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CN102585000A - Tumor marker CD25 autoantibody and application thereof - Google Patents

Tumor marker CD25 autoantibody and application thereof Download PDF

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CN102585000A
CN102585000A CN2012100411739A CN201210041173A CN102585000A CN 102585000 A CN102585000 A CN 102585000A CN 2012100411739 A CN2012100411739 A CN 2012100411739A CN 201210041173 A CN201210041173 A CN 201210041173A CN 102585000 A CN102585000 A CN 102585000A
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autoantibody
antigen
tumor
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tumor marker
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尉军
孙世龙
关松磊
李光辉
刘宝刚
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尉军
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Abstract

The invention discloses a tumor marker CD25 autoantibody and application of the tumor marker CD25 autoantibody, belonging to the technical field of immunology. The invention provides an amino acid sequence of antigen of immune response regulation gene CD25. The CD25 polypeptide antigen is used for detecting corresponding specific autoantibody in blood of lung cancer and esophageal cancer patients; and the autoantibody can be used as a tumor marker to evaluate risk level of occurrence of lung cancer and esophageal cancer. The antigen polypeptide and the antibody can be used for preparing early-stage tumor diagnostic reagent and developing target drugs for treating tumor.

Description

A kind of tumor markers CD25 autoantibody and application
Technical field
The invention belongs to the immunological technique field, is a kind of targeted drug that is used to prepare early diagnosis of tumor reagent and exploitation treatment tumour.
Background technology
Big quantity research shows that the taa in serum or the blood plasma can induce body to produce autoantibody, in tumour patient serum, has both had tumour antigen, also has the autoantibody to this tumour antigen.Therefore, both can utilize the antibody test tumour antigen, and also can utilize Detection of antigen tumour autoantibody, but it is much higher with tumour antigen detection tumour with the equal Billy of susceptibility to utilize the tumour autoantibody to detect the specificity of tumour.A lot of taas not only exist in the tumour patient body, in the normal human, also exist, and it is credible poor as diagnosis basis therefore to detect taa.And autoantibody the very low detection of normal human's intensive amount less than or exist; If the autoantibody level obviously increases in the body; Show then to have the abnormal immune situation in the body that show that the related antigen level fluctuates in the body, existence or original disease of indication disease increase the weight of.
Research in recent years shows, develops into available modern iconography technology at the malignant tumour volume and detects 3-5 before, can occur the taa autoantibody of high density in patient's blood.Therefore, the taa autoantibody has the important value of predicting tumor invasion risk and early diagnosis tumour in the detection blood.Be the clinical tumor diagnostic field give priority to one of direction.The early diagnosis kit of existing abroad diagnosing and mammary cancer is commercially available.Yet the present antibody detection method susceptibility of reporting is low, poor specificity, and the false negative ratio can be up to more than 50%.Its major cause be since the positive detection rate of each taa autoantibody in the patient on average about 10%.How improving the diagnostic reagent susceptibility is the key issue that current needs need to be resolved hurrily.Relatively efficient ways is to seek the autoantibody of new served as tumor markers, is combined into the diagnostic kit with susceptibility height and high specificity with existing known autoantibody then.
Tumour can be escaped the monitoring of body immune system through various direct or indirect mechanism.A series of research is verified, and regulatory T reg cell and tumour immunity escape mechanism are closely related.In lung cancer, mammary cancer, ovarian cancer and occur existing the Treg cell proportion to increase phenomenon in the peripheral blood lymphocyte and tumor infiltrating lymphocyte of melanoma patients of nodus lymphoideus transferring rate.Treg directly contact with cell through cell or the release through cytokine, pairing effect property CD4+/CD8+T cell activation and breed and bring into play restraining effect.Its effect mechanism mainly is that inhibition CD4+T hyperplasia, inhibition tsa activated CD4+ effector cell secrete IL-2; Suppressing CD8+IFN 2C and TNF2A produces; And in tumor microenvironment, can limit CTLs cytotoxicity particle release, make tumour cell escape immunologic cytotoxicity.CD25 among the present invention is the main surface marker of Treg cell.
Regulatory T reg cell is the CD4+T cell that derives from thymus gland, and the α chain of its constructive expression's IL 2 acceptors is named as CD25, and CD25 is the important symbol of Treg cell activation.CD25 also brings into play keying action as I type transmembrane protein to multiple T cell and B cell activation.CD25 and CD122 form IL 2 acceptors of high-affinity jointly, and their soluble receptorss are that sIL-2R is proved and takes place relevantly with kinds of tumors, become several kinds of tumours the clinical marker thing that makes progress takes place.Research both at home and abroad shows in the CD4+/CD25+T cell, to have only the CD4+/CD25hight cell to be only the Tregs with immune suppression function.Discover kinds of tumors patient's peripheral blood and tumor by local Tregs increases such as lung cancer, ovarian cancer, gastroenteric tumor simultaneously.Tregs limits immunoreactive generation through suppressing the activated T cell, thereby in keeping the tumour immunity tolerance, plays a significant role.Experimentation on animals confirms, uses anti-CD25 monoclonal antibody to tumor-bearing mice and can suppress Tregs in the animal body, can improve mouse anti tumour immunity function.Experiment in vitro confirms from peripheral blood, to remove Tregs, can produce more cytotoxic cell, comprises CTL and LAK/NK cell etc.Current research is found, in the cerebral glioma patient, with disease process, follows the height of CD25 to express when CD4+/FOXP3+Tregs cell time-dependent manner increases, and uses the increase that anti-CD25 monoclonal antibody can significantly suppress the CD4+/FoxP3+Tregs cell.The present invention is through the antigen epitope polypeptide of CD25 of design voluntarily, detects in tumour patient serum and the blood plasma autoantibody level and develops reagent corresponding, predicts tumorigenic danger, and reliable data is provided for the tumour new drug research.
Summary of the invention
The technical problem that the present invention will solve is to disclose a kind of tumor markers CD25 autoantibody.
The present invention discloses the purposes of CD25 autoantibody.
The aminoacid sequence of a kind of tumor markers CD25 autoantibody provided by the invention is:
EIYHFVVGQMVYYQCVQGYRALHRGPAESVE purity>95%, pH>7.0.
The application of CD25 antigenic peptide of the present invention in preparation prediction early diagnosis of tumor test kit.
The proteic linear polypeptide of the CD25 that utilization of the present invention designs voluntarily adopts the proteic specificity of anti-CD25 self IgG antibody in ELISA method detection of lung cancer and esophagus cancer patient blood serum and the blood plasma.Self IgG antibody horizontal raises and shows that the proteic expression amount of CD25 increases in the tumour patient body, and primary or secondary tumors possibly appear in the indication patient, can predict that the danger with recurrence takes place tumour, and direct clinical doctor is to the early diagnosis of tumour.
The CD25 protein amino acid sequence is seen Tab.1
The sequence table of Tab.1 CD25 antigenic peptide
Figure BDA0000137446700000031
In fact the combination of antigen-antibody only occurs between the antigen binding site of antigenic determinant and antibody, and both are complementary fully on space structure and sterie configuration.Therefore antigenic determinant just can be represented the state and the affinity characteristic of whole albumen and antibodies.In addition, be antigen with the recombinant protein, pass through loaded down with trivial details processes such as vector construction, transfection, expression, screening, purifying, the albumen space structure is complicated, and epitope is difficult for exposing, so antigen-antibody bonded poor specificity.In addition, the high sensitivity of ELISA method is high to the stability requirement of purification technique, and cost is expensive.
The contriver follows following principle and designs linear polypeptide antigen: 1. select the epicyte protein surf zone; 2. select not form the sequence of a-helix; 3. the peptide section at two ends is arranged rationally than intermediary; 4. avoid active site of protein to repeat; 5. avoid the strong peptide section of homology; 6. avoid Cys and Glu in the sequence as far as possible, too many Pro cannot be arranged, but there have 1-2 Pro to be beneficial to peptide chain structure to be stable, useful to producing specific antibody.In addition, this polypeptide antigen must contain the restricted epitope of two types of antigens of human leucocyte (HLA) system, comprises HLA-DR, the restricted epitope of HLA-DP and HLA-DQ.These epi-positions can be discerned by two types of antigen systems of HLA of 90% above Chinese colony.
Based on above antigen principle of design and the proteic biological characteristics of CD25, the present invention utilizes information biology and a plurality of epi-position prognosis modelling software, analyzes and antigenicity associated parameter designed linear aminoacid sequence (seeing Tab.1).Adding frame partly is the position of polypeptide fragment in protein.
CD25:interleukin-2?receptor?subunit?alpha?precursor[Homo?sapiens]
1?mdsyllmwglltfimvpgcqaelcdddppeiphatfkamaykegtmlnceckrgfrriks
61?gslymlctgnsshsswdnqcqctssatrnttkqvtpqpeeqkerkttemqspmqpvdqas
121?lpghcrepppweneater
Figure BDA0000137446700000041
ckmthgktrwtqp
181?qlictgemetsqfpgeekpqaspegrpesetsclvtttdfqiqtemaatmetsiftteyq
241?vavagcvfllisvlllsgltwqrrqrksrrti
Can know that by above protein sequence CD25 linear polypeptide antigen is made up of 31 amino-acid residues, contain 11 overlapping epi-positions altogether, can detect at least 11 kinds of monoclonal antibodies, have the specificity of height.
The ELISA method detects autoantibody
(1) enzyme plate design: every part of plasma sample established the two multiple holes of people CD25 antigenic peptide, two multiple holes of goat polypeptide contrast antigen (gAg) and the two multiple holes (NC) of negative control.GAg antigen and human protein organize no homology, and purpose is the interference of lowering the non-specific binding reaction, the working concentration scope 10-20 μ g/ml of gAg.
(2) encapsulate: antigenic peptide encapsulates in 96 hole enzyme plate (COSTAR with coating buffer (pH7.0~7.4 0.01M PBS/0.1%NaN3); The U.S.), every hole 100 μ l, the CD25 antigenic peptide encapsulates concentration 7.5~15.0 μ g/ml; It is 15~20 μ g/ml that gAg encapsulates concentration, and 4 ℃ are spent the night.
(3) one anti-/ blood plasma are hatched: 0.01M PBS/0.005%TWEEN-20 cleans every hole 3 times, utilizes analytic liquid (0.01M PBS+1%BSA+2% sheep blood plasma) with blood plasma dilution in 1: 500, and every hole 100 μ l are hatched 2~3h for 25 ℃;
(4) two anti-hatching: 0.01M PBS/0.005%TWEEN-20 cleans every hole 5 times, utilize analytic liquid (ditto) dilute horseradish peroxidase-labeled the goat anti-human igg (U.S., Sigma), every hole adds 200 μ l, hatches 2h for 25 ℃; The goat anti-human igg ELISA working range of horseradish peroxidase-labeled: 1: 30000~1: 50000.
(5) colour developing: 0.01M PBS/0.005%TWEEN-20 cleans every hole 5 times, utilize 3,3 ', 5,5 '-substrate (Invtrogen, the U.S.) of TMB (TMB) px, every hole adds 100 μ l, room temperature lucifuge 15~30min.
(6) detect: every hole adds 50 μ l 10%H 2SO 4Be reaction terminating liquid, use ELIASA (BioTeck ELx800, the U.S.) to detect the OD value in the 10min, the detection wavelength is 450nm, and reference wavelength is 630nm.Each sample of Quality Control is established two multiple holes, the equal OD value of making even.OD value plastisied dispersion is judged: plastisied dispersion=OD1-OD2/OD1+OD2, and plastisied dispersion≤0.1 is effective result; Plastisied dispersion>0.1 is null result.Getting 100 parts of healthy subjects serum equal-volumes mixes as Quality Control blood (Quality control; QC); Representative crowd's common situation; Every plate is all established 2 QC blood plasma holes, with the stability of the horizontal result of determination of the OD value in QC blood plasma hole variation, all batches of SD/ QC hole, all batches of batch variation CV=QC hole OD average<20%.Variation within batch CV=each plate QC hole SD/ each plate QC hole average<10% every day every day.
Data analysis adopts SPSS17.0 for windows to carry out statistical analysis.Adopt the specific combination index (Specific binding index SBI) judges the combination degree of CD25 antigenic peptide and blood plasma autoantibody, SBI=CD25OD value-NC OD/gAg OD value-NC OD, NC is the negative control of each sample.The ROC curve is according to a series of two different mode classifications (cut off value or decision threshold), is ordinate zou with True Positive Rate (sensitivity), the curve that false positive rate (1-specific degree) is drawn for X-coordinate.ROC area under a curve value is between 1.0 and 0.5.Under the situation of AU>0.5, AU approaches 1 more, explains that diagnosis accuracy is good more.The ROC curve combines sensitivity and specificity with graphic technique, can accurately reflect the relation of certain analytical procedure specificity and susceptibility, is the comprehensive representative of test accuracy.This invention adopts Analyse-it for Microsoft Excel software to draw the ROC curve, and area under the calculated curve (AU) is judged to the positive with healthy subjects SBI MV+2SD, judges sensitivity and specific degree; Carry out sum of ranks (Z) check, checking one type of wrong level is a=0.05.
The present invention uses the CD25 antigenic peptide and detects specificity self the IgG antibody in lung cancer and esophagus cancer patient blood serum and the blood plasma, and this reaction has high specific and high sensitivity.
The CD25 antigenic peptide can be used for preparing the early diagnosis of tumor test kit.
Description of drawings
Accompanying drawing is CD25 antigenic peptide and blood plasma IgG bonded SBI graphic representation.
Embodiment
Embodiment 1
CD25 antigenic peptide and serum and blood plasma IgG bonded process
Can be known that by Fig. 1 during CD25 concentration 5~10 μ g/ml, along with the increase of concentration, the SBI value descends gradually, when CD25 antigenic peptide concentration 10~15 μ g/ml, along with the increase of concentration, the SBI value rises gradually.This SBI binding curve shows, when the CD25 antigenic peptide is the low concentration of 5 μ g/ml (0.5 μ g/well), is not paved with at the bottom of the plate of 96 hole enzyme plates, causes nonspecific reaction high, so this moment, the SBI value was higher, is false positive results; Along with CD25 antigenic peptide concentration increases, antigen is paved with at the bottom of the whole plate gradually, and its blocking effect manifests; Nonspecific reaction reduces gradually; Nonspecific reaction is minimum during to 10 μ g/ml, and this moment, the CD25 antigenic peptide combined to begin appearance with the specificity of IgG antibody, and along with the enhancing gradually of increasing of antigen concentration; Bonding force is the strongest during to 15 μ g/ml, tends to be steady afterwards.This SBI binding curve has fully represented in CD25 antigenic peptide and the blood plasma specificity association reaction process of self IgG antibody.
Embodiment 2
The test kit preparation
Tab.2~9 are seen in the preparation of 1 reagent reagent.
Figure BDA0000137446700000071
Figure BDA0000137446700000081
2 operations
(1) encapsulate: work antigen and reference antigen are diluted to working concentration with coating buffer, encapsulate in enzyme plate, and 4 ℃ are spent the night.
(2) add blood plasma (one anti-): enzyme plate is used lavation buffer solution and is cleaned 3 times, utilize analytic liquid with diluted plasma to suitable concn, be generally every hole 100 μ l, 25 ℃ or incubated at room 2~3h 1: 200~1: 500;
(3) two anti-hatching: lavation buffer solution cleans 3~5 times, utilizes analytic liquid to dilute two anti-reference liquid IgG, and every hole adds 200 μ l, 25 ℃/incubated at room 2h;
(4) colour developing: lavation buffer solution cleans 3~5 times, and every hole adds 100 μ l substrates colour developing liquid, room temperature lucifuge 15~30min.
(5) detect: every hole adds 50 μ l stop buffers, and 10min detects, and wavelength is 450nm, and reference wavelength is 630nm.
Embodiment 3
The CD25 of patients with lung cancer self IgG antibody test
1 sample collection: collect 501 parts of tumour patients and human normal plasma sample.Healthy group 227 examples, the mean age is 57.07 ± 10.36 years old, wherein male 134 examples, women 92 examples.Lung cancer group 274 examples, the mean age is 57.5 ± 9.2 years old, wherein male 177 examples, women 97 examples.Healthy group and lung cancer group have comparability (P>0.05) in sex, age-matched
2 detected results: can be known that by Tab.10-11 the IgG antibody ROC TG-AUC (AU) of CD25 antigenic peptide is 0.7 in the patients with lung cancer blood plasma, sensitivity is 35%, and specific degree is 90%.In the patients with lung cancer blood plasma with CD25 polypeptide antigen bonded IgG antibody positive rate apparently higher than health group (Z=-7.48, P<0.001).Above data show that fully the antigenic peptide that utilizes the present invention to design detects the patients with lung cancer autoantibody IgG level and the normal health group that obtain relatively has notable statistics difference.
Embodiment 4
Patient with esophageal carcinoma CD25 self IgG antibody test
1 sample source: collect 501 parts of tumour patients and human normal plasma sample.Healthy group 227 examples, at the age, the mean age is 57.07 ± 10.36 years old, wherein male 134 examples, women 92 examples.Esophagus cancer 95 examples.Esophagus cancer group 95 examples, the mean age is 58.62 ± 7.46 years old, wherein male 48 examples, women 47 examples.Healthy group and esophageal carcinoma group have comparability (P>0.05) in sex, age-matched.
2 detected results: can be known that by Tab.10-11 the IgG antibody ROC TG-AUC (AU) of CD25 antigenic peptide is 0.68 in the patient with esophageal carcinoma blood plasma, sensitivity is 38.0%, and specific degree is 90%.In the patient with esophageal carcinoma blood plasma with CD25 polypeptide antigen bonded IgG antibody positive rate apparently higher than health group (Z=-4.87, P<0.001).Above data show that fully the antigenic peptide that utilizes the present invention to design detects the patient with esophageal carcinoma autoantibody IgG level and the normal health group that obtain relatively has notable statistics difference.
CD25 self IgG antibody test ROC tracing analysis result in Tab.10 esophagus cancer and the patients with lung cancer
Figure BDA0000137446700000101
CD25 self IgG antibody test comparative analysis result in Tab.11 esophagus cancer and the patients with lung cancer
Figure BDA0000137446700000102

Claims (2)

1. tumor markers CD25 autoantibody, it is characterized in that: aminoacid sequence does
EIYHFVVGQMVYYQCVQGYRALHRGPAESVE purity>95%, pH>7.0.
2. the application of tumor markers CD25 autoantibody according to claim 1 in preparation prediction early diagnosis of tumor test kit.
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Cited By (8)

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CN103293308A (en) * 2013-05-24 2013-09-11 尉军 Amino acid sequence for detecting tumor marker P16 antigenic epitope and application of amino acid sequence
CN106279403A (en) * 2016-08-16 2017-01-04 长春市海兰深生物医学技术有限公司 Composition, kit and method for detecting natural lung cancer related antibody
CN108084263A (en) * 2016-12-16 2018-05-29 苏州旭光科星生物技术有限公司 A kind of anti-human CD25 chimeric mAbs and its preparation method and application
CN108427003A (en) * 2018-02-11 2018-08-21 上海英邈生物科技有限公司 Detect polypeptide sequence, kit and the method for anti-IL-2R subunit A natural antibodies
CN110174515A (en) * 2019-05-09 2019-08-27 青岛海兰深生物科技有限公司 A kind of composition, kit and method detecting anti-lung cancer natural antibody
CN110687281A (en) * 2019-08-26 2020-01-14 中国医学科学院肿瘤医院 Application of PD-L1 autoantibody in tumor prognosis evaluation
CN111458510A (en) * 2020-04-30 2020-07-28 郑州大学第一附属医院 A set of early-stage esophageal cancer and high-risk groups screening markers and associated check cards
CN114113611A (en) * 2021-12-13 2022-03-01 郑州大学 Biomarker for liver cancer diagnosis and detection kit

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CN1729203A (en) * 2002-10-17 2006-02-01 根马布股份公司 Human monoclonal antibodies against CD20
CN101098891A (en) * 2005-01-05 2008-01-02 F-星生物技术研究与开发有限公司 Synthetic immunoglobulin domains with binding properties engineered in regions of the molecule different from the complementarity determining regions

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WO2001077302A1 (en) * 2000-04-12 2001-10-18 Institut National De La Sante Et De La Recherche Medicale Method for obtaining specific t-lymphocytes, and for identifying unknown epitopes
CN1729203A (en) * 2002-10-17 2006-02-01 根马布股份公司 Human monoclonal antibodies against CD20
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103293308A (en) * 2013-05-24 2013-09-11 尉军 Amino acid sequence for detecting tumor marker P16 antigenic epitope and application of amino acid sequence
CN106279403A (en) * 2016-08-16 2017-01-04 长春市海兰深生物医学技术有限公司 Composition, kit and method for detecting natural lung cancer related antibody
CN106279403B (en) * 2016-08-16 2019-06-11 长春市海兰深生物医学技术有限公司 A kind of composition, kit and method detecting natural lung cancer associated antibodies
CN108084263B (en) * 2016-12-16 2021-07-13 苏州旭光科星抗体生物科技有限公司 Anti-human CD25 chimeric monoclonal antibody and preparation method and application thereof
CN108084263A (en) * 2016-12-16 2018-05-29 苏州旭光科星生物技术有限公司 A kind of anti-human CD25 chimeric mAbs and its preparation method and application
CN108427003A (en) * 2018-02-11 2018-08-21 上海英邈生物科技有限公司 Detect polypeptide sequence, kit and the method for anti-IL-2R subunit A natural antibodies
CN108427003B (en) * 2018-02-11 2021-01-01 杭州英邈生物科技有限公司 Polypeptide sequence, kit and method for detecting natural antibody of anti-interleukin 2receptor subunit A
CN110174515A (en) * 2019-05-09 2019-08-27 青岛海兰深生物科技有限公司 A kind of composition, kit and method detecting anti-lung cancer natural antibody
CN110174515B (en) * 2019-05-09 2022-07-01 青岛海兰深生物科技有限公司 Composition, kit and method for detecting anti-lung cancer natural antibody
CN110687281A (en) * 2019-08-26 2020-01-14 中国医学科学院肿瘤医院 Application of PD-L1 autoantibody in tumor prognosis evaluation
CN111458510A (en) * 2020-04-30 2020-07-28 郑州大学第一附属医院 A set of early-stage esophageal cancer and high-risk groups screening markers and associated check cards
CN114113611A (en) * 2021-12-13 2022-03-01 郑州大学 Biomarker for liver cancer diagnosis and detection kit
CN114113611B (en) * 2021-12-13 2023-07-14 郑州大学 A biomarker and detection kit for liver cancer diagnosis

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