US20110027303A1 - Partial peptide of survivin presented on mhc class ii molecule and use therof - Google Patents

Partial peptide of survivin presented on mhc class ii molecule and use therof Download PDF

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US20110027303A1
US20110027303A1 US12/935,761 US93576109A US2011027303A1 US 20110027303 A1 US20110027303 A1 US 20110027303A1 US 93576109 A US93576109 A US 93576109A US 2011027303 A1 US2011027303 A1 US 2011027303A1
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cells
amino acid
hla
acid sequence
polypeptide
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Takashi Nishimura
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Tella Inc
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Bioimmulance Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001148—Regulators of development
    • A61K39/00115—Apoptosis related proteins, e.g. survivin or livin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464448—Regulators of development
    • A61K39/46445—Apoptosis related proteins, e.g. survivin or livin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4747—Apoptosis related proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/998—Proteins not provided for elsewhere

Definitions

  • the present invention relates to an antigenic polypeptide that can be used in cancer immunotherapy and to a therapeutic agent for malignant neoplasms comprising the polypeptide.
  • cancers malignant neoplasms
  • cancer immunotherapy causes regression of cancer cells by utilizing an immune system of individual patients.
  • the important point in this method is how to make the immune system recognize the cancer cells as foreign and induce immune cells that are aggressive to the cancer cells.
  • CD8-positive T cell cytotoxic T cell expressing cell surface protein CD8
  • CD4-positive T cell a T cell expressing cell surface protein CD4
  • CD8-positive T cells are those that, when activated, lyse a cell presenting antigens bound to an HLA class I molecule.
  • CD4-positive T cells are cytokine-secreting Th cells, which, upon being activated by macrophages and/or dendritic cells which present antigens on HLA class II molecules, exert a helper function for inducing and maintaining CD8-positive T cells.
  • Th cells are known to be classified by the type of cytokine that they secrete into Th1 cells (producing IFN- ⁇ or the like), Th2 cells (producing IL-4 or the like), and Th0 cells (having a low cytokine-producing ability or producing both IFN- ⁇ and IL-4), and the roles of each cell are now being elucidated.
  • CD4-positive T cells can be provided with an effector function by their indirect mechanism against MHC class II molecule-negative tumors (MHC class II-tumors) via, for example, activation of macrophages or by their direct mechanism against MHC class II-positive tumors.
  • Patent Document 1 Previous studies of T cells in human cancer immunotherapy have mainly focused on identification and induction of CD8-positive HLA class I restricted CTL response (Patent Document 1). As for CD4-positive T cells, tyrosinase, a cancer antigen; the identification of its epitope to CD4-positive T cells; and some other epitopes have been reported (Patent Document 2), but the number of reports on CD4-positive T cells is much smaller than that on CD8-positive HLA class I restricted peptide.
  • Non-Patent Document 1 Reported tyrosinase, which is expressed in normal and tumor cells of the melanocyte lineage and shown to be a specific target of CD4-positive melanoma-reactive T cells, is the only melanoma-associated and tissue-specific antigen that binds to MHC class II molecules.
  • Non-Patent Document 1 Reported tyrosinase, which is expressed in normal and tumor cells of the melanocyte lineage and shown to be a specific target of CD4-positive melanoma-reactive T cells, is the only melanoma-associated and tissue-specific antigen that binds to MHC class II molecules.
  • tyrosinase is expressed only in limited types of tumors, it can hardly be said to be a promising cancer antigen in cancer immunotherapy.
  • Non-Patent Document 2 A gene, referred to as Survivin, which encodes tumor-specific antigens that can be recognized by CD8-positive T cells has recently been reported (Non-Patent Document 2).
  • Survivin is a 142-amino acid residue protein identified as a substance that inhibits apoptotic action. It has been reported that Survivin is distinctively characterized by its upregulated expression in limited normal tissues such as fetal tissues, and thymus and testis of adult; and in tumor tissues, particularly tumorigenic lung, colon, mammary gland, spleen, prostate gland, and lymphoma (Non-Patent Document 2).
  • Non-Patent Document 3 since the peptide reported in Non-Patent Document 3 restricts limited HLA types of HLA class II, it is necessary to use multiple peptides, which are applicable to more HLA types, to be clinically available.
  • Patent Document 1
  • Patent Document 2
  • the present invention provides a novel tumor antigen, a novel therapeutic agent useful in the method of treating malignant neoplasms by using the tumor antigen, and a tumor antigen that can be used in the therapeutic agent.
  • the present inventors experimentally found that a therapeutic agent containing tumor antigens and Th cells specific to the tumor antigens has an effect of causing a significant regression of malignant neoplasms expressing the tumor antigens, and further identified a novel antigenic peptide that can be used as the tumor antigens, thereby completing each of the following inventions.
  • a polypeptide comprising any of the amino acid sequences a) to g) below and having an activity to produce cytokines in Th cells specific to Survivin:
  • polypeptide according to (1) wherein a polypeptide comprising amino acid sequences b) to g) has an epitope of a polypeptide comprising the amino acid sequence represented by SEQ ID No:17, the epitope inducing Th cells specific to Survivin from CD4-positive T cells.
  • a method for inducing Th cells specific to Survivin comprising a process for incubating in vitro at least one of the polypeptides according to (1) and (2), antigen-presenting cells and CD4-positive T cells.
  • a therapeutic agent for malignant neoplasms comprising the polypeptide according to (1) or (2) and Th cells specific to the polypeptide or Survivin.
  • the peptide of the present invention induces Th cells specific to Survivin (hereinafter referred to as Sur/Th cells) by incubating the peptide with antigen-presenting cells and CD4-positive T cells and has an activity to produce cytokines in the Sur/Th cells. Since the Sur/Th cells specifically attacks the malignant neoplasms expressing Survivin, the Peptide of the present invention can be used as an ingredient of a therapeutic agent for malignant neoplasms.
  • polypeptide of the present invention having a small number of constituent amino acid residues, can be produced in large quantities not only by gene recombination techniques but also by organic synthetic methods, the polypeptide can be supplied in clinical studies and applications stably and inexpensively.
  • a therapeutic agent for malignant neoplasms comprising the polypeptide of the present invention, by combining tumor antigens with Th cells specific to the tumor antigens, can more strongly promote the production of cytokines in the Th cells.
  • the cytokines produced induce in vivo antitumor immune response specific to the malignant neoplasms expressing the tumor antigens to cause regression of the tumor.
  • FIG. 1 shows the results of the intracellular staining showing the measurements of the production of INF- ⁇ by Sur/Th cells where each of the mixed peptides MIX1 to MIX5 was added to the group of cells comprising the Sur/Th cells induced from a human whose HLA genotype is HLA-DRB1*0101/HLA-DRB1*0901.
  • the ordinate indicates the CD4 expression level and the abscissa the INF- ⁇ expression level
  • FIG. 2 shows the results of the intracellular staining showing the measurements of the production of INF- ⁇ by Sur/Th cells where each of the polypeptides SU16 to SU22 was added to the group of cells comprising the Sur/Th cells induced from a human whose HLA genotype is HLA-DRB1*0101/HLA-DRB1*0901.
  • the ordinate indicates the CD4 expression level and the abscissa the INF- ⁇ expression level
  • FIG. 3 shows the results of the measurements by ELISA of the production of INF- ⁇ by Sur/Th cells where each of the anti-HLA-DP antibodies, anti-HLA-DQ antibodies, and anti-HLA-DR antibodies was added to the group of cells comprising the Sur/Th cells induced from a human whose HLA genotype is HLA-DRB1*0101/HLA-DRB1*0901.
  • the ordinate indicates the production amount of IFN- ⁇ (IFN-g);
  • FIG. 4 shows the results of the measurements by ELISA of the production of INF- ⁇ by Sur/Th cells where SU18 (cognate) was added to the group of cells comprising the Sur/Th cells induced from a human whose HLA genotype is HLA-DRB1*0101/HLA-DRB1*0901 and control peptides (irrelevant) were added to allogeneic PBMCs, each HLA genotype of which is HLA-DRB1*1201/HLA-DRB1*1405, HLA-DRB1*0410/HLA-DRB1*1201, HLA-DRB1*0405/HLA-DRB1*0901, HLA-DRB1*0401/HLA-DRB1*0901, HLA-DRB1*0101/HLA-DRB1*0802, and HLA-DRB1*0101/HLA-DRB1*0101.
  • the ordinate indicates the each HLA genotype of PBMCs used as antigen-presenting
  • FIG. 5 shows the results of the measurements by ELISA of the production of INF- ⁇ by Sur/Th cells where each of the polypeptides T1 to T11 was added to the Sur/Th cell induced from a human whose HLA genotype is HLA-DRB1*0101.
  • the ordinate indicates amino acid sequence of polypeptide added and the abscissa indicates the production amount of IFN- ⁇ (IFN-g);
  • FIG. 6 shows the results of the measurements by the ELISPOT assay for the INF- ⁇ (IFN-g)-producing cell numbers in Sur/Th cells where each of the polypeptides T1 to T10 was added to the Sur/Th cells induced from a human whose HLA genotype is HLA-DRB1*1201/HLA-DRB1*1502;
  • FIG. 7 shows the results of the measurements by ELISA of the production of INF- ⁇ by Sur/Th cells where each of the anti-HLA-DP monoclonal antibody (mAb), anti-HLA-DQ mAb, and anti-HLA-DR mAb was added to the Sur/Th cells induced from a human whose HLA genotype is HLA-DQB1*0302/HLA-DQB1*0601.
  • the ordinate indicates the production amount of IFN- ⁇ (IFN-g);
  • FIG. 8 shows the results of the measurements by ELISA of the production of INF- ⁇ by Sur/Th cells where SU18 (cognate) or control (irrelevant) peptides were added to the cells comprising the Sur/Th cells induced from a human whose HLA genotype is HLA-DQB1*0302/HLA-DQB1*0601 with allogeneic PBMCs, each HLA genotype of which is HLA-DQB1*0301/HLA-DQB1*0302, HLA-DQB1*0401/HLA-DQB1*0602, HLA-DQB1*0302/HLA-DQB1*0401, and HLA-DQB1*0301/HLA-DQB1*0601.
  • the ordinate indicates amino acid sequence of polypeptide added and the abscissa indicates the production amount of IFN- ⁇ (IFN-g);
  • FIG. 9 shows the results of the measurements by ELISA of the production of INF- ⁇ by Sur/Th cells where each of the polypeptides T1 to T10 was added to the Sur/Th cells induced from a human whose HLA genotype is HLA-DQB1*0601.
  • the ordinate indicates amino acid sequence of polypeptide added and the abscissa indicates the production amount of IFN- ⁇ (IFN-g); and
  • FIG. 10 shows the results of the measurements by ELISA of the production of INF- ⁇ by Sur/Th cells where each of the polypeptides S1 to S17 was added to the Sur/Th cells induced from a human whose HLA genotype is HLA-DQB1*0601.
  • the ordinate indicates amino acid sequence of polypeptide added and the abscissa indicates the production amount of IFN- ⁇ (IFN-g).
  • the present invention relates to a partial polypeptide of Survivin, a tumor antigen comprising the partial polypeptide, and a therapeutic agent for malignant neoplasms comprising the tumor antigen and Th cells specific to the tumor antigen.
  • This invented therapeutic agent for malignant neoplasms is the therapeutic agent preferably comprising tumor antigen comprising partial polypeptide of Survivin and cognate tumor antigen-specific Th cells induced from CD4-positive T cells of patient to be treated.
  • this invented therapeutic agent for malignant neoplasms comprises tumor antigens, a partial polypeptide of Survivin, in combination with Th cells specific to the tumor antigens, the agent exerts a significant effect in regression of malignant neoplasms compared to the case where the tumor antigens or the Th cells specific to the tumor antigens are separately administered to a patient.
  • Th cells specific to the tumor antigens comprising a partial polypeptide of Survivin may be any of Th0 cells, Th1 cells, or Th2 cells as long as they are Th cells that produce cytokines by specific stimulation by the tumor antigens, and more preferably Th1 cell.
  • Th cells specific to such tumor antigens can be induced and prepared from the CD4-positive T cells by incubating the tumor antigens, antigen-presenting cells expressing HLA class II molecules, and the CD4-positive T cells under appropriate conditions.
  • CD4-positive T cells that can be used in the method of the present invention can be isolated from the collected blood by common methods, for example, a method using MACS (Miltenyi Biotech) or the like.
  • CD4-positive T cells collected from a patient with malignant neoplasms to be treated are preferably used.
  • Antigen-presenting cells that can be used in the method of the present invention may be any cell expressing HLA class II molecules on their surface, examples of which include B cell, macrophage, monocyte and non-proliferative transfectant as well as dendritic cell, but are not limited thereto.
  • tumor antigens comprising a partial polypeptide of Survivin, antigen-presenting cells, and CD4-positive T cells may be simultaneously incubated, or after the tumor antigens and the antigen-presenting cells are incubated, they may be incubated together with the CD4-positive T cells.
  • the incubation may be carried out under the conditions in accordance with a common method by which, in the presence of IL-2, the desired antigen is presented by the antigen-presenting cells via HLA Class II molecules and mature Th cells specific to the antigen are induced from CD4-positive T cells, e.g., the method described in Tim et al., (Immunology Today, 1996, Vol. 17, No. 3, pp. 138-146).
  • any of Th0 cells, Th1 cells, or Th2 cells can be specifically induced from CD4-positive T cells by changing incubation conditions variously.
  • Th0 cells, Th1 cells, or Th2 cells can be confirmed by observing cytokines in each cell produced when the cell was restimulated with a tumor antigen, a partial polypeptide of Survivin (e.g., Tim et al., mentioned above). Cytokine production can be confirmed, using ELISA, intracellular staining, ELISPOT, and other various methods.
  • polypeptide of the present invention is an antigen polypeptide corresponding to an amino acid sequence of NO. 76 to 94 of a tumor antigen protein (the above Non-Patent Document 2) (SEQ ID NO:17, hereinafter referred to as SU18), referred to as Survivin.
  • SEQ ID NO:17 the above Non-Patent Document 2
  • SU18 a tumor antigen protein
  • polypeptides comprising the amino acid sequences having such relations as b) to g) below with the amino acid sequences of the polypeptide, SU18 (SEQ ID NO:17), also can be used as the tumor antigen of the present invention.
  • amino acid sequences of b) to g) described above are defined as an amino acid sequence constituting a polypeptide that retains epitopes existing in SU18 and has an activity to produce cytokines in Sur/Th cells, or that has epitopes that induces Th cells specific to Survivin or SU18 from CD4-positive T cells.
  • amino acid residues that are substituted, deleted, or added, as defined in b) to g), are not particularly limited within a range where the activities or functions of the polypeptide described above are maintained, addition of one to several tens of amino acids in b) and f) means addition of 1 to 50 amino acids, preferably 1 to 30 amino acids, and more preferably 1 to 15 amino acids.
  • Preferred examples of the substitution, deletion, or addition of the amino acid as described above are silent substitution, deletion, and addition; especially preferred is conservative amino acid substitution. These examples do not change an activity to produce cytokines in the Sur/Th cells of the polypeptide in the present invention or epitopes that induce Th cells specific to Survivin or SU18 from CD4-positive T cells.
  • Typical examples of the conservative substitution include mutual substitution of hydrophobic amino acids, Ala, Val, Leu, and Ile; mutual substitution of hydroxyl amino acids, Ser and Thr; mutual substitution of acidic residues, Asp and Glu; mutual substitution of amide type amino acids, Asn and Gln; mutual substitution of basic amino acids; Lys and Arg; and mutual substitution of aromatic amino acids, Phe and Tyr.
  • SU18 has an activity to produce cytokines in Sur/Th cells induced from CD4-positive T cells by incubating Survivin, antigen-presenting cells, and CD4-positive T cells, meaning that SU18 has epitopes that can be recognized by the Sur/Th cells and the epitopes are presented by MHC class II molecules expressing on the surface of antigen-presenting cells in which Survivin is taken up. Therefore, a therapeutic agent for malignant neoplasms comprising Survivin, SU18, and Sur/Th cells is one aspect of the present invention.
  • SU18 is believed to be a polypeptide that can be a tumor antigen not only inhuman having HLA genotype of HLA-DRB1*0101 but also in human whose HLA genotype is HLA-DRB1*1201/HLA-DRB1*1502 or HLA-DQB1*0601.
  • Every polypeptide described above is a novel polypeptide that can be used as an ingredient of a therapeutic agent for malignant neoplasms, having an activity to induce Th cells specific to the polypeptide from CD4-positive T cells and/or an activity to produce cytokines in such Th cells or Sur/Th cells.
  • the activity to produce cytokines in Th cells specific to the polypeptide or Survivin in each polypeptide described above can be confirmed by stimulating the Th cells with the polypeptide and measuring the produced cytokines by various known methods. For example, the production of interferon ⁇ (INF- ⁇ ) can be readily measured and confirmed by using commercially available ELISA kits from BD Biosciences or the like.
  • amino acid sequence constituting the polypeptide for example, His-Tag widely used as a tag sequence useful in separation and purification of proteins, an appropriate linker sequence, and an amino acid sequence of a marker protein such as GFP can be further added.
  • labeled compounds such as biotin can also be added to each polypeptide.
  • polypeptide comprising an amino acid sequence in which any amino acid residue used for the purpose of other than producing cytokines in Th cells and Sur/Th cells specific to the polypeptide and inducing the cells from CD4-positive T cells is added to the amino acid sequence constituting the polypeptide which is one aspect of the present invention
  • a polypeptide in which an appropriate labeled compound is added to the polypeptide of the present invention are still within the scope of the present invention as long as they have an activity to produce cytokines in the cells or they have an epitope that induces specific Th cells from CD4-positive T cells.
  • the polypeptide of the present invention can be produced as a recombinant protein by applying various known gene recombination techniques to DNA encoding the polypeptide.
  • the polypeptide may be produced by synthesizing the DNA, encoding the polypeptide of the present invention by using an appropriate DNA synthesizer, constructing an expression vector that expresses the polypeptide of the present invention by appropriately selecting or combining various techniques described in reference books in the art such as Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd edition (Cold Spring Harbor Laboratory Press, 1989), and transforming an appropriate host cell such as E. coli by the expression vector.
  • various operations, such as addition of His-tag used in the production of a recombinant polypeptide can be applied.
  • the polypeptide of the present invention can also be chemosynthetically produced using an amino acid modified by various protecting groups as a raw material.
  • Methods for organochemically synthesizing a polypeptide without using a gene or a host cell are well known to those skilled in the art.
  • “Jikken Kagaku Koza (Courses in Experimental Chemistry) 16, 5th edition, Yukikagobutsu-no-Gosei (Synthesis of Organic Compounds) IV” (Saburo Aimoto et al., The Chemical Society of Japan) or the like describes various methods for chemical synthesis of a polypeptide, by any of which methods the polypeptide of the present invention can be synthesized.
  • the polypeptide can also be synthesized by using a commercially available apparatus commonly referred to as a peptide synthesizer.
  • the present invention provides a method for inducing Th cells specific to the above-described polypeptide and/or Survivin by incubating in vitro antigen-presenting cells expressing HLA class II molecules, CD4-positive T cells, and the above-described polypeptide.
  • Th1 cells in addition to IL-2, one or more of IFN- ⁇ , IL-12, and anti-IL-4 antibodies are preferably added, under which conditions, Th1 cells can be induced which produces IFN- ⁇ and produces IL-4 little.
  • any antigen-presenting cell as mentioned above, can be used in this method as long as the cell expresses HLA class II molecules on its surface, examples of which include B cell, macrophage, monocyte and non-proliferative transfectant as well as dendritic cell, but are not limited thereto.
  • HLA class II molecules examples of which include B cell, macrophage, monocyte and non-proliferative transfectant as well as dendritic cell, but are not limited thereto.
  • the above-described polypeptide, antigen-presenting cells, and CD4-positive T cells may be simultaneously incubated, or after the polypeptide of the present invention and the antigen-presenting cells are incubated, they may be incubated together with the CD4-positive T cells.
  • Sur/Th cells can be induced and cultured in vitro by collecting antigen-presenting cells and CD4-positive T cells from a patient and incubating these cells and the polypeptide of the present invention. It is expected that return of the Sur/Th cells induced by this method into the patient can activate the immune system of the patient him/herself and cause regression of tumor cells.
  • the therapeutic agent for malignant neoplasms of the present invention may contain tumor antigens and Th cells specific to the tumor-specific antigen; it may also contain, to the extent that their actions are not inhibited, various excipients commonly used for formulation of drugs, other pharmaceutically active ingredients or the like.
  • the therapeutic agent for malignant neoplasms of the present invention is preferably in the form of a buffer solution or a liquid medium that can stably retain the tumor antigens and the Th cells specific to the tumor-specific antigens.
  • Non-limiting examples of the buffer solution include a neutral buffered saline or a phosphate-buffered saline.
  • the buffer solution may further contain saccharides such as glucose, mannose, sucrose, dextran, and mannitol, proteins, amino acids, antioxidants, bacteriostatic agents, chelating agents (e.g., EDTA or glutathione), adjuvants (e.g. aluminum hydroxide), osmoregulatory agents, suspensions, thickening agents, and/or preservatives.
  • the therapeutic agent for malignant neoplasms of the present invention is preferably in the form of a mixture of tumor antigens and Th cells specific to the tumor-specific antigens
  • the agent may also be in the form of so-called a kit in which the tumor antigens and the Th cells specific to the tumor-specific antigens, which can be administered in admixture when used, are stored separately.
  • peptide mixtures composed of five peptides were prepared in the order from SU1 to SU27 (SU17 and SU19 were retired), for example, the peptide mixture of SU1 to SU5, the peptide mixture of SU6 to SU10, etc.
  • PBMC Peripheral blood mononuclear cells
  • PBMC-Ad monocyte-derived antigen-presenting cells
  • PBMC-nonAd non-adherent PBMCs obtained in induction of PBMCs-Ad using Easy Sep (VERITAS).
  • the cells were collected, and in a 96-well U-bottom plate (BD Biosciences) with 200 ⁇ L of 5% human serum in AIM-V, each of MIX1, MIX2, MIX3, MIX4, and MIX5 (10 ⁇ g/mL) was added to the PBMCs (1 ⁇ 10 5 cells/well) and the Th cell group (4 ⁇ 10 4 cell/well) comprising Sur/Th cells previously stained with PE-labeled anti-CD4 antibodies, and the resultants were co-cultured in a CO 2 incubator at 37° C. for 2 hours. Thereafter ⁇ L of brefeldine A 500 ⁇ g/mL (BFA; Sigma, Ayrshire) was added and the resultants were further co-cultured for 4 hours.
  • BFA brefeldine A 500 ⁇ g/mL
  • the cells were collected, and 200 ⁇ L of Fixation and Permeabilization solution (BD Biosciences) was added thereto. After being left to stand at room temperature for 20 minutes, the resultant was washed with 0.5% BSA/PBS. FITC-labeled IFN- ⁇ antibodies were added to the resultant, which was stained at room temperature for 15 minutes. The resultant was washed with 0.5% BSA/PBS, and a fluorescence signal was incorporated thereinto using flowcytometry (FACS Calibur, BD Biosciences). By using CellQuestTM (BD Biosciences), 3-colour analysis was performed. The results are shown in FIG. 1 .
  • Th cell group comprising Sur/Th cells which react specifically with MIX4 was obtained.
  • the polypeptide was identified by using the Th cell group obtained in this Example 3) comprising Sur/Th cells which react specifically with MIX4.
  • each of SU16, SU18, SU20, SU21, and SU22 was added, to a final concentration of 10 ⁇ g/mL, to the PBMCs (1 ⁇ 10 5 cells/well) and the Th cell group (4 ⁇ 10 4 cell/well) previously stained with PE-labeled anti-CD4 antibodies, the cell group comprising the above-described Sur/Th cells which react specifically with cells using MIX4.
  • the resultants were co-cultured in a CO 2 incubator at 37° C. for 2 hours.
  • brefeldine A 500 ⁇ g/mL (BFA; Sigma, Ayrshire) was added and the resultants were further co-cultured for 4 hours.
  • the cells were collected, and 200 ⁇ L of Fixation and Permeabilization solution (BD Biosciences) was added thereto. After being left to stand at room temperature for 20 minutes, the resultant was washed with 0.5% BSA/PBS. FITC-labeled. IFN- ⁇ antibodies were added to each resultant, which was stained at room temperature for 15 minutes.
  • HLA-restrictivity for SU18 was confirmed by using inhibitory antibodies and the Th cell group obtained in Example 1-4) comprising Sur/Th cells which react specifically with SU18.
  • each of anti-HLA-DP antibodies (Serotech), anti-HLA-DQ antibodies (Serotech) and anti-HLA-DR antibodies was added, to a final concentration of 5 ⁇ g/mL, to the PBMCs (1 ⁇ 10 5 cells/well) and the above-described Th cell group (5'10 4 cell/well) comprising Sur/Th cells which react specifically with SU18.
  • the resultants were co-cultured in the presence of SU18 peptides in a CO 2 incubator at 37° C. for 24 hours. After the culturing, the IFN- ⁇ contained in the culture supernatant was measured by using an ELISA kit (BD Biosciences). The results are shown in FIG. 3 .
  • HLA-DRB1*0101 and HLA-DRB1*0901 HLA-DR-restrictivity was confirmed by using allogeneic antigen-presenting cells to the Th cell group obtained in Example 1-4) comprising Sur/Th cells which react specifically with SU18.
  • each resultant was co-cultured with the above-described Th cell group (5 ⁇ 10 4 cell/well) comprising Sur/Th cells which react specifically with SU18 in a 96-well U-bottom plate (BD Biosciences) with 200 ⁇ L, of 5% human serum in AIM-V in a CO 2 incubator at 37° C. for 24 hours.
  • the IFN- ⁇ contained in the culture supernatant was measured by using an ELISA kit (BD Biosciences). The results are shown in FIG. 4 .
  • the recognition site in partially deleted SU18 was confirmed by using the Th cell group obtained in Example 1-4) comprising Sur/Th cells which react specifically with SU18 and the overlapping peptides T1 to T11 shown in Table 2, which are peptides for stimulation.
  • each of the overlapping peptides T1 to T11 was added, to a final concentration of 10 ⁇ g/mL, to the PBMCs (1 ⁇ 10 5 cells/well) and the above-described Th cell group (5 ⁇ 10 4 cell/well) comprising Sur/Th cells which react specifically with SU18.
  • the resultants were co-cultured in a CO 2 incubator at 37° C. for 24 hours. After the culturing, the IFN- ⁇ contained in the culture supernatant was measured by using an ELISA kit (BD Biosciences). The results are shown in FIG. 5 .
  • Th cell group comprising Sur/Th cells was prepared from peripheral blood of a healthy individual whose HLA genotype is HLA-DRB1*1201/HLA-DRB1*1502.
  • a 96-well U-bottom plate was provided with the culture containing 200 ⁇ L of the complex medium of human serum and fetal calf serum (2.5% human serum, 2.5% fetal calf serum in AIM-V), PBMCs-Ad (5 ⁇ 10 4 cells/well), recombinant IL-2 (final concentration of 20U/mL), recombinant IL-7 (final concentration of 10 ng/mL), and phytohemagglutinin (PHA, SEIKAGAKU Co., final concentration of 5 ⁇ g/mL).
  • the Th cell group (1 cell/well) was added thereto and the resultant was co-cultured in a CO 2 incubator at 37° C.
  • the wells which showed blast transformation of the cells were scaled up into a 48-well plate with 500 ⁇ L of 5% fetal calf serum in AIM-V. Thereafter, restimulation was performed with the PBMCs-Ad pulsed with SU18 at 1-week intervals to obtain Sur/Th cell clones.
  • the recognition site in partially deleted SU18 was confirmed by the ELISPOT assay described below using the Sur/Th cell clones prepared in this Example 1) and the peptides for stimulation, T1 to T10 shown in Table 3.
  • the ELISPOT assay was performed by using an ELISPOT plate (MAHA S4510, Millipore) and an ELISPOT kit (Mabtech, Nacka). According to the method of using the kit, specifically-induced Th cells and T-APCs were cultured on the ELISPOT plate coated with anti-human IFN- ⁇ antibodies (clone name 1-D1K, mAb) at a concentration of 2 ⁇ g/mL in the presence of sufficient amount of antigen peptides. After 20 hours from the start of the culture, the culture supernatant was washed with the washing solution (0.05% Tween 20/PBS).
  • the biotinylated anti-human IFN- ⁇ antibodies (mAb) at a concentration of 0.2 ⁇ g/mL was further added to the plate, and the resultant was allowed to react at 4° C. for 16 hours. After the resultant was washed again with the washing solution above, each well was filled with 100 ⁇ L of PBS/streptavidin-AP solution (the kit above) and allowed to react at room temperature for 1 hour. Then, the supernatant was washed away with the washing solution above and the resultant was filled with BCIP/NBT-Bule Liquid substrate solution (Sigma). After 10-minute reaction, the resultant was washed with distilled water to stop the reaction. After completion of the reaction, the plate was dried and then the measurements were made by using CTL ImmunoSpot Plate Reader (Cellular Technology). The results are shown in FIG. 6 .
  • SU18 was a polypeptide which has immunotherapeutic effect not only in patients whose HLA genotype is HLA-DRB1*0101/HLA-DRB1*0901 but also in those whose HLA genotype is HLA-DRB1*1201/HLA-DRB1*1502.
  • CD4-positive T cells were prepared from the peripheral blood of healthy individual Y whose HLA genotype is HLA-DQB1*0302/HLA-DQB1*0601 by the same technique as that used in Example 1-2) and a Th cell group comprising Sur/Th cells which react specifically with SU18 was obtained by the same technique as that used in Example 1-3) and 4). HLA-restrictivity for SU18 was confirmed by using inhibitory antibodies and this Sur/Th cell group which reacts specifically with SU18.
  • each of anti-HLA-DP antibodies (Serotech), anti-HLA-DQ antibodies (Serotech) and anti-HLA-DR antibodies was added, to a final concentration of 5 ⁇ g/mL, to the PBMCs (1 ⁇ 10 5 cells/well) and the above-described Th cell group (5 ⁇ 10 4 cell/well) comprising Sur/Th cells which react specifically with SU18.
  • the resultants were co-cultured in the presence of SU18 peptides in a CO 2 incubator at 37° C. for 24 hours. After the culturing, the IFN- ⁇ contained in the culture supernatant was measured by using an ELISA kit (BD Biosciences). The results are shown in FIG. 7 .
  • HLA-DQ-restrictivity was confirmed by using allogeneic antigen-presenting cells to the Th cell group obtained in this Example 1) comprising Sur/Th cells which react specifically with SU18.
  • each resultant was co-cultured with the above-described Th cell group (5 ⁇ 10 4 cell/well) comprising Sur/Th cells which react specifically with SU18 in a 96-well U-bottom plate (BD Biosciences) with 200 ⁇ L of 5% human serum in AIM-V in a CO 2 incubator at 37° C. for 24 hours.
  • the IFN- ⁇ contained in the culture supernatant was measured by using an ELISA kit (BD Biosciences). The results are shown in FIG. 8 .
  • the recognition site in partially deleted SU18 was confirmed by using the Th cell group obtained in this Example 1-1) comprising Sur/Th cells which react specifically with SU18 and the overlapping peptides T1 to T10 shown in Table 3, which are peptides for stimulation.
  • each of the overlapping peptides T1 to T10 was added, to a final concentration of 10 ⁇ g/mL, to the PBMCs (1 ⁇ 10 5 cells/well) and the above-described Th cell group (5 ⁇ 10 4 cell/well) comprising Sur/Th cells which react specifically with SU18.
  • the resultants were co-cultured in a CO 2 incubator at 37° C. for 24 hours. After the culturing, the IFN- ⁇ contained in the culture supernatant was measured by using an ELISA kit (BD Biosciences). The results are shown in FIG. 9 .
  • the recognition site in partially substituted SU18 was confirmed by using the Th cell group obtained in this Example 1) comprising Sur/Th cells which react specifically with SU18 and the partially substituted peptides S1 to S17, peptides for stimulation shown in Table 4, in which each amino acid of SU18 was substituted with alanine (A) or glycine (G).
  • each of the partially substituted peptides S1 to S17 was added, to a final concentration of 10 ⁇ g/mL, to the PBMCs (1 ⁇ 10 5 cells/well) and the above-described Th cell group (5 ⁇ 10 4 cell/well) comprising Sur/Th cells which react specifically with SU18.
  • the resultants were co-cultured in a CO 2 incubator at 37° C. for 24 hours. After the culturing, the IFN- ⁇ contained in the culture supernatant was measured by using an ELISA kit (BD Biosciences). The results are shown in FIG. 10 .

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