CN114716565A - Novel chimeric antigen receptor - Google Patents

Abstract

The present application relates to a novel chimeric antigen receptor comprising at least one intracellular domain selected from a receptor of a cytokine or a variant thereof. The application also relates to immune cells comprising the novel chimeric antigen receptor structures. In addition, the application also relates to a method for enhancing the amplification capacity of the immune cell containing the novel chimeric antigen receptor structure and a method for enhancing the signal of a JAK-STAT signal pathway in the immune cell containing the novel chimeric antigen receptor structure.

Description

Novel chimeric antigen receptor

Technical Field

The application relates to the field of biomedicine, in particular to a novel chimeric antigen receptor.

Background

At present, Chimeric antigen receptor-engineered T cell immunotherapy (CART) is an effective adoptive cellular immunotherapy, and the method carries out genetic engineering transformation on autologous T cells to enable effector T lymphocytes to generate targeted cytotoxic action aiming at tumor cells so as to achieve the purpose of clearing the tumor cells in vivo.

A Chimeric Antigen Receptor (CAR) includes an extracellular antigen recognition domain, a transmembrane domain, a costimulatory domain, and an intracellular signaling domain. CARs redirect the specificity of immune effector cells and trigger proliferation, cytokine production, and can also mediate cell death of target antigen expressing cells in a Major Histocompatibility (MHC) -independent manner.

In recent years, CAR-modified T cell technology has shown good antitumor effects in the treatment of malignant tumors such as leukemia and lymphoma. However, due to foreign body environment and the like, CART (e.g., universal CART) is not highly amplifiable, which is an obstacle to further development of therapeutic effects of CART therapy.

Disclosure of Invention

The present application provides a modified chimeric antigen receptor having one or more of the following properties: 1) the ability to expand edited T cells is enhanced; and 2) enabling the edited T cells to exhibit better ability to secrete the cytokine IFN gamma.

In one aspect, the present application provides a modified chimeric antigen receptor comprising at least one intracellular domain derived from a cytokine receptor.

In certain embodiments, the intracellular domain of the modified chimeric antigen receptor is located in the intracellular portion of the modified chimeric antigen receptor.

In certain embodiments, the modified chimeric antigen receptor wherein the cytokine receptor comprises IL7RA, IL15RA, IL9R, IL3RA, IL21R and/or IL 23R.

In certain embodiments, the cytokine receptor comprises IL7 RA.

In certain embodiments, the cytokine receptor comprises IL 21R.

In certain embodiments, the modified chimeric antigen receptor comprises a costimulatory domain.

In certain embodiments, the modified chimeric antigen receptor comprises a costimulatory domain of a protein selected from the group consisting of: 4-1BB, CD28, CD137, CD27, CD2, CD7, CD8, CD80, CD86, OX40, CD226, DR3, SLAM, CDS, ICAM, NKG2D, NKG2C, B7-H3, 2B4, Fc ε RI γ, BTLA, GITR, HVEM, DAP10, DAP12, CD30, CD40, CD40L, TIM1, PD-1, PD-L1, PD-L2, 4-1BBL, OX40L, ICOS-L, CD30L, CD70, CD83, HLA-G, MICA, MICB, lymphotoxin β receptor, LIGHT, JAML, CD244, CD100, ICOS, CD83 ligand, CD40, and MyD 88.

In certain embodiments, the co-stimulatory domain comprises a co-stimulatory domain derived from 4-1 BB.

In certain embodiments, the co-stimulatory domain comprises a co-stimulatory domain derived from CD 28.

In certain embodiments, the modified chimeric antigen receptor comprises an intracellular signaling domain.

In certain embodiments, the modified chimeric antigen receptor comprises an intracellular signaling domain selected from the group consisting of: CD3zeta, CD3delta, CD3gamma, CD3 epsilon, CD79a, CD79b, CD66d, CD5, CD22, FcR gamma, FcR beta, FcR epsilon, FceRI gamma, FceRI beta, fcyriia, Bovine Leukemia Virus (BLV) gp30, Epstein-Barr virus (EBV) LMP2A, Simian Immunodeficiency Virus (SIV) PBj14 Nef, Kaposi Sarcoma Herpesvirus (KSHV) K1, DAP10, DAP12 and a domain comprising at least one ITAM.

In certain embodiments, the intracellular signaling domain comprises a CD3 zeta-derived intracellular signaling domain.

In certain embodiments, the modified chimeric antigen receptor comprises the short peptide fragment YRHQ.

In certain embodiments, the N-terminus of the short peptide fragment YRHQ in the modified chimeric antigen receptor is linked to the C-terminus of the intracellular signaling domain.

In certain embodiments, the N-terminus of the short peptide fragment YRHQ is linked to the C-terminus of the co-stimulatory domain or intracellular domain, and the C-terminus of the short peptide fragment YRHQ is linked to the N-terminus of the intracellular signaling domain.

In certain embodiments, the modified chimeric antigen receptor comprises a transmembrane domain.

In certain embodiments, the modified chimeric antigen receptor comprises a transmembrane domain comprising a protein selected from the group consisting of: CD8, CD28, 4-1BB, CD4, CD27, CD7, PD-1, TCR α, TCR β, TCR γ, TCR δ, CD3 ε, CD3 δ, CD3 γ, CD3 ζ, cytokine receptors, CD5, ICOS, OX40, NKG2D, 2B4, CD244, Fc ε R, Fc ε RI γ, BTLA, CD30, GITR, HVEM, DAP10, CD2, NKG2C, LIGHT, DAP12, CD40L, TIM1, CD226, DR3, CD45, CD80, CD86, CD9, CD16, CD22, CD33, CD37, CD64, CD134, CD137, CD154 and SLAM.

In certain embodiments, the transmembrane domain comprises a transmembrane domain derived from CD8a in the CD 8.

In certain embodiments, the transmembrane domain comprises a transmembrane domain derived from CD 28.

In certain embodiments, the transmembrane domain comprises a transmembrane domain derived from a cytokine receptor.

In certain embodiments, the modified chimeric antigen receptor comprises a hinge region.

In certain embodiments, the modified chimeric antigen receptor wherein the hinge region comprises a hinge region derived from a protein selected from the group consisting of: CD8, CD28, IgG, 4-1BB, CD4, CD27, CD7, PD-1 and CH2CH 3.

In certain embodiments, the modified chimeric antigen receptor comprises an antigen binding domain.

In certain embodiments, the modified chimeric antigen receptor has the antigen binding domain specifically binding to a tumor antigen.

In certain embodiments, the modified chimeric antigen receptor comprises a tumor antigen selected from the group consisting of: CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, CD79, CD, CD, CD, CD123, CD133, CD137, CD151, CD171, CD276, CLL, B7H, BCMA, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, ErbB, ITER-2, HER, ErbB/HER-4, EphA, IGF1, GD, O-acetyl GD, O-acetyl, GHRHR, GHR, Flt, KDR, Flt, Flt, FBR, CEA, CA125, CTLA-4, GITR, BTLA, FBR, TGR, FBRD, IL6, gPLS, Lewis, TNFR, TNFR, LRP, LRPD, LRPL, MULRP-L, HVCTLA, TFPR, TFLRP-4, TFLRP, TCPR, TFR, TFPR, TCPR, TFLRP, TCPR, LTPR, TFLRP-LRP, TFPR, TCPR-LR-4, TFPR-LR, TFPR, and TFPR, TF, robol, Frizzled, 0X40, Notch-l-4, APRIL, CS1, MAGE3, Claudin 18.2, fonatereceiver a, fonatereceiver b, GPC2, CD70, BAFF-R, TROP-2.

In certain embodiments, the antigen binding domain of the modified chimeric antigen receptor is a single chain antibody and/or a corresponding ligand for an antigen.

In certain embodiments, the modified chimeric antigen receptor comprises one of the intracellular domains.

In certain embodiments, the modified chimeric antigen receptor has the N-terminus of the intracellular domain linked to the C-terminus of the costimulatory domain, and the C-terminus of the intracellular domain linked to the N-terminus of the intracellular signaling domain.

In certain embodiments, the modified chimeric antigen receptor has the N-terminus of the endodomain linked to the C-terminus of the transmembrane domain, and the C-terminus of the endodomain linked to the N-terminus of the costimulatory domain.

In certain embodiments, the N-terminus of the intracellular domain is linked to the C-terminus of the hinge region, and the C-terminus of the intracellular domain is linked to the N-terminus of the costimulatory domain. In certain embodiments, the modified chimeric antigen receptor comprises a first intracellular domain and a second intracellular domain different from the first intracellular domain.

In certain embodiments, the first intracellular domain and the second intracellular domain of the modified chimeric antigen receptor each independently comprise an intracellular domain derived from a cytokine receptor selected from the group consisting of: IL7RA and IL15RA, IL7RA and IL21R, IL15RA and IL21R, IL9R and IL21R, IL3RA and IL21R, IL7RA and IL23R, IL15RA and IL23R, IL9R and IL23R, and IL3RA and IL 23R.

In certain embodiments, the modified chimeric antigen receptor has the N-terminus of the first intracellular domain linked to the C-terminus of the costimulatory domain, and the C-terminus of the first intracellular domain linked to the N-terminus of the intracellular signaling domain.

In certain embodiments, the modified chimeric antigen receptor has the N-terminus of the second intracellular domain linked to the C-terminus of the intracellular signaling domain.

In certain embodiments, the N-terminus of the first intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the first intracellular domain is linked to the N-terminus of the second intracellular domain.

In certain embodiments, the C-terminal domain of the second intracellular domain is linked to the N-terminal of the intracellular signaling domain.

In certain embodiments, the N-terminus of the first intracellular domain is linked to the C-terminus of the transmembrane domain, and the C-terminus of the first intracellular domain is linked to the N-terminus of the costimulatory domain.

In certain embodiments, the N-terminus of the second intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the second intracellular domain is linked to the N-terminus of the intracellular signaling domain.

In certain embodiments, the N-terminus of the first endodomain is linked to the C-terminus of the transmembrane domain, and the C-terminus of the first endodomain is linked to the N-terminus of the second endodomain.

In certain embodiments, the C-terminus of the second intracellular domain is linked to the N-terminus of the co-stimulatory domain.

In certain embodiments, the intracellular domain in the modified chimeric antigen receptor comprises SEQ ID NO: 7. 9, 11, 13 and 15.

In certain embodiments, the first intracellular domain comprises SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the second intracellular domain comprises SEQ ID NO:15, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the modified chimeric antigen receptor comprises SEQ ID NO: 16-33.

In another aspect, the present application provides an isolated nucleic acid molecule encoding a modified chimeric antigen receptor described herein.

In certain embodiments, the nucleic acid molecule comprises SEQ ID NO: 34-51.

In another aspect, the present application provides a vector comprising the isolated nucleic acid molecule.

In another aspect, the present application provides an immune cell comprising or expressing the fusion protein, the nucleic acid molecule, and/or the vector.

In certain embodiments, the immune cell comprises a T cell, a B cell, a natural killer cell (NK cell), a macrophage, an NKT cell, a monocyte, a dendritic cell, a granulocyte, a lymphocyte, a leukocyte, and/or a peripheral blood mononuclear cell.

In another aspect, the present application provides a pharmaceutical composition comprising the modified chimeric antigen receptor, the nucleic acid molecule, the vector, the immune cell, and/or a pharmaceutically acceptable adjuvant.

In certain embodiments, the use of said modified chimeric antigen receptor, said nucleic acid molecule, said vector, and/or said pharmaceutical composition in the manufacture of a medicament for the treatment and/or amelioration of a tumor.

In another aspect, the present application provides a method of enhancing the expansion capacity of an immune cell comprising a chimeric antigen receptor, comprising the steps of: such that the chimeric antigen receptor comprises at least one intracellular domain selected from cytokine receptors.

In another aspect, the present application provides a method of enhancing a signal of a JAK-STAT signaling pathway in an immune cell, comprising the steps of: such that the immune cell comprises a chimeric antigen receptor comprising at least one intracellular domain selected from a cytokine receptor.

In certain embodiments, the method wherein the enhancing signaling of the JAK-STAT signaling pathway comprises upregulating the level of secretion of secretions by the immune cell.

In certain embodiments, the intracellular domain is located in an intracellular portion of the chimeric antigen receptor in the method.

In certain embodiments, the cytokine receptor in the methods comprises IL7RA, IL15RA, IL9R, IL3RA, IL21R, and/or IL 23R.

In certain embodiments, the cytokine receptor in the methods comprises IL7 RA.

In certain embodiments, the cytokine receptor in the method comprises IL 21R.

In certain embodiments, the method wherein the chimeric antigen receptor comprises a co-stimulatory domain.

In certain embodiments, the method wherein the co-stimulatory domain comprises a co-stimulatory domain from a protein selected from the group consisting of: 4-1BB, CD28, CD137, CD27, CD2, CD7, CD8, CD80, CD86, OX40, CD226, DR3, SLAM, CDS, ICAM, NKG2D, NKG2C, B7-H3, 2B4, Fc ε RI γ, BTLA, GITR, HVEM, DAP10, DAP12, CD30, CD40, CD40L, TIM1, PD-1, PD-L1, PD-L2, 4-1BBL, OX40L, ICOS-L, CD30L, CD70, CD83, HLA-G, MICA, MICB, lymphotoxin β receptor, LIGHT, JAML, CD244, CD100, ICOS, CD83 ligand, CD40, andMyD 88.

In certain embodiments, the co-stimulatory domain comprises a co-stimulatory domain derived from 4-1 BB.

In certain embodiments, the co-stimulatory domain comprises a co-stimulatory domain derived from CD 28.

In certain embodiments, the method wherein the chimeric antigen receptor comprises an intracellular signaling domain.

In certain embodiments, the method wherein the intracellular signaling domain comprises an intracellular signaling domain selected from the following proteins, or a combination thereof: CD3zeta, CD3delta, CD3gamma, CD3 epsilon, CD79a, CD79b, CD66d, CD5, CD22, FcR gamma, FcR beta, FcR epsilon, FceRI gamma, FceRI beta, fcyriia, Bovine Leukemia Virus (BLV) gp30, Epstein-Barr virus (EBV) LMP2A, Simian Immunodeficiency Virus (SIV) PBj14 Nef, Kaposi Sarcoma Herpesvirus (KSHV) K1, DAP10, DAP12 and a domain comprising at least one ITAM.

In certain embodiments, the intracellular signaling domain comprises a CD3 zeta-derived intracellular signaling domain.

In certain embodiments, the method wherein the chimeric antigen receptor comprises the short peptide fragment YRHQ.

In certain embodiments, the N-terminus of the short peptide fragment YRHQ is linked to the C-terminus of the intracellular signaling domain in the method.

In certain embodiments, the N-terminus of the short peptide fragment YRHQ is linked to the C-terminus of the intracellular domain, and the C-terminus of the short peptide fragment YRHQ is linked to the N-terminus of the intracellular signaling domain.

In certain embodiments, the N-terminus of the short peptide fragment YRHQ is linked to the C-terminus of the co-stimulatory domain, and the C-terminus of the short peptide fragment YRHQ is linked to the N-terminus of the intracellular signaling domain.

In certain embodiments, the method wherein the chimeric antigen receptor comprises a transmembrane domain.

In certain embodiments, the transmembrane domain in the method comprises a transmembrane domain of a protein selected from the group consisting of: CD8, CD28, 4-1BB, CD4, CD27, CD7, PD-1, TCR α, TCR β, TCR γ, TCR δ, CD3 ε, CD3 δ, CD3 γ, CD3 ζ, cytokine receptors, CD5, ICOS, OX40, NKG2D, 2B4, CD244, Fc ε R, Fc ε RI γ, BTLA, CD30, GITR, HVEM, DAP10, CD2, NKG2C, LIGHT, DAP12, CD40L, TIM1, CD226, DR3, CD45, CD80, CD86, CD9, CD16, CD22, CD33, CD37, CD64, CD134, CD137, CD154 and SLAM.

In certain embodiments, the transmembrane domain comprises a transmembrane domain derived from the CD8a in the CD 8.

In certain embodiments, the transmembrane domain comprises a transmembrane domain derived from CD 28.

In certain embodiments, the transmembrane domain comprises a transmembrane domain derived from a cytokine receptor.

In certain embodiments, the method wherein the chimeric antigen receptor comprises a hinge region.

In certain embodiments, the method wherein the hinge region comprises a hinge region derived from a protein selected from the group consisting of: CD8, CD28, IgG, 4-1BB, CD4, CD27, CD7, PD-1 and CH2CH 3.

In certain embodiments, the method wherein the chimeric antigen receptor comprises an antigen binding domain.

In certain embodiments, the method wherein the antigen binding domain specifically binds to a tumor antigen.

In certain embodiments, the method wherein the tumor antigen is selected from the group consisting of: CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, CD79, CD, CD, CD, CD123, CD133, CD137, CD151, CD171, CD276, CLL, B7H, BCMA, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, ErbB, ITER-2, HER, ErbB/HER-4, EphA, IGF1, GD, O-acetyl GD, O-acetyl, GHRHR, GHR, Flt, KDR, Flt, Flt, FBR, CEA, CA125, CTLA-4, GITR, BTLA, FBR, TGR, FBRD, IL6, gPLS, Lewis, TNFR, TNFR, LRP, LRPD, LRPL, MULRP-L, HVCTLA, TFPR, TFLRP-4, TFLRP, TCPR, TFR, TFPR, TCPR, TFLRP, TCPR, LTPR, TFLRP-LRP, TFPR, TCPR-LR-4, TFPR-LR, TFPR, and TFPR, TF, robol, Frizzled, 0X40, Notch-l-4, APRIL, CS1, MAGE3, Claudin 18.2, template receiver a, template receiver b, GPC2, CD70, BAFF-R, TROP-2.

In certain embodiments, the antigen binding domain in the methods comprises a single chain antibody and/or a corresponding ligand for an antigen.

In certain embodiments, the method wherein the chimeric antigen receptor comprises one of the intracellular domains.

In certain embodiments, the method wherein the N-terminus of the intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the intracellular domain is linked to the N-terminus of the intracellular signaling domain.

In certain embodiments, the method wherein the N-terminus of the endodomain is linked to the C-terminus of the transmembrane domain and the C-terminus of the endodomain is linked to the N-terminus of the costimulatory domain.

In certain embodiments, the N-terminus of the intracellular domain is linked to the C-terminus of the hinge region, and the C-terminus of the intracellular domain is linked to the N-terminus of the costimulatory domain.

In certain embodiments, the method wherein the chimeric antigen receptor comprises a first intracellular domain and a second intracellular domain different from the first intracellular domain.

In certain embodiments, the method wherein the first intracellular domain and the second intracellular domain each independently comprise one or more intracellular domains derived from receptors for the following group of cytokines or variants thereof:

IL7RA and IL15RA, IL7RA and IL21R, IL15RA and IL21R, IL9R and IL21R, IL3RA and IL21R, IL7RA and IL23R, IL15RA and IL23R, IL9R and IL23R, and IL3RA and IL 23R.

In certain embodiments, the N-terminus of the first intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the first intracellular domain is linked to the N-terminus of the intracellular signaling domain.

In certain embodiments, the N-terminus of the second intracellular domain is linked to the C-terminus of the intracellular signaling domain. In certain embodiments, the N-terminus of the first intracellular domain is linked to the C-terminus of the costimulatory domain, and the C-terminus of the first intracellular domain is linked to the N-terminus of the second intracellular domain.

In certain embodiments, the C-terminus of the second intracellular domain is linked to the N-terminus of the intracellular signaling domain.

In certain embodiments, the N-terminus of the first endodomain is linked to the C-terminus of the transmembrane domain, and the C-terminus of the first endodomain is linked to the N-terminus of the costimulatory domain.

In certain embodiments, the N-terminus of the second intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the second domain is linked to the N-terminus of the intracellular signaling domain.

In certain embodiments, the N-terminus of the first intracellular domain is linked to the C-terminus of the transmembrane domain, and the C-terminus of the first intracellular domain is linked to the N-terminus of the second intracellular domain.

In certain embodiments, the C-terminus of the second intracellular domain is linked to the N-terminus of the co-stimulatory domain.

In certain embodiments, the method wherein the intracellular domain comprises SEQ ID NO: 7. 9, 11, 13 and 15.

In certain embodiments, the first intracellular domain comprises SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the second intracellular domain comprises SEQ ID NO:15, or a pharmaceutically acceptable salt thereof.

Other aspects and advantages of the present application will be readily apparent to those skilled in the art from the following detailed description. Only exemplary embodiments of the present application have been shown and described in the following detailed description. As those skilled in the art will recognize, the disclosure of the present application enables those skilled in the art to make changes to the specific embodiments disclosed without departing from the spirit and scope of the invention as it is directed to the present application. Accordingly, the descriptions in the drawings and the specification of the present application are illustrative only and not limiting.

Drawings

The specific features of the invention to which this application relates are set forth in the appended claims. The features and advantages of the invention to which this application relates will be better understood by reference to the exemplary embodiments described in detail below and the accompanying drawings. The drawings are briefly described as follows:

FIGS. 1A-1C show the component compositions of the exemplary "modified chimeric antigen receptor" BBz structure and 28z structure of the present application.

FIG. 2 shows the results of measurements of proliferation of exemplary "UCART cells" of the present application, U-BBz-IL1, U-BBz-IL2, U-BBz-IL4, U-BBz-IL5, U-BBz-ILC, BBz and U-BBz.

FIG. 3 shows the results of the measurement of proliferation fold of exemplary "UCART cells" of the present application, U-BBz-IL3, U-BBz-IL4 and BBz.

FIG. 4 shows the results of measurement of proliferation rates of U-28z-IL1, U-28z-IL2, U-28z-IL4, U-28z-IL5, U-28z-ILC, 28z and U-28z, which are exemplary "UCART cells" of the present application.

FIG. 5 shows the results of measurement of the proliferation fold of U-28z-IL3, U-28z-IL4 and U-28z-ILC, which are exemplary "UCART cells" of the present application.

FIG. 6 shows the results of measurements of the ability of exemplary "UCART cells" of the present application, U-BBz-IL6, U-BBz-IL7, U-BBz-IL8, U-BBz-ILC, BBz and U-BBz, to secrete the cytokine IFN γ.

FIG. 7 shows the results of measurement of the ability of U-28z-IL6, U-28z-IL7, U-28z-IL8, U-28z-ILC, 28z and U-28z, which are exemplary "UCART cells" of the present application, to secrete the cytokine IFN γ.

Detailed Description

The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification.

Definition of terms

In the present application, the term "modified chimeric antigen receptor" generally refers to a recombinant polypeptide comprising an intracellular signaling domain. The modified chimeric antigen receptor may comprise an antigen binding domain, a transmembrane domain, a costimulatory domain, and an intracellular signaling domain. The modified chimeric antigen receptor may also comprise at least one intracellular domain derived from a cytokine receptor, as compared to the common chimeric antigen receptor. In some embodiments, the cytokine receptor may comprise IL7RA, IL15RA, IL9R, IL3RA, IL21R, and/or IL 23R. In some embodiments, the intracellular domain of the cytokine receptor may comprise a first intracellular domain and a second intracellular domain different from the first intracellular domain. In some embodiments, the first intracellular domain and the second intracellular domain may each independently comprise one or more intracellular domains derived from the following group of cytokine receptors: IL7RA and IL15RA, IL7RA and IL21R, IL15RA and IL21R, IL9R and IL21R, IL3RA and IL21R, IL7RA and IL23R, IL15RA and IL23R, IL9R and IL23R, and IL3RA and IL 23R. The amino acid sequence of the human IL7 receptor can be found in UniProt/Swiss-Prot accession No. P16871, the amino acid sequence of the human IL21 receptor can be found in UniProt/Swiss-Prot accession No. Q9HBE5, and the amino acid sequence of the human IL15 receptor can be found in UniProt/Swiss-Prot accession No. Q13261.

In the present application, the term "cytokine receptor" or "ILR" generally refers to a cell-binding protein, or polypeptide subunit of such a protein, that binds to a biologically active molecule and mediates the effect of the biologically active molecule on the cell. Binding of a biologically active molecule (e.g., a cytokine) to a receptor causes a conformational change in the receptor (and in some cases, receptor multimerization, i.e., binding of the same or different receptor subunits) that results in the interaction of the intracellular signaling domain with other molecules within the cell. In the present application, the cytokine receptor may include an interleukin receptor. For example, cytokine receptors may include interleukin-7 receptor (IL7R), interleukin-15 receptor (IL15R), interleukin-9 receptor (IL9R), interleukin-3 receptor (IL3R), interleukin-21 receptor (IL21R), or interleukin-23 receptor (IL 23R). In the present application, the cytokine receptor may also comprise one or more subunits. For example, the subunit of a cytokine receptor may include an alpha-subunit. For example, the subunit of a cytokine receptor may comprise a β -subunit. In the present application, the intracellular domain may comprise an intracellular domain derived from IL7R, IL15R, IL9, IL3R, IL21R, or IL 23R. In certain instances, the intracellular domain may comprise an intracellular domain derived from the α -subunit of IL7R (also referred to as "IL 7 RA"). In certain instances, the intracellular domain may comprise an intracellular domain derived from the α -subunit of IL15R (also referred to as "IL 15 RA"). In certain instances, the intracellular domain may comprise an intracellular domain derived from the α -subunit of IL3R (also referred to as "IL 3 RA"). In the present application, the term "isolated nucleic acid molecule" generally refers to an isolated form of nucleotides, deoxyribonucleotides or ribonucleotides or analogs thereof of any length, isolated from their natural environment, or artificially synthesized. In the present application, an isolated nucleic acid molecule may be an isolated form of nucleotides, deoxyribonucleotides or ribonucleotides or analogs thereof of any length that are artificially synthesized and which may encode a modified chimeric antigen receptor.

In the present application, the term "vector" generally refers to a nucleic acid molecule capable of self-replication in a suitable host, which transfers the inserted nucleic acid molecule into and/or between host cells. In the present application, the vector may include a vector mainly for inserting a DNA into a cell, a vector mainly for replicating a DNA, and a vector mainly for expression of transcription and/or translation of a DNA. The vector may also include vectors having a variety of the functions described above. In the present application, the vector may be a lentiviral vector.

In the present application, the term "immune cell" generally refers to a cell capable of producing an immune response (e.g., an antigen-specific immune response). For example, the immune cell may or may already contain an individual cell, cell line or cell culture that includes a modified chimeric antigen receptor, nucleic acid molecule, and/or vector described herein, or is capable of expressing a modified chimeric antigen receptor described herein. In the present application, the immune cells may include T cells, B cells, natural killer cells (NK cells), macrophages, NKT cells, monocytes, dendritic cells, granulocytes, lymphocytes, leukocytes, and/or peripheral blood mononuclear cells. In some embodiments, the immune cell described herein can be a T cell.

In the present application, the term "pharmaceutical composition" generally refers to a composition that may comprise the modified chimeric antigen receptor, the nucleic acid molecule, the vector, the immune cell and/or a pharmaceutically acceptable adjuvant described herein.

In the present application, the term "a method of enhancing the expansion capacity of an immune cell comprising a chimeric antigen receptor" generally refers to a method of enhancing the expansion capacity of an immune cell comprising at least one intracellular domain selected from cytokine receptors. In some embodiments, the cytokine may comprise IL7, IL21, and/or IL 15. The amino acid sequence of the human IL7 receptor can be found in UniProt/Swiss-Prot accession number P16871, the amino acid sequence of the human IL21 receptor can be found in UniProt/Swiss-Prot accession number Q9HBE5, and the amino acid sequence of the human IL15 receptor can be found in UniProt/Swiss-Prot accession number Q13261.

In the present application, the term "a method of enhancing a signal of a JAK-STAT signaling pathway in an immune cell" generally refers to a method of enhancing a signal of a JAK-STAT signaling pathway in an immune cell by allowing a chimeric antigen receptor comprised by the immune cell to comprise at least one intracellular domain selected from cytokine receptors. In some embodiments, the cytokine may include IL7, IL21, and/or IL 15. The amino acid sequence of the human IL7 receptor can be found in UniProt/Swiss-Prot accession No. P16871, the amino acid sequence of the human IL21 receptor can be found in UniProt/Swiss-Prot accession No. Q9HBE5, and the amino acid sequence of the human IL15 receptor can be found in UniProt/Swiss-Prot accession No. Q13261. In the present application, the signal that enhances the JAK-STAT signaling pathway may upregulate the level of secretion of secretions by the immune cell. For example, the secretion may include a cytokine such as IFN γ.

In addition to the specific proteins and nucleotides mentioned herein, the present application may also include functional variants, derivatives, analogs, homologs, and fragments thereof.

The term "functional variant" refers to a polypeptide that has substantially the same amino acid sequence as a naturally occurring sequence or is encoded by substantially the same nucleotide sequence and is capable of having one or more of the activities of a naturally occurring sequence. In the context of this application, a variant of any given sequence refers to a sequence in which the particular sequence of residues (whether amino acid or nucleotide residues) has been modified such that the polypeptide or polynucleotide substantially retains at least one endogenous function. Variant sequences having a certain homology may be obtained by addition, deletion, substitution, modification, substitution and/or variation of at least one amino acid residue and/or nucleotide residue present in a naturally occurring protein and/or polynucleotide, as long as the original functional activity is maintained.

In the present application, the term "derivative" generally refers to a polypeptide or polynucleotide of the present application including any substitution, variation, modification, substitution, deletion and/or addition of one (or more) amino acid residues from/to the sequence, so long as the resulting polypeptide or polynucleotide substantially retains at least one of its endogenous functions.

In the present application, the term "analog" generally with respect to a polypeptide or polynucleotide includes any mimetic of a polypeptide or polynucleotide, i.e., a chemical compound that possesses at least one endogenous function of the polypeptide or polynucleotide that the mimetic mimics.

Typically, amino acid substitutions, such as at least 1 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 20) amino acid substitutions can be made so long as the modified sequence substantially retains the desired activity or ability. Amino acid substitutions may include the use of non-naturally occurring analogs.

The proteins or polypeptides used in the present application may also have deletions, insertions or substitutions of amino acid residues which produce silent changes and result in a functionally equivalent protein. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the residues, as long as endogenous function is retained. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with similar hydrophilicity values without an electrically polar head group include asparagine, glutamine, serine, threonine, and tyrosine.

In the present application, the term "homology" may be equated with sequence "identity". A homologous sequence can include an amino acid sequence that can be at least 80%, 85%, 90%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to the subject sequence. Typically, homologues will comprise the same active site etc. as the subject amino acid sequence. Homology may be considered in terms of similarity (i.e., amino acid residues with similar chemical properties/functions), or may be expressed in terms of sequence identity. In the present application, a sequence having a percent identity of any one of SEQ ID NOs of the referenced amino acid sequence or nucleotide sequence refers to a sequence having said percent identity over the entire length of the referenced SEQ ID NOs.

To determine sequence identity, sequence alignments can be performed, which can be performed by various means known to those skilled in the art, e.g., using BLAST, BLAST-2, ALIGN, needlet, or megalign (dnastar) software, etc. One skilled in the art can determine appropriate parameters for alignment, including any algorithms needed to achieve optimal alignment over the full-length sequences being compared.

In the present application, the term "antigen binding domain" generally refers to a domain capable of binding to a target antigen. In the present application, the antigen binding domain may comprise a single chain antibody. In the present application, the antigen binding domain may also include the corresponding ligand of the antigen. In the present application, the term "corresponding ligand of an antigen" generally refers to any biological molecule that binds to a target antigen. For example, the corresponding ligand of the antigen may include, but is not limited to, a monoclonal antibody, a single chain antibody, a chimeric antibody, a multispecific antibody, a humanized antibody, and a fully human antibody. For example, corresponding ligands for an antigen may include Fab, Fab ', F (ab)2, Fv, F (ab') 2, scFv, VHH, di-scFv, and dAb fragments. The antigen binding domain can bind to tumor associated antigens, which can include but are not limited to: CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, CD79, CD, CD, CD, CD123, CD133, CD137, CD151, CD171, CD276, CLL, B7H, BCMA, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, ErbB, ITER-2, HER, ErbB/HER-4, EphA, IGF1, GD, O-acetyl GD, O-acetyl, GHRHR, GHR, Flt, KDR, Flt, Flt, FBR, CEA, CA125, CTLA-4, GITR, BTLA, FBR, TGR, FBRD, IL6, gPLS, Lewis, TNFR, TNFR, LRP, LRPD, LRPL, MULRP-L, HVCTLA, TFPR, TFLRP-4, TFLRP, TCPR, TFR, TFPR, TCPR, TFLRP, TCPR, LTPR, TFLRP-LRP, TFPR, TCPR-LR-4, TFPR-LR, TFPR, and TFPR, TF, robol, Frizzled, 0X40, Notch-l-4, APRIL, CS1, MAGE3, Claudin 18.2, template receiver a, template receiver b, GPC2, CD70, BAFF-R, TROP-2. For example, the tumor associated antigen may be CD 70. For example, the tumor associated antigen may be BCMA. For example, the tumor associated antigen may be CD 19.

In the present application, the term "comprising" is generally intended to include the explicitly specified features, but not to exclude other elements.

In the present application, the term "about" generally means varying from 0.5% to 10% above or below the stated value, for example, varying from 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below the stated value.

Detailed Description

Modified chimeric antigen receptors

In one aspect, the present application provides a modified chimeric antigen receptor comprising at least one intracellular domain selected from a cytokine receptor. In the present application, the modified chimeric antigen receptor may further include an antigen binding domain, a hinge region, a transmembrane domain, a costimulatory domain, and an intracellular signaling domain.

In the present application, the modified chimeric antigen receptor, wherein the intracellular domain may be located in the intracellular portion of the modified chimeric antigen receptor. In the present application, the modified chimeric antigen receptor, wherein the cytokine receptor may include IL7RA, IL15RA, IL9R, IL3RA, IL21R, and/or IL 23R. For example, the modified chimeric antigen receptor, wherein the cytokine receptor may include IL7 RA. For example, the cytokine receptor may include IL 21R. For example, the cytokine receptor may include IL 9R. For example, the cytokine receptor may include IL3 RA. For example, the cytokine receptor may include IL15 RA. For example, the cytokine receptor may include IL 23R.

In the present application, the modified chimeric antigen receptor, which may comprise a co-stimulatory domain. For example, the modified chimeric antigen receptor, wherein the co-stimulatory domain may comprise a co-stimulatory domain selected from the group consisting of: 4-1BB, CD28, CD137, CD27, CD2, CD7, CD8, CD80, CD86, OX40, CD226, DR3, SLAM, CDS, ICAM, NKG2D, NKG2C, B7-H3, 2B4, Fc ε RI γ, BTLA, GITR, HVEM, DAP10, DAP12, CD30, CD40, CD40L, TIM1, PD-1, PD-L1, PD-L2, 4-1BBL, OX40L, ICOS-L, CD30L, CD70, CD83, HLA-G, MICA, MICB, lymphotoxin β receptor, LIGHT, JAML, CD244, CD100, ICOS, CD83 ligand, CD40, andMyD 88. For example, the co-stimulatory domain may be selected from the group consisting of co-stimulatory domains derived from CD 28. For example, the co-stimulatory domain may be selected from co-stimulatory domains derived from 4-1 BB. For example, the co-stimulatory domain may comprise SEQ ID NO:56 and 57.

In the present application, the modified chimeric antigen receptor, which may comprise an intracellular signaling domain. For example, the modified chimeric antigen receptor, wherein the intracellular signaling domain may comprise an intracellular signaling domain selected from the following proteins, or a combination thereof: CD3zeta, CD3delta, CD3gamma, CD3 epsilon, CD79a, CD79b, CD66d, CD5, CD22, FcR gamma, FcR beta, FcR epsilon, FceRI gamma, FceRI beta, fcyriia, bovine leukemia virus gp30, Epstein-Barr virus (EBV) LMP2A, simian immunodeficiency virus PBj14 Nef, kaposi's sarcoma Herpesvirus (HSKV), DAP10, DAP12, and a domain comprising at least one ITAM. For example, the intracellular signaling domain may comprise an intracellular signaling domain derived from CD3 zeta. For example, the intracellular signaling domain may comprise SEQ ID NO:59, or a pharmaceutically acceptable salt thereof.

In the present application, the modified chimeric antigen receptor, which may include a short peptide fragment.

For example, the short peptide fragment may be YRHQ. For example, the short peptide fragment can comprise SEQ ID NO:60, or a pharmaceutically acceptable salt thereof.

In the present application, the modified chimeric antigen receptor, which may comprise a transmembrane domain. For example, the modified chimeric antigen application, wherein the transmembrane domain may comprise a transmembrane domain of a protein selected from the group consisting of: CD8, CD28, 4-1BB, CD4, CD27, CD7, PD-1, TCR α, TCR β, TCR γ, TCR δ, CD3 ε, CD3 δ, CD3 γ, CD3 ζ, cytokine receptors, CD5, ICOS, OX40, NKG2D, 2B4, CD244, Fc ε R, Fc ε RI γ, BTLA, CD30, GITR, HVEM, DAP10, CD2, NKG2C, LIGHT, DAP12, CD40L, TIM1, CD226, DR3, CD45, CD80, CD86, CD9, CD16, CD22, CD33, CD37, CD64, CD134, CD137, CD154 and SLAM. For example, the transmembrane domain may comprise a transmembrane domain derived from the CD8a in the CD 8. For example, the transmembrane domain may comprise a transmembrane domain derived from CD 28. For example, the transmembrane domain may comprise a transmembrane domain derived from a cytokine receptor (e.g., IL2 receptor, IL7 receptor). For example, the transmembrane domain may comprise SEQ ID NO: 55. 58 and 63.

In the present application, the modified chimeric antigen receptor, which may comprise a hinge region. For example, the modified chimeric antigen receptor, wherein the hinge region may comprise a hinge region derived from a protein selected from the group consisting of: CD8, CD28, IgG, 4-1BB, CD4, CD27, CD7, PD-1 and CH2CH 3. For example, the hinge region may comprise a hinge region derived from the CD8a in the CD 8. For example, the hinge region may comprise SEQ ID NO: 54, or a pharmaceutically acceptable salt thereof. In the present application, the modified chimeric antigen receptor, which may comprise an antigen binding domain. For example, the modified chimeric antigen receptor, wherein the antigen binding domain can specifically bind to a tumor antigen. For example, the modified chimeric antigen receptor, wherein the tumor antigen may be selected from the group consisting of: CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, CD79, CD, CD, CD, CD123, CD133, CD137, CD151, CD171, CD276, CLL, B7H, BCMA, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, ErbB, ITER-2, HER, ErbB/HER-4, EphA, IGF1, GD, O-acetyl GD, O-acetyl, GHRHR, GHR, Flt, KDR, Flt, Flt, FBR, CEA, CA125, CTLA-4, GITR, BTLA, FBR, TGR, FBRD, IL6, gPLS, Lewis, TNFR, TNFR, LRP, LRPD, LRPL, MULRP-L, HVCTLA, TFPR, TFLRP-4, TFLRP, TCPR, TFR, TFPR, TCPR, TFLRP, TCPR, LTPR, TFLRP-LRP, TFPR, TCPR-LR-4, TFPR-LR, TFPR, and TFPR, TF, robol, Frizzled, 0X40, Notch-l-4, APRIL, CS1, MAGE3, Claudin 18.2, template receiver a, template receiver b, GPC2, CD70, BAFF-R, TROP-2.

In the present application, the modified chimeric antigen receptor, wherein the antigen binding domain may include a single chain antibody and/or a natural ligand of an antigen.

In the present application, the modified chimeric antigen receptor may comprise one of the intracellular domains.

In the present application, the N-terminus of the intracellular domain in the modified chimeric antigen receptor may be linked to the C-terminus of the costimulatory domain, and the C-terminus of the intracellular domain may be linked to the N-terminus of the intracellular signaling domain.

In the present application, the N-terminus of the intracellular domain in the modified chimeric antigen receptor may be linked to the C-terminus of the transmembrane domain, and the C-terminus of the intracellular domain may be linked to the N-terminus of the co-stimulatory domain.

In the present application, the N-terminus of the intracellular domain is linked to the C-terminus of the hinge region, and the C-terminus of the intracellular domain is linked to the N-terminus of the costimulatory domain.

For example, the modified chimeric antigen receptor, wherein the first intracellular domain and the second intracellular domain each independently comprise one or more intracellular domains derived from receptors for the following group of cytokines or variants thereof: IL7RA and IL15RA, IL7RA and IL21R, IL15RA and IL21R, IL9R and IL21R, IL3RA and IL21R, IL7RA and IL23R, IL15RA and IL23R, IL9R and IL23R, and IL3RA and IL 23R.

In the present application, the modified chimeric antigen receptor may include a first intracellular domain and a second intracellular domain different from the first intracellular domain.

For example, the first intracellular domain may be the intracellular domain of IL7RA or a variant thereof and the second intracellular domain may be the intracellular domain of IL15RA or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL7RA or a variant thereof and the second intracellular domain may be the intracellular domain of IL21R or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL7RA or a variant thereof and the second intracellular domain may be the intracellular domain of IL23R or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL15RA or a variant thereof and the second intracellular domain may be the intracellular domain of IL21R or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL15RA or a variant thereof and the second intracellular domain may be the intracellular domain of IL23R or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL9R or a variant thereof, and the second intracellular domain may be the intracellular domain of IL21R or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL9R or a variant thereof and the second intracellular domain may be the intracellular domain of IL23R or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL3RA or a variant thereof and the second intracellular domain may be the intracellular domain of IL21R or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL3RA or a variant thereof and the second intracellular domain may be the intracellular domain of IL23R or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL15RA or a variant thereof and the second intracellular domain may be the intracellular domain of IL7RA or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL21R or a variant thereof and the second intracellular domain may be the intracellular domain of IL7RA or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL21R or a variant thereof and the second intracellular domain may be the intracellular domain of IL15RA or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL21R or a variant thereof and the second intracellular domain may be the intracellular domain of IL9R or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL21R or a variant thereof and the second intracellular domain may be the intracellular domain of IL3RA or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL23R or a variant thereof, and the second intracellular domain may be the intracellular domain of IL7RA or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL23R or a variant thereof and the second intracellular domain may be the intracellular domain of IL15RA or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL23R or a variant thereof and the second intracellular domain may be the intracellular domain of IL9R or a variant thereof.

For example, the first intracellular domain may be the intracellular domain of IL23R or a variant thereof and the second intracellular domain may be the intracellular domain of IL3RA or a variant thereof.

In the present application, the modified chimeric antigen receptor, which may include the same first intracellular domain and second intracellular domain.

For example, both the first intracellular domain and the second intracellular domain may be the intracellular domain of IL7RA or a variant thereof.

For example, both the first intracellular domain and the second intracellular domain may be the intracellular domain of IL15RA or a variant thereof.

For example, both the first intracellular domain and the second intracellular domain may be the intracellular domain of IL21R or a variant thereof.

For example, both the first intracellular domain and the second intracellular domain may be the intracellular domain of IL9R or a variant thereof.

For example, both the first intracellular domain and the second intracellular domain may be the intracellular domain of IL3RA or a variant thereof.

For example, both the first intracellular domain and the second intracellular domain may be the intracellular domain of IL23R or a variant thereof.

In the present application, the N-terminus of the first intracellular domain in the modified chimeric antigen receptor may be linked to the C-terminus of the co-stimulatory domain, and the C-terminus of the first intracellular domain may be linked to the N-terminus of the intracellular signaling domain. In the present application, the N-terminus of the first intracellular domain in the modified chimeric antigen receptor may be linked to the C-terminus of the transmembrane domain, and the C-terminus of the first intracellular domain may be linked to the N-terminus of the co-stimulatory domain. In the present application, the N-terminus of the first intracellular domain in the modified chimeric antigen receptor may be linked to the C-terminus of the hinge region, and the C-terminus of the first intracellular domain may be linked to the N-terminus of the co-stimulatory domain. In the present application, the N-terminus of the first intracellular domain may be linked to the C-terminus of the co-stimulatory domain, and the C-terminus of the first intracellular domain may be linked to the N-terminus of the second intracellular domain. In the present application, the N-terminus of the first intracellular domain may be linked to the C-terminus of the transmembrane domain, and the C-terminus of the first intracellular domain may be linked to the N-terminus of the second intracellular domain.

In the present application, the N-terminus of the second intracellular domain in the modified chimeric antigen receptor may be linked to the C-terminus of the intracellular signaling domain. In the present application, the N-terminus of the second intracellular domain in the modified chimeric antigen receptor may be linked to the C-terminus of the first intracellular domain, and the C-terminus of the second intracellular domain may be linked to the N-terminus of the intracellular activation signaling domain. In the present application, the second intracellular domain may be linked to the C-terminus of the co-stimulatory domain, and the C-terminus of the second intracellular domain is linked to the N-terminus of the intracellular signaling domain. In the present application, the C-terminus of the second intracellular domain is linked to the N-terminus of the co-stimulatory domain.

In the present application, the N-terminus of the short peptide fragment in the modified chimeric antigen receptor may be linked to the C-terminus of the intracellular signaling domain. In the present application, the N-terminus of the short peptide fragment in the modified chimeric antigen receptor may be linked to the C-terminus of the co-stimulatory domain. In the present application, the N-terminus of the short peptide fragment may be linked to the C-terminus of the intracellular domain.

For example, the short peptide fragment may be YRHQ.

In the present application, the N-terminus of the transmembrane domain may be linked to the C-terminus of the hinge region, and the C-terminus of the transmembrane domain may be linked to the N-terminus of the costimulatory domain. In the present application, the N-terminus of the transmembrane domain may be linked to the C-terminus of the hinge region, and the C-terminus of the transmembrane domain may be linked to the N-terminus of the first intracellular domain.

In the present application, the N-terminus of the co-stimulatory domain may be linked to the C-terminus of the transmembrane domain, and the C-terminus of the co-stimulatory domain may be linked to the N-terminus of the first intracellular domain.

In the present application, the N-terminus of the co-stimulatory domain may be linked to the C-terminus of the transmembrane domain, and the C-terminus of the co-stimulatory domain may be linked to the N-terminus of the intracellular signaling domain.

In the present application, the N-terminus of the co-stimulatory domain may be linked to the C-terminus of the first intracellular domain, and the C-terminus of the co-stimulatory domain may be linked to the N-terminus of the intracellular signaling domain.

In the present application, the C-terminus of the antigen binding domain may be linked to the N-terminus of the transmembrane domain.

In the present application, the N-terminus of the intracellular signaling domain may be linked to the C-terminus of the co-stimulatory domain. In the present application, the N-terminus of the intracellular signaling domain may be linked to the C-terminus of the first intracellular domain.

In the present application, the modified chimeric antigen receptor may comprise, from N-terminus to C-terminus, an antigen binding domain, a hinge region, a transmembrane domain, a costimulatory domain, an intracellular signaling domain, a short peptide fragment.

In the present application, the modified chimeric antigen receptor, from N-terminus to C-terminus, may comprise an antigen binding domain, a hinge region, a transmembrane domain, a costimulatory domain, an intracellular signaling domain.

In the present application, the modified chimeric antigen receptor may comprise, from N-terminus to C-terminus, an antigen binding domain, a hinge region, a transmembrane domain, a costimulatory domain, an intracellular signaling domain, a short peptide fragment.

In the present application, the modified chimeric antigen receptor, from N-terminus to C-terminus, may comprise an antigen binding domain, a hinge region, a transmembrane domain, a costimulatory domain, a first intracellular domain, an intracellular signaling domain, a second intracellular domain.

In the present application, the modified chimeric antigen receptor, from N-terminus to C-terminus, may comprise an antigen binding domain, a hinge region, a transmembrane domain, an intracellular domain, a costimulatory domain, an intracellular signaling domain.

In the present application, the modified chimeric antigen receptor may comprise, from N-terminus to C-terminus, an antigen binding domain, a hinge region, a transmembrane domain, an intracellular domain, a co-stimulatory domain, an intracellular signaling domain, a short peptide fragment. In the present application, the modified chimeric antigen receptor, from N-terminus to C-terminus, may comprise an antigen binding domain, a hinge region, a transmembrane domain, a costimulatory domain, a first intracellular domain, a second intracellular domain, an intracellular signaling domain.

In the present application, the modified chimeric antigen receptor, from N-terminus to C-terminus, may comprise an antigen binding domain, a hinge region, a transmembrane domain, a first intracellular domain, a costimulatory domain, a second intracellular domain, an intracellular signaling domain.

In the present application, the modified chimeric antigen receptor, from N-terminus to C-terminus, may comprise an antigen binding domain, a hinge region, a transmembrane domain, a first intracellular domain, a second intracellular domain, a costimulatory domain, an intracellular signaling domain.

In the present application, the modified chimeric antigen receptor, from N-terminus to C-terminus, may comprise an antigen binding domain, a hinge region, a transmembrane domain, a costimulatory domain, an intracellular domain, a short peptide fragment, an intracellular signaling domain.

In the present application, the modified chimeric antigen receptor, from N-terminus to C-terminus, may comprise an antigen binding domain, a hinge region, a transmembrane domain, an intracellular domain, a co-stimulatory domain, a short peptide fragment, an intracellular signaling domain.

For example, the antigen binding domain of the modified chimeric antigen receptor can specifically bind to a tumor antigen. For example, the tumor antigen may be CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD44V, CD, CD, CD, CD, CD, CD79, CD, CD, CD, CD, CD123, CD133, CD137, CD151, CD171, CD276, CLL, B7H, BCMA, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, ErbB/HER, ITER-2, HER, ErbB/HER-4, EphA, IGF1, GD, O-acetyl GD, GHRHR, GHR, TLFlt, KDR, HVCA, CA, Flt 125, CTLA-4, GITR, LA, TGFBR, TGFBR, TGFBR, IL6, TNFPL, Lewis, TNFPD, TNFR, TNFR, LRPR, HVR, Flt, CTLA, TFLRPR, TFLRP, TCRP, TCRORP, TCRP, TCROPR, TCRP, TLR7, TLR9, PTCH1, WT-l, Robol, Frizzled, 0X40, Notch-l-4, APRIL, CS1, MAGE3, Claudin 18.2, template receiver a, template receiver b, GPC2, CD70, BAFF-R, TROP-2.

For example, the tumor antigen may be CD 19. The antigen binding domain can target CD19, and the amino acid sequence thereof is shown in SEQ ID NO: shown at 52. For example, the amino acid sequence of the tumor antigen can comprise an amino acid sequence having at least 80% (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) sequence homology to the amino acid sequence set forth in SEQ ID NO. 52.

For example, the tumor antigen may be BCMA. The antigen binding domain can target BCMA, and the amino acid sequence thereof is shown as SEQ ID NO: shown at 53. For example, the amino acid sequence of the tumor antigen can comprise an amino acid sequence having at least 80% (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) sequence homology to the amino acid sequence set forth in SEQ ID NO. 53.

For example, the transmembrane domain of the modified chimeric antigen receptor may comprise a transmembrane domain of a protein selected from the group consisting of: CD8, CD28, 4-1BB, CD4, CD27, CD7, PD-1, TCR α, TCR β, TCR γ, TCR δ, CD3 ε, CD3 δ, CD3 γ, CD3 ζ, cytokine receptors, CD5, ICOS, OX40, NKG2D, 2B4, CD244, Fc ε R, Fc ε RI γ, BTLA, CD30, GITR, HVEM, DAP10, CD2, NKG2C, LIGHT, DAP12, CD40L, TIM1, CD226, DR3, CD45, CD80, CD86, CD9, CD16, CD22, CD33, CD37, CD64, CD134, CD137, CD154 and SLAM. For example, the transmembrane domain of the modified chimeric antigen receptor may comprise a transmembrane domain of a cytokine receptor. For example, the transmembrane domain of the modified chimeric antigen receptor may comprise a transmembrane domain of a protein selected from the group consisting of: IL7RA, IL15RA, IL9R, IL3RA, IL21R and IL 23R.

For example, the transmembrane domain may be selected from the transmembrane domain of CD8 α in CD8, the amino acid sequence of which is set forth in SEQ ID NO: as shown at 55. For example, the transmembrane domain may be selected from the transmembrane domain of CD28, the amino acid sequence of which is set forth in SEQ ID NO: shown at 58. For example, the transmembrane domain may be selected from the transmembrane domain of IL7RA, the amino acid sequence being as set forth in SEQ ID NO: 63, respectively. For example, the transmembrane domain may comprise an amino acid sequence having at least 80% (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) sequence homology to the amino acid sequence set forth in any one of SEQ ID NOs: 55, 58, and 63.

For example, the modified chimeric antigen receptor, wherein the co-stimulatory domain may comprise a co-stimulatory domain selected from the group consisting of: 4-1BB, CD28, CD137, CD27, CD2, CD7, CD8, CD80, CD86, OX40, CD226, DR3, SLAM, CDS, ICAM, NKG2D, NKG2C, B7-H3, 2B4, Fc ε RI γ, BTLA, GITR, HVEM, DAP10, DAP12, CD30, CD40, CD40L, TIM1, PD-1, PD-L1, PD-L2, 4-1BBL, OX40L, ICOS-L, CD30L, CD70, CD83, HLA-G, MICA, MICB, lymphotoxin β receptor, LIGHT, JAML, CD244, CD100, ICOS, CD83 ligand, CD40, andMyD 88. For example, the co-stimulatory domain may be selected from the group consisting of the co-stimulatory domains of 4-1BB, the amino acid sequences of which are set forth in SEQ ID NO: as shown at 56. For example, the co-stimulatory domain may comprise an amino acid sequence having at least 80% (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) sequence homology to the amino acid sequence set forth in SEQ ID NO: 56.

For example, the costimulatory domain can be selected from the costimulatory domain of CD28, the amino acid sequence of which is set forth in SEQ ID NO: as shown at 57. For example, the co-stimulatory domain may comprise an amino acid sequence having at least 80% (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) sequence homology to the amino acid sequence set forth in SEQ ID NO: 57.

For example, the modified chimeric antigen receptor, wherein the intracellular signaling structure may comprise an intracellular signaling domain selected from the group consisting of: CD3zeta, CD3delta, CD3gamma, CD3 epsilon, CD79a, CD79b, CD66d, CD5, CD22, FcR gamma, FcR beta, FcR epsilon, FceRI gamma, FceRI beta, fcyriia, bovine leukemia virus gp30, Epstein-Barr virus (EBV) LMP2A, simian immunodeficiency virus PBj14 Nef, kaposi's sarcoma Herpesvirus (HSKV), DAP10, DAP12, and a domain comprising at least one ITAM. For example, the intracellular signaling structure may be selected from the intracellular signaling domain of CD3zeta with an amino acid sequence as set forth in SEQ ID NO: shown at 59. For example, the intracellular signaling domain can comprise an amino acid sequence having at least 80% (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) sequence homology to the amino acid sequence set forth in SEQ ID NO. 59.

For example, the modified chimeric antigen receptor, wherein the short peptide fragment can be YRHQ, and the amino acid sequence is as set forth in SEQ ID NO: shown at 60. For example, the short peptide fragment can comprise an amino acid sequence having at least 80% (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) sequence homology to the amino acid sequence set forth in SEQ ID NO: 60.

For example, the modified chimeric antigen receptor, wherein the first intracellular domain and the second intracellular domain may optionally be intracellular domains of receptors or variants thereof for cytokines selected from the group consisting of: IL7RA and IL15RA, IL7RA and IL21R, IL15RA and IL21R, IL9R and IL21R, IL3RA and IL21R, IL7RA and IL23R, IL15RA and IL23R, IL9R and IL23R, and IL3RA and IL 23R. For example, the first intracellular domain may be the intracellular domain of IL7RA or a variant thereof, having the amino acid sequence as set forth in SEQ ID NO: 9. 11 and 13, respectively. For example, the first intracellular domain can comprise an amino acid sequence having at least 80% (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) sequence homology to the amino acid sequence set forth in any one of SEQ ID NOS 9, 11 and 13.

For example, the second intracellular domain may be an intracellular domain of IL21R or a variant thereof, having an amino acid sequence as set forth in SEQ ID NO: shown at 15. For example, the second intracellular domain may comprise an amino acid sequence having at least 80% (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) sequence homology to the amino acid sequence set forth in SEQ ID NO. 15.

In the present application, the modified chimeric antigen receptor, which may comprise a hinge region. For example, the modified chimeric antigen receptor, wherein the hinge region may comprise a hinge region derived from a protein selected from the group consisting of: CD8, CD28, IgG, 4-1BB, CD4, CD27, CD7, PD-1 and CH2CH 3. For example, the hinge region may comprise a hinge region derived from the CD8a in the CD 8. For example, the hinge region may comprise SEQ ID NO: 54, or a pharmaceutically acceptable salt thereof. For example, the hinge region may comprise a sequence identical to SEQ ID NO: 54 (e.g., at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) sequence homology.

In the present application, the modified chimeric antigen receptor may comprise the amino acid sequence of SEQ ID NO: 16-33.

Nucleic acids, vectors, immune cells, pharmaceutical compositions and methods of treatment

In another aspect, the present application provides isolated one or more nucleic acid molecules that can encode a modified chimeric antigen receptor described herein. For example, the isolated one or more nucleic acid molecules can comprise SEQ ID NOs: 34-51.

The nucleic acid molecules described herein can be isolated. For example, it may be produced or synthesized by: (i) in vitro amplified, e.g., by Polymerase Chain Reaction (PCR) amplification, (ii) recombinantly produced by cloning, (iii) purified, e.g., fractionated by enzymatic cleavage and gel electrophoresis, or (iv) synthesized, e.g., by chemical synthesis.

In the present application, the isolated nucleic acid may be a nucleic acid molecule prepared by recombinant DNA techniques.

In the present application, the nucleic acid or nucleic acids encoding the isolate can be prepared by a variety of methods known in the art, including, but not limited to, overlap extension PCR using restriction fragment procedures or using synthetic oligonucleotides, as described in Sambrook et al, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989; and Ausube et al Current Protocols in Molecular Biology, Greene Publishing and Wiley-Interscience, New York N.Y., 1993.

In another aspect, the present application also provides one or more vectors comprising one or more of the nucleic acid molecules described herein. One or more of the nucleic acid molecules may be contained in each vector. In addition, other genes may be included in the vector, such as marker genes that allow selection of the vector in an appropriate host cell and under appropriate conditions. In addition, the vector may contain expression control elements that allow for the proper expression of the coding region in an appropriate host. Such control elements are well known to those skilled in the art and may include, for example, promoters, ribosome binding sites, enhancers and other control elements which regulate gene transcription or mRNA translation, among others.

The vector may include, for example, a plasmid, cosmid, virus, phage, or other vector commonly used in, for example, genetic engineering. For example, the vector may be a lentiviral vector.

In another aspect, the present application provides an immune cell comprising one or more fusion proteins described herein, one or more nucleic acid molecules, and/or one or more vectors described herein. For example, the immune cells can include T cells, B cells, natural killer cells (NK cells), macrophages, NKT cells, monocytes, dendritic cells, granulocytes, lymphocytes, leukocytes, and/or peripheral blood mononuclear cells.

In the present application, the immune cells may include T lymphocytes. The T lymphocytes may include thymocytes, natural T lymphocytes, immature T lymphocytes, mature T lymphocytes, resting T lymphocytes, or activated T lymphocytes. The T cell may be a helper T cell (Th), such as a helper T cell 1(Th1) or a helper T cell 2(Th2) cell. The T lymphocytes may be CD4+ helper T cells (HTL; CD4+ T cells), cytotoxic T cells (CTL; CD8+ T cells), tumor infiltrating cytotoxic T cells (TIL; CD8+ T cells), CD4+/CD8+ T cells, CD4-/CD8-T cells or any other T lymphocyte subset. For example, the T cell may be a human T cell. Prior to expansion and genetic modification of the immune cells of the present application, a source of cells can be obtained from a subject, e.g., a patient, by various non-limiting methods. T cells can be obtained from a number of non-limiting sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue at the site of infection, ascites, pleural effusion, spleen tissue, and tumors. For example, any number of T cell lines available and known to those skilled in the art may be used. As another example, the immune cells can be derived from a healthy donor, from a patient diagnosed with cancer, or from a patient diagnosed with an infection. As another example, the immune cells are part of a mixed population of cells that have different phenotypic properties.

For example, the immune cells can include B cells. For example, the B cells may include effector B cells (plasma cells), memory B cells. The B cells may include B2 cells, B1 cells, marginal zone B cells, follicular B cells, regulatory B cells. For example, the immune cells may comprise macrophages. The B cells may include type I macrophages (M1), type II macrophages (e.g., M2a, M2B, M2 c).

For example, the immune cells can include NK cells. For example, the NK cells may include CD56bright and CD56 dim. In certain instances, the NK cells can include NK1 andNK 2. For example, the NK cells can include A-NK and NA-NK.

For example, the immune cells may comprise leukocytes. Leukocytes generally refer to nucleated blood cells that have active motility and can migrate from within a blood vessel to outside the blood vessel, or from extravascular tissue to within the blood vessel. In addition to the blood, leukocytes can also be present in the lymphatic system, spleen, tonsils and other tissues of the body. In the present application, the leukocytes may include granulocytes (e.g., neutrophils, eosinophils, basophils), agranulocytes (e.g., lymphocytes, monocytes, macrophages, phagocytes, mast cells).

For example, the immune cells can include lymphocytes, which can include any mononuclear cells, non-phagocytic leukocytes, such as B lymphocytes, T lymphocytes, Natural Killer (NK) cells found in blood, lymph, and lymphoid tissues.

For example, the immune cells may include peripheral blood mononuclear cells, which may include any cells having a mononuclear in peripheral blood. For example, in the present application, the peripheral blood mononuclear cells may include T cells, B cells, NK cells, lymphocytes, monocytes, and dendritic cells.

For example, the immune cells may comprise macrophages. Macrophages are a substance that phagocytose and digest cell debris, microorganisms, cancer cells, and all other substances that lack surface markers expressed on the surface of normal cells, a process called phagocytosis. Macrophages are present in almost all tissues and seek potential pathogens through amoebic movements. In addition to their important role in nonspecific innate immune responses, they may also help to initiate adaptive immunity by recruiting other immune cell types, such as lymphocytes.

An immune cell comprising a novel chimeric antigen receptor, which does not express a T Cell Receptor (TCR), as described herein. The non-expression of a T Cell Receptor (TCR) may comprise down-regulation of expression and/or activity of a T Cell Receptor (TCR). The downregulation can include expressing no active TCR, expressing no endogenous TCR, expressing no exogenous TCR, comprising a TCR structure, comprising an inactivated TCR, and/or deleting a TCR.

For example, expression and/or activity of a T cell receptor alpha constant region protein and/or a T cell receptor beta constant region protein in the immune cell may be down-regulated. For example, the downregulation may comprise downregulating expression and/or activity of a nucleic acid molecule encoding the cellular receptor alpha constant region protein and/or the T cell receptor beta constant region protein; and/or, comprising downregulating expression and/or activity of said cellular receptor alpha constant region protein and/or T cell receptor beta constant region protein.

For example, the down-regulation may down-regulate the expression and/or activity of a TCR of the immune cell by gene knock-out (knock-out), gene knock-down (knock-down), gene mutation, gene deletion, gene silencing, or any combination of the above.

For example, down-regulation may be achieved by administering to the immune cells one or more agents selected from the group consisting of: antisense RNA, siRNA, shRNA, CRISPR/Cas systems, RNA editing systems such as RNA Adenosine Deaminase (ADAR), RNA-guided endonucleases, Zinc Finger Nucleases (ZFNs), Mega-TAL nucleases, transcription activator-like effector nucleases (TALENs), meganucleases (Meganuclasees), base editing, CRISPR interference, and, Zinc finger protein (Zinc finger) gene repressor and/or transcription activator-like effector (TALE) gene repressor-mediated transcriptional inhibition.

In another aspect, the present application also provides a pharmaceutical composition, which may comprise the modified chimeric antigen receptor, the nucleic acid molecule, the immune cell and/or a pharmaceutically acceptable adjuvant.

The pharmaceutically acceptable adjuvants may include buffers, antioxidants, preservatives, low molecular weight polypeptides, proteins, hydrophilic polymers, amino acids, sugars, chelating agents, counter ions, metal complexes, and/or non-ionic surfactants, and the like.

In the present application, the pharmaceutical composition may be formulated for oral administration, intravenous administration, intramuscular administration, in situ administration at the tumor site, inhalation, rectal administration, vaginal administration, transdermal administration or administration via subcutaneous depot.

In the present application, the pharmaceutical composition may be used to inhibit or delay the development or progression of a disease or disorder, and/or may alleviate and/or stabilize the state of a disease or disorder.

In another aspect, the present application provides the use of the modified chimeric antigen receptor, the nucleic acid molecule, the vector, and/or the pharmaceutical composition for the treatment and/or amelioration of a tumor.

In another aspect, the present application provides one or more of the modified chimeric antigen receptors, nucleic acid molecules, vectors, and/or pharmaceutical compositions for treating and/or ameliorating a tumor.

In another aspect, the present application provides a method of preventing and/or treating a tumor comprising administering to a subject in need thereof an effective amount of a modified chimeric antigen receptor, a nucleic acid molecule, a vector, and/or a pharmaceutical composition.

Method for enhancing immune cell expansion capacity containing chimeric antigen receptor

In another aspect, the present application also provides a method of enhancing the expansion capacity of immune cells comprising a chimeric antigen receptor, which may comprise the steps of: such that the chimeric antigen receptor may comprise at least one intracellular domain selected from a receptor for a cytokine or a variant thereof.

For example, the cytokine receptor may include IL7RA, IL15RA, IL9R, IL3RA, IL21R, and/or IL 23R.

For example, the intracellular domain of the immune cell comprising the chimeric antigen receptor may comprise an intracellular domain selected from IL7RA or a variant thereof.

Provided herein are methods of making an immune cell comprising a chimeric antigen receptor, which can comprise the steps of: 1. obtaining peripheral blood T cells from a healthy donor; 2. activating T cells using magnetic beads loaded with CD3 and CD28 antibodies; after T cells are activated, transferring the chimeric antibody receptor gene into the T cells by using lentivirus; 4. removing the magnetic beads; 5. the culture was continued and the cells were harvested.

Provided herein are methods of detecting the expansion capacity of an immune cell comprising a chimeric antigen receptor, which may comprise the steps of: 1. raji cells ═ 1: 1, Raji cells were put into the culture onday 0 andday 5, respectively, to form test groups; 2. raji cells ═ 1: 1, Raji cells were added onday 0 andday 5, respectively, and cocultured with Raji cells as a control group; 3. the expansion capacity of the immune cells is determined by a method of staining and counting by a flow cytometer.

For example, an immune cell comprising a chimeric antigen receptor can have an increased expansion capacity of at least 20% (e.g., 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or more) compared to an immune cell that does not comprise a chimeric antigen receptor.

Method for enhancing JAK-STAT signal channel signal in immune cell

In another aspect, the present application also provides a method of enhancing a signal of a JAK-STAT signaling pathway in an immune cell, which may comprise the steps of: such that the chimeric antigen receptor comprised by the immune cell may comprise at least one intracellular domain selected from a receptor of a cytokine or a variant thereof.

For example, the cytokine receptor may include IL7RA, IL15RA, IL9R, IL3RA, IL21R, and/or IL 23R. For example, the cytokine receptor may be IL7 RA.

In the present application, the JAK-STAT signal pathway is a downstream pathway of cytokine signaling, regulating development, differentiation, proliferation, apoptosis, etc. of cells. The JAK-STAT signaling pathway can be composed of three components, tyrosine kinase-associated receptors, JAKs, and STATs. Tyrosine kinase related receptors do not have kinase activity per se, but the intracellular segment has a binding site of JAK, when the receptors are combined with ligands (comprising various cytokines and growth factors, such as interleukins, colony stimulating factors, epidermal growth factors, platelet derived factors, interferons and the like), JAK is activated to catalyze STAT proteins combined on the receptors to be subjected to phosphorylation modification, and the activated STAT proteins enter cell nuclei in a form of dimers to be combined with target genes so as to regulate and control the transcription of the genes. STAT is closely related to Interferon (IFN) signaling pathway and plays a role in inhibiting cell growth and promoting apoptosis.

In the present application, the chimeric antigen receptor comprised by the immune cell may comprise at least one intracellular domain selected from receptors for cytokines or variants thereof, which may result in enhanced signaling of the JAK-STAT signaling pathway in the immune cell.

In the present application, the enhancing the signal of the JAK-STAT signaling pathway may comprise up-regulating the level of secretion of secretions by the immune cell. For example, the secretion may include a cytokine such as IFN γ.

Provided herein are methods of detecting cytokine secretion by an immune cell comprising a chimeric antigen receptor, which may comprise the steps of: 1. raji cells ═ 1: 1, Raji cells were put into the culture onday 0 andday 5, respectively, to form test groups; 2. raji cells ═ 1: 1, Raji cells were added onday 0 andday 5, respectively, and cocultured with Raji cells as a control group; 3. the ability of immune cells to secrete cytokines was determined by ELISA.

For example, an immune cell comprising a chimeric antigen receptor can have at least a 20% increase in the ability to secrete the cytokine IFN γ (e.g., 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or more) as compared to an immune cell that does not comprise the chimeric antigen receptor.

The present application will relate to the following embodiments:

1. a modified chimeric antigen receptor comprising at least one intracellular domain derived from a cytokine receptor.

2. The modified chimeric antigen receptor ofembodiment 1, wherein the intracellular domain is located in an intracellular portion of the modified chimeric antigen receptor.

3. The modified chimeric antigen receptor of any one of embodiments 1-2, wherein the cytokine receptor comprises IL7RA, IL15RA, IL9R, IL3RA, IL21R, and/or IL 23R.

4. The modified chimeric antigen receptor of any one of embodiments 1-3, wherein the cytokine receptor comprises IL7 RA.

5. The modified chimeric antigen receptor of any one of embodiments 1-4, wherein the cytokine receptor comprises IL 21R.

6. The modified chimeric antigen receptor of any one of embodiments 1-5, comprising a co-stimulatory domain.

7. The modified chimeric antigen receptor of embodiment 6, wherein the co-stimulatory domain comprises a co-stimulatory domain selected from the group consisting of: 4-1BB, CD28, CD137, CD27, CD2, CD7, CD8, CD80, CD86, OX40, CD226, DR3, SLAM, CDS, ICAM, NKG2D, NKG2C, B7-H3, 2B4, Fc ε RI γ, BTLA, GITR, HVEM, DAP10, DAP12, CD30, CD40, CD40L, TIM1, PD-1, PD-L1, PD-L2, 4-1BBL, OX40L, ICOS-L, CD30L, CD70, CD83, HLA-G, MICA, MICB, lymphotoxin β receptor, LIGHT, JAML, CD244, CD100, ICOS, CD83 ligand, CD40, andMyD 88.

8. The modified chimeric antigen receptor of embodiment 7, wherein the co-stimulatory domain comprises a co-stimulatory domain derived from 4-1 BB.

9. The modified chimeric antigen receptor of any one of embodiments 7-8, wherein the co-stimulatory domain comprises a co-stimulatory domain derived from CD 28.

10. The modified chimeric antigen receptor according to any one of embodiments 1-9, comprising an intracellular signaling domain.

11. The modified chimeric antigen receptor ofembodiment 10, wherein the intracellular signaling domain comprises an intracellular signaling domain selected from the following proteins, or a combination thereof: CD3zeta, CD3delta, CD3gamma, CD3 epsilon, CD79a, CD79b, CD66d, CD5, CD22, FcRy, FcRbeta, FcRepsilon, FceRy, FceRbeta, FcyRIa, bovine leukemia virus gp30, Epstein-Barr virus (EBV) LMP2A, Simian immunodeficiency virus PBj14 Nef, Kaposi's sarcoma Herpesvirus (HSKV), DAP10, DAP12, and a domain comprising at least one ITAM.

12. The modified chimeric antigen receptor of embodiment 11, wherein the intracellular signaling domain comprises an intracellular signaling domain derived from CD3 zeta.

13. The modified chimeric antigen receptor according to any one of embodiments 1-12, which comprises the short peptide fragment YRHQ.

14. The modified chimeric antigen receptor of embodiment 13, wherein the N-terminus of the short peptide fragment YRHQ is linked to the C-terminus of the intracellular signaling domain.

15. The modified chimeric antigen receptor of any one of embodiments 13-14, wherein the N-terminus of the short peptide fragment YRHQ is linked to the C-terminus of the co-stimulatory domain or intracellular domain, and the C-terminus of the short peptide fragment YRHQ is linked to the N-terminus of the intracellular signaling domain.

16. The modified chimeric antigen receptor of any one of embodiments 1-15, comprising a transmembrane domain.

17. The modified chimeric antigen receptor of embodiment 16, wherein the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: CD8, CD28, 4-1BB, CD4, CD27, CD7, PD-1, TCR α, TCR β, TCR γ, TCR δ, CD3 ε, CD3 δ, CD3 γ, CD3 ζ, cytokine receptors, CD5, ICOS, OX40, NKG2D, 2B4, CD244, Fc ε R, Fc ε RI γ, BTLA, CD30, GITR, HVEM, DAP10, CD2, NKG2C, LIGHT, DAP12, CD40L, TIM1, CD226, DR3, CD45, CD80, CD86, CD9, CD16, CD22, CD33, CD37, CD64, CD134, CD137, CD154 and SLAM.

18. The modified chimeric antigen receptor of embodiment 17, wherein the transmembrane domain comprises a transmembrane domain derived from CD8a in the CD 8.

19. The modified chimeric antigen receptor of any one of embodiments 17-18, wherein the transmembrane domain comprises a transmembrane domain derived from CD 28.

20. The modified chimeric antigen receptor of any one of embodiments 17-19, wherein the transmembrane domain comprises a transmembrane domain derived from a cytokine receptor.

21. The modified chimeric antigen receptor of any one of embodiments 1-20, which comprises a hinge region.

22. The modified chimeric antigen receptor of embodiment 21, wherein the hinge region comprises a hinge region derived from a protein selected from the group consisting of: CD8, CD28, IgG, 4-1BB, CD4, CD27, CD7, PD-1 and CH2CH 3.

23. The modified chimeric antigen receptor of any one of embodiments 1-22, comprising an antigen binding domain.

24. The modified chimeric antigen receptor of embodiment 23, wherein the antigen binding domain specifically binds to a tumor antigen.

25. The modified chimeric antigen receptor of embodiment 24, wherein the tumor antigen is selected from the group consisting of: CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, CD79, CD, CD, CD, CD123, CD133, CD137, CD151, CD171, CD276, CLL, B7H, BCMA, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, ErbB, ITER-2, HER, ErbB/HER-4, EphA, IGF1, GD, O-acetyl GD, O-acetyl, GHRHR, GHR, Flt, KDR, Flt, Flt, FBR, CEA, CA125, CTLA-4, GITR, BTLA, FBR, TGR, FBRD, IL6, gPLS, Lewis, TNFR, TNFR, LRP, LRPD, LRPL, MULRP-L, HVCTLA, TFPR, TFLRP-4, TFLRP, TCPR, TFR, TFPR, TCPR, TFLRP, TCPR, LTPR, TFLRP-LRP, TFPR, TCPR-LR-4, TFPR-LR, TFPR, and TFPR, TF, robol, Frizzled, 0X40, Notch-l-4, APRIL, CS1, MAGE3, Claudin 18.2, template receiver a, template receiver b, GPC2, CD70, BAFF-R, TROP-2.

26. The modified chimeric antigen receptor of any one of embodiments 23-25, wherein the antigen binding domain comprises a single chain antibody and/or a corresponding ligand of an antigen.

27. The modified chimeric antigen receptor of any one of embodiments 1-26, comprising one of the intracellular domains.

28. The modified chimeric antigen receptor of embodiment 27, wherein the N-terminus of the intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the intracellular domain is linked to the N-terminus of the intracellular signaling domain.

29. The modified chimeric antigen receptor of any one of embodiments 27-28, wherein the N-terminus of the endodomain is linked to the C-terminus of the transmembrane domain, and the C-terminus of the endodomain is linked to the N-terminus of the costimulatory domain.

30. The modified chimeric antigen receptor of any one of claims 27-29, wherein the N-terminus of the intracellular domain is linked to the C-terminus of the hinge region and the C-terminus of the intracellular domain is linked to the N-terminus of the co-stimulatory domain.

31. The modified chimeric antigen receptor of any one of embodiments 1-26, comprising a first intracellular domain and a second intracellular domain different from the first intracellular domain.

32. The modified chimeric antigen receptor of embodiment 31, wherein the first intracellular domain and the second intracellular domain each independently comprise one or more intracellular domains derived from a cytokine receptor selected from the group consisting of:

IL7RA and IL15RA, IL7RA and IL21R, IL15RA and IL21R, IL9R and IL21R, IL3RA and IL21R, IL7RA and IL23R, IL15RA and IL23R, IL9R and IL23R, and IL3RA and IL 23R.

33. The modified chimeric antigen receptor of any one of embodiments 31-32, wherein the N-terminus of the first intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the first intracellular domain is linked to the N-terminus of the intracellular signaling domain.

34. The modified chimeric antigen receptor of any one of embodiments 31-33, wherein the N-terminus of the second intracellular domain is linked to the C-terminus of the intracellular signaling domain.

35. The modified chimeric antigen receptor of any one of embodiments 31-34, wherein the N-terminus of the first intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the first intracellular domain is linked to the N-terminus of the second intracellular domain.

36. The modified chimeric antigen receptor of any one of embodiments 31-35, wherein the C-terminus of the second intracellular domain is linked to the N-terminus of the intracellular signaling domain.

37. The modified chimeric antigen receptor of any one of embodiments 31-36, wherein the N-terminus of the first intracellular domain is linked to the C-terminus of the transmembrane domain and the C-terminus of the first intracellular domain is linked to the N-terminus of the costimulatory domain.

38. The modified chimeric antigen receptor of any one of embodiments 31-37, wherein the N-terminus of the second intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the second intracellular domain is linked to the N-terminus of the intracellular signaling domain.

39. The modified chimeric antigen receptor of any one of claims 31-38, wherein the N-terminus of the first intracellular domain is linked to the C-terminus of the transmembrane domain and the C-terminus of the first intracellular domain is linked to the N-terminus of the second intracellular domain.

40. The modified chimeric antigen receptor of any one of embodiments 31-39, wherein the C-terminus of the second intracellular domain is linked to the N-terminus of the co-stimulatory domain.

41. The modified chimeric antigen receptor of any one of embodiments 1-40, wherein the intracellular domain comprises the amino acid sequence of SEQ ID NO: 7. 9, 11, 13 and 15.

42. The modified chimeric antigen receptor of any one of embodiments 31-41, wherein the first intracellular domain comprises the amino acid sequence of SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof.

43. The modified chimeric antigen receptor of any one of embodiments 31-42, wherein the second intracellular domain comprises the amino acid sequence of SEQ ID NO:15, or a pharmaceutically acceptable salt thereof.

44. The modified chimeric antigen receptor of any one of embodiments 1-43, comprising the amino acid sequence of SEQ ID NO: 16-33.

45. An isolated nucleic acid molecule encoding the modified chimeric antigen receptor of any one of embodiments 1-44.

46. The nucleic acid molecule of embodiment 45, comprising the nucleotide sequence of SEQ ID NO: 34-51.

47. A vector comprising the isolated nucleic acid molecule of any one of embodiments 45-46.

48. An immune cell comprising or expressing the modified chimeric antigen receptor of any one of embodiments 1-44, the nucleic acid molecule of any one of embodiments 45-46, and/or the vector of embodiment 47.

49. The immune cell of embodiment 48, comprising a T cell, a B cell, a natural killer cell (NK cell), a macrophage, an NKT cell, a monocyte, a dendritic cell, a granulocyte, a lymphocyte, a leukocyte, and/or a peripheral blood mononuclear cell.

50. A pharmaceutical composition comprising a modified chimeric antigen receptor of any one of embodiments 1-44, a nucleic acid molecule of any one of embodiments 45-46, a vector of embodiment 47, and/or an immune cell of any one of embodiments 48-49 and a pharmaceutically acceptable adjuvant.

51. Use of a modified chimeric antigen receptor of any one ofembodiments 1 to 44, a nucleic acid molecule of any one of embodiments 45 to 46, a vector of embodiment 47, an immune cell of any one of embodiments 48 to 49 and/or a pharmaceutical composition of embodiment 50 in the manufacture of a medicament for the treatment and/or amelioration of a tumor.

52. A method of enhancing the expansion capacity of an immune cell comprising a chimeric antigen receptor comprising the steps of: such that the chimeric antigen receptor comprises at least one intracellular domain derived from a cytokine receptor.

53. A method of enhancing a signal of a JAK-STAT signaling pathway in an immune cell, comprising the steps of: allowing said immune cell to comprise a chimeric antigen receptor comprising at least one intracellular domain derived from a cytokine receptor.

54. The method of embodiment 53, wherein said enhancing the signal of the JAK-STAT signaling pathway comprises upregulating the level of secretion of secretions by said immune cell.

55. The method according to any one of embodiments 52-54, wherein the intracellular domain is located in an intracellular portion of the chimeric antigen receptor.

56. The method according to any one of embodiments 52-55, wherein the cytokine receptor comprises IL7RA, IL15RA, IL9R, IL3RA, IL21R, and/or IL 23R.

57. The method according to any one of embodiments 52-56, wherein the cytokine receptor comprises IL7 RA.

58. The method according to any one of embodiments 52-57, wherein the cytokine receptor comprises IL 21R.

59. The method according to any one of embodiments 52-58, wherein the chimeric antigen receptor comprises a co-stimulatory domain.

60. The method according to embodiment 59, wherein the co-stimulatory domain comprises a co-stimulatory domain from a protein selected from the group consisting of: 4-1BB, CD28, CD137, CD27, CD2, CD7, CD8, CD80, CD86, OX40, CD226, DR3, SLAM, CDS, ICAM, NKG2D, NKG2C, B7-H3, 2B4, Fc ε RI γ, BTLA, GITR, HVEM, DAP10, DAP12, CD30, CD40, CD40L, TIM1, PD-1, PD-L1, PD-L2, 4-1BBL, OX40L, ICOS-L, CD30L, CD70, CD83, HLA-G, MICA, MICB, lymphotoxin β receptor, LIGHT, JAML, CD244, CD100, ICOS, CD83 ligand, CD40, andMyD 88.

61. The method ofembodiment 60, wherein the co-stimulatory domain comprises a co-stimulatory domain derived from 4-1 BB.

62. The method according to any one of embodiments 60-61, wherein the co-stimulatory domain comprises a co-stimulatory domain derived from CD 28.

63. The method according to any one of embodiments 52-62, wherein said chimeric antigen receptor comprises an intracellular signaling domain.

64. The method of embodiment 63, wherein said intracellular signaling domain comprises an intracellular signaling domain selected from the group consisting of: CD3zeta, CD3delta, CD3gamma, CD3 epsilon, CD79a, CD79b, CD66d, CD5, CD22, FcR gamma, FcR beta, FcR epsilon, FceRI gamma, FceRI beta, fcyriia, bovine leukemia virus gp30, Epstein-Barr virus (EBV) LMP2A, simian immunodeficiency virus PBj14 Nef, kaposi's sarcoma Herpesvirus (HSKV), DAP10, DAP12, and a domain comprising at least one ITAM.

65. The method according to embodiment 64, wherein the intracellular signaling domain comprises an intracellular signaling domain derived from CD3 zeta.

66. The method according to any one of embodiments 52-65, wherein said chimeric antigen receptor comprises the short peptide fragment YRHQ.

67. The method of embodiment 66, wherein the N-terminus of the short peptide fragment YRHQ is linked to the C-terminus of the intracellular signaling domain.

68. The method of any one of embodiments 66-67, wherein the N-terminus of the short peptide fragment YRHQ is linked to the C-terminus of the co-stimulatory domain or intracellular domain and the C-terminus of the short peptide fragment YRHQ is linked to the N-terminus of the intracellular signaling domain.

69. The method according to any one of embodiments 52-68, wherein the chimeric antigen receptor comprises a transmembrane domain.

70. The method ofembodiment 69, wherein the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: CD8, CD28, 4-1BB, CD4, CD27, CD7, PD-1, TCR α, TCR β, TCR γ, TCR δ, CD3 ε, CD3 δ, CD3 γ, CD3 ζ, cytokine receptors, CD5, ICOS, OX40, NKG2D, 2B4, CD244, Fc ε R, Fc ε RI γ, BTLA, CD30, GITR, HVEM, DAP10, CD2, NKG2C, LIGHT, DAP12, CD40L, TIM1, CD226, DR3, CD45, CD80, CD86, CD9, CD16, CD22, CD33, CD37, CD64, CD134, CD137, CD154 and SLAM.

71. The method of embodiment 70, wherein the transmembrane domain comprises a transmembrane domain derived from CD8a in the CD 8.

72. The method according to any one of embodiments 70-71, wherein the transmembrane domain comprises a transmembrane domain derived from CD 28.

73. The method according to any one of embodiments 70-72, wherein the transmembrane domain comprises a transmembrane domain derived from a cytokine receptor.

74. The method of any one of embodiments 52-73, wherein said chimeric antigen receptor comprises a hinge region.

75. The method of embodiment 74, wherein the hinge region comprises a hinge region derived from a protein selected from the group consisting of: CD8, CD28, IgG, 4-1BB, CD4, CD27, CD7, PD-1 and CH2CH 3.

76. The method according to any one of embodiments 52-75, wherein the chimeric antigen receptor comprises an antigen binding domain.

77. The method of embodiment 76, wherein the antigen binding domain specifically binds to a tumor antigen.

78. The method of embodiment 77, wherein said tumor antigen is selected from the group consisting of: CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, CD79, CD, CD, CD, CD123, CD133, CD137, CD151, CD171, CD276, CLL, B7H, BCMA, VEGFR-2, EGFR, GPC, PMSA, CEACAM, c-Met, EGFRvIII, ErbB, ITER-2, HER, ErbB/HER-4, EphA, IGF1, GD, O-acetyl GD, O-acetyl, GHRHR, GHR, Flt, KDR, Flt, Flt, FBR, CEA, CA125, CTLA-4, GITR, BTLA, FBR, TGR, FBRD, IL6, gPLS, Lewis, TNFR, TNFR, LRP, LRPD, LRPL, MULRP-L, HVCTLA, TFPR, TFLRP-4, TFLRP, TCPR, TFR, TFPR, TCPR, TFLRP, TCPR, LTPR, TFLRP-LRP, TFPR, TCPR-LR-4, TFPR-LR, TFPR, and TFPR, TF, robol, Frizzled, 0X40, Notch-l-4, APRIL, CS1, MAGE3, Claudin 18.2, template receiver a, template receiver b, GPC2, CD70, BAFF-R, TROP-2.

79. The method according to any one of embodiments 76-78, wherein the antigen binding domain comprises a single chain antibody and/or a corresponding ligand of an antigen.

80. The method according to any one of embodiments 52-79, wherein said chimeric antigen receptor comprises one said intracellular domain.

81. The method ofembodiment 80, wherein the N-terminus of the intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the intracellular domain is linked to the N-terminus of the intracellular signaling domain.

82. The method according to any one of embodiments 80-81, wherein the N-terminus of the endodomain is linked to the C-terminus of the transmembrane domain, and the C-terminus of the endodomain is linked to the N-terminus of the costimulatory domain.

83. The method of any one of embodiments 80-82, wherein the N-terminus of the intracellular domain is linked to the C-terminus of the hinge region and the C-terminus of the intracellular domain is linked to the N-terminus of the co-stimulatory domain.

84. The method according to any one of embodiments 52-79, wherein the chimeric antigen receptor comprises a first intracellular domain and a second intracellular domain different from the first intracellular domain.

85. The method of embodiment 84, wherein the first intracellular domain and the second intracellular domain each independently comprise one or more intracellular domains derived from receptors for the following group of cytokines or variants thereof:

IL7RA and IL15RA, IL7RA and IL21R, IL15RA and IL21R, IL9R and IL21R, IL3RA and IL21R, IL7RA and IL23R, IL15RA and IL23R, IL9R and IL23R, and IL3RA and IL 23R.

86. The method according to any one of embodiments 84-85, wherein the N-terminus of the first intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the first intracellular domain is linked to the N-terminus of the intracellular signaling domain.

87. The method according to any one of embodiments 84-86, wherein the N-terminus of the second intracellular domain is linked to the C-terminus of the intracellular signaling domain.

88. The method according to any one of embodiments 84-87, wherein the N-terminus of the first intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the first intracellular domain is linked to the N-terminus of the second intracellular domain.

89. The method according to any one of embodiments 84-88, wherein the C-terminus of the second intracellular domain is linked to the N-terminus of the intracellular signaling domain.

90. The method according to any one of embodiments 84-89, wherein the N-terminus of the first intracellular domain is linked to the C-terminus of the transmembrane domain and the C-terminus of the first intracellular domain is linked to the N-terminus of the co-stimulatory domain.

91. The method according to any one of embodiments 84-90, wherein the N-terminus of the second intracellular domain is linked to the C-terminus of the co-stimulatory domain and the C-terminus of the second intracellular domain is linked to the N-terminus of the intracellular signaling domain.

92. The method according to any one of embodiments 84-91, wherein the N-terminus of the first endodomain is linked to the C-terminus of the transmembrane domain and the C-terminus of the first endodomain is linked to the N-terminus of the second endodomain.

93. The method according to any one of embodiments 84-92, wherein the C-terminus of the second intracellular domain is linked to the N-terminus of the co-stimulatory domain.

94. The method according to any one of embodiments 52-93, wherein the intracellular domain comprises SEQ ID NO: 7. 9, 11, 13 and 15.

95. The method according to any one of embodiments 84-94, wherein the first intracellular domain comprises SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof.

96. The method according to any one of embodiments 84-95, wherein the second intracellular domain comprises SEQ ID NO:15, or a pharmaceutically acceptable salt thereof.

Without intending to be bound by any theory, the following examples are merely intended to illustrate the fusion proteins, preparation methods, uses, etc. of the present application, and are not intended to limit the scope of the invention of the present application.

Examples

Example 1 construction of novel CAR structures

1.1 construction of BBz-ILR and 28z-ILR structures

1.1.1 Synthesis of nucleic acid sequences BBz and 28z

The nucleic acid sequences of BBz (SEQ ID NO:1) and 28z (SEQ ID NO:2) were obtained by gene synthesis. The corresponding amino acid sequence is BBz: 3, 28z: SEQ ID NO. 4.

1.1.2 ligation of nucleic acid sequences BBz and 28z to Lentiviral vectors pELPs

BBz or 28z was ligated into lentiviral vectors pELPs (SEQ ID NO: 5) by restriction with the restriction enzyme BamHI.

1.1.3 Synthesis of ILR sequence fragments

Synthesis of the nucleic acid sequence of a truncated fragment of the intracellular domain of IL2RB (IL2RB-F) (SEQ ID NO:6, the amino acid sequence is shown as SEQ ID NO: 7), the nucleic acid sequence of YRRHQ in BBz (SEQ ID NO: 61), the nucleic acid sequence of YRRHQ in 28z (SEQ ID NO: 62), the nucleic acid sequence of IL7RA intracellular domain fragment 1(IL7RA-F1) (SEQ ID NO: 8, the amino acid sequence is shown as SEQ ID NO: 9), the nucleic acid sequence of IL7RA intracellular domain fragment 2(IL7RA-F2) (SEQ ID NO: 10, the amino acid sequence is shown as SEQ ID NO: 11), the nucleic acid sequence of the transmembrane domain of IL7RA and the nucleic acid sequence of the intracellular domain fragment 3(IL7RA-F3) (SEQ ID NO: 12, the amino acid sequence is shown as SEQ ID NO: 13), the nucleic acid sequence of the intracellular domain fragment of IL21 (IL 21-F R) is shown as SEQ ID NO: 73714, the amino acid sequence is shown as SEQ ID NO: 15) the nucleic acid sequence of a truncated fragment of the intracellular domain of IL23R (IL23R-F), the nucleic acid sequences of the transmembrane domain and fragment of the intracellular domain of IL15RA (IL15RA-F), and the nucleic acid sequence of a truncated fragment of the intracellular domain of IL9R (IL 9R-F).

1.1.4 sequence Assembly

The following exemplary BBz and 28z variant structures were constructed by inserting the above sequences into pELPs-BBz/28z by Gibson homologous recombination, as shown in FIG. 1:

BBz: antigen binding domain CD19 scFv, hinge and transmembrane domain of CD8 α, costimulatory domain 4-1BB, intracellular signaling domain CD3 zeta;

BBz-ILC antigen binding domain CD19 scFv, hinge and transmembrane domain of CD8 alpha, costimulatory domain 4-1BB, IL2RB-F, intracellular signaling domain CD3zeta, YRRHQ;

BBz-IL1 antigen binding domain CD19 scFv, hinge and transmembrane domain of CD8 alpha, costimulatory domain 4-1BB, intracellular signaling domain CD3zeta, YRRHQ;

BBz-IL2 antigen binding domain CD19 scFv, hinge and transmembrane domain of CD8 alpha, costimulatory domain 4-1BB, IL7RA-F1, intracellular signaling domain CD3 zeta;

BBz-IL3 antigen binding domain CD19 scFv, hinge and transmembrane domains of CD8 alpha, costimulatory domain 4-1BB, IL7RA-F1, intracellular signaling domain CD3zeta, YRRHQ;

BBz-IL4 antigen binding domain CD19 scFv, hinge and transmembrane domain of CD8 alpha, costimulatory domain 4-1BB, IL7RA-F2, intracellular signaling domain CD3 zeta;

BBz-IL5 antigen binding domain CD19 scFv, hinge and transmembrane domain of CD8 α, costimulatory domain 4-1BB, IL7RA-F2, intracellular signaling domain CD3zeta, YRRHQ;

BBz-IL6 antigen binding domain CD19 scFv, hinge and transmembrane domain of CD8 α, costimulatory domain 4-1BB, IL7RA-F2, intracellular signaling domain CD3zeta, IL 21R-F;

BBz-IL7 antigen binding domain CD19 scFv, CD8 alpha hinge region, transmembrane domain and intracellular domain IL7RA-F3, costimulatory domain 4-1BB, intracellular signal transduction domain CD3 zeta;

BBz-IL8 antigen binding domain CD19 scFv, hinge and transmembrane domain of CD8 alpha, costimulatory domain 4-1BB, IL21R-F, intracellular signaling domain CD3 zeta;

BBz-IL9 antigen binding domain CD19 scFv, hinge and transmembrane domain of CD8 alpha, costimulatory domain 4-1BB, IL23R-F, intracellular signaling domain CD3 zeta;

BBz-IL10 antigen binding domain CD19 scFv, hinge and transmembrane domain of CD8 alpha, costimulatory domain 4-1BB, IL15RA-F, intracellular signaling domain CD3 zeta;

BBz-IL11 antigen binding domain CD19 scFv, hinge and transmembrane domain of CD8 α, costimulatory domain 4-1BB, IL7RA-F2, IL15RA-F, intracellular signaling domain CD3 zeta;

BBz-IL12 antigen binding domain CD19 scFv, hinge and transmembrane domains of CD8 alpha, costimulatory domain 4-1BB, IL9R-F, IL23R-F, intracellular signaling domain CD3 zeta.

28z antigen binding domain CD19 scFv, hinge region of CD8 alpha, transmembrane domain and costimulatory domain CD28 of CD28, intracellular signaling domain CD3 zeta;

28z-ILC antigen binding domain CD19 scFv, hinge region of CD8 α, transmembrane domain of CD28 and costimulatory domain CD28, IL2RB-F, intracellular signaling domain CD3zeta, YRRHQ;

28z-IL1 antigen binding domain CD19 scFv, hinge region of CD8 α, transmembrane domain and costimulatory domain of CD28 CD28, intracellular signaling domain CD3zeta, YRRHQ;

28z-IL2 antigen binding domain CD19 scFv, hinge region of CD8 α, transmembrane domain and costimulatory domain of CD28 CD28, IL7RA-F1, intracellular signaling domain CD3 zeta;

28z-IL3 antigen binding domain CD19 scFv, hinge region of CD8 α, transmembrane domain of CD28 and costimulatory domain CD28, IL7RA-F1, intracellular signaling domain CD3zeta, YRRHQ;

28z-IL4 antigen binding domain CD19 scFv, hinge region of CD8 α, transmembrane domain of CD28 and costimulatory domain CD28, IL7RA-F2, intracellular signaling domain CD3 zeta;

28z-IL5 antigen binding domain CD19 scFv, hinge region of CD8 α, transmembrane domain of CD28 and costimulatory domain CD28, IL7RA-F2, intracellular signaling domain CD3zeta, YRRHQ;

28z-IL6 antigen binding domain CD19 scFv, hinge region of CD8 α, transmembrane domain of CD28 and costimulatory domain CD28, IL7RA-F2, intracellular signaling domain CD3zeta, IL 21R-F;

28z-IL7 antigen binding domain CD19 scFv, hinge region of CD8 α, transmembrane and intracellular domains of IL7RA IL7RA-F3, co-stimulatory domain CD28, intracellular signaling domain CD3 zeta;

28z-IL8 antigen binding domain CD19 scFv, hinge region of CD8a, transmembrane domain and costimulatory domain CD28 of CD28, IL21R-F, intracellular signaling domain CD3 zeta.

As shown in fig. 1C, the remaining exemplary structures:

antigen binding domain scFv, hinge and transmembrane domain of CD8 α, ILR, costimulatory domain 4-1BB, intracellular signaling domain CD3zeta, YRRHQ;

antigen binding domain scFv, hinge and transmembrane domain of CD8 α, ILR, costimulatory domain 4-1BB, YRRHQ, intracellular signaling domain CD3 zeta;

antigen binding domain scFv, hinge and transmembrane domain of CD8 α, 4-1BB, ILR, YRRHQ, intracellular signaling domain CD3 zeta;

antigen binding domain scFv, hinge and transmembrane domain of CD8 α, 4-1BB, ILR-1 (first intracellular domain/first ILR), ILR-2 (second intracellular domain/second ILR), intracellular signaling domain CD3 zeta;

antigen binding domain scFv, hinge and transmembrane domain of CD8 α, ILR-1 (first intracellular domain/first ILR), 4-1BB, ILR-2 (second intracellular domain/second ILR), intracellular signaling domain CD3 zeta;

antigen binding domain scFv, hinge and transmembrane domain of CD8 α, ILR-1 (first intracellular domain/first ILR), ILR-2 (second intracellular domain/second ILR), 4-1BB, intracellular signaling domain CD3 zeta.

Example 2 preparation of lentivirus with recombinant vector

2.1 extraction of recombinant vectors

Coli was retransformed with the recombinant vectors pELPs-BBz, pELPs-28z, pELPs-BBz-ILC, pELPs-28z-ILC, pELPs-BBz-IL1 to 8 and pELPs-28z-IL1 to 8 constructed as described above. Picking the monoclonals from the transformed plate to a shaking tube of 3ml of liquid LB culture medium containing ampicillin, rotating the shaking tube at 220rpm, and shaking and culturing for 8 h; and (3) sucking 500 mu l of the activated bacterial liquid, inoculating the liquid into 250ml of liquid LB culture medium containing ampicillin, and carrying out shaking culture on a shaking table at 220rpm for 12-16 h. Recombinant vector extraction was performed using Qiagen high speed Plasmid Maxi Kit (cat # 12662) following the protocol provided in the Kit. After extracting the recombinant vector, the concentration of the recombinant vector is detected by using a nanodrop (thermo Fisher scientific) and the content of the recombinant vector is detected by DNA agarose gel.

2.2 culturing 293T cells

After the frozen 293T cells (ATCC) were removed from the liquid nitrogen, they were thawed by shaking in a 37 ℃ water bath. Transferring into 15ml centrifuge tube containing 10ml preheated DMEM complete culture medium, and gently blowing; centrifuging at 1000rpm for 3min, and sucking and removing supernatant; adding 10ml DMEM complete medium, gently blowing uniformly, inoculating into 10cm dish, and adding 5% CO at 37 deg.C₂Culturing in a cell culture box; when the cell density reaches 80% -90%, removing the culture medium, and washing with 10ml PBS for 1 time; adding 3ml trypsin containing 0.25% EDTA, placing in incubator for 1-2min (during which time it is necessary to take out and observe whether the cells become round under microscope); after the cells were rounded, 1ml of DMEM complete medium was added to stop the trypsinization, and the cells were transferred to a 15ml centrifugeThe tube was centrifuged at 1000rpm for 3min and the supernatant was discarded. Subculturing at a ratio of 1:3 or 1:5, inoculating into new 10cm dishes, or freezing according to experiment requirements.

2.3 transfection of 293T cells and harvesting of lentiviruses

2.3.1day 1, 293T cells were seeded

According to about 15-16X 10⁶Cells were seeded in T175 flasks (35-40ml medium).

2.3.2day 2, transfection: the medium before transfection was changed to medium with 10% FBS but no double antibody. First, a plasmid complex is prepared: the following plasmids were added to 1.5ml of Opti-MEM (Thermo Fisher Scientific; 31985-. Viral vector plasmid: 18 μ g of psPAX2 plasmid (Addgene; cat # 12260): 9 μ g, pMD2.G plasmid (Addgene; cat # 12259): 18 μ g. Preparing a transfection reagent complex: adding 100 μ l Lipofectamine 2000 (invitrogen; 11668-019) into 1.5ml Opti-MEM, mixing, and standing at room temperature for 5 min; then adding the plasmid compound into the transfection reagent compound, uniformly mixing, and standing for 25 min; finally, the transfection complex was added to the cell culture medium and shaken gently.

2.3.3 day 4 lentivirus was harvested

Collecting cell supernatant, centrifuging at 2000rpm for 10 min; filtering the supernatant with 0.45um filter membrane, transferring the filtrate into a special centrifuge tube, and balancing; performing ultracentrifugation for 2-3h by using an ultracentrifuge at 20000 rpm; after decanting the supernatant, the lentiviruses were resuspended in serum-free medium, aliquoted and stored at-80 ℃. According to this protocol, lentiviruses containing recombinant vectors pELPs-BBz, pELPs-28z, pELPs-BBz-ILC, pELPs-28z-ILC, pELPs-BBz-IL1 to 8 and pELPs-28z-IL1 to 8 were prepared, respectively.

Example 3 Lentiviral transfection of T cells

PMBCs from peripheral blood of healthy donors (purchased from Shanghai Miaoshun) were used. Diluting PBMCs to2X 10⁶. T cells were activated using CD3/CD28 magnetic beads (Thermo Fisher Scientific) at a cell to magnetic bead ratio of 1: 2. Onday 2 post-activation, the concentrated recombinant vectors harboring pELPs-BBz, pELPs-28z, pELPs-BBz-ILC, pELPs-28z-ILC, pELPs-BBz-IL1 to 8 and pELPs-28z-IL1 to 8The lentivirus of (a) is added into a T cell culture flask to transfect T cells. On day 4 after T cell activation, TRAC and B2M genes in T cells were knocked out using CRISPR/Cas9 to construct different UCART. The UCART cells obtained were U-BBz, U-28z, U-BBz-ILC, U-28z-ILC, U-BBz-IL1 to 8 and U-28z-IL1 to 8, respectively.

Example 4 fold detection of U-BBz-IL1, U-BBz-IL2, U-BBz-IL4, U-BBz-IL5 and U-28z-IL1, U-28z-IL2, U-28z-IL4, U-28z-IL5

4.1 detection of the fold proliferation of UCART expressing a structure comprising BBz-IL1, BBz-IL2, BBz-IL4, BBz-IL5

Raji cells ═ 1: 1, Raji cells were put in ondays 0 and 5, respectively, and cocultured with Raji cells, and the Raji cells and CAR + cells were counted ondays 0, 1, 3, 5, 6, and 8 after the addition of Raji cells, and an expansion line graph of CAR + cells was made. The tendency of the test groups U-BBz-IL1, U-BBz-IL2, U-BBz-IL4 and U-BBz-IL5 to expand was compared with the control groups U-BBz-ILC, BBz and U-BBz. As shown in FIG. 2, in the co-culture experiment in which Raji cells were added in multiple times, UCART (U-BBz-IL1, U-BBz-IL2, U-BBz-IL4, U-BBz-IL5) having BBz structure of IL1, IL2, IL4, IL5 showed stronger amplification ability than UCART (U-BBz) having only 4-1BB co-stimulatory domain.

4.2 detection of fold proliferation of UCART expressing a structure comprising BBz-IL3

The experimental procedure is as in example 4.1. The amplification tendency of the test group U-BBz-IL3 and U-BBz-IL4 was compared with that of the control group BBz. As shown in FIG. 3, in the co-culture experiment of multiple Raji cells, the amplification capacity of UCART (U-BBz-IL3, U-BBz-IL4) with BBz structure of IL3 and IL4 was close to that of CART (BBz) which was not modified by gene knockout.

4.3 detection of fold proliferation of UCART expressing a structure comprising 28z-IL1, 28z-IL2, 28z-IL4, 28z-IL5

Raji cells ═ 1: 1, Raji cells were added ondays 0 and 5, respectively, and cocultured with Raji cells, and Raji cells and CAR + cells were counted ondays 0, 1, 3, 5, and 6 after addition of Raji cells, and a CAR + cell expansion line graph was prepared. The amplification trends of the test groups U-28z-IL1, U-28z-IL2, U-28z-IL4 and U-28z-IL5 were compared with those of the control groups U-28z-ILC, 28z and U-28 z. As shown in FIG. 4, in the co-culture experiment in which Raji cells were added in multiple portions, U-28z-IL1, U-28z-IL2, U-28z-IL4, and U-28z-IL5 showed stronger amplification than UCART (U-28z) having only CD28 costimulatory domain.

4.4 detection of fold proliferation of UCART expressing a construct comprising 28z-IL3

Raji cells ═ 1: 1, Raji cells were added ondays 0 and 5, respectively, and cocultured with Raji cells, and Raji cells and CAR + cells were counted ondays 0, 3, 5, 8, and 10 after addition of Raji cells, and a CAR + cell expansion line graph was prepared. Comparing the test group U-28z-IL3 and U-28z-IL4 with the control group U-28z-ILC, as shown in FIG. 5, U-28z-IL3 and U-28z-IL4 showed better amplification ability than U-28z-ILC in the co-culture experiment with multiple Raji additions.

Example 5 examination of the ability of UCART to secrete the cytokine IFN γ

5.1 testing the ability of UCART containing BBz Structure to secrete cytokine IFN gamma

Raji cells ═ 1: 1, respectively throwing Raji cells on the 0 th day and the 5 th day, co-culturing with the Raji cells, and collecting supernatant 24 hours after the second throwing of the Raji cells on the 5 th day to carry out ELISA detection on the content of IFN gamma in the supernatant. Test groups U-BBz-IL6, U-BBz-IL7, U-BBz-IL8 were compared with control groups U-BBz-ILC, BBz and U-BBz, and T cells (NT) which had not been subjected to any treatment served as negative control groups. As shown in FIG. 6, U-BBz-IL6, U-BBz-IL7 and U-BBz-IL8 showed better ability to secrete the cytokine IFN gamma in Raji killing experiments.

5.2 testing the Capacity of UCART containing 28z Structure to secrete cytokine IFN gamma

Raji cells ═ 1: 1, respectively throwing Raji cells on the 0 th day and the 5 th day, co-culturing with the Raji cells, and collecting supernatant 24 hours after the first throwing of the Raji cells on the 0 th day to carry out ELISA detection on the content of IFN gamma in the supernatant. The test groups U-28z-IL6, U-28z-IL7, U-28z-IL8 were compared with the control groups U-28z-ILC, 28z and U-28z, and T cells (NT) which had not been subjected to any treatment served as negative control groups. As shown in FIG. 7, U-28z-IL6, U-28z-IL7, U-28z-IL8 showed better ability to secrete the cytokine IFN γ in Raji killing experiments.

Example 6 examination of the amplification Capacity of UCART expressing BBz-IL9, BBz-IL10, BBz-IL11, BBz-IL12

The experimental procedure is as in example 4.1. Raji cells ═ 1: 1, Raji cells were put in ondays 0 and 5, respectively, and cocultured with Raji cells, and the Raji cells and CAR + cells were counted ondays 0, 1, 3, 5, 6, and 8 after the addition of Raji cells, and an expansion line graph of CAR + cells was made. The tendency of the test groups U-BBz-IL9, U-BBz-IL10, U-BBz-IL11 and U-BBz-IL12 to expand was compared with the control groups U-BBz-ILC, BBz and U-BBz.

Example 7 examination of the amplification Capacity of UCART expressing CAR-BCMA-BBz-IL5

An BBz-IL5 construct was constructed that recognized BCMA extracellularly, and the corresponding lentiviruses were packaged as in examples 2-3, and transfected into T cells. The cells were cultured as CAR + cells K562-BCMA cells ═ 1: 1, K562-BCMA cells were dosed onday 0 andday 5, respectively, and K562-BCMA cells and CAR + cells were counted ondays 0, 1, 3, 5, 6 after K562-BCMA cells were added, and a CAR + cell expansion line graph was made.

Example 8 examination of the amplification Capacity of UCART expressing BBz-IL1, BBz-IL4, BBz-IL5 in a mouse model

Immunodeficient mice were tumor-bearing with a cell line expressing CD19, as in table 1, and divided into 7 groups of 5 mice each. Corresponding T cells are respectively input into each group of mice, and the survival condition, the tumor size and the T cell amplification condition in the mice are observed. In group U-BBz, mice survived much less than in group BBz. Compared with the U-BBz group, the U-BBz-IL1, the U-BBz-IL4 and the U-BBz-IL5 groups can obviously prolong the survival time of mice and better expand T cells.

TABLE 1 mouse grouping Table

Grouping	Transfused T cell species	Number of mice (only)
			1	NA(PBS)	5
2	NT	5
			3	BBz	5
4	U-BBz	5
			5	U-BBz-IL1	5
6	U-BBz-IL4	5
			7	U-BBz-IL5	5

Sequence listing

<110> Suzhou croi gene biotechnology limited

<120> a novel chimeric antigen receptor

<130> 0141-PA-026

<160> 63

<170> PatentIn version 3.5

<210> 1

<211> 1458

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz nucleic acid sequence

<400> 1

atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60

ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120

accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180

ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240

tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300

caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360

ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420

ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480

ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540

cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600

tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660

gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720

cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780

gtatcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840

cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900

agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960

gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020

tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080

agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1140

agcgcagacg cccccgcgta caagcagggc cagaaccagc tctataacga gctcaatcta 1200

ggacgaagag aggagtacga tgttttggac aagaggcgtg gccgggaccc tgagatgggg 1260

ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1320

atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1380

gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1440

caggccctgc cccctcgc 1458

<210> 2

<211> 1467

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z nucleic acid sequence

<400> 2

atggctctgc ctgtgaccgc cctgctgctg cctctggctc tgctgctgca cgccgctcgg 60

cctgacattc agatgactca gaccacaagc agcctcagtg cgagcctggg ggacagggtg 120

actatcagct gccgggccag ccaggacatt tccaagtacc tgaattggta ccagcagaag 180

cccgatggta ctgtgaaact cctgatatat catacttcta ggctccattc cggggttcca 240

agccgattca gtggctccgg ttccggtaca gattattccc tgaccattag caacttggaa 300

caggaggaca ttgcaacgta tttctgtcag caaggcaaca cattgcccta cacattcggg 360

ggcgggacta aactcgaaat aactggcggc gggggttctg gtggcggcgg cagcggcggt 420

ggaggatcag aagtgaagct gcaggaaagt ggccccgggc tggtagcccc aagtcagtcc 480

ctgagtgtaa cctgtacagt gagtggagtg tctcttcctg actacggggt aagttggatt 540

cggcaacctc cacgcaaggg cctggagtgg ctcggcgtga tttggggatc tgagacaact 600

tactacaatt ccgccctgaa gagcaggctg accatcatta aggacaatag caagtcacag 660

gtgtttctga agatgaactc actgcagacc gacgacaccg ccatctatta ctgcgccaaa 720

cattattatt atggcgggag ttatgctatg gactactggg gccagggcac tagcgtcacc 780

gtcagcagta ctacaactcc agcacccaga ccccctacac ctgctccaac tatcgcaagt 840

cagcccctgt cactgcgccc tgaagcctgt cgccctgctg ccgggggagc tgtgcatact 900

cggggactgg actttgcctg tgatatctac ttctgggtgc tggtcgtggt cggaggggtg 960

ctggcctgtt atagcctgct ggtgactgtc gccttcatta tcttctgggt gcggagcaag 1020

aggtctcgcg gtgggcattc cgactacatg aacatgaccc ctagaaggcc tggcccaacc 1080

agaaagcact accagccata cgcccctccc agagatttcg ccgcttatcg aagcgtgaag 1140

ttctcccgaa gcgcagatgc cccagcctat cagcagggac agaatcagct gtacaacgag 1200

ctgaacctgg gaagacggga ggaatacgat gtgctggaca aaaggcgggg cagagatcct 1260

gagatgggcg gcaaaccaag acggaagaac ccccaggaag gtctgtataa tgagctgcag 1320

aaagacaaga tggctgaggc ctactcagaa atcgggatga agggcgaaag aaggagagga 1380

aaaggccacg acggactgta ccaggggctg agtacagcaa caaaagacac ctatgacgct 1440

ctgcacatgc aggctctgcc accaaga 1467

<210> 3

<211> 486

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz amino acid sequence

<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 Lys 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 Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

465 470 475 480

Gln Ala Leu Pro Pro Arg

485

<210> 4

<211> 489

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z amino acid sequence

<400> 4

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 Phe Trp Val Leu Val Val Val Gly Gly Val

305 310 315 320

Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp

325 330 335

Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met

340 345 350

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

355 360 365

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser 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 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

485

<210> 5

<211> 8247

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> nucleic acid sequence of lentiviral vector pELPs

<400> 5

gcgcgctcac tggccgtcgt tttacaacgt cgtgactggg aaaaccctgg cgttacccaa 60

cttaatcgcc ttgcagcaca tccccctttc gccagctggc gtaatagcga agaggcccgc 120

accgatcgcc cttcccaaca gttgcgcagc ctgaatggcg aatgggacgc gccctgtagc 180

ggcgcattaa gcgcggcggg tgtggtggtt acgcgcagcg tgaccgctac acttgccagc 240

gccctagcgc ccgctccttt cgctttcttc ccttcctttc tcgccacgtt cgccggcttt 300

ccccgtcaag ctctaaatcg ggggctccct ttagggttcc gatttagtgc tttacggcac 360

ctcgacccca aaaaacttga ttagggtgat ggttcacgta gtgggccatc gccctgatag 420

acggtttttc gccctttgac gttggagtcc acgttcttta atagtggact cttgttccaa 480

actggaacaa cactcaaccc tatctcggtc tattcttttg atttataagg gattttgccg 540

atttcggcct attggttaaa aaatgagctg atttaacaaa aatttaacgc gaattttaac 600

aaaatattaa cgcttacaat ttaggtggca cttttcgggg aaatgtgcgc ggaaccccta 660

tttgtttatt tttctaaata cattcaaata tgtatccgct catgagacaa taaccctgat 720

aaatgcttca ataatattga aaaaggaaga gtatgagtat tcaacatttc cgtgtcgccc 780

ttattccctt ttttgcggca ttttgccttc ctgtttttgc tcacccagaa acgctggtga 840

aagtaaaaga tgctgaagat cagttgggtg cacgagtggg ttacatcgaa ctggatctca 900

acagcggtaa gatccttgag agttttcgcc ccgaagaacg ttttccaatg atgagcactt 960

ttaaagttct gctatgtggc gcggtattat cccgtattga cgccgggcaa gagcaactcg 1020

gtcgccgcat acactattct cagaatgact tggttgagta ctcaccagtc acagaaaagc 1080

atcttacgga tggcatgaca gtaagagaat tatgcagtgc tgccataacc atgagtgata 1140

acactgcggc caacttactt ctgacaacga tcggaggacc gaaggagcta accgcttttt 1200

tgcacaacat gggggatcat gtaactcgcc ttgatcgttg ggaaccggag ctgaatgaag 1260

ccataccaaa cgacgagcgt gacaccacga tgcctgtagc aatggcaaca acgttgcgca 1320

aactattaac tggcgaacta cttactctag cttcccggca acaattaata gactggatgg 1380

aggcggataa agttgcagga ccacttctgc gctcggccct tccggctggc tggtttattg 1440

ctgataaatc tggagccggt gagcgtgggt ctcgcggtat cattgcagca ctggggccag 1500

atggtaagcc ctcccgtatc gtagttatct acacgacggg gagtcaggca actatggatg 1560

aacgaaatag acagatcgct gagataggtg cctcactgat taagcattgg taactgtcag 1620

accaagttta ctcatatata ctttagattg atttaaaact tcatttttaa tttaaaagga 1680

tctaggtgaa gatccttttt gataatctca tgaccaaaat cccttaacgt gagttttcgt 1740

tccactgagc gtcagacccc gtagaaaaga tcaaaggatc ttcttgagat cctttttttc 1800

tgcgcgtaat ctgctgcttg caaacaaaaa aaccaccgct accagcggtg gtttgtttgc 1860

cggatcaaga gctaccaact ctttttccga aggtaactgg cttcagcaga gcgcagatac 1920

caaatactgt tcttctagtg tagccgtagt taggccacca cttcaagaac tctgtagcac 1980

cgcctacata cctcgctctg ctaatcctgt taccagtggc tgctgccagt ggcgataagt 2040

cgtgtcttac cgggttggac tcaagacgat agttaccgga taaggcgcag cggtcgggct 2100

gaacgggggg ttcgtgcaca cagcccagct tggagcgaac gacctacacc gaactgagat 2160

acctacagcg tgagctatga gaaagcgcca cgcttcccga agggagaaag gcggacaggt 2220

atccggtaag cggcagggtc ggaacaggag agcgcacgag ggagcttcca gggggaaacg 2280

cctggtatct ttatagtcct gtcgggtttc gccacctctg acttgagcgt cgatttttgt 2340

gatgctcgtc aggggggcgg agcctatgga aaaacgccag caacgcggcc tttttacggt 2400

tcctggcctt ttgctggcct tttgctcaca tgttctttcc tgcgttatcc cctgattctg 2460

tggataaccg tattaccgcc tttgagtgag ctgataccgc tcgccgcagc cgaacgaccg 2520

agcgcagcga gtcagtgagc gaggaagcgg aagagcgccc aatacgcaaa ccgcctctcc 2580

ccgcgcgttg gccgattcat taatgcagct ggcacgacag gtttcccgac tggaaagcgg 2640

gcagtgagcg caacgcaatt aatgtgagtt agctcactca ttaggcaccc caggctttac 2700

actttatgct tccggctcgt atgttgtgtg gaattgtgag cggataacaa tttcacacag 2760

gaaacagcta tgaccatgat tacgccaagc gcgcaattaa ccctcactaa agggaacaaa 2820

agctggagct gcaagcttaa tgtagtctta tgcaatactc ttgtagtctt gcaacatggt 2880

aacgatgagt tagcaacatg ccttacaagg agagaaaaag caccgtgcat gccgattggt 2940

ggaagtaagg tggtacgatc gtgccttatt aggaaggcaa cagacgggtc tgacatggat 3000

tggacgaacc actgaattgc cgcattgcag agatattgta tttaagtgcc tagctcgata 3060

cataaacggg tctctctggt tagaccagat ctgagcctgg gagctctctg gctaactagg 3120

gaacccactg cttaagcctc aataaagctt gccttgagtg cttcaagtag tgtgtgcccg 3180

tctgttgtgt gactctggta actagagatc cctcagaccc ttttagtcag tgtggaaaat 3240

ctctagcagt ggcgcccgaa cagggacttg aaagcgaaag ggaaaccaga ggagctctct 3300

cgacgcagga ctcggcttgc tgaagcgcgc acggcaagag gcgaggggcg gcgactggtg 3360

agtacgccaa aaattttgac tagcggaggc tagaaggaga gagatgggtg cgagagcgtc 3420

agtattaagc gggggagaat tagatcgcga tgggaaaaaa ttcggttaag gccaggggga 3480

aagaaaaaat ataaattaaa acatatagta tgggcaagca gggagctaga acgattcgca 3540

gttaatcctg gcctgttaga aacatcagaa ggctgtagac aaatactggg acagctacaa 3600

ccatcccttc agacaggatc agaagaactt agatcattat ataatacagt agcaaccctc 3660

tattgtgtgc atcaaaggat agagataaaa gacaccaagg aagctttaga caagatagag 3720

gaagagcaaa acaaaagtaa gaccaccgca cagcaagcgg ccgctgatct tcagacctgg 3780

aggaggagat atgagggaca attggagaag tgaattatat aaatataaag tagtaaaaat 3840

tgaaccatta ggagtagcac ccaccaaggc aaagagaaga gtggtgcaga gagaaaaaag 3900

agcagtggga ataggagctt tgttccttgg gttcttggga gcagcaggaa gcactatggg 3960

cgcagcgtca atgacgctga cggtacaggc cagacaatta ttgtctggta tagtgcagca 4020

gcagaacaat ttgctgaggg ctattgaggc gcaacagcat ctgttgcaac tcacagtctg 4080

gggcatcaag cagctccagg caagaatcct ggctgtggaa agatacctaa aggatcaaca 4140

gctcctgggg atttggggtt gctctggaaa actcatttgc accactgctg tgccttggaa 4200

tgctagttgg agtaataaat ctctggaaca gatttggaat cacacgacct ggatggagtg 4260

ggacagagaa attaacaatt acacaagctt aatacactcc ttaattgaag aatcgcaaaa 4320

ccagcaagaa aagaatgaac aagaattatt ggaattagat aaatgggcaa gtttgtggaa 4380

ttggtttaac ataacaaatt ggctgtggta tataaaatta ttcataatga tagtaggagg 4440

cttggtaggt ttaagaatag tttttgctgt actttctata gtgaatagag ttaggcaggg 4500

atattcacca ttatcgtttc agacccacct cccaaccccg aggggacccg acaggcccga 4560

aggaatagaa gaagaaggtg gagagagaga cagagacaga tccattcgat tagtgaacgg 4620

atctcgacgg tatcgattag actgtagccc aggaatatgg cagctagatt gtacacattt 4680

agaaggaaaa gttatcttgg tagcagttca tgtagccagt ggatatatag aagcagaagt 4740

aattccagca gagacagggc aagaaacagc atacttcctc ttaaaattag caggaagatg 4800

gccagtaaaa acagtacata cagacaatgg cagcaatttc accagtacta cagttaaggc 4860

cgcctgttgg tgggcgggga tcaagcagga atttggcatt ccctacaatc cccaaagtca 4920

aggagtaata gaatctatga ataaagaatt aaagaaaatt ataggacagg taagagatca 4980

ggctgaacat cttaagacag cagtacaaat ggcagtattc atccacaatt ttaaaagaaa 5040

aggggggatt ggggggtaca gtgcagggga aagaatagta gacataatag caacagacat 5100

acaaactaaa gaattacaaa aacaaattac aaaaattcaa aattttcggg tttattacag 5160

ggacagcaga gatccagttt ggctgcattg atcacgtgag gctccggtgc ccgtcagtgg 5220

gcagagcgca catcgcccac agtccccgag aagttggggg gaggggtcgg caattgaacc 5280

ggtgcctaga gaaggtggcg cggggtaaac tgggaaagtg atgtcgtgta ctggctccgc 5340

ctttttcccg agggtggggg agaaccgtat ataagtgcag tagtcgccgt gaacgttctt 5400

tttcgcaacg ggtttgccgc cagaacacag gtaagtgccg tgtgtggttc ccgcgggcct 5460

ggcctcttta cgggttatgg cccttgcgtg ccttgaatta cttccacctg gctgcagtac 5520

gtgattcttg atcccgagct tcgggttgga agtgggtggg agagttcgag gccttgcgct 5580

taaggagccc cttcgcctcg tgcttgagtt gaggcctggc ctgggcgctg gggccgccgc 5640

gtgcgaatct ggtggcacct tcgcgcctgt ctcgctgctt tcgataagtc tctagccatt 5700

taaaattttt gatgacctgc tgcgacgctt tttttctggc aagatagtct tgtaaatgcg 5760

ggccaagatc tgcacactgg tatttcggtt tttggggccg cgggcggcga cggggcccgt 5820

gcgtcccagc gcacatgttc ggcgaggcgg ggcctgcgag cgcggccacc gagaatcgga 5880

cgggggtagt ctcaagctgg ccggcctgct ctggtgcctg gcctcgcgcc gccgtgtatc 5940

gccccgccct gggcggcaag gctggcccgg tcggcaccag ttgcgtgagc ggaaagatgg 6000

ccgcttcccg gccctgctgc agggagctca aaatggagga cgcggcgctc gggagagcgg 6060

gcgggtgagt cacccacaca aaggaaaagg gcctttccgt cctcagccgt cgcttcatgt 6120

gactccactg agtaccgggc gccgtccagg cacctcgatt agttctcgag cttttggagt 6180

acgtcgtctt taggttgggg ggaggggttt tatgcgatgg agtttcccca cactgagtgg 6240

gtggagactg aagttaggcc agcttggcac ttgatgtaat tctccttgga atttgccctt 6300

tttgagtttg gatcttggtt cattctcaag cctcagacag tggttcaaag tttttttctt 6360

ccatttcagg tgtcgtgatc tagaggatcc ggagccacga acttctctct gttaaagcaa 6420

gcaggagatg tggaagaaaa ccccggtcct atgggcacaa gcctgctgtg ttggatggcc 6480

ctgtgtctgc tgggagccga tcatgctgat gcctgtcctt acagcaaccc cagcctgtgt 6540

tctggcggcg gaggatctga actgcctaca cagggcacct tcagcaacgt gtccaccaat 6600

gtgtccccag ccaagcctac caccaccgct tgtccctact ccaatcctag cctgtgtagc 6660

ggaggtggcg gaagccctgc tcctagacct cctacaccag ctcctacaat cgccagccag 6720

cctctgtctc tgaggccaga agcttgtaga cctgctgctg gcggagccgt gcatacaaga 6780

ggactggatt tcgcctgcga catctacatc tgggcccctc tggctggaac atgtggcgtt 6840

ctgctgctga gcctggtcat caccctgtac tgcaaccacc ggaacaggcg gagagtgtgc 6900

aagtgcccta gacctgtggt gtaagtcgac aatcaacctc tggattacaa aatttgtgaa 6960

agattgactg gtattcttaa ctatgttgct ccttttacgc tatgtggata cgctgcttta 7020

atgcctttgt atcatgctat tgcttcccgt atggctttca ttttctcctc cttgtataaa 7080

tcctggttgc tgtctcttta tgaggagttg tggcccgttg tcaggcaacg tggcgtggtg 7140

tgcactgtgt ttgctgacgc aacccccact ggttggggca ttgccaccac ctgtcagctc 7200

ctttccggga ctttcgcttt ccccctccct attgccacgg cggaactcat cgccgcctgc 7260

cttgcccgct gctggacagg ggctcggctg ttgggcactg acaattccgt ggtgttgtcg 7320

gggaagctga cgtcctttcc atggctgctc gcctgtgttg ccacctggat tctgcgcggg 7380

acgtccttct gctacgtccc ttcggccctc aatccagcgg accttccttc ccgcggcctg 7440

ctgccggctc tgcggcctct tccgcgtctt cgccttcgcc ctcagacgag tcggatctcc 7500

ctttgggccg cctccccgcc tggaattcga gctcggtacc tttaagacca atgacttaca 7560

aggcagctgt agatcttagc cactttttaa aagaaaaggg gggactggaa gggctaattc 7620

actcccaacg aagacaagat ctgctttttg cttgtactgg gtctctctgg ttagaccaga 7680

tctgagcctg ggagctctct ggctaactag ggaacccact gcttaagcct caataaagct 7740

tgccttgagt gcttcaagta gtgtgtgccc gtctgttgtg tgactctggt aactagagat 7800

ccctcagacc cttttagtca gtgtggaaaa tctctagcag tagtagttca tgtcatctta 7860

ttattcagta tttataactt gcaaagaaat gaatatcaga gagtgagagg aacttgttta 7920

ttgcagctta taatggttac aaataaagca atagcatcac aaatttcaca aataaagcat 7980

ttttttcact gcattctagt tgtggtttgt ccaaactcat caatgtatct tatcatgtct 8040

ggctctagct atcccgcccc taactccgcc catcccgccc ctaactccgc ccagttccgc 8100

ccattctccg ccccatggct gactaatttt ttttatttat gcagaggccg aggccgcctc 8160

ggcctctgag ctattccaga agtagtgagg aggctttttt ggaggcctag ggacgtaccc 8220

aattcgccct atagtgagtc gtattac 8247

<210> 6

<211> 282

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> IL2RB-F nucleic acid sequence

<400> 6

aactgcagga acaccgggcc atggctgaag aaggtcctga agtgtaacac cccagacccc 60

tcgaagttct tttcccagct gagctcagag catggaggag atgtccagaa gtggctctct 120

tcgcccttcc cctcatcgtc cttcagccct ggcggcctgg cacctgagat ctcgccacta 180

gaagtgctgg agagggacaa ggtgacgcag ctgctgcccc tgaacactga tgcctacttg 240

tccctccaag aactccaggg tcaggaccca actcacttgg tg 282

<210> 7

<211> 94

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of IL2RB-F

<400> 7

Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys Lys Val Leu Lys Cys Asn

1 5 10 15

Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser Ser Glu His Gly

20 25 30

Gly Asp Val Gln Lys Trp Leu Ser Ser Pro Phe Pro Ser Ser Ser Phe

35 40 45

Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu Glu Val Leu Glu

50 55 60

Arg Asp Lys Val Thr Gln Leu Leu Pro Leu Asn Thr Asp Ala Tyr Leu

65 70 75 80

Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro Thr His Leu Val

85 90

<210> 8

<211> 585

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> IL7RA-F1 nucleic acid sequence

<400> 8

aaaaaaagga ttaagcctat cgtatggccc agtctccccg atcataagaa gactctggaa 60

catctttgta agaaaccaag aaaaaattta aatgtgagtt tcaatcctga aagtttcctg 120

gactgccaga ttcatagggt ggatgacatt caagctagag atgaagtgga aggttttctg 180

caagatacgt ttcctcagca actagaagaa tctgagaagc agaggcttgg aggggatgtg 240

cagagcccca actgcccatc tgaggatgta gtcatcactc cagaaagctt tggaagagat 300

tcatccctca catgcctggc tgggaatgtc agtgcatgtg acgcccctat tctctcctct 360

tccaggtccc tagactgcag ggagagtggc aagaatgggc ctcatgtgta ccaggacctc 420

ctgcttagcc ttgggactac aaacagcacg ctgccccctc cattttctct ccaatctgga 480

atcctgacat tgaacccagt tgctcagggt cagcccattc ttacttccct gggatcaaat 540

caagaagaag catatgtcac catgtccagc ttctaccaaa accag 585

<210> 9

<211> 195

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> IL7RA-F1 amino acid sequence

<400> 9

Lys Lys Arg Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp His Lys

1 5 10 15

Lys Thr Leu Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu Asn Val

20 25 30

Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys Gln Ile His Arg Val Asp

35 40 45

Asp Ile Gln Ala Arg Asp Glu Val Glu Gly Phe Leu Gln Asp Thr Phe

50 55 60

Pro Gln Gln Leu Glu Glu Ser Glu Lys Gln Arg Leu Gly Gly Asp Val

65 70 75 80

Gln Ser Pro Asn Cys Pro Ser Glu Asp Val Val Ile Thr Pro Glu Ser

85 90 95

Phe Gly Arg Asp Ser Ser Leu Thr Cys Leu Ala Gly Asn Val Ser Ala

100 105 110

Cys Asp Ala Pro Ile Leu Ser Ser Ser Arg Ser Leu Asp Cys Arg Glu

115 120 125

Ser Gly Lys Asn Gly Pro His Val Tyr Gln Asp Leu Leu Leu Ser Leu

130 135 140

Gly Thr Thr Asn Ser Thr Leu Pro Pro Pro Phe Ser Leu Gln Ser Gly

145 150 155 160

Ile Leu Thr Leu Asn Pro Val Ala Gln Gly Gln Pro Ile Leu Thr Ser

165 170 175

Leu Gly Ser Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr

180 185 190

Gln Asn Gln

195

<210> 10

<211> 165

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> IL7RA-F2 nucleic acid sequence

<400> 10

aaaaaaagga ttaagcctat cgtatggccc agtctccccg atcataagaa gactctggaa 60

catctttgta agaaaccaag aaaaaattta aatgtgagtc ttacttccct gggatcaaat 120

caagaagaag catatgtcac catgtccagc ttctaccaaa accag 165

<210> 11

<211> 55

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> IL7RA-F2 amino acid sequence

<400> 11

Lys Lys Arg Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp His Lys

1 5 10 15

Lys Thr Leu Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu Asn Val

20 25 30

Ser Leu Thr Ser Leu Gly Ser Asn Gln Glu Glu Ala Tyr Val Thr Met

35 40 45

Ser Ser Phe Tyr Gln Asn Gln

50 55

<210> 12

<211> 669

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> IL7RA-F3 nucleic acid sequence

<400> 12

cctatcttac taacttgtcc caccatcagc attttgagtt ttttctctgt cgctctgttg 60

gtcatcttgg cctgtgtgtt atggaaaaaa aggattaagc ctatcgtatg gcccagtctc 120

cccgatcata agaagactct ggaacatctt tgtaagaaac caagaaaaaa tttaaatgtg 180

agtttcaatc ctgaaagttt cctggactgc cagattcata gggtggatga cattcaagct 240

agagatgaag tggaaggttt tctgcaagat acgtttcctc agcaactaga agaatctgag 300

aagcagaggc ttggagggga tgtgcagagc cccaactgcc catctgagga tgtagtcatc 360

actccagaaa gctttggaag agattcatcc ctcacatgcc tggctgggaa tgtcagtgca 420

tgtgacgccc ctattctctc ctcttccagg tccctagact gcagggagag tggcaagaat 480

gggcctcatg tgtaccagga cctcctgctt agccttggga ctacaaacag cacgctgccc 540

cctccatttt ctctccaatc tggaatcctg acattgaacc cagttgctca gggtcagccc 600

attcttactt ccctgggatc aaatcaagaa gaagcatatg tcaccatgtc cagcttctac 660

caaaaccag 669

<210> 13

<211> 223

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> IL7RA-F3 amino acid sequence

<400> 13

Pro Ile Leu Leu Thr Cys Pro Thr Ile Ser Ile Leu Ser Phe Phe Ser

1 5 10 15

Val Ala Leu Leu Val Ile Leu Ala Cys Val Leu Trp Lys Lys Arg Ile

20 25 30

Lys Pro Ile Val Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu Glu

35 40 45

His Leu Cys Lys Lys Pro Arg Lys Asn Leu Asn Val Ser Phe Asn Pro

50 55 60

Glu Ser Phe Leu Asp Cys Gln Ile His Arg Val Asp Asp Ile Gln Ala

65 70 75 80

Arg Asp Glu Val Glu Gly Phe Leu Gln Asp Thr Phe Pro Gln Gln Leu

85 90 95

Glu Glu Ser Glu Lys Gln Arg Leu Gly Gly Asp Val Gln Ser Pro Asn

100 105 110

Cys Pro Ser Glu Asp Val Val Ile Thr Pro Glu Ser Phe Gly Arg Asp

115 120 125

Ser Ser Leu Thr Cys Leu Ala Gly Asn Val Ser Ala Cys Asp Ala Pro

130 135 140

Ile Leu Ser Ser Ser Arg Ser Leu Asp Cys Arg Glu Ser Gly Lys Asn

145 150 155 160

Gly Pro His Val Tyr Gln Asp Leu Leu Leu Ser Leu Gly Thr Thr Asn

165 170 175

Ser Thr Leu Pro Pro Pro Phe Ser Leu Gln Ser Gly Ile Leu Thr Leu

180 185 190

Asn Pro Val Ala Gln Gly Gln Pro Ile Leu Thr Ser Leu Gly Ser Asn

195 200 205

Gln Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn Gln

210 215 220

<210> 14

<211> 405

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> IL21R-F nucleic acid sequence

<400> 14

agcctgaaga cccatccatt gtggaggcta tggaagaaga tatgggccgt ccccagccct 60

gagcggttct tcatgcccct gtacaagggc tgcagcggag acttcaagaa atgggtgggt 120

gcacccttca ctggctccag cctggagctg ggaccctgga gcccagaggt gccctccacc 180

ctggaggtgt acagctgcca cccaccacgg agcccggcca agaggctgca gctcacggag 240

ctacaagaac cagcagagct ggtggagtct gacggtgtgc ccaagcccag cagccctgtg 300

gagtgtgact tcaccagccc cggggacgaa ggaccccccc ggagctacct ccgccagtgg 360

gtggtcattc ctccgccact ttcgagccct ggaccccagg ccagc 405

<210> 15

<211> 135

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of IL21R-F

<400> 15

Ser Leu Lys Thr His Pro Leu Trp Arg Leu Trp Lys Lys Ile Trp Ala

1 5 10 15

Val Pro Ser Pro Glu Arg Phe Phe Met Pro Leu Tyr Lys Gly Cys Ser

20 25 30

Gly Asp Phe Lys Lys Trp Val Gly Ala Pro Phe Thr Gly Ser Ser Leu

35 40 45

Glu Leu Gly Pro Trp Ser Pro Glu Val Pro Ser Thr Leu Glu Val Tyr

50 55 60

Ser Cys His Pro Pro Arg Ser Pro Ala Lys Arg Leu Gln Leu Thr Glu

65 70 75 80

Leu Gln Glu Pro Ala Glu Leu Val Glu Ser Asp Gly Val Pro Lys Pro

85 90 95

Ser Ser Pro Val Glu Cys Asp Phe Thr Ser Pro Gly Asp Glu Gly Pro

100 105 110

Pro Arg Ser Tyr Leu Arg Gln Trp Val Val Ile Pro Pro Pro Leu Ser

115 120 125

Ser Pro Gly Pro Gln Ala Ser

130 135

<210> 16

<211> 580

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-ILC amino acid sequence

<400> 16

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 Asn Cys Arg Asn Thr Gly Pro Trp Leu Lys

370 375 380

Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe Phe Ser Gln

385 390 395 400

Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu Ser Ser Pro

405 410 415

Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro Glu Ile Ser

420 425 430

Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu Leu Pro Leu

435 440 445

Asn Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly Gln Asp Pro

450 455 460

Thr His Leu Val Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

465 470 475 480

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

485 490 495

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

500 505 510

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

515 520 525

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

530 535 540

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

545 550 555 560

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His Gln Ala

565 570 575

Leu Pro Pro Arg

580

<210> 17

<211> 486

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-amino acid sequence of IL1

<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 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 Lys 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 Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His

465 470 475 480

Gln Ala Leu Pro Pro Arg

485

<210> 18

<211> 681

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-amino acid sequence of IL2

<400> 18

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 Lys Lys Arg Ile Lys Pro Ile Val Trp Pro

370 375 380

Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro

385 390 395 400

Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys

405 410 415

Gln Ile His Arg Val Asp Asp Ile Gln Ala Arg Asp Glu Val Glu Gly

420 425 430

Phe Leu Gln Asp Thr Phe Pro Gln Gln Leu Glu Glu Ser Glu Lys Gln

435 440 445

Arg Leu Gly Gly Asp Val Gln Ser Pro Asn Cys Pro Ser Glu Asp Val

450 455 460

Val Ile Thr Pro Glu Ser Phe Gly Arg Asp Ser Ser Leu Thr Cys Leu

465 470 475 480

Ala Gly Asn Val Ser Ala Cys Asp Ala Pro Ile Leu Ser Ser Ser Arg

485 490 495

Ser Leu Asp Cys Arg Glu Ser Gly Lys Asn Gly Pro His Val Tyr Gln

500 505 510

Asp Leu Leu Leu Ser Leu Gly Thr Thr Asn Ser Thr Leu Pro Pro Pro

515 520 525

Phe Ser Leu Gln Ser Gly Ile Leu Thr Leu Asn Pro Val Ala Gln Gly

530 535 540

Gln Pro Ile Leu Thr Ser Leu Gly Ser Asn Gln Glu Glu Ala Tyr Val

545 550 555 560

Thr Met Ser Ser Phe Tyr Gln Asn Gln Arg Val Lys Phe Ser Arg Ser

565 570 575

Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu

580 585 590

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

595 600 605

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

610 615 620

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

625 630 635 640

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

645 650 655

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

660 665 670

Leu His Met Gln Ala Leu Pro Pro Arg

675 680

<210> 19

<211> 681

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-amino acid sequence of IL3

<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 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 Lys Lys Arg Ile Lys Pro Ile Val Trp Pro

370 375 380

Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro

385 390 395 400

Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys

405 410 415

Gln Ile His Arg Val Asp Asp Ile Gln Ala Arg Asp Glu Val Glu Gly

420 425 430

Phe Leu Gln Asp Thr Phe Pro Gln Gln Leu Glu Glu Ser Glu Lys Gln

435 440 445

Arg Leu Gly Gly Asp Val Gln Ser Pro Asn Cys Pro Ser Glu Asp Val

450 455 460

Val Ile Thr Pro Glu Ser Phe Gly Arg Asp Ser Ser Leu Thr Cys Leu

465 470 475 480

Ala Gly Asn Val Ser Ala Cys Asp Ala Pro Ile Leu Ser Ser Ser Arg

485 490 495

Ser Leu Asp Cys Arg Glu Ser Gly Lys Asn Gly Pro His Val Tyr Gln

500 505 510

Asp Leu Leu Leu Ser Leu Gly Thr Thr Asn Ser Thr Leu Pro Pro Pro

515 520 525

Phe Ser Leu Gln Ser Gly Ile Leu Thr Leu Asn Pro Val Ala Gln Gly

530 535 540

Gln Pro Ile Leu Thr Ser Leu Gly Ser Asn Gln Glu Glu Ala Tyr Val

545 550 555 560

Thr Met Ser Ser Phe Tyr Gln Asn Gln Arg Val Lys Phe Ser Arg Ser

565 570 575

Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu

580 585 590

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

595 600 605

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

610 615 620

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

625 630 635 640

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

645 650 655

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

660 665 670

Tyr Arg His Gln Ala Leu Pro Pro Arg

675 680

<210> 20

<211> 541

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-amino acid sequence of IL4

<400> 20

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 Lys Lys Arg Ile Lys Pro Ile Val Trp Pro

370 375 380

Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro

385 390 395 400

Arg Lys Asn Leu Asn Val Ser Leu Thr Ser Leu Gly Ser Asn Gln Glu

405 410 415

Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn Gln Arg Val Lys

420 425 430

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln

435 440 445

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

450 455 460

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

465 470 475 480

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

485 490 495

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

500 505 510

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

515 520 525

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

530 535 540

<210> 21

<211> 541

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-amino acid sequence of IL5

<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 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 Lys Lys Arg Ile Lys Pro Ile Val Trp Pro

370 375 380

Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro

385 390 395 400

Arg Lys Asn Leu Asn Val Ser Leu Thr Ser Leu Gly Ser Asn Gln Glu

405 410 415

Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn Gln Arg Val Lys

420 425 430

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln

435 440 445

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

450 455 460

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

465 470 475 480

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

485 490 495

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

500 505 510

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

515 520 525

Thr Tyr Asp Ala Tyr Arg His Gln Ala Leu Pro Pro Arg

530 535 540

<210> 22

<211> 676

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-amino acid sequence of IL6

<400> 22

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 Lys Lys Arg Ile Lys Pro Ile Val Trp Pro

370 375 380

Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro

385 390 395 400

Arg Lys Asn Leu Asn Val Ser Leu Thr Ser Leu Gly Ser Asn Gln Glu

405 410 415

Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn Gln Arg Val Lys

420 425 430

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln

435 440 445

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

450 455 460

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

465 470 475 480

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

485 490 495

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

500 505 510

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

515 520 525

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Ser Leu Lys

530 535 540

Thr His Pro Leu Trp Arg Leu Trp Lys Lys Ile Trp Ala Val Pro Ser

545 550 555 560

Pro Glu Arg Phe Phe Met Pro Leu Tyr Lys Gly Cys Ser Gly Asp Phe

565 570 575

Lys Lys Trp Val Gly Ala Pro Phe Thr Gly Ser Ser Leu Glu Leu Gly

580 585 590

Pro Trp Ser Pro Glu Val Pro Ser Thr Leu Glu Val Tyr Ser Cys His

595 600 605

Pro Pro Arg Ser Pro Ala Lys Arg Leu Gln Leu Thr Glu Leu Gln Glu

610 615 620

Pro Ala Glu Leu Val Glu Ser Asp Gly Val Pro Lys Pro Ser Ser Pro

625 630 635 640

Val Glu Cys Asp Phe Thr Ser Pro Gly Asp Glu Gly Pro Pro Arg Ser

645 650 655

Tyr Leu Arg Gln Trp Val Val Ile Pro Pro Pro Leu Ser Ser Pro Gly

660 665 670

Pro Gln Ala Ser

675

<210> 23

<211> 685

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-amino acid sequence of IL7

<400> 23

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 Pro Ile Leu Leu Thr Cys Pro Thr Ile Ser Ile Leu

305 310 315 320

Ser Phe Phe Ser Val Ala Leu Leu Val Ile Leu Ala Cys Val Leu Trp

325 330 335

Lys Lys Arg Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp His Lys

340 345 350

Lys Thr Leu Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu Asn Val

355 360 365

Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys Gln Ile His Arg Val Asp

370 375 380

Asp Ile Gln Ala Arg Asp Glu Val Glu Gly Phe Leu Gln Asp Thr Phe

385 390 395 400

Pro Gln Gln Leu Glu Glu Ser Glu Lys Gln Arg Leu Gly Gly Asp Val

405 410 415

Gln Ser Pro Asn Cys Pro Ser Glu Asp Val Val Ile Thr Pro Glu Ser

420 425 430

Phe Gly Arg Asp Ser Ser Leu Thr Cys Leu Ala Gly Asn Val Ser Ala

435 440 445

Cys Asp Ala Pro Ile Leu Ser Ser Ser Arg Ser Leu Asp Cys Arg Glu

450 455 460

Ser Gly Lys Asn Gly Pro His Val Tyr Gln Asp Leu Leu Leu Ser Leu

465 470 475 480

Gly Thr Thr Asn Ser Thr Leu Pro Pro Pro Phe Ser Leu Gln Ser Gly

485 490 495

Ile Leu Thr Leu Asn Pro Val Ala Gln Gly Gln Pro Ile Leu Thr Ser

500 505 510

Leu Gly Ser Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr

515 520 525

Gln Asn Gln Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln

530 535 540

Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser

545 550 555 560

Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys

565 570 575

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln

580 585 590

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

595 600 605

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

610 615 620

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

625 630 635 640

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

645 650 655

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

660 665 670

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

675 680 685

<210> 24

<211> 621

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-amino acid sequence of IL8

<400> 24

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 Ser Leu Lys Thr His Pro Leu Trp Arg Leu

370 375 380

Trp Lys Lys Ile Trp Ala Val Pro Ser Pro Glu Arg Phe Phe Met Pro

385 390 395 400

Leu Tyr Lys Gly Cys Ser Gly Asp Phe Lys Lys Trp Val Gly Ala Pro

405 410 415

Phe Thr Gly Ser Ser Leu Glu Leu Gly Pro Trp Ser Pro Glu Val Pro

420 425 430

Ser Thr Leu Glu Val Tyr Ser Cys His Pro Pro Arg Ser Pro Ala Lys

435 440 445

Arg Leu Gln Leu Thr Glu Leu Gln Glu Pro Ala Glu Leu Val Glu Ser

450 455 460

Asp Gly Val Pro Lys Pro Ser Ser Pro Val Glu Cys Asp Phe Thr Ser

465 470 475 480

Pro Gly Asp Glu Gly Pro Pro Arg Ser Tyr Leu Arg Gln Trp Val Val

485 490 495

Ile Pro Pro Pro Leu Ser Ser Pro Gly Pro Gln Ala Ser Arg Val Lys

500 505 510

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln

515 520 525

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

530 535 540

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

545 550 555 560

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

565 570 575

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

580 585 590

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

595 600 605

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

610 615 620

<210> 25

<211> 583

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of 28z-ILC

<400> 25

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 Phe Trp Val Leu Val Val Val Gly Gly Val

305 310 315 320

Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp

325 330 335

Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met

340 345 350

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

355 360 365

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Asn Cys Arg Asn Thr Gly

370 375 380

Pro Trp Leu Lys Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys

385 390 395 400

Phe Phe Ser Gln Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp

405 410 415

Leu Ser Ser Pro Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala

420 425 430

Pro Glu Ile Ser Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln

435 440 445

Leu Leu Pro Leu Asn Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln

450 455 460

Gly Gln Asp Pro Thr His Leu Val Val Lys Phe Ser Arg Ser Ala Asp

465 470 475 480

Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn

485 490 495

Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg

500 505 510

Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly

515 520 525

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

530 535 540

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

545 550 555 560

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Tyr Arg

565 570 575

His Gln Ala Leu Pro Pro Arg

580

<210> 26

<211> 489

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of 28z-IL1

<400> 26

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 Phe Trp Val Leu Val Val Val Gly Gly Val

305 310 315 320

Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp

325 330 335

Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met

340 345 350

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

355 360 365

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser 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 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

Tyr Arg His Gln Ala Leu Pro Pro Arg

485

<210> 27

<211> 684

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-IL2 amino acid sequence

<400> 27

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 Phe Trp Val Leu Val Val Val Gly Gly Val

305 310 315 320

Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp

325 330 335

Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met

340 345 350

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

355 360 365

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Lys Arg Ile Lys Pro

370 375 380

Ile Val Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu

385 390 395 400

Cys Lys Lys Pro Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu Ser

405 410 415

Phe Leu Asp Cys Gln Ile His Arg Val Asp Asp Ile Gln Ala Arg Asp

420 425 430

Glu Val Glu Gly Phe Leu Gln Asp Thr Phe Pro Gln Gln Leu Glu Glu

435 440 445

Ser Glu Lys Gln Arg Leu Gly Gly Asp Val Gln Ser Pro Asn Cys Pro

450 455 460

Ser Glu Asp Val Val Ile Thr Pro Glu Ser Phe Gly Arg Asp Ser Ser

465 470 475 480

Leu Thr Cys Leu Ala Gly Asn Val Ser Ala Cys Asp Ala Pro Ile Leu

485 490 495

Ser Ser Ser Arg Ser Leu Asp Cys Arg Glu Ser Gly Lys Asn Gly Pro

500 505 510

His Val Tyr Gln Asp Leu Leu Leu Ser Leu Gly Thr Thr Asn Ser Thr

515 520 525

Leu Pro Pro Pro Phe Ser Leu Gln Ser Gly Ile Leu Thr Leu Asn Pro

530 535 540

Val Ala Gln Gly Gln Pro Ile Leu Thr Ser Leu Gly Ser Asn Gln Glu

545 550 555 560

Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn Gln Val Lys Phe

565 570 575

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

580 585 590

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

595 600 605

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

610 615 620

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

625 630 635 640

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

645 650 655

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

660 665 670

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

675 680

<210> 28

<211> 684

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-IL3 amino acid sequence

<400> 28

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 Phe Trp Val Leu Val Val Val Gly Gly Val

305 310 315 320

Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp

325 330 335

Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met

340 345 350

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

355 360 365

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Lys Arg Ile Lys Pro

370 375 380

Ile Val Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu

385 390 395 400

Cys Lys Lys Pro Arg Lys Asn Leu Asn Val Ser Phe Asn Pro Glu Ser

405 410 415

Phe Leu Asp Cys Gln Ile His Arg Val Asp Asp Ile Gln Ala Arg Asp

420 425 430

Glu Val Glu Gly Phe Leu Gln Asp Thr Phe Pro Gln Gln Leu Glu Glu

435 440 445

Ser Glu Lys Gln Arg Leu Gly Gly Asp Val Gln Ser Pro Asn Cys Pro

450 455 460

Ser Glu Asp Val Val Ile Thr Pro Glu Ser Phe Gly Arg Asp Ser Ser

465 470 475 480

Leu Thr Cys Leu Ala Gly Asn Val Ser Ala Cys Asp Ala Pro Ile Leu

485 490 495

Ser Ser Ser Arg Ser Leu Asp Cys Arg Glu Ser Gly Lys Asn Gly Pro

500 505 510

His Val Tyr Gln Asp Leu Leu Leu Ser Leu Gly Thr Thr Asn Ser Thr

515 520 525

Leu Pro Pro Pro Phe Ser Leu Gln Ser Gly Ile Leu Thr Leu Asn Pro

530 535 540

Val Ala Gln Gly Gln Pro Ile Leu Thr Ser Leu Gly Ser Asn Gln Glu

545 550 555 560

Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn Gln Val Lys Phe

565 570 575

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

580 585 590

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

595 600 605

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

610 615 620

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

625 630 635 640

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

645 650 655

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

660 665 670

Tyr Asp Ala Tyr Arg His Gln Ala Leu Pro Pro Arg

675 680

<210> 29

<211> 544

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of 28z-IL4

<400> 29

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 Phe Trp Val Leu Val Val Val Gly Gly Val

305 310 315 320

Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp

325 330 335

Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met

340 345 350

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

355 360 365

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Lys Arg Ile Lys Pro

370 375 380

Ile Val Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu

385 390 395 400

Cys Lys Lys Pro Arg Lys Asn Leu Asn Val Ser Leu Thr Ser Leu Gly

405 410 415

Ser Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn

420 425 430

Gln Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

435 440 445

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

450 455 460

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

465 470 475 480

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

485 490 495

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

500 505 510

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

515 520 525

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

530 535 540

<210> 30

<211> 544

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of 28z-IL5

<400> 30

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 Phe Trp Val Leu Val Val Val Gly Gly Val

305 310 315 320

Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp

325 330 335

Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met

340 345 350

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

355 360 365

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Lys Arg Ile Lys Pro

370 375 380

Ile Val Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu

385 390 395 400

Cys Lys Lys Pro Arg Lys Asn Leu Asn Val Ser Leu Thr Ser Leu Gly

405 410 415

Ser Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn

420 425 430

Gln Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

435 440 445

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

450 455 460

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

465 470 475 480

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

485 490 495

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

500 505 510

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

515 520 525

Thr Lys Asp Thr Tyr Asp Ala Tyr Arg His Gln Ala Leu Pro Pro Arg

530 535 540

<210> 31

<211> 679

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-IL6 amino acid sequence

<400> 31

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 Phe Trp Val Leu Val Val Val Gly Gly Val

305 310 315 320

Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp

325 330 335

Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met

340 345 350

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

355 360 365

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Lys Arg Ile Lys Pro

370 375 380

Ile Val Trp Pro Ser Leu Pro Asp His Lys Lys Thr Leu Glu His Leu

385 390 395 400

Cys Lys Lys Pro Arg Lys Asn Leu Asn Val Ser Leu Thr Ser Leu Gly

405 410 415

Ser Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser Phe Tyr Gln Asn

420 425 430

Gln Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

435 440 445

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

450 455 460

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

465 470 475 480

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

485 490 495

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

500 505 510

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

515 520 525

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

530 535 540

Ser Leu Lys Thr His Pro Leu Trp Arg Leu Trp Lys Lys Ile Trp Ala

545 550 555 560

Val Pro Ser Pro Glu Arg Phe Phe Met Pro Leu Tyr Lys Gly Cys Ser

565 570 575

Gly Asp Phe Lys Lys Trp Val Gly Ala Pro Phe Thr Gly Ser Ser Leu

580 585 590

Glu Leu Gly Pro Trp Ser Pro Glu Val Pro Ser Thr Leu Glu Val Tyr

595 600 605

Ser Cys His Pro Pro Arg Ser Pro Ala Lys Arg Leu Gln Leu Thr Glu

610 615 620

Leu Gln Glu Pro Ala Glu Leu Val Glu Ser Asp Gly Val Pro Lys Pro

625 630 635 640

Ser Ser Pro Val Glu Cys Asp Phe Thr Ser Pro Gly Asp Glu Gly Pro

645 650 655

Pro Arg Ser Tyr Leu Arg Gln Trp Val Val Ile Pro Pro Pro Leu Ser

660 665 670

Ser Pro Gly Pro Gln Ala Ser

675

<210> 32

<211> 685

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of 28z-IL7

<400> 32

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 Pro Ile Leu Leu Thr Cys Pro Thr Ile Ser

305 310 315 320

Ile Leu Ser Phe Phe Ser Val Ala Leu Leu Val Ile Leu Ala Cys Val

325 330 335

Leu Trp Lys Lys Arg Ile Lys Pro Ile Val Trp Pro Ser Leu Pro Asp

340 345 350

His Lys Lys Thr Leu Glu His Leu Cys Lys Lys Pro Arg Lys Asn Leu

355 360 365

Asn Val Ser Phe Asn Pro Glu Ser Phe Leu Asp Cys Gln Ile His Arg

370 375 380

Val Asp Asp Ile Gln Ala Arg Asp Glu Val Glu Gly Phe Leu Gln Asp

385 390 395 400

Thr Phe Pro Gln Gln Leu Glu Glu Ser Glu Lys Gln Arg Leu Gly Gly

405 410 415

Asp Val Gln Ser Pro Asn Cys Pro Ser Glu Asp Val Val Ile Thr Pro

420 425 430

Glu Ser Phe Gly Arg Asp Ser Ser Leu Thr Cys Leu Ala Gly Asn Val

435 440 445

Ser Ala Cys Asp Ala Pro Ile Leu Ser Ser Ser Arg Ser Leu Asp Cys

450 455 460

Arg Glu Ser Gly Lys Asn Gly Pro His Val Tyr Gln Asp Leu Leu Leu

465 470 475 480

Ser Leu Gly Thr Thr Asn Ser Thr Leu Pro Pro Pro Phe Ser Leu Gln

485 490 495

Ser Gly Ile Leu Thr Leu Asn Pro Val Ala Gln Gly Gln Pro Ile Leu

500 505 510

Thr Ser Leu Gly Ser Asn Gln Glu Glu Ala Tyr Val Thr Met Ser Ser

515 520 525

Phe Tyr Gln Asn Gln Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp

530 535 540

Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr

545 550 555 560

Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Val Lys

565 570 575

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln

580 585 590

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

595 600 605

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

610 615 620

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

625 630 635 640

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

645 650 655

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

660 665 670

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

675 680 685

<210> 33

<211> 624

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of 28z-IL8

<400> 33

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 Phe Trp Val Leu Val Val Val Gly Gly Val

305 310 315 320

Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp

325 330 335

Val Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met

340 345 350

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

355 360 365

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Ser Leu Lys Thr His Pro

370 375 380

Leu Trp Arg Leu Trp Lys Lys Ile Trp Ala Val Pro Ser Pro Glu Arg

385 390 395 400

Phe Phe Met Pro Leu Tyr Lys Gly Cys Ser Gly Asp Phe Lys Lys Trp

405 410 415

Val Gly Ala Pro Phe Thr Gly Ser Ser Leu Glu Leu Gly Pro Trp Ser

420 425 430

Pro Glu Val Pro Ser Thr Leu Glu Val Tyr Ser Cys His Pro Pro Arg

435 440 445

Ser Pro Ala Lys Arg Leu Gln Leu Thr Glu Leu Gln Glu Pro Ala Glu

450 455 460

Leu Val Glu Ser Asp Gly Val Pro Lys Pro Ser Ser Pro Val Glu Cys

465 470 475 480

Asp Phe Thr Ser Pro Gly Asp Glu Gly Pro Pro Arg Ser Tyr Leu Arg

485 490 495

Gln Trp Val Val Ile Pro Pro Pro Leu Ser Ser Pro Gly Pro Gln Ala

500 505 510

Ser Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

515 520 525

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

530 535 540

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

545 550 555 560

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

565 570 575

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

580 585 590

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

595 600 605

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

610 615 620

<210> 34

<211> 1740

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-ILC nucleic acid sequence

<400> 34

atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60

ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120

accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180

ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240

tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300

caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360

ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420

ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480

ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540

cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600

tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660

gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720

cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780

gtatcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840

cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900

agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960

gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020

tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080

agctgccgat ttccagaaga agaagaagga ggatgtgaac tgaactgcag gaacaccggg 1140

ccatggctga agaaggtcct gaagtgtaac accccagacc cctcgaagtt cttttcccag 1200

ctgagctcag agcatggagg agatgtccag aagtggctct cttcgccctt cccctcatcg 1260

tccttcagcc ctggcggcct ggcacctgag atctcgccac tagaagtgct ggagagggac 1320

aaggtgacgc agctgctgcc cctgaacact gatgcctact tgtccctcca agaactccag 1380

ggtcaggacc caactcactt ggtgagagtg aagttcagca ggagcgcaga cgcccccgcg 1440

tacaagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1500

gatgttttgg acaagaggcg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1560

aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1620

gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1680

ctcagtacag ccaccaagga cacctacgac gcctaccgcc accaggccct gccccctcgc 1740

<210> 35

<211> 1458

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-IL1 nucleic acid sequence

<400> 35

atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60

ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120

accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180

ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240

tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300

caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360

ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420

ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480

ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540

cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600

tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660

gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720

cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780

gtatcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840

cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900

agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960

gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020

tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080

agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1140

agcgcagacg cccccgcgta caagcagggc cagaaccagc tctataacga gctcaatcta 1200

ggacgaagag aggagtacga tgttttggac aagaggcgtg gccgggaccc tgagatgggg 1260

ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1320

atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1380

gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ctaccgccac 1440

caggccctgc cccctcgc 1458

<210> 36

<211> 2043

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-IL2 nucleic acid sequence

<400> 36

atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60

ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120

accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180

ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240

tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300

caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360

ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420

ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480

ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540

cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600

tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660

gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720

cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780

gtatcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840

cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900

agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960

gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020

tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080

agctgccgat ttccagaaga agaagaagga ggatgtgaac tgaaaaaaag gattaagcct 1140

atcgtatggc ccagtctccc cgatcataag aagactctgg aacatctttg taagaaacca 1200

agaaaaaatt taaatgtgag tttcaatcct gaaagtttcc tggactgcca gattcatagg 1260

gtggatgaca ttcaagctag agatgaagtg gaaggttttc tgcaagatac gtttcctcag 1320

caactagaag aatctgagaa gcagaggctt ggaggggatg tgcagagccc caactgccca 1380

tctgaggatg tagtcatcac tccagaaagc tttggaagag attcatccct cacatgcctg 1440

gctgggaatg tcagtgcatg tgacgcccct attctctcct cttccaggtc cctagactgc 1500

agggagagtg gcaagaatgg gcctcatgtg taccaggacc tcctgcttag ccttgggact 1560

acaaacagca cgctgccccc tccattttct ctccaatctg gaatcctgac attgaaccca 1620

gttgctcagg gtcagcccat tcttacttcc ctgggatcaa atcaagaaga agcatatgtc 1680

accatgtcca gcttctacca aaaccagaga gtgaagttca gcaggagcgc agacgccccc 1740

gcgtacaagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1800

tacgatgttt tggacaagag gcgtggccgg gaccctgaga tggggggaaa gccgagaagg 1860

aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1920

agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1980

ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 2040

cgc 2043

<210> 37

<211> 2043

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-IL3 nucleic acid sequence

<400> 37

atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60

ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120

accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180

ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240

tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300

caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360

ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420

ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480

ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540

cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600

tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660

gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720

cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780

gtatcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840

cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900

agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960

gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020

tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080

agctgccgat ttccagaaga agaagaagga ggatgtgaac tgaaaaaaag gattaagcct 1140

atcgtatggc ccagtctccc cgatcataag aagactctgg aacatctttg taagaaacca 1200

agaaaaaatt taaatgtgag tttcaatcct gaaagtttcc tggactgcca gattcatagg 1260

gtggatgaca ttcaagctag agatgaagtg gaaggttttc tgcaagatac gtttcctcag 1320

caactagaag aatctgagaa gcagaggctt ggaggggatg tgcagagccc caactgccca 1380

tctgaggatg tagtcatcac tccagaaagc tttggaagag attcatccct cacatgcctg 1440

gctgggaatg tcagtgcatg tgacgcccct attctctcct cttccaggtc cctagactgc 1500

agggagagtg gcaagaatgg gcctcatgtg taccaggacc tcctgcttag ccttgggact 1560

acaaacagca cgctgccccc tccattttct ctccaatctg gaatcctgac attgaaccca 1620

gttgctcagg gtcagcccat tcttacttcc ctgggatcaa atcaagaaga agcatatgtc 1680

accatgtcca gcttctacca aaaccagaga gtgaagttca gcaggagcgc agacgccccc 1740

gcgtacaagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1800

tacgatgttt tggacaagag gcgtggccgg gaccctgaga tggggggaaa gccgagaagg 1860

aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1920

agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1980

ggtctcagta cagccaccaa ggacacctac gacgcctacc gccaccaggc cctgccccct 2040

cgc 2043

<210> 38

<211> 1623

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-IL4 nucleic acid sequence

<400> 38

atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60

ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120

accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180

ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240

tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300

caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360

ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420

ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480

ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540

cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600

tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660

gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720

cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780

gtatcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840

cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900

agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960

gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020

tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080

agctgccgat ttccagaaga agaagaagga ggatgtgaac tgaaaaaaag gattaagcct 1140

atcgtatggc ccagtctccc cgatcataag aagactctgg aacatctttg taagaaacca 1200

agaaaaaatt taaatgtgag tcttacttcc ctgggatcaa atcaagaaga agcatatgtc 1260

accatgtcca gcttctacca aaaccagaga gtgaagttca gcaggagcgc agacgccccc 1320

gcgtacaagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1380

tacgatgttt tggacaagag gcgtggccgg gaccctgaga tggggggaaa gccgagaagg 1440

aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1500

agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1560

ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1620

cgc 1623

<210> 39

<211> 1623

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-IL5 nucleic acid sequence

<400> 39

atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60

ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120

accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180

ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240

tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300

caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360

ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420

ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480

ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540

cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600

tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660

gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720

cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780

gtatcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840

cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900

agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960

gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020

tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080

agctgccgat ttccagaaga agaagaagga ggatgtgaac tgaaaaaaag gattaagcct 1140

atcgtatggc ccagtctccc cgatcataag aagactctgg aacatctttg taagaaacca 1200

agaaaaaatt taaatgtgag tcttacttcc ctgggatcaa atcaagaaga agcatatgtc 1260

accatgtcca gcttctacca aaaccagaga gtgaagttca gcaggagcgc agacgccccc 1320

gcgtacaagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1380

tacgatgttt tggacaagag gcgtggccgg gaccctgaga tggggggaaa gccgagaagg 1440

aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1500

agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1560

ggtctcagta cagccaccaa ggacacctac gacgcctacc gccaccaggc cctgccccct 1620

cgc 1623

<210> 40

<211> 2028

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-IL6 nucleic acid sequence

<400> 40

atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60

ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120

accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180

ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240

tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300

caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360

ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420

ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480

ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540

cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600

tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660

gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720

cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780

gtatcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840

cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900

agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960

gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020

tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080

agctgccgat ttccagaaga agaagaagga ggatgtgaac tgaaaaaaag gattaagcct 1140

atcgtatggc ccagtctccc cgatcataag aagactctgg aacatctttg taagaaacca 1200

agaaaaaatt taaatgtgag tcttacttcc ctgggatcaa atcaagaaga agcatatgtc 1260

accatgtcca gcttctacca aaaccagaga gtgaagttca gcaggagcgc agacgccccc 1320

gcgtacaagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1380

tacgatgttt tggacaagag gcgtggccgg gaccctgaga tggggggaaa gccgagaagg 1440

aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1500

agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1560

ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1620

cgcagcctga agacccatcc attgtggagg ctatggaaga agatatgggc cgtccccagc 1680

cctgagcggt tcttcatgcc cctgtacaag ggctgcagcg gagacttcaa gaaatgggtg 1740

ggtgcaccct tcactggctc cagcctggag ctgggaccct ggagcccaga ggtgccctcc 1800

accctggagg tgtacagctg ccacccacca cggagcccgg ccaagaggct gcagctcacg 1860

gagctacaag aaccagcaga gctggtggag tctgacggtg tgcccaagcc cagcagccct 1920

gtggagtgtg acttcaccag ccccggggac gaaggacccc cccggagcta cctccgccag 1980

tgggtggtca ttcctccgcc actttcgagc cctggacccc aggccagc 2028

<210> 41

<211> 2055

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-IL7 nucleic acid sequence

<400> 41

atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60

ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120

accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180

ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240

tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300

caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360

ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420

ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480

ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540

cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600

tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660

gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720

cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780

gtatcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840

cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900

agggggctgg acttcgcctg tgatcctatc ttactaactt gtcccaccat cagcattttg 960

agttttttct ctgtcgctct gttggtcatc ttggcctgtg tgttatggaa aaaaaggatt 1020

aagcctatcg tatggcccag tctccccgat cataagaaga ctctggaaca tctttgtaag 1080

aaaccaagaa aaaatttaaa tgtgagtttc aatcctgaaa gtttcctgga ctgccagatt 1140

catagggtgg atgacattca agctagagat gaagtggaag gttttctgca agatacgttt 1200

cctcagcaac tagaagaatc tgagaagcag aggcttggag gggatgtgca gagccccaac 1260

tgcccatctg aggatgtagt catcactcca gaaagctttg gaagagattc atccctcaca 1320

tgcctggctg ggaatgtcag tgcatgtgac gcccctattc tctcctcttc caggtcccta 1380

gactgcaggg agagtggcaa gaatgggcct catgtgtacc aggacctcct gcttagcctt 1440

gggactacaa acagcacgct gccccctcca ttttctctcc aatctggaat cctgacattg 1500

aacccagttg ctcagggtca gcccattctt acttccctgg gatcaaatca agaagaagca 1560

tatgtcacca tgtccagctt ctaccaaaac cagaaacggg gcagaaagaa actcctgtat 1620

atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1680

tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1740

gcagacgccc ccgcgtacaa gcagggccag aaccagctct ataacgagct caatctagga 1800

cgaagagagg agtacgatgt tttggacaag aggcgtggcc gggaccctga gatgggggga 1860

aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1920

gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1980

ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 2040

gccctgcccc ctcgc 2055

<210> 42

<211> 1863

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BBz-IL8 nucleic acid sequence

<400> 42

atggccttac cagtgaccgc cttgctcctg ccgctggcct tgctgctcca cgccgccagg 60

ccggacatcc agatgacaca gactacatcc tccctgtctg cctctctggg agacagagtc 120

accatcagtt gcagggcaag tcaggacatt agtaaatatt taaattggta tcagcagaaa 180

ccagatggaa ctgttaaact cctgatctac catacatcaa gattacactc aggagtccca 240

tcaaggttca gtggcagtgg gtctggaaca gattattctc tcaccattag caacctggag 300

caagaagata ttgccactta cttttgccaa cagggtaata cgcttccgta cacgttcgga 360

ggggggacca agctggagat cacaggtggc ggtggctcgg gcggtggtgg gtcgggtggc 420

ggcggatctg aggtgaaact gcaggagtca ggacctggcc tggtggcgcc ctcacagagc 480

ctgtccgtca catgcactgt ctcaggggtc tcattacccg actatggtgt aagctggatt 540

cgccagcctc cacgaaaggg tctggagtgg ctgggagtaa tatggggtag tgaaaccaca 600

tactataatt cagctctcaa atccagactg accatcatca aggacaactc caagagccaa 660

gttttcttaa aaatgaacag tctgcaaact gatgacacag ccatttacta ctgtgccaaa 720

cattattact acggtggtag ctatgctatg gactactggg gccaaggaac ctcagtcacc 780

gtatcctcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 840

cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 900

agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 960

gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 1020

tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1080

agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagcctgaa gacccatcca 1140

ttgtggaggc tatggaagaa gatatgggcc gtccccagcc ctgagcggtt cttcatgccc 1200

ctgtacaagg gctgcagcgg agacttcaag aaatgggtgg gtgcaccctt cactggctcc 1260

agcctggagc tgggaccctg gagcccagag gtgccctcca ccctggaggt gtacagctgc 1320

cacccaccac ggagcccggc caagaggctg cagctcacgg agctacaaga accagcagag 1380

ctggtggagt ctgacggtgt gcccaagccc agcagccctg tggagtgtga cttcaccagc 1440

cccggggacg aaggaccccc ccggagctac ctccgccagt gggtggtcat tcctccgcca 1500

ctttcgagcc ctggacccca ggccagcaga gtgaagttca gcaggagcgc agacgccccc 1560

gcgtacaagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1620

tacgatgttt tggacaagag gcgtggccgg gaccctgaga tggggggaaa gccgagaagg 1680

aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1740

agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1800

ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1860

cgc 1863

<210> 43

<211> 1749

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-ILC nucleic acid sequence

<400> 43

atggctctgc ctgtgaccgc cctgctgctg cctctggctc tgctgctgca cgccgctcgg 60

cctgacattc agatgactca gaccacaagc agcctcagtg cgagcctggg ggacagggtg 120

actatcagct gccgggccag ccaggacatt tccaagtacc tgaattggta ccagcagaag 180

cccgatggta ctgtgaaact cctgatatat catacttcta ggctccattc cggggttcca 240

agccgattca gtggctccgg ttccggtaca gattattccc tgaccattag caacttggaa 300

caggaggaca ttgcaacgta tttctgtcag caaggcaaca cattgcccta cacattcggg 360

ggcgggacta aactcgaaat aactggcggc gggggttctg gtggcggcgg cagcggcggt 420

ggaggatcag aagtgaagct gcaggaaagt ggccccgggc tggtagcccc aagtcagtcc 480

ctgagtgtaa cctgtacagt gagtggagtg tctcttcctg actacggggt aagttggatt 540

cggcaacctc cacgcaaggg cctggagtgg ctcggcgtga tttggggatc tgagacaact 600

tactacaatt ccgccctgaa gagcaggctg accatcatta aggacaatag caagtcacag 660

gtgtttctga agatgaactc actgcagacc gacgacaccg ccatctatta ctgcgccaaa 720

cattattatt atggcgggag ttatgctatg gactactggg gccagggcac tagcgtcacc 780

gtcagcagta ctacaactcc agcacccaga ccccctacac ctgctccaac tatcgcaagt 840

cagcccctgt cactgcgccc tgaagcctgt cgccctgctg ccgggggagc tgtgcatact 900

cggggactgg actttgcctg tgatatctac ttctgggtgc tggtcgtggt cggaggggtg 960

ctggcctgtt atagcctgct ggtgactgtc gccttcatta tcttctgggt gcggagcaag 1020

aggtctcgcg gtgggcattc cgactacatg aacatgaccc ctagaaggcc tggcccaacc 1080

agaaagcact accagccata cgcccctccc agagatttcg ccgcttatcg aagcaactgc 1140

aggaacaccg ggccatggct gaagaaggtc ctgaagtgta acaccccaga cccctcgaag 1200

ttcttttccc agctgagctc agagcatgga ggagatgtcc agaagtggct ctcttcgccc 1260

ttcccctcat cgtccttcag ccctggcggc ctggcacctg agatctcgcc actagaagtg 1320

ctggagaggg acaaggtgac gcagctgctg cccctgaaca ctgatgccta cttgtccctc 1380

caagaactcc agggtcagga cccaactcac ttggtggtga agttctcccg aagcgcagat 1440

gccccagcct atcagcaggg acagaatcag ctgtacaacg agctgaacct gggaagacgg 1500

gaggaatacg atgtgctgga caaaaggcgg ggcagagatc ctgagatggg cggcaaacca 1560

agacggaaga acccccagga aggtctgtat aatgagctgc agaaagacaa gatggctgag 1620

gcctactcag aaatcgggat gaagggcgaa agaaggagag gaaaaggcca cgacggactg 1680

taccaggggc tgagtacagc aacaaaagac acctatgacg cttaccgcca ccaggctctg 1740

ccaccaaga 1749

<210> 44

<211> 1467

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-IL1 nucleic acid sequence

<400> 44

atggctctgc ctgtgaccgc cctgctgctg cctctggctc tgctgctgca cgccgctcgg 60

cctgacattc agatgactca gaccacaagc agcctcagtg cgagcctggg ggacagggtg 120

actatcagct gccgggccag ccaggacatt tccaagtacc tgaattggta ccagcagaag 180

cccgatggta ctgtgaaact cctgatatat catacttcta ggctccattc cggggttcca 240

agccgattca gtggctccgg ttccggtaca gattattccc tgaccattag caacttggaa 300

caggaggaca ttgcaacgta tttctgtcag caaggcaaca cattgcccta cacattcggg 360

ggcgggacta aactcgaaat aactggcggc gggggttctg gtggcggcgg cagcggcggt 420

ggaggatcag aagtgaagct gcaggaaagt ggccccgggc tggtagcccc aagtcagtcc 480

ctgagtgtaa cctgtacagt gagtggagtg tctcttcctg actacggggt aagttggatt 540

cggcaacctc cacgcaaggg cctggagtgg ctcggcgtga tttggggatc tgagacaact 600

tactacaatt ccgccctgaa gagcaggctg accatcatta aggacaatag caagtcacag 660

gtgtttctga agatgaactc actgcagacc gacgacaccg ccatctatta ctgcgccaaa 720

cattattatt atggcgggag ttatgctatg gactactggg gccagggcac tagcgtcacc 780

gtcagcagta ctacaactcc agcacccaga ccccctacac ctgctccaac tatcgcaagt 840

cagcccctgt cactgcgccc tgaagcctgt cgccctgctg ccgggggagc tgtgcatact 900

cggggactgg actttgcctg tgatatctac ttctgggtgc tggtcgtggt cggaggggtg 960

ctggcctgtt atagcctgct ggtgactgtc gccttcatta tcttctgggt gcggagcaag 1020

aggtctcgcg gtgggcattc cgactacatg aacatgaccc ctagaaggcc tggcccaacc 1080

agaaagcact accagccata cgcccctccc agagatttcg ccgcttatcg aagcgtgaag 1140

ttctcccgaa gcgcagatgc cccagcctat cagcagggac agaatcagct gtacaacgag 1200

ctgaacctgg gaagacggga ggaatacgat gtgctggaca aaaggcgggg cagagatcct 1260

gagatgggcg gcaaaccaag acggaagaac ccccaggaag gtctgtataa tgagctgcag 1320

aaagacaaga tggctgaggc ctactcagaa atcgggatga agggcgaaag aaggagagga 1380

aaaggccacg acggactgta ccaggggctg agtacagcaa caaaagacac ctatgacgct 1440

taccgccacc aggctctgcc accaaga 1467

<210> 45

<211> 2052

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-IL2 nucleic acid sequence

<400> 45

atggctctgc ctgtgaccgc cctgctgctg cctctggctc tgctgctgca cgccgctcgg 60

cctgacattc agatgactca gaccacaagc agcctcagtg cgagcctggg ggacagggtg 120

actatcagct gccgggccag ccaggacatt tccaagtacc tgaattggta ccagcagaag 180

cccgatggta ctgtgaaact cctgatatat catacttcta ggctccattc cggggttcca 240

agccgattca gtggctccgg ttccggtaca gattattccc tgaccattag caacttggaa 300

caggaggaca ttgcaacgta tttctgtcag caaggcaaca cattgcccta cacattcggg 360

ggcgggacta aactcgaaat aactggcggc gggggttctg gtggcggcgg cagcggcggt 420

ggaggatcag aagtgaagct gcaggaaagt ggccccgggc tggtagcccc aagtcagtcc 480

ctgagtgtaa cctgtacagt gagtggagtg tctcttcctg actacggggt aagttggatt 540

cggcaacctc cacgcaaggg cctggagtgg ctcggcgtga tttggggatc tgagacaact 600

tactacaatt ccgccctgaa gagcaggctg accatcatta aggacaatag caagtcacag 660

gtgtttctga agatgaactc actgcagacc gacgacaccg ccatctatta ctgcgccaaa 720

cattattatt atggcgggag ttatgctatg gactactggg gccagggcac tagcgtcacc 780

gtcagcagta ctacaactcc agcacccaga ccccctacac ctgctccaac tatcgcaagt 840

cagcccctgt cactgcgccc tgaagcctgt cgccctgctg ccgggggagc tgtgcatact 900

cggggactgg actttgcctg tgatatctac ttctgggtgc tggtcgtggt cggaggggtg 960

ctggcctgtt atagcctgct ggtgactgtc gccttcatta tcttctgggt gcggagcaag 1020

aggtctcgcg gtgggcattc cgactacatg aacatgaccc ctagaaggcc tggcccaacc 1080

agaaagcact accagccata cgcccctccc agagatttcg ccgcttatcg aagcaaaaaa 1140

aggattaagc ctatcgtatg gcccagtctc cccgatcata agaagactct ggaacatctt 1200

tgtaagaaac caagaaaaaa tttaaatgtg agtttcaatc ctgaaagttt cctggactgc 1260

cagattcata gggtggatga cattcaagct agagatgaag tggaaggttt tctgcaagat 1320

acgtttcctc agcaactaga agaatctgag aagcagaggc ttggagggga tgtgcagagc 1380

cccaactgcc catctgagga tgtagtcatc actccagaaa gctttggaag agattcatcc 1440

ctcacatgcc tggctgggaa tgtcagtgca tgtgacgccc ctattctctc ctcttccagg 1500

tccctagact gcagggagag tggcaagaat gggcctcatg tgtaccagga cctcctgctt 1560

agccttggga ctacaaacag cacgctgccc cctccatttt ctctccaatc tggaatcctg 1620

acattgaacc cagttgctca gggtcagccc attcttactt ccctgggatc aaatcaagaa 1680

gaagcatatg tcaccatgtc cagcttctac caaaaccagg tgaagttctc ccgaagcgca 1740

gatgccccag cctatcagca gggacagaat cagctgtaca acgagctgaa cctgggaaga 1800

cgggaggaat acgatgtgct ggacaaaagg cggggcagag atcctgagat gggcggcaaa 1860

ccaagacgga agaaccccca ggaaggtctg tataatgagc tgcagaaaga caagatggct 1920

gaggcctact cagaaatcgg gatgaagggc gaaagaagga gaggaaaagg ccacgacgga 1980

ctgtaccagg ggctgagtac agcaacaaaa gacacctatg acgctctgca catgcaggct 2040

ctgccaccaa ga 2052

<210> 46

<211> 2052

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-IL3 nucleic acid sequence

<400> 46

atggctctgc ctgtgaccgc cctgctgctg cctctggctc tgctgctgca cgccgctcgg 60

cctgacattc agatgactca gaccacaagc agcctcagtg cgagcctggg ggacagggtg 120

actatcagct gccgggccag ccaggacatt tccaagtacc tgaattggta ccagcagaag 180

cccgatggta ctgtgaaact cctgatatat catacttcta ggctccattc cggggttcca 240

agccgattca gtggctccgg ttccggtaca gattattccc tgaccattag caacttggaa 300

caggaggaca ttgcaacgta tttctgtcag caaggcaaca cattgcccta cacattcggg 360

ggcgggacta aactcgaaat aactggcggc gggggttctg gtggcggcgg cagcggcggt 420

ggaggatcag aagtgaagct gcaggaaagt ggccccgggc tggtagcccc aagtcagtcc 480

ctgagtgtaa cctgtacagt gagtggagtg tctcttcctg actacggggt aagttggatt 540

cggcaacctc cacgcaaggg cctggagtgg ctcggcgtga tttggggatc tgagacaact 600

tactacaatt ccgccctgaa gagcaggctg accatcatta aggacaatag caagtcacag 660

gtgtttctga agatgaactc actgcagacc gacgacaccg ccatctatta ctgcgccaaa 720

cattattatt atggcgggag ttatgctatg gactactggg gccagggcac tagcgtcacc 780

gtcagcagta ctacaactcc agcacccaga ccccctacac ctgctccaac tatcgcaagt 840

cagcccctgt cactgcgccc tgaagcctgt cgccctgctg ccgggggagc tgtgcatact 900

cggggactgg actttgcctg tgatatctac ttctgggtgc tggtcgtggt cggaggggtg 960

ctggcctgtt atagcctgct ggtgactgtc gccttcatta tcttctgggt gcggagcaag 1020

aggtctcgcg gtgggcattc cgactacatg aacatgaccc ctagaaggcc tggcccaacc 1080

agaaagcact accagccata cgcccctccc agagatttcg ccgcttatcg aagcaaaaaa 1140

aggattaagc ctatcgtatg gcccagtctc cccgatcata agaagactct ggaacatctt 1200

tgtaagaaac caagaaaaaa tttaaatgtg agtttcaatc ctgaaagttt cctggactgc 1260

cagattcata gggtggatga cattcaagct agagatgaag tggaaggttt tctgcaagat 1320

acgtttcctc agcaactaga agaatctgag aagcagaggc ttggagggga tgtgcagagc 1380

cccaactgcc catctgagga tgtagtcatc actccagaaa gctttggaag agattcatcc 1440

ctcacatgcc tggctgggaa tgtcagtgca tgtgacgccc ctattctctc ctcttccagg 1500

tccctagact gcagggagag tggcaagaat gggcctcatg tgtaccagga cctcctgctt 1560

agccttggga ctacaaacag cacgctgccc cctccatttt ctctccaatc tggaatcctg 1620

acattgaacc cagttgctca gggtcagccc attcttactt ccctgggatc aaatcaagaa 1680

gaagcatatg tcaccatgtc cagcttctac caaaaccagg tgaagttctc ccgaagcgca 1740

gatgccccag cctatcagca gggacagaat cagctgtaca acgagctgaa cctgggaaga 1800

cgggaggaat acgatgtgct ggacaaaagg cggggcagag atcctgagat gggcggcaaa 1860

ccaagacgga agaaccccca ggaaggtctg tataatgagc tgcagaaaga caagatggct 1920

gaggcctact cagaaatcgg gatgaagggc gaaagaagga gaggaaaagg ccacgacgga 1980

ctgtaccagg ggctgagtac agcaacaaaa gacacctatg acgcttaccg ccaccaggct 2040

ctgccaccaa ga 2052

<210> 47

<211> 1632

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-IL4 nucleic acid sequence

<400> 47

atggctctgc ctgtgaccgc cctgctgctg cctctggctc tgctgctgca cgccgctcgg 60

cctgacattc agatgactca gaccacaagc agcctcagtg cgagcctggg ggacagggtg 120

actatcagct gccgggccag ccaggacatt tccaagtacc tgaattggta ccagcagaag 180

cccgatggta ctgtgaaact cctgatatat catacttcta ggctccattc cggggttcca 240

agccgattca gtggctccgg ttccggtaca gattattccc tgaccattag caacttggaa 300

caggaggaca ttgcaacgta tttctgtcag caaggcaaca cattgcccta cacattcggg 360

ggcgggacta aactcgaaat aactggcggc gggggttctg gtggcggcgg cagcggcggt 420

ggaggatcag aagtgaagct gcaggaaagt ggccccgggc tggtagcccc aagtcagtcc 480

ctgagtgtaa cctgtacagt gagtggagtg tctcttcctg actacggggt aagttggatt 540

cggcaacctc cacgcaaggg cctggagtgg ctcggcgtga tttggggatc tgagacaact 600

tactacaatt ccgccctgaa gagcaggctg accatcatta aggacaatag caagtcacag 660

gtgtttctga agatgaactc actgcagacc gacgacaccg ccatctatta ctgcgccaaa 720

cattattatt atggcgggag ttatgctatg gactactggg gccagggcac tagcgtcacc 780

gtcagcagta ctacaactcc agcacccaga ccccctacac ctgctccaac tatcgcaagt 840

cagcccctgt cactgcgccc tgaagcctgt cgccctgctg ccgggggagc tgtgcatact 900

cggggactgg actttgcctg tgatatctac ttctgggtgc tggtcgtggt cggaggggtg 960

ctggcctgtt atagcctgct ggtgactgtc gccttcatta tcttctgggt gcggagcaag 1020

aggtctcgcg gtgggcattc cgactacatg aacatgaccc ctagaaggcc tggcccaacc 1080

agaaagcact accagccata cgcccctccc agagatttcg ccgcttatcg aagcaaaaaa 1140

aggattaagc ctatcgtatg gcccagtctc cccgatcata agaagactct ggaacatctt 1200

tgtaagaaac caagaaaaaa tttaaatgtg agtcttactt ccctgggatc aaatcaagaa 1260

gaagcatatg tcaccatgtc cagcttctac caaaaccagg tgaagttctc ccgaagcgca 1320

gatgccccag cctatcagca gggacagaat cagctgtaca acgagctgaa cctgggaaga 1380

cgggaggaat acgatgtgct ggacaaaagg cggggcagag atcctgagat gggcggcaaa 1440

ccaagacgga agaaccccca ggaaggtctg tataatgagc tgcagaaaga caagatggct 1500

gaggcctact cagaaatcgg gatgaagggc gaaagaagga gaggaaaagg ccacgacgga 1560

ctgtaccagg ggctgagtac agcaacaaaa gacacctatg acgctctgca catgcaggct 1620

ctgccaccaa ga 1632

<210> 48

<211> 1632

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-IL5 nucleic acid sequence

<400> 48

atggctctgc ctgtgaccgc cctgctgctg cctctggctc tgctgctgca cgccgctcgg 60

cctgacattc agatgactca gaccacaagc agcctcagtg cgagcctggg ggacagggtg 120

actatcagct gccgggccag ccaggacatt tccaagtacc tgaattggta ccagcagaag 180

cccgatggta ctgtgaaact cctgatatat catacttcta ggctccattc cggggttcca 240

agccgattca gtggctccgg ttccggtaca gattattccc tgaccattag caacttggaa 300

caggaggaca ttgcaacgta tttctgtcag caaggcaaca cattgcccta cacattcggg 360

ggcgggacta aactcgaaat aactggcggc gggggttctg gtggcggcgg cagcggcggt 420

ggaggatcag aagtgaagct gcaggaaagt ggccccgggc tggtagcccc aagtcagtcc 480

ctgagtgtaa cctgtacagt gagtggagtg tctcttcctg actacggggt aagttggatt 540

cggcaacctc cacgcaaggg cctggagtgg ctcggcgtga tttggggatc tgagacaact 600

tactacaatt ccgccctgaa gagcaggctg accatcatta aggacaatag caagtcacag 660

gtgtttctga agatgaactc actgcagacc gacgacaccg ccatctatta ctgcgccaaa 720

cattattatt atggcgggag ttatgctatg gactactggg gccagggcac tagcgtcacc 780

gtcagcagta ctacaactcc agcacccaga ccccctacac ctgctccaac tatcgcaagt 840

cagcccctgt cactgcgccc tgaagcctgt cgccctgctg ccgggggagc tgtgcatact 900

cggggactgg actttgcctg tgatatctac ttctgggtgc tggtcgtggt cggaggggtg 960

ctggcctgtt atagcctgct ggtgactgtc gccttcatta tcttctgggt gcggagcaag 1020

aggtctcgcg gtgggcattc cgactacatg aacatgaccc ctagaaggcc tggcccaacc 1080

agaaagcact accagccata cgcccctccc agagatttcg ccgcttatcg aagcaaaaaa 1140

aggattaagc ctatcgtatg gcccagtctc cccgatcata agaagactct ggaacatctt 1200

tgtaagaaac caagaaaaaa tttaaatgtg agtcttactt ccctgggatc aaatcaagaa 1260

gaagcatatg tcaccatgtc cagcttctac caaaaccagg tgaagttctc ccgaagcgca 1320

gatgccccag cctatcagca gggacagaat cagctgtaca acgagctgaa cctgggaaga 1380

cgggaggaat acgatgtgct ggacaaaagg cggggcagag atcctgagat gggcggcaaa 1440

ccaagacgga agaaccccca ggaaggtctg tataatgagc tgcagaaaga caagatggct 1500

gaggcctact cagaaatcgg gatgaagggc gaaagaagga gaggaaaagg ccacgacgga 1560

ctgtaccagg ggctgagtac agcaacaaaa gacacctatg acgcttaccg ccaccaggct 1620

ctgccaccaa ga 1632

<210> 49

<211> 2037

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-IL6 nucleic acid sequence

<400> 49

atggctctgc ctgtgaccgc cctgctgctg cctctggctc tgctgctgca cgccgctcgg 60

cctgacattc agatgactca gaccacaagc agcctcagtg cgagcctggg ggacagggtg 120

actatcagct gccgggccag ccaggacatt tccaagtacc tgaattggta ccagcagaag 180

cccgatggta ctgtgaaact cctgatatat catacttcta ggctccattc cggggttcca 240

agccgattca gtggctccgg ttccggtaca gattattccc tgaccattag caacttggaa 300

caggaggaca ttgcaacgta tttctgtcag caaggcaaca cattgcccta cacattcggg 360

ggcgggacta aactcgaaat aactggcggc gggggttctg gtggcggcgg cagcggcggt 420

ggaggatcag aagtgaagct gcaggaaagt ggccccgggc tggtagcccc aagtcagtcc 480

ctgagtgtaa cctgtacagt gagtggagtg tctcttcctg actacggggt aagttggatt 540

cggcaacctc cacgcaaggg cctggagtgg ctcggcgtga tttggggatc tgagacaact 600

tactacaatt ccgccctgaa gagcaggctg accatcatta aggacaatag caagtcacag 660

gtgtttctga agatgaactc actgcagacc gacgacaccg ccatctatta ctgcgccaaa 720

cattattatt atggcgggag ttatgctatg gactactggg gccagggcac tagcgtcacc 780

gtcagcagta ctacaactcc agcacccaga ccccctacac ctgctccaac tatcgcaagt 840

cagcccctgt cactgcgccc tgaagcctgt cgccctgctg ccgggggagc tgtgcatact 900

cggggactgg actttgcctg tgatatctac ttctgggtgc tggtcgtggt cggaggggtg 960

ctggcctgtt atagcctgct ggtgactgtc gccttcatta tcttctgggt gcggagcaag 1020

aggtctcgcg gtgggcattc cgactacatg aacatgaccc ctagaaggcc tggcccaacc 1080

agaaagcact accagccata cgcccctccc agagatttcg ccgcttatcg aagcaaaaaa 1140

aggattaagc ctatcgtatg gcccagtctc cccgatcata agaagactct ggaacatctt 1200

tgtaagaaac caagaaaaaa tttaaatgtg agtcttactt ccctgggatc aaatcaagaa 1260

gaagcatatg tcaccatgtc cagcttctac caaaaccagg tgaagttctc ccgaagcgca 1320

gatgccccag cctatcagca gggacagaat cagctgtaca acgagctgaa cctgggaaga 1380

cgggaggaat acgatgtgct ggacaaaagg cggggcagag atcctgagat gggcggcaaa 1440

ccaagacgga agaaccccca ggaaggtctg tataatgagc tgcagaaaga caagatggct 1500

gaggcctact cagaaatcgg gatgaagggc gaaagaagga gaggaaaagg ccacgacgga 1560

ctgtaccagg ggctgagtac agcaacaaaa gacacctatg acgctctgca catgcaggct 1620

ctgccaccaa gaagcctgaa gacccatcca ttgtggaggc tatggaagaa gatatgggcc 1680

gtccccagcc ctgagcggtt cttcatgccc ctgtacaagg gctgcagcgg agacttcaag 1740

aaatgggtgg gtgcaccctt cactggctcc agcctggagc tgggaccctg gagcccagag 1800

gtgccctcca ccctggaggt gtacagctgc cacccaccac ggagcccggc caagaggctg 1860

cagctcacgg agctacaaga accagcagag ctggtggagt ctgacggtgt gcccaagccc 1920

agcagccctg tggagtgtga cttcaccagc cccggggacg aaggaccccc ccggagctac 1980

ctccgccagt gggtggtcat tcctccgcca ctttcgagcc ctggacccca ggccagc 2037

<210> 50

<211> 2055

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-IL7 nucleic acid sequence

<400> 50

atggctctgc ctgtgaccgc cctgctgctg cctctggctc tgctgctgca cgccgctcgg 60

cctgacattc agatgactca gaccacaagc agcctcagtg cgagcctggg ggacagggtg 120

actatcagct gccgggccag ccaggacatt tccaagtacc tgaattggta ccagcagaag 180

cccgatggta ctgtgaaact cctgatatat catacttcta ggctccattc cggggttcca 240

agccgattca gtggctccgg ttccggtaca gattattccc tgaccattag caacttggaa 300

caggaggaca ttgcaacgta tttctgtcag caaggcaaca cattgcccta cacattcggg 360

ggcgggacta aactcgaaat aactggcggc gggggttctg gtggcggcgg cagcggcggt 420

ggaggatcag aagtgaagct gcaggaaagt ggccccgggc tggtagcccc aagtcagtcc 480

ctgagtgtaa cctgtacagt gagtggagtg tctcttcctg actacggggt aagttggatt 540

cggcaacctc cacgcaaggg cctggagtgg ctcggcgtga tttggggatc tgagacaact 600

tactacaatt ccgccctgaa gagcaggctg accatcatta aggacaatag caagtcacag 660

gtgtttctga agatgaactc actgcagacc gacgacaccg ccatctatta ctgcgccaaa 720

cattattatt atggcgggag ttatgctatg gactactggg gccagggcac tagcgtcacc 780

gtcagcagta ctacaactcc agcacccaga ccccctacac ctgctccaac tatcgcaagt 840

cagcccctgt cactgcgccc tgaagcctgt cgccctgctg ccgggggagc tgtgcatact 900

cggggactgg actttgcctg tgatatctac cctatcttac taacttgtcc caccatcagc 960

attttgagtt ttttctctgt cgctctgttg gtcatcttgg cctgtgtgtt atggaaaaaa 1020

aggattaagc ctatcgtatg gcccagtctc cccgatcata agaagactct ggaacatctt 1080

tgtaagaaac caagaaaaaa tttaaatgtg agtttcaatc ctgaaagttt cctggactgc 1140

cagattcata gggtggatga cattcaagct agagatgaag tggaaggttt tctgcaagat 1200

acgtttcctc agcaactaga agaatctgag aagcagaggc ttggagggga tgtgcagagc 1260

cccaactgcc catctgagga tgtagtcatc actccagaaa gctttggaag agattcatcc 1320

ctcacatgcc tggctgggaa tgtcagtgca tgtgacgccc ctattctctc ctcttccagg 1380

tccctagact gcagggagag tggcaagaat gggcctcatg tgtaccagga cctcctgctt 1440

agccttggga ctacaaacag cacgctgccc cctccatttt ctctccaatc tggaatcctg 1500

acattgaacc cagttgctca gggtcagccc attcttactt ccctgggatc aaatcaagaa 1560

gaagcatatg tcaccatgtc cagcttctac caaaaccagc ggagcaagag gtctcgcggt 1620

gggcattccg actacatgaa catgacccct agaaggcctg gcccaaccag aaagcactac 1680

cagccatacg cccctcccag agatttcgcc gcttatcgaa gcgtgaagtt ctcccgaagc 1740

gcagatgccc cagcctatca gcagggacag aatcagctgt acaacgagct gaacctggga 1800

agacgggagg aatacgatgt gctggacaaa aggcggggca gagatcctga gatgggcggc 1860

aaaccaagac ggaagaaccc ccaggaaggt ctgtataatg agctgcagaa agacaagatg 1920

gctgaggcct actcagaaat cgggatgaag ggcgaaagaa ggagaggaaa aggccacgac 1980

ggactgtacc aggggctgag tacagcaaca aaagacacct atgacgctct gcacatgcag 2040

gctctgccac caaga 2055

<210> 51

<211> 1872

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> 28z-IL8 nucleic acid sequence

<400> 51

atggctctgc ctgtgaccgc cctgctgctg cctctggctc tgctgctgca cgccgctcgg 60

cctgacattc agatgactca gaccacaagc agcctcagtg cgagcctggg ggacagggtg 120

actatcagct gccgggccag ccaggacatt tccaagtacc tgaattggta ccagcagaag 180

cccgatggta ctgtgaaact cctgatatat catacttcta ggctccattc cggggttcca 240

agccgattca gtggctccgg ttccggtaca gattattccc tgaccattag caacttggaa 300

caggaggaca ttgcaacgta tttctgtcag caaggcaaca cattgcccta cacattcggg 360

ggcgggacta aactcgaaat aactggcggc gggggttctg gtggcggcgg cagcggcggt 420

ggaggatcag aagtgaagct gcaggaaagt ggccccgggc tggtagcccc aagtcagtcc 480

ctgagtgtaa cctgtacagt gagtggagtg tctcttcctg actacggggt aagttggatt 540

cggcaacctc cacgcaaggg cctggagtgg ctcggcgtga tttggggatc tgagacaact 600

tactacaatt ccgccctgaa gagcaggctg accatcatta aggacaatag caagtcacag 660

gtgtttctga agatgaactc actgcagacc gacgacaccg ccatctatta ctgcgccaaa 720

cattattatt atggcgggag ttatgctatg gactactggg gccagggcac tagcgtcacc 780

gtcagcagta ctacaactcc agcacccaga ccccctacac ctgctccaac tatcgcaagt 840

cagcccctgt cactgcgccc tgaagcctgt cgccctgctg ccgggggagc tgtgcatact 900

cggggactgg actttgcctg tgatatctac ttctgggtgc tggtcgtggt cggaggggtg 960

ctggcctgtt atagcctgct ggtgactgtc gccttcatta tcttctgggt gcggagcaag 1020

aggtctcgcg gtgggcattc cgactacatg aacatgaccc ctagaaggcc tggcccaacc 1080

agaaagcact accagccata cgcccctccc agagatttcg ccgcttatcg aagcagcctg 1140

aagacccatc cattgtggag gctatggaag aagatatggg ccgtccccag ccctgagcgg 1200

ttcttcatgc ccctgtacaa gggctgcagc ggagacttca agaaatgggt gggtgcaccc 1260

ttcactggct ccagcctgga gctgggaccc tggagcccag aggtgccctc caccctggag 1320

gtgtacagct gccacccacc acggagcccg gccaagaggc tgcagctcac ggagctacaa 1380

gaaccagcag agctggtgga gtctgacggt gtgcccaagc ccagcagccc tgtggagtgt 1440

gacttcacca gccccgggga cgaaggaccc ccccggagct acctccgcca gtgggtggtc 1500

attcctccgc cactttcgag ccctggaccc caggccagcg tgaagttctc ccgaagcgca 1560

gatgccccag cctatcagca gggacagaat cagctgtaca acgagctgaa cctgggaaga 1620

cgggaggaat acgatgtgct ggacaaaagg cggggcagag atcctgagat gggcggcaaa 1680

ccaagacgga agaaccccca ggaaggtctg tataatgagc tgcagaaaga caagatggct 1740

gaggcctact cagaaatcgg gatgaagggc gaaagaagga gaggaaaagg ccacgacgga 1800

ctgtaccagg ggctgagtac agcaacaaaa gacacctatg acgctctgca catgcaggct 1860

ctgccaccaa ga 1872

<210> 52

<211> 242

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD19 scFv amino acid sequence

<400> 52

Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile

35 40 45

Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Gly Gly Gly Gly Ser

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu

115 120 125

Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys

130 135 140

Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg

145 150 155 160

Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser

165 170 175

Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile

180 185 190

Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln

195 200 205

Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly

210 215 220

Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val

225 230 235 240

Ser Ser

<210> 53

<211> 249

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> BCMA scFv amino acid sequence

<400> 53

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Ser Val Ile

20 25 30

Gly Ala His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Thr Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ala Glu Asp Ala Ala Ile Tyr Tyr Cys Leu Gln Ser Arg

85 90 95

Ile Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly

100 105 110

Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys

115 120 125

Gly Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly

130 135 140

Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp

145 150 155 160

Tyr Ser Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp

165 170 175

Met Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp

180 185 190

Phe Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala

195 200 205

Tyr Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr

210 215 220

Cys Ala Arg Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr

225 230 235 240

Leu Val Thr Val Ser Ser Ala Ala Ala

245

<210> 54

<211> 45

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of CD8a hinge region

<400> 54

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

1 5 10 15

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

20 25 30

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

35 40 45

<210> 55

<211> 24

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of CD8 alpha transmembrane region

<400> 55

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

1 5 10 15

Ser Leu Val Ile Thr Leu Tyr Cys

20

<210> 56

<211> 42

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of 4-1BB co-stimulatory domain

<400> 56

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

1 5 10 15

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

20 25 30

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

35 40

<210> 57

<211> 41

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of CD28 costimulatory domain

<400> 57

Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr

1 5 10 15

Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro

20 25 30

Pro Arg Asp Phe Ala Ala Tyr Arg Ser

35 40

<210> 58

<211> 27

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of CD28 transmembrane region

<400> 58

Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu

1 5 10 15

Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val

20 25

<210> 59

<211> 112

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of intracellular signaling domain of CD3zeta

<400> 59

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly

1 5 10 15

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

20 25 30

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

35 40 45

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

50 55 60

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

65 70 75 80

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

85 90 95

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

100 105 110

<210> 60

<211> 4

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of YRRHQ

<400> 60

Tyr Arg His Gln

1

<210> 61

<211> 12

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> nucleic acid sequence of YRRHQ in BBz

<400> 61

taccgccacc ag 12

<210> 62

<211> 12

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> nucleic acid sequence of YRHQ in 28z

<400> 62

tatcgccacc ag 12

<210> 63

<211> 28

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> amino acid sequence of transmembrane domain of IL7RA

<400> 63

Pro Ile Leu Leu Thr Cys Pro Thr Ile Ser Ile Leu Ser Phe Phe Ser

1 5 10 15

Val Ala Leu Leu Val Ile Leu Ala Cys Val Leu Trp

20 25

Claims (10)

1. A modified chimeric antigen receptor comprising at least one intracellular domain derived from a cytokine receptor.

2. The modified chimeric antigen receptor of claim 1, wherein the intracellular domain is located in an intracellular portion of the modified chimeric antigen receptor.

3. The modified chimeric antigen receptor of any one of claims 1-2, wherein the cytokine receptor comprises IL7RA, IL15RA, IL9R, IL3RA, IL21R, and/or IL 23R.

4. The modified chimeric antigen receptor of any one of claims 1-3, which comprises a co-stimulatory domain.

5. The modified chimeric antigen receptor of any one of claims 1-4, which comprises an intracellular signaling domain.

6. The modified chimeric antigen receptor of any one of claims 1-5, which comprises the short peptide fragment YRRHQ.

7. The modified chimeric antigen receptor of claim 6, wherein the N-terminus of the short peptide fragment YRRHQ is linked to the C-terminus of the intracellular signaling domain.

8. The modified chimeric antigen receptor of any one of claims 1-7, which comprises a transmembrane domain.

9. The modified chimeric antigen receptor of any one of claims 1-8, which comprises a hinge region.

10. The modified chimeric antigen receptor of any one of claims 1-9, which comprises an antigen binding domain.

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