WO2004018667A1 - ペプチド及びこれを含む医薬 - Google Patents

ペプチド及びこれを含む医薬 Download PDF

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WO2004018667A1
WO2004018667A1 PCT/JP2003/010459 JP0310459W WO2004018667A1 WO 2004018667 A1 WO2004018667 A1 WO 2004018667A1 JP 0310459 W JP0310459 W JP 0310459W WO 2004018667 A1 WO2004018667 A1 WO 2004018667A1
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Prior art keywords
peptide
gpc3
fmoc
cells
hla
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PCT/JP2003/010459
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English (en)
French (fr)
Japanese (ja)
Inventor
Yasuharu Nishimura
Tetsuya Nakatsura
Yusuke Nakamura
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Kirin Beer Kabushiki Kaisha
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Priority to AU2003254950A priority Critical patent/AU2003254950A1/en
Priority to JP2004530567A priority patent/JP4406607B2/ja
Publication of WO2004018667A1 publication Critical patent/WO2004018667A1/ja

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4725Proteoglycans, e.g. aggreccan
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407Specifically defined cancers
    • G01N33/57438Specifically defined cancers of liver, pancreas or kidney

Definitions

  • the present invention relates to a novel peptide effective as a cancer vaccine, a medicament for treating and preventing a tumor containing the peptide, and a novel diagnostic agent for hepatocellular carcinoma.
  • HCC Primary hepatocellular carcinoma
  • AFP and PIVKA-II are well-known tumor markers for HCC.
  • SGBS Simpson-Golabi-Behmel syndrome
  • the clinical features of SGBS include distinct facial appearance, cleft palate, syndactyly, polydactyly, accessory breast, cystic and dysplastic kidneys, and congenital heart defects (Behmel, A. Hum. Genet. 67, 409-413 (1984); Garganta, CL and Bodurtha, JN, Am. J. Med. Genet. 44, 129-135 (1992); Golabi, M. and ⁇ Rosen, L. , Am. J. Med. Genet. 17, 345-358 (1984); Gurrieri, F. et al., Am. J. Med. Genet. 44, 136-137 (1992)).
  • GPC3 mutations have been reported to be point mutations or deletions of small genes containing some exons (Hughes-Benzie, RM et al., Am. J. Med. Genet. 66, 227). -234 (1996); Lindsay, S. et al., J. Med. Genet. 34, 480-483 (1997); Veugelers. M. et al., Hum. Mol. Genet. 9, 1321-1328 (2000); Xuan, JY et al., J. Med. Genet. 36, 57-58 (1999)).
  • SGBS is characterized by functional GPC3 protein deficiency and other genetic factors that produce phenotypic differences within and between families.
  • Hughes-Benzie, RM, et al., Am. J. Med. Genet. 66, 227-234 (1996) and studies of GPC3-deficient mice support this hypothesis.
  • Cano-Gauci, DF et al., J. Cell Biol. 146, 255-264 (1999) These mice have some of the abnormalities found in patients with SGBS, including overgrowth, cystic and dysplastic kidneys.
  • TL is expected to show cytotoxicity only against cancers that overexpress the antigen, and not show any side effects on normal tissues. From studies using Northern plot analysis, GP C
  • GPC3 has an inhibitory effect on cell growth and can induce apoptosis in certain types of tumor cells (Duenas Gonzales, A. et al., J. Cell Biol. 141,
  • GPC3 was not expressed in human breast cancer (Xiang, YY et al., Oncogene 20, 7408-7412 (2001)). These data suggest that GPC 3 may act as a negative regulator of cell proliferation in these cancers. That is, GPC3 expression is reduced during tumor progression in cancers arising from adult GPC3-positive tissues, and this reduction appears to play a role in the development of the malignant phenotype.
  • HS PG paran sulfate proteodalican
  • Glypican is a family of GPI-anchored cell-surface HSPGs, and this tissue-specific difference in the relationship between tumorigenesis and GPC3 expression levels indicates that GPC3 regulates growth and survival factors in different ways in each tissue It is presumed that it is because. GPC 3 appears to act as an oncofetal protein at least in these organs. In general, oncofetal proteins have not been found to play a significant role in tumor progression, but have been used as tumor markers or immunotherapeutic targets (Coggin,
  • HCC Despite various treatments for HCC, it has a poorer prognosis than other cancers and is one of the refractory cancers. This is due to the cirrhosis at the base of HCC, the poor liver function of the original patient, and the fact that treating one cancer causes it to come from another location. There is an urgent need for new treatment strategies. If immunotherapy targeting antigens that are specifically expressed in HCC could be developed, it could be a therapeutic method that effectively eliminates only cancer without damaging its own normal organs. It can also be a treatment that can be used for any terminally ill cancer patient whose liver function is too poor for other treatments. In Japan, it is said that there are more than 2 million hepatitis C infected people in the HCC reserve group.
  • AFP and PIVKA-II are known as tumor markers for HCC, but may not be detected in some patients or may be false-positive in patients with benign liver disease cirrhosis or chronic hepatitis. Diagnosis of HCC is considered difficult. Other useful tumor markers are needed for early diagnosis of HCC. Disclosure of the invention
  • the present inventors have identified Daribican 3 (GPC 3) as a novel oncofetal protein specifically overexpressed in human hepatocellular carcinoma based on cDNA microarray interpretation data, Novel peptides have been discovered that could be potential candidates for target antigens.
  • GPC3 Daribican 3
  • the present invention provides the following (1) to (18).
  • the second amino acid from the N-terminus is phenylalanine, tyrosine, The peptide according to the above (2), which is nin or tributophan.
  • a medicament for treating and / or preventing or treating a tumor comprising at least one peptide according to any one of the above (1) to (4).
  • a diagnostic agent for hepatocellular carcinoma comprising an antibody against GPC3.
  • a method for diagnosing HCC comprising contacting a sample with an antibody against GPC3.
  • the method according to (16) further comprising quantifying GPC3 in the sample.
  • FIG. 1 shows HCC-specific expression of GPC3 mRNA in adult tissues.
  • FIG. 2 shows the expression of mRNA of GPC 3 and ⁇ -actin (control) detected by RT-PCR in a human HCC cell line.
  • Lane 1 HepG2
  • Lane 2 Hep3B
  • Lane 3 PLC / PRF / 5
  • Lane 4 SK—Hep-1; Lane 5: HuH-7
  • FIG. 3 shows that PBMCs stimulated with GPC 3 peptide (peptides (pep) 1 to 12: SEQ ID NOs: 5 to 16) and further expanded were subjected to CTL using a 6 hr 51 Cr release assay. A part of the results obtained by examining the activity is shown. The value on the vertical axis indicates the specific cell lysis rate (%) calculated based on the average value of three assays.
  • HCC cell lines as HLA- A 24 + GPC 3 + + + in HepG2, using HLA- A 24+ GPC 3- Roh SK- Hep- 1, HLA one A 24- GPC 3 +++ of Hep3B and HuH- 7 , Patient 1, peptide 1,
  • FIG. 4 shows the presence of GPC3 protein in the culture supernatant of HepG2 using Western blot.
  • Lanes 2, 4, 6, and 8 20 ⁇ l of HepG2 culture supernatant after culturing for 6, 12, 24, and 48 hours
  • FIG. 5 shows the results of quantification by ELISA of GPC3 protein secreted into the culture supernatant of three types of HCC cell lines (HepG2, Hep 3B and SK-Hep-1).
  • the concentration of GPC 3 protein in the culture supernatant 1 m 1 after HepG2 cells 1 X 1 0 5 or 24 hours of culture was defined as lUZm l.
  • FIG. 6 shows detection of soluble GPC3 protein in serum of HC C patients by Western blot.
  • FIG. 7 shows the results of ELISA quantification of GPC3 protein in the sera of 28 HCC patients and 54 healthy donors (HD). 1.71 is the upper normal limit of soluble GPC3 protein in serum, defined as the mean of GPC3 protein in serum from 54 HDs + 3SD. BEST MODE FOR CARRYING OUT THE INVENTION
  • the present inventors used the method described in Okabe, H. et al. (Cancer Res. 61, 2129-2137 (2001)) to specifically overexpress human hepatocellular carcinoma based on cDNA microarrays.
  • Glypican 3 GPC3 was identified as a novel oncofetal protein expressed.
  • GPC3 was negative in cancers other than hepatocellular carcinoma, such as stomach, esophagus, lung, breast, pancreas, bile duct, and colon, and liver cirrhosis and chronic The results were confirmed to be negative for benign liver diseases such as hepatitis.
  • the present inventors have also confirmed that postoperative serum GPC 3 becomes negative in patients after surgical treatment for hepatocellular carcinoma.
  • the amino acid sequence of the human GPC3 protein is known, and is registered in, for example, GenBank's protein database as Accession No. NP 004475. Can be easily obtained.
  • the present inventors next considered that various proteins are presented in vivo on antigen-presenting cells after being decomposed into a peptide (nonapeptide) consisting of 9 amino acids.
  • a peptide nonapeptide
  • Selection of a peptide having a binding motif for HLA-A24 can be performed, for example, based on the method described in (J. Immunol., 152, 3913, 1994; J. Immunol. 155: 4307, 1994). .
  • peptides can be selected for HLA types other than HLA-A24.
  • various peptides and HLA molecules also called HLA antigens may be used using software recently available on the Internet, such as those described in Parker KC, J. Immunol. 152, 1994. Can be calculated in insilico.
  • the binding affinity with the HLA molecule can be determined by, for example, using the above-mentioned software.
  • BIMAS HLA Binding Prediction: http://bimas.dcrt.nih.gov/molbio/hla_bind/ , 152, 1994), or Nukaya, I., Int. J. Cancer, 80, 1999 and the like.
  • 9-mer and 10-mer peptides can be obtained by synthesizing a peptide from any position based on the entire amino acid sequence of the obtained GPC3 protein.
  • the peptide can be synthesized according to the method used in ordinary peptide chemistry. Synthetic methods commonly used include, for example, Peptide Synthesis, Interscience, New
  • LA class I molecules can be quantified and measured using a flow cytometer (for example, Immunol. Lett. 2002 Aug 1, 83 (1): 21-30; Immunogenetics, 44: 233-241,
  • the HLA molecule it is preferable to use the A24 type possessed by many Japanese (60%) in order to obtain effective results, and more preferably a subtype such as A * 2402. It is.
  • the type of HLA molecule in patients requiring treatment is determined in advance, and a peptide with high binding affinity to the HLA molecule or the ability to induce cytotoxic T cells (CTL) by antigen presentation can be appropriately selected. You can choose.
  • one or two amino acids may be substituted or added based on the amino acid sequence of a naturally occurring GPC tri-partial peptide. it can.
  • the sequence regularity of peptides presented to HLA molecules is already known (J. Immunol., 152, 3913, 1994; Imraunogenetics. 41). : 178, 1995; J. Immunol. 155: 4307, 1994), and the obtained peptide may be modified based on these regularities.
  • those with high HLA-A24 binding affinity have the amino acid at the N-terminus of the peptide replaced with phenylalanine, tyrosine, methionine or tributophane, or the C-terminal amino acid with phenylalanine.
  • Peptides substituted with leucine, isoleucine, tryptophan or methionine can also be suitably used.
  • the sequence of the peptide is identical to a part of the amino acid sequence of an endogenous or exogenous protein having another function, side effects such as an autoimmune disease may occur, or a specific substance Because of the possibility of causing allergic symptoms, it is preferable to perform a homology search using an available database to avoid a match with the amino acid sequence of another protein. Furthermore, if it is clear from the homology search that no peptide differs by one or two amino acids, the above amino acid sequence for enhancing the binding affinity to the HLA molecule and the ability to induce Z or CTL Does not cause such a problem.
  • a peptide having a high binding affinity to an HLA molecule is expected to be highly likely to be effective as a cancer vaccine, but a candidate selected as an index because it has a high binding affinity It is necessary to examine whether the peptide actually has the ability to induce CTL. Confirmation of CTL inducibility can be performed, for example, using antigen-presenting cells (eg, B-lymphocytes, macrophages, dendritic cells) containing HLA molecules Induces dendritic cells derived from human peripheral blood mononuclear cells, stimulated with peptides, and stimulated CD
  • antigen-presenting cells eg, B-lymphocytes, macrophages, dendritic cells
  • peptide-specific CTL can be derived from PBMC based on the method described in Nakatsura, T. et al. (Eur. J. Immunol. 32, 826-836 (2002)).
  • transgenic animals prepared to express human HLA molecules (for example, Hum. Immunol.
  • HLA class II restricted T (H) response BenMohamed L., Krishnan R., Longmate J., Auge C., Low L., Primus J., Diamond DJ.
  • the cytotoxic activity can be calculated from the radioactivity released from the target cell, for example, by radiolabeling the target cell with 5 ⁇ Cr or the like.
  • CTLs are produced in the presence of peptide-loaded antigen-presenting cells. Observation can be made by measuring spots visualized on the medium by the released IFN- ⁇ and anti-IFN- ⁇ monoclonal antibodies. .
  • non-peptides or decaptides selected from peptides having the amino acid sequences shown in SEQ ID NOs: 5 to 16 have particularly high CTL-inducing ability It became clear.
  • Trp-Tyr-Cys-Ser-Tyr-Cys-Gln-Gly-Leu SEQ ID NO: 10.
  • the present invention further provides a peptide in which one or two amino acids are substituted or added in the amino acid sequence shown in any of SEQ ID NOs: 5 to 16, and which has an ability to induce cytotoxic T cells. Substitution or addition of one or two amino acids may be capable of inducing CTL as long as there is no match with the amino acid sequence of another protein.
  • amino acid substitutions such as substitution of the second amino acid from the N-terminus with phenylalanine, tyrosine, methionine or tryptophan, and substitution of a C-terminal amino acid with phenylalanine, leucine, isoleucine, tryptophan or methionine are not allowed. This is a preferred example.
  • the above-mentioned peptide of the present invention can be used as one or a combination of two or more thereof as a cancer vaccine capable of inducing CTL in vivo.
  • the peptide is presented at a high density on HLA molecules of antigen-presenting cells, and CTLs that specifically react with the complex of the presented peptide and the HLA molecule are induced.
  • the offensive power against hepatocellular carcinoma cells to be targeted cells increases.
  • dendritic cells are removed from a subject and stimulated with the peptide of the present invention to obtain antigen-presenting cells loaded with the peptide of the present invention on the cell surface. It can induce CTLs and increase the attack power on target cells.
  • the present invention provides a medicament for treating a tumor or preventing the growth and metastasis of a tumor, which comprises one or more peptides of the present invention.
  • a medicament for treating a tumor or preventing the growth and metastasis of a tumor which comprises one or more peptides of the present invention.
  • peptide stimulation of antigen-presenting cells according to the present invention by the presence of high concentrations of peptide in to cells, the exchange of the peptide which is previously loaded into the cell Occurs and is easily performed. For this reason, the binding affinity with the HLA molecule needs to be higher than a certain level.
  • the medicament of the present invention may be directly administered with the peptide of the present invention alone, or may be administered as a pharmaceutical composition formulated by a commonly used pharmaceutical method.
  • a pharmaceutical composition formulated by a commonly used pharmaceutical method.
  • carriers, excipients and the like usually used for pharmaceuticals can be appropriately contained, and there is no particular limitation.
  • a medicament for treating and / or preventing hepatocellular carcinoma containing the peptide of the present invention as an active ingredient can be administered with an adjuvant so that cellular immunity can be effectively established, It can be administered together with other active ingredients such as anticancer agents, or can be administered in the form of particles.
  • an adjuvant those described in the literature (Clin. Microbiol. Rev., 7: 277-289, 1994) can be applied.
  • a ribosome preparation, a particulate preparation bonded to beads having a diameter of several ⁇ , a preparation bonded to a lipid, and the like can be considered.
  • oral administration intradermal administration, subcutaneous administration, intravenous injection and the like can be used, and systemic administration or local administration near a target tumor can be used.
  • the dose of the peptide of the present invention can be appropriately adjusted depending on the disease to be treated, the age and weight of the patient, the administration method, etc., but is usually 0.001 mg to; L000 mg, preferably 0.001 to 1000 mg, More preferably, the dose is 0.1 mg to: 10 mg, and it is preferable to administer it once every few days to several months. Those skilled in the art can appropriately select an appropriate dose.
  • the present invention provides an intracellular vesicle called exosome, which displays a complex of the peptide of the present invention and an HLA molecule on the surface.
  • Exosomes can be prepared, for example, using the methods described in detail in JP-A No. 11-151,073 and JP-A No. 2000-512,161. However, it is preferably prepared using antigen-presenting cells obtained from a subject to be treated and / or prevented.
  • the exosome of the present invention can be inoculated as a cancer vaccine in the same manner as the above-mentioned peptide of the present invention.
  • the HLA molecule must be of the same type as the HLA molecule of the subject in need of treatment and / or prevention.
  • HLA-A24 especially HLA-A * 2402.
  • the present invention also provides a method for inducing antigen-presenting cells using the peptide of the present invention.
  • dendritic cells After dendritic cells are derived from peripheral blood monocytes, they can be contacted (stimulated) with the peptide of the present invention in vitro or in vivo to induce antigen-presenting cells.
  • antigen-presenting cells loaded with the peptide of the present invention are induced in the subject.
  • the peptide of the present invention can be administered as a vaccine to a subject after in vitro loading the peptide of the present invention on the antigen-presenting cells.
  • the present invention also provides a cytotoxic T cell-inducing ability, which comprises introducing a gene encoding a partial peptide thereof containing the GPC3 protein or the peptide of the present invention into an antigen-presenting cell in vitro.
  • Methods for inducing high antigen presenting cells are provided.
  • Guidance The gene to be input may be in the form of DNA or RNA.
  • the method of introduction may be any of various methods usually used in this field, such as ribofusion, electroporation, and calcium phosphate method, and is not particularly limited. Specifically, for example, it is described in Cancer Res., 56: 5672, 1996; J. Immunol., 161: 5607, 1998; J. Exp.
  • the present invention further provides a method for inducing CTL using the above-described peptide of the present invention.
  • CTL is induced in the subject, and immunity targeting hepatocellular carcinoma cells is enhanced.
  • exogenous antigen-presenting cells and CD8-positive cells or peripheral blood mononuclear cells from a subject are contacted (stimulated) with the peptide of the present invention in vitro to induce CTL and then return to the subject. It can also be used for treatment.
  • the present invention further provides an isolated cytotoxic T cell induced using the peptide of the present invention.
  • the cytotoxic T cells induced based on stimulation by the antigen-presenting cells presenting the peptide of the present invention are preferably derived from a subject to be treated and / or prevented, alone or in the present invention. It can be administered for the purpose of antitumor effect together with other drugs including the peptide of the present invention, exosomes and the like.
  • the present invention further provides an antigen-presenting cell that presents a complex of an HLA molecule and a peptide of the present invention.
  • the antigen-presenting cells obtained by contacting the peptide of the present invention, or the GPC3 protein containing the peptide of the present invention, or a gene encoding a partial peptide thereof, are preferably targets for treatment and prevention or prevention. And can be administered alone or as a vaccine together with other drugs including the peptide of the present invention, exosomes, cytotoxic T cells and the like.
  • the present invention further provides a diagnostic agent for hepatocellular carcinoma, comprising an antibody against GPC3.
  • Antibodies to GPC3 may be either polyclonal or monoclonal antibodies, and can be prepared by methods known to those skilled in the art (for example, see “Shinsei Kagaku Jikken Kozai 1, Protein 1, 389-406, Tokyo Kagaku Dojin”). It is possible.
  • GPC 3 protein The amino acid sequence of the protein is known as described above, and can be produced using ordinary protein expression techniques based on the amino acid sequence, or a commercially available product (Santa Cruz, CA) can be used.
  • SDS-Out TM Sodium Dodecyl Sulfate Precipitation Reagent; purchased from PIERCE, Rockford, IL
  • the partial peptide of GPC3 can be produced by selecting an appropriate partial sequence from the amino acid sequence of GPC3 and using a general peptide synthesis technique.
  • a GPC3 protein or a partial peptide thereof is administered as a sensitizing antigen to animals such as rabbits, guinea pigs, mice, rats, hamsters, -birds, and monkeys.
  • Administration may be with an adjuvant (FIA or FCA) that promotes antibody production.
  • FFA or FCA adjuvant
  • Administration is usually performed every few weeks. Multiple immunizations can increase antibody titers.
  • antiserum can be obtained by collecting blood from the immunized animal.
  • a polyclonal antibody can be prepared by subjecting the anticoagulant to, for example, ammonium sulfate precipitation, fractionation by anion chromatography, and affinity purification using protein A or immobilized antigen.
  • a monoclonal antibody for example, an animal is immunized with the GPC3 protein or a partial peptide thereof in the same manner as described above, and after the final immunization, a spleen or lymph node is collected from the immunized animal.
  • Antibody-producing cells contained in the spleen or lymph nodes and myeloma cells are fused using polyethylene glycol or the like to prepare a hybridoma.
  • Cell fusion is basically performed by known methods, for example, the method of Kohler and Milstein et al. (Kohler. G. and Milstein, Methods Enzymol. (1981)
  • the obtained hybridomas are selected by culturing them in a normal selective culture medium, for example, a HAT culture medium (a culture medium containing hypoxanthine, aminopterin and thymidine). Culture in the above HAT culture solution is continued for a time sufficient for killing cells other than the target hybridoma (non-fused cells). Next, the desired hybridoma is screened, cultured, and a monoclonal antibody can be prepared from the culture supernatant.
  • a normal selective culture medium for example, a HAT culture medium (a culture medium containing hypoxanthine, aminopterin and thymidine).
  • the antibody of the present invention can be expressed by an expression vector containing an antibody gene by a genetic engineering technique. May be produced in a host transformed with-.
  • a recombinant antibody produced by cloning an antibody gene from a hybridoma into a suitable vector, introducing this into a host, and producing the same using a gene recombination technique can be used as a monoclonal antibody.
  • Vanda Thigh e, AM et al., Eur. J. Biochem. (1990) 192, 767-775, 1990 See, for example, Vanda Thigh e, AM et al., Eur. J. Biochem. (1990) 192, 767-775, 1990).
  • any expression system can be used, for example a eukaryotic or prokaryotic cell system.
  • Eukaryotic cells include, for example, established mammalian cell lines, insect cell lines, animal cells such as filamentous fungal cells and yeast cells, and prokaryotic cells include, for example, bacterial cells such as E. coli cells. Is mentioned.
  • the transformed host cells are cultured in vitro or in vivo to produce the desired antibody. Culture of the host cell is performed according to a known method.
  • the monoclonal antibody can be purified, for example, by precipitation with ammonium sulfate or fractionation by anion chromatography, or by affinity chromatography using protein A or immobilized antigen.
  • the separation and purification methods used for ordinary proteins may be used.For example, a chromatography column other than the above-mentioned affinity column, a filter, ultrafiltration, salting-out, dialysis, etc. may be appropriately selected. By combining them, antibodies can be separated and purified.
  • the antibody used in the present invention is not limited to the whole antibody molecule, and may be an antibody fragment or a modified product thereof as long as it binds to GPC3, and includes both bivalent antibodies and monovalent antibodies.
  • the antibody fragment Fab, F (ab ') 2, Fv, Fab / c having one Fab and complete Fc, or Fv of H chain or L chain were linked by an appropriate linker.
  • Single-chain Fv scFv
  • the antibody may recognize any epitope of GPC3.
  • the antibody is preferably a human antibody or a human antibody.
  • a human antibody is isolated from a mouse cell that produces an antibody against the GPC3 protein, and the H chain constant region is recombined into a human IgE H chain constant region gene. It can be prepared by introduction into mouse myeloma cells.
  • the human antibody binds the immunoglobulin gene to human. It can be prepared by immunizing the replaced mouse with GPC3 protein.
  • the antibody in the diagnostic agent of the present invention, can be used at, for example, but not limited to, a concentration of 1 ⁇ g / ml.
  • a diagnostically acceptable carrier or the like can be appropriately contained in the diagnostic agent, if necessary.
  • the present invention further provides a method for diagnosing hepatocellular carcinoma, which comprises contacting a sample with an antibody against GPC3.
  • the diagnostic method may further include quantifying GPC3 in the sample.
  • the sample includes serum, saliva, urine, and the like obtained from a subject who may be suffering from HCC, and is particularly preferably serum.
  • the contact between the sample and the above antibody may be performed by a method generally used in the art, and is not particularly limited. Diagnosis is, for example, after contact between the sample and the above antibody, the specific binding between the antibody and GPC3, which may be present in the sample, is determined using a fluorescent or luminescent substance, or a secondary antibody labeled with an enzyme This can be done by quantitative detection.
  • the reaction for diagnosis may be performed in a liquid phase such as a well, or may be performed on a solid support on which an antibody against GPC3 is immobilized.
  • the measured value is HCC-positive by comparing with a standard value prepared in advance using a normal sample without HCC or a sample known to be HCC. Can be determined.
  • it is preferable to set the cut-off value by measuring the amount of GPC3 in the serum of a large number of HCC patients and healthy persons.
  • the diagnostic method of the present invention can be used for diagnosing whether or not the subject has HCC, and can be performed over time to confirm the effect of treatment for HCC.
  • the present invention provides a kit for diagnosing HCC, comprising an antibody against GPC3.
  • the kit can include an antibody against GPC3, a secondary antibody, a standard sample for quantification, a buffer, and the like.
  • the present invention will be further described with reference to examples, but the present invention is not limited to these examples.
  • Example 1 Identification of GPC3 gene specifically overexpressed in HCC Profiling of gene expression by cDNA microarray was performed as previously reported (Okabe, H. et al., Cancer Res. 61, 2129-2137 (2001)). Primary HCC and corresponding non-cancerous liver tissue were obtained from 20 patients who underwent hepatectomy. Of these, 10 were positive for hepatitis B surface antigen, 10 were positive for hepatitis C virus (HCV), and none were infected with both HBV and HCV. HBV-positive and ⁇ HCV-positive, with significant differences in age, gender, degree of differentiation, vascular invasion, and tumor stage.
  • HCV hepatitis C virus
  • a “genome-wide” cDNA microarray containing 23,040 cDNAs selected from the UniGene database of the National Center for Biotechnology Information was generated. Comparison of expression profiles between HCC and corresponding non-cancerous liver tissues to search for genes that are specifically over-expressed in HCC, and as a result, are candidates for immunotherapy for HCC patients, possibly GP C3, which could be an ideal target, was identified.
  • the expression of GPC 3 niRNA in cancerous tissues was more than 5-fold higher than in non-cancerous tissues (FIG. 1). That is, GPC3 was overexpressed in most HC C and was not associated with hepatitis B virus (HBV) or HCV infection.
  • HBV hepatitis B virus
  • GPC3 mRNA was highly expressed in the placenta, fetal liver, fetal lung, and fetal kidney, and was low in most adult normal tissues (Figure 1). These data for GPC3 were consistent with those published based on Northern plotting studies (Zhu, ZW et al., Gut 48, 558-564 (2001); Hsu. HC et al., Cancer Res. 57, 5179-5184 (1997); Pellegrini, M. et al., Dev Dyn. 213, 431-439 (1998)). These results revealed that GPC3, like ⁇ -phytoprotein (AFP), is a novel carcinoembryonic antigen in HCC.
  • AFP ⁇ -phytoprotein
  • HCC cell lines Hep G2, Hep 3B, PLC / PRF / 5, and HuH-7 were obtained from the Medical Cell Resources Center, Institute of Aging and Medicine, Tohoku University.
  • SK-Hep-1 was provided by Dr. K. Itoh of Kurume University.
  • RT-PCR was performed according to a known method (for example, Nakatsura, T. et al., Biochem. Biophys. Res. Comraun. 281, 936-944 (2001)).
  • a GPC3 gene-specific PCR primer was designed to amplify a 939 bp fragment and was used with RT-P consisting of 30 amplification cycles at 94 ° C, 5 min initial transformation, and 58 ° C annealing temperature.
  • a CR reaction was performed.
  • the GP C 3 P CR primer sequence used was
  • Antisense 5'-CTGGTGCCCAGCACATGT-3, (SEQ ID NO: 2)
  • Antisense 5, -GGATCTTCATGAGGTAGTCAGTC-3 '(SEQ ID NO: 4).
  • Example 3 Induction of Tumor-Responsive CTL by Stimulating Peripheral Blood Mononuclear Cells (PBMC) Based on the prior art (Kubo, RT et al., J. Immunol. 152, 3913-3924 (1994)), HLA-A24 We searched for GPC3-derived peptides that are expected to bind to the molecule and synthesized and used 12 different peptides (Table 1). These peptides were synthesized using the Fffloc / PyBOP method (see Reference Examples 1 to 12 below) and purchased from biologica (Tokyo). The purity of the peptide was confirmed to exceed 95% in all cases by HP LC.
  • PBMC Peripheral Blood Mononuclear Cells
  • PBMC peripheral blood mononuclear cells
  • the method for inducing peptide-specific CTL from P BMC is based on the method reported previously (Nakatsura, T. et al., Eur. J. Immunol. 32,
  • the surface phenotype of CTL was examined by direct immunofluorescence staining using a FITC-conjugated anti-CD3, CD4, or CD8 monoclonal antibody (Nichirei, Tokyo). To determine effector cells and HLA restriction, 20 ⁇ g Zm1 of each anti-HLA—Class I
  • IgG2a anti-HLA-DR (H-DR-1, IgG2a), and anti-CD4 (Nu-Th / I, IgGl) monoclonal antibodies were added.
  • AA24 + GPC3 + showed strong cytotoxicity against HepG2. This cytotoxicity indicates peptide specificity, anti-HLA-class I, anti-CD8 or anti-H
  • Western blotting was performed as follows. Dissolve the sample in an appropriate volume of lysis buffer (1 50 mM NaC1, 50 mM Tris, pH 7.4, 1% Nonidet P_40, 1 mM sodium orthovanadate (Wako Pure Chemical Industries, Ltd.), 1 mM EDTA and protease inhibitor tablets (Amersham, Arlington Heights, Ill.). Lysate supernatants were electrophoresed on SDS-PAGE gels and transferred to nitrocellulose membranes (Bio-Rad, Hercules, CA).
  • the membrane was ligated against an anti-GPC3 antibody prepared against a recombinant protein corresponding to the amino acid GPC3303-464. ⁇ Incubate with a heron polyclonal antibody (Santa Cruz, California) and wash well with PBS. Peroxidase conjugation anti-Egret Ig, horseradish peroxidase-bound F (ab ') 2 fragment (from donkey ) Chemiluminescence detection was performed using (Amersham) and ECL kit (Amercham).
  • Anti-GPC was prepared by diluting a 4 ⁇ m-thick tissue sample section 1: 200 diluted in OCT embedding compound.
  • GPC 3 303-464 (Santa Cruz, CA) produced from E. coli as a 45 kDa tagged fusion protein for positive control and FluoReporter Mini-Biotin for biotinting of anti-glypican-3ansagi polyclonal antibody -XX
  • the antibody was added together with 3 antibodies, and incubated at room temperature for 2 hours. After washing three times with PBS, add HRP—Conjugate Streptavidin (END0GEN, Woburn) was added. After a 30 minute incubation, the plates were washed three times with PBS and TMB substrate solution (END0GEN) was added. An ELI SA — der (model 550, Bio-Rad) was used at 405 nm for analysis.
  • GPC3 is a GPI-anchored membrane protein and has been reported to be a secreted protein (Filmus J., Glycobiology 11, 19R-23R (2001)). Therefore, we next attempted to detect the secreted GPC3 protein.
  • a standard curve for quantifying GPC3 protein was evaluated.
  • the 1 X 1 0 5 or concentrations of GP C 3 protein in the culture supernatant 1 m 1 after 24 hours of culture the HepG2 cells was defined as 1 m 1.
  • the amount of GPC3 protein in the HepG2 culture supernatant was much higher than in Hep3B, whereas it was not detectable in SK-Hep-1 ( Figure 5).
  • We detected soluble GPC3 protein in the serum of HCC patients Fig. 6). Blood samples were collected from eighteen HCC patients, and patient profiles were collected from medical records to determine the clinical stage based on the UICC T-Wake Classification.
  • a band of 60 kDa GPC3 protein was detected in 20 ⁇ l of serum from patient 7 (Pt7, lane 3 in Figure 6), but serum from two other HCC patients and four healthy donors was not detected.
  • the serum levels of GPC3 protein in 28 HCC patients and 54 healthy donors (HD) were then assessed by ELISA ( Figure 7).
  • the mean of GPC3 protein in the HD serum of 54 patients was 0.75 U / ml and the standard deviation (SD) was 0.32. There was no difference in expression between males and females, and therefore weak expression of GPC3 in the ovaries was considered negligible for this system.
  • the mean for 28 HCC patients was 1,98 UZ ml.
  • Fmoc-Phe-0H Fmoc-Phe-0H Fmoc-Ser (tBu) -OH was subjected to random coupling to obtain a peptide-bound resin. Is the peptide a resin by reacting with the reagent shown in Step 6? It was cut off, filtered into cold methyl tart butyl ether (MTBE) and precipitated. The precipitated peptide was washed twice with cold MTBE and lyophilized under nitrogen. Table 3 Schedule A
  • Mass spectrometry of the main peak occupying 90% or more in area ratio was performed using Lasermat 2000 (Finnigan Mat, San Jose, Calif.) Using MALD! [-TOF method, and the theoretical value was [MH +] 1109.3. On the other hand, the measured value was 1109.9.
  • Fmoc-Ser (tBu) -OH, Fmoc-Pro-0H, Fmoc-Tyr (tBu) -OH, Fmoc-Asn (Trt) -OH, Fmoc-Asn (Trt) -OH, Fmoc-Lys (Boc) -OH , Fmoc-Phe-0H and Fmoc-Met-OH were sequentially bonded.
  • Fmoc-Leu-Wang resin was used as the starting resin as in [Reference Example 1].
  • Fmoc-Asp (Otbu) -OH, Fmoc-Thr (tBu) -0H, and Fmoc-Phe-OH were sequentially bonded.
  • Fmoc-Leu-Wang resin was used as the starting resin as in [Reference Example 1].
  • Fmoc-Ser (tBu) -0H, Fmoc-Cys (Trt) -0H, Fmoc-Tyr (tBu) -0H, and Fmoc-Trp (Boc) -OH were sequentially bonded.
  • Fmoc-Leu-Wang resin was used as the starting resin, Fmoc-Ser (tBu) -0H, Fraoc-Leu-0H, Fmoc-lie-0H, Fmoc-Tyr (tBu) -0H,
  • Fmoc-Glu Otbu
  • Fmoc-Arg Pbf
  • Fmoc-Trp Boc
  • Fmoc-Tyr tBu
  • Fmoc-Lys Boc
  • Fmoc-Leu-Wang resin was used as the starting resin as in [Reference Example 1].
  • Fmoc-Glu (Otbu) -OH, Fmoc-Glu (Otbu) -OH, Fmoc-Leu-0H, Fmoc-Ser (tBu) -OH, Fmoc-Leu_0H, Fmoc-Ile-0H, Fmoc- Tyr (tBu)- 0H and Fmoc-Glu (Otbu) -OH were sequentially bonded.
  • the measured value was 130.7.
  • Fmoc-Asp (Otbu) -0H, Fmoc-Tyr (tBu) -0H, and Fmoc-lie-OH were sequentially bonded.
  • Fmoc-lie-Wang resin as an open resin, Fmoc-Phe-0H, Fmoc-Leu-0H,
  • Fraoc-Tyr (tBu) -OH and Fmoc-Ala-OH were sequentially bonded.
  • the present inventors have identified 12 peptides from GPC3, an oncofetal protein, as target candidates for immunotherapy of HLA-A24 + HCC patients. Regardless of GPC3 overexpression in HCC patients, GPC3 expression is significantly lower in normal adult organs, except for the placenta, making GPC3 an ideal target for HCC immunotherapy It has been found.
  • the method of the present invention has been shown to be a very useful method for diagnosing whether or not the subject has HCC.
  • the present inventors have further identified a GPC3-derived peptide capable of preparing HLA-A24-restricted and HCC-reactive CTL.
  • the HLA-A24 allele is owned by 60% of all Japanese and 95% of its genotype is A * 2402.

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