[go: up one dir, main page]

WO2008007711A1 - Peptide dérivé de sart3, utile dans une thérapie du cancer par vaccin pour patient présentant un cancer de la prostate, positif á l'allèle hla-supertype a3 - Google Patents

Peptide dérivé de sart3, utile dans une thérapie du cancer par vaccin pour patient présentant un cancer de la prostate, positif á l'allèle hla-supertype a3 Download PDF

Info

Publication number
WO2008007711A1
WO2008007711A1 PCT/JP2007/063838 JP2007063838W WO2008007711A1 WO 2008007711 A1 WO2008007711 A1 WO 2008007711A1 JP 2007063838 W JP2007063838 W JP 2007063838W WO 2008007711 A1 WO2008007711 A1 WO 2008007711A1
Authority
WO
WIPO (PCT)
Prior art keywords
hla
peptide
sart3
prostate cancer
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2007/063838
Other languages
English (en)
Japanese (ja)
Inventor
Kyogo Itoh
Mamoru Harada
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kurume University
Original Assignee
Kurume University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kurume University filed Critical Kurume University
Priority to JP2008524824A priority Critical patent/JP5114403B2/ja
Publication of WO2008007711A1 publication Critical patent/WO2008007711A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4274—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; Prostatic acid phosphatase [PAP]; Prostate-specific G-protein-coupled receptor [PSGR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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
    • A61K2039/884—Vaccine for a specifically defined cancer prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a SART3-derived peptide useful for the treatment or prevention of HLA-A3 supertype allele positive prostate cancer patients.
  • Prostate cancer is a cancer that is common in elderly men (Non-patent Document 1).
  • Non-patent Document 1 the ability of androgon-removal therapy to be transiently successful S, effective treatment for relapse as hormone-resistant or bone-metastatic prostate cancer.
  • Specific immunotherapy can be a promising option for such patients. This is because prostate cancer reactive cytotoxic ⁇ cells can specifically find metastases.
  • Many cancer antigen peptides that can be used for specific immunotherapy for prostate cancer patients have been identified so far (Non-patent Document 2).
  • Non-Patent Document 3 because of the high frequency of HLA-A2 and -A24 alleles worldwide, most of the conventional cancer antigen peptides were for patients positive for HLA-A2 or -A24 alleles (Non-Patent Document 3). ).
  • HLA-A2, -A3, _B7 and -B44 supertype alleles have been proposed for HLA class I alleles based on structural homology and peptide binding motif analysis (Non-Patent Document 4).
  • the HLA-A3 supertype allele is found in 38% of Caucasians, 53% of Chinese, 46% of Japanese, and 43% of North American African Americans and Hispanics (Non-patent Document 4). Nonetheless, cancer antigen peptides that can be used to treat HLA-A3 supertype allele positive prostate cancer patients are limited (Non-patent Documents 5-7)
  • Non-patent Document 1 Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000; 50: 7-33.
  • Non-patent literature 2 Renkvist N, Castelli C, Robbins PF, Policyani GA listing of human tu mor antigens recognized by T cells. Cancer Immunol Immunother 2001; 50: 3-15.
  • Non-patent literature 3 Imanishi T, Akazawa Satoshi, Kimura A. Allele and haplotype frequencies fo r HLA and complement loci in various ethnic groups. In Tsuji, Aizawa M, Sasazuki T. editors. HLA 1991.Vol.
  • Non-Patent Document 5 Wang RF, Johnston SL, Southwood S, Sette A, Rosenberg SA.Recognition of an antigenic peptide derived from tyrosinase-related protein-2 by CTL in t he context of HLA-A31 and A33. J Immunol 1998 ; 160: 890-897.
  • Non-Patent Document 6 Takedatsu H, Shichijo S, atagiri, Sawamizu H, Sata M, Itoh. Identification of peptide vaccine candidates sharing among HLA-A3 +, -A11 +, -A31 +, and nd -A33 + cancer patients. Clin Cancer Res 2004 ; 10: 1112-1120.
  • Non-Patent Document 7 Matsueda S, Takedatsu H, Yao A, Tanaka M, Noguchi M, Itoh, Harada M. identification of peptide vaccine candidates for prostate cancer patients with
  • An object of the present invention is to provide a cancer antigen peptide useful for cancer vaccine therapy for HLA-A3 supertype allele positive prostate cancer patients.
  • the present invention provides a SART3-derived peptide that can bind to an HLA-A3 supertype allele molecule and is recognized by cellular immunity.
  • the present invention relates to a peptide consisting of the amino acid sequence shown in SEQ ID NO: 16 or 20, and substitution, deletion and / or addition of 1 or 2 amino acids in the amino acid sequence shown in SEQ ID NO: 16 or 20 And a derivative thereof having a property that is functionally equivalent to the peptide consisting of the amino acid sequence introduced with and having the amino acid sequence shown in SEQ ID NO: 16 or 20.
  • the present invention also provides a nucleic acid molecule encoding the peptide or derivative of the present invention and a vector comprising the nucleic acid molecule.
  • the present invention also provides a pharmaceutical composition for treating or preventing prostate cancer, particularly the pharmaceutical composition which is a cancer vaccine, comprising the peptide, derivative or vector of the present invention.
  • the present invention relates to prostate cancer reactive cytotoxicity, which comprises contacting peripheral blood mononuclear cells collected from HLA-A3 supertype allele positive prostate cancer patients with the peptide or derivative of the present invention. Methods of inducing sex T cells are provided.
  • the present invention also includes introducing a peptide or derivative of the present invention into a cell having an antigen-presenting ability derived from an HLA-A3 supertype allele-positive prostate cancer patient, or introducing the vector of the present invention. And a method for preparing an antigen-presenting cell that presents a complex of a SART3-derived peptide or a derivative thereof and a HLA-A3 supertype allele molecule on the cell surface.
  • the present invention has expanded the options for peptide-based immunotherapy, particularly cancer vaccine therapy, for HLA-A3 supertype allele positive prostate cancer patients.
  • the present invention is particularly useful for the treatment of prostate cancer patients who are negative for HLA-A2 or HLA-A24 molecules for which many cancer vaccine candidate peptides have been identified so far.
  • FIG. 1 A: SART3 mRNA expression in esophageal cancer cell line KE4, normal PBMC, and three prostate cancer cell lines (PC3, PC93, and LNCaP). B: Expression of HLA-A11, _A31, and A33 molecules in three types of LNCaP transfectants established in the present invention. The dotted line shows the result of staining without the primary antibody.
  • FIG. 2A Cytotoxic activity of peptide-stimulated PBMC from HLA-A3 supertype allele positive prostate cancer patients. * p ⁇ 0.05.
  • FIG. 2B Cytotoxic activity of peptide-stimulated PBMC derived from HLA-A3 supertype allele positive prostate cancer patients. * p ⁇ 0.05.
  • FIG. 3A Cytotoxic activity against prostate cancer cells depending on peptide-specific CD8-positive T cells. * ⁇ ⁇ 0 ⁇ 05.
  • the peptide of the present invention is a peptide comprising a part of the amino acid sequence of SART3 identified as a cancer antigen.
  • the amino acid sequence of SART3 is disclosed in Genebank at ⁇ 020880.
  • HLA-A3 supertype allele molecule means that the peptide can form a complex with the HLA-A3 supertype allele molecule and be displayed on the cell surface.
  • the amino acid sequence of a peptide that binds to an HLA molecule has regularity that depends on the type of HLA.
  • the amino acid sequence according to the regularity is called a binding motif.
  • HLA-A3 supertype allele molecules include HLA-A11, -A31, _A33, -A0301 and —A6801 molecules, which share the binding motif (Sette, A., and Sidney, J.
  • the phrase “recognized by cellular immunity” means that the peptide has the ability to induce peptide-specific CTL.
  • Peptide-specific CTL inducibility can be achieved, for example, by stimulating peripheral blood mononuclear cells (PBMC) with a peptide and reacting with antigen-presenting cells in which the peptide-stimulated PB MC is pulsed with the corresponding peptide (eg, IFN- ⁇ ). ) Can be measured by ELISA or the like.
  • the cytotoxic activity of the induced CTL can be confirmed by a 51 Cr release measurement method or the like.
  • the number of amino acid residues of the peptide of the present invention should be in the range of 8-14. S is preferable, more preferably 8 to; 11, particularly preferably 9 or 10. is there.
  • the phrase "recognized by humoral immunity” means that IgG specific to the peptide exists in the living body, that is, peptide-specific IgG is detected from plasma. Peptides recognized by both cellular immunity and humoral immunity are preferred as the peptides of the present invention because they are expected to have high immunogenicity and excellent CTL inducing ability. Specific IgG in plasma can be measured by a conventional ELISA method or the like.
  • amino acid represented by SEQ ID NO: 16 or 20 is particularly preferred as the peptide of the present invention.
  • substitution, deletion and / or addition of 1 or 2 amino acids in the amino acid sequence shown in SEQ ID NO: 16 or 20 It has the functionally equivalent properties of a peptide consisting of the introduced amino acid sequence and consisting of the amino acid sequence shown in SEQ ID NO: 16 or 20.
  • “Has functionally equivalent properties to the peptide consisting of the amino acid sequence shown in SEQ ID NO: 16 or 20” means that it can bind to the HLA-A3 supertype allele molecule and is recognized by cellular immunity. To do. Whether or not they have functionally equivalent properties is determined by the ability S to investigate according to the method described above.
  • Substitution of amino acids from the viewpoint of not changing the properties of peptides such as homologous amino acids (polar amino acids, nonpolar amino acids, hydrophobic amino acids, hydrophilic amino acids, positively charged amino acids, negatively charged amino acids, aromatic amino acids, etc.) ) Is preferable. Deletion and attachment of amino acids are preferably performed so that the derivative has 8 to 11 amino acid residues.
  • amino acid substitutions, deletions and / or additions are preferably allowed on the HLA molecule-binding motif. That is, amino acid substitution, deletion and / or addition is preferably performed so that the peptide terminal amino acid force S-lysine or arginine of the peptide derivative is obtained.
  • substitution, deletion and / or addition of other amino acids with the C-terminal amino acid of SEQ ID NO: 16 or 20 preserved in arginine substitution of its C-terminal amino acid with lysine, or its C-terminal
  • substitution of its C-terminal amino acid with lysine, or its C-terminal substitution of its C-terminal amino acid with lysine, or its C-terminal
  • the amino acid is replaced with lysine, and other amino acid substitutions, deletions and / or additions are performed.
  • derivatives comprising an amino acid sequence in which the C-terminal amino acid of the amino acid sequence shown in SEQ ID NO: 16 or 20 is substituted with lysine are particularly suitable for the
  • the amino acids constituting the peptides and derivatives of the present invention may be natural amino acids or amino acid analogs.
  • amino acid analogs include N-acylated, 0-acylated, esterified, and acid amino acids. Examples include amidated products and alkylated products.
  • the peptides and derivatives of the present invention may be modified in their constituent amino acids or carboxyl groups as long as the functions are not significantly impaired. Modifications include binding of formyl, acetyl, and t-butoxycarbonyl groups to the N-terminus and free amino groups, and C-terminus and free amino groups. And those having a methyl group, an ethyl group, a t-butyl group, a benzyl group or the like bonded to the carboxyl group.
  • the peptides and derivatives of the present invention can be produced by ordinary peptide synthesis.
  • Peptide Synthesis Interscience, New York, 1966; The Proteins, Vol2, Academic Press Inc., New York, 1976; peptide synthesis, Maruzen Co., Ltd., 1975; Experiment, Maruzen Co., Ltd., 1985; Development of pharmaceuticals, Vol. 14-Peptide synthesis, Hirokawa Shoten, 1991).
  • the peptide and derivative of the present invention may be produced by fragmenting a polypeptide containing the amino acid sequence IJ of the peptide or derivative of the present invention in a cell and provided as a complex with an HLA molecule. . It is also within the scope of the present invention to utilize the peptides or derivatives of the present invention in such embodiments. As long as the peptide or derivative of the present invention can be provided, the number of amino acid residues and the amino acid sequence of the polypeptide are arbitrary.
  • the peptides and derivatives of the present invention can efficiently induce and proliferate CTLs that damage HLA-A3 supertype allele-positive prostate cancer cells. That is, the peptides and derivatives of the present invention can be used for inducing prostate cancer-reactive CTLs and for producing pharmaceutical compositions for prostate cancer, etc., in the treatment or prevention of prostate cancer. Useful.
  • the pharmaceutical composition of the present invention contains one or more of the peptides or derivatives of the present invention, and has a therapeutic effect by inducing prostate cancer reactive CTL specific for the peptides or derivatives. Demonstrate.
  • the pharmaceutical composition of the present invention can be used as a cancer vaccine. Since CTL of cancer patients is a collection of cells that recognize different cancer antigen peptides, it is more effective to use a combination of multiple types of peptides and / or derivatives. You may combine with cancer antigen peptides other than the peptide of this invention.
  • the pharmaceutical composition of the present invention can be administered together with an adjuvant conventionally known to be used for vaccine administration so that an immune response is effectively established. Further, a liposomal preparation, a particulate preparation bound to beads having a diameter of several meters, or a preparation bound to lipid may be used.
  • the administration method is, for example, intradermal administration or subcutaneous administration. Dosage, disease state
  • the amount of the peptide or derivative of the present invention in the pharmaceutical composition is usually 0.0001 mg to 1000 mg, preferably 0.0001 mg to 100 mg, more preferably 0.001 mg. ⁇ 10mg. It is preferable to administer this once every several days, weeks or months for 1 to 3 years.
  • the nucleic acid molecule of the present invention can provide the peptide or derivative of the present invention.
  • a vector containing the nucleic acid molecule of the present invention is introduced into an antigen-presenting cell and expressed, the peptide or derivative of the present invention is produced and forms a complex with the HLA molecule and presented on the cell surface.
  • This antigen-presenting cell is capable of efficiently proliferating peptide-specific prostate cancer reactive CTL.
  • the vector of the present invention can be used for administration to a patient to express the peptide or derivative of the present invention in the patient. Further, after the vector of the present invention is introduced into an appropriate cell outside the body, for example, a dendritic cell derived from a patient, the cell may be returned to the patient.
  • a dendritic cell derived from a patient the cell may be returned to the patient.
  • Examples of the vector of the present invention include various plasmids and viral vectors such as adenovirus, adeno-associated virus, retrovirus, vaccinia virus and the like (Liu M, Acres B, Balloul jM, Bizouarne N, Paul S, MOS). P, ⁇ quioan P. Gene-based vaccines and immunotherapeutics. Proc Natl Acad Sci USA 101 Suppl, 14567-71, 2004). Vector preparation methods are well known in the art (Molecular Cloning: A laboraroy manual, 2nd edn. New York, Cold Spring Harbor Laboratory).
  • the dosage varies depending on the disease state, individual patient age, weight, etc.
  • the DNA content is 0.1 ⁇ g to 100 mg, preferably 1 ⁇ g to 50 mg.
  • Examples of the administration method include intravenous injection, subcutaneous administration, intradermal administration and the like.
  • the CTL induction method of the present invention provides a CTL that damages HLA-A3 supertype allele-positive prostate cancer cells.
  • prostate cancer reactivity means that it has a property of recognizing a complex of a cancer antigen peptide on a prostate cancer cell and an HLA molecule and damaging the cell.
  • Induction of CTL is, for example, HLA-A3 supertype array PBMC collected from a patient with le-positive prostate cancer is cultured in vitro in the presence of the peptide or derivative of the present invention.
  • the CTL induced by the method of the present invention is useful for adoptive immunotherapy, that is, a cancer treatment method in which CTL induced in a patient's body from which PBMCs are collected and cancer cells are damaged. That is, CTL induced by the method of the present invention can be used as a medicament for treating or preventing prostate cancer.
  • the CTL induction kit of the present invention is used for carrying out the CTL induction method.
  • the kit of the present invention contains one or more of the peptides or derivatives of the present invention, and further includes an appropriate buffer or medium.
  • the antigen-presenting cell preparation method of the present invention provides an antigen-presenting cell for inducing CTL that damages HLA-A3 supertype allele-positive prostate cancer cells.
  • Antigen-presenting cells can be prepared, for example, by the ability of the peptide or derivative of the present invention to be incorporated into cells having antigen-presenting ability derived from HLA-A3 supertype allele-positive prostate cancer patients, or such This is carried out by introducing and expressing the vector of the present invention in cells by a well-known method.
  • Cells with antigen-presenting ability are, for example, dendritic cells, and are prepared by separating cultured plate adherent cells from PBMC collected from patients and culturing them in the presence of IL-4 and GM-CSF for about 1 week. be able to.
  • Antigen-presenting cells prepared by the method of the present invention can induce CTLs that specifically recognize complexes of peptides or derivatives presented on the cell surface and HLA molecules, and when administered to patients, It can promote the induction of prostate cancer reactive CTL in the body. That is, the antigen-presenting cells prepared by the method of the present invention can be used as a medicament for treating or preventing prostate cancer.
  • the antigen-presenting cell preparation kit of the present invention is used for performing the antigen-presenting cell preparation method.
  • the kit of the present invention contains one or more kinds of the peptide or derivative of the present invention, and can further contain an appropriate buffer or medium.
  • PBMCs were collected with prior written consent from HLA-A3 supertype allele positive prostate cancer patients and healthy volunteers (HD). Patients included HLA-A11 positive, -A31 positive, and -A33 positive patients. HLA-A3 positive or -A68.1 positive patients are extremely infrequent in Japanese (1.6% and 0.5%) (Aizawa M. The Proceedings of the 3ra Asia-Oceania Histocompaatioility Workshop Conference, pp. 1090-1103 uxror d: Oxford University Press, 1986 ⁇ ), PBMCs derived from them were not available. None of the patients who collected PBM C were HIV-infected.
  • HLA-A11, -A31 and -A33 molecules on PBMC was confirmed by flow cytometry using the following antibody: anti-HLA-A11 monoclonal antibody (mAb) (C at # 0284HA; One Lambda Inc., Canoga, CA, USA); anti-HLA-A31 mAb (Cat # 0273 HA; One Lambda); anti-HLA- A33 mAb (Cat # 0612HA; One Lambda); and FITC-conjugated anti-mouse immunoglobulin G (IgG) mAb .
  • mAb monoclonal antibody
  • IgG FITC-conjugated anti-mouse immunoglobulin G
  • the level of SART3-derived peptide-specific IgG in plasma was measured by the Luminex (trademark) method as previously reported ( Komatsu N, Shichijo S, Nakagawa M, Itoh ⁇ , Scand J Clin Invest 2004; 64: 1-11 ⁇ ).
  • diluted serum 100 L was added to SART3-derived peptide-coated color-coded beads (Luminex Corp (Austin, TX, USA) (5 ⁇ 1)) and 96-well filter plate (MABVN1250, Millipore Corp., Incubated for 2 hours at room temperature on a plate shaker in Bedford, MA, USA After 2 hours, the plate was washed with T-PBS and biotinylated anti-human IgG (BA-3080 (VECTOR LAB, (CA, USA) (100 1) for 1 hour at room temperature, wash the plate, add streptavidin-labeled PE (100) (S-866, Invitrogen Detection Technologies, Eugene, Oregon, USA), 30 The bound beads were washed 4 times, followed by addition of Tween-PBS dOO l) to each well 50 1 samples were used for measurements by the Luminex TM method SART3-derived peptides In order to confirm the specificity of IgG for Control The cells were cultured on
  • C1R_A11, -A31, and -A33 are C1R subcell lines that stably express the HLA-A1101, -A3101, and -A3303 genes, respectively. Expression of HLA-A11, -A31 and -A33 molecules on these subcell lines has been reported previously (Takedatsu H, Shichijo S, Katagiri K, Saw amizu H, Sata M, Itoh ⁇ , Clin Cancer Res 2004; 10: 1112-1120 ⁇ ).
  • PC3, PC-93, and LNCaP are prostate cancer cell lines, and KE4 is an esophageal cancer cell line.
  • LNCaP subcell lines expressing HLA_A11, -A 31 and -A33 molecules were transformed into the eukaryotic expression vector pCR3.1 (Invitrogen, Carlsbad , CA, USA) and electoral positioning was performed using Gene Panoresa (Bio RAD, Richmond, CA, USA).
  • LNCaP_All, -A31 and -A33 are subcell lines that stably express the HLA-A1101, -A3101 and -A3303 genes, respectively (Fig. 1). All these cell lines were cultured in RPMI 1640 (Invitrogen) containing 10% FCS.
  • RNA of cancer cell lines was isolated using RNAzol TM B (Tel-Test Inc., Friendswood, TX, USA).
  • cDNA was prepared using the Superscript TM Preamplification System for First-Strand cDNA Synthesis (Invitrogen) and amplified using the following primers: SART3: 5′-AAGTACGCCAACATGTGGC-3 ′ (sense, SEQ ID NO: 34) , 5,-CTCTG CTCATTGACACGAGC-3 '(antisense, SEQ ID NO: 35)); ⁇ -actin: 5, -CTTCG CGGGCGATGC-3' (sense, SEQ ID NO: 36), 5, -CGTACATGGCTGGGGTGTTG-3 '(antisense, sequence Number 37).
  • PCR is 95 in a DNA thermorecycler (ICycler, Bio-Rad laboratories, Hercules, CA, USA) using Taq DNA polymerase. C1 min, 60 ° C 1 min, 72 ° C 1 min, 30 cycles. PCR products were separated by electrophoresis on a 2% agarose gel.
  • All SART3-derived peptides shown in Table 1 were prepared based on the binding motif for the HLA-A3 supertype allele molecule (Parker C, Bednarek MA, Coligan JE., J Immu nol 1994; 152: 163-175.) 0 Influenza (Flu) virus-derived peptide, Epstein's virus (EBV) -derived peptide, tyrosinase-related protein 2 (TRP2) -derived peptide, and HIV-derived peptide, HLA- Used as a binding control for the A3 supertype allele. All peptides were purchased from Biologica Co. (Nagoya, Japan) and dissolved in dimethyl sulfoxide at a dose of 10 Hg / ml.
  • T.P2 LLGPORPYR 9.0a The binding score was calculated based on the expected half-life of dissociation from the HLA class molecule.
  • HIV-derived nucleotides are not calculated because they are composed of 11 amino acids.
  • This culture is 45% RPMI 1640, 45% AIM-V medium (Gib co-BRL, Gaithersburg, MD), 10% FCS, 100 U / ml interleukin-2 (IL-2) and 0. ImM MEM not required It consisted of an amino acid solution (Gibco_BRL). Every 3 or 4 days, half of the culture was removed and replaced with a new culture containing the corresponding peptide (20 g / ml) and IL-2 (100 U / ml). On the 15th day of culture, the cultured cells were divided into 4 wells.
  • the cytotoxic activity of peptide-stimulated PBM C against LNCaP, LNCaP_All, LNCaP_A31 or LNCaP_A33 was measured by standard 6 hour 51 Cr release assay.
  • Phyto-Magnolechun (PHA) activated T cells were used as negative control cells.
  • PHA Phyto-Magnolechun
  • 2000 51 Cr-labeled cells were cultured with effector cells at the indicated effector cell / target cell ratio.
  • CD8 positive T cells were isolated using a CD8 Positive Isolation Kit (Dynal, Oslo, Norway). Specifically, purified CD8 positive T cells (2 x 10 4 cells / well) were placed in a round bottom 96-well plate in the presence of cold target cells (4 x 10 4 cells) with 51 Cr labeled target cells ( 2 ⁇ 10 3 cells / well). Corresponding SART3 peptide or HIV peptide C1R_A11, -A31, and -A33 pre-pulsed with either of these were used as cold target cells.
  • HLA-A3 and HLA-A68 molecules also belong to the HLA-A3 supertype allele (Sette A, Sidney J., Immunogenetics 1999; 50: 201-21 2.), but they are extremely rare in Japanese.
  • the binding ability to HLA-A11, -A31, and -A33 molecules was preferentially examined. The purpose of this study is to identify peptides that have the ability to induce cancer-reactive CTL in HLA-A3 supertype positive prostate cancer patients.
  • IgG response to chido was detected in plasma of 5, 7, 13, 5, and 5 of 20 prostate cancer patients, respectively (Table 2). IgG that reacts with these five SART3-derived peptides was also detected in plasma of 2, 2, 8, 1, and 4 of 20 HDs (data not shown). SART3-derived peptide-reactive IgG for these five types was detected more frequently in the plasma of prostate cancer patients than in HD. Against 24 other SART3-derived peptides 0064
  • PBMCs were stimulated with each SART3-derived peptide or control peptide, and the stimulated cells responded to C1R_A11, C1R-A31, or C1R-A33 cells with the corresponding peptide nors in response to IFN- ⁇ . The production was examined.
  • Table 3 shows representative results of 15 HLA-A3 supertype allele positive prostate cancer patients (5 per allele). Induction of peptide-specific CTL was considered successful when p ⁇ 0.05 and the difference from IFN- ⁇ production by the control HIV peptide was greater than 100 pg / ml.
  • SART3 SEQ ID NO: 6
  • SART3 SEQ ID NO: 16
  • SART3 SEQ ID NO: 16
  • SART3 SEQ ID NO: 20
  • SART3 SEQ ID NO: 16
  • SART3 SEQ ID NO: 20
  • Prostate cancer cell lines PC3, PC93, and LNCaP also expressed SART3 mRNA. Furthermore, in order to clarify the ability of HLA-A3 supertype allele-restricted cytotoxic activity, LNCaP transfectants expressing each of the HLA-A11, -A31, and -A33 molecules were prepared (Fig. 1B).
  • PBMC from HLA-A3 supertype allele-positive prostate cancer patients were stimulated with either SART3 or SART3 peptide and induced thereby
  • HLA-A11 positive patients (Pt. 1, 2, 5) stimulated with each of SART3 (SEQ ID NO: 20)
  • PBMCs derived from 17 showed higher levels of cytotoxic activity against LNCaP-All cells than against LNCaP cells and HLA-A11-positive immunized T cells.
  • these peptides had the ability to induce LNCaP transfectant-reactive CTLs from PBMCs of HLA-A31 positive patients and HLA-A33 positive patients. That is, these peptide-reactive CTLs showed higher levels of cytotoxic activity against LNCaP_A31 cells and LNCaP_A33 cells than to LNCaP cells or immunized T cells.
  • SART3 SEQ ID NO: 16
  • SART3 SEQ ID NO: 16
  • the SART3-derived peptide of the present invention can induce prostate cancer-reactive CTL in HLA-A3 supertype allele-positive prostate cancer patients and is useful for specific immunotherapy, particularly cancer vaccine therapy.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Urology & Nephrology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un peptide dérivé de SART3, qui peut lier une molécule allélique HLA-supertype A3 et qui peut être reconnu par l'immunité cellulaire. Le peptide est particulièrement utile pour le traitement d'un patient souffrant d'un cancer de la prostate, qui est négatif pour une molécule HLA-A2 ou HLA-A24, pour lesquelles molécules beaucoup de peptides candidats en tant que vaccin pour le cancer ont été identifiés précédemment.
PCT/JP2007/063838 2006-07-11 2007-07-11 Peptide dérivé de sart3, utile dans une thérapie du cancer par vaccin pour patient présentant un cancer de la prostate, positif á l'allèle hla-supertype a3 Ceased WO2008007711A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2008524824A JP5114403B2 (ja) 2006-07-11 2007-07-11 Ｈｌａ−ａ３スーパータイプアレル陽性前立腺癌患者に対する癌ワクチン療法に有用なｓａｒｔ３由来ペプチド

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006-190276 2006-07-11
JP2006190276 2006-07-11

Publications (1)

Publication Number Publication Date
WO2008007711A1 true WO2008007711A1 (fr) 2008-01-17

Family

ID=38923267

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2007/063838 Ceased WO2008007711A1 (fr) 2006-07-11 2007-07-11 Peptide dérivé de sart3, utile dans une thérapie du cancer par vaccin pour patient présentant un cancer de la prostate, positif á l'allèle hla-supertype a3

Country Status (2)

Country Link
JP (1) JP5114403B2 (fr)
WO (1) WO2008007711A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2801367A1 (fr) 2007-09-18 2014-11-12 Green Peptide Co., Ltd. Composition inductrice CTL
WO2015060235A1 (fr) * 2013-10-21 2015-04-30 大鵬薬品工業株式会社 Nouveau peptide à quatre épitopes ctl
WO2015083763A1 (fr) * 2013-12-06 2015-06-11 オンコセラピー・サイエンス株式会社 Peptide dérivé du vegfr2, et vaccin le contenant
WO2016021506A1 (fr) * 2014-08-04 2016-02-11 オンコセラピー・サイエンス株式会社 Peptide dérivé de koc1 et vaccin le comprenant
JP2016060710A (ja) * 2014-09-17 2016-04-25 学校法人近畿大学 細胞性免疫に認識されるペプチド、及びそれを利用した医薬薬剤
JP2016065027A (ja) * 2014-09-26 2016-04-28 学校法人近畿大学 Ｈｌａ−ａ３スーパータイプアレル陽性の前立腺癌患者に対する癌ワクチン療法に有用なｅｚｈ２由来ペプチド
US9701729B2 (en) 2013-03-08 2017-07-11 Taiho Pharmaceutical Co., Ltd. Peptide having 5 linked CTL epitopes
WO2020004622A1 (fr) 2018-06-29 2020-01-02 大鵬薬品工業株式会社 Agent antitumoral et sa méthode d'évaluation
WO2021132550A1 (fr) 2019-12-26 2021-07-01 大鵬薬品工業株式会社 Agent de thérapie adjuvante post-opératoire

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005194237A (ja) * 2004-01-08 2005-07-21 Univ Kurume 抗ｓａｒｔ３モノクローナル抗体

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1264980C (zh) * 1998-08-28 2006-07-19 伊东恭悟 新型肿瘤抗原蛋白sart－3及其肿瘤抗原肽

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005194237A (ja) * 2004-01-08 2005-07-21 Univ Kurume 抗ｓａｒｔ３モノクローナル抗体

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
MATSUEDA S. ET AL.: "Identification of peptide vaccine candidates for prostate cancer patients with HLA-A3 supertype alleles", CLIN. CANCER RES., vol. 11, 2005, pages 6933 - 6943, XP003004983 *
TAKEDATSU H. ET AL.: "Identification of peptide vaccine candidates sharing among HLA-A3+, -A31+, and A33+ cancer patients", CLIN. CANCER RES., vol. 10, no. 3, 2004, pages 1112 - 1120, XP003004980 *
WANG R.-F. ET AL.: "Recognition of an antigenic peptide derived from tyrosinase-related protein-2 by CTL in the context of HLA-A31 and -A33", THE JOURNAL OF IMMUNOLOGY, vol. 160, no. 2, 1998, pages 890 - 897, XP002309396 *
YANG D. ET AL.: "Identification of a gene coding for a gene coding for a protein possessing shared tumor epitopes capable of induction HLA-A24-restricted cytototic T lymphomcytes in cancer patients", CANCER RESEARCH, vol. 59, 1999, pages 4056 - 4063, XP002182055 *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3156061A1 (fr) 2007-09-18 2017-04-19 Green Peptide Co., Ltd. Composition d'inducteur en ctl
EP3494981A1 (fr) 2007-09-18 2019-06-12 BrightPath Biotherapeutics Co., Ltd. Composition d'inducteur en ctl
EP2801367A1 (fr) 2007-09-18 2014-11-12 Green Peptide Co., Ltd. Composition inductrice CTL
US9102715B2 (en) 2007-09-18 2015-08-11 Green Peptide Co., Ltd. CTL inducer composition
US9642900B2 (en) 2007-09-18 2017-05-09 Green Peptide Co., Ltd. CTL inducer composition
US9701729B2 (en) 2013-03-08 2017-07-11 Taiho Pharmaceutical Co., Ltd. Peptide having 5 linked CTL epitopes
US10137183B2 (en) 2013-10-21 2018-11-27 Taiho Pharmaceutical Co., Ltd. Peptide compositions having 4 linked CTL epitopes and uses thereof
AU2014337643B2 (en) * 2013-10-21 2017-07-13 Taiho Pharmaceutical Co., Ltd. Novel four-CTL epitope-joined peptide
JPWO2015060235A1 (ja) * 2013-10-21 2017-03-09 大鵬薬品工業株式会社 新規ｃｔｌエピトープ４連結ペプチド
CN105658673A (zh) * 2013-10-21 2016-06-08 大鹏药品工业株式会社 新型的具有4个连接的ctl表位的肽
CN105658673B (zh) * 2013-10-21 2019-07-26 大鹏药品工业株式会社 新型的具有4个连接的ctl表位的肽
WO2015060235A1 (fr) * 2013-10-21 2015-04-30 大鵬薬品工業株式会社 Nouveau peptide à quatre épitopes ctl
JP2017171678A (ja) * 2013-10-21 2017-09-28 大鵬薬品工業株式会社 新規ｃｔｌエピトープ４連結ペプチド
WO2015083763A1 (fr) * 2013-12-06 2015-06-11 オンコセラピー・サイエンス株式会社 Peptide dérivé du vegfr2, et vaccin le contenant
AU2015300256B2 (en) * 2014-08-04 2020-01-30 Oncotherapy Science, Inc. KOC1-Derived peptide and vaccine including same
JP7070945B2 (ja) 2014-08-04 2022-05-18 オンコセラピー・サイエンス株式会社 Ｋｏｃ１由来ペプチドおよびそれを含むワクチン
CN106715461A (zh) * 2014-08-04 2017-05-24 肿瘤疗法科学股份有限公司 Koc1衍生的肽和包含它们的疫苗
JPWO2016021506A1 (ja) * 2014-08-04 2017-05-18 オンコセラピー・サイエンス株式会社 Ｋｏｃ１由来ペプチドおよびそれを含むワクチン
EP4353321A3 (fr) * 2014-08-04 2024-07-10 OncoTherapy Science, Inc. Peptide dérivé de koc1 et vaccin le comprenant
RU2699542C2 (ru) * 2014-08-04 2019-09-06 Онкотерапи Сайенс, Инк. Пептид, полученный из koc1, и содержащая его вакцина
US11547723B2 (en) 2014-08-04 2023-01-10 Oncotherapy Science, Inc. KOC1-derived peptide and vaccine including same
EP3981416A3 (fr) * 2014-08-04 2022-07-06 OncoTherapy Science, Inc. Peptide dérivé de koc1 et vaccin le comportant
US10576102B2 (en) 2014-08-04 2020-03-03 Oncotherapy Science, Inc. KOC1-derived peptide and vaccine including same
EP3590954A3 (fr) * 2014-08-04 2020-03-25 OncoTherapy Science, Inc. Peptide dérivé de koc1 et vaccin le comportant
JP2020182487A (ja) * 2014-08-04 2020-11-12 オンコセラピー・サイエンス株式会社 Ｋｏｃ１由来ペプチドおよびそれを含むワクチン
CN111925431A (zh) * 2014-08-04 2020-11-13 肿瘤疗法科学股份有限公司 Koc1衍生的肽和包含它们的疫苗
CN106715461B (zh) * 2014-08-04 2020-11-24 肿瘤疗法科学股份有限公司 Koc1衍生的肽和包含它们的疫苗
TWI723958B (zh) * 2014-08-04 2021-04-11 日商腫瘤療法 科學股份有限公司 來自ｋｏｃ１的胜肽及含其之疫苗
WO2016021506A1 (fr) * 2014-08-04 2016-02-11 オンコセラピー・サイエンス株式会社 Peptide dérivé de koc1 et vaccin le comprenant
TWI754234B (zh) * 2014-08-04 2022-02-01 日商腫瘤療法 科學股份有限公司 來自koc1的胜肽及含其之疫苗
JP2016060710A (ja) * 2014-09-17 2016-04-25 学校法人近畿大学 細胞性免疫に認識されるペプチド、及びそれを利用した医薬薬剤
JP2016065027A (ja) * 2014-09-26 2016-04-28 学校法人近畿大学 Ｈｌａ−ａ３スーパータイプアレル陽性の前立腺癌患者に対する癌ワクチン療法に有用なｅｚｈ２由来ペプチド
WO2020004622A1 (fr) 2018-06-29 2020-01-02 大鵬薬品工業株式会社 Agent antitumoral et sa méthode d'évaluation
US12251447B2 (en) 2018-06-29 2025-03-18 Taiho Pharmaceutical Co., Ltd. Combined formulation comprising four linked cytotoxic T lymphocyte (CTL) epitopes and a PD-1 pathway inhibitor and methods of use thereof to treat cancer
WO2021132550A1 (fr) 2019-12-26 2021-07-01 大鵬薬品工業株式会社 Agent de thérapie adjuvante post-opératoire

Also Published As

Publication number Publication date
JP5114403B2 (ja) 2013-01-09
JPWO2008007711A1 (ja) 2009-12-10

Similar Documents

Publication Publication Date Title
ES2373907T3 (es) Péptidos asociados a tumores unidos promiscuamente a moléculas del antígeno de leucocito humano (hla) de clase ii.
US20190077832A1 (en) Novel cell epitopes and combination of cell epitopes for use in the immunotherapy of myeloma and other cancers
US7148326B2 (en) Tumor antigen
JP5114403B2 (ja) Ｈｌａ−ａ３スーパータイプアレル陽性前立腺癌患者に対する癌ワクチン療法に有用なｓａｒｔ３由来ペプチド
IL309003A (en) Novel peptides, combination of peptides and scaffolds for use in immunothera-peutic treatment of various cancers
JP5065273B2 (ja) Ｈｌａ−ａ２４分子結合性ｋｉｆ由来ペプチド
JP4972691B2 (ja) ＨＬＡ−Ａ３スーパータイプアレル陽性癌患者に対する癌ワクチン療法に有用なＬｃｋ由来ペプチド
JP2023040149A (ja) ポリオーマウイルスのための免疫療法
CN105163754A (zh) 前列腺特异性肿瘤抗原及其用途
JP4945444B2 (ja) Ｈｌａ−ａ３スーパータイプアレル分子陽性前立腺癌患者に対する癌ワクチン候補となる前立腺関連蛋白由来ペプチド
JP2018508181A (ja) Ｔｈ１細胞のためのＧＰＣ３エピトープペプチドおよびこれを含有するワクチン
JP5736333B2 (ja) 無差別的にヒト白血球抗体（ｈｌａ）クラスｉｉ分子に結合する腫瘍関連ペプチド
JP5736334B2 (ja) 無差別的にヒト白血球抗体（ｈｌａ）クラスｉｉ分子に結合する腫瘍関連ペプチド
JPWO2003008450A1 (ja) 腫瘍抗原
EP2891663B1 (fr) Peptides dérivés de psf1
JP6784964B2 (ja) Ｈｌａ−ａ３スーパータイプアレル陽性の前立腺癌患者に対する癌ワクチン療法に有用なｅｚｈ２由来ペプチド
KR20250158026A (ko) 폐암에 대한 신규한 종양 항원 및 이의 용도
JP2008260689A (ja) Ｈｌａ−ａ２４分子結合性副甲状腺ホルモン関連蛋白由来ペプチドを含有する医薬組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07790642

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2008524824

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07790642

Country of ref document: EP

Kind code of ref document: A1