcaaga ttacactcag 240 gagtcccatc aaggttcagt ggcagtgggt ctggaacaga ttattctctc accattagca 300 acctggagca agaagatatt gccacttact tttgccaaca gggtaatacg cttccgtaca 360 cgttcggagg ggggaccaag ctggagatca caggtggcgg tggctcgggc ggtggtgggt 420 cgggtggcgg cggatctgag gtgaaactgc aggagtcagg acctggcctg gtggcgccct 480 cacagagcct gtccgtcaca tgcactgtct caggggtctc attacccgac tatggtgtaa 540 gctggattcg ccagcctcca cgaaagggtc tggagtggct gggagtaata tggggtagtg 600 aaaccacata ctataattca gctctcaaat ccagactgac catcatcaag gacaactcca 660 agagccaagt tttcttaaaa atgaacagtc tgcaaactga tgacacagcc atttactact 720 gtgccaaaca ttattactac ggtggtagct atgctatgga ctactggggc caaggaacct 780 cagtcaccgt ctcctcaacc acgacgccag cgccgcgacc accaacaccg gcgcccacca 840 tcgcgtcgca gcccctgtcc ctgcgcccag aggcgtgccg gccagcggcg gggggcgcag 900 tgcacacgag gggggctggac ttcgcctgtg atatctacat ctgggcgccc ttggccggga 960 cttgtggggt ccttctcctg tcactggtta tcacccttta ctgcaaacgg ggcaagaaga 1020 aactcctgta tatattcaaa caaccattta tgagaccagt acaaactact caagaggaag 1080 atgggcttag ctgccgattt ccagaagaag aagaaggagg atgtgaactg agagtgaagt 1140 tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc tataacgagc 1200 tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc cgggaccctg 1260 agatgggggg aaagccgaga aggagaacc ctcaggaagg cctgtacaat gaactgcaga 1320 aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc cggaggggca 1380 aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc tacgacgccc 1440 ttcacatgca ggccctgccc cctcgcggaa gcggagccac caacttcagc ctgctgaagc 1500 aggccggcga cgtgggagg aaccccggcc ccatggcctt accagtgacc gccttgctcc 1560 tgccgctggc cttgctgctc cacgccgcca ggccggatat ccagatgacc cagagcccca 1620 gctccctgtc cgcatccgtg ggcgacagag tgacaattac ctgtagaagc agccaaagca 1680 tcgtgcatag cgtcggcaac acttttctgg agtggtatca agaagccc gggaaggccc 1740 ccaaactgct gatctacaag gtgagcaaca gattcagcgg ggtcccaagc agattctccg 1800 gcagcggctc cgggactgac ttcaccctga ccattagcag cctgcagcca gaggacttcg 1860 ccacatacta ctgcttccaa gggagccagt tcccctacac cttcggccaa ggcactaagg 1920 tggagatcaa agggggggga ggaagcggcg gaggagggag cggaggcggg ggatccgaag 1980 tgcaactggt cgaatccgga ggggggctgg tccagcctgg agggtccctg agactgagct 2040 gcgccgcaag cggctacgag ttctccaggt cctggatgaa ctgggtgagg caggccccag 2100 gaaaagggct ggaatgggtg ggcaggatct accctggcga cggcgatacc aactactccg 2160 gaaagttcaa gggcaggttc actatcagcg ccgacactag caagaatacc gcctacctgc 2220 agatgaatag cctgagggcc gaggacaccg ccgtgtatta ctgcgctaga gacggcagca 2280 gctgggattg gtacttcgac gtgtggggcc agggcactct ggtgactgtg agcagcacca 2340 cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag cccctgtccc 2400 tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg gggctggact 2460 tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc cttctcctgt 2520 cactggttat caccctttac tgcaaacggg gcaagaaa actcctgtat atattcaaac 2580 aaccatttat gagaccagta caaactactc aagagaaga tggctgtagc tgccgatttc 2640 2700 ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga cgaagagagg 2760 agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga aagccgagaa 2820 ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg gcggaggcct 2880 acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat ggcctttacc 2940 agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag gccctgcccc 3000 ctcgctaagt ttaaac 3016 <![CDATA[<210> 7]]> <![CDATA[<211>990]]> <![CDATA[<212>PRT]]> <![CDATA[<213>Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223>Synthetic Sequence]]> <![CDATA[<400> 7]]>[[ID=~50]] 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 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu 20 25 30 Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln 35 40 45 Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr 50 55 60 Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro 65 70 75 80 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile 85 90 95 Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly 100 105 110 Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 130 135 140 Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser 145 150 155 160 Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly 165 170 175 Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly 180 185 190 Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser 195 200 205 Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys 210 215 220 Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys 225 230 235 240 His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly 245 250 255 Thr Ser Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro 260 265 270 Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu 275 280 285 Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp 290 295 300 Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly 305 310 315 320 Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg 325 330 335 Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln 340 345 350 Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu 355 360 365 Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala 370 375 380 Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu 385 390 395 400 Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp 405 410 415 Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly 420 425 430 Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 435 440 445 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu 450 455 460 Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 465 470 475 480 Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu 485 490 495 Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu 500 505 510 Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala 515 520 525 Arg Pro Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser 530 535 540 Pro Gly Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Lys Ser Ile Ser 545 550 555 560 Lys Asp Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu 565 570 575 Leu Ile Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Ser Arg Phe 580 585 590 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 595 600 605 Glu Pro Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln His Asn Lys Tyr 610 615 620 Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly 625 630 635 640 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu 645 650 655 Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala Ser Val Lys Leu 660 665 670 Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Met Asn Trp 675 680 685 Val Lys Gln Arg Pro Asp Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp 690 695 700 Pro Tyr Asp Ser Glu Thr His Tyr Asn Gln Lys Phe Lys Asp Lys Ala 705 710 715 720 Ile Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser 725 730 735 Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Gly Asn 740 745 750 Trp Asp Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Thr 755 760 765 Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser 770 775 780 Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly 785 790 795 800 Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp 805 810 815 Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile 820 825 830 Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr 835 840 845 Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln 850 855 860 Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys 865 870 875 880 Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln 885 890 895 Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu 900 905 910 Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg 915 920 925 Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys 930 935 940 Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg 945 950 955 960 Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys 965 970 975 Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 980 985 990 <![CDATA[<210> 八股]]> <![CDATA[<211> 2989]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> / <![CDATA[<220>]]> <![CDATA[<223> 合成序列]]> <![CDATA[<400> 8]]> It should be noted that the description of "人工序列" as "artificial sequence" and "合成序列" as "synthetic sequence" is a common translation in the context of biological and patent texts. Also, the specific meaning and interpretation of these sequences would depend on the overall context of the patent content. Additionally, the "八股" translation for "<210> 8" seems rather unusual and might need further clarification based on the actual context. It's possible that there is a misrepresentation or this is a very specialized term within a particular field that requires more domain knowledge for an accurate translation or understanding. If this is a technical term in a specific area, it might be beneficial to refer to relevant technical literature or consult an expert in that field for a more precise translation.gcgatcgcat ggccttacca gtgaccgcct tgctcctgcc gctggccttg ctgctccacg 60 ccgccaggcc ggacatccag atgacacaga ctacatcctc cctgtctgcc tctctgggag 120 acagagtcac catcagttgc agggcaagtc aggacattag taatattta aattggtatc 180 agcagaaacc agatggaact gttaaactcc tgatctacca tacatcaaga ttacactcag 240 gagtcccatc aaggttcagt ggcagtgggt ctggaacaga ttattctctc accattagca 300 acctggagca agaagatatt gccacttact tttgccaaca gggtaatacg cttccgtaca 360 cgttcggagg ggggaccaag ctggagatca caggtggcgg tggctcgggc ggtggtgggt 420 cgggtggcgg cggatctgag gtgaaactgc aggagtcagg acctggcctg gtggcgccct 480 cacagagcct gtccgtcaca tgcactgtct caggggtctc attacccgac tatggtgtaa 540 gctggattcg ccagcctcca cgaaagggtc tggagtggct gggagtaata tggggtagtg 600 aaaccacata ctataattca gctctcaaat ccagactgac catcatcaag gacaactcca 660 agagccaagt tttcttaaaa atgaacagtc tgcaaactga tgacacagcc atttactact 720 gtgccaaaca ttattactac ggtggtagct atgctatgga ctactggggc caaggaacct 780 cagtcaccgt ctcctcaacc acgacgccag cgccgcgacc accaacaccg gcgcccacca 840 tcgcgtcgca gcccctgtcc ctgcgcccag aggcgtgccg gccagcggcg gggggcgcag 900 tgcacacgag gggggctggac ttcgcctgtg atatctacat ctgggcgccc ttggccggga 960 cttgtggggt ccttctcctg tcactggtta tcacccttta ctgcaaacgg ggcaagaaga 1020 aactcctgta tatattcaaa caaccattta tgagaccagt acaaactact caagaggaag 1080 atgggcttag ctgccgattt ccagaagaag aagaaggagg atgtgaactg agagtgaagt 1140 tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc tataacgagc 1200 tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc cgggaccctg 1260 agatgggggg aaagccgcag agaaggaaga accctcagga aggcctgtac aatgaactgc 1320 agaaagataa gatggcggag gcctacagtg agattgggat gaaggcgag cgccggaggg 1380 gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac acctacgacg 1440 cccttcacat gcaggccctg ccccctcgcg gaagcggagc caccaacttc agcctgctga 1500 agcaggccgg cgacgtggag gagaaccccg gccccatggc cttaccagtg accgccttgc 1560 tcctgccgct ggccttgctg ctccacgccg ccaggccgga cgtgcagatc acccagagcc 1620 ccagctacct ggccgccagc cccggcgaga ccatcaccat caactgcaga gccagcaaga 1680 gcatcagcaa ggacctggcc tggtaccagg agaagcccgg caagaccaac aagctgctga 1740 tctacagcgg cagcaccctg cagagcggca tccccagcag attcagcggc agcggcagcg 1800 gcaccgactt caccctgacc atcagcagcc tggagcccga ggacttcgcc atgtactact 1860 gccagcagca caacaagtac ccctacacct tcggcggcgg caccaagctg gagatcaagg 1920 gagggggggg atccggggga ggaggctccg gcggaggcgg aagccaggtg cagctgcagc 1980 agcccggcgc cgagctggtg agacccggcg ccagcgtgaa gctgagctgc aaggccagcg 2040 gctacacctt caccagctac tggatgaact gggtgaagca gagacccgac cagggcctgg 2100 agtggatcgg cagaatcgac ccctacgaca gcgagaccca ctacaaccag aagttcaagg 2160 acaaggccat cctgaccgtg gacaagagca gcagcaccgc ctacatgcag ctgagcagcc 2220 tgaccagcga ggacagcgcc gtgtactact gcgccagagg caactgggac gactactggg 2280 gccagggcac caccctgacc gtgagcagca ccacgacgcc agcgccgcga ccaccaacac 2340 cggcgcccac catcgcgtcg cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg 2400 cggggggcgc agtgcacacg agggggctgg acttcgcctg tgatatctac atctgggcgc 2460 ccttggccgg gacttgtggg gtccttctcc tgtcactggt tatcaccctt tactgcagga 2520 gtaagaggag caggctcctg cacagtgact acatgaacat gactccccgc cgccccgggc 2580 ccacccgcaa gcattaccag ccctatgccc caccacgcga cttcgcagcc tatcgctcca 2640 gagtgaagtt cagcaggagc gcagacgccc ccgcgtacca gcagggccag aaccagctct 2700 ataacgagct caatctagga cgaagagagg agtacgatgt tttggacaag agacgtggcc 2760 gggaccctga gatgggggga aagccgcaga gaaggaagaa ccctcaggaa ggcctgtaca 2820 atgaactgca gaaagataag atggcggagg cctacagtga gattgggatg aaaggcgagc 2880 gccggagggg caaggggcac gatggccttt accagggtct cagtacagcc accaaggaca 2940 cctacgacgc ccttcacatg caggccctgc cccctcgcta agtttaaac 2989 <![CDATA[<210> 9]]> <![CDATA[<211> 1066]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic Sequence]]> <![CDATA[<400> 9]]> 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 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met 20 25 30 Ser Ala Ser Pro Gly Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser 35 40 45 Ser Ile Ser Tyr Met His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro 50 55 60 Lys Leu Trp Ile Tyr Thr Thr Ser Asn Leu Ala Ser Gly Val Pro Ala 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser 85 90 95 Arg Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Ser 100 105 110 Thr Tyr Pro Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Leu Lys Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 130 135 140 Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Lys Pro Gly Ala Ser Val 145 150 155 160 Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Arg Met 165 170 175 His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr 180 185 190 Ile Asn Pro Ser Thr Gly Tyr Thr Glu Tyr Asn Gln Lys Phe Lys Asp 195 200 205 Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln 210 215 220 Leu Ser Ser Leu Thr Phe Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 225 230 235 240 Gly Gly Gly Val Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val 245 250 255 Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr 260 265 270 Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala 275 280 285 Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile 290 295 300 Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser 305 310 315 320 Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His 325 330 335 Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys 340 345 350 His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser 355 360 365 Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 370 375 380 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 385 390 395 400 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg 405 410 415 Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn 420 425 430 Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg 435 440 445 Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro 450 455 460 Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala 465 470 475 480 Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His 485 490 495 Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp 500 505 510 Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn 515 520 525 Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro 530 535 540 Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 545 550 555 560 His Ala Ala Arg Pro Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu 565 570 575 Ala Ala Ser Pro Gly Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Lys 580 585 590 Ser Ile Ser Lys Asp Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr 595 600 605 Asn Lys Leu Leu Ile Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro 610 615 620 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 625 630 635 640 Ser Ser Leu Glu Pro Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln His 645 650 655 Asn Lys Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 660 665 670 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 675 680 685 Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala Ser 690 695 700 Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp 705 710 715 720 Met Asn Trp Val Lys Gln Arg Pro Asp Gln Gly Leu Glu Trp Ile Gly 725 730 735 Arg Ile Asp Pro Tyr Asp Ser Glu Thr His Tyr Asn Gln Lys Phe Lys 740 745 750 Asp Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met 755 760 765 Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 770 775 780 Arg Gly Asn Trp Asp Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val 785 790 795 800 Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr 805 810 815 Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala 820 825 830 Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile 835 840 845 Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser 850 855 860 Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His 865 870 875 880 Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys 885 890 895 His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser 900 905 910 Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 915 920 925 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 930 935 940 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg 945 950 955 960 Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn 965 970 975 Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg 980 985 990 Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro 995 1000 1005 Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu 1010 1015 1020 Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys 1025 1030 1035 Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp 1040 1045 1050 Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 1055 1060 1065 <![CDATA[<210> 10]]> <![CDATA[<211> 3217]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 10]]> gcgatcgcat ggccttacca gtgaccgcct tgctcctgcc gctggccttg ctgctccacg 60 ccgccaggcc gcagatcgtg ctgacccaga gccccgccat catgagcgcc agccccggcg 120 agaaggtgac catcacctgc agcgccagca gcagcatcag ctacatgcac tggttccagc 180 agaagcccgg caccagcccc aagctgtgga tctacaccac cagcaacctg gccagcggcg 240 tgcccgccag attcagcggc agcggcagcg gcaccagcta cagcctgacc atcagcagaa 300 tggaggccga ggacgccgcc acctactact gccaccagag aagcacctac cccctgacct 360 tcggcagcgg caccaagctg gagctgaagg gagggggggg atccggggga ggaggctccg 420 gcggaggcgg aagccaggtg cagctgcagc agagcggcgc cgagctggcc aagcccggcg 480 ccagcgtgaa gatgagctgc aaggccagcg gctacacctt caccagctac agaatgcact 540 gggtgaagca gagacccggc cagggcctgg agtggatcgg ctacatcaac cccagcaccg 600 gctacaccga gtacaaccag aagttcaagg acaaggccac cctgaccgcc gacaagagca 660 gcagcaccgc ctacatgcag ctgagcagcc tgaccttcga ggacagcgcc gtgtactact 720 gcgccagagg cggcggcgtg ttcgactact ggggccaggg caccaccctg accgtgagca 780 gcaccacgac gccagcgccg cgaccaccaa caccggcgcc caccatcgcg tcgcagcccc 840 tgtccctgcg cccagaggcg tgccggccag cggcgggggg cgcagtgcac acgagggggc 900 tggacttcgc ctgtgatatc tacatctggg cgcccttggc cgggacttgt ggggtccttc 960 tcctgtcact ggttatcacc ctttactgca ggagtaagag gagcaggctc ctgcacagtg 1020 actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac cagccctatg 1080 ccccaccacg cgacttcgca gcctatcgct ccaaacgggg cagaaagaaa ctcctgtata 1140 tattcaaaca accatttatg agaccagtac aaactactca agaggaagat ggctgtagct 1200 gccgatttcc agaagaagaa gaaggaggat gtgaactgag agtgaagttc agcaggagcg 1260 cagacgcccc cgcgtacaag cagggccaga accagctcta taacgagctc aatctaggac 1320 gaagagagga gtacgatgtt ttggacaaga gacgtggccg ggaccctgag atggggggaa 1380 agccgagaag gaagaaccct caggaaggcc tgtacaatga actgcagaaa gataagatgg 1440 cggaggccta cagtgagatt gggatgaaag gcgagcgccg gaggggcaag gggcacgatg 1500 gccttacca gggtctcagt acagccacca aggacaccta cgacgccctt cacatgcagg 1560 ccctgccccc tcgcggaagc ggagctacta acttcagcct gctgaagcag gctggagacg 1620 tgggagaa ccctggacct atggccttac cagtgaccgc cttgctcctg ccgctggcct 1680 tgctgctcca cgccgccagg ccggacgtgc agatcaccca gagccccagc tacctggccg 1740 ccagccccgg cgagaccatc accatcaact gcagagccag caagagcatc agcaaggacc 1800 tggcctggta ccaggagaag cccggcaaga ccaacaagct gctgatctac agcggcagca 1860 ccctgcagag cggcatcccc agcagattca gcggcagcgg cagcggcacc gacttcacccc 1920 tgaccatcag cagcctggag cccgaggact tcgccatgta ctactgccag cagcaacaa 1980 agtaccccta caccttggc ggcggcacca agctggagat cagggggggggggatccg 2040 ggggaggagg ctccgggcgga ggcggaagcc aggtgcagct gcagcagccc ggcgccgagc 2100 tggtgagacc cggcgccagc gtgaagctga gctccaaggc cagcggctac accttcacca 2160 gctactggat gaactgggtg aagcagagac ccgaccaggg cctggagtgg atcggcagaa 2220 tcgaccccta cgacagcgag acccactaca accagaagtt caaggacaag gccatcctga 2280 2340 gcgccgtgta ctactgcgcc agaggcaact gggacgacta ctggggccag ggcaccaccc 2400 tgaccgtgag cagcaccacg acgccagcgc cgcgaccacc aacaccggcg cccaccatcg 2460 cgtcgcagcc cctgtccctg cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc 2520 acacgagggg gctggacttc gcctgtgata tctacatctg ggcgccccttg gccgggactt 2580 gtggggtcct tctcctgtca ctggttatca ccctttactg caggagtag aggagcaggc 2640 tcctgcacag tgactacatg aacatgactc cccgccgcccc cgggcccacc cgcaagcatt 2700 accagcccta tgccccacca cgcgacttcg cagcctatcg ctccaaacgg ggcaagaaga 2760 aactcctgta tatattcaaa caaccattta tgagaccagt acaaactact caagaggaag 2820 atgggcttag ctgccgattt ccagaagaag aagaaggagg atgtgaactg agagtgaagt 2880 tcagcaggag cgcagacgcc cccgcgtaca agcagggcca gaaccagctc tataacgagc 2940 tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc cgggaccctg 3000 agatgggggg aaagccgaga aggagaacc ctcaggaagg cctgtacaat gaactgcaga 3060 aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc cggaggggca 3120 aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc tacgacgccc 3180 ttcacatgca ggccctgccc cctcgctaag tttaaac 3217 <![CDATA[<210> 11]]> <![CDATA[<211> 985]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Synthetic sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 11]]> 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 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met 20 25 30 Ser Ala Ser Pro Gly Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser 35 40 45 Ser Ile Ser Tyr Met His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro 50 55 60 Lys Leu Trp Ile Tyr Thr Thr Ser Asn Leu Ala Ser Gly Val Pro Ala 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser 85 90 95 Arg Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Ser 100 105 110 Thr Tyr Pro Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Leu Lys Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val 130 135 140 Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Lys Pro Gly Ala Ser Val 145 150 155 160 Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Arg Met 165 170 175 His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr 180 185 190 Ile Asn Pro Ser Thr Gly Tyr Thr Glu Tyr Asn Gln Lys Phe Lys Asp 195 200 205 Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln 210 215 220 Leu Ser Ser Leu Thr Phe Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 225 230 235 240 Gly Gly Gly Val Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val 245 250 255 Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr 260 265 270 Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala 275 280 285 Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile 290 295 300 Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser 305 310 315 320 Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr 325 330 335 Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu 340 345 350 Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu 355 360 365 Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln 370 375 380 Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu 385 390 395 400 Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly 405 410 415 Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu 420 425 430 Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly 435 440 445 Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser 450 455 460 Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro 465 470 475 480 Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly 485 490 495 Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu 500 505 510 Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Asp Val Gln 515 520 525 Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser Pro Gly Glu Thr Ile 530 535 540 Thr Ile Asn Cys Arg Ala Ser Lys Ser Ile Ser Lys Asp Leu Ala Trp 545 550 555 560 Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu Leu Ile Tyr Ser Gly 565 570 575 Ser Thr Leu Gln Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser 580 585 590 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe 595 600 605 Ala Met Tyr Tyr Cys Gln Gln His Asn Lys Tyr Pro Tyr Thr Phe Gly 610 615 620 Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly 625 630 635 640 Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Pro Gly Ala 645 650 655 Glu Leu Val Arg Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser 660 665 670 Gly Tyr Thr Phe Thr Ser Tyr Trp Met Asn Trp Val Lys Gln Arg Pro 675 680 685 Asp Gln Gly Leu Glu Trp Ile Gly Arg Ile Asp Pro Tyr Asp Ser Glu 690 695 700 Thr His Tyr Asn Gln Lys Phe Lys Asp Lys Ala Ile Leu Thr Val Asp 705 710 715 720 Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu 725 730 735 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Gly Asn Trp Asp Asp Tyr Trp 740 745 750 Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Thr Thr Thr Pro Ala Pro 755 760 765 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 770 775 780 Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 785,790,795,800 Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly 805 810 815 Thr Cys Gly Can Lead to Ser Cys Val Ile Thr Tyr Cys Arg 820 825 830 Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro 835 840 845 Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro 850 855 860 Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala 865 870 875 880 Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu 885 890 895 Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly 900 905 910 Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln 915 920 925 Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr 930 935 940 Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp 945 950 955 960 Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala 965 970 975 Leu His Met Gln Ala Leu Pro Pro Arg 980 985 <![CDATA[<210> 12]]> <![CDATA[<211> 2974]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 12]]> gcgatcgcat ggccttacca gtgaccgcct tgctcctgcc gctggccttg ctgctccacg 60 ccgccaggcc gcagatcgtg ctgacccaga gccccgccat catgagcgcc agccccggcg 120 agaaggtgac catcacctgc agcgccagca gcagcatcag ctacatgcac tggttccagc 180 agaagcccgg caccagcccc aagctgtgga tctacaccac cagcaacctg gccagcggcg 240 tgcccgccag attcagcggc agcggcagcg gcaccagcta cagcctgacc atcagcagaa 300 tggaggccga ggacgccgcc acctactact gccaccagag aagcacctac cccctgacct 360 tcggcagcgg caccaagctg gagctgaagg gagggggggg atccggggga ggaggctccg 420 gcggaggcgg aagccaggtg cagctgcagc agagcggcgc cgagctggcc aagcccggcg 480 ccagcgtgaa gatgagctgc aaggccagcg gctacacctt caccagctac agaatgcact 540 gggtgaagca gagacccggc cagggcctgg agtggatcgg ctacatcaac cccagcaccg 600 gctacaccga gtacaaccag aagttcaagg acaaggccac cctgaccgcc gacaagagca 660 gcagcaccgc ctacatgcag ctgagcagcc tgaccttcga ggacagcgcc gtgtactact 720 gcgccagagg cggcggcgtg ttcgactact ggggccaggg caccaccctg accgtgagca 780 gcaccacgac gccagcgccg cgaccaccaa caccggcgcc caccatcgcg tcgcagcccc 840 tgtccctgcg cccagaggcg tgccggccag cggcgggggg cgcagtgcac acgagggggc 900 tggacttcgc ctgtgatatc tacatctggg cgcccttggc cgggacttgt ggggtccttc 960 tcctgtcact ggttatcacc ctttactgca aacggggcag aaagaaactc ctgtatatat 1020 tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc 1080 gatttccaga agaagaagaa ggaggatgtg aactgagagt gaagttcagc aggagcgcag 1140 acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat ctaggacgaa 1200 gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg gggggaaagc 1260 cgcagagaag gaagaaccct caggaaggcc tgtacaatga actgcagaaa gataagatgg 1320 cggaggccta cagtgagatt gggatgaaag gcgagcgccg gaggggcaag gggcacgatg 1380 gccttacca gggtctcagt acagccacca aggacaccta cgacgccctt cacatgcagg 1440 ccctgccccc tcgcggaagc ggagctacta acttcagcct gctgaagcag gctggagacg 1500 tggaggagaa ccctggacct atggccttac cagtgaccgc cttgctcctg ccgctggcct 1560 tgctgctcca cgccgccagg ccggacgtgc agatcaccca gagccccagc tacctggccg 1620 ccagccccgg cgagaccatc accatcaact gcagagccag caagagcatc agcaaggacc 1680 tggcctggta ccaggagaag cccggcaaga ccaacaagct gctgatctac agcggcagca 1740 ccctgcagag cggcatcccc agcagattca gcggcagcgg cagcggcacc gacttcacccc 1800 tgaccatcag cagcctggag cccgaggact tcgccatgta ctactgccag cagcacaca 1860 agtaccccta caccttggc ggcggcacca agctggagat cagggggggggggatccg 1920 ggggaggagg ctccgggcgga ggcggaagcc aggtgcagct gcagcagccc ggcgccgagc 1980 tggtgagacc cggcgccagc gtgaagctga gctccaaggc cagcggctac accttcacca 2040 gctactggat gaactgggtg aagcagagac ccgaccaggg cctggagtgg atcggcagaa 2100 tcgaccccta cgacagcgag acccactaca accagaagtt caaggacaag gccatcctga 2160 2220 gcgccgtgta ctactgcgcc agaggcaact gggacgacta ctggggccag ggcaccaccc 2280 tgaccgtgag cagcaccacg acgccagcgc cgcgaccacc aacaccggcg cccaccatcg 2340 cgtcgcagcc cctgtccctg cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc 2400 acacgagggg gctggacttc gcctgtgata tctacatctg ggcgccccttg gccgggactt 2460 gtggggtcct tctcctgtca ctggttatca ccctttactg caggagtag aggagcaggc 2520 tcctgcacag tgactacatg aacatgactc cccgccgccc cgggcccacc cgcaagcatt 2580 accagcccta tgccccacca cgcgacttcg cagcctatcg ctccagagtg aagttcagca 2640 ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac gagctcaatc 2700 taggacgaag agaggagtac gatgttttgg acagagacg tggccgggac cctgagatgg 2760 ggggaaagcc gcagagaagg aagaaccctc aggaggctc gtacaatgaa ctgcagaaag 2820 ataagatggc ggaggcctac agtgagattg ggatgaagg cgagcgccgg agggggcaagg 2880 ggcacgatgg cctttaccag ggtctcagta cagccaccaa ggacacctac gacgccctc 2940 acatgcaggc cctgccccct cgctaagtttt aaac 2974 <![CDATA[ <210> 13]]> <![CDATA[ <211> 546]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> artificial sequence]]> <![CDATA[ <220> ]]> <![CDATA[ <223> composite sequence]]> <![CDATA[ <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 Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser 20 25 30 Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser 35 40 45 Lys Ser Val Ser Thr Ser Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln 50 55 60 Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu 65 70 75 80 Glu Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 85 90 95 Phe Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr 100 105 110 Tyr Cys Gln His Ser Arg Glu Leu Pro Phe Thr Phe Gly Ser Gly Thr 115 120 125 Lys Leu Glu Ile Lys Lys Ile Ser Gly Gly Gly Gly Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 145 150 155 160 Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 165 170 175 Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg 180 185 190 Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 195 200 205 Ile Gly Glu Ile Asn Pro Thr Ser Ser Thr Ile Asn Phe Thr Pro Ser 210 215 220 Leu Lys Asp Lys Val Phe Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu 225 230 235 240 Tyr Leu Gln Met Ser Lys Val Arg Ser Glu Asp Thr Ala Leu Tyr Tyr 245 250 255 Cys Ala Arg Gly Asn Tyr Tyr Arg Tyr Gly Asp Ala Met Asp Tyr Trp 260 265 270 Gly Gln Gly Thr Ser Val Thr Val Ser Thr Thr Thr Pro Ala Pro Arg 275 280 285 Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg 290 295 300 Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly 305 310 315 320 Leu Asp Phe with Cys Asp with Tyr and Trp with Pro and with Gly Thr 325 330 335 How Does Gly Become a Leopard How Does Arg Become 340 345 350 Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg 355 360 365 Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg 370 375 380 Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu Leu Tyr 385 390 395 400 Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu 405 410 415 Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu 420 425 430 Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln 435 440 445 Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu 450 455 460 Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly 465 470 475 480 Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu 485 490 495 Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly 500 505 510 Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser 515 520 525 Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro 530 535 540 Pro Arg 545 <![CDATA[<210> 14]]> <![CDATA[<211> 1657]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic Sequence]]> <![CDATA[<400> 14]]> gcgatcgcat ggccttacca gtgaccgcct tgctcctgcc gctggccttg ctgctccacg 60 <00054*67> ccgccaggcc gagcgacatc gtgctgaccc agagccccgc cagcctggcc gtgagcctgg 120 gccagagagc caccatcagc tgcagagcca gcaagagcgt gagcaccagc ggctacagct 180 acctgcactg gtaccagcag aagcccggcc agccccccaa gctgctgatc tacctggcca 240 [[ID=3*]] gcaacctgga gagcggcgtg cccgccagat tcagcggcag cggcagcggc accgacttca 300 ccctgaacat ccaccccgtg gaggaggagg acgccgccac ctactactgc cagcacagca 360 It should be noted that there is a possible error in the original text where and seem to be misspelled. They are presented as such in the translation to maintain consistency with the original. gagagctgcc cttcaccttc ggcagcggca ccaagctgga gatcaagaag atcagcggcg 420 gcggcggcag cggcggcggc ggcagcggcg gcggcggcag cggcggcggc ggcagcggcg 480 gcggcggcag ccaggtgcag ctggtggaga gcggcggcgg cctggtgcag cccggcggca 540 gcctgaagct gagctgcgcc gccagcggct tcgacttcag cagatactgg atgagctggg 600 tgagacaggc ccccggcaag ggcctggagt ggatcggcga gatcaacccc accagcagca ccatcaactt cacccccagc ctgaaggaca aggtgttcat cagcagagac aacgccaaga 720. acaccctgta cctgcagatg agcaaggtga gaagcgagga caccgccctg tactactgcg 840. ccgaggcaa ctactacaga ctggcgacg ctggggccag ggcaccagcg tgaccgtgag caccacgacg ccagcgccgc gaccaccaac accggcgccc accatcgcgt 900 cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcgggggc gcagtgcaca 960 cgaggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc gggacttgtg 1020 gggtccttct cctgtcactg gttatcaccc tttactgcag gagtaagagg agcaggctcc 1080 tgcacagtga ctacatgaac atgactcccc gccgccccgg gcccacccg aagcattacc 1140 agccctatgc cccaccacgc gacttcgcag cctatcgctc caaacggggc agaagaaac 1200 1260 gctgtagctg ccgatttcca gaagagaag aaggaggatg tgaactgaga gtgaagttca 1320 gcaggagcgc agacgccccc gcgtaccagc agggccagaa ccagctctat aacgagctca 1380 atctaggacg aagagaggag tacgatgttt tggacaagag acgtggccgg gaccctgaga 1440 tggggggaaa gccgcagaga aggaagaacc ctcaggaagg cctgtacaat gaactgcaga 1500 aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc cggaggggca 1560 aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc tacgacgccc 1620 ttcacatgca ggccctgccc cctcgctaag tttaaac 1657 <![CDATA[<210> 15]]> <![CDATA[<211> 490]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[ <223> composite sequence]]> <![CDATA[ <400> 15]]> 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 Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu 20 25 30 Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Lys 35 40 45 Ser Val Ser Thr Ser Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys 50 55 60 Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu 65 70 75 80 Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr 100 105 110 Cys Gln His Ser Arg Glu Leu Pro Phe Thr Phe Gly Ser Gly Thr Lys 115 120 125 Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 130 135 140 Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 145 150 155 160 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe 165 170 175 Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 180 185 190 Glu Trp Ile Gly Glu Ile Asn Pro Thr Ser Ser Thr Ile Asn Phe Thr 195 200 205 Pro Ser Leu Lys Asp Lys Val Phe Ile Ser Arg Asp Asn Ala Lys Asn 210 215 220 Thr Leu Tyr Leu Gln Met Ser Lys Val Arg Ser Glu Asp Thr Ala Leu 225 230 235 240 Tyr Tyr Cys Ala Arg Gly Asn Tyr Tyr Arg Tyr Gly Asp Ala Met Asp 245 250 255 Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Thr Thr Thr Pro Ala 260 265 270 Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 275 280 285 Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 290 295 300 Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala 305 310 315 320 Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys 325 330 335 Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr 340 345 350 Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro 355 360 365 Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser 370 375 380 Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu 385 390 395 400 Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg 405 410 415 Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro 420 425 430 Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala 435 440 445 Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His 450 455 460 Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp 465 470 475 480 Ala Leu His Met Gln Ala Leu Pro Pro Arg 485 490 <![CDATA[<210> 16]]> <![CDATA[<211> 1489]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 16]]> gcgatcgcat ggccttacca gtgaccgcct tgctcctgcc gctggccttg ctgctccacg 60 ccgccaggcc ggacatcgtg ctgacccaga gccccgccag cctggccgtg agcctgggcc 120 agagggccac catcagctgc agggccagca agagcgtgag caccagcggc tacagctacc 180 tgcactggta ccagcagaag cccggccagc cccccaagct gctgatctac ctggccagca 240 acctggagag cggcgtgccc gccaggttca gcggcagcgg cagcggcacc gacttcaccc 300 tgaacatcca ccccgtggag gaggaggacg ccgccaccta ctactgccag cacagcaggg 360 agctgccctt caccttcggc agcggcacca agctggagat caagggaggg gggggatccg 420 ggggaggagg ctccggcgga ggcggaagcc aggtgcagct ggtggagagc ggcggcggcc 480 tggtgcagcc cggcggcagc ctgaagctga gctgcgccgc cagcggcttc gacttcagca 540 ggtactggat gagctgggtg aggcaggccc ccggcaaggg cctggagtgg atcggcgaga 600 tcaaccccac cagcagcacc atcaacttca cccccagcct gaaggacaag gtgttcatca 660 gcagggacaa cgccaagaac accctgtacc tgcagatgag caaggtgagg agcgaggaca 720 ccgccctgta ctactgcgcc aggggcaact actacaggta cggcgacgcc atggactact 780 ggggccaggg caccagcgtg accgtgagca ccacgacgcc agcgccgcga ccaccaacac 840 cggcgcccac catcgcgtcg cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg 900 cggggggcgc agtgcacacg agggggctgg acttcgcctg tgatatctac atctgggcgc 960 ccttggccgg gacttgtggg gtccttctcc tgtcactggt tatcaccctt tactgcagga 1020 gtaagaggag caggctcctg cacagtgact acatgaacat gactccccgc cgccccgggc 1080 ccacccgcaa gcattaccag ccctatgccc caccacgcga cttcgcagcc tatcgctcca 1140 gagtgaagtt cagcaggagc gcagacgccc ccgcgtacca gcagggccag aaccagctct 1200 ataacgagct caatctagga cgaagagagg agtacgatgt tttggacaag agacgtggcc 1260 gggaccctga gatgggggga aagccgcaga gaaggaagaa ccctcaggaa ggcctgtaca 1320 atgaactgca gaaagataag atggcggagg cctacagtga gattgggatg aaaggcgagc 1380 gccggagggg caaggggcac gatggccttt accagggtct cagtacagcc accaaggaca 1440 cctacgacgc ccttcacatg caggccctgc cccctcgcta agtttaaac 1489 <![CDATA[<210> 17]]> <![CDATA[<211> 491]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic Sequence]]> <![CDATA[<400> 17]]> 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 Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu 20 25 30 Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Lys 35 40 45 Ser Val Ser Thr Ser Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys 50 55 60 Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu 65 70 75 80 Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95 Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr 100 105 110 Cys Gln His Ser Arg Glu Leu Pro Phe Thr Phe Gly Ser Gly Thr Lys 115 120 125 Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 130 135 140 Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 145 150 155 160 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe 165 170 175 Ser Arg Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 180 185 190 Glu Trp Ile Gly Glu Ile Asn Pro Thr Ser Ser Thr Ile Asn Phe Thr 195 200 205 Pro Ser Leu Lys Asp Lys Val Phe Ile Ser Arg Asp Asn Ala Lys Asn 210 215 220 Thr Leu Tyr Leu Gln Met Ser Lys Val Arg Ser Glu Asp Thr Ala Leu 225 230 235 240 Tyr Tyr Cys Ala Arg Gly Asn Tyr Tyr Arg Tyr Gly Asp Ala Met Asp 245 250 255 Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Thr Thr Thr Pro Ala 260 265 270 Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 275 280 285 Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 290 295 300 Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala 305 310 315 320 Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys 325 330 335 Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 340 345 350 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 355 360 365 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg 370 375 380 Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn 385 390 395 400 Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg 405 410 415 Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn 420 425 430 Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu 435 440 445 Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly 450 455 460 His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr 465 470 475 480 Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 485 490 <![CDATA[<210> 18]]> <![CDATA[<211> 1492]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 18]]> gcgatcgcat ggccttacca gtgaccgcct tgctcctgcc gctggccttg ctgctccacg 60 ccgccaggcc ggacatcgtg ctgacccaga gccccgccag cctggccgtg agcctgggcc 120 agagggccac catcagctgc agggccagca agagcgtgag caccagcggc tacagctacc 180 tgcactggta ccagcagaag cccggccagc cccccaagct gctgatctac ctggccagca 240 acctggagag cggcgtgccc gccaggttca gcggcagcgg cagcggcacc gacttcaccc 300 tgaacatcca ccccgtggag gaggaggacg ccgccaccta ctactgccag cacagcaggg 360 agctgccctt caccttcggc agcggcacca agctggagat caagggaggg gggggatccg 420 ggggaggagg ctccggcgga ggcggaagcc aggtgcagct ggtggagagc ggcggcggcc 480 tggtgcagcc cggcggcagc ctgaagctga gctgcgccgc cagcggcttc gacttcagca 540 ggtactggat gagctgggtg aggcaggccc ccggcaaggg cctggagtgg atcggcgaga 600 tcaaccccac cagcagcacc atcaacttca cccccagcct gaaggacaag gtgttcatca 660 gcagggacaa cgccaagaac accctgtacc tgcagatgag caaggtgagg agcgaggaca 720 ccgccctgta ctactgcgcc aggggcaact actacaggta cggcgacgcc atggactact 780 ggggccaggg caccagcgtg accgtgagca ccacgacgcc agcgccgcga ccaccaacac 840 cggcgcccac catcgcgtcg cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg 900 cggggggcgc agtgcacacg aggggctgg acttcgcctg tgatatctac atctgggcgc 960 ccttggccgg gacttgtggg gtccttctcc tgtcactggt tatcaccctt tactgcaaac 1020 ggggcagaaa gaaactcctg tatatattca aacaaccatt tatgagacca gtacaaacta 1080 1140 1200 tctataacga gctcaatcta ggacgaag aggagtacga tgttttggac aagagacgtg 1260 gccgggaccc tgagatgggg ggaaagccgc agaaaggaa gaaccctcag gaaggcctgt 1320 acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg atgaaaggcg 1380 agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca gccaccaagg 1440 acacctacga cgcccttcac atgcaggccc tgccccctcg ctaagtttaa ac 1492 <![CDATA[<210> 19]]> <![CDATA[<211> 997]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic Sequence]]> <![CDATA[<400> 19]]> 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 Asp Val Val Met Thr Gln Ser His Arg Phe Met 20 25 30 Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Arg Ala Ser Gln 35 40 45 Asp Val Asn Thr Ala Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ser 50 55 60 Pro Lys Leu Leu Ile Phe Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro 65 70 75 80 Asp Arg Phe Thr Gly Ser Gly Ser Gly Ala Asp Phe Thr Leu Thr Ile 85 90 95 Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His 100 105 110 Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 130 135 140 Ile Gln Leu Val Gln Ser Gly Pro Asp Leu Lys Lys Pro Gly Glu Thr 145 150 155 160 Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Phe Gly 165 170 175 Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Phe Lys Trp Met Ala 180 185 190 Trp Ile Asn Thr Thr Arg Tyr Thr Gly Glu Ser Tyr Phe Ala Asp Asp 195 200 205 Phe Lys Gly Arg Phe Ala Phe Ser Val Glu Thr Ser Ala Thr Thr Ala 210 215 220 Tyr Leu Gln Ile Asn Asn Leu Lys Thr Glu Asp Thr Ala Thr Tyr Phe 225 230 235 240 Cys Ala Arg Gly Glu Ile Tyr Tyr Gly Tyr Asp Gly Gly Phe Ala Tyr 245 250 255 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Thr Thr Thr Pro Ala 260 265 270 Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 275 280 285 Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 290 295 300 Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala 305 310 315 320 Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys 325 330 335 Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 340 345 350 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 355 360 365 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg 370 375 380 Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn 385 390 395 400 Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg 405 410 415 Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn 420 425 430 Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu 435 440 445 Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly 450 455 460 His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr 465 470 475 480 Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr 485 490 495 Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly 500 505 510 Pro Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu 515 520 525 His Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 530 535 540 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln 545 550 555 560 Asp Val Gly Ile Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val 565 570 575 Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro 580 585 590 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 595 600 605 Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr 610 615 620 Ser Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 625 630 635 640 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 645 650 655 Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser 660 665 670 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr Trp 675 680 685 Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 690 695 700 Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu Lys 705 710 715 720 Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 725 730 735 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 740 745 750 Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr 755 760 765 Leo Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr 770 775 780 Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala 785 790 795 800 Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe 805 810 815 Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val 820 825 830 Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser 835 840 845 Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly 850 855 860 Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala 865 870 875 880 Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala 885 890 895 Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg 900 905 910 Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu 915 920 925 Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr 930 935 940 Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly 945 950 955 960 Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln 965 970 975 Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln 980 985 990 Ala Leu Pro Pro Arg 995 <![CDATA[ <210> 20]]> <![CDATA[ <211> 2994]]> <![CDATA[ <212> DNA <![CDATA[ <213> Artificial Sequence]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Synthetic sequence]]> <![CDATA[ <400> 20]]> atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60 ccggatgtgg tgatgaccca gagccatcgc tttatgagca ccagcgtggg cgatcgcgtg 120 agcattacct gccgcgcgag ccaggatgtg aacaccgcgg tgagctggta tcagcagaaa 180 ccgggccaga gcccgaaact gctgattttt agcgcgagct atcgctatac cggcgtgccg 240 gatcgcttta ccggcagcgg cagcggcgcg gattttaccc tgaccattag cagcgtgcag 300 gcggaagatc tggcggtgta ttattgccag cagcattata gcaccccgtg gacctttggc 360 ggcggcacca aactggaaat taaaggaggg gggggatccg ggggaggagg ctccggcgga 420 ggcggaagcc agattcagct ggtgcagagc ggcccggatc tgaaaaaacc gggcgaaacc 480 gtgaaactga gctgcaaagc gagcggctat acctttacca actttggcat gaactgggtg 540 aaacaggcgc cgggcaaagg ctttaaatgg atggcgtgga ttaacaccac ccgctatacc 600 ggcgaaagct attttgcgga tgattttaaa ggccgctttg cgtttagcgt ggaaaccagc 660 gcgaccaccg cgtatctgca gattaacaac ctgaaaaccg aagataccgc gacctatttt 720 tgcgcgcgcg gcgaaattta ttatggctat gatggcggct ttgcgtattg gggccagggc 780 accctggtga ccgtgagcgc gaccacgacg ccagcgccgc gaccaccaac accggcgccc 840 accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 900 gcagtgcaca cgaggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 960 gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 1020 aagaaactcc tgtatatatt caaacaacca tttatgagac cagtaccaaac tactcaagag 1080 gaagatggct gtagctgccg atttccagaa gaagagaag gagatgtga actgagagtg 1140 aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1200 gagctcaatc taggacgaag agaggatc gatgttttgg acaagagacg tggccgggac 1260 cctgagatgg ggggaaagcc gcagagaagg aagaaccctc aggaagcct gtacaatgaa 1320 1380 aggggcaagg ggcacgatgg cctttaccag ggtctcagta cagccaccaa ggacacctac 1440 gacgcccttc acatgcaggc cctgccccct cgcggaagcg gagccaccaa cttcagcctg 1500 ctgaagcagg ccggcgacgt ggaggagaac cccggccccg ccttaccagt gaccgccttg 1560 ctcctgccgc tggccttgct gctccacgcc gccaggccgg atattcagat gacccagagc 1620 ccgagcagcc tgagcgcgag cgtgggcgat cgcgtgacca ttacctgcaa agcgagccag 1680 gatgtgggca ttgcggtggc gtggtatcag cagaaaccgg gcaaagtgcc gaaactgctg 1740 atttattgg cgagcacccg ccataccggc gtgccggatc gctttagcgg cagcggcagc 1800 ggcaccgatt ttaccctgac cattagcagc ctgcagccgg aagatgtggc gacctattat 1860 tgccagcagt atagcagcta tccgtatacc tttggccagg gcaccaaagt ggaaattaaa 1920 ggaggggggg gatccggggg aggaggctcc ggcggaggcg gaagcgaagt gcagctggtg 1980 gaaagcggcg gcggcctggt gcagccgggc ggcagcctgc gcctgagctg cgcggcgagc 2040 ggctttgatt ttagccgcta ttggatgagc tgggtgcgcc aggcgccggg caaaggcctg 2100 gaatggattg gcgaaattaa cccggatagc agcaccatta actatgcgcc gagcctgaaa 2160 gataaattta ttattagccg cgataacgcg aaaaacagcc tgtatctgca gatgaacagc 2220 ctgcgcgcgg aagataccgc ggtgtattat tgcgcgcgcc cggatggcaa ctattggtat 2280 tttgatgtgt ggggccaggg caccctggtg accgtgagca gcaccacgac gccagcgccg 2340 cgaccaccaa caccggcgcc caccatcgcg tcgcagcccc tgtccctgcg cccagaggcg 2400 tgccggccag cggcgggggg cgcagtgcac acgaggggc tggacttgc ctgtgatatc 2460 tacatctggg cgcccttggc cgggacttgt ggggtccttc tcctgtcact ggttatcacc 2520 ctttactgca ggagtaagag gagcaggctc ctgcacagtg actacatgaa catgactccc 2580 cgccgccccg ggcccacccg caagcattac cagccctatg ccccaccacg cgacttcgca 2640 gcctatcgct ccagagtgaa gttcagcagg agcgcagacg ccccgcgta ccagcagggc 2700 cagaaccagc tctataacga gctcaatcta ggacgaagag aggagtacga tgttttggac 2760 aagagacgtg gccgggaccc tgagatgggg ggaaagccgc agaaaggaa gaaccctcag 2820 gaaggcctgt aaatgaact gcaagaagat aagatggcgg aggcctacag tgagattggg 2880 atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 2940 gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctaa 2994 <![CDATA[<210> 21]]> <![CDATA[<211> 997]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic Sequence]]> <![CDATA[<400> 21]]> 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 Asp Val Val Met Thr Gln Ser His Arg Phe Met 20 25 30 Ser Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Arg Ala Ser Gln 35 40 45 Asp Val Asn Thr Ala Val Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ser 50 55 60 Pro Lys Leu Leu Ile Phe Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro 65 70 75 80 Asp Arg Phe Thr Gly Ser Gly Ser Gly Ala Asp Phe Thr Leu Thr Ile 85 90 95 Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His 100 105 110 Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Asp Ile Lys 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 130 135 140 Ile Gln Leu Val Gln Ser Gly Pro Asp Leu Lys Lys Pro Gly Glu Thr 145 150 155 160 Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Phe Gly 165 170 175 Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Phe Lys Trp Met Ala 180 185 190 Trp Ile Asn Thr Tyr Thr Gly Glu Ser Tyr Phe Ala Asp Asp Phe Lys 195 200 205 Gly Arg Phe Ala Phe Ser Val Glu Thr Ser Ala Thr Thr Ala Tyr Leu 210 215 220 Gln Ile Asn Asn Leu Lys Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala 225 230 235 240 Arg Gly Glu Ile Tyr Tyr Gly Tyr Asp Gly Gly Phe Ala Tyr Trp Gly 245 250 255 Gln Gly Thr Leu Val Thr Val Ser Ala Thr Thr Thr Pro Ala Pro Arg 260 265 270 Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg 275 280 285 Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly 290 295 300 Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr 305 310 315 320 Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Rec 325 330 335 Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro 340 345 350 Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu 355 360 365 Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala 370 375 380 Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu 385 390 395 400 Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly 405 410 415 Arg Asp Pro Glu Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln 420 425 430 Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr 435 440 445 Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp 450 455 460 Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala 465 470 475 480 Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe 485 490 495 Serum Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met 500 505 510 Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His 515 520 525 Ala Ala Arg Pro Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 530 535 540 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp 545 550 555 560 Val Gly Ile Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro 565 570 575 Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp 580 585 590 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 595 600 605 Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser 610 615 620 Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Gly 625 630 635 640 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val 645 650 655 Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu 660 665 670 Arg Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr Trp Met 675 680 685 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Glu 690 695 700 Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu Lys Asp 705 710 715 720 Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln 725 730 735 Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 740 745 750 Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Gln Gly Thr Leu 755 760 765 Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro 770 775 780 Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys 785 790 795 800 Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala 805 810 815 Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu 820 825 830 Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys 835 840 845 Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr 850 855 860 Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly 865 870 875 880 Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala 885 890 895 Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg 900 905 910 Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu 915 920 925 Met Gly Gly Lys Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr 930 935 940 Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly 945 950 955 960 Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln 965 970 975 Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln 980 985 990 Ala Leu Pro Pro Arg 995 <![CDATA[<210> 22]]> <![CDATA[<211> 3009]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic Sequence]]> <![CDATA[<400> 22]]> cgatcgcatg gccttaccag tgaccgcctt gctcctgccg ctggccttgc tgctccacgc 60 cgccaggccg gatgtggtga tgacccagag ccatcgcttt atgagcacca gcgtgggaga 120 tcgagtgagc attacctgcc gcgcgagcca ggatgtgaac accgcggtga gctggtatca 180 gcagaaaccg ggccagagcc cgaaactgct gatttttagc gcgagctatc gctataccgg 240 cgtgccggat cgctttaccg gcagcggcag cggcgcggat tttaccctga ccattagcag 300 cgtgcaggcg gaagatctgg cggtgtatta ttgccagcag cattatagca ccccgtggac 360 ctttggcggc ggcaccaaac tggatattaa aggagggggg ggatccgggg gaggaggctc 420 cggcggaggc ggaagccaga ttcagctggt gcagagcggc ccggatctga aaaaaccggg 480 cgaaaccgtg aaactgagct gcaaagcgag cggctatacc tttaccaact ttggcatgaa 540 ctgggtgaaa caggcgccgg gcaaaggctt taaatggatg gcgtggatta acacctatac 600 cggcgaaagc tattttgcgg atgattttaa aggccgcttt gcgtttagcg tggaaaccag 660 cgcgaccacc gcgtatctgc agattaacaa cctgaaaacc gaagataccg cgacctattt 720 ttgcgcgcgc ggcgaaattt attatggcta tgatggcggc tttgcgtatt ggggccaggg 780 caccctggtg accgtgagcg cgaccacgac gccagcgccg cgaccaccaa caccggcgcc 840 caccatcgcg tcgcagcccc tgtccctgcg cccagaggcg tgccggccag cggcgggggg 900 cgcagtgcac acgagggggc tggacttcgc ctgtgatatc tacatctggg cgcccttggc 960 cgggacttgt ggggtccttc tcctgtcact ggttatcacc ctttactgca aacggggcag 1020 aaagaaactc ctgtatatat tcaagcaacc atttatgaga ccagtacaaa ctactcaaga 1080 ggaagatggc tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgagagt 1140 gaagttcagc aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa 1200 cgagctcaat ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga 1260 ccctgagatg gggggaaagc cgcagagaag gaagaaccct caggaaggcc tgtacaatga 1320 actgcagaaa gataagatgg cggaggccta cagtgagatt gggatgaaag gcgagcgccg 1380 gaggggcaag gggcacgatg gcctttacca gggtctcagt acagccacca aggacaccta 1440 cgacgccct cacatgcagg ccctgccccc tcgcggaagc ggagccacca acttcagcct 1500 gctgaagcag gccggcgacg tggaggagaa ccccggcccc atggccttac cagtgaccgc 1560 cttgctcctg ccgctggcct tgctgctcca cgccgccagg ccggatattc agatgaccca 1620 gagcccgagc agcctgagcg cgagcgtggg cgaccgcgtg accattacct gcaaagcgag 1680 ccaggatgtg ggcattgcgg tggcgtggta tcagcagaaa ccgggcaaag tgccgaaact 1740 gctgatttat tgggcgagca cccgccatac cggcgtgccg gatcgcttta gcggcagcgg 1800 cagcggcacc gattttaccc tgaccattag cagcctgcag ccggaagatg tggcgaccta 1860 ttattgccag cagtatagca gctatccgta tacctttggc cagggcacca aagtggaaat 1920 taaaggaggg ggggatccg ggggaggagg ctccggcgga ggcggaagcg aagtgcagct 1980 ggtggaaagc ggcggcggcc tggtgcagcc gggcggcagc ctgcgcctga gctgcgcggc 2040 gagcggcttt gattttagcc gctattggat gagctgggtg cgccaggcgc cgggcaaagg 2100 cctggaatgg attggcgaaa ttaacccgga tagcagcacc attaactatg cgccgagcct 2160 gaaagataaa tttattatta gccgcgataa cgcgaaaaac agcctgtatc tgcagatgaa 2220 cagcctgcgc gcggaagata ccgcggtgta ttattgcgcg cgcccggatg gcaactattg 2280 gtattttgat gtgtggggcc agggcaccct ggtgaccgtg agcagcacca cgacgccagc 2340 gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag cccctgtccc tgcgcccaga 2400 ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg gggctggact tcgcctgtga 2460 tatctacatc tgggcgccct tggccgggac ttgtggggtc cttctcctgt cactggttat 2520 caccctttac tgcaaacggg gcaagaagaa actcctgtat atattcaagc aaccatttat 2580 gagaccagta caaactactc aagagaagaa tggctgtagc tgccgatttc cagaagaa 2640 2700 gcagggccag aaccagctct ataacgagct caatctagga cgaagagagg agtacgatgt 2760 tttggacaag agacgtggcc gggaccctga gatggggggga aagccgcaga gaaggaagaa 2820 ccctcaggaa ggcctgtaca atgaactgca gaagataag atggcggagg cctacagtga 2880 gattgggatg aaaggcgagc gccggagggg caaggggcac gatggccttt accagggtct 2940 footcagcc accaaggaca cctacgacgc ccttcacatg caggccctgc cccctcgcta 3000 agtttaaac 3009 <![CDATA[<210> 23]]> <![CDATA[<211> 423]]> <![CDATA[<212> DNA]]> <![CDATA[<213> Artificial sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 23]]> agctagctgc agtaacgcca ttttgcaagg catggaaaaa taccaaacca agaatagaga 60 agttcagatc aagggcgggt acatgaaaat agctaacgtt gggccaaaca ggatatctgc 120 ggtgagcagt ttcggccccg gcccggggcc aagaacagat ggtcaccgca gtttcggccc 180 cggcccgagg ccaagaacag atggtcccca gatatggccc aaccctcagc agtttcttaa 240 gacccatcag atgtttccag gctcccccaa ggacctgaaa tgaccctgcg ccttatttga 300 gacccatcag atgtttccag gctcccccaa ggacctgaaa tgaccctgcg ccttatttga 300 attaaccaat cagcctgctt ctcgcttctg ttcgcgcgct tctgcttccc gagctctata 360 attaaccaat cagcctgctt ctcgcttctg ttcgcgcgct tctgcttccc gagctctata 360 aaagagctca caacccctca ctcggcgcgc cagtcctccg acagactgag tcgcccgggt 420 aaagagctca caacccctca ctcggcgcgc cagtcctccg acagactgag tcgcccgggt 420 acc 423 acc 423 <![CDATA[<210> 24]]><![CDATA[<210> 24]]> <![CDATA[<211> 165]]><![CDATA[<211> 165]]> <![CDATA[<212> PRT]]><![CDATA[<212> PRT]]> <0OO7904> <![CDATA[<213> 人工序列]]> <![CDATA[<213> Artificial sequence]]> <000T905> <![CDATA[<220>]]> <![CDATA[<220>]]> <![CDATA[<223> 合成序列]]> <![CDATA[<223> Synthetic sequence]]> <0OO7914> <![CDATA[<400> 24]]> <![CDATA[<400> 24]]> Met Ser Gly Leu Gly Arg Ser Arg Arg Gly Gly Arg Ser Arg Val Asp Met Ser Gly Leu Gly Arg Ser Arg Arg Gly Gly Arg Ser Arg Val Asp 1 5 10 15 1 5 10 15 Gln Glu Glu Arg Phe Pro Gln Gly Leu Trp Thr Gly Val Ala Met Arg 20 25 30 Ser Cys Pro Glu Glu Gln Tyr Trp Asp Pro Leu Leu Gly Thr Cys Met 35 40 45 Ser Cys Lys Thr Ile Cys Asn His Gln Ser Gln Arg Thr Cys Ala Ala 50 55 60 Phe Cys Arg Ser Leu Ser Cys Arg Lys Glu Gln Gly Lys Phe Tyr Asp 65 70 75 80 His Leu Leu Arg Asp Cys Ile Ser Cys Ala Ser Ile Cys Gly Gln His 85 90 95 Pro Lys Gln Cys Ala Tyr Phe Cys Glu Asn Lys Leu Arg Ser Pro Val 100 105 110 Asn Leu Pro Pro Glu Leu Arg Arg Gln Arg Ser Gly Glu Val Glu Asn 115 120 125 Asn Ser Asp Asn Ser Gly Arg Tyr Gln Gly Leu Glu His Arg Gly Ser 130 135 140 Glu Ala Ser Pro Ala Leu Pro Gly Leu Lys Leu Ser Ala Asp Gln Val 145 150 155 160 Ala Leu Val Tyr Ser 165 <![CDATA[<210> 25]]> <![CDATA[<211> 54]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 25]]> Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser 1 5 10 15 Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr 20 25 30 Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser 35 40 45 Val Lys Gly Thr Asn Ala 50 <![CDATA[<210> 26]]>​​​ <![CDATA[<211> 204]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 26]]> Ser Gly Pro Val Lys Glu Leu Val Gly Ser Val Gly Gly Ala Val Thr 1 5 10 15 Phe Pro Leu Lys Ser Lys Val Lys Gln Val Asp Ser Ile Val Trp Thr 20 25 30 Phe Asn Thr Thr Pro Leu Val Thr Ile Gln Pro Glu Gly Gly Thr Ile 35 40 45 Ile Val Thr Gln Asn Arg Asn Arg Glu Arg Val Asp Phe Pro Asp Gly 50 55 60 Gly Tyr Ser Leu Lys Leu Ser Lys Leu Lys Lys Asn Asp Ser Gly Ile 65 70 75 80 Tyr Tyr Val Gly Ile Tyr Ser Ser Ser Leu Gln Gln Pro Ser Thr Gln 85 90 95 Glu Tyr Val Leu His Val Tyr Glu His Leu Ser Lys Pro Lys Val Thr 100 105 110 Met Gly Leu Gln Ser Asn Lys Asn Gly Thr Cys Val Thr Asn Leu Thr 115 120 125 Cys Cys Met Glu His Gly Glu Glu Asp Val Ile Tyr Thr Trp Lys Ala 130 135 140 Leu Gly Gln Ala Ala Asn Glu Ser His Asn Gly Ser Ile Leu Pro Ile 145 150 155 160 Ser Trp Arg Trp Gly Glu Ser Asp Met Thr Phe Ile Cys Val Ala Arg 165 170 175 Asn Pro Val Ser Arg Asn Phe Ser Ser Pro Ile Leu Ala Arg Lys Leu 180 185 190 Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser Ser Met 195 200 <![CDATA[ <210> 27]]> <![CDATA[ <211> 46]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> artificial sequence]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Synthetic sequence]]> <![CDATA[ <400> 27]]> Met Asp Asp Ser Thr Glu Arg Glu Gln Ser Arg Leu Thr Ser Cys Leu 1 5 10 15 Lys Lys Arg Glu Glu Met Lys Leu Lys Glu Cys Val Ser Ile Leu Pro 20 25 30 Arg Lys Glu Ser Pro Ser Val Arg Ser Ser Lys Asp Gly Lys 35 40 45 <![CDATA[ <210> 28]]> <![CDATA[ <211> 242]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial Sequence]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Synthetic sequence]]> <![CDATA[<400> 28]]> Asp Pro Asn Phe Trp Leu Gln Val Gln Glu Ser Val Thr Val Gln Glu 1 5 10 15 Gly Leu Cys Val Leu Val Pro Cys Thr Phe Phe His Pro Ile Pro Tyr 20 25 30 Tyr Asp Lys Asn Ser Pro Val His Gly Tyr Trp Phe Arg Glu Gly Ala 35 40 45 Ile Ile Ser Arg Asp Ser Pro Val Ala Thr Asn Lys Leu Asp Gln Glu 50 55 60 Val Gln Glu Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Pro Ser 65 70 75 80 Arg Asn Asn Cys Ser Leu Ser Ile Val Asp Ala Arg Arg Arg Asp Asn 85 90 95 Gly Ser Tyr Phe Phe Arg Met Glu Arg Gly Ser Thr Lys Tyr Ser Tyr 100 105 110 Lys Ser Pro Gln Leu Ser Val His Val Thr Asp Leu Thr His Arg Pro 115 120 125 Lys Ile Leu Ile Pro Gly Thr Leu Glu Pro Gly His Ser Lys Asn Leu 130 135 140 Thr Cys Ser Val Ser Trp Ala Cys Glu Gln Gly Thr Pro Pro Ile Phe 145 150 155 160 Ser Trp Leu Ser Ala Ala Pro Thr Ser Leu Gly Pro Arg Thr Thr His 165 170 175 Ser Ser Val Leu Ile Ile Thr Pro Arg Pro Gln Asp His Gly Thr Asn 180 185 190 Leu Thr Cys Gln Val Lys Phe Ala Gly Ala Gly Val Thr Thr Glu Arg 195 200 205 Thr Ile Gln Leu Asn Val Thr Tyr Val Pro Gln Asn Pro Thr Thr Gly 210 215 220 Ile Phe Pro Gly Asp Gly Ser Gly Lys Gln Glu Thr Arg Ala Gly Val 225 230 235 240 Val His <![CDATA[ <210> 29]]> <![CDATA[ <211> 287]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial Sequence]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Synthetic sequence]]> <![CDATA[ <400> 29]]> Thr Lys Glu Asp Pro Asn Pro Pro Ile Thr Asn Leu Arg Met Lys Ala 1 5 10 15 Lys Ala Gln Gln Leu Thr Trp Asp Leu Asn Arg Asn Val Thr Asp Ile 20 25 30 Glu Cys Val Lys Asp Ala Asp Tyr Ser Met Pro Ala Val Asn Asn Ser 35 40 45 Tyr Cys Gln Phe Gly Ala Ile Ser Leu Cys Glu Val Thr Asn Tyr Thr 50 55 60 Val Arg Val Ala Asn Pro Pro Phe Ser Thr Trp Ile Leu Phe Pro Glu 65 70 75 80 Asn Ser Gly Lys Pro Trp Ala Gly Ala Glu Asn Leu Thr Cys Trp Ile 85 90 95 His Asp Val Asp Phe Leu Ser Cys Ser Trp Ala Val Gly Pro Gly Ala 100 105 110 Pro Ala Asp Val Gln Tyr Asp Leu Tyr Leu Asn Val Ala Asn Arg Arg 115 120 125 Gln Gln Tyr Glu Cys Leu His Tyr Lys Thr Asp Ala Gln Gly Thr Arg 130 135 140 Ile Gly Cys Arg Phe Asp Asp Ile Ser Arg Leu Ser Ser Gly Ser Gln 145 150 155 160 Ser Ser His Ile Leu Val Arg Gly Arg Ser Ala Ala Phe Gly Ile Pro 165 170 175 Cys Thr Asp Lys Phe Val Val Phe Ser Gln Ile Glu Ile Leu Thr Pro 180 185 190 Pro Asn Met Thr Ala Lys Cys Asn Lys Thr His Ser Phe Met His Trp 195 200 205 Lys Met Arg Ser His Phe Asn Arg Lys Phe Arg Tyr Glu Leu Gln Ile 210 215 220 Gln Lys Arg Met Gln Pro Val Ile Thr Glu Gln Val Arg Asp Arg Thr 225 230 235 240 Ser Phe Gln Leu Leu Asn Pro Gly Thr Tyr Thr Val Gln Ile Arg Ala 245 250 255 Arg Glu Arg Val Tyr Glu Phe Leu Ser Ala Trp Ser Thr Pro Gln Arg 260 265 270 Phe Glu Cys Asp Gln Glu Glu Gly Ala Asn Thr Arg Ala Trp Arg 275 280 285 <![CDATA[<210> 30]]> <![CDATA[<211> 272]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 30]]> Pro Glu Glu Pro Leu Val Val Lys Val Glu Glu Gly Asp Asn Ala Val 1 5 10 15 Leu Gln Cys Leu Lys Gly Thr Ser Asp Gly Pro Thr Gln Gln Leu Thr 20 25 30 Trp Ser Arg Glu Ser Pro Leu Lys Pro Phe Leu Lys Leu Ser Leu Gly 35 40 45 Leu Pro Gly Leu Gly Ile His Met Arg Pro Leu Ala Ile Trp Leu Phe <![CDATA[ ]]> 50 55 60 Ile Phe Asn Val Ser Gln Gln Met Gly Gly Phe Tyr Leu Cys Gln Pro 65 70 75 80 Gly Pro Pro Ser Glu Lys Ala Trp Gln Pro Gly Trp Thr Val Asn Val 85 90 95 Glu Gly Ser Gly Glu Leu Phe Arg Trp Asn Val Ser Asp Leu Gly Gly 100 105 110 Leu Gly Cys Gly Leu Lys Asn Arg Ser Ser Glu Gly Pro Ser Ser Pro 115 120 125 Ser Gly Lys Leu Met Ser Pro Lys Leu Tyr Val Trp Ala Lys Asp Arg 130 135 140 Pro Glu Ile Trp Glu Gly Glu Pro Pro Cys Leu Pro Pro Arg Asp Ser 145 150 155 160 Leu Asn Gln Ser Leu Ser Gln Asp Leu Thr Met Ala Pro Gly Ser Thr 165 170 175 Leu Trp Leu Ser Cys Gly Val Pro Pro Asp Ser Val Ser Arg Gly Pro 180 185 190 Leu Ser Trp Thr His Val His Pro Lys Gly Pro Lys Ser Leu Leu Ser 195 200 205 Leu Glu Leu Lys Asp Asp Arg Pro Ala Arg Asp Met Trp Val Met Glu 210 215 220 Thr Gly Leu Leu Leu Pro Arg Ala Thr Ala Gln Asp Ala Gly Lys Tyr 225 230 235 240 Tyr Cys His Arg Gly Asn Leu Thr Met Ser Phe His Leu Glu Ile Thr 245 250 255 Ala Arg Pro Val Leu Trp His Trp Leu Leu Arg Thr Gly Gly Trp Lys 260 265 270 <![CDATA[ <210> 31]]> <![CDATA[ <211> 6]]> <![CDATA[ <212> PRT]]> <![CDATA[ <213> Artificial Sequence]]> <![CDATA[ <220> ]]> <![CDATA[ <223> Synthetic sequence]]> <![CDATA[ <400> 31]]> Pro Ile Cys Val Thr Val 1 5 <![CDATA[ <210> 32]]> <![CDATA[ <211> 47]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic Sequence]]> <![CDATA[<400> 32]]> Lys Ile Ser His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala <![CDATA[ ]]><![CDATA[ ]]>1 5 10 15 <![CDATA[ ]]><![CDATA[ ]]><![CDATA[ ]]><![CDATA[ ]]><![CDATA[ ]]><![CDATA[ ]]>His Thr Pro Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser <![CDATA[ ]]><![CDATA[ ]]> 20 25 30 <![CDATA[ ]]><![CDATA[ ]]><![CDATA[ ]]><![CDATA[ ]]<![CDATA[ ]]><![CDATA[ ]]>Glu Lys Asn Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser <![CDATA[ ]]><![CDATA[ ]]> 35 40 45 <![CDATA[ ]]><![CDATA[ ]]><![CDATA[ ]]><![CDATA[ ]]><![CDATA[ ]]> <![CDATA[<210> 33]]> <![CDATA[<211> 480]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial Sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic Sequence]]> <![CDATA[<400> 33]]> Asp Ser Ser Lys Trp Val Phe Glu His Pro Glu Thr Leu Tyr Ala Trp 1 5 10 15 Glu Gly Ala Cys Val Trp Ile Pro Cys Thr Tyr Arg Ala Leu Asp Gly 20 25 30 Asp Leu Glu Ser Phe Ile Leu Phe His Asn Pro Glu Tyr Asn Lys Asn 35 40 45 Thr Ser Lys Phe Asp Gly Thr Arg Leu Tyr Glu Ser Thr Lys Asp Gly [[ID=5l]] 50 55 60 Lys Val Pro Ser Glu Gln Lys Arg Val Gln Phe Leu Gly Asp Lys Asn 65 70 75 80 Lys Asn Cys Thr Leu Ser Ile His Pro Val His Leu Asn Asp Ser Gly 85 90 95 Gln Leu Gly Leu Arg Met Glu Ser Lys Thr Glu Lys Trp Met Glu Arg 100 105 110 Ile His Leu Asn Val Ser Glu Arg Pro Phe Pro Pro His Ile Gln Leu 115 120 125 Pro Pro Glu Ile Gln Glu Ser Gln Glu Val Thr Leu Thr Cys Leu Leu 130 135 140 Asn Phe Ser Cys Tyr Gly Tyr Pro Ile Gln Leu Gln Trp Leu Leu Glu 145 150 155 160 Gly Val Pro Met Arg Gln Ala Ala Val Thr Ser Thr Ser Leu Thr Ile 165 170 175 Lys Ser Val Phe Thr Arg Ser Glu Leu Lys Phe Ser Pro Gln Trp Ser 180 185 190 His His Gly Lys Ile Val Thr Cys Gln Leu Gln Asp Ala Asp Gly Lys 195 200 205 Phe Leu Ser Asn Asp Thr Val Gln Leu Asn Val Lys His Thr Pro Lys 210 215 220 Leu Glu Ile Lys Val Thr Pro Ser Asp Ala Ile Val Arg Glu Gly Asp 225 230 235 240 Ser Val Thr Met Thr Cys Glu Val Ser Ser Ser Asn Pro Glu Tyr Thr 245 250 255 Thr Val Ser Trp Leu Lys Asp Gly Thr Ser Leu Lys Lys Gln Asn Thr 260 265 270 Phe Thr Leu Asn Leu Arg Glu Val Thr Lys Asp Gln Ser Gly Lys Tyr 275 280 285 Cys Cys Gln Val Ser Asn Asp Val Gly Pro Gly Arg Ser Glu Glu Val 290 295 300 Phe Leu Gln Val Gln Tyr Ala Pro Glu Pro Ser Thr Val Gln Ile Leu 305 310 315 320 His Ser Pro Ala Val Glu Gly Ser Gln Val Glu Phe Leu Cys Met Ser 325 330 335 Leu Ala Asn Pro Leu Pro Thr Asn Tyr Thr Trp Tyr His Asn Gly Lys 340 345 350 Glu Met Gln Gly Arg Thr Glu Glu Lys Val His Ile Pro Lys Ile Leu 355 360 365 Pro Trp His Ala Gly Thr Tyr Ser Cys Val Ala Glu Asn Ile Leu Gly 370 375 380 Thr Gly Gln Arg Gly Pro Gly Ala Glu Leu Asp Val Gln Tyr Pro Pro 385 390 395 400 Lys Lys Val Thr Thr Val Ile Gln Asn Pro Met Pro Ile Arg Glu Gly 405 410 415 Asp Thr Val Thr Leu Ser Cys Asn Tyr Asn Ser Ser Asn Pro Ser Val 420 425 430 Thr Arg Tyr Glu Trp Lys Pro His Gly Ala Trp Glu Glu Pro Ser Leu 435 440 445 Gly Val Leu Lys Ile Gln Asn Val Gly Trp Asp Asn Thr Thr Ile Ala 450 455 460 Cys Ala Ala Cys Asn Ser Trp Cys Ser Trp Ala Ser Pro Val Ala Leu 465 470 475 480 <![CDATA[<210> 34]]> <![CDATA[<211> 480]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Artificial sequence]]> <![CDATA[<220>]]> <![CDATA[<223> Synthetic sequence]]> <![CDATA[<400> 34]]> Gln Ser Pro Thr Pro Ser Pro Thr Gly Leu Thr Thr Ala Lys Met Pro 1 5 10 15 Ser Val Pro Leu Ser Ser Asp Pro Leu Pro Thr His Thr Thr Ala Phe 20 25 30 Ser Pro Ala Ser Thr Phe Glu Arg Glu Asn Asp Phe Ser Glu Thr Thr 35 40 45 Thr Ser Leu Ser Pro Asp Asn Thr Ser Thr Gln Val Ser Pro Asp Ser 50 55 60 Leu Asp Asn Ala Ser Ala Phe Asn Thr Thr Gly Val Ser Ser Val Gln 65 70 75 80 Thr Pro His Leu Pro Thr His Ala Asp Ser Gln Thr Pro Ser Ala Gly 85 90 95 Thr Asp Thr Gln Thr Phe Ser Gly Ser Ala Ala Asn Ala Lys Leu Asn 100 105 110 Pro Thr Pro Gly Ser Asn Ala Ile Ser Asp Val Pro Gly Glu Arg Ser 115 120 125 Thr Ala Ser Thr Phe Pro Thr Asp Pro Val Ser Pro Leu Thr Thr Thr 130 135 140 Leu Ser Leu Ala His His Ser Ser Ala Ala Leu Pro Ala Arg Thr Ser 145 150 155 160 Asn Thr Thr Ile Thr Ala Asn Thr Ser Asp Ala Tyr Leu Asn Ala Ser 165 170 175 Glu...

Claims

1. An engineered T cell or NK cell comprising an engineered chimeric antigen receptor (CAR) polynucleotide encoding a chimeric antigen receptor polypeptide comprising a signal peptide, an antibody-binding domain, a hinge region, a transmembrane domain, at least one co-stimulatory domain, and a signal transduction domain, wherein the antibody-binding domain is a CD45-binding domain, and wherein when the engineered T cell or NK cell contains an endogenous cell surface antigen targeted by the antibody-binding domain, the gene encoding the cell surface antigen CD45 is blocked or destroyed, or the cell surface antigen CD45 is missing.

2. Engineered T cells or NK cells as described in claim 1, wherein the CAR binds to CD45.

3. The engineered T cells or NK cells as claimed in claim 1, wherein the engineered T cells and / or NK cells are resistant to CAR T cell or NK cell suicide (cannibalism).

4. The engineered T cells or NK cells as claimed in claim 1, wherein the antibody-binding domain comprises a binding portion or variable region of a monoclonal antibody selective for CD45.

5. The engineered T cell or NK cell of claim 1, wherein the antibody-binding domain comprises a polypeptide selected from SEQ ID NO: 13, SEQ ID NO: 15 and SEQ ID NO: 17, and the corresponding polynucleotide sequences SEQ ID NO: 14, SEQ ID NO: 16 and SEQ ID NO:

18.

6. The engineered T cells or NK cells of claim 1 further comprise at least one enhancer selected from the group consisting of: PD-1, PD-L1, CSF1R, CTAL-4, TIM-3, TGFRβ, IL-2, IL-7, IL-12, IL-15, sushi / IL-15 (IL-15 / IL-15 sushi), IL-21, a functional fragment thereof or a combination thereof, and an enhancer receptor comprising IL-15RA or a functional fragment thereof.

7. The engineered T cells or NK cells of claim 1 further comprising the enhancer sushi / IL-15 (IL-15 / IL-15 sushi).

8. The engineered T cells or NK cells of claim 1, further comprising an enhancer of sushi / IL-15 (IL-15 / IL-15 sushi) having a polypeptide selected from SEQ ID NO: 35 and SEQ ID NO:

36.

9. Use of an engineered T-cell or NK-cell as claimed in any one of claims 1 to 8, for the preparation of a medicament for treating proliferative disorders, wherein the antibody-binding domain targets CD45, and wherein the proliferative disorder is selected from the group consisting of: lymphoma, leukemia, plasmacytoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma, chronic myeloid leukemia, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia, precursor acute lymphoblastic leukemia, chronic myeloproliferative neoplasm, chronic myeloid leukemia, myelodysplastic syndrome, blastic plasmacytoid dendritic neoplasm (BPDCN), mastocytosis, hairy cell leukemia cells, primary exudative lymphoma, reticulocytoma, lymphocyte-dominant Hodgkin's lymphoma. Lymphoma), bone marrow leukemia or sarcoma, dendritic cell sarcoma, histiocytic sarcoma, giant cell tumor of tendon sheath, occlusive dendritic cell sarcoma, and post-transplant lymphoproliferative disorders.

10. Use of an engineered T cell or NK cell as claimed in any one of claims 1 to 8, for the preparation of a drug for creating space in the bone marrow of a patient preparing for bone marrow stem cell transplantation, wherein the antibody-binding domain targets CD45.

11. Use of an engineered T cell or NK cell as claimed in any one of claims 1 to 8, for the preparation of a medicament for pre-treating a patient prior to undergoing bone marrow transplantation to receive stem cells, wherein the antibody-binding domain targets CD45.

12. Use of an engineered T cell or NK cell as claimed in any one of claims 1 to 8, for the preparation of a drug for regulating spinal cord suppression for hematopoietic cell transplantation in patients in need, wherein the antibody-binding domain is targeted at CD45.

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