WO2023163094A1 - 成人ｔ細胞白血病の治療又は予防のための医薬組成物 - Google Patents

成人ｔ細胞白血病の治療又は予防のための医薬組成物 Download PDF

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WO2023163094A1
WO2023163094A1 PCT/JP2023/006691 JP2023006691W WO2023163094A1 WO 2023163094 A1 WO2023163094 A1 WO 2023163094A1 JP 2023006691 W JP2023006691 W JP 2023006691W WO 2023163094 A1 WO2023163094 A1 WO 2023163094A1
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hla
peptide
peptides
seq
amino acid
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English (en)
French (fr)
Japanese (ja)
Inventor
薫 内丸
和民 中野
慶子 吉原
卓也 福島
勇悦 田中
謙之輔 加留部
裕章 益崎
孝一 大島
寛明 三好
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NEC Corp
University of the Ryukyus NUC
Kurume University
University of Tokyo NUC
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NEC Corp
University of the Ryukyus NUC
Kurume University
University of Tokyo NUC
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Priority to US18/838,470 priority Critical patent/US20250236642A1/en
Priority to CN202380020568.7A priority patent/CN118678966A/zh
Priority to JP2024503250A priority patent/JPWO2023163094A1/ja
Priority to EP23760093.7A priority patent/EP4483894A4/en
Publication of WO2023163094A1 publication Critical patent/WO2023163094A1/ja
Anticipated expiration legal-status Critical
Priority to JP2025147367A priority patent/JP2025172927A/ja
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4747—Apoptosis related proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0693—Tumour cells; Cancer cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/80—Vaccine for a specifically defined cancer
    • A61K2039/804—Blood cells [leukemia, lymphoma]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2510/00—Genetically modified cells

Definitions

  • the present invention relates to pharmaceutical compositions for treating or preventing adult T-cell leukemia (ATL). More specifically, it relates to a pharmaceutical composition for treatment or prevention of ATL containing a peptide consisting of a specific amino acid sequence.
  • Patent Document 1 discloses cancer immunotherapy using a peptide derived from the cancer antigen glypican 3 (GPC3). It has been clarified that GPC3 is expressed in almost all hepatocellular carcinomas, while it is rarely expressed in normal liver, liver cirrhosis, and the like. In addition, GPC3 is known to be highly expressed in melanoma, ovarian cancer, and the like, in addition to hepatocellular carcinoma.
  • GPC3 cancer antigen glypican 3
  • HLA epitope a cancer antigen
  • TCR T cell antigen receptor
  • HLA molecules are roughly classified into class I molecules (HLA-A type, B type and C type) and class II molecules (HLA-DP type, DQ type and DR type).
  • HTLV-1 Human T-cell leukemia virus type 1
  • ATL adult T-cell leukemia
  • ATL is a malignant hematologic tumor that invades various organs throughout the body, and is classified into four disease types: acute, lymphoma, chronic, and smoldering. Acute and lymphoma types, also called “aggressive ATL”, are hematopoietic malignancies with the worst prognosis. Chronic and smoldering ATL are also called “indolent ATL", and the majority of them undergo blast crisis during their course, and their prognosis is poor.
  • Treatment for ATL includes multidrug chemotherapy.
  • the median survival time for "aggressive ATL” is only 13 months, which is not satisfactory.
  • Patients with "indolent ATL” may survive for a long time without treatment, and are often followed up without treatment until the disease worsens due to blast crisis.
  • the main purpose of this disclosure is to provide technology that can be used for ATL cancer immunotherapy.
  • a pharmaceutical composition for treating or preventing adult T-cell leukemia comprising a peptide consisting of any one of the amino acid sequences of SEQ ID NOS: 1-68.
  • ATL adult T-cell leukemia
  • HLA major histocompatibility antigen
  • CTL cytotoxic T cells
  • the pharmaceutical composition of any one of [1]-[6] which is in the form of a vaccine.
  • a method for producing antigen-presenting cells having cytotoxic T cell-inducing activity comprising the step of contacting the peptide of any one of [8]-[13] with antigen-presenting cells in vitro.
  • the present disclosure provides technologies that can be used for ATL cancer immunotherapy.
  • PBMC peripheral blood mononuclear cells
  • PBMC of an ATL patient were stimulated with a peptide, and the results of measuring the amount of IFN- ⁇ production are shown.
  • PBMC of an ATL patient (sample 24) were stimulated with a peptide, and the results of measuring the amount of IFN- ⁇ production are shown.
  • PBMC of an ATL patient (sample 29) were stimulated with a peptide, and the results of measuring the amount of IFN- ⁇ production are shown.
  • Immunogenic Peptides consist of the amino acid sequence of any of SEQ ID NOs: 1-68.
  • the peptides according to the present disclosure are 6 proteins (Casp-8, c-Myb, Fas, Helios, Wnt5a, gp46) with abnormal amino acid sequences or high expression in adult T-cell leukemia (ATL) patients Derived from 4 proteins (c-Myb, CADM1, EVC1, EVC2, p19, tax).
  • the amino acid sequence of the peptide according to the present disclosure may contain the abnormal amino acid sequence of the protein.
  • the abnormal amino acid sequence of the protein may be a sequence different from the wild-type amino acid sequence, for example, fusion (fusion) by deletion of all or part of the amino acid sequence of the exon; alternative usage of exon; insertion of amino acid sequence derived from all or part of intron (Inclusion); substitution, deletion or substitution of one or more amino acid sequences of exon amino acid sequence insertion; and the like.
  • the amino acid sequence of the peptide according to the present disclosure consists of part of the wild-type amino acid sequence of the protein.
  • HLA major histocompatibility antigen
  • JP-A-8-151396 active learning experiment method
  • a sequence consisting of 9 amino acid residues predicted to exhibit Peptides consisting of the selected amino acid sequences were synthesized, and their ability to bind to HLA molecules and their ability to induce cytotoxic T cells (CTL) using interferon- ⁇ (IFN- ⁇ ) production as indices were evaluated in vitro.
  • CTL cytotoxic T cells
  • IFN- ⁇ interferon- ⁇
  • Table 1 shows the amino acid sequences of the peptides and their ability to bind to HLA molecules.
  • the ability to bind to HLA molecules is indicated by the dissociation constant Kd value (-logKd value).
  • Kd value -logKd value
  • “>-3.0” indicates a Kd value greater than -3.0 and no significant binding ability.
  • the description ">-3.37” as seen in the measurement value of "vs. A*02:06" of SEQ ID NO: 26 has a significant binding ability with a Kd value smaller than -3.0. , indicating that the Kd value could not be determined conclusively and was between -3.37 and -3.0.
  • Peptides of SEQ ID NOs: 1-4, 23, 48 are derived from CADM1.
  • Peptides of SEQ ID NOS: 5, 6, 24, 25, 36, 37, 52-60, 76-78 are derived from c-Myb.
  • Peptides of SEQ ID NOS: 7-10, 26-28, 38, 39 are derived from EVC1.
  • Peptides of SEQ ID NOs: 11-15, 40-43, 61, 79 are derived from EVC2.
  • Peptides of SEQ ID NOS: 16, 17, 29, 30, 44-46, 62, 63 are derived from Fas.
  • Peptides of SEQ ID NOs: 18 and 31 are derived from gp46.
  • Peptides of SEQ ID NOs: 19, 478, 64, 65, 80, 81 are derived from Helios.
  • the peptide of SEQ ID NO:20 is derived from p19.
  • Peptides of SEQ ID NOS: 21, 22, 32 and 33 are derived from tax.
  • Peptides of SEQ ID NOS: 34, 35, 49-51, 69-75 are derived from Casp-8.
  • Peptides of SEQ ID NOS: 66-68 are derived from Wnt5a.
  • Peptides of the present disclosure bind to one or more types (subtypes) of HLA molecules.
  • Peptides according to the present disclosure preferably bind to two or more, more preferably three or more types of HLA molecules.
  • the peptides of SEQ ID NOS: 1-33 are HLA-A*24:02 gene products (HLA-A*24:02 molecules) and HLA-A*02:01 gene products (HLA-A*02:01 molecules). and HLA-A*02:06 gene products (HLA-A*02:06 molecules).
  • Peptides of SEQ ID NOS: 34-47 exhibit binding to any two or more of HLA-A*24:02 molecules, HLA-A*02:01 molecules and HLA-A*02:06 molecules.
  • Peptides of SEQ ID NOS: 48-68 exhibit binding to any one of HLA-A*24:02, HLA-A*02:01 and HLA-A*02:06 molecules.
  • HLA subtypes to which the peptides of the present disclosure can bind are not limited to HLA-A*24:02, HLA-A*02:01 and HLA-A*02:06. However, since these HLA subtypes cover about 85% of Asians including Japanese and about 55% of Westerners, the multi-HLA peptide of the present invention has a wide patient coverage rate in immunotherapy and the like. considered to have
  • the peptide according to the present disclosure induces CTL.
  • the peptides of SEQ ID NOs: 16, 19, 20, 21, 47 and 66 exhibit CTL inducing activity in ATL patients.
  • Peptides of the present disclosure are HLA-binding and immunogenic.
  • immunogenicity means the ability to induce an immune response (immune induction ability), for example, increasing the cytotoxic T cell (CTL) inducing activity of antigen-presenting cells, and means to increase the cytotoxic activity of CTL against cancer cells.
  • CTL induction refers to CTLs that specifically recognize a certain antigen by presenting the peptide according to the present disclosure on the surface of antigen-presenting cells in vitro or in vivo. or to differentiate naive T cells into effector cells with the ability to kill target cells such as cancer cells (cytotoxic activity), and/or to increase the cytotoxic activity of CTL do.
  • CTL-inducing activity can be measured by evaluating cytokine (eg, IFN- ⁇ ) production by CTL.
  • cytokine eg, IFN- ⁇
  • the increase in cytokine-producing cells induced from progenitor cells by antigen-presenting cells such as peripheral blood mononuclear cells stimulated with the peptides of the present disclosure can be measured by an ELISPOT (Enzyme-Linked ImmunoSpot) method or an ELISA (Enzyme-Linked ImmunoSorbent) method.
  • CTL induction activity may be measured by evaluation using a known highly sensitive immunoassay such as the Assay method.
  • the cytotoxic activity of CTL can also be measured by a known technique such as the 51 Cr release method. If the above activity is significantly increased compared to the control, for example, if it is increased by 5% or more, 10% or more, 20% or more, preferably 50% or more, it is evaluated that immunity or CTL is induced. can do.
  • the peptide according to the present disclosure has high HLA-binding ability and high CTL-inducing ability, so it is highly expected to be useful as a cancer vaccine.
  • Application to various immunotherapies, particularly dendritic cell therapy, is also envisioned.
  • peptides of the present disclosure may bind to multiple HLA types. Therefore, according to the peptides of the present disclosure, it is possible to provide cancer vaccines, dendritic cell therapy, etc. covering an extremely wide range of ATL patient groups.
  • the peptides according to the present disclosure may have modified amino acid residues constituting the amino acid sequences of SEQ ID NOS: 1-68 or part thereof, as long as they retain immunogenicity.
  • the amino acid sequences represented by SEQ ID NOS: 1-68 are intended to be amino acid sequences in the state presented on antigen-presenting cells, but when peptides are administered directly into the body, depending on the route of administration, the peptides may be digested in the digestive organs and the like. may undergo changes such as digestion of the end of the Therefore, the peptide according to the present disclosure is incorporated into antigen-presenting cells so that the amino acid residues represented by SEQ ID NOS: 1-68 are retained when binding to a given HLA class I molecule on antigen-presenting cells. It may exist in the form of a precursor in which one or more amino acid residues or the like are added to the N-terminus and/or C-terminus.
  • amino acid is used in its broadest sense and includes artificial amino acid mutants and derivatives in addition to natural amino acids. D-amino acids; chemically modified amino acids such as amino acid variants and derivatives; natural non-protein amino acids such as norleucine, beta-alanine, ornithine; and chemically synthesized compounds having properties known in the art.
  • unnatural amino acids include ⁇ -methyl amino acids (such as ⁇ -methylalanine), D-amino acids, histidine-like amino acids (such as ⁇ -hydroxy-histidine, homohistidine, ⁇ -fluoromethyl-histidine and ⁇ -methyl-histidine). , amino acids with an extra methylene in the side chain (“homo” amino acids) and amino acids in which the carboxylic acid functional amino acid in the side chain is replaced with a sulfonic acid group (such as cysteic acid).
  • ⁇ -methyl amino acids such as ⁇ -methylalanine
  • D-amino acids such as ⁇ -methylalanine
  • histidine-like amino acids such as ⁇ -hydroxy-histidine, homohistidine, ⁇ -fluoromethyl-histidine and ⁇ -methyl-histidine
  • amino acids with an extra methylene in the side chain (“homo” amino acids)
  • the second amino acid constituting the peptide may be substituted with tyrosine, phenylalanine, methionine or tryptophan, and/or the C-terminal may be substituted with phenylalanine, leucine, isoleucine, tryptophan or methionine.
  • the second amino acid may be substituted with leucine or methionine, and/or the C-terminal amino acid may be substituted with valine or leucine. good.
  • the second amino acid may be substituted with valine or glutamine, and/or the C-terminal amino acid may be substituted with valine or leucine. good.
  • Peptides of SEQ ID NOS: 3 and 4 derived from CADM1 are peptides of SEQ ID NO: 2 into which a second amino acid substitution has been introduced.
  • the peptides of SEQ ID NOS: 6 and 25 derived from c-Myb are the peptides of SEQ ID NO: 5 with the second amino acid substitution introduced.
  • Peptides of SEQ ID NOS: 10, 27, 28, and 39 derived from EVC1 are peptides of SEQ ID NOS: 7 and 9 with a second amino acid substitution introduced.
  • Peptides of SEQ ID NOS: 40-43, 61, and 79 derived from EVC2 are peptides of SEQ ID NO: 13 with a second amino acid substitution introduced.
  • Fas-derived peptides of SEQ ID NOS: 17, 29, 30, 45, 46, and 63 are peptides of SEQ ID NO: 16 with a second amino acid substitution introduced.
  • the peptide according to the present disclosure can be produced using techniques known to those skilled in the art. For example, it may be artificially synthesized by a solid-phase method such as the Fmoc method or the tBoc method or a liquid-phase method.
  • a desired peptide may also be produced by expressing a polynucleotide encoding a peptide according to the present disclosure or a recombinant vector containing the polynucleotide. Any of the peptides thus obtained can be identified using techniques known to those skilled in the art. For example, it can be identified using the Edman degradation method, mass spectrometry, or the like.
  • compositions for treating or preventing ATL according to the present disclosure contains, for example, a peptide consisting of amino acid residues of SEQ ID NOs: 1-68 as an active ingredient.
  • the active ingredient of the pharmaceutical composition according to the present disclosure is not limited to the peptide according to the present disclosure, but a component capable of directly or indirectly inducing CTL, such as a polynucleotide encoding the same peptide or a vector containing the same, Alternatively, they may be antigen-presenting cells presenting complexes of the same peptide and HLA molecules on their surface, exosomes secreted from antigen-presenting cells, or a combination thereof.
  • Antigen-presenting cells to be used include macrophages, dendritic cells, and the like, and dendritic cells with high CTL-inducing ability are preferably used.
  • Other ingredients known to be used in cancer therapy such as chemokines, cytokines, tumor necrosis factors, chemotherapeutic agents, etc., may be included in the pharmaceutical compositions of the present disclosure.
  • the dose of peptide may be, for example, about 1-10 mg per day if the patient is an adult. However, since the dose varies depending on the patient's age, body weight, administration method, etc., it can be appropriately determined by those skilled in the art.
  • the pharmaceutical composition according to the present disclosure is believed to be useful for killing cancer cells due to the following mechanism of action.
  • the peptides in the pharmaceutical composition are presented on the surface of antigen-presenting cells in a state bound to HLA molecules.
  • CTL recognize peptides on such antigen-presenting cells they become activated, proliferate, and circulate in the systemic circulation.
  • peptide-specific CTLs invade cancer tissues, they recognize the same peptides derived from specific cancer antigens naturally bound to HLA molecules on the surface of cancer cells and kill the cancer cells. do. This function can contribute to the treatment of cancer.
  • the pharmaceutical composition according to the present disclosure can be used not only for cancer treatment but also for cancer prevention.
  • CTLs are induced, and the induced CTLs remain in the body, so when cancer cells develop, they are damaged. be able to.
  • recurrence of cancer may be prevented by administration to a human body after cancer treatment.
  • the pharmaceutical composition according to the present disclosure can be dissolved in a water-soluble solvent, formulated in the form of a pharmaceutically acceptable salt, and administered to a patient.
  • a pharmaceutically acceptable salt forms include physiologically acceptable water-soluble salts, such as sodium, potassium, magnesium, calcium, etc., buffered at physiological pH. mentioned.
  • non-water-soluble solvents can also be used, and examples of such non-water-soluble solvents include alcohols such as ethanol and propylene glycol.
  • formulations containing the pharmaceutical composition of the present embodiment may contain agents for various purposes, and examples of such agents include preservatives, buffering agents, and the like.
  • Preservatives include sodium bisulfite, sodium bisulfate, benzalkonium sodium thiosulfate, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methylparaben, polyvinyl alcohol, phenylethyl alcohol, ammonia, dithiothreitol, beta and mercaptoethanol.
  • Buffers include sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate and the like. These agents can be present in an amount capable of maintaining the pH of the system between 2-9, preferably between 4-8.
  • the dosage form of the pharmaceutical composition according to the present disclosure is also not particularly limited, but when used in the form of a vaccine, the dosage form is exemplified by injections (muscular, subcutaneous, intradermal), oral preparations, nasal spray preparations, and the like. be.
  • the pharmaceutical composition according to the present disclosure may be a mixed cocktail vaccine containing multiple types of active ingredients.
  • such vaccines may contain any two or more of the peptides of SEQ ID NOS: 1-68, or multiple active ingredients in combination with other active ingredients.
  • the vaccine is a component other than the pharmaceutical composition, even if it is an inactive component-containing vaccine containing a component that has no activity by itself and has the effect of further enhancing the effect of the pharmaceutical composition as a vaccine. good.
  • Inactive ingredients include adjuvants, toxoids, and the like. Examples of adjuvants include, but are not intended to be limited to, precipitating types such as aluminum hydroxide, aluminum phosphate, calcium phosphate, and oily types such as Freund's complete adjuvant and Freund's incomplete adjuvant. be done.
  • the pharmaceutical composition according to the present disclosure when present in the form of a vaccine, is preferably injected or infused, such as by intradermal, subcutaneous, intravenous, intramuscular administration, or transdermal, or inhaled through mucous membranes such as the nose, pharynx, etc. It is administered into the body by, for example.
  • the single dose can be set between an amount that significantly induces cytotoxic T cells and an amount that does not damage a significant number of non-cancer cells.
  • the pharmaceutical composition according to the present disclosure is intended not only for administration to the human body but also for extracorporeal use. More specifically, the pharmaceutical compositions of the present disclosure may be used to stimulate antigen-presenting cells in vitro or ex vivo to increase CTL induction activity.
  • the pharmaceutical composition according to the present disclosure contains antigen-presenting cells such as dendritic cells derived from a patient in need of cancer treatment or prevention. can be administered to the patient by returning the antigen-presenting cells to the patient's body after being pre-contacted with .
  • Peptides contained in pharmaceutical compositions can be introduced into antigen-presenting cells by, for example, lipofection, injection, and the like.
  • the polynucleotides can be introduced into antigen-presenting cells by techniques known in the art. For example, patient-derived antigen-presenting cells are transduced in vitro with a polynucleotide of interest or a vector encoding the polynucleotide by lipofection, electroporation, microinjection, cell fusion, DEAE dextran, calcium phosphate, or the like. You may convert.
  • Method for producing antigen-presenting cells includes, for example, the step of contacting a peptide consisting of the amino acid sequences of SEQ ID NOS: 1-68 with antigen-presenting cells in vitro.
  • the peptides used in the production method according to the present disclosure are thought to bind to HLA class I molecules on the surface of antigen-presenting cells and be presented to CTL as antigen peptides, thereby inducing CTL activity of antigen-presenting cells. Therefore, what is brought into contact with antigen-presenting cells is not limited to the peptide according to the present disclosure. It may be an antigen-presenting cell that presents a complex of HLA and HLA molecules on its surface, an exosome secreted from the antigen-presenting cell, or a combination thereof. Antigen-presenting cells to be used include macrophages, dendritic cells, and the like, and dendritic cells with high CTL-inducing ability are preferably used.
  • Antigen-presenting cells produced by the production method according to the present disclosure are intended not only to be used as the active ingredient of the pharmaceutical composition or immunity-inducing agent, but also to be used for immunotherapy and the like.
  • the antigen-presenting cells to be produced are antigen-presenting cells such as dendritic cells with low CTL-inducing ability derived from patients requiring immune induction.
  • the antigen-presenting cells can be administered to the patient by returning them to the patient's body.
  • the peptide according to the present disclosure can be introduced into antigen-presenting cells by, for example, liposome-mediated transfection (lipofection method), injection method, or the like.
  • the polynucleotides can be introduced into antigen-presenting cells by techniques known in the art. For example, patient-derived antigen-presenting cells are transduced in vitro with a polynucleotide of interest or a vector encoding the polynucleotide by lipofection, electroporation, microinjection, cell fusion, DEAE dextran, calcium phosphate, or the like. You may convert.
  • HLA-A*24:02 gene product HLA-A*24:02 molecule
  • HLA-A*02:01 gene product HLA-A*02:01 molecule
  • HLA-A An amino acid sequence was selected that had a binding prediction score of 3 or more in terms of ⁇ log Kd value with the product of the *02:06 gene (HLA-A*02:06 molecule).
  • Peptide Synthesis and Purification Peptides having the amino acid sequences of SEQ ID NOS: 1-81 were manually synthesized using Fmoc amino acids by the Merrifield solid-phase method. Deprotection was followed by reverse phase HPLC purification using a C18 column to >95% purity. Peptide identification and purity confirmation were performed by MALDI-TOF mass spectrometry (AB SCIEX MALDI-TOF/TOF5800). Peptides were quantified by Micro BCA assay (Thermo Scientific) using BSA as a standard protein.
  • HLA-A*24:02 molecule and C1R-A24 cells expressing HLA-A*24:02 molecules (prepared by Professor Masafumi Takiguchi, Kumamoto University, provided with permission from Assistant Professor Masataka Yasukawa, Ehime University).
  • C1R-A24 cells were exposed to acidic conditions of pH 3.3 for 30 seconds, and endogenous peptides originally bound to HLA-A*24:02 molecules, commonly associated with HLA class I molecules, were detected. Light chain ⁇ 2m was dissociated and removed. After neutralization, C1R-A24 cells were spiked with purified ⁇ 2m, added to a dilution series of peptides, and incubated on ice for 4 hours. Staining was performed using a fluorescence-labeled monoclonal antibody 17A12 that recognizes the 3-part assembly (MHC-pep) of HLA-A*24:02 molecule, peptide, and ⁇ 2m reassociated during this period.
  • MHC-pep 3-part assembly
  • the number of MHC-pep (proportional to the fluorescence intensity of the fluorescent antibody) per individual C1R-A24 cell was quantitatively measured using a fluorescent cell analyzer FACScan (Becton-Dickinson). From the average fluorescence intensity per cell, the binding between the HLA-A*24:02 molecule and the peptide by the method published in the paper by the present inventor (Udaka et al., Immunogenetics, 51, 816-828, 2000) Dissociation constant Kd values were calculated.
  • HLA-A*02:01 molecule The HLA-A*02:01 gene product, HLA-A*02:01 molecule, is measured for the ability of a peptide to bind to the HLA-A*02:01 molecule. It was performed using the expressing cell line T2 (purchased from ATCC).
  • HLA-A * 02: 06 molecule HLA-A * 02: 06 gene product HLA-A * 02: 06 gene
  • the binding ability of peptides to HLA-A * 02: 06 measurement is performed by mouse TAP (transporter associated with antigen processing ) RA2.6 cells (a cell line newly prepared at Kochi University) into which the cDNA of the HLA-A*02:06 gene was introduced into the defective cell line RMAS.
  • RA2.6 cells were cultured overnight at 26°C, and HLA-A*02:06 molecules with no peptide bound to the cell surface were accumulated. Ta.
  • HLA-A*02:06 molecules that do not bind peptides are denatured and lose their three-dimensional structure.
  • a fluorescence-labeled monoclonal antibody BB7.2 that specifically recognizes the peptide-bound HLA-A*02:06 molecule was added thereto, incubated on ice for 20 minutes, and the cells were stained.
  • the peptides of SEQ ID NOS: 1-33 exhibited binding properties to all of HLA-A*24:02, HLA-A*02:01 and HLA-A*02:06 molecules.
  • Peptides of SEQ ID NOS: 34-47 showed binding to any two or more of HLA-A*24:02 molecule, HLA-A*02:01 molecule and HLA-A*02:06 molecule.
  • Peptides of SEQ ID NOS: 48-68 showed binding to any one of HLA-A*24:02, HLA-A*02:01 and HLA-A*02:06 molecules.
  • the peptides of SEQ ID NOS: 69-81 did not show binding to any of HLA-A*24:02, HLA-A*02:01 and HLA-A*02:06 molecules. .
  • PBMC Peripheral blood mononuclear cells isolated from ATL patients were cultured, stimulated with peptides, and the production of IFN- ⁇ was measured by ELISA.
  • a suspension of PBMCs (2 ⁇ 10 6 cells/ml) was seeded in a 96-well plate (100-200 ⁇ l/well), and a medium containing 5 ⁇ g/ml of peptide (ASF-104, autologous serum 2%, IL-2 20U). /ml) for 2-3 days. After washing the cells, they were resuspended in the same medium, added with 5 ⁇ g/ml of peptide, and further cultured for 3 to 5 days. PBMC without peptide stimulation served as a control. The culture supernatant was collected and subjected to measurement of IFN- ⁇ production by ELISA (Human IFN- ⁇ ELISA MAX Deluxe Set, BioLegend).
  • FIG. 1 shows the results of a patient (sample 1) with HLA-A*24:02 in one of the alleles.
  • FIG. 2 shows the results for a patient (sample 3) with HLA-A*02:06 in one of the alleles.
  • FIG. 3 shows the results for a patient (sample 4) with HLA-A*02:06 in one of the alleles.
  • FIG. 4 shows the results of a patient (sample 12) with HLA-A*02:01 in one of the alleles.
  • FIG. 5 shows the results for a patient (sample 21) with HLA-A*02:01 in one of the alleles.
  • FIG. 6 shows the results for a patient (sample 24) with HLA-A*24:02 in one of the alleles.
  • FIG. 7 shows the results of a patient (sample 29) with HLA-A*24:02/*02:06.
  • H1 is the peptide of SEQ ID NO: 47
  • A15 is the peptide of SEQ ID NO: 66
  • A10 is the peptide of SEQ ID NO: 16
  • A19-1 is the peptide of SEQ ID NO: 20
  • at-1 means the peptide of SEQ ID NO:21
  • A13 means the peptide of SEQ ID NO:19.

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