CN100402551C - Antigen epitope of beta2-microglobulin and its application - Google Patents
Antigen epitope of beta2-microglobulin and its application Download PDFInfo
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Abstract
The present invention relates to an antigen epitope for analyzing flight time mass spectra by substrate assisting laser desorption and for researching beta2-microglobulin by an affinity separation method. An amino acid sequence of the antigen epitope is placed from 61 to 67 site points, and the sequence is SFYLLYY. The antigen epitope of the present invention can be used for researching and developing new peptide fragment vaccines, and can also be used as treating target points. The antigen epitope can be used for providing scientific bases for diagnosing diseases relevant to tumors and for prognostic judgement.
Description
Technical field
The invention belongs to bio-pharmaceutical engineer technology domain, relate to the epitope and the application of B2M.
Background technology
The single chain polypeptide low molecular protein that B2M is made up of 99 amino acid.Its aminoacid sequence is:
Ile-Gln-Arg-Thr-Pro-Lys-Ile-Gln-Val-Tyr-Ser-Arg-His-Pro-Ala-Glu-Asn-Gly
-Lys-Ser-Asn-Phe-Leu-Asn-Cys-Tyr-Val-Ser-Gly-Phe-His-Pro-Ser-Asp-Ile-Glu
-Val-Asp-Leu-Leu-Lys-Asn-Gly-Glu-Arg-Ile-Glu-Lys-Val-Glu-His-Ser-Asp-Leu
-Ser-Phe-Ser-Lys-Asp-Trp-Ser-Phe-Tyr-Leu-Leu-Tyr-Tyr-Thr-Glu-Phe-Thr-Pro
-Thr-Glu-Lys-Asp-Glu-Tyr-Ala-Cys-Arg-Val-Asn-His-Val-Thr-Leu-Ser-Gln-Pro
-Lys-Ile-Val-Lys-Trp-Asp-Arg-Asp-Met
At Cys 25 and Cys 80 disulfide linkage is arranged, molecular-weight average is: 11729.1694, and single isotopic molecule amount: 11721.7718.
B2M is that Berggard at first separated from uriniferous tubules pathology patient urine in nineteen sixty-eight.B2M is a kind of low molecular ball albumen of karyocyte excretory, can freely see through glomerular filtration 99.0% heavily absorbs at proximal convoluted tubule, the single chain polypeptide of forming by 99 amino-acid residues, molecular weight is 11800, it extensively be present in people's the various body fluid such as blood plasma, urine and cerebrospinal fluid and the surface of karyocyte film in normal circumstances, B2M on the cell surface repeatedly in conjunction with dissociating, is kept running balance with free B2M in the body fluid.
B2M is subjected to suitable attention in recent years, because kinds of tumors patient's serum B2M level rises.A lot of scholars have carried out deep research to its biological property, pathologic, physiologic and clinical meaning.Having the B2M of kinds of tumors such as lung cancer, kidney, mammary cancer, alimentary system malignant tumour blood, urine that ANOMALOUS VARIATIONS is all arranged clinically, generally is to be higher than normal level.Therefore, B2M has been used for multiple malignant tumour early stage blood serum diagnosis.
Summary of the invention
One of purpose of the present invention provides an epitope of B2M.
Two of purpose of the present invention provides the application of an epitope of B2M.
The invention provides an epitope of B2M, be positioned at antigenic 61-67 site, is that aminoacid sequence is: the polypeptide of SFYLLYY.
In order to realize the invention provides the epitope of B2M.We utilize affine mass-spectrometric technique (MALDI-TOF/MS), immune affinity extraction method is combined with modern soft ionization mass-spectrometric technique, the specific reaction of systematic research B2M and its antibody, and then site and the aminoacid sequence of definite its antigenic determinant, and the influence condition to antigen-antibody reaction carried out detailed research, explore the immunologic novel method that optimum experimental condition on the active protein immobilization carrier is set up micro-rapid sensitive.Experimental result shows: mass spectrum is strong means of analyzing antigenic determinant as a kind of fast and effectively analytical procedure.
At first it is produced a series of peptide sections with protease hydrolysis, with the monoclonal antibody that is fixed on the sepharose 4B immune compatible reaction takes place then.The reaction back is collected pearl and is washed repeatedly with suitable damping fluid.The peptide Duan Ze with antibodies is not rinsed, and the peptide section that contains antigenic determinant forms mixture with antibodies and remains with pearl, directly carries out mass spectroscopy at last, obtains the peptide section mass-spectrometric data with antibodies.We have used Endoproteinase Lys-C, the Glu-C proteolytic enzyme with three kinds of different cleavage sites of Trypsin respectively in the experiment, and take the mode of section of synthesized peptide to determine that antigen and antibody binding site are that the site of epi-position is 61-67:SFYLLYY.
Epitope is as the target structure and the basic substance that excites specific immune response of immunocyte identification, and is significant for immunoreactive correlative study.
An epitope peptide SFYLLYY of B2M of the present invention can stimulate the antibody of human body generation at B2M.B2M can combine with its corresponding antibodies specific, and therefore the antibody of an epitope peptide SFYLLYY generation of B2M of the present invention can be used as probe, and the identification B2M also the immunosedimentation reaction takes place with it.Therefore the judgement of an epitope peptide SFYLLYY of B2M of the present invention and early stage blood serum diagnosis, treatment and prognosis that corresponding antibody can be used for disease.
Micromolecule polypeptide of the present invention can make by chemosynthesis or the recombinant expressed method of genetically engineered.
Experiment shows: an epitope peptide SFYLLYY of B2M of the present invention can compete with B2M, participates in many anti-specific combinations; The function that can effectively suppress antibody and has the immunogenicity similar to B2M behind the suitable carriers coupling connection.This just provides the foundation of science for being used to prepare new generation vaccine and medicine.
In conjunction with some biotechnologys, PCR, elisa technique, protein chip utilizes an epitope peptide SFYLLYY of B2M of the present invention can be used to develop new diagnostic kit and as the target protein of diagnosing chip, potential applicability in clinical practice is arranged all.
An epitope of B2M of the present invention is a kinds of tumors, lays a good foundation as lung cancer, kidney, mammary cancer, alimentary system malignant tumour early stage blood serum diagnosis and treatment; And opened up new technological approaches and new application, provide the foundation of science for being used to prepare new generation vaccine and medicine.
Embodiment
Embodiment 1:
Present embodiment is that the epitope of B2M is measured:
(1) preparation of reagent: take by weighing 10mgCHCA and be dissolved in the matrix solution that is mixed with 10mg/ml among the 50%ACN+0.1%TFA.5 μ g Endoproteinase Lys-C are dissolved in the 20 μ LMillpore ultrapure waters, and being mixed with concentration is the solution of 0.25 μ g/ μ L.50 μ gEndoproteinase Glu-C are dissolved in and are mixed with the solution that concentration is 0.25 μ g/ μ L in the 200 μ L Millpore ultrapure waters.The Trypsin of 100 μ g is dissolved in and is mixed with the solution that concentration is 0.5 μ g/ μ L in the 200 μ L Millpore ultrapure waters.
(2) enzyme digestion reaction of B2M: in the 1.5mL centrifuge tube, add the 60 μ LEndoproteinase Glu-C (ammonium acetate solutions of enzymolysis buffered soln 50mM, pH=4.5) experiment is that 1: 20 ratio joins in the enzymolysis buffered soln in enzyme/substrate, in 37 ℃ of reaction 2h, place-20 ℃ of enzymolysis reaction again.Enzymolysis solution carries out desalting treatment by the ZiptipC18 operation instruction.Draw enzymolysis solution and 1 μ L CHCA matrix solution point target after the 1 μ L desalination, after the air at room temperature seasoning, be MALDI-TOF-MS and analyze.Trypsin (50mMTris-HCl 1mM CaCl2pH8.0) and Endoproteinase Lys-C (enzymolysis buffered soln: 50mM Tris-HCl, 0.5mM EDTA pH=8.0) carries out according to the operation steps of Endoproteinase Glu-C enzymolysis B2M.
(3) immunity is affine: add 100 μ L TSO (75mMTris-HCl in enzymolysis mixed peptide section solution again, 200mM NaCl, 0.5%N-octyl glucoside, pH=8.0) buffered soln and 10 μ g monoclonal antibodies (Clone:GJ14, mouse IgGl) were in 4 ℃ of reactions 4 hours.Getting 4 μ L Protein G/Protein AAgarose mixes in solution in 4 ℃ of reactions 2 hours.It is centrifugal in 14000r/min that reaction finishes the back, removes supernatant liquor and collect sepharose 4B.Wash sepharose 4B 3 times with 200 μ L TSO buffered soln at every turn, more then with 200 μ L TSMK buffered soln (10mM Tris-HCl, 200mM NaCl, the 5mM beta-mercaptoethanol, pH=8.0).Sepharose 4B after getting 4 μ L matrix solutions and washing mixes, and finally gets 1.5 μ L mixed solution point targets, in the air at room temperature seasoning, does the MALDI-TOF-MS analysis after to be dried.
Adopting the continuous epitope scope of the resulting B2M of Endoproteinase Glu-C is peptide section (51-69), and aminoacid sequence is: HSDLSFSKDWSFYLLYYTE; The continuous epitope scope that Endoproteinase Lys-C obtains B2M is peptide section (59-75), and aminoacid sequence is: DWSFYLLYYTEFTPTEK; The continuous epitope scope that Trypsin obtains B2M is peptide section (59-75), and aminoacid sequence is: DWSFYLLYYTEFTPTEK.The epi-position scope of learning B2M within peptide section (59-69), that is: DWSFYLLYYTE.
(4) the affine mass spectroscopy of section of synthesized peptide
01--SFYLLYYTE, 02---DWSFYLLYY, 03---SFYLLY, 04---FYLLYY; These four peptide sections respectively with the monoclonal antibody immunity co-precipitation, and carry out mass spectrometry results and show that 01 and 02 sample can combine with antibody, 03 and 04 does not then react with antibody generation co-immunoprecipitation.01 and 02 sample can combine with antibody, so the peptide section-SFYLLYY of both identical sequences can with antibodies, so the conclusion that the affine mass spectroscopy of 01 and 02 sample is obtained is: SFYLLYY contains the B2M antigenic determinant.03 synthetic peptide section sequence then is that SFYLLYY has lacked amino-acid residue Y, that is: a SFYLLY at C-terminal.04 synthetic peptide section sequence then is that SFYLLYY has lacked an amino-acid residue S at its N-terminal, and to the 03 and 04 affine mass spectroscopy of being done as can be known: 03 and 04 is not reacted with antibody generation co-immunoprecipitation, and discord antibody combines.
Therefore the result's that obtains of the affine spectrum analysis by 01,02,03 and 04 sample is: the aminoacid sequence of B2M antigenic determinant is: SFYLLYY
Embodiment 2:
Utilize epitope peptide of the present invention from the patients serum, to filter out positive serum, prepare corresponding antibody, and adopt enzyme linked immunosorbent assay (ELISA) to detect the titre level of corresponding antibodies in the patients serum and between the serum of healthy person of epitope SFYLLYY, 50 routine samples confirm patients' serum titer level apparently higher than healthy person, significant difference p＜0.01.
The B2M epitope peptide is implanted immune mouse in the mouse body, after the immunity 2 times, the production of antibodies of utilization ELISA and Westen Blot detection specificity.Experimental results show that: the antibody serum of generation can combine with B2M specially property.Have the immunogenicity similar behind epitope peptide SFYLYY that this experimental result shows B2M and the suitable carriers coupling connection, further just can use it for and prepare new generation vaccine and medicine to B2M.
Sequence table
＜110〉Changchun Inst. of Applied Chemistry, Chinese Academy of Sciences
＜120〉epitope of B2M and application
<160>1
<210>1
<211>7
<212>PRT
<400>1
Ser?Phe?Tyr?Leu?Leu?Tyr?Tyr
1 5
Claims (3)
1. the epitope of B2M, it is characterized in that having the aminoacid sequence shown in the following formula: be positioned at antigenic 61-67 site, aminoacid sequence is: SFYLLYY.
2. the application of the epitope of B2M as claimed in claim 1 is characterized in that being used to prepare anti-lung cancer, kidney, mammary cancer, alimentary system malignant tumour vaccine or medicine.
3. the application of the epitope of the described B2M of claim 1 is characterized in that being used to develop medicine relevant with tumour and diagnostic kit as target protein.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2006100167679A CN100402551C (en) | 2006-04-14 | 2006-04-14 | Antigen epitope of beta2-microglobulin and its application |
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| CNB2006100167679A CN100402551C (en) | 2006-04-14 | 2006-04-14 | Antigen epitope of beta2-microglobulin and its application |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106636101A (en) * | 2012-09-24 | 2017-05-10 | 杭州耀洲生物科技有限公司 | Nucleic acid aptamer for binding human-derived beta-microglobulin |
| CN103509760B (en) * | 2013-10-10 | 2015-04-22 | 深圳市菲鹏生物股份有限公司 | Hybridoma cell capable of secreting anti-beta2-microglobulin monoclonal antibody, and application thereof |
| CN104098694B (en) * | 2014-07-17 | 2016-08-31 | 大连理工大学 | Single domain antibody of anti-human β2-microglobulin and its production and use |
| CN106749602A (en) * | 2016-12-30 | 2017-05-31 | 武汉金开瑞生物工程有限公司 | It is a kind of to help expressed sequence and its application in acellular expression ADCY2 albumen |
| KR20200051699A (en) * | 2017-09-07 | 2020-05-13 | 아뎁트릭스 코퍼레이션 | Multiplexed bead array for proteomics |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999013095A2 (en) * | 1997-09-11 | 1999-03-18 | The Johns Hopkins University School Of Medicine | Use of multivalent chimeric peptide-loaded, mhc/ig molecules to detect, activate or suppress antigen-specific t cell-dependent immune responses |
| WO2001036452A2 (en) * | 1999-11-18 | 2001-05-25 | Epimmune Inc. | Heteroclitic analogs of class i epitodes |
| CN1439877A (en) * | 2003-01-09 | 2003-09-03 | 中国人民解放军第四军医大学 | Method for quantitatively EL1SA determining soluble WBC concerned immunoglabulin receptor I |
| CN1492768A (en) * | 2001-02-19 | 2004-04-28 | Ĭ��ר������˾ | Artificial proteins with reduced immunogenicity |
| CN1665840A (en) * | 2002-04-30 | 2005-09-07 | 阿雷斯贸易股份有限公司 | Immunoglobulin-domain containing cell surface recognition molecules |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999013095A2 (en) * | 1997-09-11 | 1999-03-18 | The Johns Hopkins University School Of Medicine | Use of multivalent chimeric peptide-loaded, mhc/ig molecules to detect, activate or suppress antigen-specific t cell-dependent immune responses |
| WO2001036452A2 (en) * | 1999-11-18 | 2001-05-25 | Epimmune Inc. | Heteroclitic analogs of class i epitodes |
| CN1492768A (en) * | 2001-02-19 | 2004-04-28 | Ĭ��ר������˾ | Artificial proteins with reduced immunogenicity |
| CN1665840A (en) * | 2002-04-30 | 2005-09-07 | 阿雷斯贸易股份有限公司 | Immunoglobulin-domain containing cell surface recognition molecules |
| CN1439877A (en) * | 2003-01-09 | 2003-09-03 | 中国人民解放军第四军医大学 | Method for quantitatively EL1SA determining soluble WBC concerned immunoglabulin receptor I |
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