WO2013183964A1 - Protéine cible pour le diagnostic et le traitement du cancer du poumon - Google Patents

Protéine cible pour le diagnostic et le traitement du cancer du poumon Download PDF

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WO2013183964A1
WO2013183964A1 PCT/KR2013/005039 KR2013005039W WO2013183964A1 WO 2013183964 A1 WO2013183964 A1 WO 2013183964A1 KR 2013005039 W KR2013005039 W KR 2013005039W WO 2013183964 A1 WO2013183964 A1 WO 2013183964A1
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canx
lung cancer
group
seq
atp1a1
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PCT/KR2013/005039
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English (en)
Korean (ko)
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임태연
정주영
이보람
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한양대학교 산학협력단
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Publication of WO2013183964A1 publication Critical patent/WO2013183964A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57423—Specifically defined cancers of lung
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/115—Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith ; Nucleic acids binding to non-nucleic acids, e.g. aptamers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/563—Immunoassay; Biospecific binding assay; Materials therefor involving antibody fragments
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere

Definitions

  • the present invention relates to a target protein for the diagnosis and treatment of lung cancer, and more particularly to a composition for diagnosing or treating lung cancer comprising a substance that specifically binds to a novel lung cancer target protein as an active ingredient.
  • Lung cancer refers to a malignant tumor in the lung, and can be classified into primary lung cancer, in which cancer cells first develop in the bronchus or alveoli, and metastatic lung cancer in which cancer cells are formed in other organs and travel through the blood vessels or lymphatic vessels to the lungs. Histologically, they are classified into non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).
  • NSCLC non small cell lung cancer
  • SCLC small cell lung cancer
  • Non-small cell lung cancer accounts for 75% of the total lung cancer distribution.
  • the non-small cell lung cancer (NSCLC) is classified into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, among which adenocarcinoma is gradually showing a high frequency.
  • lung cancer began to increase rapidly in the 20th century as smoking became more common, and in Korea, according to the Korea Central Cancer Registry released in 2008, the average annual cancer development of lung cancer in Korea in 2003-2005 was It ranks second with 12.1% of all cancer cases, and the incidence rate per 100,000 population is increasing rapidly to 33.2 cases.
  • the sex ratio of males and females was 3.83: 1, which occurred more frequently in males.
  • the number of occurrences was second to male cancers and fifth to female cancers.
  • 60's were the highest with 34.33 ⁇ 4>, followed by 70's with 31.03 ⁇ 4 and 50's with 14.6% (Data released October 15, 2008, Central Cancer Registry, Ministry of Health, Welfare and Family Affairs).
  • the increase in the smoking population and air pollution is rapidly increasing in Korea, and the mortality rate by type of cancer is 21.4%, which is the 1st, and 24.9% in males and 15.1% in females, respectively, 1st and 2nd, respectively.
  • Lung cancer usually causes symptoms such as surrounding tissue involvement or airway obstruction or lymph node metastasis due to the growth of cancer cells, but about 10-15% of patients are diagnosed at regular checkups without any symptoms. In addition, since most lung cancers are diagnosed as being quite advanced at the time of diagnosis, most cases are difficult to cure. Therefore, it is urgent to reduce lung cancer-related death by early diagnosis of lung cancer.
  • DNA biomarkers In the case of DNA biomarkers, data using cDNA microarrays have been studied so much that the National Cancer Institute has released a database of cancer-specific expression genes on the web (http: // ww.cancer.gov), which is also being developed as a marker for the development or diagnosis of targeted drugs for some cancer-specific proteins (http://www.clinicaltrial.gov). Is most likely as a DNA biomarker, such as promoter factor hypermethylation or K-ras, p53 mutations.
  • the reason why the conventionally known DNA biomarkers and protein markers in the blood are not clinically applied is (1) gene expression analysis through DNA microarrays for normal tissues versus diseased tissues.
  • the sensitization is not directly linked to the problem of protein expression
  • blood proteins have the advantage of being easy to sample, but there are many systemic problems that can be considered to reflect the condition of a particular tissue. Exclusion of abundant proteins in the blood is difficult (99% of the total protein is 22 proteins), so there is a problem that cannot be generalized as a marker of a specific disease.
  • An object of the present invention is a lung cancer diagnostic composition comprising a novel target protein for the diagnosis or treatment of lung cancer that can be detected in a non-invasive way, but specifically expressed in lung cancer tissues or cells, and an active ingredient specifically binding thereto, the treatment It provides a composition for use, lung cancer diagnostic and therapeutic uses, lung cancer diagnostic method, and treatment method of the composition.
  • AP00 Apo lipoprotein 0
  • ATPlAKATPase A + / K + transporting
  • alpha 1 polypeptide alpha 1 polypeptide
  • CANX calnexin
  • another aspect of the present invention is a pharmaceutical composition for treating lung cancer containing as an active ingredient an inhibitor of the expression or activity of at least one polypeptide selected from the group consisting of AP00, ATP1A1, CANX and DD0ST.
  • the AP00, ATP1A1, CANX and DD0ST polypeptides of the present invention are specifically overexpressed in lung cancer tissues or cells and thus are suitable as target materials for diagnosis or treatment of lung cancer.
  • the four biomarkers are membrane proteins located on the surface of the cell (more specifically, the outer cell membrane surface). The protein can be easily bound to and detected or regulated. That is, the material that binds to the four biomarkers has an advantage that can display the function by binding to the biomarker without the help of CPP cell penetrating peptide.
  • an overdose is generally administered to allow the medicine to spread and enter the cell.
  • the therapeutic agent of the present invention is a substance that specifically binds to a protein on the cell surface, an effective therapeutic effect can be achieved at a relatively low dosage. Therefore, according to the present invention, the diagnosis and treatment of lung cancer can be performed very efficiently.
  • 1 is a gel photograph obtained by SDS-PAGE of cell membrane proteins isolated from a control cell line and A549, SK-MES-1, H460 and H146 cell lines.
  • Figure 2 is a graph showing the results of performing HPLC after cleaving the cell membrane proteins isolated from the control cell line and A549, SK-MES-1, H460 and H146 cell line.
  • Figure 3 is a photograph showing the results confirmed by Western blot whether the specific expression of APOO, ATP1A1, CANX and DDOST in the control cell line and A549, SK-MES-1, H460 and H146 cell line.
  • 4 to 7 are graphs confirming the cell surface expression of ' APOO, ATP1A1, CANX and DDOST in A549 cell line, H460 cell line, SK-MES-1 cell line and H146 cell line, respectively, through flow cytometry.
  • 8 to 10 are micrographs confirmed by immunocytochemical analysis of cell surface expression of APOO, ATP1A1, CANX and DDOST in A549 cell line, H460 cell line, and SK—MES-1 cell line, respectively.
  • Figure 11 shows the results of spectral fluorescence imaging after 30 minutes, 1 hour, 1.5 hours, 3 hours, 4.5 hours, 24 hours after injection of Cy5.5-labeled Ant i -DD0ST antibody and control It is a photograph.
  • FIG. 12 is a photograph showing the results of imaging the cancer tissue surface of xenograft model constructed by intravenous injection.
  • 13 to 15 are graphs confirming death or growth inhibition of lung cancer cells by inducing ADCC reactions using antibodies against AP00, CANX and DDOST in A549 cell line, H460 cell line and SK-MES-1 cell line, respectively.
  • FIG. 16 is a graph confirming that tumor growth is suppressed using an antibody against DD0ST in nude mice in which tumors are generated by the A549 cell line.
  • Figure 17 is a graph showing the results of inhibiting the growth of cancer cells when intraperitoneal injection of the antibody against DD0ST in tumor-generated nude mice by SK-MES-1 cell line.
  • One aspect of the present invention is APCXKApo lipoprotein 0), ATPlAKATPase, Na + / + transporting, al ha 1 polypeptide), CANX (calnexin) and DDOST (do 1 i chy 1 ⁇ di phosphoo 1 i gosacchar i de-prote in glycosyltransferase) It provides a composition for diagnosing lung cancer comprising an antibody or folimer specifically binding to any one polypeptide selected from the group consisting of.
  • Another aspect of the present invention is selected from the group consisting of APOC Apolipoprotein 0), ATPlAKATPase, Na + / K + transporting, alpha 1 polypeptide), CANX (calnexin) and DDOSKdol ichyl-diphosphool igosacchari de-protein glycosyltransferase
  • APOC Apolipoprotein 0 ATPlAKATPase
  • Na + / K + transporting alpha 1 polypeptide
  • CANX calnexin
  • DDOSKdol ichyl-diphosphool igosacchari de-protein glycosyltransferase Provided is the use of an antibody or 3 ⁇ 4 timer that specifically binds to any one of the polypeptides.
  • the lung cancer diagnostic composition of the present invention is selected from the group consisting of 1) an antibody specifically binding to any one polypeptide selected from the group consisting of AP00, ATP1A1, CANX and DD0ST or 2) AP00, ATP1A1, CANX and DD0ST Aptamers that specifically bind to either polypeptide.
  • the AP00 polypeptide preferably has an amino acid sequence as set forth in SEQ ID NO: 2.
  • the AP00 polypeptide is preferably encoded by the nucleotide sequence set forth in SEQ ID NO: 1.
  • the APT1A1 polypeptide has an amino acid sequence as set forth in SEQ ID NO: 4.
  • the AP00 polypeptide is preferably encoded by the nucleotide sequence set forth in SEQ ID NO: 3.
  • the CANX polypeptide preferably has an amino acid sequence set forth in SEQ ID NO: 6.
  • the AP00 polypeptide is preferably encoded by the nucleotide sequence set forth in SEQ ID NO: 5.
  • the DD0ST polypeptide preferably has an amino acid sequence set forth in SEQ ID NO: 8.
  • the DD0ST polypeptide is preferably encoded by the nucleotide sequence set forth in SEQ ID NO: 7.
  • the antibody means that a part or all of any one polypeptide selected from the group consisting of AP00, ATP1A1, CANX and DD0ST is recognized as an antigenic site and specifically and directly binds to the antigenic site.
  • Polyclonal antibodies or monoclonal All antibodies are included.
  • Antibodies specifically binding to any one of the polypeptides selected from the group consisting of the AP00, ATP1A1, CANX DD0ST and may be manufactured as known to those skilled in the art ball "method or not.
  • the monoclonal antibody is a fusion method (see Kohler and Mistein (1976) European Jounral of Immunology, 6: 511-519), recombinant DNA method or phage antibody library (Clackson et. al., Nature, 352: 624-628, 1991; Marks et al., J. Mol. Biol., 222: 58, 1—597, 1991).
  • the polyclonal antibody can be prepared by injecting the antigen AP00, ATP1A1, CANX or DD0ST polypeptide to an external host including mammals such as mice, rats, sheep, rabbits.
  • the antigen is injected by intramuscular, intraperitoneal or subcutaneous injection methods, and can generally be administered with an adjuvant to increase antigenicity, and by regularly taking blood from an external host to form titers and antigens. Serum that exhibits specificity can be obtained and used by isolating antibodies. In addition, the antibody can be used by purchasing a commercially known AP00, ATP1A1, CANX or DD0ST antibody.
  • the aptamer is a single-stranded DNA or RNA molecule and has a high affinity for a specific chemical or biological molecule by an evolutionary method using an oligonucleotide library called SELEX Systemic Evolution of 1 igands by exponential enrichment. Can be obtained by isolating oligomers having binding and selection ability (C. Tuerand L. Gold, Science 249, 505-510, 2005; AD Ellington and JW Szostak, Nature 346, 818-822, 1990; M. Famulok, et al., Acc. Chem. Res. 33, 591-599, 2000; DS Wilson and Szostak, Annu. Rev. Biochem. 68, 611-647, 1999).
  • Aptamers can specifically bind to a target and modulate the target's activity, such as by blocking the ability of the target to function through binding.
  • an aptamer having high affinity and selectivity can be obtained and used for any one polypeptide selected from the group consisting of AP00, ATP1A1, CANX, and DD0ST by an evolutionary method using SELEX.
  • the antibody or aptamer may be tagged with the detector have.
  • the detector is for easily identifying, detecting, and quantifying whether the antibody or aptamer specifically binds to any one polypeptide target selected from the group consisting of APOO, ATP1A1, CANX, and DD0ST.
  • the detector When the detector is tagged to the antibody or aptamer, the detector is preferably attached so as not to affect the specificity or selectivity for the target in the antibody or aptamer, and for this purpose, a link (sharing) to the antibody or aptamer Combined or crosslinked).
  • the tagging position of the detector can be easily determined by a person skilled in the art through repeated experiments.
  • the lung cancer may be non-small cell lung cancer (NSCLC) or small cell lung cancer (sac), in particular the non-small cell lung cancer may be adenocarcinoma, squamous cell carcinoma or large cell carcinoma have.
  • NSCLC non-small cell lung cancer
  • sac small cell lung cancer
  • the non-small cell lung cancer may be adenocarcinoma, squamous cell carcinoma or large cell carcinoma have.
  • the composition is preferably for nasal administration. This is to improve the binding specificity and selectivity of the antibody or aptamer, and more selectively to a target (APOO, ATP1A1, CANX or DD0ST polypeptide) expressed in lung cancer tissues or cells other than other tissues when the composition is administered nasal. It can be combined.
  • a target APOO, ATP1A1, CANX or DD0ST polypeptide
  • the antibody or aptamer in the composition will specifically and selectively bind to an APOO, ATP1A1, CANX or DD0ST polypeptide expressed in lung tissue or cells, and tagged to the antibody or aptamer
  • the reactions occurring in the detected detectors can measure the position or expression level of the antibody or aptamer bound to the target as described above. In other words, if a large number of reactions of the detector occur in lung tissue or cells of a subject, an excessive amount of APOO, ATP1A1, CANX, or DD0ST polypeptide is present in the lung tissue of the subject, and the subject has lung cancer. It can be diagnosed.
  • the composition is administered in the subject by nasal administration Lung cancer cell presence can be confirmed non-invasively.
  • the four polypeptides, APOO, ATP1A1, CANX, or DD0ST were specifically overexpressed in the lung cancer cell lines A549, SK-MES-1, H460, and H146 (see FIGS. 3 to 5).
  • the composition comprising an antibody or 3 ⁇ 4 tammer specifically binding to the APOO, ATP1A1, CANX or DD0ST polypeptide of the present invention can be usefully used for the diagnosis of lung cancer.
  • An aspect of the invention is selected from the group consisting of APOO, ATP1A1, CANX and DDOST, or an antibody or aptamer specifically binding to at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST
  • a kit for diagnosing lung cancer comprising a primer or probe complementarily binding to a polynucleotide encoding at least one polypeptide.
  • Lung cancer diagnostic kit of the present invention is 1) an antibody that specifically binds to at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST or 2) in the group consisting of APOO, ATP1A1, CANX and DDOST An aptamer that specifically binds to at least one polypeptide selected, or 3) complementarily binds to a polynucleotide encoding at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST Primer or 4) a probe that complementarily binds to a polynucleotide encoding at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST.
  • the kit is not intended to be administered into a subject, unlike the composition of the item for diagnosing lung cancer, and the lung cancer of the subject is determined using a biological sample such as lung washing fluid, biopsy, blood, saliva, and urine derived from the subject. Therefore, to detect the protein or nucleic acid contained in the biological sample, and in particular, the kit of the present invention is selected from the group consisting of APOO, ATP1A1, CANX and DDOST contained in the biological sample. Any one polypeptide, or APOO, ATP1A1, CANX and It is used to detect polynucleotides encoding at least one polypeptide selected from the group consisting of DDOST.
  • the lung cancer diagnostic kit of the present invention may include an antibody or aptamer specifically binding to any one polypeptide selected from the group consisting of AP00, ATPIAI, CA X and DD0ST.
  • An additional antibody or aptamer is for detecting the AP00, ATPIAI, CANX or DD0ST, the "lung cancer diagnostic
  • the antibody or aptamer specifically binding to any one polypeptide selected from the group consisting of AP00, ATP1A1, CANX and DD0ST is described in "1.
  • the polynucleotides encoding the polypeptides of AP00, ATPIAI, CANX, and DD0ST have a nucleic acid sequence as set forth in SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, and SEQ ID NO: 7, respectively.
  • the primers allow the synthesis of DNA complementary to template DNA under appropriate conditions and circumstances, and can be localized to polynucleotides encoding polypeptides of the APOO, ATPIAI, CANX or DDOST. Single stranded oligonucleotides.
  • the length of the primer is modified depending on various factors such as temperature, reaction conditions, and the use of the primer, but it is generally preferred that the polynucleotide is 10 to 30 nt in length.
  • the primer sequence need not be a sequence that is completely complementary to the polynucleotide sequence encoding the polypeptides of AP00, ATPIAI, CANX, and DD0ST to be the template (target), and is unique to the template (target) sequence to be native to the primer. It is only necessary to have sufficient complementarity to the extent that can be achieved.
  • the design of such primers can be readily carried out by those skilled in the art with reference to a target polynucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5 or SEQ ID NO: 7, for example, a program for primer design.
  • the probe refers to a polynucleotide that can specifically hybridize to a target polynucleotide sequence, and includes a single strand that can be localized to a polynucleotide encoding the polypeptides of the AP00, ATP1A1, CANX, and DD0ST. Linear polynucleotides.
  • the probe may be naturally present or artificially synthesized.
  • the probe may be constructed of deoxyribonucleotides or ribonucleotides if the probe is naturally present, and if the probe is artificially synthesized, the probe may be a peptide nucleic acid (PNA) (M.
  • PNA peptide nucleic acid
  • the primer or probe may be tagged with the detector.
  • the detector easily identifies, detects, and quantifies whether the primer or probe specifically binds to a polynucleotide target encoding at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX, and DD0ST.
  • a polypeptide selected from the group consisting of APOO, ATP1A1, CANX, and DD0ST.
  • chromosome peroxidase, alkaline phosphatase, etc.
  • fluorescent material FTTC, RITC, rhodamine, Texas red
  • fluorescein phycoery
  • phycoery At least one selected from the group consisting of phycoerythrin, quantum dots, chromophores, and radioisotopes (1241 1251, lllln, 99mTc, 32P, 35S, etc.).
  • the detector is tagged to the primer or probe
  • the detector is preferably attached so as not to affect specificity or selectivity to the target in the primer or probe, and for this purpose, the detector may be provided by linking (covalently or crosslinking) to the primer or probe.
  • the tagging position of the detector can be easily determined by a person skilled in the art through repeated experiments.
  • the kit is preferably a microarray chip.
  • the microarray chip is composed of an antibody or aptamer specifically binding to at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX, and DD0ST
  • the microarray chip is APOO, ATP1A1, CANX and DDOST. It is for detecting the expression level of at least one polypeptide selected from the group consisting of at the translated protein level.
  • the microarray chip when the microarray chip is composed of a primer or a probe complementary to a polynucleotide encoding at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST, the microarray chip It is for detecting the expression level of at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST at the level of transcription mRNA.
  • kits comprising an antibody or aptamer for the APOO, ATP1A1, CANX or DDOST polypeptide, or a primer or probe for a polynucleotide encoding the polypeptide can be usefully used as a kit for diagnosing lung cancer.
  • the polypeptide detection method may be performed in vivo or in vitro.
  • Polypeptide detection method for providing information necessary for diagnosing lung cancer of the present invention 1) an antibody that specifically binds to at least one target polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST Or binding an aptamer to the target polypeptide; 2) measuring the expression level of at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DD0ST by measuring the amount and location of the antibody bound to the target polypeptide of step 1); And 3) determining a subject at risk of developing lung cancer in a subject having an increased expression level of at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX, and DD0ST measured in step 2) above the control group. Steps.
  • the antibody or aptamer of step 1) is for detecting the APOO, ATP1A1, CANX or DDOST, and is the same as described in "1. Lung Cancer Diagnosis. Thus, the group consisting of the APOO, ATP1A1, CANX and DDOST. Regarding an antibody or aptamer that specifically binds to any one polypeptide selected from "1. The detailed description will be omitted by using the description of the lung cancer diagnosis item, and hereinafter, only the configuration specific to the polypeptide detection method (step of determining the expression level of the polypeptide and determining the lung cancer) for providing the information necessary for diagnosing lung cancer Explain.
  • the subject of step 1) is a subject suspected of having lung cancer or a subject in need of diagnosis for risk of developing lung cancer, such as a human, monkey, dog, goat, pig or rat, and the like, preferably a mammal. to be.
  • the polypeptide expression level of step 2) can be measured indirectly in the subject of step 1) by measuring the presence of a tag tagged with an antibody or aptamer bound to the target polypeptide of step 1). And DDOST can be confirmed, detected and quantified in any tissue to what extent any one polypeptide selected from the group consisting of.
  • the detector may be fluorescence such as FTTC, RITC, rhodamine (1 " 110 (13 ⁇ 116), Texas Red, fluorescein, phycoerythrin, quantum dots, etc.
  • the amount and position of the antibody or aptamer bound to the target polypeptide can be measured by fluorescence mediated tomography (FMT).
  • FMT fluorescence mediated tomography
  • the control group of step 3) is an individual recognized as not suffering from lung cancer, and the expression level of the target polypeptide in the control group of step 3) is obtained by administering the antibody or aptamer of step 1) to the control group and performing step 2). It is determined by measuring as follows.
  • the target polypeptide expression level in the control measured in step 3) is basically the amount expressed in the individual even when lung cancer is not developed.
  • Determining the subject of step 3) as an individual at risk for lung cancer is performed by comparing the expression level of the target polypeptide in the control group with the expression level of the target polypeptide in the subject. If the amount of the target polypeptide expressed in the subject is better than the expression level of the target polypeptide in the control group, the subject is recognized as having lung cancer.
  • Polypeptide detection method for providing information necessary for the diagnosis of other lung cancer of the present invention 1 ') specifically binding to at least one target polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DD0ST to the subject-derived sample Treating the antibody or aptamer to bind to the target polypeptide; 2 ') measuring the expression level of at least one polypeptide selected from the group consisting of AP00, ATP1A1, CANX and DD0ST by measuring the amount and location of the antibody bound to the target polypeptide of step 1'); And 3 ′) determining a subject having an increased expression level of the target polypeptide of step 2 ′) than the control group as an individual at risk for lung cancer.
  • the antibody or aptamer of step 1 ') is for detecting the AP00, ATP1A1, CANX or DD0ST, and is the same as described in the section "1. Lung cancer diagnostic composition". Accordingly, the antibody or aptamer specifically binding to any one polypeptide selected from the group consisting of AP00, ATP1A1, CANX and DD0ST will be described in detail using the description of the item "1. In the following description, only the configuration specific to the polypeptide detection method (step of determining the expression level of the polypeptide and determining the lung cancer) for providing the information necessary for diagnosing lung cancer will be described.
  • the subject in step ⁇ ') is a subject suspected of having lung cancer or a subject in need of diagnosis for risk of developing lung cancer, a vertebrate such as a human, monkey, dog, goat, pig or rat, preferably a mammal. to be.
  • the subject-derived sample of step 1 ') may be any biological sample such as lung washing liquid, biopsy, blood, saliva, urine, etc. derived from the subject.
  • the expression level of the polypeptide of step 2 ') is determined by indirectly measuring AP00 in the subject of step 1') by measuring the presence of an antibody or aptamer specifically bound to the target polypeptide of step 1 '). It is possible to identify, detect, and quantify to what extent any one polypeptide selected from the group consisting of ATP1A1, CANX, and DD0ST exists in which tissue. Determination of the expression level of the target polypeptide is immunoprecipitation, radioimmunoassay (RI A), enzyme immunoassay (ELISA), immunohistochemistry, RT-PCR, Western Blotting and flow cytometry (FACS). It may be performed by any one method selected from the group consisting of), but is not limited thereto, and those skilled in the art can be selected appropriately.
  • RI A radioimmunoassay
  • ELISA enzyme immunoassay
  • FACS flow cytometry
  • the control group of step 3 ') is all biological samples such as lavage fluid, biopsy, blood, saliva, urine, etc. derived from an individual not recognized as having lung cancer, and the expression level of the target polypeptide in the control group of step 3'). Is determined by treatment of the antibody or aptamer of step 1 ') to the control and measurement as in step 2').
  • the target polypeptide expression level in the control measured in step 3 ′) is basically the amount expressed and present in the subject even when lung cancer is not developed.
  • Determining the subject of step 3 ') as an individual at risk for lung cancer is performed by comparing the expression level of the target polypeptide in the control group with the expression level of the target polypeptide in the subject. do. If the amount of the target polypeptide expressed in the subject is better than the expression level of the target polypeptide in the control group, the subject is recognized as having lung cancer.
  • the polypeptide detection method of the present invention can be usefully used to provide information necessary for diagnosing lung cancer by measuring the expression level of APOO, ATP1A1, CANX or DD0ST polypeptide. 4. Pharmaceutical Compositions and Uses for Lung Cancer Treatment
  • Another aspect of the present invention provides a pharmaceutical composition for treating lung cancer, which contains as an active ingredient an inhibitor of the expression or activity of at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST.
  • Another aspect of the invention provides the use of a pharmaceutical composition containing as an active ingredient an inhibitor of the expression or activity of at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST for the treatment of lung cancer. do.
  • the pharmaceutical composition for treating lung cancer of the present invention is 1) an inhibitor of expression of any one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST or 2) an agent selected from the group consisting of APOO, ATP1A1, CANX and DDOST. Inhibitors of the activity of either polypeptide.
  • the AP00 polypeptide preferably has an amino acid sequence as set forth in SEQ ID NO: 2.
  • the AP0O polypeptide is preferably encoded by the nucleotide sequence set forth in SEQ ID NO: 1.
  • the APT1A1 polypeptide has an amino acid sequence as set forth in SEQ ID NO: 4.
  • the AP00 polypeptide is preferably encoded by the nucleotide sequence set forth in SEQ ID NO: 3.
  • the CANX polypeptide preferably has an amino acid sequence set forth in SEQ ID NO: 6.
  • the AP00 polypeptide is preferably encoded by the nucleotide sequence set forth in SEQ ID NO: 5.
  • the DD0ST polypeptide preferably has an amino acid sequence set forth in SEQ ID NO: 8.
  • the DD0ST polypeptide is preferably encoded by the nucleotide sequence set forth in SEQ ID NO: 7.
  • the inhibitor of expression of at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST is expressed in mRNA of at least one gene selected from the group consisting of APOO, ATP1A1, CANX and DDOST. It may be any one selected from the group consisting of complementary antisense nucleotides, short hairpin RNA (shR A) and small interfering RA (siRNA), but is not limited thereto.
  • the antisense nucleotides bind to (combine) the complementary sequences of DNA, immature -mRNA, or mature mRNA as defined in Watson-click base pairs to disrupt the flow of genetic information from DNA to protein. Since the antisense nucleotides are long chains of monomeric units they can be easily synthesized for the target RNA sequence. Many recent studies have demonstrated the utility of antisense nucleotides as biochemical means for studying target proteins (Rothenberg et al., J. Natl. Cancer Inst., 81: 1539-1544, 1999).
  • antisense nucleotides can be considered as a new type of inhibitor because of recent advances in nucleotide synthesis and in the field of nucleotide synthesis that exhibit improved cell adsorption, target binding affinity and nuclease resistance.
  • the small interfering RNA binds to (activates) the mRNA encoding the target polypeptide in a cell and interferes with the flow of genetic information from the DNA of the target polypeptide to the protein, and the AP00, ATP1A1 And a sense sequence having a length of 15 to 30 nt selected from within the mRNA base sequence of at least one gene selected from the group consisting of CANX and DD0ST, and an antisense sequence complementarily binding to the sense sequence.
  • the sense sequence is not particularly limited thereto, but is preferably composed of 25 nt long polynucleotides.
  • the short hairpin RNA is a single strand of RNA having a length of 50 to 100 nt to form a stem-loop structure in the cell, and both sides of the loop region of 5 to 30 nt long nucleotides
  • Complementary 15-50 nt long renal RNA is base paired to form a double stranded stem and further comprises 1 to 500 nt long nucleotides before and after each of said stem forming strands. It means the RNA.
  • Such a shRNA is a loop break in the cell, and acts to disrupt the flow of genetic information from the DNA of the target polypeptide to the protein like the siRNA.
  • the shRNA is cleaved in the cell, the AP00, ATP1A1, CANX and It is preferable to have a sense sequence of 15 to 30 nt length selected from within the mRNA base sequence of at least one gene selected from the group consisting of DDOST and an antisense sequence complementarily binding to the sense sequence, but not limited thereto. shall not. "
  • the antisense nucleotides short hairpin R A (shRNA) and small interference
  • RNA inhibits the expression of APOO, ATP1A1, CANX or DD0ST polypeptide by binding complementarily to mRNA of a gene encoding at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DD0ST. Therefore, it acts as an active ingredient for treating lung cancer.
  • the inhibitor of activity of at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST binds complementarily to at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DDOST. It may be any one selected from the group consisting of aptamers, antibodies, and peptide mimetics, but is not limited thereto.
  • the antibody or aptamer is for detecting the APOO, ATP1A1, CANX or DDOST, and is the same as described in "1. Lung Cancer Diagnosis. Therefore, any one selected from the group consisting of the APOO, ATP1A1, CANX and DDOST.
  • antibodies or aptamers that specifically bind to one polypeptide see "1. Detailed explanations will be omitted by using the description of the lung cancer diagnosis item, and only the peptide mimetics will be described below.
  • the peptide mimetics inhibit the activity of the target polypeptide by inhibiting the binding domain of the target polypeptide, and inhibit the binding domain of any one polypeptide selected from the group consisting of APOO, ATP1A1, CANX, and DDOST.
  • the peptide mimetics may be peptides or non-peptides and may be bound by non-peptide bonds, such as p S i bonds (Benkirane, N., et al. J. Biol. Chem., 271: 33218-33224, 1996). Composed of amino acids.
  • a "conformational ly constrained" peptide, between cyclic mimetics, at least one exocyclic domain, binding moiety (binding amino acid) and active site Click mematics have.
  • Peptide mimetics are structured similar to the secondary structural properties of the MAP7D2 protein and are either antibodies (Park, BW et al. Nat Biotechnol 18, 194-198, 2000) or water soluble receptors (Takasaki, W. et al. Nat Biotechnol 15, 1266- 1270, 1997), which can mimic the inhibitory properties of large molecules, and may be novel small molecules that can act equivalent to natural antagonists (Wrighton, NC et al. Nat Biotechnol 15, 1261-1265, 1997). .
  • the aptamer, antibody, and peptide mimetics bind to the active domain of at least one polypeptide selected from the group consisting of AP00, ATP1A1, CANX, and DD0ST, thereby preventing the AP00, ATP1A1, CANX, or DD0ST polypeptide. It inhibits activity and thus acts as an active ingredient for treating lung cancer.
  • the composition preferably includes 0.0001 to 50 weight 3 ⁇ 4 of the active ingredient based on the total weight of the composition, but is not limited thereto.
  • the composition may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredient for administration.
  • Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, complete saline, dextrose solution, maltodextrin solution, glycerol, ethane, liposomes and one or more of these ingredients.
  • Other conventional additives, such as antioxidants, buffers, bacteriostatics, can be added.
  • injectable formulations pills, capsules, granules or tablets, such as aqueous solutions, suspensions, emulsions, etc.
  • diluents dispersants, surfactants, binders and lubricants, which may act specifically on target organs.
  • Sudodotock target organ specific antibodies or other ligands can be used in combination with the carrier.
  • it is preferably formulated according to each disease or component using an appropriate method in the art or using the method disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA. can do.
  • the composition is preferably for nasal administration. This is to improve the binding specificity and selectivity of the expression or activity inhibitor, and when the composition is administered nasal to targets (AP00, ATP1A1, CANX or DD0ST polypeptide) expressed in lung cancer tissues or cells other than other tissues. It can be combined more selectively.
  • targets AP00, ATP1A1, CANX or DD0ST polypeptide
  • the dosage of the composition varies depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate and the severity of the disease, the daily dosage of the composition is 0.0001 rag / to 10 mg /, preferably 0.0001 rag / to 5 rag /, and is preferably administered once to several times a day.
  • lung cancer cell lines A549, SK-MES-1, H460 and H146 cell lines inhibit the expression or activity of the four polypeptides APOO, ATPIAI, CANX or DD0ST
  • growth of the lung cancer cell line is It was confirmed that the results were inhibited, and by inhibiting the expression or activity of APOO, ATPIAI, CANX or DD0ST polypeptide using the pharmaceutical composition for treating lung cancer of the present invention, the possibility of treating lung cancer was confirmed (see FIGS. 11 to 14).
  • the inhibitor of the expression or activity of the APOO, ATPIAI, CANX or DD0ST polypeptide can be usefully used as an active ingredient of the composition for treating lung cancer.
  • Another aspect of the invention provides a method for treating lung cancer.
  • the method for treating lung cancer of the present invention includes administering to a subject a composition containing as an active ingredient an inhibitor of the expression or activity of at least one polypeptide selected from the group consisting of APOO, ATPIAI, CANX and DDOST. .
  • polypeptides of APOO, ATPIAI, CANX and DDOST are described in SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 and SEQ ID NO: 8, respectively.
  • the expression inhibitor of at least one polypeptide selected from the group consisting of AP00, ATPIAI, CANX and DDOST is at least any one selected from the group consisting of AP00, ATPIAI, CANX and DDOST It is any one selected from the group consisting of antisense nucleotides, short hairpin RA (shRNA) and small interfering RNA (siRNA) that complementarily bind to mRNA of the gene of.
  • shRNA short hairpin RA
  • siRNA small interfering RNA
  • the activity inhibitor of at least one polypeptide selected from the group consisting of APOO, ATP1A1, CANX and DD0ST is at least any one selected from the group consisting of APOO, ATP1A1, CANX and DDOST It is any one selected from the group consisting of aptamers, antibodies and peptide mimetics that complementarily bind to one polypeptide.
  • the step of administering the composition to the subject may be administered through the nasal cavity of the subject.
  • another aspect of the present invention provides a method for screening a candidate substance for treating lung cancer.
  • the method for screening a candidate substance for treating lung cancer of the present invention comprises the steps of: 1) treating a test substance to a cell line expressing any one target polypeptide selected from the group consisting of AP00, ATP1A1, CANX, and DDOST; 2) measuring the expression level of the target polypeptide in the cell line of step 1); and 3) selecting the test substance whose expression level of the target polypeptide measured in step 2) is reduced compared to the control group not treated with the test substance. Steps.
  • Determination of the expression level of the target polypeptide of step 2) is performed by reverse sedimentation method (i ⁇ unoprecipi tat ion), radioimmunoassay (RIA), enzyme immunoassay (ELISA), immunohistochemistry, RT-PCR, Western blotting ) And flow cytometry (FACS). Any method of determining the amount of transcript or protein encoded therefrom may be used, although it is preferred to measure with any one selected from the group consisting of.
  • the test substance selected in step 3) is a substance that inhibits the expression of any one of the target polypeptides selected from the group consisting of APOO, ATP1A1, CANX and DDOST, and the "4. It can be used as an expression inhibitor described in.
  • Another method for screening a candidate substance for treating lung cancer of the present invention comprises the steps of: 1) treating a test substance with any one of the target polypeptides selected from the group consisting of APOO, ATP1A1, CANX, and DD0ST; 2) measuring the activity of the target polypeptide; And 3) selecting the test substance whose activity of the target polypeptide is reduced compared to the control which has not been treated with the test substance.
  • the activity of the target polypeptide of step 2) is preferably measured by any one selected from the group consisting of SDS-PAGE, immunofluorescence, enzyme immunoassay (ELISA), mass spectrometry and protein chips, but is not limited thereto. Any method of measuring the activity of known proteins can be used.
  • test substance selected in step 3) is a substance that inhibits the activity of any one of the target polypeptides selected from the group consisting of APOO, ATP1A1, CA X, and DD0ST, wherein the "4. pharmaceutical composition for treating lung cancer" It can be used as an activity inhibitor described in the section.
  • the screening method of the present invention can be usefully used for screening candidate substances for lung cancer treatment by screening a test substance capable of inhibiting the expression or activity of APOO, ATP1A1, CANX or DD0ST polypeptide. .
  • the present invention will be described in detail by experimental examples.
  • HPLC was performed by treating trypsin to membrane proteins of the five cell lines isolated as in Example ⁇ 1-1>, and compared to the HPLC protein profiles of normal tissues. Peak proteins were selected and identified by MS / MS. More specifically, membranes electrophoresed with membrane proteins were washed with distilled water for 5 minutes and then stained with bio-safe Coomassie stain solution (Coomassie G250 Stain) (BioRad, USA) for 1 hour at room temperature. It was. The gel was then destained for 30 minutes in distilled water. Only the protein bands stained from the gel were cut out and destained again with 75 mM ammonium bicarbonate (Sigma, USA) I 40% ethanol (Duksan, Korea) (1: 1), followed by gel fragments.
  • LC-MS / MS analysis was performed using Thermo Finnigan's ProteomeX workstation LTQ linear IT MS (Thermo Electron, USA) equipped with NSI sources (San Jose, Calif.). A peptide mixture of 12 ⁇ was injected and loaded into a peptide trap cartridge (Agilent, USA) and then separated into columns by gradient elution.
  • Apolipoprotein 0 Apolipoprotein 0
  • ATPlAKATPase A + / K + transporting, alpha 1 polypeptide
  • CANX calnexin
  • DDOSTWolichyl-diphosphoo 1 i gosacchar i de-pr ot ein glycosyl transferase)- ⁇ were finally selected.
  • Example ⁇ 1-1> The membrane protein sample obtained in Example ⁇ 1-1> was electrophoresed, and Western blot was performed on the four proteins. After cell disruption by sonication method per cell line, only membrane protein was separated by 10% SDS-PAGE through centrifuge, TE70X SEMI -DRY TRANSFER UNIT with PVDF membrane (Mi 111 ipore, Italy) Transfer was performed at 14V for 1 hour using 14 ⁇ 16 CM (Hoefer, San Francisco USA). Deceased After blocking the membrane (membrane) with 5% skim milk (Skim Mi lk) for 1 hour, the primary antibody (primary antibody) was allowed to react at room temperature for 2 hours.
  • Anti-AP00 (Sigma, USA), Ant i-ATPlAKAbClon, Korea) Anti-CANX (sigma, USA), Ant i-DD0ST (Sigma, USA) was used as the primary antibody. Secondary antibodies were then reacted at room temperature for 2 hours. As the secondary antibody, Goat ant i-mouse IgG and Goat ant i-rabbit IgG (Ab frontier, Korea) were used.
  • the membrane protein sample obtained in Example ⁇ 1-1> was electrophoresed and flow cytometry was performed on the four proteins. More specifically, each cell line was reacted with the primary antibody for 30 minutes at room temperature. Ant i-AP00 (Sigma, USA), Anti-ATPlAKAbClon, Korea), Ant i-CANX (Sigma, USA) and Ant i-DD0ST (Sigma, USA) were used as the primary antibodies. After treatment with the primary antibody, the secondary antibody was reacted at room temperature for 30 minutes, and the secondary antibody was a Goat Anti- Mouse IgG (FITC) and Goat Ant i -rabbit to which the fluorescent substance FITCCFluorescein isothiocyanate was bound. IG (FITC) (Ab frontier, Seoul, Korea) was used. Then, flow cytometry was performed using a flow cytometer BD FACSCal ibur (BD Biosciences, USA).
  • the cell lines A549 (adenocarcinoma), SK-MES-1 (squamous cell carcinoma) and H460 (large cell carcinoma) were subjected to immunocytochemical analysis on the four proteins.
  • the primary antibody was treated for 3 hours at room temperature using Lab-Tek chamber Slide (Nunc, USA), and the primary antibody was Ant i-AP00 (Sigma, USA), Ant i -ATPlAl (AbC Ion, Korea), Ant i-CANX (Sigma, USA) and Ant i-DD0ST (Sigma, USA) were used.
  • mice Male nude mice have four types of lung cancer cells: A549 (adenocarcinoma), NCI-H460 non-small cell lung carcinoma), and NCI-H146 (small cell lung carcinoma). And SK-MES-1 (squamous cell lung carcinoma) were implanted with 6 subcutaneous injections on the back of nude mice.
  • FIG. 11 The results of fluorescence imaging after each antibody was shown in FIG. 11.
  • the top 6 photographs show the injection of Cy5.5'-labeled Anti-DDOST antibody, and the bottom 6 photos show the injection of isotype control.
  • the control group was discharged to the body within 30 minutes after injection, indicating that only a small amount of fluorescence remained in the bladder region.
  • anti-DD0ST antibody lung cancer masses growing on the back were correctly labeled. Similar results were obtained with experiments involving H460 other than A549. This resulted in in vivo imaging targeting DD0ST.
  • the three cell lines were treated with Anti-APCXX Sigma, USA), Anti-CANX (Sigma, USA) and Ant i-DD0ST (Sigma, USA) antibodies in a continuous dilution method, respectively.
  • Anti-APCXX Sigma, USA Anti-APCXX Sigma, USA
  • Anti-CANX Anti-CANX
  • Ant i-DD0ST Ant i-DD0ST
  • the lethal concentration (LC50, 50%) of the cells was measured.
  • the half lethal concentrations were 7.9 fig / mi, 0.06 g / mt and 0.06 // g / i for DDOST, CANX and AP00, respectively (FIG. 15).
  • AP00 Polipoprotein 0
  • ATPlAKATPase Na + / K + transporting
  • alpha 1 polypeptide alpha 1 polypeptide
  • CANX calnexin
  • DDOST do lichyl-di phosphoo 1 i gosacchar i de-pr ot ein glycosyltransferase
  • Tumors were generated by subcutaneous injection of A549 cell line, a lung cancer cell line, to nude mice (MARA, seoul, Korea). Then, the antibody (Anti-DD0ST (Sigma, USA)) was treated twice by dose (100 iig and 200 // g), the tumor volume was measured.
  • V 1/2 X (W2 XL)" (where V is tumor volume, W is minimum diameter, L represents the maximum diameter).
  • mice were divided into five treatment groups.
  • Treatment was started when the tumor diameter averaged about 5 mm.
  • Treatment was performed by intraperitoneal injection of Anti-DDOST antibody, rabbit IgG control and PBS-control twice a week.
  • DD0ST protein expression was demonstrated by paraffin-embedded IHC.
  • Each lung tissue sample is 4 ⁇ ! It was partitioned to thickness and diparaffinized in xylene, which was hydrated in alcohol cereals. Nonspecific binding was blocked and slides were incubated with Anti-DDOST antibody (Sigma USA) for one day at 4 ° C.
  • IHC reaction was performed with a vectortasteine ABC kit (Vector Laboratories Inc., USA) using 3'3-diaminobenzidine (DAB).

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Abstract

La présente invention concerne une composition pour le diagnostic ou le traitement du cancer du poumon, contenant un principe actif pour la liaison spécifique à une nouvelle protéine cible du cancer du poumon, et fournit une composition pour le diagnostic ou le traitement du cancer du poumon, contenant, en tant que principe actif, une matière pour la liaison spécifique à l'un quelconque des polypeptides cibles choisis dans le groupe consistant en apolipoprotéine O (APOO), ATP1A1 (ATPase, polypeptide alpha 1 de transport de Na+/K+), calnexine (CANX) et dolichyl-diphospho oligosaccharide protéine glycosyltransférase (DDOST). Le peptide cible est spécifiquement surexprimé dans les tissus ou cellules du cancer du poumon, et est par conséquent approprié en tant que matière cible pour le diagnostic ou le traitement du cancer du poumon. De plus, le polypeptide cible, qui est une protéine membranaire exprimée sur la surface de cellules, peut être facilement détecté même par un procédé non invasif, et par conséquent peut être utile en tant que matière cible pour le diagnostic ou le traitement du cancer du poumon.
PCT/KR2013/005039 2012-06-07 2013-06-07 Protéine cible pour le diagnostic et le traitement du cancer du poumon WO2013183964A1 (fr)

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