Pharmaceutical composition and method for treatment or prevention of cancer

Abstract

THE present invention includes a pharmaceutical composition for the treatment or prevention of cancer in HLA-A*11:01-, HLA-A*02:01-, HLA-A*02:06-, HLA-A*02:07-, HLA-A*26:01-, HLA-A*26:03-, HLA-A*01:01-, HLA-B*15:01-, HLA-B*35:01-, HLA-C*03:03-, HLA-C*05-01-, HLA-C*07:01-, or HLA-C*07:02-positive subjects. The pharmaceutical composition includes a peptide that comprises an amino acid sequence of WAPVLDFAPPGASAYGSL (SEQ ID NO: 2), a modified peptide thereof that is CTL-inducing, or a pharmacologically acceptable salt thereof.

Description

Pharmaceutical compositions and methods for treating or preventing cancer

[0001] This application claims priority to Japanese Patent Application No. 2021-131636, the entire contents of which are incorporated herein by reference. The present disclosure relates to the field of cancer immunotherapy, and in particular to the use of cancer antigen peptides derived from the WT1 protein.

[0002] Cellular immunity, particularly cytotoxic T cells (cytotoxic T lymphocytes or cytotoxic T cells, hereinafter referred to as CTLs), plays an important role in the body's elimination of cancer cells. CTLs are generated by the differentiation and proliferation of precursor T cells that recognize complexes formed by peptides derived from cancer antigen proteins and MHC class I molecules, and attack cancer cells. It is also known that activation of helper T cells is important for enhancing CTL function. Helper T cells are generated from precursor T cells that recognize complexes of cancer antigen peptides and MHC class II molecules.

[0003] The WT1 gene was isolated as the causative gene for Wilms tumor, a childhood renal tumor. Its gene product (WT1) is highly expressed in leukemia and various solid cancers, and is a cancer antigen protein that has attracted particular attention as a target antigen for cancer vaccines. Regarding the WT1 protein, WT1 is a peptide that binds to MHC class II molecules and induces helper T cells. ３４－５１ The peptide (WAPVLDFAPPGASAYGSL) (SEQ ID NO: 2) is known (Patent Document 1).

[0004] International Publication No. 2010 / 123065

[0005] The present disclosure relates to WT1 ３４－５１ The purpose is to expand the range of applications of peptides or pharmaceutical compositions containing the same.

[0006] In one aspect, the present disclosure provides a method for detecting HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ A pharmaceutical composition is provided which comprises a peptide consisting of the amino acid sequence of WAPVLDFAPPGASAYGSL (SEQ ID NO: 2) or a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a 07:02-positive subject.

[0007] WT1 ３４－５１ The peptide or a pharmaceutical composition containing the same inhibits HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ Cancer can be treated or prevented in 07:02 positive subjects.

[0008] Figure 1 shows HLA-A ＊ 02:01 / 24:02 NAD cells of one positive case were converted to mDC / WT1 ３４－５１ After four stimulations with imDC / WT1 ３４－５１ 2 shows the frequency of IFN-γ-producing CD8-positive T cells when the cells were restimulated with HLA-A or imDC. ＊ 02:01 / 24:02 NAD cells of one positive case were converted to mDC / WT1 ３４－５１ After four stimulations with imDC / WT1３７－４５ The results are shown in Table 1. The results are compared between the case of restimulation with imDC / WT1 and the case of restimulation with imDC / WT1 without four stimulations. ３７－４５ Figure 3 shows the frequency of IFN-γ-producing CD8-positive T cells after only one stimulation with HLA-A. ＊ 02:06 / 26:03 NAD cells of one positive case were converted to mDC / WT1 ３４－５１ After four stimulations with imDC / WT1 ３７－４５ 4 shows the frequency of IFN-γ-producing CD8-positive T cells when the cells were restimulated with HLA-A or imDC. ＊ 02:07 / 24:02 NAD cells of one positive case were converted to mDC / WT1 ３４－５１ After four stimulations with imDC / WT1 ３７－４５ 5 shows the frequency of IFN-γ-producing CD8-positive T cells when the cells were restimulated with HLA-A or imDC. ＊ 26:01 / 24:02 NAD cells of one positive case were mDC / WT1 ３４－５１ or imDC / WT1 after four stimulations with mDC. ４０－４８ Figure 6 shows the frequency of IFN-γ-producing CD8-positive T cells when re-stimulated with WT1. ３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ WT1 in PBMCs of 02:01 / 24:02 positive individuals (1 case) ３７－４５ or WT1 ４０－４８ The frequency (%) of CD8-positive, IFN-γ-positive, TNF-α-positive, or IFN-γ and TNF-α-positive T cells after stimulation is shown. ３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ 02:01 / 24:02 HLA-A in PBMC of a positive individual (1 case) ＊ 02:01WT1 ３７－４５ The frequency of tetramer-positive cells is shown in Figure 8. ３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ WT1 in PBMCs of 02:06 / 24:02 positive individuals (1 case) ３７－４５ or WT1 ４０－４８ The frequency (%) of CD8-positive, IFN-γ-positive, TNF-α-positive, or IFN-γ and TNF-α-positive T cells after stimulation is shown.３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ 02:06 / 24:02 HLA-A in PBMC of a positive individual (1 case) ＊ 02:01WT1 ３７－４５ The frequency of tetramer-positive cells is shown in FIG. ３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ WT1 in PBMCs of 02:07 / 24:02 positive individuals (1 case) ３７－４５ or WT1 ４０－４８ The frequency (%) of CD8-positive, IFN-γ-positive, TNF-α-positive, or IFN-γ and TNF-α-positive T cells after stimulation is shown. ３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ 02:07 / 24:02 HLA-A in PBMC of a positive individual (1 case) ＊ 02:01WT1 ３７－４５ The frequency of tetramer-positive cells is shown in FIG. ３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ WT1 in PBMCs of 24:02 / 24:02 positive individuals (1 case) ３７－４５ or WT1 ４０－４８ The frequency (%) of CD8-positive, IFN-γ-positive, TNF-α-positive, or IFN-γ and TNF-α-positive T cells after stimulation is shown. ３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ HLA-A in PBMCs from 24:02 / 24:02 positive individuals (1 case) ＊ 02:01WT1 ３７－４５ The frequency of tetramer-positive cells is shown in FIG. ３４－５１ HLA-A stimulated by ＊ WT1 in PBMCs of 02:01 / 24:02 positive individuals (1 case) ３７－４５ or WT1 ４０－４８ The frequency (%) of CD8-positive, IFN-γ-positive, TNF-α-positive, or IFN-γ and TNF-α-positive T cells after stimulation is shown. ３４－５１ HLA-A stimulated by ＊02:01 / 24:02 HLA-A in PBMC of a positive individual (1 case) ＊ 02:01WT1 ３７－４５ The frequency of tetramer-positive cells is shown in FIG. ３４－５１ HLA-A stimulated by ＊ WT1 in PBMCs of 02:06 / 24:02 positive individuals (1 case) ３７－４５ or WT1 ４０－４８ The frequency (%) of CD8-positive, IFN-γ-positive, TNF-α-positive, or IFN-γ and TNF-α-positive T cells after stimulation is shown. ３４－５１ HLA-A stimulated by ＊ 02:06 / 24:02 HLA-A in PBMC of a positive individual (1 case) ＊ 02:01WT1 ３７－４５ The frequency of tetramer-positive cells is shown in FIG. ３４－５１ HLA-A stimulated by ＊ WT1 in PBMCs of 02:07 / 24:02 positive individuals (1 case) ３７－４５ or WT1 ４０－４８ The frequency (%) of CD8-positive, IFN-γ-positive, TNF-α-positive, or IFN-γ and TNF-α-positive T cells after stimulation is shown. ３４－５１ HLA-A stimulated by ＊ 02:07 / 24:02 HLA-A in PBMC of a positive individual (1 case) ＊ 02:01WT1 ３７－４５ The frequency of tetramer-positive cells is shown in FIG. ３４－５１ HLA-A stimulated by ＊ WT1 in PBMCs of 24:02 / 24:02 positive individuals (1 case) ３７－４５ or WT1 ４０－４８ The frequency (%) of CD8-positive, IFN-γ-positive, TNF-α-positive, or IFN-γ and TNF-α-positive T cells after stimulation is shown. ３４－５１ HLA-A stimulated by ＊ HLA-A in PBMCs from 24:02 / 24:02 positive individuals (1 case) ＊ 02:01WT1 ３７－４５ The frequency of tetramer-positive cells is shown in FIG.３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ WT1 in CD8-positive T cells in PBMCs of 01:01-positive individuals (1 case) ３７－４５ or WT1 ４０－４８ 23 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ WT1 in CD8-positive T cells in PBMCs of 01:01-positive individuals (1 case) ３７－４５ or WT1 ４０－４８ Figure 24 shows the results of flow cytometry showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ HLA-A in PBMCs from 01:01 positive individuals (1 case) ＊ 01:01 WT1 ４０－４８ The frequency of tetramer-positive cells is shown in FIG. ３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ WT1 in CD8-positive T cells in PBMCs of 26:01-positive individuals (1 case) ４０－４８ 26 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ and HLA-A stimulated by the compound of formula (5) ＊ WT1 in CD8-positive T cells in PBMCs of 26:01-positive individuals (1 case) ４０－４８ Figure 27 shows the results of flow cytometry showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ and HLA-B stimulated by the compound of formula (5) ＊ WT1 in CD8-positive T cells in PBMCs of a 35:01-positive individual (1 case) ４０－４８ 28 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ and HLA-B stimulated by the compound of formula (5) ＊WT1 in CD8-positive T cells in PBMCs of a 35:01-positive individual (1 case) ４０－４８ Figure 29 shows the results of flow cytometry showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ and HLA-B stimulated by the compound of formula (5) ＊ HLA-B in PBMCs from a 35:01 positive individual (1 case) ＊ 35:01 WT1 ４０－４８ The frequency of tetramer-positive cells is shown in Figure 30. ３４－５１ and HLA-C stimulated by the compound of formula (5) ＊ WT1 in CD8-positive T cells in PBMCs of one 03:03 positive individual (case) ４０－４８ 31 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ and HLA-C stimulated by the compound of formula (5) ＊ WT1 in CD8-positive T cells in PBMCs of one 03:03 positive individual (case) ４０－４８ Figure 32 shows the results of flow cytometry showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ and HLA-C stimulated by the compound of formula (5) ＊ WT1 in CD8-positive T cells in PBMCs of one 05:01-positive individual ３７－４５ or WT1 ４０－４８ 33 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ and HLA-C stimulated by the compound of formula (5) ＊ WT1 in CD8-positive T cells in PBMCs of one 05:01-positive individual ３７－４５ or WT1 ４０－４８ Figure 34 shows the results of flow cytometry showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ and HLA-C stimulated by the compound of formula (5) ＊ WT1 in CD8-positive T cells in PBMCs of one 07:01 positive individual (case) ４０－４８35 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ and HLA-C stimulated by the compound of formula (5) ＊ WT1 in CD8-positive T cells in PBMCs of one 07:01 positive individual (case) ４０－４８ Figure 36 shows the results of flow cytometry showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ HLA-A stimulated by ＊ WT1 in CD8-positive T cells in PBMCs of 01:01-positive individuals (1 case) ３７－４５ or WT1 ４０－４８ 37 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ HLA-A stimulated by ＊ WT1 in CD8-positive T cells in PBMCs of 01:01-positive individuals (1 case) ３７－４５ or WT1 ４０－４８ Figure 38 shows the results of flow cytometry showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ HLA-A stimulated by ＊ HLA-A in PBMCs from 01:01 positive individuals (1 case) ＊ 01:01 WT1 ４０－４８ The frequency of tetramer-positive cells is shown. ３４－５１ HLA-A stimulated by ＊ WT1 in CD8-positive T cells in PBMCs of 26:01-positive individuals (1 case) ４０－４８ 40 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ HLA-A stimulated by ＊ WT1 in CD8-positive T cells in PBMCs of 26:01-positive individuals (1 case) ４０－４８ Figure 41 shows the results of flow cytometry showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ HLA-B stimulated by ＊WT1 in CD8-positive T cells in PBMCs of a 35:01-positive individual (1 case) ４０－４８ 42 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ HLA-B stimulated by ＊ WT1 in CD8-positive T cells in PBMCs of a 35:01-positive individual (1 case) ４０－４８ Figure 43 shows the results of flow cytometry showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ HLA-B stimulated by ＊ HLA-B in PBMCs from a 35:01 positive individual (1 case) ＊ 35:01 WT1 ４０－４８ The frequency of tetramer-positive cells is shown in Figure 44. ３４－５１ HLA-C stimulated by ＊ WT1 in CD8-positive T cells in PBMCs of one 03:03 positive individual (case) ４０－４８ 45 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ HLA-C stimulated by ＊ WT1 in CD8-positive T cells in PBMCs of one 03:03 positive individual (case) ４０－４８ Flow cytometry results showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ HLA-C stimulated by ＊ WT1 in CD8-positive T cells in PBMCs of one 05:01-positive individual ３７－４５ or WT1 ４０－４８ 47 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ HLA-C stimulated by ＊ WT1 in CD8-positive T cells in PBMCs of one 05:01-positive individual ３７－４５ or WT1 ４０－４８ Figure 48 shows the results of flow cytometry showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１HLA-C stimulated by ＊ WT1 in CD8-positive T cells in PBMCs of one 07:01 positive individual (case) ４０－４８ 49 is a graph showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation. ３４－５１ HLA-C stimulated by ＊ WT1 in CD8-positive T cells in PBMCs of one 07:01 positive individual (case) ４０－４８ Flow cytometry results showing the frequency (%) of IFN-γ and / or TNF-α positive T cells after stimulation.

[0009] As used herein, "amino acid residue" refers to a portion of a peptide or protein molecule that corresponds to one unit of an amino acid that constitutes the peptide or protein. "Amino acid residue" includes natural or unnatural α-amino acid residues, β-amino acid residues, γ-amino acid residues, and δ-amino acid residues. Specific examples include natural α-amino acid residues, ornithine residues, homoserine residues, homocysteine ​​residues, β-alanine residues, γ-aminobutanoic acid, and δ-aminopentanoic acid. When the "amino acid residue" may be optically active, it may be either the L- or D-form, with the L-form being preferred.

[0010] When "amino acid residues" are abbreviated herein, they are represented by the following abbreviations: Ala or A: alanine residue, Arg or R: arginine residue, Asn or N: asparagine residue, Asp or D: aspartic acid residue, Cys or C: cysteine ​​residue, Gln or Q: glutamine residue, Glu or E: glutamic acid residue, Gly or G: glycine residue, His or H: histidine residue, Ile or I: isoleucine residue, Leu or L: leucine residue, Lys or K: lysine residue, Met or M: methionine residue, Phe or F: phenylalanine residue, Pro or P: proline residue, Ser or S: serine residue, Thr or T: threonine residue, Trp or W: tryptophan residue, Tyr or Y: tyrosine residue, Val or V: valine residue, Abu: 2-aminobutyric acid residue (also called α-aminobutyric acid residue), Orn: ornithine residue, Cit: citrulline residue

[0011] In this specification, the amino acid sequence of a "peptide" is written according to the conventional method, with the N-terminal amino acid residue located on the left and the C-terminal amino acid residue located on the right. Furthermore, in a "peptide," unless otherwise specified, the amino group of the N-terminal amino acid residue is bonded to a hydrogen atom, and the carbonyl group of the C-terminal amino acid residue is bonded to a hydroxyl group. A divalent group of a peptide refers to a group bonded via the amino group of the N-terminal amino acid residue and the carbonyl group of the C-terminal amino acid residue. In a compound represented by formula (1), for example, a compound of formula (4) or (5), for a peptide corresponding to a partial structure thereof, the amino group of the N-terminal amino acid residue is bonded to a hydrogen atom, and the carbonyl group of the C-terminal amino acid residue is bonded to a hydroxyl group, unless otherwise specified.

[0012] As used herein, the term "cancer antigen peptide" refers to a peptide consisting of a partial amino acid sequence of a cancer antigen protein, a modified peptide thereof, and a conjugate thereof, including an MHC class I-restricted peptide, an MHC class II-restricted peptide, and a conjugate thereof.

[0013] "MHC class I restriction" refers to the property of inducing CTLs by binding to MHC class I molecules, which are class I of the major histocompatibility complex (MHC). As used herein, "MHC class I-restricted peptide" refers to a peptide that has the ability to bind to MHC class I molecules in vitro and / or in vivo and induce cytotoxic T cells (CTLs) (i.e., a peptide that has CTL-inducing activity). "MHC class I-restricted peptides" are also sometimes referred to as "killer peptides."

[0014] In humans, MHC is called human leukocyte antigen (HLA). HLA, which corresponds to MHC class I molecules, is classified into subtypes such as HLA-A, B, C, F, and G. "MHC class I restriction" preferably includes HLA-A restriction, HLA-B restriction, and HLA-C restriction.

[0015] Polymorphisms (alleles) are known for each HLA subtype. Examples of polymorphisms include HLA-A1, HLA-A2, HLA-A24, HLA-A26, HLA-A3, HLA-A11, HLA-A33, HLA-B7, HLA-B15, HLA-B27, HLA-B35, HLA-B40, HLA-B44, HLA-C3, HLA-C5, HLA-C7, HLA-C1, HLA-C3, HLA-C4, and HLA-C6. ＊ 01:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 24:02, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 03:01, HLA-A ＊ 11:01, HLA-A ＊ 33:01, HLA-A ＊ 33:03, HLA-B ＊ 15:01, HLA-B ＊ 27:05, HLA-B ＊ 35:01, HLA-B＊ 40:01, HLA-B ＊ 40:02, HLA-B ＊ 40:03, HLA-B ＊ 40:06, HLA-B ＊ 44:03, HLA-C ＊ 01:01, HLA-C ＊ 03:01, HLA-C ＊ 03:03, HLA-C ＊ 04:01, HLA-C ＊ 05:01, HLA-C ＊ 06:02, HLA-C ＊ 07:01, HLA-C ＊ An example is 07:02.

[0016] "MHC class II restriction" refers to the property of binding to an MHC class II molecule and inducing helper T cells. "MHC class II restricted peptide" refers to a peptide that has the ability to bind to an MHC class II molecule in vitro and / or in vivo and induce helper T cells (i.e., a peptide having helper T cell inducing activity). "MHC class II restricted peptide" is also referred to as "helper peptide" in this specification.

[0017] HLA, which corresponds to MHC class II molecules, is classified into subtypes such as HLA-DR, DQ, and DP. "MHC class II restriction" preferably includes HLA-DR restriction, HLA-DQ restriction, or HLA-DP restriction.

[0018] Polymorphisms (alleles) are known for each HLA subtype. ＊ 0101, DRB1 ＊ 0405, DRB1 ＊ 0802, DRB1 ＊ 0803, DRB1 ＊ 0901, DRB1 ＊ 1201, DRB1 ＊ 1403, DRB1 ＊ 1501, DRB1 ＊ 1502, DPB1 ＊ 0201, DPB1 ＊0202, DPB1 ＊ 0402, DPB1 ＊ 0501, DPB1 ＊ 0901, DQB1 ＊ 0301, DQB1 ＊ 0302, DQB1 ＊ 0401, DQB1 ＊ 0501, DQB1 ＊ 0601, DQB1 ＊ 0602, or DRB5 ＊ Examples include 0102.

[0019] As used herein, the term "modified peptide" refers to a peptide consisting of an amino acid sequence in which one or more amino acid residues have been modified in the amino acid sequence of the original peptide. A modified peptide consists of an amino acid sequence in which one or more, for example, 1 to 9, preferably 1 to 5, 1 to 4, 1 to 3, more preferably 1 to 2, and more preferably 1 amino acid has been deleted, substituted, inserted, and / or added to the amino acid sequence of the original peptide. The number of amino acids deleted, substituted, inserted, or added is preferably 1 to 5, 1 to 4, 1 to 3, more preferably 1 to 2, and more preferably 1. Amino acid substitutions in the modified peptide may occur at any position with any type of amino acid. Conservative amino acid substitutions are preferred. For example, a Glu residue may be substituted with an Asp residue, a Phe residue with a Tyr residue, a Leu residue with an Ile residue, an Ala residue with a Ser residue, or a His residue with an Arg residue. The addition or deletion of amino acids is preferably at the N-terminus or C-terminus of the peptide, but may also be within the sequence. The substituted, inserted or added amino acids may be unnatural amino acids other than the 20 gene-encoded amino acids.

[0020] As used herein, a peptide comprising a certain amino acid sequence refers to a peptide in which additional amino acids may be added to the N-terminal amino acid and / or C-terminal amino acid of the amino acid sequence, as is customary. For example, a peptide comprising a certain amino acid sequence includes a peptide consisting of the amino acid sequence and longer peptides. For example, a peptide comprising the amino acid sequence of SEQ ID NO: 2 includes a peptide consisting of the amino acid sequence of SEQ ID NO: 2 and a peptide consisting of an amino acid sequence in which additional amino acids are added to the N-terminal amino acid and / or C-terminal amino acid of the amino acid sequence of SEQ ID NO: 2.

[0021] WT1 is a cancer antigen protein known to be highly expressed in various cancers. A representative amino acid sequence of human WT1 is shown in SEQ ID NO: 1. As used herein, "WT1 peptide" refers to a peptide consisting of consecutive amino acid residues in the amino acid sequence of SEQ ID NO: 1. The WT1 peptide can be represented by the positions of consecutive amino acid residues in the amino acid sequence of SEQ ID NO: 1. For example, WT1 ３４－５１ The peptide consists of the amino acid sequence from 34 to 51 of SEQ ID NO: 1 (WAPVLDFAPPGASAYGSL) (SEQ ID NO: 2). MGSDVRDLNALLPAVPSLGGGGGCALPVSGAAQWAPVLDFAPPGASAYGSLGGPAPPAPPPPPPPPHSFIKQEPSWGGAEPHEEQCLSAFTVHFSGQFTGTAGACRYGPF GPPPPSQASSGQARMFPNAPYLPSCLESQPAIRNQGYSTVTFDGTPSYGHTPSHHAAQFPNHSFKHEDPMGQQGSLGEQQYSVPPPVYGCHTPTDSCTGSQALLLRTPYSSD NLYQMTSQLECMTWNQMNLGATLKGVAAGSSSSSVKWTEGQSNHSTGYESDNHTTPILCGAQYRIHTHGVFRGIQDVRRVPGVAPTLVRSASETSEKRPFMCAYPGCNKRYFK LSHLQMHSRKHTGEKPYQCDFKDCERRFSRSDQLKRHQRRHTGVKPFQCKTCQRKFSRSDHLKTHTRTHTGKTSEKPFSCRWPSCQKKFARSDELVRHHNMHQRNMTKLQLAL

[0022] WT1 ３４－５１ The peptide is known to function as a helper peptide, but ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ Therefore, a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity (also referred to as the peptide of the present disclosure in this specification) functions as a killer peptide in HLA-A 07:02-positive subjects. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The modified peptide of "a peptide consisting of the amino acid sequence of SEQ ID NO: 2" having CTL inducing activity can be used for the treatment or prevention of cancer in a subject positive for HLA-A 07:02. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ In one embodiment, the modified peptide of "a peptide consisting of the amino acid sequence of SEQ ID NO: 2" has CTL inducing activity and helper T cell inducing activity.

[0023] HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ 07:02 positive subjects were HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊The term "subject" refers to a subject having an HLA haplotype including 07:02. HLA alleles (HLA types) are identified by commonly used HLA typing (particularly genotyping) methods. The term "subject" includes humans and non-human animals such as non-human primates, sheep, dogs, cats, horses, and cows, but is preferably humans.

[0024] In one embodiment, the subject has HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ In one embodiment, the subject is an HLA-A 07:02 positive subject. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, or HLA-A ＊ In one embodiment, the subject is HLA-A 26:03 positive. ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, or HLA-A ＊ In one embodiment, the subject is HLA-A 26:01 positive. ＊ 02:01, HLA-A ＊ 02:06, or HLA-A ＊ In one embodiment, the subject is an HLA-A positive subject. ＊ 11:01, HLA-A ＊ 26:01, or HLA-A ＊In one embodiment, the subject is HLA-A 26:03 positive. ＊ 11:01 or HLA-A ＊ In one embodiment, the subject is HLA-A 26:03 positive. ＊ In one embodiment, the subject is an HLA-A 11:01 positive subject. ＊ In one embodiment, the subject is an HLA-A 02:01 positive subject. ＊ In one embodiment, the subject is HLA-A positive. ＊ In one embodiment, the subject is an HLA-A positive subject. ＊ In one embodiment, the subject is HLA-A 26:01 positive. ＊ In one embodiment, the subject is HLA-A 26:03 positive. ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ In one embodiment, the subject is an HLA-A 07:02 positive subject. ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ In one embodiment, the subject is an HLA-A 07:01 positive subject. ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, or HLA-C ＊ In one embodiment, the subject is an HLA-A 05:01 positive subject. ＊ In one embodiment, the subject is an HLA-B 01:01 positive subject. ＊ In one embodiment, the subject is HLA-B 15:01 positive. ＊ In one embodiment, the subject is HLA-C 35:01 positive. ＊In one embodiment, the subject is an HLA-C positive subject. ＊ In one embodiment, the subject is an HLA-C positive subject. ＊ In one embodiment, the subject is an HLA-C positive subject. ＊ In one embodiment, the subject is an HLA-A 07:02 positive subject. ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ In one embodiment, the subject is an HLA-A 07:01 positive subject. ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ In one embodiment, the subject is an HLA-A 07:01 positive subject. ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, or HLA-C ＊ 05:01 Positive subject.

[0025] The length of the peptide of the present disclosure is not particularly limited, but if the peptide is too long it will be susceptible to the action of proteases, and if it is too short it will not bind well to the peptide-accommodating groove. The number of amino acid residues of the peptide of the present disclosure may be, for example, 9 to 30 residues, 10 to 25 residues, 12 to 24 residues, 15 to 22 residues, 16 to 20 residues, 18 residues, or 19 residues.

[0026] Examples of peptides of the present disclosure include peptides consisting of any of the following amino acid sequences: WAPVLDFAPPGASAYGSL (SEQ ID NO: 2), CWAPVLDFAPPGASAYGSL (SEQ ID NO: 3), and WAPVLDFAPPGASAYGSLC (SEQ ID NO: 4).

[0027] In one embodiment, the peptide of the present disclosure is a peptide consisting of the amino acid sequence of SEQ ID NO:2.

[0028] As used herein, "pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic acid salts such as citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, and paratoluenesulfonate. Base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and ammonium salt, and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt, as well as amino acid salts such as basic or acidic amino acids such as arginine, aspartic acid, and glutamic acid. As used herein, unless inappropriate in the context, the terms "peptide" and "compound" encompass pharmaceutically acceptable salts thereof.

[0029] As used herein, treating cancer includes completely or partially inhibiting the progression of cancer or at least partially alleviating one or more symptoms of cancer. Treating cancer also includes inducing remission, maintaining remission, and suppressing recurrence. Preventing cancer means preventing the onset of cancer in a subject who has not yet developed cancer. The subject may be, for example, a subject at high risk of developing cancer. Subjects at high risk of developing cancer include subjects diagnosed with hereditary breast and ovarian cancer syndrome (HBOC) with BRCA1 and BRCA2 mutations, heavy smokers, elderly people, and hepatitis virus-infected individuals.

[0030] In one embodiment, the pharmaceutical composition is a cancer vaccine. In another embodiment, the pharmaceutical composition is a composition for inducing CTLs in cellular immunotherapy of cancer.

[0031] In one embodiment, the cancer is a cancer in which WT1 is expressed or a cancer associated with elevated expression levels of the WT1 gene.

[0032] In one embodiment, the cancer is a hematological cancer or a solid cancer. In a further embodiment, the cancer is a chronic or acute leukemia including acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, multiple myeloma, malignant lymphoma, gastric cancer, colon cancer, lung cancer, breast cancer, germ cell cancer, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, cervical cancer, ovarian cancer, brain tumor, glioma, primary central nervous system malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, T-cell lymphoma, lymphocytic lymphoma, T-cell lymphoma, bone cancer, pancreatic cancer, head and neck cancer, skin or The cancer is selected from orbital malignant melanoma, rectal cancer, anal cancer, testicular cancer, carcinoma of the fallopian tubes, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, solid tumors of childhood, cancer of the kidney or ureter, renal pelvis carcinoma, central nervous system tumors, tumor angiogenesis, spinal tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, squamous cell carcinoma, squamous cell carcinoma, environmentally induced cancers including asbestos induced cancer, and combinations of the foregoing cancers. In further embodiments, the cancer is selected from acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, multiple myeloma, malignant lymphoma, gastric cancer, colon cancer, lung cancer, breast cancer, germ cell cancer, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, cervical cancer, ovarian cancer, brain cancer, and glioma.

[0033] The peptides of the present disclosure can be used alone or in combination with one or more other drugs (also referred to herein as combination drugs) to treat or prevent cancer.

[0034] The peptide of the present disclosure and the concomitant drug may be contained in the same composition or in different compositions. In one embodiment, the peptide of the present disclosure and the concomitant drug are contained in the same composition. In another embodiment, the peptide of the present disclosure and the concomitant drug are contained in different compositions. A composition containing each active ingredient may be provided together with instructions, etc., describing the dosage and administration when used in combination with other active ingredients. Alternatively, compositions containing each active ingredient may be combined and provided as a kit. The kit may be provided together with instructions (including package inserts), packaging containers, etc., describing the dosage and administration when used in combination. When multiple active ingredients are used in combination, they may be administered according to the same administration schedule or different administration schedules.

[0035] In one embodiment, the concomitant medication includes other anticancer agents, for example, immune checkpoint inhibitors, immunomodulatory agents such as costimulatory molecule agonists, hormone therapy agents, growth factors, growth factor inhibitors, growth factor receptor inhibitors, chemotherapeutic agents, etc. Examples of growth factor inhibitors include vascular endothelial growth factor inhibitors (VEGF inhibitors) (e.g., bevacizumab), etc. Examples of immune checkpoint inhibitors include anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab), anti-PD-L1 antibodies (e.g., durvalumab), etc.

[0036] In one embodiment, the concomitant drug comprises a cancer antigen peptide, such as an MHC class I-restricted peptide, an MHC class II-restricted peptide, or a conjugate thereof, or a pharmaceutically acceptable salt thereof. Examples of the cancer antigen peptide include peptides or derivatives thereof, or conjugates thereof, as described in the following documents: WO 2000 / 006602, WO 2000 / 018795, WO 2002 / 028414, WO 2002 / 079253, WO 2003 / 037060, WO 2003 / 106682, WO 2004 / 026897, and WO 2005 / 045027. , No. 2004 / 100870, No. 2005 / 053618, No. 2007 / 047764, No. 2007 / 063903, No. 2007 / 120673, No. 2010 / 037395 , No. 2010 / 123065, No. 2014 / 157692, No. 2014 / 157704, No. 2014 / 098012, No. 2018 / 181648, No. 2019 / 131722.

[0037] In one embodiment, the concomitant drug is a compound of formula (1): [In the formula, X ａ and Y ａ each independently represents a single bond or a divalent radical of a peptide consisting of 1 to 4 amino acid residues, and X ａ The number of amino acid residues and Y ａ is an integer of 0 to 4; cancer antigen peptide A represents an MHC class I restricted peptide consisting of 7 to 30 amino acid residues, and the amino group of the N-terminal amino acid of cancer antigen peptide A is Y in formula (1). ａ and the carbonyl group of the C-terminal amino acid of cancer antigen peptide A binds to the hydroxyl group in formula (1); R １ is a hydrogen atom, formula (2): (In the formula, X ｂ and Y ｂ each independently represents a single bond or a divalent radical of a peptide consisting of 1 to 4 amino acid residues, and X ｂ The number of amino acid residues and Y ｂis an integer of 0 to 4, cancer antigen peptide B represents an MHC class I restricted peptide consisting of 7 to 30 amino acid residues, and the amino group of the N-terminal amino acid of cancer antigen peptide B is Y in formula (2). ｂ wherein the carbonyl group of the C-terminal amino acid of cancer antigen peptide B is bonded to the hydroxyl group in formula (2), and the sulfur atom in formula (2) is bonded to the sulfur atom in formula (1) via a disulfide bond.) or cancer antigen peptide C, wherein cancer antigen peptide C is an MHC class I-restricted peptide consisting of 7 to 30 amino acid residues including one cysteine ​​residue, or an MHC class II-restricted peptide consisting of 7 to 30 amino acid residues including one cysteine ​​residue, and the sulfur atom of the cysteine ​​residue of cancer antigen peptide C is bonded to the sulfur atom in formula (1) via a disulfide bond, and a peptide consisting of 1 to 4 amino acid residues may be bonded to the N-terminus of cancer antigen peptide C; R １ is a group represented by formula (2), and cancer antigen peptide B contains one cysteine ​​residue, the sulfur atom of the cysteine ​​residue of cancer antigen peptide B is a group represented by formula (3): (In the formula, X ｄ and Y ｄ each independently represents a single bond or a divalent radical of a peptide consisting of 1 to 4 amino acid residues, and X ｄ The number of amino acid residues and Y ｄ is an integer of 0 to 4, and cancer antigen peptide D represents an MHC class II restricted peptide consisting of 7 to 30 amino acid residues, and the amino group of the N-terminal amino acid of cancer antigen peptide D is Y in formula (3). ｄ and the carbonyl group of the C-terminal amino acid of cancer antigen peptide D is bonded to the hydroxyl group in formula (3). Alternatively, cancer antigen peptide E may be bonded via a disulfide bond to a sulfur atom in formula (3) or to a sulfur atom of a cysteine ​​residue in cancer antigen peptide E, which is an MHC class II restricted peptide consisting of 7 to 30 amino acid residues including one cysteine ​​residue; R １is a cancer antigen peptide C, and a peptide consisting of 1 to 4 amino acid residues including one cysteine ​​residue is bound to the N-terminus of the cancer antigen peptide C, the sulfur atom of the cysteine ​​residue of the peptide bound to the N-terminus of the cancer antigen peptide C is a group represented by the formula (3): (In the formula, X ｄ and Y ｄ each independently represents a single bond or a divalent radical of a peptide consisting of 1 to 4 amino acid residues, and X ｄ The number of amino acid residues and Y ｄ is an integer of 0 to 4, and cancer antigen peptide D represents an MHC class II restricted peptide consisting of 7 to 30 amino acid residues, and the amino group of the N-terminal amino acid of cancer antigen peptide D is Y in formula (3). ｄ and the carbonyl group of the C-terminal amino acid of cancer antigen peptide D is bonded to the hydroxyl group in formula (3). Alternatively, cancer antigen peptide E, which is an MHC class II restricted peptide consisting of 7 to 30 amino acid residues including one cysteine ​​residue, may be bonded via a disulfide bond to a sulfur atom in formula (3), or to a sulfur atom of a cysteine ​​residue in cancer antigen peptide E, or a pharmaceutically acceptable salt thereof.

[0038] In one embodiment, the compound of formula (1) or a pharmaceutically acceptable salt thereof is represented by formula (4): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 8, respectively), or a pharmaceutically acceptable salt thereof; or a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[0039] In one embodiment, the compound of formula (1) or a pharmaceutically acceptable salt thereof is represented by formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[0040] In one embodiment, the pharmaceutical composition of the present disclosure comprises a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof, and a peptide represented by formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[0041] In one embodiment, the pharmaceutical composition of the present disclosure comprises a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or an acetate salt thereof, and a peptide of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a trifluoroacetate salt thereof.

[0042] The peptides of the present disclosure may be used for the treatment or prevention of cancer without the use of other cancer antigen peptides. In one embodiment, the pharmaceutical composition does not contain any cancer antigen peptides or pharmaceutically acceptable salts thereof other than the peptides of the present disclosure or pharmaceutically acceptable salts thereof. In one embodiment, the method for treating or preventing cancer does not include administering any cancer antigen peptides or pharmaceutically acceptable salts thereof other than the peptides of the present disclosure or pharmaceutically acceptable salts thereof.

[0043] The amino acid residues in the amino acid sequence of the peptide may be modified. The amino acid residues can be modified by known methods. For example, functional groups in the side chains of the amino acid residues constituting the peptide may be esterified, alkylated, halogenated, phosphorylated, sulfonated, amidated, or the like. Various substances can also be attached to the N-terminus and / or C-terminus of the peptide. The substance attached to the peptide may regulate the solubility of the peptide, improve its stability (e.g., protease resistance), or deliver the peptide specifically to a specific tissue or organ, or may have the effect of enhancing the uptake efficiency of antigen-presenting cells.

[0044] The peptide may be modified at the amino group of its N-terminal amino acid or the carboxyl group of its C-terminal amino acid. Examples of modifying groups for the amino group of the N-terminal amino acid include 1 to 3 alkyl groups having 1 to 6 carbon atoms, phenyl groups, cycloalkyl groups, and acyl groups. Specific examples of acyl groups include alkanoyl groups having 1 to 6 carbon atoms, alkanoyl groups having 1 to 6 carbon atoms substituted with a phenyl group, carbonyl groups substituted with a cycloalkyl group having 5 to 7 carbon atoms, alkylsulfonyl groups having 1 to 6 carbon atoms, phenylsulfonyl groups, alkoxycarbonyl groups having 2 to 6 carbon atoms, alkoxycarbonyl groups substituted with a phenyl group, carbonyl groups substituted with a cycloalkoxy group having 5 to 7 carbon atoms, and phenoxycarbonyl groups. Examples of peptides in which the carboxy group of the C-terminal amino acid is modified include esters and amides. Specific examples of esters include alkyl esters having 1 to 6 carbon atoms, alkyl esters having 0 to 6 carbon atoms and substituted with a phenyl group, and cycloalkyl esters having 5 to 7 carbon atoms. Specific examples of amides include amides substituted with one or two alkyl groups having 1 to 6 carbon atoms, amides substituted with one or two alkyl groups having 0 to 6 carbon atoms and substituted with a phenyl group, and amides that include the nitrogen atom of the amide group to form a 5- to 7-membered azacycloalkane ring.

[0045] A peptide may have amino acid residues linked by bonds other than peptide bonds, such as carbon-carbon bonds, carbon-nitrogen bonds, carbon-sulfur bonds, etc. Furthermore, a peptide may contain one or more D-amino acids.

[0046] Those skilled in the art can appropriately confirm whether a peptide has CTL-inducing activity or helper T cell-inducing activity. For example, CTL-inducing activity can be confirmed by measuring the number of CTLs using the HLA tetramer method (Int. J. Cancer: 100, 565-570 (2002)) or the limiting dilution method (Nat. Med.: 4, 321-327 (1998)). Helper T cell-inducing activity can be determined, for example, by the method described in Cancer Immunol. Immunother. 51: 271 (2002).

[0047] The peptides and compounds described herein, as well as their intermediate peptides, can be produced according to methods commonly used in peptide synthesis. For example, see "Peptide Synthesis, Interscience, New York, 1966; The Proteins, Vol. 2, Academic Press Inc., New York, 1976; Peptide Synthesis, Maruzen Co., Ltd., 1975; Fundamentals and Experiments of Peptide Synthesis, Maruzen Co., Ltd., 1985; Pharmaceutical Development, Continued, Vol. 14, Peptide Synthesis, Hirokawa Shoten, 1991. Examples of such methods include production using a solid-phase synthesizer using the Fmoc or Boc method, and production by sequential condensation of Boc-amino acids or Z-amino acids using liquid-phase synthesis (Fmoc represents a 9-fluorenylmethoxycarbonyl group, Boc represents a t-butoxycarbonyl group, and Z represents a benzyloxycarbonyl group, respectively). Peptides can also be produced using genetic engineering techniques based on nucleotide sequence information encoding the peptide. Such genetic engineering techniques are well known to those skilled in the art and can be carried out according to the descriptions in, for example, Molecular Cloning, T. Maniatis et al., CSH Laboratory (1983) and DNA Cloning, DM. Glover, IRL PRESS (1985).

[0048] The compound represented by formula (1) can be produced by the method described in WO 2014 / 157692. For example, the compound represented by formula (1) can be synthesized by linking two cancer antigen peptides via a disulfide bond.

[0049] The resulting peptides, compounds, and intermediates can be purified by methods known to those skilled in the art or in accordance with methods commonly used in peptide chemistry. For example, they can be purified by various types of chromatography (e.g., silica gel column chromatography, ion exchange column chromatography, gel filtration, or reverse-phase chromatography) or recrystallization. Examples of recrystallization solvents that can be used include alcoholic solvents such as methanol, ethanol, or 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene or toluene, ketone solvents such as acetone, hydrocarbon solvents such as hexane, aprotic solvents such as dimethylformamide or acetonitrile, water, or mixtures thereof. Other purification methods that can be used include those described in Volume 1 of "Experimental Chemistry Lectures" (edited by the Chemical Society of Japan, Maruzen). Methods for purifying disulfide compounds are described in the aforementioned publications (Peptide Synthesis, Interscience, New York, 1966; The Proteins, Vol. 2, Academic Press Inc., New York, 1976; Peptide Synthesis, Maruzen Co., Ltd., 1975; Peptide Synthesis Fundamentals and Experiments, Maruzen Co., Ltd., 1985; Pharmaceutical Development, Continued, Vol. 14, Peptide Synthesis, Hirokawa Shoten, 1991), etc. Among these, HPLC is preferred.

[0050] The pharmaceutical composition may contain a pharmaceutically acceptable carrier in addition to the peptide of the present disclosure or a pharmaceutically acceptable salt thereof. Furthermore, the pharmaceutical composition may contain a suitable adjuvant or may be administered together with a suitable adjuvant to enhance the efficiency of inducing CTLs and / or helper T cells.

[0051] A "pharmaceutically acceptable carrier" is non-toxic to cells or mammals exposed to the carrier at the dosages and concentrations employed. Pharmaceutically acceptable carriers are often pH buffered aqueous solutions. Examples of pharmaceutically acceptable carriers include: buffers (e.g., phosphate, citric acid, lactic acid, tartaric acid, trifluoroacetic acid, and other organic acids); antioxidants (including ascorbic acid); low molecular weight polypeptides (fewer than about 10 residues); proteins (e.g., serum albumin, gelatin, or immunoglobulins); hydrophilic polymers (e.g., polyvinylpyrrolidone); amino acids (e.g., glycine, glutamine, asparagine, arginine, methionine, or lysine); monosaccharides, disaccharides, and other carbohydrates (e.g., glucose, mannose, or dextrin); chelating agents (e.g., EDTA); sugar alcohols (e.g., mannitol, trehalose, or sorbitol); stabilizers (e.g., diethylenetriaminepentaacetic acid); salt-forming counterions (e.g., sodium); solubilizing agents (e.g., Polysorbate 80®) and / or non-ionic surfactants (e.g., TWEEN®, polyethylene glycol (PEG), and PLURONICS®). Pharmaceutically acceptable carriers may also be large, slowly metabolized macromolecules, such as proteins, polypeptides, liposomes, polysaccharides, polylactose, polyglycolic acid, polymeric amino acids, amino acid copolymers, and inactive virus particles. The peptides and compounds described herein may also be administered in liposomal formulations, in particle size formulations bound to beads of a few micrometers in diameter, or in lipid-bound formulations.

[0052] As the adjuvant, those described in the literature (Clin. Microbiol. Rev., 7: 277-289, 1994) can be used, and specific examples thereof include bacterial cell-derived components, cytokines such as GM-CSF, interleukin-2, interleukin-7, and interleukin-12, plant-derived components, marine organism-derived components, mineral gels such as aluminum hydroxide, surfactants such as lysolecithin and pluronic polyol, polyanions, peptides, and oil emulsions (emulsion preparations). Examples of bacterial cell-derived components include lipid A, its derivative monophosphoryl lipid A, killed bacterial cells (including Mycobacterium bacteria such as BCG bacteria), bacterial-derived proteins, polynucleotides, Freund's incomplete adjuvant, Freund's complete adjuvant, cell wall skeletal components (including, for example, BCG-CWS), and trehalose dimycolate (TDM).

[0053] Adjuvants include precipitating adjuvants and oil-based adjuvants. Precipitating adjuvants are inorganic suspensions to which peptides are adsorbed. Specific examples of precipitating adjuvants include sodium hydroxide, aluminum hydroxide (Alum), calcium phosphate, aluminum phosphate, alum, Pepes, and carboxyvinyl polymers. Oil-based adjuvants are oil emulsions in which an aqueous solution containing a peptide is encapsulated in mineral oil to form micelles and emulsify the aqueous solution. Specific examples of oil-based adjuvants include, but are not limited to, liquid paraffin, lanolin, Freund's adjuvant (Freund's complete adjuvant, Freund's incomplete adjuvant), Montanide, and W / O emulsions (see WO 2006 / 078059).

[0054] The pharmaceutical composition may be a formulation for oral or parenteral administration, but is preferably a formulation for parenteral administration. Examples of formulations for parenteral administration include injections, ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, aerosols, eye drops, nasal drops, suppositories, inhalants, and nasal preparations.

[0055] In one embodiment, the composition of the present disclosure is an injectable preparation. Injectable preparations include solutions, suspensions, emulsions, and solid injectable preparations that are dissolved or suspended in a solvent before use. Injectable preparations are prepared by dissolving, suspending, or emulsifying one or more active ingredients in a solvent. Examples of solvents that can be used include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof. The injectable preparation may further contain stabilizers, solubilizers (e.g., glutamic acid, aspartic acid, polysorbate 80®), suspending agents, emulsifiers, soothing agents, buffers, preservatives, and the like. These may be sterilized in the final process or produced by aseptic procedures. Alternatively, sterile solid preparations, such as lyophilized products, may be produced and dissolved in sterilized or sterile distilled water for injection or other solvents before use.

[0056] The method of administration of the peptide of the present disclosure or a pharmaceutically acceptable salt thereof can be appropriately selected depending on conditions such as the target disease, the condition of the subject, and the target site. The administration method is, for example, parenteral administration by injection or infusion, preferably intravenous, intramuscular, intradermal, or subcutaneous administration. The number of doses and the interval between doses can be appropriately selected depending on conditions such as the target disease, the condition of the subject, and the administration route. Usually, administration is performed multiple times, preferably once every few days or months.

[0057] As used herein, an effective amount refers to an amount of an active ingredient that can completely or partially inhibit the progression of cancer or at least partially alleviate one or more symptoms of cancer, or an amount that can induce or maintain remission of cancer and / or prevent recurrence. The effective amount is determined based on the age and sex of the subject, the condition to be treated, the severity of the condition, and the desired results. An effective amount for a given subject can be determined by methods known to those skilled in the art. The dosage can be appropriately selected depending on factors such as the target disease, the condition of the subject, and the route of administration. For example, the single dosage of the peptides, compounds, or pharmaceutically acceptable salts thereof described herein can typically be 0.0001 mg to 1000 mg, 0.001 mg to 1000 mg, or 0.1 mg to 10 mg.

[0058] The peptides of the present disclosure or pharmaceutically acceptable salts thereof may be used in lymphocyte therapy or DC (dendritic cell) therapy.

[0059] In one aspect, the present disclosure provides a method for administering a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity to an HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The present invention relates to antigen-presenting cells (e.g., dendritic cells, B-lymphocytes, macrophages, etc.) that present antigens via HLA-A 07:02. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ CTL can be induced in 07:02 positive subjects. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ Antigen-presenting cells that present the peptide via 07:02 react with HLA-A in the presence of the peptide. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ It can be obtained by culturing 07:02-positive immature antigen-presenting cells.

[0060] In another aspect, the present disclosure provides a method for inducing antigen-presenting cells, comprising: inducing HLA-A in the presence of a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The present disclosure relates to a method for inducing antigen-presenting cells, comprising culturing 07:02-positive immature antigen-presenting cells. As used herein, "immature antigen-presenting cells" refers to cells that can mature into antigen-presenting cells (e.g., dendritic cells, B-lymphocytes, macrophages, etc.). Since immature antigen-presenting cells are contained in, for example, peripheral blood mononuclear cells (PBMCs), such cells may be cultured in the presence of the peptide. That is, the present disclosure relates to a method for inducing antigen-presenting cells, comprising culturing an HLA-A peptide in the presence of a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL-inducing activity. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The method comprises culturing PBMCs from a 07:02 positive subject.

[0061] In another aspect, the present disclosure provides a method for treating HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ 07:02 A method of treating or preventing cancer in an HLA-A positive subject, comprising: ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The present invention relates to a method for administering antigen-presenting cells that present a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity via 07:02 to a subject positive for the corresponding HLA subtype. The method for administering the antigen-presenting cells can be appropriately selected depending on conditions such as the type of disease, the condition of the subject, and the target site. Examples of administration methods include, but are not limited to, intravenous administration, intradermal administration, subcutaneous administration, intramuscular administration, and nasal administration.

[0062] In another aspect, the present disclosure relates to CTLs induced by a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL-inducing activity. ＊11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ It can damage cancer cells in 07:02 positive subjects.

[0063] In another aspect, the present disclosure provides a method for inducing CTLs, comprising: inducing HLA-A in the presence of a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The present invention relates to a method for detecting HLA-A1-positive CTLs, comprising culturing PBMCs from a subject positive for 07:02. By culturing the PBMCs in the presence of the peptide, CTLs specific to the peptide are induced from progenitor cells in the PBMCs. The resulting peptide-specific CTLs are then subjected to immunohistochemistry. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ Administration to 07:02 positive subjects can treat or prevent cancer.

[0064] In another aspect, the present disclosure provides a method for treating HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The present invention relates to a method for treating or preventing cancer in a 07:02-positive subject, comprising administering to the subject CTLs specific to a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL-inducing activity. The method for administering the peptide-specific CTLs can be appropriately selected depending on conditions such as the type of disease, the condition of the subject, and the target site. Examples of the administration method include, but are not limited to, intravenous administration, intradermal administration, subcutaneous administration, intramuscular administration, nasal administration, and oral administration.

[0065] In another aspect, the present disclosure relates to a kit comprising, as a component, a peptide consisting of the amino acid sequence of SEQ ID NO: 2, a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, or a composition comprising the same. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The kit is used for treating or preventing cancer in 07:02-positive subjects. In another embodiment, the kit is used in the above-mentioned antigen-presenting cell induction method or CTL induction method. In addition to the peptide, a pharmaceutically acceptable salt thereof, or composition, the kit may also include, for example, a means for obtaining a subject's sample (e.g., PBMC), an adjuvant, a reaction vessel, a package insert, etc. Alternatively, or in addition, the kit may include one or more concomitant drugs or compositions containing the same. Generally, the kit is accompanied by an instruction manual.

[0066] In one aspect, the present disclosure provides a method for detecting HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ A method for treating or preventing cancer in a 07:02-positive subject, comprising administering a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, to an HLA-A positive subject in need of treatment or prevention. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ 07:02.

[0067] In one aspect, the present disclosure provides a method for detecting HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The present invention provides a peptide consisting of the amino acid sequence of SEQ ID NO: 2, or a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer in a 07:02-positive subject.

[0068] In one aspect, the present disclosure provides a method for detecting HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C＊ 07:01, or HLA-C ＊ The present invention provides use of a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing cancer in a 07:02-positive subject.

[0069] In another aspect, the present disclosure provides a method for treating HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The present invention provides a pharmaceutical composition for treating or preventing a benign tumor in a 07:02-positive subject, the pharmaceutical composition comprising a peptide consisting of the amino acid sequence of SEQ ID NO: 2, a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof. This embodiment can be carried out in accordance with the description for the treatment or prevention of cancer described above.

[0070] A "benign tumor" is a tumor that does not have pathological findings of malignancy and is distinguished from a malignant tumor or cancer. Benign tumors usually do not show a tendency to metastasize or infiltrate. A diagnosis of a benign tumor does not necessarily mean that the clinical prognosis is good. For example, a low-grade meningioma occurring in the brainstem is a benign tumor, but because it is difficult to treat and compresses the brainstem, resulting in a poor prognosis, it is clinically malignant and may require treatment or prevention.

[0071] In one embodiment, the benign tumor is a benign tumor in which WT1 is expressed or a benign tumor associated with an elevated expression level of the WT1 gene.

[0072] In one embodiment, the benign tumor is familial adenomatous polyposis, non-hereditary colorectal adenoma, intraductal papillary mucinous neoplasm of the pancreas, brain meningioma, neurilemmoma, epithelial adenoma of each organ, papilloma, nonepithelial myoma, lipoma, chondroma, or hemangioma.

[0073] In one embodiment, the benign tumor is familial adenomatous polyposis. Familial adenomatous polyposis is a genetic disease characterized by mutations in the tumor suppressor gene APC (adenoma polyposis coli), resulting in the formation of multiple adenomas in the intestinal tract. The terms "familial adenomatous polyposis," "familial colitic polyposis," "familial adenomatous polyposis," and "FAP" may be used interchangeably. As used herein, familial adenomatous polyposis also includes diseases accompanied by tumors in tissues other than the intestinal tract, such as Gardner's syndrome.

[0074] In a further aspect, the present disclosure provides a method for detecting HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ A method for treating or preventing a benign tumor in a 07:02-positive subject, comprising administering a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, to an HLA-A subject in need of treatment or prevention. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ 07:02 A method comprising administering to a subject positive for HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ A peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a benign tumor in a 07:02-positive subject; and HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The present invention provides use of a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a benign tumor in a 07:02-positive subject.

[0075] In a further aspect, the present disclosure provides a method for detecting HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ 07:02 A method of treating or preventing benign tumors in a subject positive for HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ a method comprising administering antigen-presenting cells presenting a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity via HLA-A; ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ A method for treating or preventing a benign tumor in an HLA-A positive subject, the method comprising administering to the subject CTLs specific to a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity; and ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The present invention relates to a kit comprising, as a component, a peptide consisting of the amino acid sequence of SEQ ID NO: 2, or a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, or a composition containing the same, for treating or preventing benign tumors in 07:02-positive subjects.

[0076] It is known that a peptide consisting of the amino acid sequence of SEQ ID NO: 2 is effective against intraocular neovascular disease (WO 2016 / 093326). Therefore, in another aspect, the present disclosure relates to a peptide that binds to HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊07:01, or HLA-C ＊ The present invention provides a pharmaceutical composition for treating or preventing intraocular neovascular disease in a 07:02-positive subject, the pharmaceutical composition comprising a peptide consisting of the amino acid sequence of SEQ ID NO: 2, a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof. This embodiment can be carried out in accordance with the description for the treatment or prevention of cancer described above.

[0077] In one embodiment, the intraocular neovascular disease is wet age-related macular degeneration, myopic macular degeneration, angioid streaks, central serous chorioretinopathy, various retinal pigment epithelial diseases, choroideremia, choroidal osteoma, diabetic retinopathy, retinopathy of prematurity, neovascular glaucoma, or corneal neovascularization.

[0078] In a further aspect, the present disclosure provides a method for detecting HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ A method for treating or preventing intraocular neovascular disease in a 07:02-positive subject, comprising administering a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, to an HLA-A subject in need of treatment or prevention. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ 07:02 A method comprising administering to a subject positive for HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ A peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, for use in treating or preventing intraocular neovascular disease in a 07:02-positive subject; and HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The present invention provides use of a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing intraocular neovascular disease in a 07:02-positive subject.

[0079] In a further aspect, the present disclosure provides a method for detecting HLA-A＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C[[ID=2.) ＊ A method for treating or preventing intraocular angiogenesis disease in a subject positive for 07:02, comprising administering to the subject an antigen-presenting cell presenting a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL-inducing activity via HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ A method comprising administering to a subject positive for the corresponding HLA subtype an antigen-presenting cell presenting a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL-inducing activity via 07:02; HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊05:01, HLA-C ＊ 07:01, or HLA-C ＊ A method for treating or preventing intraocular neovascular disease in a 07:02-positive subject, the method comprising administering to the subject CTLs specific to a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL-inducing activity; and an HLA-A peptide comprising, as a component, a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a modified peptide thereof having CTL-inducing activity, or a pharmaceutically acceptable salt thereof, or a composition containing the same. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The present invention relates to a kit for treating or preventing intraocular neovascular disease in a 07:02 positive subject.

[0080] In the various aspects of the present disclosure, the peptide of the present disclosure or a pharmaceutically acceptable salt thereof may be used in combination with the concomitant drugs described above for the treatment or prevention of cancer. For example, the peptide of the present disclosure or a pharmaceutically acceptable salt thereof is used in combination with a compound of formula (4) or formula (5) or a pharmaceutically acceptable salt thereof.

[0081] In the various aspects of the present disclosure, the HLA is HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ 07:02. In one embodiment, the HLA is HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, or HLA-A ＊ 26:03. In one embodiment, the HLA is HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, or HLA-A ＊ 26:01. In one embodiment, the HLA is HLA-A ＊ 02:01, HLA-A ＊ 02:06, or HLA-A ＊ 02:07. In one embodiment, the HLA is HLA-A ＊ 11:01, HLA-A ＊ 26:01, or HLA-A ＊ 26:03. In one embodiment, the HLA is HLA-A ＊ 11:01 or HLA-A ＊ 26:03. In one embodiment, the HLA is HLA-A ＊ 11:01. In one embodiment, the HLA is HLA-A ＊ 02:01. In one embodiment, the HLA is HLA-A ＊ 02:06. In one embodiment, the HLA is HLA-A ＊ 02:07. In one embodiment, the HLA is HLA-A ＊ 26:01. In one embodiment, the HLA is HLA-A ＊ 26:03. In one embodiment, the HLA is HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ In one embodiment, the subject has HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ In one embodiment, the subject is an HLA-A 07:01 positive subject. ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, or HLA-C ＊ In one embodiment, the HLA is HLA-A ＊ In one embodiment, the HLA is HLA-B ＊ 15:01. In one embodiment, the HLA is HLA-B ＊ 35:01. In one embodiment, the HLA is HLA-C ＊ 03:03. In one embodiment, the HLA is HLA-C ＊ 05:01. In one embodiment, the HLA is HLA-C ＊ 07:01. In one embodiment, the HLA is HLA-C ＊ In one embodiment, the subject has HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ In one embodiment, the subject is an HLA-A 07:01 positive subject. ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ In one embodiment, the subject is an HLA-A 07:01 positive subject. ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, or HLA-C ＊ 05:01 Positive subject.

[0082] Exemplary embodiments of the present disclosure are described below. [1] HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ [2] A pharmaceutical composition for treating or preventing cancer in a 07:02-positive subject, comprising a peptide consisting of the amino acid sequence of WAPVLDFAPPGASAYGSL (SEQ ID NO: 2), a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, or HLA-A ＊ [3] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 26:03 positive subject. ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊02:07, or HLA-A ＊ [4] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 26:01 positive subject. ＊ 02:01, HLA-A ＊ 02:06, or HLA-A ＊ [5] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 02:07 positive subject. ＊ [6] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 11:01 positive subject. ＊ [7] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 02:01 positive subject. ＊ [8] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 02:06 positive subject. ＊ [9] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 02:07 positive subject. ＊

[10] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 26:01 positive subject. ＊

[11] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 26:03 positive subject. ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊

[12] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 07:02 positive subject. ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊

[13] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 07:01 positive subject. ＊

[14] The pharmaceutical composition according to 1, wherein the subject is an HLA-B 01:01 positive subject. ＊

[15] The pharmaceutical composition according to 1, wherein the subject is an HLA-B 15:01 positive subject. ＊

[16] The pharmaceutical composition according to 1, wherein the subject is an HLA-C 35:01 positive subject. ＊

[17] The pharmaceutical composition according to 1, wherein the subject is an HLA-C 03:03 positive subject. ＊

[18] The pharmaceutical composition according to 1, wherein the subject is an HLA-C 05:01 positive subject. ＊

[19] The pharmaceutical composition according to 1, wherein the subject is an HLA-C 07:01 positive subject. ＊

[20] The pharmaceutical composition according to 1, wherein the subject is an HLA-A 07:02 positive subject. ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊

[21] The pharmaceutical composition according to any one of 1 to 20, which is a 07:01 positive control.

[22] A peptide represented by the formula (4): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 8, respectively), or a pharmaceutically acceptable salt thereof, or a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[23] The pharmaceutical composition according to any one of 1 to 21 above, further comprising a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively) or a pharmaceutically acceptable salt thereof.

[24] The pharmaceutical composition according to 22 above, comprising a compound of formula (4): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 8, respectively), or a pharmaceutically acceptable salt thereof, or a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[25] The pharmaceutical composition according to any one of 1 to 21 above, for use in combination with a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[26] A peptide consisting of the amino acid sequence of SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, and a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[27] The pharmaceutical composition according to any of 1 to 26, wherein the cancer is a cancer in which WT1 is expressed or a cancer accompanied by an elevated expression level of the WT1 gene.

[28] The pharmaceutical composition according to any of 1 to 27, wherein the cancer is acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, multiple myeloma, malignant lymphoma, gastric cancer, colorectal cancer, lung cancer, breast cancer, germ cell cancer, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, cervical cancer, ovarian cancer, brain tumor, or glioma.

[0083]

[29] HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊

[30] A kit for treating or preventing cancer in a 07:02-positive subject, comprising a peptide consisting of the amino acid sequence of WAPVLDFAPPGASAYGSL (SEQ ID NO: 2), a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, or HLA-A ＊

[31] The kit according to 29, wherein the subject is an HLA-A 26:03 positive subject. ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, or HLA-A ＊

[32] The kit according to 29, wherein the subject is HLA-A 26:01 positive. ＊ 02:01, HLA-A ＊ 02:06, or HLA-A ＊ The kit according to 29, wherein the subject is an HLA-A 02:07 positive subject.

[33] ＊

[34] The kit according to 29, wherein the subject is an HLA-A 11:01 positive subject. ＊

[35] The kit according to 29, wherein the subject is an HLA-A 02:01 positive subject. ＊

[36] The kit according to 29, wherein the subject is an HLA-A 02:06 positive subject. ＊

[37] The kit according to 29, wherein the subject is an HLA-A 02:07 positive subject. ＊ The kit according to 29, wherein the subject is HLA-A 26:01 positive. ＊

[39] The kit according to 29, wherein the subject is an HLA-A 26:03 positive subject. ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊05:01, HLA-C ＊ 07:01, or HLA-C ＊

[40] The kit according to 29, wherein the subject is an HLA-A 07:02 positive subject. ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊

[41] The kit according to 29, wherein the subject is an HLA-A 07:01 positive subject. ＊ 42. The kit according to 29, wherein the subject is an HLA-B 01:01 positive subject. ＊ 15:01 positive subject.

[43] The kit according to 29, wherein the subject is HLA-B ＊ 35:01 positive subject.

[44] The kit according to 29, wherein the subject is HLA-C ＊

[45] The kit according to 29, wherein the subject is an HLA-C 03:03 positive subject. ＊

[46] The kit according to 29, wherein the subject is an HLA-C 05:01 positive subject. ＊

[47] The kit according to 29, wherein the subject is an HLA-C 07:01 positive subject. ＊

[48] ​​The kit according to 29, wherein the subject is an HLA-A 07:02 positive subject. ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊

[49] The kit according to any one of 29 to 48, comprising a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof.

[50] A peptide represented by the formula (4): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 8, respectively), or a pharmaceutically acceptable salt thereof, or a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[51] The kit according to any one of 29 to 49 above, further comprising a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[52] A peptide consisting of the amino acid sequence of SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof, and a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[53] The kit according to any of the above 29 to 52, wherein the cancer is a cancer in which WT1 is expressed or a cancer accompanied by an elevated expression level of the WT1 gene.

[54] The kit according to any of the above 29 to 53, wherein the cancer is acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, multiple myeloma, malignant lymphoma, gastric cancer, colorectal cancer, lung cancer, breast cancer, germ cell cancer, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, cervical cancer, ovarian cancer, brain tumor, or glioma.

[0084]

[55] A method for treating or preventing cancer, comprising administering to an HLA-A antibody in need of said treatment or prevention. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊05:01, HLA-C ＊ 07:01, or HLA-C ＊

[56] A method comprising administering to a 07:02-positive subject a peptide consisting of the amino acid sequence of WAPVLDFAPPGASAYGSL (SEQ ID NO: 2), a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, or HLA-A ＊ 57. The method according to claim 55, wherein the subject is HLA-A 26:03 positive. ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, or HLA-A ＊ 58. The method according to claim 55, wherein the subject is HLA-A 26:01 positive. ＊ 02:01, HLA-A ＊ 02:06, or HLA-A ＊ 59. The method according to claim 55, wherein the subject is an HLA-A 02:07 positive subject. ＊ 60. The method according to claim 55, wherein the subject is an HLA-A 11:01 positive subject. ＊ 61. The method according to claim 55, wherein the subject is an HLA-A 02:01 positive subject. ＊ 62. The method according to claim 55, wherein the subject is an HLA-A 02:06 positive subject. ＊ 63. The method according to claim 55, wherein the subject is an HLA-A 02:07 positive subject. ＊ 64. The method according to claim 55, wherein the subject is HLA-A 26:01 positive. ＊

[65] The method according to 55, wherein the subject is HLA-A 26:03 positive. ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ 66. The method according to claim 55, wherein the subject is an HLA-A 07:02 positive subject. ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ 67. The method according to claim 55, wherein the subject is an HLA-A 07:01 positive subject. ＊ 68. The method according to claim 55, wherein the subject is an HLA-B 01:01 positive subject. ＊ 69. The method according to claim 55, wherein the subject is an HLA-B 15:01 positive subject. ＊ 56. The method according to claim 55, wherein the subject is a subject positive for HLA-C 35:01. ＊ 71. The method according to claim 55, wherein the subject is an HLA-C 03:03 positive subject. ＊ 72. The method according to claim 55, wherein the subject is an HLA-C 05:01 positive subject. ＊ 73. The method according to claim 55, wherein the subject is an HLA-C 07:01 positive subject. ＊ 74. The method according to claim 55, wherein the subject is an HLA-A 07:02 positive subject. ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊

[75] The method according to any one of the above items 55 to 74, wherein the subject is a 07:01 positive subject.

[76] The method according to any one of the above items 55 to 74, comprising administering a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof.

[77] A peptide represented by formula (4): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 8, respectively), or a pharmaceutically acceptable salt thereof, or a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[77] The method according to any one of 55 to 75 above, further comprising administering a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[78] A peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof, and a compound represented by formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[79] The method according to any one of the above items 55 to 78, wherein the cancer is a cancer in which WT1 is expressed or a cancer accompanied by an elevated expression level of the WT1 gene.

[80] The method according to any one of the above items 55 to 79, wherein the cancer is acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, multiple myeloma, malignant lymphoma, gastric cancer, colorectal cancer, lung cancer, breast cancer, germ cell cancer, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, cervical cancer, ovarian cancer, brain tumor, or glioma.

[0085]

[81] HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊07:01, or HLA-C ＊

[82] A pharmaceutical composition for treating or preventing a benign tumor in a 07:02-positive subject, comprising a peptide consisting of the amino acid sequence of WAPVLDFAPPGASAYGSL (SEQ ID NO: 2), a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof. ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, or HLA-A ＊

[83] The pharmaceutical composition according to 81, wherein the subject is an HLA-A 26:03 positive subject. ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, or HLA-A ＊

[84] The pharmaceutical composition according to 81, wherein the subject is an HLA-A 26:01 positive subject. ＊ 02:01, HLA-A ＊ 02:06, or HLA-A ＊

[85] The pharmaceutical composition according to 81, wherein the subject is an HLA-A 02:07 positive subject. ＊

[86] The pharmaceutical composition according to 81, wherein the subject is an HLA-A 11:01 positive subject. ＊

[87] The pharmaceutical composition according to 81, wherein the subject is an HLA-A 02:01 positive subject. ＊

[88] The pharmaceutical composition according to 81, wherein the subject is an HLA-A 02:06 positive subject. ＊

[89] The pharmaceutical composition according to 81, wherein the subject is an HLA-A 02:07 positive subject. ＊ 82. The pharmaceutical composition according to claim 81, wherein the subject is an HLA-A 26:01 positive subject. ＊

[91] The pharmaceutical composition according to 81, wherein the subject is an HLA-A 26:03 positive subject. ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ 92. The pharmaceutical composition according to claim 81, wherein the subject is an HLA-A 07:02 positive subject. ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ 93. The pharmaceutical composition according to claim 81, wherein the subject is an HLA-A 07:01 positive subject. ＊ 84. The pharmaceutical composition according to claim 81, wherein the subject is an HLA-B 01:01 positive subject. ＊ 85. The pharmaceutical composition according to claim 81, wherein the subject is a subject positive for HLA-B 15:01. ＊ 86. The pharmaceutical composition according to claim 81, wherein the subject is a subject positive for HLA-C 35:01. ＊ 87. The pharmaceutical composition according to claim 81, wherein the subject is an HLA-C 03:03 positive subject. ＊ 98. The pharmaceutical composition according to claim 81, wherein the subject is an HLA-C 05:01 positive subject. ＊ 99. The pharmaceutical composition according to claim 81, wherein the subject is an HLA-C 07:01 positive subject. ＊ 81. The pharmaceutical composition according to claim 81, wherein the subject is a subject positive for HLA-A 07:02. ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊07:01 positive control.

[101] The pharmaceutical composition according to any one of 81 to 100, comprising a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof.

[102] A compound represented by the formula (4): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 8, respectively), or a pharmaceutically acceptable salt thereof, or a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[103] The pharmaceutical composition according to any one of 81 to 101 above, further comprising a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively) or a pharmaceutically acceptable salt thereof.

[104] The pharmaceutical composition according to 102 above, comprising a compound of formula (4): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 8, respectively), or a pharmaceutically acceptable salt thereof, or a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[105] The pharmaceutical composition according to any one of 81 to 101 above, for use in combination with a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[106] A peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof, and a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[107] The pharmaceutical composition according to any of the above items 81 to 106, wherein the benign tumor is a benign tumor in which WT1 is expressed, or a benign tumor accompanied by an elevated expression level of the WT1 gene.

[108] The pharmaceutical composition according to any of the above items 81 to 107, wherein the benign tumor is familial adenomatous polyposis, non-hereditary colorectal adenoma, pancreatic intraductal papillary mucinous neoplasm, brain meningioma, schwannoma, epithelial adenoma of each organ, papilloma, nonepithelial myoma, lipoma, chondroma, or hemangioma.

[109] The pharmaceutical composition according to the above item 108, wherein the benign tumor is familial adenomatous polyposis.

[0086]

[110] HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 26:03, HLA-A ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ A pharmaceutical composition for treating or preventing intraocular neovascular disease in a 07:02-positive subject, comprising a peptide consisting of the amino acid sequence of WAPVLDFAPPGASAYGSL (SEQ ID NO: 2), a modified peptide thereof having CTL inducing activity, or a pharmaceutically acceptable salt thereof.

[111] The subject is an HLA-A ＊ 11:01, HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, or HLA-A ＊ The pharmaceutical composition according to claim 110, wherein the subject is a subject positive for HLA-A 26:03.＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, or HLA-A ＊ The pharmaceutical composition according to claim 110, wherein the subject is a subject positive for HLA-A 26:01. ＊ 02:01, HLA-A ＊ 02:06, or HLA-A ＊ The pharmaceutical composition according to claim 110, wherein the subject is a 02:07 positive subject.

[114] The pharmaceutical composition according to claim 110, wherein the subject is a 02:07 positive subject. ＊ The pharmaceutical composition according to claim 110, wherein the subject is an HLA-A 11:01 positive subject. ＊ The pharmaceutical composition according to claim 110, wherein the subject is an HLA-A 02:01 positive subject. ＊ The pharmaceutical composition according to claim 110, wherein the subject is a 02:06 positive subject.

[117] The pharmaceutical composition according to claim 110, wherein the subject is a 02:06 positive subject. ＊ The pharmaceutical composition according to claim 110, wherein the subject is an HLA-A 02:07 positive subject. ＊ The pharmaceutical composition according to claim 110, wherein the subject is a subject positive for HLA-A 26:01. ＊ The pharmaceutical composition according to claim 110, wherein the subject is a subject positive for HLA-A 26:03. ＊ 01:01, HLA-B ＊ 15:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, HLA-C ＊ 07:01, or HLA-C ＊ The pharmaceutical composition according to claim 110, wherein the subject is an HLA-A 07:02 positive subject. ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ The pharmaceutical composition according to claim 110, wherein the subject is an HLA-A 07:01 positive subject. ＊The pharmaceutical composition according to claim 110, wherein the subject is an HLA-B 01:01 positive subject. ＊ The pharmaceutical composition according to claim 110, wherein the subject is a subject positive for HLA-B 15:01. ＊ The pharmaceutical composition according to claim 110, wherein the subject is a subject positive for HLA-C 35:01. ＊ The pharmaceutical composition according to claim 110, wherein the subject is an HLA-C 03:03 positive subject. ＊ The pharmaceutical composition according to claim 110, wherein the subject is a subject positive for HLA-C. ＊ The pharmaceutical composition according to claim 110, wherein the subject is a subject positive for HLA-C 07:01. ＊ The pharmaceutical composition according to claim 110, wherein the subject is a 07:02 positive subject. ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊

[130] The pharmaceutical composition according to any one of the above items 110 to 129, which comprises a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof.

[131] A compound represented by the formula (4): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 8, respectively), or a pharmaceutically acceptable salt thereof, or a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[132] The pharmaceutical composition according to any one of 110 to 130 above, further comprising a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively) or a pharmaceutically acceptable salt thereof.

[133] The pharmaceutical composition according to the above item 131, comprising a compound of formula (4): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 8, respectively), or a pharmaceutically acceptable salt thereof, or a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[134] The pharmaceutical composition according to any one of 110 to 130, for use in combination with a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively), or a pharmaceutically acceptable salt thereof.

[135] A peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof, and a compound of formula (5): (wherein the bond between C and C represents a disulfide bond) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively) or a pharmaceutically acceptable salt thereof.

[136] The pharmaceutical composition according to any of the above 110 to 135, wherein the intraocular neovascular disease is wet age-related macular degeneration, myopic macular degeneration, angioid streaks, central serous chorioretinopathy, retinal pigment epitheliopathy, choroidal atrophy, choroideremia, choroidal osteoma, diabetic retinopathy, retinopathy of prematurity, neovascular glaucoma, or corneal neovascularization.

[0087] The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples in any way.

[0088] I. WT1 ３４－５１ Induction of WT1-specific CD8-positive T cells by peptide WT1 ３４－５１ (WAPVLDFAPPGASAYGSL) (SEQ ID NO: 2), WT1 ３７－４５ (VLDFAPPGA) (SEQ ID NO: 5) or WT1 ４０－４８(FAPPGASAY) (SEQ ID NO: 6) was used. Analysis using NetMHC-4.0 (http: / / www.cbs.dtu.dk / services / NetMHC-4.0) revealed that WT1 ３７－４５ is HLA-A ＊ 02:01, HLA-A ＊ 02:06, and HLA-A ＊ At 02:07, WT1 ４０－４８ is HLA-A ＊ 26:01 and HLA-A ＊ It had high affinity for 26:03.

[0089] Generation of immature dendritic cells (imDC) HLA-A ＊ 02:01 (5 cases), HLA-A ＊ 02:06 (7 cases), HLA-A ＊ 02:07 (2 cases) or HLA-A ＊ Cryopreserved peripheral blood mononuclear cells (PBMCs) from 16 cancer patients (oropharyngeal cancer, lung cancer, esophageal cancer, gastric cancer, breast cancer, pancreatic cancer, ovarian cancer, gallbladder cancer, bile duct cancer, prostate cancer, and uterine cancer) who were 26:01 (2 cases) positive were thawed, and the cells were isolated by density gradient centrifugation using Ficoll-Plaque Premium and suspended in serum-free AIM-V medium. The cells were seeded into 10 cm Primaria cell culture dishes and incubated at 37°C with 5% CO. ２ The cells were separated into monocytes that adhered to plastic and non-adherent (NAD) cells by leaving them in an incubator for 30 minutes or more, and then cryopreserved. The adherent monocytes were then cryopreserved in serum-free AIM-V medium containing granulocyte-macrophage colony-stimulating factor (GM-CSF) (50 ng / ml) and IL-4 (50 ng / ml) at 37°C in 5% CO. ２ Immature dendritic cells (imDCs) were prepared by culturing in an incubator for 5 days and then cryopreserved.

[0090] Preparation of WT1 peptide-pulsed mature dendritic cells (mDCs) and WT1 peptide-pulsed immature dendritic cells (imDCs) Cryopreserved imDCs (1 × 10 ５ Cells) were thawed and incubated with 100 μg of WT1 in the presence of 5 ng / ml GM-CSF, 50 ng / ml prostaglandin E2, and 10 μg / ml OK-432.３４－５１ After adding the above, the mixture was incubated at 37°C and 5% CO ２ The WT1 peptide-pulsed mature dendritic cells (mDC / WT1 ３４－５１ On the other hand, cryopreserved imDCs (1 × 10 ５ The cells were thawed and incubated at 37°C in 5% CO in the presence of 5 ng / ml GM-CSF, 50 ng / ml prostaglandin E2, and 10 μg / ml OK-432. ２ WT1 peptide-unpulsed mature dendritic cells (mDCs) were generated by incubating the cells with 1×10 ４ cells) with 25 μg of WT1 ３４－５１ , WT1 ３７－４５ , or WT1 ４０－４８ After adding the above, the mixture was incubated at 37°C and 5% CO ２ The WT1 peptide-pulsed immature dendritic cells (imDC / WT1) were incubated with WT1 for 24 hours. ３４－５１ , imDC / WT1 ３７－４５ or imDC / WT1 ４０－４８ ) was prepared.

[0091] Induction of WT1 peptide-specific CD8-positive T cells Cryopreserved NAD cells were thawed and suspended in RPMI-1640 medium containing 1% non-essential amino acids, 1 mM sodium pyruvate, 50 μM 2-mercaptoethanol, 10% heat-inactivated fetal bovine serum, 20 U / ml IL-2, and 20 ng / ml IL-7. The cells were cultured in a 24-well plate at 37°C in 5% CO ２ The cells were cultured in an incubator for 24 hours. ３４－５１ (1 x 10 ５ cells) and NAD cells (1 × 10 ６ The cells were suspended in RPMI-1640 medium containing 1% non-essential amino acids, 1 mM sodium pyruvate, 50 μM 2-mercaptoethanol, 10 U / ml IL-2, 10 ng / ml IL-7, and 10% inactivated fetal bovine serum, and incubated at 37°C in 5% CO ２ The cells were cultured in an incubator. After 7 days (day 8), mDC / WT1 ３４－５１ (1 x 10 ５Freshly prepared NAD cells were cultured in fresh cell culture medium containing 10 U / ml IL-2 and 10 ng / ml IL-7. This procedure was repeated two more times (on days 15 and 22), for a total of four stimulations (on days 1, 8, 15, and 22). As a control, IL-2 (10 U / ml) and IL-7 (10 ng / ml) were added to NAD cells four times at 7-day intervals (on days 1, 8, 15, and 22).

[0092] Detection of IFN-γ-producing WT1 peptide-specific CD8-positive T cells mDC / WT1 ３４－５１ (1 x 10 ５ T cells induced by four stimulation cultures with imDC / WT1 ３４－５１ , imDC / WT1 ３７－４５ or imDC / WT1 ４０－４８ (1 x 10 ５ The cells were seeded in a 96-well U-bottom plate together with GolgiStop cells, and incubated at 37°C with 5% CO ２ The cells were cultured for 6 hours in an incubator. Then, a human Fc receptor blocker was added and incubated at 4°C for 5 minutes. After incubation with a PE / Cy5-labeled anti-human CD8 antibody (clone RPA-T8; eBioscience) and an APC / Cy7-labeled anti-human CD4 antibody (clone OKT4; BioLegend) for 20 minutes at 4°C, the cells were permeabilized using BD Cytofix / Cytoperm Plus Fixation / permeabilized with BD GolgiStop (BD Biosciences). The cells were then incubated with an APC-labeled anti-human IFN-γ antibody (clone B27; BioLegend), and the frequency of IFN-γ-producing cells among the CD8+ cells was analyzed.

[0093] Statistical Analysis: Paired t-test or Wilcoxon signed-rank test was used for the analysis.

[0094] 2. Result HLA-A ＊ 02:01 Restrictive WT1 ３７－４５ Induction of specific CD8-positive T cells HLA-A ＊ 02:01 NAD cells from positive individuals (5 cases) were transfected with mDC / WT1 every 7 days. ３４－５１After 4 stimulations with imDC / WT1 ３７－４５ The results showed that in 3 out of 5 cases (60%), the frequency of IFN-γ-producing CD8-positive T cells was higher in imDC / WT1 than in imDC / WT1. ３７－４５ Restimulation increased the frequency of IFN-γ-producing CD8-positive T cells among CD8-positive T cells by 10% or more.

[0095] HLA-A ＊ 02:01 / 24:02 NAD cells of one positive case were converted to mDC / WT1 ３４－５１ After four stimulations with imDC / WT1 ３４－５１ The frequency of IFN-γ-producing CD8-positive T cells among CD8-positive T cells was analyzed when the cells were restimulated with imDC or imDC. ３４－５１ When the frequency of IFN-γ-producing CD8-positive T cells was compared between the cases of restimulation with imDC and that with imDC, it was approximately 7.3% and approximately 0.05%, respectively (FIG. 1).

[0096] NAD cells from the same patient were transfected with mDC / WT1 ３４－５１ After four stimulations with imDC / WT1 ３７－４５ The results are shown in Table 1. The results are compared between the case of restimulation with imDC / WT1 and the case of restimulation with imDC / WT1 without four stimulations. ３７－４５ We analyzed the frequency of IFN-γ-producing CD8-positive T cells among CD8-positive T cells stimulated only once with IFN-γ. When comparing the frequency of IFN-γ-producing CD8-positive T cells in the cases where four stimulations were performed with that in which no stimulation was performed, the frequency was approximately 8.0% and approximately 0.6%, respectively (Figure 2).

[0097] From the above, WT1 ３４－５１ is IFN-γ-producing HLA-A ＊ 02:01 Restrictive WT1 ３７－４５ It was shown that specific CD8-positive T cells could be induced.

[0098] HLA-A ＊ 02:06 Restrictive WT1 ３７－４５ Induction of specific CD8-positive T cells HLA-A ＊ 02:06 NAD cells from positive individuals (7 cases) were transfected with mDC / WT1 every 7 days. ３４－５１ After 4 stimulations with imDC / WT1 ３７－４５The results showed that in 2 out of 7 cases (28.6%), the frequency of IFN-γ-producing CD8-positive T cells was higher in imDC / WT1 than in imDC / WT1. ３７－４５ Restimulation increased the frequency of IFN-γ-producing CD8-positive T cells among CD8-positive T cells by 10% or more.

[0099] HLA-A ＊ 02:06 / 26:03 NAD cells of one positive case were converted to mDC / WT1 ３４－５１ After four stimulations with imDC / WT1 ３７－４５ The frequency of IFN-γ-producing CD8-positive T cells among CD8-positive T cells was analyzed when the cells were restimulated with imDC or imDC. ３７－４５ When the frequency of IFN-γ-producing CD8-positive T cells was compared between the cases of restimulation with imDC and that with imDC, it was approximately 18.2% and approximately 12.6%, respectively (FIG. 3).

[0100] From the above, WT1 ３４－５１ is IFN-γ-producing HLA-A ＊ 02:06 Restrictive WT1 ３７－４５ It was shown that specific CD8-positive T cells could be induced.

[0101] HLA-A ＊ 02:07 Restrictive WT1 ３７－４５ Induction of specific CD8-positive T cells HLA-A ＊ 02:07 NAD cells from positive individuals (2 cases) were transfected with mDC / WT1 every 7 days. ３４－５１ After 4 stimulations with imDC / WT1 ３７－４５ The results showed that in one of two cases (50%), the frequency of IFN-γ-producing CD8-positive T cells was significantly higher in imDC / WT1 than in imDC / WT1. ３７－４５ Restimulation increased the frequency of IFN-γ-producing CD8-positive T cells among CD8-positive T cells by 10% or more.

[0102] HLA-A ＊ 02:07 / 24:02 NAD cells of one positive case were converted to mDC / WT1 ３４－５１ After four stimulations with imDC / WT1 ３７－４５The frequency of IFN-γ-producing CD8-positive T cells among CD8-positive T cells was analyzed when the cells were restimulated with imDC or imDC. ３７－４５ When the frequency of IFN-γ-producing CD8-positive T cells was compared between the cases of restimulation with imDC and that with imDC, it was approximately 1.1% and approximately 0.7%, respectively (FIG. 4).

[0103] From the above, WT1 ３４－５１ is IFN-γ-producing HLA-A ＊ 02:07 Restrictive WT1 ３７－４５ It was shown that specific CD8-positive T cells could be induced.

[0104] HLA-A ＊ 26:01 Restrictive WT1 ４０－４８ Induction of specific CD8-positive T cells HLA-A ＊ NAD cells from 26:01 positive individuals (2 cases) were transfected with mDC / WT1 every 7 days. ３４－５１ After 4 stimulations with imDC / WT1 ４０－４８ The cells were then restimulated with IFN-γ, and the frequency of IFN-γ-producing CD8-positive T cells was analyzed. As a result, IFN-γ-producing CD8-positive T cells were observed in two out of two cases (100%).

[0105] HLA-A ＊ 26:01 / 24:02 NAD cells of one positive case were mDC / WT1 ３４－５１ After four stimulations with imDC / WT1 ４０－４８ ImDC / WT1 was stimulated four times with mature dendritic cells (mDCs) that had not been pulsed with WT1 peptide. ４０－４８ The frequency of IFN-γ-producing CD8-positive T cells was analyzed when the cells were restimulated with mDC / WT1. ３４－５１ When comparing the frequency of IFN-γ-producing CD8+ T cells after four stimulations with IFN-γ and four stimulations with mDC, the frequency of IFN-γ-producing CD8+ T cells among CD8+ T cells was approximately 54.5% and approximately 50%, respectively (Figure 5).

[0106] From the above, WT1 ３４－５１ is IFN-γ-producing HLA-A ＊ 26:01 Restrictive WT1 ４０－４８ It was shown that specific CD8-positive T cells could be induced.

[0107] II. WT1 ３４－５１ and a compound of formula (5), or WT1 ３４－５１ Induction of WT1-specific CD8+ T cells by HLA-A ＊ 02:01 / 24:02 Positive (3 cases), HLA-A ＊ 02:06 / 24:02 Positive person (1 case), HLA-A ＊ 02:07 / 24:02 Positive cases (2 cases) and HLA-A ＊ Peripheral blood was collected from a 24:02 / 24:02 positive individual (one case) (cancer patient or healthy individual), and the mononuclear cell fraction was isolated by density gradient centrifugation using lymphocyte separation solution (Nacalai Tesque) to obtain PBMCs.

[0108] PBMCs were cultured at 3 × 10 in human complete medium (hCM) containing equal amounts of RPMI1640 (Nacalai Tesque) and AIM-V (Gibco) supplemented with 10% heat-inactivated human AB serum, 1 × MEM non-essential amino acid solution (Nacalai Tesque), 100 μM 2-mercaptoethanol (Fujifilm Wako Pure Chemical Industries, Ltd.), 50 IU / ml penicillin G (Meiji Seika Pharma), and 50 mg / ml streptomycin (Meiji Seika Pharma). ６ The PBMC / hCM suspension was prepared at 27 μg / ml. The compound of formula (5) and WT1 ３４－５１ (20 μg / ml) (1:0.75 ratio), or WT1 ３４－５１ Only IL-2 (20 μg / ml) was added, and 1 ml of the medium was dispensed into a 24-well plate. Two to four wells were prepared for each condition. On days 2 to 3, 500 μl of hCM containing 40 IU / ml IL-2 (Immunace, Kyowa Pharmaceutical Industry Co., Ltd.) was added. Two to three days later, 500 μl of the medium was removed from each well, and 500 μl of hCM containing 40 IU / ml IL-2 was added (half-medium exchange). Half-medium exchange was performed in the same manner every 2 to 3 days while observing the color of the medium.

[0109] In some experiments, the second stimulation was performed 7 to 10 days after the first stimulation. Autologous PBMCs were used as antigen-presenting cells (APCs). 3 to 4 × 10 cells were used to generate APCs. ６The PBMC cells were suspended in 1 ml of RPMI 1640 (serum-free) and treated with the compound of formula (5) (27 μg / ml) and WT1 ３４－５１ (20 μg / ml), or WT1 ３４－５１ (20 μg / ml) alone was added and reacted at 37° C. for 2 hours. The cells were irradiated with 30 Gy of radiation. After irradiation, the cells were washed twice with PBS and diluted to 1×10 ６ hCM was added to prepare an APC suspension at a concentration of 500 μl per cell. 7 to 12 days after the first stimulation, 500 μl of medium was removed from each well, and 1 × 10 ６ The APC suspension was added at a ratio of cells / 500 μl. After 2 to 3 days, 500 μl of medium was removed from each well, and 500 μl of hCM containing 40 IU / ml IL-2 was added (half of the medium was replaced). Half of the medium was replaced in the same manner every 2 to 3 days.

[0110] Intracellular cytokine assay Seven to 12 days after each stimulation, the cells and medium in each well of a 24-well plate were mixed thoroughly by pipetting, and 500 μl of cell-containing medium was collected. After centrifugation to remove the supernatant, 800 μl of hCM containing 10 μg / ml brefeldin A (BFA, SIGMA) was added to the cells to prepare a cell suspension. WT1 ３７－４５ and WT1 ４０－４８ Each well was added to a final concentration of 20 μg / ml. Wells without peptide addition were also prepared as controls. 200 μl of the prepared cell suspension was added to each well, and the mixture was incubated at 37° C. for 4 hours.

[0111] Cells were collected from each well, centrifuged to remove the supernatant, and then washed twice with FACS buffer (PBS containing 2% FCS). For surface antigen staining, the cells were incubated with eFluor450-labeled anti-human CD3 antibody (clone UCHT1, eBioscience), APC / Cy7-labeled anti-human CD8 antibody (clone RPA-T8, BioLegend), and FITC-labeled anti-human CD4 antibody (clone OKT4, eBioscience) on ice for 30 minutes, and then washed twice with FACS buffer.

[0112] Next, 50 μl of BD Fixation / Permeabilization solution (BD Biosciences) was added to each well to fix the cells and permeabilize the membrane, and the cells were incubated on ice for 30 minutes. After washing twice with 10-fold diluted BD Perm / Wash Buffer (BD Biosciences), the cells were incubated with PE-labeled anti-human IFN-γ antibody (clone 4S.B3, eBioscience) and APC-labeled anti-human TNF-α antibody (clone MAb11, eBioscience) for 30 minutes on ice to stain for intracellular cytokines.

[0113] The cells reacted with the antibody were suspended in FACS buffer, measured using a BD FACSCanto II flow cytometer (BD Biosciences), and analyzed using FLOWJO software (BD Biosciences).

[0114] Tetramer assay: 7 to 12 days after each stimulation, the cells and medium in each well of a 24-well plate were mixed thoroughly by pipetting, and 500 μl of the cell-containing medium was collected and divided into two equal portions and placed in two FACS tubes. The cells were washed twice with FACS buffer, and then ClearBack (Human FcR blocking reagent, MBL) was added and incubated at room temperature for 5 minutes. PE-labeled HLA-A was added to one of the two tubes. ＊ 02:01 WT1 ３７－４５Tetramer (MBL) was added to one tube and incubated on ice for 60 minutes. The other tube was left untreated. Pacific Blue-labeled anti-human CD3 antibody (clone UCHT1, BD Biosciences) and FITC-labeled anti-human CD8 antibody (clone T8, Cytostat / Coulter Clone, BECKMAN COULTER) were added to these tubes and incubated on ice for 30 minutes. After washing the cells twice with FACS Buffer, they were suspended in FACS Buffer supplemented with 7-AAD Viability Staining Solution (BioLegend), measured using a BD FACSCanto II flow cytometer (BD Biosciences), and analyzed using FLOWJO software (BD Biosciences).

[0115] 2. Results The following results are shown in Figures 6 to 21.

[0116] WT1 ３４－５１ and a compound of formula (5), or WT1 ３４－５１ HLA-A stimulated with only ＊ 02:01 / 24:02 Positive person, HLA-A ＊ 02:06 / 24:02 positive cases and HLA-A ＊ 02:07 / 24:02 WT1 was detected from PBMCs of positive individuals. ３７－４５ Upon stimulation, CD8-positive cells producing TNF-α and / or IFN-γ were induced, and WT1 ３７－４５ It was shown that specific CD8-positive T cells were induced (Fig. 6, Fig. 8, Fig. 10, Fig. 14, Fig. 16, Fig. 18). ＊ In PBMCs from 24:02 / 24:02-positive individuals, WT1 ３７－４５ No induction of specific CD8-positive T cells was observed (Fig. 12, Fig. 20). ４０－４８ No CD8-positive cells producing TNF-α and / or INF-γ were observed upon stimulation with HLA-A. ＊ 02:01 Restrictive WT1 ３７－４５Not only specific CD8-positive T cells, but also HLA-A of the same HLA-A2 subtype, although with lower sensitivity. ＊ 02:06 or HLA-A ＊ 02:07 Restrictive WT1 ３７－４５ It is believed that specific CD8-positive T cells can also be detected. ３４－５１ and a compound of formula (5), or WT1 ３４－５１ HLA-A stimulated with only ＊ 02:01 / 24:02 Positive person, HLA-A ＊ 02:06 / 24:02 positive cases and HLA-A ＊ An increase in tetramer-positive cells was confirmed in the PBMCs of 02:07 / 24:02 positive individuals (Figures 7, 9, 11, 15, 17, and 19). The tetramer used in this experiment was HLA-A without the HLA-A2 subtype. ＊ No specific staining was observed in PBMCs from 24:02 / 24:02-positive individuals (Fig. 13, Fig. 21). ３４－５１ and PBMC stimulated with the compound of formula (5) showed HLA-A ＊ Not 24:02, but HLA-A ＊ 02:01, HLA-A ＊ 02:06, or HLA-A ＊ 02:07 Restricted WT1 ３７－４５ It was confirmed that specific CD8-positive T cells were induced.

[0117] III. WT1 ３４－５１ and a compound of formula (5), or WT1 ３４－５１ Induction of WT1-specific CD8+ T cells by HLA-A (2) 1. Methods Stimulation of PBMCs ＊ 01:01 Positive person, HLA-A ＊ 26:01 Positive person, HLA-B ＊ 35:01 Positive person, HLA-C ＊ 03:03 Positive person, HLA-C ＊ 05:01 Positive cases and HLA-C ＊ Peripheral blood was collected from 07:01 positive individuals (one case each) (cancer patients or healthy individuals), and the mononuclear cell fraction was isolated by density gradient centrifugation using lymphocyte separation solution (Nacalai Tesque) to obtain PBMCs.

[0118] PBMCs were cultured at 2-3 × 10 cells / well in human complete medium (hCM) containing equal parts RPMI 1640 (Nacalai Tesque) and AIM-V (Gibco) supplemented with 10% heat-inactivated human AB serum, 1 × MEM non-essential amino acid solution (Nacalai Tesque), 100 μM 2-mercaptoethanol (Fujifilm Wako Pure Chemical Industries, Ltd.), 50 IU / ml penicillin G (Meiji Seika Pharma), and 50 mg / ml streptomycin (Meiji Seika Pharma). ６ The PBMC / hCM suspension was prepared at 27 μg / ml. The compound of formula (5) and WT1 ３４－５１ (20 μg / ml) (1:0.75 ratio), or WT1 ３４－５１ Only IL-2 (20 μg / ml) was added and 1 ml of the medium was dispensed into a 24-well plate. Two to three wells were prepared for each condition. On days 2 and 3, 500 μl of hCM containing 40 IU / ml IL-2 (Recombinant Human IL-2, PeproTech) was added. Two to three days later, 750 μl of the medium was removed from each well, and 750 μl of hCM containing 40 IU / ml IL-2 was added (half-medium exchange). Half of the medium was exchanged in the same manner every 2 to 3 days while observing the color of the medium.

[0119] The second stimulation was performed 7 to 10 days after the first stimulation, and the third stimulation was performed 14 to 20 days after. Autologous PBMCs were used as APCs. 1 × 10 ６ The PBMC cells were suspended in 800 μl of AIM-V (serum-free) and treated with the compound of formula (5) (27 μg / ml) and WT1 ３４－５１ (20 μg / ml), or WT1 ３４－５１ (20 μg / ml) alone was added and incubated at 37°C for 2 hours. The cells were irradiated with 30 Gy of radiation to prepare an APC suspension. 7 to 10 days and 14 to 20 days after the first stimulation, 800 μl of medium was removed from each well, and 1 × 10 ６The APC suspension was added at a ratio of cells / 800 μl. After 2 to 3 days, 750 μl of medium was removed from each well, and 750 μl of hCM containing 40 IU / ml IL-2 was added (half of the medium was replaced). Half of the medium was replaced in the same manner every 2 to 3 days.

[0120] Intracellular cytokine assay. PBMCs (see Table 4) that differed from the PBMCs used in the previous three stimulations by only one HLA class I allele were transfected with WT1. ３７－４５ or WT1 ４０－４8 Cells pulsed with or without peptide were used as APCs for intracellular cytokine assays and tetramer assays. ５ PBMC cells were suspended in 300 μl of RPMI 1640 (serum-free) and WT1 ３７－４５ (20 μg / ml) or WT1 ４０－４８ The cells were incubated at 37°C for 1 hour with or without peptide (20 μg / ml). The cells were washed twice with PBS and diluted to 1 × 10 ５ Brefeldin A (BFA) (SIGMA)-supplemented hCM was added to give a cell / 100 μl ratio to prepare an APC suspension. After 21 days from the first stimulation, the stimulated cells and medium were mixed thoroughly by pipetting, and 900 μl of cell-containing medium was collected from each well. The supernatant was removed by centrifugation, and BFA-supplemented hCM was added to prepare a cell suspension. 100 μl each of the prepared APC and cell suspension was added to a round-bottom 96-well plate and incubated at 37°C and 5% CO ２ The cells were co-cultured for 4 hours at 100°C for 1 hour. Reactions were performed in triplicate.

[0121] After stimulation, the cells were centrifuged to remove the supernatant and then washed twice with FACS buffer (PBS containing 2% FCS). For surface antigen staining, the cells were incubated with PE / Cy7-labeled anti-human CD3 antibody (clone SK-7, BioLegend), APC / Cy7-labeled anti-human CD8 antibody (clone RPA-T8, BioLegend), and FITC-labeled anti-human CD4 antibody (clone RPA-T, BioLegend) on ice for 30 minutes, and then washed twice with FACS buffer.

[0122] Next, 50 μl of BD Fixation / Permeabilization solution (BD Biosciences) was added to each well to fix the cells and permeabilize the membrane, and the cells were incubated on ice for 20 minutes. After washing twice with 10-fold diluted BD Perm / Wash Buffer (BD Biosciences), the cells were incubated with PE-labeled anti-human IFN-γ antibody (clone 4S.B3, eBioscience) and APC-labeled anti-human TNF-α antibody (clone MAb11, eBioscience) on ice for 30 minutes to stain for intracellular cytokines.

[0123] The cells reacted with the antibody were suspended in FACS buffer, measured using a BD FACSCanto II flow cytometer (BD Biosciences), and analyzed using FLOWJO software (BD Biosciences).

[0124] For the tetramer assay, the stimulated cells and medium were mixed thoroughly by pipetting, and 500 μl of the cell-containing medium was collected and divided into two equal portions and placed in two FACS tubes. The cells were washed twice with FACS buffer, and then ClearBack (Human FcR blocking reagent, MBL) was added and incubated at room temperature for 5 minutes. PE-labeled HLA-A was added to one of the two tubes. ＊ 01:01 WT1 ４０－４８ Tetramer (MBL) or PE labeled HLA-B ＊ 35:01 WT1 ４０－４８Tetramer (MBL) was added to one tube and incubated on ice for 60 minutes. A Pacific Blue-labeled anti-human CD3 antibody (clone UCHT1, BioLegend) and an FITC-labeled anti-human CD8 antibody (clone T8, Cytostat / Coulter Clone, Beckman Coulter) were added to the other tube and incubated on ice for 30 minutes. After washing the cells twice with FACS Buffer, they were suspended in FACS Buffer supplemented with 7-AAD Viability Staining Solution (BioLegend), measured using a BD FACSCanto II flow cytometer (BD Biosciences), and analyzed using FLOWJO software (BD Biosciences).

[0125] 2. Result WT1 ３４－５１ A 9-mer peptide capable of binding to MHC class I molecules contained in the sequence (WAPVLDFAPPGASAYGSL) (SEQ ID NO: 2) was analyzed using NetMHC-4.0 (http: / / www.cbs.dtu.dk / services / NetMHC-4.0). The analyzed peptides are shown in Table 2, and the binding prediction results are shown in Tables 3-1 to 3-32. In Tables 3-1 to 3-32, "Rank" indicates the %Rank compared to 400,000 random natural peptides, "H_Avg_Rank" indicates the harmonic mean of the %Rank calculated for all specified alleles, and "N_binders" indicates the number of alleles covered by the peptide. "WB" stands for weak binder, and "SB" stands for strong binder.

[0126] The results of Tables 4-1 and 4-2 are shown in FIGS.

[0127] WT1 ３４－５１ and a compound of formula (5), or WT1 ３４－５１ Stimulated with only HLA-A ＊ 01:01, HLA-A ＊ 26:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ 07:01WT1 was detected from PBMC of a positive individual. ３７－４５ or WT1 ４０－４８ Stimulation with WT1 induces CD8-positive cells that produce TNF-α and / or IFN-γ. ３７－４５ or WT1 ４０－４８ It was shown that specific CD8-positive T cells were induced (Figs. 22, 23, 25, 26, 27, 28, 30-37, 39-42). ３４－５１ and a compound of formula (5), or WT1 ３４－５１ HLA-A stimulated with only ＊ 01:01 positive cases and HLA-B ＊ An increase in tetramer-positive cells was confirmed in PBMCs from 35:01-positive individuals (Figs. 24, 29, 38, and 43).

[0128] From the above results, WT1 ３４－５１ and a compound of formula (5) or WT1 ３４－５１ PBMC stimulated with only HLA-A ＊ 01:01, HLA-A ＊ 26:01, HLA-B＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ 07:01 Restricted WT1 ３７－４５ Specific CD8-positive T cells and / or WT1 ４０－４８ It was confirmed that specific CD8-positive T cells were induced.

[0129] IV. WT1 ３４－５１ and a compound of formula (5), or WT1 ３４－５１ Induction of WT1-specific CD8+ T cells by HLA-A (3) ＊ 11:01 Positive person, HLA-A ＊ 26:03 Positive person, HLA-A ＊ 15:01 Positive or HLA-C ＊ PBMCs are obtained from the peripheral blood of 07:02-positive individuals and subjected to intracellular cytokine assays and / or tetramer assays as described in I, II, or III above. ３４－５１ and a compound of formula (5), or WT1 ３４－５１ PBMC stimulated with only HLA-A ＊ 11:01, HLA-A ＊ 26:03, HLA-A ＊ 15:01, or HLA-C ＊ 07:02 Restricted WT1 ３７－４５ Specific CD8-positive T cells and / or WT1 ４０－４８ It is confirmed that specific CD8-positive T cells are induced.

Claims

Claim 1 HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, HLA-A ＊ 26:01, HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ A pharmaceutical composition for treating or preventing cancer in a 07:01 positive subject, comprising a peptide consisting of the amino acid sequence of WAPVLDFFAPPGASA YGS L (SEQ ID NO: 2), a modified peptide thereof having CTL-inducing activity, or a pharmaceutically acceptable salt thereof. Claim 2 wherein the subject is HLA-A ＊ 02:01, HLA-A ＊ 02:06, HLA-A ＊ 02:07, or HLA-A ＊ The pharmaceutical composition according to claim 1, wherein the subject is positive for HLA-A 26:

01. Claim 3 wherein the subject is HLA-A ＊ 02:01, HLA-A ＊ 02:06, or HLA-A ＊ 02:07 positive subject, the pharmaceutical composition according to claim 1. Claim 4 wherein the subject is HLA-A ＊ The pharmaceutical composition according to claim 1, wherein the subject is a positive subject for 02:

01. Claim 5 wherein the subject is HLA-A ＊ The pharmaceutical composition according to claim 1, wherein the subject is positive for HLA-A 02:

06. Claim 6 wherein the subject is HLA-A ＊ The pharmaceutical composition according to claim 1, wherein the subject is a positive subject for 02:07 Claim 7 wherein the subject is an HLA-A ＊ 26:01 positive subject, the pharmaceutical composition according to claim 1. Claim 8 wherein the subject is HLA-A ＊ 01:01, HLA-B ＊ 35:01, HLA-C ＊ 03:03, HLA-C ＊ 05:01, or HLA-C ＊ The pharmaceutical composition according to claim 1, wherein the subject is positive for 07:

01. Claim 9 wherein the subject is HLA-A ＊ The pharmaceutical composition according to claim 1, wherein the subject is a HLA-A ＊ 01:01 positive subject. Claim 10 wherein the subject is HLA-B ＊ The pharmaceutical composition according to claim 1, wherein the subject is positive for 35:

01. Claim 11 wherein the subject is HLA-C ＊ The pharmaceutical composition according to claim 1, wherein the subject is a 03:03 positive subject. Claim 12 wherein the subject is HLA-C ＊ The pharmaceutical composition according to claim 1, wherein the subject is a 05:01 positive subject. Claim 13 wherein the subject is HLA-C ＊ The pharmaceutical composition according to claim 1, wherein the subject is a 07:01 positive subject. Claim 14 The pharmaceutical composition according to claim 1, comprising a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof. Claim 15 Formula (4): 【Chemical 1】 (In the formula, the bond between C and C represents a disulfide bond.) (SEQ ID NO: 7 and SEQ ID NO: 8, respectively) a compound of or a pharmaceutically acceptable salt thereof, or Formula (5): [Chemical Formula 2] (In the formula, the bond between C and C represents a disulfide bond.) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively) The pharmaceutical composition according to claim 1, further comprising a compound of or a pharmaceutically acceptable salt thereof. Claim 16 Formula (5): [Chemical Formula 3] (In the formula, the bond between C and C represents a disulfide bond.) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively) The pharmaceutical composition according to claim 15, comprising a compound of or a pharmaceutically acceptable salt thereof. Claim 17 Formula (4): [Chemical Formula 4] (In the formula, the bond between C and C represents a disulfide bond.) (SEQ ID NO: 7 and SEQ ID NO: 8, respectively) a compound of or a pharmaceutically acceptable salt thereof, or Formula (5): [Chemical Formula 5] (In the formula, the bond between C and C represents a disulfide bond.) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively) The pharmaceutical composition according to claim 1, for use in combination with a compound of or a pharmaceutically acceptable salt thereof. Claim 18 Formula (5): 【Chemical Formula 6】 (In the formula, the bond between C and C represents a disulfide bond.) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively) The pharmaceutical composition according to claim 17, for use in combination with a compound of or a pharmaceutically acceptable salt thereof. Claim 19 a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof, and Formula (5): 【Chemical Formula 7】 (In the formula, the bond between C and C represents a disulfide bond.) (SEQ ID NO: 7 and SEQ ID NO: 9, respectively) a compound of or a pharmaceutically acceptable salt thereof The pharmaceutical composition according to claim 1, comprising. Claim 20 The pharmaceutical composition according to claim 1, wherein the cancer is a cancer in which WT1 is expressed or a cancer accompanied by an increase in the expression level of the WT1 gene. Claim 21 The pharmaceutical composition according to any one of claims 1 to 20, wherein the cancer is acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, multiple myeloma, malignant lymphoma, gastric cancer, colorectal cancer, lung cancer, breast cancer, germ cell carcinoma, liver cancer, skin cancer, bladder cancer, prostate cancer, uterine cancer, cervical cancer, ovarian cancer, brain tumor, or glioma.

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