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URINARY BIOMARKER FOR USE IN TEST FOR PROSTATE CANCER

Foreign code F150008505
File No. 3629
Posted date Nov 5, 2015
Country WIPO
International application number 2013JP059208
International publication number WO 2013146997
Date of international filing Mar 28, 2013
Date of international publication Oct 3, 2013
Priority data
  • P2012-078963 (Mar 30, 2012) JP
Title URINARY BIOMARKER FOR USE IN TEST FOR PROSTATE CANCER
Abstract Disclosed is a novel means which is non-invasive and enables a more highly accurate test for prostate cancer compared with the conventional test methods. The inventors of the present application intensively analyzed urine samples from prostate cancer patients and urine samples from non-cancer subject who are not suffering from prostate cancer. As a result, a urinary peptide that can serve as a measure for the test for prostate cancer was newly found. When the urinary peptide is used as a measure, it becomes possible to achieve various tests associated with prostate cancer, including the detection of prostate cancer, the discrimination between prostate cancer and benign prostatic hypertrophy, the monitoring for the therapeutic effect of a prostate cancer therapy and the monitoring for postoperative recurrence.
Outline of related art and contending technology BACKGROUND ART
Prostate cancer is the high morbidity in the Western countries and malignant disease, the increased prevalence in recent years in Japan (non-patent document 1) there is substantial. Prostate cancer is the number of deaths in the year 2009 million people in Japan and the person 10,036 exceeds 1, this tends to increase as well (non-patent document 2). Therefore, the improvement of diagnostic techniques for prostate cancer development of new therapies that both socially highly desired.
1979 Wang et al. in the seminal plasma was separated from the prostate-specific antigen (PSA: prostate-specific antigen) 34kDa is 237 amino acids having a molecular weight of the glycoprotein, human kallikrein 3 is the same material as the (non-patent document 3). PSA in serum is measured, and the diagnosis of prostate cancer recurrence is now not only the determination of the, prognosis and treatment effect has been widely used for determination. Serum PSA is, the detection sensitivity may be prostate cancer, prostate-specific antigen or not a specific antigen for prostate cancer, prostatic hyperplasia, prostatitis and benign disease such as rectal, the ejaculatory duct and the increase in PSA may act to, the cancer detection specificity is low. Therefore, the reference value of the serum PSA value cutoff 4ng/ml and the detailed examination, the false positive rate is high, as a result, a large burden on the patient unnecessary prostatic biopsies are to be enforced. In fact, serum PSA value of a so-called gray zone in 4-10ng/ml of 25-30% and the positive rate for prostate cancer, about 70% in the range of values which is unnecessary for the biopsy is being performed (the non-patent document 4). Therefore, the non-cancer patients to avoid unnecessary biopsies, serum PSA prostate cancer patient compared to more efficiently detect the dire need of a new biomarker.
Further, also of a clinical sample obtained from the patient is required to improve the method of collecting. A typical clinical sample is blood, in the case of monitoring the disease over time to a blood collection is frequent is a limit to the amount of blood. Reduce the burden on the clinical sample can be collected than if available, a more preferred. Daily urinary excretion can be collected non-invasively, urinary markers are also ethical ideal test material. Furthermore, the urethra of the prostate gland and therefore it is, and the urine at any time after the prostate massage urine secreted directly from the prostate by comparing the various substances can be detected. In fact, the sample and the urine as a method of diagnosis in the urine, (1) RNA, (2) DNA in the urine, (3) urinary protein, (4) metabolite in the urine and the like. Among these, 3 Non-coding RNA (PCA3) is a prostate cancer gene, increased expression in prostate cancer, normal prostate and a lower expression is reported (Non-Patent Document 5), the PCA3 detected in the urine a method of diagnosing prostate cancer has recently been reported (Non-Patent Document 6) is found in, clinical assay is superior to serum PSA method not to a level, also in other diagnostic methods for using the urine components in the research stage. Therefore, new disease-related peptide or protein fragments in the urine of prostate diseases is established in a test, the clinical significance is very high.
Is in the urine, a molecular weight of 10kDa or less has a variety of fragments present in the peptide or protein, the amount of the outbreak SICREX also typically reaches several tens of mg/day (Non-Patent Document 7). Urine, and non-invasive sampling, the lower the activity of a protease, blood, kidney, bladder, ovarian, prostate or the like that it contains a substance, molecular weight of 10kDa or more of the targeting of disease-associated markers to search for the proteomics study has been performed a multifaceted (Non-Patent Document 8, 9).
Exhaustive peptide or protein as a method of analyzing a general method, a two-dimensional electrophoresis or liquid chromatography is, in general a molecular weight of 1 million or more molecules that are suitable for fractionation, low molecular weight proteins and peptides is not suitable for specific detection. In addition, time-of-flight mass spectrometer and Surface Enhanced Laser Desorption/Ionization (SELDI) (Time-of-flight/Mass spectromery: TOF/MS) has been developed combined , new tumor markers have been used for purposes such as detection of (non-patent document 10), SELDI-TOF/MS disease-related marker peak is detected, the structure determination (determining the amino acid sequence) can not be, are not suitable for a clinical examination such as verification.
For prostate cancer, Theodorescu (capillary electrophoresis capillary electrophoresis in a urine sample et al.: CE) - TOF/MS analysis, the detection of 12 peptide, to identify and, as a candidate for the prostate cancer-associated markers are reported (Non-Patent Document 11), does not reach a practical use yet. Further, Okamoto et al., the urine as a specimen after the prostate massage, sinapinic acid as the matrix in the mass range of m/500 z2,-150,000 SELDI-TOF/MS analysis, prostatic hyperplasia significantly different detected peaks 72 (the non-patent document 12) is, a number of detected peaks were identified for, not the clinical application.
Aiming at the industrial application is Patent Document 1-8, residues 20-30 or less than the disclosed fragments of the PSA, PSA analyzes the sequence of any of these, the biological effects of a specific epitope such as to induce a peptide composed of a region, an artificial object that is not naturally occurring. These short PSA in the urine and the actual fragment is present, it can be utilized as markers for testing for prostate cancer that is not any information disclosure, clinical tests on the practical use of the term or phrase.
Scope of claims (In Japanese)請求の範囲 [請求項1]
 下記(a)~(d)のペプチドから選択される少なくとも1種のペプチドからなる前立腺疾患検査用尿中バイオマーカー。
(a) 配列番号1に示すアミノ酸配列からなるペプチド
(b) 配列番号2に示すアミノ酸配列からなるペプチド
(c) 配列番号3に示すアミノ酸配列からなるペプチド
(d) 配列番号4に示すアミノ酸配列からなるペプチド

[請求項2]
 下記(a)~(d)のペプチドから選択される少なくとも1種のペプチドからなる前立腺がん検査用尿中バイオマーカー。
(a) 配列番号1に示すアミノ酸配列からなるペプチド
(b) 配列番号2に示すアミノ酸配列からなるペプチド
(c) 配列番号3に示すアミノ酸配列からなるペプチド
(d) 配列番号4に示すアミノ酸配列からなるペプチド

[請求項3]
 前記(a)~(d)は、前立腺がん患者において高値で検出されるペプチドである請求項1又は2記載の尿中バイオマーカー。

[請求項4]
 前記(a)~(d)は、前立腺がん患者において、既知の非前立腺がん患者集団における尿中ペプチド量の平均値の2倍以上の値を示すペプチドである請求項3記載の尿中バイオマーカー。

[請求項5]
 前記(a)~(c)から選択される少なくとも1種のペプチドからなる請求項1ないし4のいずれか1項に記載の尿中バイオマーカー。

[請求項6]
 前記(a)及び(d)から選択される少なくとも1種のペプチドからなる請求項1ないし4のいずれか1項に記載の尿中バイオマーカー。

[請求項7]
 前記(a)のペプチドからなる請求項5記載の尿中バイオマーカー。

[請求項8]
 下記(1)~(4)のペプチドから選択される少なくとも1種のペプチドからなる前立腺疾患検査用尿中バイオマーカー。
(1) 質量分析によるm/zが2332±4であるペプチド
(2) 質量分析によるm/zが1243±3であるペプチド
(3) 質量分析によるm/zが1314±3であるペプチド
(4) 質量分析によるm/zが2444±4であるペプチド

[請求項9]
 下記(1)~(4)のペプチドから選択される少なくとも1種のペプチドからなる前立腺がん検査用尿中バイオマーカー。
(1) 質量分析によるm/zが2332±4であるペプチド
(2) 質量分析によるm/zが1243±3であるペプチド
(3) 質量分析によるm/zが1314±3であるペプチド
(4) 質量分析によるm/zが2444±4であるペプチド

[請求項10]
 前記(1)~(4)は、前立腺がん患者において高値で検出されるペプチドである請求項8又は9記載の尿中バイオマーカー。

[請求項11]
 前記(1)~(4)は、前立腺がん患者において、既知の非前立腺がん患者集団における尿中ペプチド量の平均値の2倍以上の値を示すペプチドである請求項10記載の尿中バイオマーカー。

[請求項12]
 前記(1)~(3)から選択される少なくとも1種のペプチドからなる請求項8ないし11のいずれか1項に記載の尿中バイオマーカー。

[請求項13]
 前記(1)及び(4)から選択される少なくとも1種のペプチドからなる請求項8ないし11のいずれか1項に記載の尿中バイオマーカー。

[請求項14]
 前記(3)のペプチドからなる請求項12記載の尿中バイオマーカー。

[請求項15]
 被検者から採取された尿検体を分析し、請求項1ないし14のいずれか1項に記載の尿中バイオマーカーの存否又は存在量を調べることを含む、前立腺疾患の検査方法。

[請求項16]
 被検者から採取された尿検体を分析し、請求項1ないし14のいずれか1項に記載の尿中バイオマーカーの存否又は存在量を調べることを含む、前立腺がんの検査方法。

[請求項17]
 尿検体の分析が、質量分析法、クロマトグラフィー法、電気泳動法、イムノアッセイ法、マイクロアレイ法又はこれらのうちのいずれかの組み合わせにより行なわれる請求項15又は16記載の方法。

[請求項18]
 尿検体を前処理した後に分析が行なわれる請求項15ないし17のいずれか1項に記載の方法。

[請求項19]
 尿検体をイオン交換処理した後に質量分析法による分析が行なわれる請求項17記載の方法。

[請求項20]
 前記尿検体が、被検者に対し前立腺マッサージを実施した後に採取された尿検体である請求項15ないし19のいずれか1項に記載の方法。

[請求項21]
 前記被検者が前立腺がんの疑いのある被検者であり、前記尿中バイオマーカーを指標として前立腺がんと前立腺肥大症とを判別する、請求項15ないし20のいずれか1項に記載の方法。

[請求項22]
 前記被検者が前立腺がん治療中又は治療後の患者であり、前記尿中バイオマーカーを指標として前立腺がんの治療効果をモニタリングする、請求項15ないし20のいずれか1項に記載の方法。

[請求項23]
 前記被検者が前立腺がん治療後の患者であり、前記尿中バイオマーカーを指標として前立腺がんの再発をモニタリングする、請求項15ないし20のいずれか1項に記載の方法。

[請求項24]
 前立腺疾患検査において尿中バイオマーカーとして用いるための、下記(a)~(d)のペプチドから選択される少なくとも1種のペプチド。
(a) 配列番号1に示すアミノ酸配列からなるペプチド
(b) 配列番号2に示すアミノ酸配列からなるペプチド
(c) 配列番号3に示すアミノ酸配列からなるペプチド
(d) 配列番号4に示すアミノ酸配列からなるペプチド

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • KYOTO UNIVERSITY
  • Inventor
  • NAKAYAMA, Kenji
  • SHIMIZU, Kazuharu
  • UTSUMI, Jun
  • INOUE, Takahiro
  • OGAWA, Osamu
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
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