CN1365983A - Human alpha interferon derivative with superstrong antiviral activity - Google Patents
Human alpha interferon derivative with superstrong antiviral activity Download PDFInfo
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Abstract
A human alpha-interferon derivative (IFN-SA) composed of 171 amino acids with ultra-high antivirus specific activity is prepared by recombination. Its antivirus specific activity is increased by 50-100 times, reaching 5-10X10 to the power 9 IU/mg, so it can be used to treat viral diseases.
Description
The present invention relates to a kind of novel human alpha interferon derivative with superstrong antiviral specific activity (IFN-SA) and its production and use, it is characterized in that antiviral specific activity that it has is up to 5-10 * 10
9IU/mg has the treatment and the great potential of prophylaxis of viral infections disease aspect.
Interferon, rabbit is the protein polypeptide of a class by the molecular relative small molecular weight of singly-bound, and it is produced after virus infection and the antigenic stimulation being subjected to by various kinds of cell in the body.That Interferon, rabbit has is antiviral, antiproliferative and immunoregulatory function, therefore has huge clinical value, as treatment virus disease and tumour, multiple scleroderma etc.Though Interferon, rabbit is found existing many decades, researchs such as its protein and gene structure are the work of recent two decades, have many problems to wait deeply.It is α, β and γ type that human interferon is divided into three major types, is produced by white corpuscle, inoblast and lymphocyte respectively and names.Human alpha interferon is made up of 166 amino acid, and molecular weight is about 19000 dalton, and is though proof contains glycosyl, irrelevant with its antigenicity and biological activity.The inferior member of human alpha type Interferon, rabbit who has at present cloned and determined aminoacid sequence has an appointment 20 kinds, may also have new hypotype and occur.If will add through sudden change or the human alpha interferon derivative of transforming, produce a considerable amount of various human alpha interferon derivatives or analogue through genetic engineering means.Wherein the most noticeable is composite type alpha interferon (concensus interferon).Composite type alpha interferon is a kind of new forms of interferon, and it is to combine according to the principle that amino acid identity is high in the aminoacid sequence of known human alpha interferon hypotype, through its corresponding gene of synthetic, gets through the colibacillus expression and purification again.The antiviral specific activity of compound Interferon, rabbit of recombinating is 10 times of any natural alpha-interferon of finding at present, reaches specific activity 1.0 * 10
9More than the unit.Reorganization composite type alpha interferon (trade(brand)name Infergen) approved is used for the treatment of chronic hepatitis C, and is evident in efficacy.
The reorganization composite type alpha interferon is invented by U.S. Amgcn company; its still bent 166 amino acid is formed; but three kinds of forms are arranged is methionyl type (methionyl), remove methionyl type (des-methionyl) and N-acetylize methionyl type (N-acytaled methionyl), promptly has the defective of structure unhomogeneity.The alpha-interferon of recombinant natural such as IFN-α 2a, 1b and 2b are made up of 166 amino acid equally, and they are a kind of important antiviral and antineoplastic medicines.But still undesirable its antiviral specific activity of the clinical therapeutic efficacy of existing interferon-alpha preparation only is 1.0 * 10
8About IU/mg, the bigger shortcoming of side effect when existing heavy dose.Superstrong antiviral activity alpha interferon derivative of the present invention is made up of 171 amino acid, and the antiviral specific activity that has reaches 5-10 * 10
9IU/mg, than the strong 5-10 of composite type alpha interferon doubly, than the strong 50-100 of natural interferon-alpha doubly.Its aminoacid sequence of superstrong antiviral activity alpha interferon derivative IFN-SA is characterised in that it is Gly Ser Gly Gly Gly that its N-end has more 5 amino acid than natural interferon-alpha, from the 6th to the amino sequence of 171 amino acids sequences based on 14 kinds of human alpha interferons, adopt homology combination principle to design.
Human alpha interferon and composite type alpha interferon all contain two pairs of disulfide linkage, and promptly Cys1 and Cys29 and Cys99 and Cys139 form.Two of the superstrong antiviral activity alpha interferon derivative pairs of disulfide linkage are positioned at Cys7 and cys34 among the present invention, and between Cys104 and the Cys144, because disulfide linkage is not in its N-terminal first amino acid position, ten minutes helps the formation of disulfide linkage and stablizes.
The scheme of sex change and renaturation is adopted in the preparation of recombinant alpha interferon and composite type alpha interferon at present more, adds and adds the methionyl that can occur methionyl or modification at N-terminal, and it is very unfavorable to infer the conformation formation of first pair of disulfide linkage (Cys1 and Cys29).Reorganization superstrong antiviral activity alpha interferon derivative IFN-SA of the present invention adopts the mode of secretor type amalgamation and expression, add that first pair of disulfide linkage is between Cys7 and Cys34, therefore avoided the process of sex change and renaturation effectively, the best conformation that has guaranteed disulfide linkage forms, its N-terminal does not contain methionyl, and end product is single by 171 amino acid whose reorganization IFN-SA.
It is stronger that reorganization superstrong antiviral activity alpha interferon derivative IFN-SA provided by the invention has an antivirus action, side effect is littler, medicine ' Bingduxiao ' removes more effective, is more suitable in the treatment and the prevention of viral infection disease such as viral hepatitis, herpes simplex infections and viral influenza, ebv infection etc.
The protein amino acid sequence of superstrong antiviral activity alpha interferon derivative IFN-SA is as follows among the present invention:
g?s?g?g?g?c?d?l?p?q?t?h?s?l?g?n?r?r?a?l?i?l?l?a?q?m?r?r?i?s?p?f?s?c?l?k?d?r?h
d?f?g?f?p?q?e?e?f?d?g?n?q?f?q?k?a?q?a?i?s?v?l?h?e?m?i?q?q?t?f?n?l?f?s?t?k?d?s
s?a?a?w?d?e?s?l?l?e?k?f?y?t?e?l?y?q?q?l?n?d?l?e?a?c?v?i?q?e?v?g?v?e?e?t?p?l
m?n?v?d?s?i?l?a?v?r?k?y?f?q?r?i?t?l?y?l?t?e?k?k?y?s?p?c?a?w?e?v?v?r?a?e?i?m?r
s?f?s?l?s?t?n?l?q?e?r?l?r?r?k?d
The corresponding gene order of above gal4 amino acid is with manually being synthesized into (seeing example for details), and the host cell of described expression vector comprises bacterium, yeast and mammalian cell.The preparation method of reorganization superstrong antiviral activity alpha interferon derivative IFN-SA comprises that corresponding gene is artificial constructed, contains the screening of the recombinant expression vector of its dna sequence dna, the conversion of host cell, steps such as fermentation and purifying.
The reorganization superstrong antiviral activity alpha interferon derivative IFN-SA that is produced by above-mentioned preparation method has 5-10 * 10
9The antiviral specific activity of IU/mg is prepared into injection liquid drugs injection or freeze-dried powder, the paste of external application type or buccal tablets or capsule, the tablet etc. of emulsion and oral type by the corresponding preparation technology.
Below by example of the present invention, for a more detailed description to the present invention.Example 1
The gene of superstrong antiviral activity alpha interferon derivative IFN-SA is artificial constructed
Amino acid sequence according to superstrong antiviral activity alpha interferon derivative IFN-SA protein of the present invention is selected the Escherichia coli preference codon; Elimination is unfavorable for that the secondary structure of expressing designs and the letter opposite sex of codon, designs following preferred DNA order example (513bp): GGATCCGGTGGTGGTTGTGACCTGCCGCAGACTCATTCCCTGGGTAACCGTCGCGC TCTGATCCTGCTGGCACAAATGCGTCGTATCAGCCCGTTTTCTTGTCTGAAGGATC GTCACGACTTTGGCTTTCCGCAAGAAGAGTTCGATGGCAACCAGTTCCAGAAAGCA CAGGCTATCAGCGTACTGCATGAAATGATCCAGCAAACCTTCAACCTGTTCTCCAC TAAAGATAGCTCTGCTGCATGGGACGAAAGCCTGCTGGAGAAATTCTACACCGAAC TGTATCAGCAGCTGAACGATCTGGAAGCATGCGTAATTCAGGAAGTAGGTGTAGAA GAGACTCCGCTGATGAACGTCGATTCTATCCTGGCAGTTAGAAAGTACTTCCAGCG TATCACCCTGTACCTGACTGAAAAAAAGTACTCTCCGTGCGCTTGGGAAGTAGTTC GTGCTGAAATCATGCGTTCCTTCTCTCTGTCTACTAACCTGCAAGAGCGTCTGCGT CGTAAGGAC
According to the dna sequence dna of above-mentioned design, synthetic respectively 8 dna fragmentations, overlapping successively mutually 20 bases, its annealing humidity is 62 ℃.Upstream primer and the downstream primer of two 33bp of resynthesis with 5` end and the pairing of 3` end, contain two restrictive restriction enzyme sites of BamHI and HindIII respectively respectively.Use the dna fragmentation that the PCR reaction system amplifies the 530bp size, after reclaiming purifying,, make up P by BamHI and HindIII double digestion
UC18Between the BamHI and HindIII of carrier.The recombinant plasmid called after P that contains the IFN-SA foreign gene
UC-IFN-SA( legend 1 ) confirms to be used for after the exactness of its dna sequence dna the structure of expression vector through automatic sequencing.8DNA：Seq1：GGA TCC GGT GGT GGT TGT GAC CTG CCG CAG ACT CAT TCC CTG GGT AAC CGT CGC GCT CTGATC CTG CTG GCA CAA ATG CGT CGSeq2：GAC GAC CGT GTT TAC GCA GCA TAG TCG GGC AAA AGA ACA GAC TTC CTA GCA GTG CTG AAA CCGAAA GGC GTT CTT CTC AAG CTSeq3：TTT CCG CAA GAA GAG TTC GAT GGC AAC CAG TTC CAG AAA GCA CAG GCT ATC AGC CTA CTG CATGAA ATG ATC CAG CAA ACC TTSeq4：CTT TAC TAG GTC GTT TGG AAG TTG GAC AAG AGG TGA TTT CTA TCG AGA CGA CGT AAC CTG CTTTCG GAC GAC CTC TTT AAG ATSeq5：AGC CTG CTG GAG AAA TTC TAC ACC GAA TCG TAT GAG CAG CTG AAC GAT CTG GAA GCA TGC GTAATT CAG GAA GTA GGT GTA GASeq6：TAA GTC CTT CAT CCA CAT CTT CTC TGA GGC GAC TAC TTG CAG CTA AGA TAG GAC CGT CAA TCTTTC ATG AAG GTC GCA TAG TGSeq7：AAG TAC TTC CAG CGT ATC ACC CTG TAC CTG ACT GAA AAA AAG TAC TCT CCG TGC GCT TGGGAA GTA GTT CGT GCT GAA ATC ATSeq8：CAT CAA GCA CGA CTT TAG TAC GCA AGG AAG AGA GAC AGA TGA TTG GAC GTT CTC GCA GACGCA GCA TTC CTG ATC ATT CGA AIFN-SADNAPCR：5`：5`-GC GGA TCC GGT GGT GGT TGT GAC CTG CCG CAG ACT-33`：5`-CG AAG CTT ACT AGT CCT TAC GAC GCA GAC GCT CTT-32
The structure of the recombinant vectors of amalgamation and expression IFN-SA
The secretor type fusion expression vector is P
MAL-P2(Bio-lab company), promotor is P
Tac, IFN-SA links to each other with the C-terminal fusion of the malE of its carrier, wherein contains proteolytic enzyme TEV (tobacco etch virus proteolytic enzyme) enzyme specific recognition site Glu Asn LeuTyr Phe Gln
↓Gly, ↓ be restriction enzyme site.Adding with the aminoacid sequence of the spacer transcribed spacer of 6 Histidines is before the recognition site of TEV; His His His His His His Asp Tyr Asp Ile Pro Thr Thr.The amino acid corresponding DNA sequence linker that is contained TEV proteolytic enzyme recognition site and spacer district by synthetic is as follows:
EcoRI5`-GAA?TTC?CAC?CAT?CAC?CAT?CAC?CAT?GAC?TAC?GAT?ATC?CCA?ACT?ACT?GAG?AAC?CTG?TAC
Glu?Phe?His?His?His?His?His?His?Asp?Tyr?Asp?Ile?Pro?Thr?Thr?Glu?Asn?Leu?Tyr
BamHI
TTT?CAA?GGA?TCC-3`
Phe?Gln?Gly?Ser
The first-selected P of insertion of linker sequence that contains restriction enzyme EcoRI and BamHI
UC18EcoRI and BamHI between, be built into P
UC-LKShown in legend 3, with P
UC-IFNIFN-SA with behind BamHI and the HindIH double digestion, insert P
UC-LKBamHI and HindIII between be built into P
UC-LK-INFThis recombinant vectors is that the DNA recon that contains the IFN-SA of TEV proteolytic enzyme recognition site can be used for and P
MBP-P2Carrying out recombinant expression vector makes up.
P
MAL-P2Carrier belongs to secretion type expression, and expressed recombination fusion protein is positioned at colibacillary born of the same parents' pericentral siphon.p
MAL-IFNConstruction process (legend 4) be with P
MAL-P2Behind EcoRI and HindIII double digestion, reclaim big fragment, with P
UC-LK-IFNBehind EcoRI and HindIII double digestion, reclaim the small segment of about 0.6kb.Under the T4 ligase, link transformed into escherichia coli BL21, screening recon.Clone's called after P after enzyme is cut evaluation and sequential analysis conclusive evidence
MAL-IFNExample 3
The amalgamation and expression of reorganization IFN-SA and fermentation will contain the recombinant expression vector P of IFN-SA gene
MAL-IFNTransformed into escherichia coli Top10F, single bacterium colony in the LB that contains 100ug/mlAmp (penbritin) (10%Yeast extract, 5%Trypton, 0.15M NaCl) substratum 37 ℃ shake bottle and spend the night, cultivated 2-3 hour by 1.30 inoculation backs, induced 4 hours behind the adding 0.3mM IPTG.Thalline cushions by behind the bacterium with sample on 2 * electrophoresis, 10%SDS-PAGE electrophoresis poststaining, and being presented at the 68KD place has a tangible expressing fusion protein band, and expression amount accounts for the 10-15% of tropina.
30 liters of system ferment tank conditions are: contain p
MAL-IFNEngineering bacteria list bacterium colony, activated back is at 37 ℃, the seed liquor 1000ml that contains incubated overnight in the LB substratum of 100ug/ml Amp and 0.5% glucose under the 250rpm is by being inoculated at 1: 20 in 20 liters M9CA (M9 basic medium+2%Casamino acids) substratum.Be cultured to OD to 6.0 under 37 ℃, 500rpm, 60% dissolved oxygen, the pH7.0 condition, add IPTG final concentration 0.5mM, inherited abduction delivering 4 hours.Thalline confirms that through the 10%SDS-PAGE electrophoresis expression amount is more than 12%.Example 4
Purifying and the evaluation of reorganization IFN-SA
Centrifugal collection thalline → infiltration crushes bacterium → centrifugal reservation supernatant → mistake Q-Sepharose post → mistake Amylose resin chromatography column → 4 ℃ of enzymes of fusion rotein adding TEV proteolytic enzyme (GIBCO product) and cuts 6 hours → Ni+-chelating Sepharose chromatography → molecular sieve Sephacryl S-200 → reorganization IFN-SA.
The reorganization IFN-SA that obtains by above-mentioned purification process dyes the single protein band that shows the about 20KD of molecular weight through 15%SDS-PAGE electrophoresis silver, is 19 through its molecular weight of MALDI-TOF mass spectroscopy, 723dalton.HPLC shows single protein peak, and purity is GSGGGCDLPQTHSLQ greater than 99% through N-terminal sequencing analysis result, and is in full accord through theoretical design load.
IFN-SA is behind Lowry method determination of protein concentration in reorganization, with can be made into liquid drugs injection after 0.15MNaCL, 20mM phosphate buffered saline buffer (pH7.4) dilution and the sterile filtration; Add 2.5% N.F,USP MANNITOL after be lyophilized into white powder pin.Example 5
The antiviral activity of reorganization IFN-SA is measured
The mensuration of the antiviral specific activity of reorganization IFN-SA is used the political reform of Wish cytopathy, and challenge virus is VSV.Calculate its antiviral specific activity by standard method.With reference to the product recombinant interferon is the IFN-α 1a of Schering company and the composite type alpha interferon Infergen of Amgen company.The antiviral specific activity of Interferon, rabbit classification (IU/mg) IFN-SA 8.1 * 10
9IFN-α 1a 0.8 * 10
8Infergen 1.1 * 10
9More than be the mean value of three measurement results.
Description of drawings: Fig. 1: 8 sections complementary IFN-SA oligonucleotide fragments of synthetic go out the full gene fragment of IFN-SA cDNA of 530bp through the recurrence pcr amplification.IFN-SA gene fragment and PUC-18 plasmid are behind BamHI and HindIII double digestion, and agarose gel electrophoresis reclaims endonuclease bamhi.The gene fragment that big fragment that the PUC18 double digestion reclaims and IFN-SA double digestion reclaim links through the T4 ligase enzyme, and transformed into escherichia coli DH5 α filters out the recombinant plasmid that contains the IFN-SA exogenous genetic fragment in vain through orchid, called after PUC-IFN-SA.Confirm that through order-checking its IFN-SA gene order is consistent entirely with the sequence shell of design, be used for the PLK-IFN plasmid construction.Fig. 2: the 69bp Linker double chain DNA fragment of synthetic and PUC18 plasmid reclaim similar fragment behind EcoRI and BamHI double digestion.Binding is identical with the construction process of Fig. 1 with conversion, filters out in vain through orchid to contain the segmental recombinant plasmid called after of Linker external source PUC-LK.Fig. 3: PUC-LK and PUC-IFN-SA recombinant plasmid are used BamHI and HindIII double digestion respectively, reclaim the big fragment of PUC-LK and the small segment of PUC-IFN-SA, after the T4 ligase links, transformed into escherichia coli DH52.Cut evaluation and screening through enzyme and go out the recombinant plasmid that PUC-LK contains the IFN-SA foreign gene, called after PLK-IFN.This plasmid successfully links at the Linker of PUC-LK 5 ' end goes up the IFN-SA gene.Fig. 4: make up the IFN-SA fusion expression vector.PMAL-P2 is the efficient escherichia coli plasmid of amalgamation and expression that contains MBP (maltose binding protein) with born of the same parents' pericentral siphon formal representation.PLK-IFN and PMAL-P2 plasmid are used BamHI and HindIII double digestion respectively, big fragment that recovery PMAL-P2 enzyme is cut and the small segment of PLK-IFN, after the T4 ligase links, transformed into escherichia coli TOP10.Cut the recombinant plasmid called after PMAL-IFN that evaluation and screening goes out to contain the LK-IFN foreign gene through enzyme.Contain the recombination fusion protein of MBP-LK-IFN through the IPTG abduction delivering, expression amount is 12%, and molecular weight is 65000 dalton.
Claims (4)
- One, the human alpha interferon derivative of superstrong antiviral activity described in the present invention (IFN-SA) is made up of 171 amino acid, has following aminoacid sequence:g?s?g?g?g?c?d?l?p?q?t?h?s?l?g?n?r?r?a?l?i?l?l?a?q?m?r?r?i?s?p?f?s?c?l?k?d?r?hd?f?g?f?p?q?e?e?f?d?g?n?q?f?q?k?a?q?a?i?s?v?l?h?e?m?i?q?q?t?f?n?l?f?s?t?k?d?ss?a?a?w?d?e?s?l?l?e?k?f?y?t?e?l?y?q?q l?n?d l?e?a?c?v?i?q?e?v?g?v?e?e?t?p?lm?n?v?d?s?i?l?a?v?r?k?y?f?q?r?i?t?l?y?l?t?e?k?k?y?s?p?c?a?w?e?v?v?r?a?e?i?m?rs?f?s?l?s?t?n?l?q?e?r?l?r?r?k?d
- Two, the human alpha interferon derivative of reorganization superstrong antiviral activity is by artificial constructed corresponding gene order among the claim l, and recombinant expression vector obtains through conversion, fermentation and purifying.
- Three, the host cell of recombinant expression vector comprises intestinal bacteria, yeast and mammalian cell among the preparation method of the human alpha interferon derivative of the reorganization superstrong antiviral activity in the claim 2.
- Four, reorganization superstrong antiviral activity human alpha interferon derivative is characterized in that can be made into medicine among the present invention, adapts to treatment and prophylaxis of viral infections disease.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1313491C (en) * | 2005-08-09 | 2007-05-02 | 中国科学院微生物研究所 | Cat omega interferon and its coding gene and uses |
| CN102266550A (en) * | 2011-07-08 | 2011-12-07 | 北京凯因科技股份有限公司 | Polyethylene glycol-consensus interferon mutant injection |
| CN102327241A (en) * | 2011-10-20 | 2012-01-25 | 北京凯因科技股份有限公司 | Polyethylene glycol-integrated interferon variant freeze-dried preparation |
| CN102327242A (en) * | 2011-10-20 | 2012-01-25 | 北京凯因科技股份有限公司 | Polyethylene glycol-integrated interferon variant lyophilized preparation |
| WO2012055205A1 (en) * | 2010-10-25 | 2012-05-03 | 重庆富进生物医药有限公司 | Pegylated recombinant consensus interferon variant conjugate and preparation mehtod and uses thereof |
| CN103933577A (en) * | 2010-10-25 | 2014-07-23 | 北京凯因科技股份有限公司 | Preparation and application of recombinant interferon variant polyethylene glycol conjugate |
| RU2575796C2 (en) * | 2010-10-25 | 2016-02-20 | Бэйцзин Кавин Текнолоджи Шеар-Холдинг Ко., Лтд. | Pegylated recombinant consensus interferon version conjugate and preparation method and use thereof |
| CN109467597A (en) * | 2018-11-28 | 2019-03-15 | 深圳市利云德生物技术有限公司 | A kind of new forms of interferon and preparation method thereof, composition and purposes |
-
2001
- 2001-01-19 CN CN 01102915 patent/CN1281623C/en not_active Expired - Lifetime
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1313491C (en) * | 2005-08-09 | 2007-05-02 | 中国科学院微生物研究所 | Cat omega interferon and its coding gene and uses |
| RU2575796C2 (en) * | 2010-10-25 | 2016-02-20 | Бэйцзин Кавин Текнолоджи Шеар-Холдинг Ко., Лтд. | Pegylated recombinant consensus interferon version conjugate and preparation method and use thereof |
| WO2012055205A1 (en) * | 2010-10-25 | 2012-05-03 | 重庆富进生物医药有限公司 | Pegylated recombinant consensus interferon variant conjugate and preparation mehtod and uses thereof |
| CN102453089A (en) * | 2010-10-25 | 2012-05-16 | 重庆富进生物医药有限公司 | Preparation and application of recombinant consensus interferon mutant polyethylene glycol conjugate |
| CN102453089B (en) * | 2010-10-25 | 2014-06-04 | 北京凯因科技股份有限公司 | Preparation and application of recombinant consensus interferon mutant polyethylene glycol conjugate |
| CN103933577A (en) * | 2010-10-25 | 2014-07-23 | 北京凯因科技股份有限公司 | Preparation and application of recombinant interferon variant polyethylene glycol conjugate |
| RU2575796C9 (en) * | 2010-10-25 | 2016-07-20 | Бэйцзин Кавин Текнолоджи Шеар-Холдинг Ко., Лтд. | Pegylated recombinant consensus interferon version conjugate and preparation method and use thereof |
| CN102266550A (en) * | 2011-07-08 | 2011-12-07 | 北京凯因科技股份有限公司 | Polyethylene glycol-consensus interferon mutant injection |
| CN102327241A (en) * | 2011-10-20 | 2012-01-25 | 北京凯因科技股份有限公司 | Polyethylene glycol-integrated interferon variant freeze-dried preparation |
| CN102327242A (en) * | 2011-10-20 | 2012-01-25 | 北京凯因科技股份有限公司 | Polyethylene glycol-integrated interferon variant lyophilized preparation |
| CN102327242B (en) * | 2011-10-20 | 2015-07-15 | 北京凯因科技股份有限公司 | Polyethylene glycol-integrated interferon variant lyophilized preparation |
| CN109467597A (en) * | 2018-11-28 | 2019-03-15 | 深圳市利云德生物技术有限公司 | A kind of new forms of interferon and preparation method thereof, composition and purposes |
| CN109467597B (en) * | 2018-11-28 | 2021-02-26 | 深圳市利云德生物技术有限公司 | Novel interferon and preparation method, composition and application thereof |
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Free format text: CORRECT: ADDRESS; FROM: 400039 ZHANG YI, 6/F, TOWER J, NO. 70, KEYUAN 3RD STREET, SHIQIAOPU HIGH-TECH. ZONE, CHONGQING CITY TO: 100176 BUILDING 3, NO. 6, RONGJING EAST STREET, ECONOMIC AND TECHNOLOGICAL DEVELOPMENT ZONE, BEIJING |
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Effective date of registration: 20110510 Address after: 3 building, No. 6, Jingdong street, Beijing economic and Technological Development Zone, 100176 Patentee after: Beijing Kawin Technology Co., Ltd. Address before: Six, J building, No. 70, Third Street, 400039 Garden Road, Shiqiaopu hi tech Zone, Chongqing Zhang Yi Patentee before: Fujin Bio-Medicine Co., Ltd., Chongqing |
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Granted publication date: 20061025 |