CN102229656A - Polypeptide against rheumatoid arthritis and application thereof in pharmacy - Google Patents
Polypeptide against rheumatoid arthritis and application thereof in pharmacy Download PDFInfo
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- CN102229656A CN102229656A CN2011101590869A CN201110159086A CN102229656A CN 102229656 A CN102229656 A CN 102229656A CN 2011101590869 A CN2011101590869 A CN 2011101590869A CN 201110159086 A CN201110159086 A CN 201110159086A CN 102229656 A CN102229656 A CN 102229656A
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- rheumatoid arthritis
- txndc5
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Abstract
The invention discloses a polypeptide against rheumatoid arthritis. The amino acid sequence of the polypeptide is shown as SEQ ID NO.3. The polypeptide is used for injecting a rat, and then animal joint inflammation is artificially induced. The result shows that corresponding antibodies are generated in the rat injected with the polypeptide, the concentrations of vascular endothelial growth factors (VEGF) are correspondingly reduced at the same time, and over 90 percent of rats injected with II-type collagen have no rheumatoid arthritis symptoms. The histopathological analysis shows that the angiogenesis in the pathological change joints of the experimental animals is obviously reduced, and the VEGF level is reduced. Therefore, the polypeptide can inhibit joint synovial membrane capillary hyperplasia of the rheumatoid arthritis in an immune intervention mode, block a nutritional path of synovial membrane cell proliferation and a T cell infiltration path and inhibit tissue inflammation and tissue damage so as to inhibit the pathological change process of the rheumatoid arthritis; and the polypeptide can be developed into a medicament against the rheumatoid arthritis.
Description
The application is dividing an application of publication number CN101696234A application, the applying date of original application: 2009.10.23, and application number: 200910019389.3, denomination of invention: the polypeptide of resisting rheumatoid arthritis and the application in pharmacy thereof.
Technical field
The present invention relates to a class polypeptide and pharmacy thereof and use, relate in particular to the polypeptide of a class resisting rheumatoid arthritis and the application in pharmacy thereof.
Background technology
Trx family is positioned on the endocytoplasmic reticulum, has protein disulfide isomerase (protein disulfide isomerase, PDI) function.The PDI pair cell breaks up unusually, and blood capillary proliferation and anti-oxidative damage play an important role
[1](thiredoxin domain containing 5 TXNDC5) is positioned on No. 6 karyomit(e)s of people (6p24.3) Trx 5, and the disulphide isomerase of its coding contains the PDI structure, high expression level under the anoxybiotic situation, catalytic proteins disulfide linkage isomate process
[1]Have the human proteomics method to find TXNDC5 in hepatocellular carcinoma, expression of tumor tissue such as colorectal cancer play the effect of protection to endotheliocyte under the environment of tissue hypoxia
[2]
(rheumatoid arthritis RA) is a kind of self-Immunological diseases to rheumatoid arthritis, and clinical manifestation is chronic, many synovial joints inflammation.The RA pathology show as the serious inflammation of synovium of joint, and tissue thickens, and the T cell infiltrates in a large number in the synovial membrane, B cell and synovial membrane fibrous cell paraplasm, and capillary vessel generates in a large number, is referred to as pannus on the anatomy.The inventor utilizes proteomic techniques relatively RA, osteoarthritis (osteoarthritis, OA) and ankylosing spondylitis (ankylosing spondilitis, AS) protein expression profiles of pathology synovial tissue is found TXNDC5 significance high expression level in the synovial tissue of RA.Immunohistochemical methods, western blotting and quantifying PCR method transcribe with protein level on all confirmed the specificity overexpression of TXNDC5 in RA synovial tissue of joint cell.In addition, the inventor finds with enzyme immunoassay side (ELISA), compares with OA, AS patient, and the expression amount of TXNDC5 increases twice or more than the twice in 53.3%RA patient's blood and 73.3%RA patient's the knuckle synovia
[3], show that TXNDC5 may be relevant with the RA pathogenic process.
Based on above-mentioned discovery, the inventor studies the mechanism of causing a disease of RA with regard to TXNDC5.Many studies have shown that, RA pathology joint is a low-oxygen environment, RA has low oxygen characteristic in essence
[4], and show response to oxidative stress
[5,6]The inventor finds, induces synovial membrane TXNDC5 high expression level under the RA hypoxia condition.The TXNDC5 of high density can raise RA synovial membrane vascular endothelial growth factor vegf expression, and VEGF stimulates synovial tissue's blood capillary proliferation, forms pannus.Pannus is that the vital tissue of RA The lesions of synovium contributed is learned feature.Just because of the generation of pannus, the T cell is able to cause inflammation to a large amount of infiltration of synovial tissue, and simultaneously, pathological tissues obtains sufficient nutrient and supports B cell and fibrous cell to breed in a large number.Given this, TXNDC5 can become potential RA treatment target spot.By suppressing the TXNDC5 enzymic activity, can suppress RA synovial tissue capillary vessel and generate, thereby the nutrition approach of blocking lesion synovial cell proliferation and T cell transfer approach reach the treatment RA purpose of killing and wounding RA synovial cell and inflammation-inhibiting process.
Reference
1.Sullivan?DC，Huminiecki?L，Moore?JW，et?al.EndoPDI，a?novel?protein-disulfide?isomerase-Like?protein?that?is?preferentially?expressed?in?endothelial?cells?acts?as?a?stress?survival?factor.J?Biol?Chem，2003，278：47079-47088.
2.Wang?Y，Ma?Y，LüB，et?al.Differential?expression?of?mimecan?and?thioredoxin?domain-containing?protein?5?in?colorectal?adenoma?and?cancer：a?proteomic?study.Exp?Biol?Med(Maywood)，2007，232：1152-9.
3.Chang?X，Cui?Y，Zong?M，et?al.Identification?of?proteins?with?increased?expression?in?rheumatoid?arthritis?synovial?tissues.J?Rheumatol，2009，36：872-880.
4Distler?JH，Wenger?RH，Gassmann?M，et?al.Physiologic?Responses?to?Hypoxia?and?Implications?for?Hypoxia-Inducible?Factors?in?the?Pathogenesis?of?Rheumatoid?Arthritis.Arthritis?Rheum，2004，50：10-23.
5.Tak?PP，Zvaifler?NJ，Green?DR，et?al.Rheumatoid?arthritis?and?p53：how?oxidative?stress?might?alter?the?course?of?inflammatory?diseases.Immunol?Today，2000，21：78-82.
6.Hitchon?CA，El-Gabalawy?HS.Oxidation?in?rheumatoid?arthritis.Arthritis?Res?Ther，2004，6：265-78.
Summary of the invention
Based on the keying action of above-mentioned TXNDC5 in the RA pathogenic process, the purpose of this invention is to provide the polypeptide of a class resisting rheumatoid arthritis and the application in pharmacy thereof.
The polypeptide of resisting rheumatoid arthritis of the present invention is characterized in that: it is the aminoacid sequence shown in the SEQ ID NO.3; Concrete sequence description is:
Arg?Thr?Glu?Thr?Gly?Ala?Thr?Glu?Thr?Val?Thr?Pro?Ser?Glu
1 5 10 。
The synthetic method of the polypeptide of above-mentioned resisting rheumatoid arthritis is conventional artificial synthesis.According to immunosuppressant principle, the small peptide of the different sections of corresponding TXNDC5, the applicant has designed 9 sections TXNDC5 polypeptide (being the aminoacid sequence shown in SEQ ID NO.1～SEQ ID NO.9), artificial synthesis has been implemented to synthesize to 9 peptide species routinely, and the polypeptide of the aminoacid sequence shown in the SEQ IDNO.3 promptly wherein.
The pannus of the polypeptide of above-mentioned resisting rheumatoid arthritis in preparation inhibition rheumatoid arthritis joint generates the application in the medicine.Further, the application of the polypeptide of above-mentioned resisting rheumatoid arthritis in resisting rheumatoid arthritis medicines such as preparation inhibition rheumatoid arthritis synovium of joint blood capillary proliferation, the nutrition approach of blocking synovial cell's propagation and T cell infiltration approach.
The application of the polypeptide of above-mentioned resisting rheumatoid arthritis in preparation Trx 5 (TXNDC5) polyclonal antibody or monoclonal antibody.
It is to adopt the approach of immunotherapy that the present invention studies thinking, the artificial RA patient's immunity system that stimulates produces anti-TXNDC5 antibody, utilize antigen, antibodies specific combination principle, TXNDC5 with anti-TXNDC5 antibodies high expression level, thereby suppress this enzymic activity, the blocking-up capillary vessel forms, and reaches the purpose of the treatment RA course of disease.At present, the effective biotechnological formulation of existing several RA, as benefit plug spectrum (Etanercept), class gram etc., all be antibody with RA inflammation-related factor TNF (tumour necrosis factor), by in patient's body, injecting anti-TNF antibodies,, suppress the biological activity of TNF in conjunction with the TNF of RA high expression level, the development of blocking-up RA inflammation obtains the RA result of treatment.This research by this RA treatment thinking, is model with the RA laboratory animal at first also, by the mode of immunologic intervention treatment, by suppressing the TXNDC5 biological function, reaches treatment RA purpose.
Basic implementation process is as follows: use 9 kinds of small peptides (being the aminoacid sequence shown in SEQ ID NO.1～SEQ ID NO.9) of each section of TXNDC5 of preparation routinely of the present invention, be injected into respectively in the big white mouse body, make animal produce anti-TXNDC5 antibody.Then, by RA sacroiliitis method for building animal model commonly used, injection II Collagen Type VI induced animal performance RA clinical symptom (injecting collagen-induced animal general arthritis to rat is RA pathological study and the most frequently used animal model of drug screening) in animal body.Compare with control group, whether the laboratory animal that observation has been injected after the injection of TXNDC5 small peptide shows the RA arthritis.If the RA symptom does not appear in animal, then anti-TXNDC5 antibody and the combination of TXNDC5 antigen-specific in the animal body after the explanation injection, by the PDI catalysis that suppresses this enzyme stoped effectively TXNDC5 downstream pathology by way of, block the hormesis that TXNDC5 generates capillary vessel, thereby reached the RA therapeutic purpose.
Experimental result shows: anti-TXNDC5 antibody horizontal obviously raises after having injected the TXNDC5 small peptide, shows that the specificity combination takes place in the rat body for TXNDC5 antibody and its antigen, can form immunosuppression to the TXNDC5 enzymic activity.The animal of having injected the TXNDC5 small peptide before collagen-induced RA no longer shows RA clinical symptom and histologic characteristics, and the pathology process that can suppress RA to the immunosuppression of TXNDC5 effectively is described.After control group comprised that α hair Keratin sulfate small peptide or BSA substitute the TXNDC5 small peptide, the RA phenomenon was not suppressed, and confirmed that it is not that immunological tolerance does not cause that the TXNDC5 small peptide suppresses the result to RA.TXNDC5 small peptide injection back does not show RA with the rat of BSA immunity, this means that TXNDC5 small peptide and polypeptide itself do not influence RA.In experiment, the TXNDC5 small peptide is respectively to C-end that should enzyme, positions such as calcium ion land, PDI reactive site, and therefore, the antibody of its generation can be by immunity in conjunction with the physiological function that suppress the TXNDC5 enzyme effectively.
Meaning of the present invention and potential use: the biotechnological formulation for the treatment of RA now mainly is the general and Ying Fuli of benefit match former times, be the monoclonal antibody of TNF, the beginning of the nineties is used abroad, plays the use in China, and has received good result of treatment in 2005.Said preparation mainly suppresses the morbidity process by inflammation-inhibiting.Another biotechnological formulation of bringing into use at present is Rituximab (Rituximab), is the monoclonal antibody at the B cell, by killing the B cell of a large amount of propagation, suppresses the self-immune response of RA.More than these biotechnological formulations all at a large amount of outgrowth synovial cells of RA or inflammatory factor, none generates at the important pathological characters of another RA-pannus.And whether all the medicine of China treatment RA no matter biotechnological formulation inscience property right.Test-results of the present invention shows, with TXNDC5 short peptide sequence prepared polypeptide drugs or antibody drug, can directly suppress the pannus generation of RA by immunosuppression TXNDC5 activity.By cutting off required nutrition channel and the T cell route of entry of a large amount of propagation of synovial cell, fundamentally reach the purpose of treatment RA.The essence of RA pathology joint tissue is hypoxemia, and low-oxygen environment is induced the pathology process.Suppressing the biological activity of the hypoxemia inductive TXNDC5 of institute, is the important channel for the treatment of RA on the whole.
Description of drawings
Fig. 1 laboratory animal RA time of occurrence figure.
Inflammation time (inflammation index) figure appears in Fig. 2 laboratory animal.
Anti-TXNDC5 antibody horizontal figure in Fig. 3 blood.
VEGF level view in Fig. 4 blood.
The immunohistochemical section photo of the synovium of joint of Fig. 5 animal.
Embodiment
According to immunosuppressant principle, the small peptide of the different sections of corresponding TXNDC5, the applicant has designed 9 sections TXNDC5 polypeptide.
It is the aminoacid sequence shown in the SEQ ID NO.1; Concrete sequence description is:
Arg?Gly?Gly?Lys?Lys?Val?Ser?Glu?His?Ser?Gly?Gly?Arg?Asp
15 10; Or
It is the aminoacid sequence shown in the SEQ ID NO.2; Concrete sequence description is:
Arg?Asp?Gly?Lys?Lys?Val?Asp?Gln?Tyr?Lys?Gly?Lys?Arg?Asp
15 10; Or
It is the aminoacid sequence shown in the SEQ ID NO.3; Concrete sequence description is:
Arg?Thr?Glu?Thr?Gly?Ala?Thr?Glu?Thr?Val?Thr?Pro?Ser?Glu
15 10; Or
It is the aminoacid sequence shown in the SEQ ID NO.4; Concrete sequence description is:
Pro?Val?Thr?Pro?Glu?Pro?Glu?Val?Glu?Pro?Pro?Ser?Ala?Pro
15 10; Or
It is the aminoacid sequence shown in the SEQ ID NO.5; Concrete sequence description is:
Thr?Trp?Asn?Asp?Leu?Gly?Asp?Lys?Tyr?Asn?Ser?Met?Glu?Asp
15 10; Or
It is the aminoacid sequence shown in the SEQ ID NO.6; Concrete sequence description is:
Lys?Pro?Gly?Gln?Glu?Ala?Val?Lys?Tyr?Gln?Gly?Pro?Arg?Asp
15 10; Or
It is the aminoacid sequence shown in the SEQ ID NO.7; Concrete sequence description is:
Pro?Pro?Ala?Ala?Asp?Gly?Glu?Asp?Gly?Gln?Asp?Pro?His?Ser
15 10; Or
It is the aminoacid sequence shown in the SEQ ID NO.8; Concrete sequence description is:
Thr?Leu?Ala?Pro?Thr?Trp?Glu?Glu?Leu?Ser?Lys?Lys?Glu?Phe
15 10; Or
It is the aminoacid sequence shown in the SEQ ID NO.9; Concrete sequence description is:
Ser?Leu?His?Ser?Phe?Val?Leu?Arg?Gln?Ala?Lys?Asp?Glu?Leu
1 5 10 。
Artificial synthesis is implemented synthetic, standby to above-mentioned 9 peptide species routinely.
The pharmaceutical use of the polypeptide of resisting rheumatoid arthritis of the present invention
Experimental technique
60 of male Lewis rats, mean body weight 120 grams, 8 ages in week.
9 kinds of small peptides of each section of TXNDC5 of synthetic (being the aminoacid sequence shown in SEQ ID NO.1～SEQ ID NO.9) routinely.
Inject the small peptide of aminoacid sequence shown in the SEQ ID NO.1～SEQ ID NO.9 of 100 micrograms respectively to every rat by the tail vein.Small peptide respectively with carrier proteins keyhole limpet hemocyanin (KLH) coupling.This aminoacid sequence is that TXNDC5 people is mated aminoacid sequence fully.The people is almost completely consistent with the TXNDC5 aminoacid sequence of mouse.The freund's adjuvant of above small peptide and equal volume concentration (5ug/ml) thorough mixing, the 1st, 14 and 28 day to the laboratory animal immunization, make it to produce anti-TXNDC5 antibody according to a conventional method.Then, RA animal model method induced animal performance RA to these animals injection ox II Collagen Type VIs (Sigma company), is set up routinely in after injection for the first time the 42nd, 56 and 70 day.The limbs of daily inspection rat are rubescent, swelling and stiff degree.RA inflammation degree is by research standards of grading judge in used 12 minutes usually, and standards of grading are as follows: 0: normal, and no swelling/rubescent, 1: slightly rubescent, 2: redden and whole foot swelling; 3: strong inflammation and sufficient gross distortion.Every mouse four limbs RA degree largest cumulative 12 minutes.Simultaneously, the 0th, 35, gathered the animal blood sample, and measured anti-TXNDC5 antibody and vascular endothelial growth factor VEGF level in the blood in 77 and 102 days with conventional ELISA method.The capillary vessel development degree is organized in the VEGF representative.The VEGF level is finished with rat VEGF ELISA test kit (Invitrogen company).The 102nd day execution of rat after injection for the first time.Dissecting the synovial tissue of coming out organizes lesion degree and TXNDC5 to express situation with the inspection of routine immunization organization method.
Experiment is provided with a series of control groups simultaneously, and every group of rat is 60, and concrete group is as follows: (1), and α hair Keratin sulfate small peptide (AAVGSRPIHCGVRFC peptide) substitutes the TXNDC5 small peptide; (2) the replacement II collagen type of bovine serum albumin (BSA, Sigma company) is induced; (3) BSA replaces TXNDC5 small peptide and II Collagen Type VI to induce; (4) it is collagen-induced only to inject II; (5) only use the BSA immune animal, replace the injection of small peptide and collagen immunization; (6) do not inject any small peptide and protein.
Experimental result
The experimental group rat is used collagen-induced RA routinely behind immune TXNDC5 small peptide.Experimental result is that example is described below with SEQ ID NO.9 small peptide: with after for the first time injecting collagen protein the 50th day (i.e. injection for the first time afterwards the 92nd day), in 60 rats (97%) 58 do not show any inflammation and extremities joint stiff.Have only two after for the first time injecting collagen the 56th day limbs slight inflammation (inflammation scoring=3) appears.Substitute with α hair Keratin sulfate small peptide in the rat of TXNDC5 small peptide injection, 55 rats (92%) obvious swelling occurs in the 34.5th ± 3.6 joint, collagen-induced back.Substituting with BSA in the rat of TXNDC5 small peptide, 50 (83%) rats were at the 39.7th ± 4.3 day that injects for the first time collagen protein, and obvious inflammation appears in the joint.All 60 (100%) substitute the clinical manifestation that the rat of TXNDC5 small peptide, polypeptide and collagen does not all show RA with BSA.56 (93%, wherein 4 in experimental session death) rats showed arthritis on the 37.3rd ± 2.1 day behind injection collagen separately.Injection TXNDC5 small peptide, 60 rats (100%) of injecting the alternative II Collagen Type VI of BSA then all do not show the RA symptom.Rat without any injection does not all show any joint inflammation symptom yet.
Laboratory animal RA time of occurrence and inflammation degree are seen Fig. 1, Fig. 2 and table 1.
Table 1:RA situation occurs and TXNDC5 expresses situation
| Processing mode (respectively organize rat and be 60) | The RA number of elements appears | The RA time of occurrence | Inflammation index | Anti-TXNDC5 level in the blood | TXNDC5 expresses in synovial membrane |
| TXNDC5 small peptide+ |
0 | Do not occur | Do not occur | High | High expression level |
| α hair Keratin sulfate small peptide+collagen | 50 | 37.2 ± 3.6 days | High | Low | High expression level |
| TXNDC5 small peptide+ |
0 | Do not occur | Do not occur | High | The low expression |
| BSA+ collagen | 55 | 39.7 ± 3.3 days | High | Low | High expression level |
| Collagen | 50 | 39.3 ± 3.1 days | High | Low | High expression level |
| BSA+ |
0 | Do not occur | Do not occur | Low | The low expression |
| There is not any |
0 | Do not occur | Do not occur | Low | The low expression |
Detect anti-TXNDC5 level in the rat blood with the ELISA method in the experiment.
The result shows, high-caliber anti-TXNDC5 antibody appears in rat 35 and 77 days after the TXNDC5 small peptide injection first time in the blood, dropped to normal level (Fig. 3) after the 102nd day.ELISA detects animal blood and also shows, the 102 day obviously risings of VEGF level after injection for the first time.But by contrast, the VEGF level obviously is reduced in the rat blood centering of having injected the TXNDC5 oligopeptides and but obviously reduces, even than the rat low (Fig. 4) that does not have treatment, illustrates that capillary vascular development degree is also low relatively in this group rat synovial tissue.
With immunohistochemical method variation of laboratory animal synovium of joint pathologic structure and TXNDC5 expression are studied in the experiment.In the rat synovial tissue behind the collagen injection, the obvious thickening of synovial membrane also contains a large amount of T cells, B cell and fibrous cell, observing a large amount of capillary vesseies simultaneously generates, this situation has been present in all injections in the rat of collagen, no matter whether they have also been injected other small peptide and or BSA simultaneously.But injected before collagen-induced in the rat of TXNDC5 small peptide of the present invention at those, their synovial membrane is thinner, and is similar to non-RA inductive control group, and simultaneously, the synovial membrane capillary vessel also is starkly lower than collagen RA inductive rat.Immunohistochemistry detects the expression of TXNDC5 in the synovium of joint of all animals, this enzyme is many expresses at the cells of superficial layer that is positioned at synovial membrane.Yet in the rat synovium of joint of injection TXNDC5 small peptide of the present invention, the intensity of TXNDC5 immunity signal is starkly lower than the level (Fig. 5) that collagen RA induces control group.
Small peptide with the aminoacid sequence shown in other SEQ ID NO.1 of the present invention～SEQ ID NO.8 all obtains and the similar result of SEQ ID NO.9 small peptide.
Laboratory animal RA time of occurrence sees Table 2.
Situation appears in table 2:RA
| Processing mode | The RA number of elements appears | The RA time of occurrence |
| SEQ ID NO.1 |
1 | 46 days |
| SEQ ID NO.2 |
2 | 47.2 ± 2.0 days |
| SEQ ID NO.3 |
4 | 43.7 ± 3.1 days |
| SEQ ID NO.4 |
2 | 47.7 ± 2.3 days |
| SEQ ID NO.5 |
3 | 39.3 ± 1.1 days |
| SEQ ID NO.6 |
5 | 40.7 ± 4.5 days |
| SEQ ID NO.7 |
3 | 47.2 ± 2.7 days |
| SEQ ID NO.8 |
0 | 52 days |
| SEQ ID NO.9 |
0 | 56 days |
Claims (2)
1. the polypeptide of a resisting rheumatoid arthritis, it is characterized in that: it is the aminoacid sequence shown in the SEQ ID NO.3; Concrete sequence description is:
Arg?Thr?Glu?Thr?Gly?Ala?Thr?Glu?Thr?Val?Thr?Pro?Ser?Glu
1 5 10 。
2. the polypeptide of the described resisting rheumatoid arthritis of claim 1 suppresses the pannus generation medicine in rheumatoid arthritis joint or the application in Trx 5 antibody in preparation.
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|---|---|---|---|
| CN2011101590869A CN102229656B (en) | 2009-10-23 | 2009-10-23 | Polypeptide against rheumatoid arthritis and application thereof in pharmacy |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101590869A CN102229656B (en) | 2009-10-23 | 2009-10-23 | Polypeptide against rheumatoid arthritis and application thereof in pharmacy |
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|---|---|---|---|
| CN2009100193893A Division CN101696234B (en) | 2009-10-23 | 2009-10-23 | Polypeptide for resisting rheumatoid arthritis and application thereof in pharmacy |
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| WO2003063905A1 (en) * | 2002-01-31 | 2003-08-07 | Center For Advanced Science And Technology Incubation, Ltd. | Preventives or remedies for immunological diseases |
| CN1225479C (en) * | 2002-12-23 | 2005-11-02 | 马菁 | Tumour necrosis factor antibody preparing method and medicinal composition thereof |
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