CN102585000B - Tumor marker CD25 autoantibody and application thereof - Google Patents
Tumor marker CD25 autoantibody and application thereof Download PDFInfo
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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
Technical field
The invention belongs to the immunological technique field, is a kind of targeted drug for the preparation of early diagnosis of tumor reagent and exploitation treatment tumour.
Background technology
Studies show that in a large number the tumor associated antigen in serum or the blood plasma can induce body to produce autoantibody, has both had tumour antigen in Serum of Cancer Patients, also has the autoantibody for this tumour antigen.Therefore, both can utilize the antibody test tumour antigen, and also can utilize Detection of antigen tumour autoantibody, to detect tumour with tumour antigen much higher but utilize the tumour autoantibody to detect the specificity of tumour and the equal Billy of susceptibility.A lot of tumor associated antigens not only exist in the tumour patient body, also exist in the normal human, and it is credible poor as diagnosis basis therefore to detect tumor associated antigen.And autoantibody can't detect or exists in that normal human's intensive amount is very low, if autoantibody 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.
Studies show that in recent years, the malignant tumour volume develop into available modern image techniques technology detect before 3-5, the tumor associated antigen autoantibody of high density can appear in patient's blood.Therefore, detect the important value that tumor associated antigen autoantibody in the blood has predicting tumors onset risk and early diagnosis tumour.It is one of prior development direction of clinical tumor diagnostic field.The early diagnosis kit of existing diagnosing and mammary cancer is commercially available abroad.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 tumor associated antigen 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.More effective method is to seek the autoantibody of new served as tumor markers, then is combined into the diagnostic kit with susceptibility height and high specificity with existing known autoantibody.
Tumour can be escaped by various direct or indirect mechanism the monitoring of body immune system.A series of research is verified, and regulatory T reg cell and immune 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 contacts with cell by cell or the release by cytokine, pairing effect CD4+/CD8+T cell activation and propagation performance restraining effect.Its effect mechanism mainly is that the CD4+ effector cell who suppresses CD4+T hyperplasia, the activation of inhibition tumour specific antigen secretes 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 occurs relevantly with kinds of tumors, become several tumours the clinical marker thing that makes progress occurs.Studies show that in the CD4+/CD25+T cell, to only have the CD4+/CD25hight cell to be only the Tregs with immune suppression function both at home and abroad.Kinds of tumors peripheral blood in patients and the tumor by local Tregs increases such as lung cancer, ovarian cancer, gastroenteric tumor are found in simultaneously research.Tregs limits immunoreactive generation by suppressing the T cell of activation, thereby plays a significant role in keeping the tumour immunity tolerance.Experimentation on animals confirms, uses anti-CD25 monoclonal antibody to tumor-bearing mice and can suppress Tregs in the animal body, can improve mouse antineoplastic immune function.Experiment in vitro confirms to remove Tregs from peripheral blood, can produce more cytotoxic cell, comprises CTL and LAK/NK cell etc.Current research is found, 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 in Patients with gliomas.The antigen epitope polypeptide of the CD25 of the present invention by designed, designed detects in Serum of Cancer Patients and the blood plasma autoantibody and develops corresponding reagent, the danger that predicting tumors occurs, and provide reliable data for the tumour new drug research.
Summary of the invention
The technical problem to be solved in the present invention is to disclose a kind of tumor marker CD 25 autoantibody.
The present invention discloses the purposes of CD25 autoantibody.
The aminoacid sequence of a kind of tumor marker CD 25 autoantibody provided by the invention is:
EIYHFVVGQMVYYQCVQGYRALHRGPAESVE purity＞95%, pH＞7.0.
The application of CD25 antigenic peptide of the present invention in preparation predicting tumors early diagnosis kit.
The present invention utilizes the linear polypeptide of the CD25 albumen of designed, designed, adopts the specificity Autologous IgG antibody of anti-CD25 albumen in ELISA method detection of lung cancer and esophagus cancer patient blood serum and the blood plasma.The Autologous IgG antibody horizontal raises and shows that the interior CD25 protein expression amount of tumour patient body increases, and primary or secondary tumors may appear in the indication patient, can occur and the danger that recurs by predicting tumors, instruct the clinician 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
In fact the combination of antigen-antibody only occurs between the antigen binding site of antigenic determinant and antibody, and both are complete complementary on space structure and sterie configuration.Therefore antigenic determinant just can represent state and the affinity characteristic of whole albumen and antibodies.In addition, take recombinant protein as antigen, pass through the 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 the poor specificity of antigen-antibody combination.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 more reasonable than middle arrangement; 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 human leucocyte two class antigen (HLA) systems, comprises HLA-DR, the restricted epitope of HLA-DP and HLA-DQ.These epi-positions can be identified by the HLA two class antigen systems of 90% above Chinese colony.
Based on the biological characteristics of above antigen principle of design and CD25 albumen, the present invention utilizes information biology and a plurality of Antigen Epitope Prediction simulation 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
ckmthgktrwtqp
181?qlictgemetsqfpgeekpqaspegrpesetsclvtttdfqiqtemaatmetsiftteyq
241?vavagcvfllisvlllsgltwqrrqrksrrti
By above protein sequence as can be known, CD25 linear polypeptide antigen is comprised of 31 amino-acid residues, contains altogether 11 overlapping epi-positions, can detect at least 11 kinds of monoclonal antibodies, has 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, the two multiple holes of goat polypeptide contrast antigen (gAg) and the two multiple holes (NC) of negative control.GAg antigen and human protein organize without 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) coated: antigenic peptide is coated 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 is coated with concentration 7.5～15.0 μ g/ml, the coated concentration of gAg is 15～20 μ g/ml, and 4 ℃ are spent the night.
(3) primary antibodie/blood plasma is 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 tetramethyl benzidine (TMB) peroxidase, 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 microplate reader (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, is averaged the OD value.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 Human 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 OD value Deflection level result of determination in QC blood plasma hole, 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 specific combination index (Specific binding index, SBI) to judge 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 that take True Positive Rate (sensitivity) as ordinate zou, false positive rate (1-specific degree) is the curve that X-coordinate is drawn according to a series of two different mode classifications (cut off value or decision threshold).ROC area under a curve value is between 1.0 and 0.5.In the situation of AU＞0.5, AU illustrates that more close to 1 diagnosis accuracy is better.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.Analyse-it for Microsoft Excel Software on Drawing ROC curve is adopted in this invention, and area under the calculated curve (AU) is judged to the positive with Healthy People SBI mean value+2SD, judges sensitivity and specific degree; Carry out sum of ranks (Z) check, checking a class mistake level is a=0.05.
The present invention uses the CD25 antigenic peptide and detects specificity Autologous 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 the SBI graphic representation that the CD25 antigenic peptide is combined with blood plasma IgG.
Embodiment
Embodiment 1
The process that the CD25 antigenic peptide is combined with serum and blood plasma IgG
As shown in Figure 1, during CD25 concentration 5～10 μ g/ml, along with the increase of concentration, the SBI value descends gradually, and 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 Enrichment, antigen is paved with at the bottom of the whole plate gradually, 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 began to occur with the specific binding of IgG antibody, and along with the gradually enhancing 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 the specific binding reaction process of Autologous IgG antibody in CD25 antigenic peptide and the blood plasma.
Embodiment 2
The test kit preparation
Tab.2～9 are seen in the preparation of 1 reagent reagent.
2 operations
(1) coated: work antigen and reference antigen are diluted to working concentration with coating buffer, are coated in enzyme plate, and 4 ℃ are spent the night.
(2) add blood plasma (primary antibodie): enzyme plate is used lavation buffer solution and is cleaned 3 times, utilize analytic liquid with diluted plasma to suitable concn, be generally 1: 200～1: 500, every hole 100 μ l, 25 ℃ or incubated at room 2～3h;
(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 substrate nitrite ions, 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 Autologous IgG antibody test of patients with lung cancer
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, male 134 examples wherein, women 92 examples.Lung cancer group 274 examples, the mean age is 57.5 ± 9.2 years old, male 177 examples wherein, women 97 examples.Healthy group and lung cancer group have comparability (P＞0.05) in sex, age-matched
2 detected results: by Tab.10-11 as can be known, the IgG antibody ROC area under curve (AU) of CD25 antigenic peptide is 0.7 in the Plasma of The Patients With Lung Cancer, and sensitivity is 35%, and specific degree is 90%.The IgG antibody positive rate of being combined with the CD25 polypeptide antigen in the Plasma of The Patients With Lung Cancer is apparently higher than health group (Z=-7.48, P＜0.001).Above data show that fully utilizing the designed antigenic peptide of the present invention to detect the patients with lung cancer autoantibody IgG level and the normal health group that obtain relatively has notable statistics difference.
Embodiment 4
The antibody test of patient with esophageal carcinoma CD25 Autologous IgG
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, male 134 examples wherein, women 92 examples.Esophagus cancer 95 examples.Esophagus cancer group 95 examples, the mean age is 58.62 ± 7.46 years old, male 48 examples wherein, women 47 examples.Healthy group and esophageal carcinoma group have comparability (P＞0.05) in sex, age-matched.
2 detected results: by Tab.10-11 as can be known, the IgG antibody ROC area under curve (AU) of CD25 antigenic peptide is 0.68 in the patient with esophageal carcinoma blood plasma, and sensitivity is 38.0%, and specific degree is 90%.The IgG antibody positive rate of being combined with the CD25 polypeptide antigen in the patient with esophageal carcinoma blood plasma is apparently higher than health group (Z=-4.87, P＜0.001).Above data show that fully utilizing the designed antigenic peptide of the present invention to detect the patient with esophageal carcinoma autoantibody IgG level and the normal health group that obtain relatively has notable statistics difference.
CD25 Autologous IgG antibody test ROC tracing analysis result in Tab.10 esophagus cancer and the patients with lung cancer
CD25 Autologous IgG antibody test comparative analysis result in Tab.11 esophagus cancer and the patients with lung cancer
Claims (2)
1. tumor markers CD25 epitope, it is characterized in that: aminoacid sequence is
EIYHFVVGQMVYYQCVQGYRALHRGPAESVE purity〉95%, pH〉7.0.
2. the application of tumor markers CD25 epitope according to claim 1 in preparation early diagnosis of tumor test kit.
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| CN103293308B (en) * | 2013-05-24 | 2014-11-26 | 尉军 | Amino acid sequence for detecting tumor marker P16 antigenic epitope and application of amino acid sequence |
| 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 |
| 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 |
| 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 |
| CN110687281B (en) * | 2019-08-26 | 2023-05-23 | 中国医学科学院肿瘤医院 | Application of PD-L1 autoantibody in tumor prognosis evaluation |
| CN111458510B (en) * | 2020-04-30 | 2020-10-30 | 郑州大学第一附属医院 | Early esophageal cancer and high risk group screening marker and related joint inspection card |
| CN114113611B (en) * | 2021-12-13 | 2023-07-14 | 郑州大学 | Biomarker for liver cancer diagnosis and detection kit |
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Inventor after: Wei Jun Inventor after: Sun Shilong Inventor after: Guan Songlei Inventor after: Li Guanghui Inventor before: Wei Jun Inventor before: Sun Shilong Inventor before: Guan Songlei Inventor before: Li Guanghui Inventor before: Liu Baogang |
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