CN1600856A - Method for constructing hybridoma cell line of heterogeneity of seereting human monoclonal antibody for anti hepatitis B - Google Patents
Method for constructing hybridoma cell line of heterogeneity of seereting human monoclonal antibody for anti hepatitis B Download PDFInfo
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- CN1600856A CN1600856A CN 03134618 CN03134618A CN1600856A CN 1600856 A CN1600856 A CN 1600856A CN 03134618 CN03134618 CN 03134618 CN 03134618 A CN03134618 A CN 03134618A CN 1600856 A CN1600856 A CN 1600856A
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Abstract
This invention provides a method for establishing hetero-hybrid tumor engineering cell sequence for producing human monoclonal antibody for anti-hepatitis B virus. The anti-HBs positive human splenic lymph cell (SL) is fused with mouse plasmacytoma sequence P3-X63/Ag8-653 cell. Limiting dilution method is used for cloning the positive antibody poro-hybrid-tumor cell to obtain hetero hybrid tumor engineering cell sequence which produces human monoclonal antibody for anti-hepatitis B virus, with stable and high product, rate. Said monoclonal antibody is proceeded with purification and cross-linkage with interferon to produce target prepn. of anti-hepatitis B virus human monoclonal antibody crosslinking with itnerferon, and passive immune prepn. for hepatitis B, and testing agent for hepatitis B.
Description
Technical field
The present invention relates to the construction process that a kind of xenogenesis hybridoma engineering cell is, especially relate to a kind of construction process of secreting the xenogenesis hybridoma cell line of anti-hepatitis b human monoclonal antibodies.
Background technology
Since the success of hybridoma technology development mouse monoclonal antibody, people have developed miscellaneous mouse monoclonal antibody, have obtained using widely, have formed huge hi-tech industry.Mouse monoclonal antibody owing to be foreign protein, can cause serious adverse effects, so be very limited as the intravital treatment preparation of people.Therefore, since the eighties in last century, the research of human monoclonal antibodies is subjected to the great attention of medical biotechnology circle, think that human monoclonal antibodies can tighten and improve the treatment to transmissible disease, and the human serum immunoglobulin is as a kind of treatment pattern, and historical urgency agrees with bringing into play the potentiality of human monoclonal antibodies strongly.
Because the research difficulty of human monoclonal antibodies is big, develop slowly relatively, but human monoclonal antibodies can be used for human body interior diagnosis, treatment and prevention to cancer, the various transmissible diseases due to the particularly various infectious agents.So, since the eighties in last century, the research of human monoclonal antibodies is surging day by day, has worldwide obtained large quantities of different types of human monoclonal antibodies to the beginning of the nineties in last century, and is particularly outstanding aspect the treatment of the diagnosis and treatment of malignant tumour and transmissible disease and prevention.1991, the European Economic Community has issued the file about " production of human monoclonal antibodies and quality control guide ", provide foundation for producing human monoclonal antibodies and quality control, file is emphasized end user's monoclonal antibody diagnosis in the human body, and treatment and preventing disease have great value.Domestic since last century the mid-80, the development human monoclonal antibodies success of several families is arranged successively, turn round and look at the human monoclonal antibodies of the poliovirus of Noah's ark as Chinese medical courses in general institute, the human monoclonal antibodies of the anti-epidemic haemorrhagic fever virus that the Cui Yun of The Fourth Military Medical University is prosperous, the human monoclonal antibodies of the anti-encephalitis b virus of the old uncle's power in institute of viruses, Beijing etc.
Currently develop human monoclonal antibodies development technically in the world and mainly show DNA recombinant technology development " humanized's antibody ", the domestic research of also carrying out this respect, but the monoclonal antibody (McAb) of gene engineering research development " humanized ", not perfect technically, also there is certain problem on antibody activity of developing and the affinity, simultaneously, no matter be not ideal in the engineering bacteria or the expression of engineering cell antagonist.
The research of anti-hepatitis B virus human monoclonal antibodies (anti-HBV hMcAb) is why important to be because it has huge application potential aspect the prevent and treat of hepatitis B and the diagnosis.As everyone knows, hepatitis B (HB) is in the world, particularly East Asia, South East Asia, South Asia and the Middle East one band wide-scale distribution popular disease, and China only, the carrier is about 1.3 hundred million, and HB patient about 30,000,000.The HB disease time is long, the chronicity tendency is arranged, there is sizable part patient to transfer chronic hepatitis, liver cirrhosis to, even transfer liver cancer to, very harmful to human beings'health, the patient who has not only loses most of work capacity, and treatment also will spend huge sums, add bad prognosis, its stress also is very important.
Summary of the invention
The purpose of this invention is to provide a kind of construction process of secreting the xenogenesis hybridoma engineering cell system of anti-hepatitis B virus human monoclonal antibodies.
The object of the present invention is achieved like this: this method may further comprise the steps:
(1), the preparation of anti--HBs (anti-hepatitis b surface antigen antibody) positive human splenic lymphocyte (SL): the blood chemical examination resists-the HBs positive before the spleen donor art, art intramuscular injection the last week Hepatitis B virus vaccine, through the surgical removal spleen, get the partial cortical tissue, homogenation of spleen tissue is isolated splenocyte, with RG (anteserum-less substrate) centrifuge washing 2 times, again with the RG SL that suspends, expect blue method of exclusion living cell counting with platform, it is standby to get desired number.
(2), mouse plasmoma clone P
3-X
63The preparation of/Ag8-653: with eugonic mouse plasmoma clone P
3-X
63/ Ag8-653 cell inoculation in RGS (training base) fully substratum, concentration 4 * 10
4Under the situation of/ml, cultivated 4 days, reach 1 * 10 at cell concn
6More than/the ml, vigor reaches 98%, the oncocyte of amount preparation on demand.
(3), the preparation of feeder cell: draw neck to put to death BALB/C mice, with 70% alcohol-pickled 3 minutes, cut a cross sections at the abdomen middle part, skin is drawn back to both sides, expose stomach wall as far as possible, inject 5mlRG with syringe to intraperitoneal, massage belly 1 minute is drawn back stoste again, and the every ml of Extract contains abdominal cavity cell more than 1,000,000 approximately, prepare the mouse peritoneal cell as required, expect blue method of exclusion counting with platform.
(4), the xenogenesis hybridoma merges technical process: will resist HBs positive human splenic lymphocyte (SL) and mouse plasmoma clone P
3-X
63The cell of/AG8-653 carries out cytogamy, from the 96 orifice plate hybridomas positive hole of growing, detects the positive hole of anti--HBs, through the positive hole of antagonist hybridoma cell clone.
(5), the clone of antibody positive hole xenogenesis hybridoma: after the fusion fused cell is added 96 orifice plates and cultivate, hybridoma is constantly bred, to merging the back 12-14 days, detect the positive hole of anti--HBs with ELISA, cell is grown, the cell of antibody titers Gao Kongzhong adopts limiting dilution assay to clone, the clone of 1 cell in every hole can carry out 3-4 time repeatedly, reach the antibody positive hole of culture plate 100%, this moment is mono-clonal China, and stable, can obtain stable yields, the secretion anti-hepatitis B virus human monoclonal antibodies xenogenesis hybridoma engineering cell system of high yield.
(6), to anti--HBs of xenogenesis hybridoma, affinity, cross reaction, growth and secretory antibody kinetics, karyotyping, cell growth stability, antibody-secreting stability, genetic stability, frozen and system's identification and analysis of recovering:
A, through ELISA calibrating, the xenogenesis hybridoma is all secreted IgM class hMcAb (human monoclonal antibodies), that be complementary with people μ chain is people " λ " light chain, i.e. μ (λ);
B, xenogenesis hybridoma excretory hMcAb have specificity, affinity to hepatitis B surface antigen(HBsAg) (HBsAg);
C, with other hepatitis B signs and some other viral no cross reactions;
D, karyotyping: the xenogenesis hybridoma contains mouse chromosome and human chromosome, contains people's No. 14, No. 22 and X chromosome;
E, the growth of xenogenesis hybridoma are stablized, and it is stable to produce antibody, and inheritance stability is more than 3 months;
F, frozen and recovery is good.
Advantage of the present invention is: the present invention is with anti-hepatitis b surface antigen antibody positive human splenic lymphocyte and mouse plasmoma clone P
3-X
63/ Ag8-653 cytogamy adopts the positive hole of limiting dilution assay clonal antibody hybridoma, the xenogenesis hybridoma cell line of the secretion anti-hepatitis B virus human monoclonal antibodies that can obtain giving stable high yields irrespective of drought or water logging.Utilizing anti-hepatitis B virus human monoclonal antibodies xenogenesis hybridoma engineering cell is excretory anti-hepatitis B virus monoclonal antibody, crosslinked with Interferon, rabbit after separation and purification, can be made into " the crosslinked Interferon, rabbit targeting preparation of anti-hepatitis B virus human monoclonal antibodies " of treatment hepatitis B and have " hepatitis B passive immunization preparation ", " the hepatitis B detection reagent " of immunization.
Description of drawings
Fig. 1 is that xenogenesis hybridoma of the present invention merges process flow sheet.
Fig. 2 is xenogenesis hybridoma engineering cell system's growth of the present invention and antibody secreted kinetics figure.
Fig. 3 is that cell strain of the present invention produces antibody stability observing figure as a result.
Embodiment
Embodiment
One, the preparation of various cells:
1, the preparation of anti--HBs positive human splenic lymphocyte (SL):
The spleen donor: man 45 years old, slow HB history is arranged, because of splenomegaly is in hospital, row spleen enucleation.The menses chemical examination resists-the HBs positive, pluck spleen art intramuscular injection the last week Hepatitis B virus vaccine, when spleen is taken out in operation, the aseptic immediately spleen cortex tissue of getting, homogenation of spleen tissue is isolated splenocyte, with RG (anteserum-less substrate) centrifuge washing 2 times, again with the RG SL that suspends, expect blue method of exclusion living cell counting with platform, it is standby to get desired number.
2, mouse plasmoma clone P
3-X
63The preparation of/AG8-653:
Get eugonic 653 cells, be seeded in RGS (perfect medium) substratum, in concentration 4 * 10
4Under the situation of/ml, cultivated 4 days.Reach 1 * 10 at cell concn
6More than/the ml, vigor reaches 98%, and amount is prepared oncocyte on demand.
3, the preparation of feeder cell:
Draw neck to put to death BALB/C mice, with 70% alcohol-pickled 3 minutes, the plate that is placed in the super clean bench covered, and cuts a cross sections in the middle part of abdomen, and skin is drawn back to both sides, exposes stomach wall as far as possible.Inject 5mlRG with syringe to intraperitoneal, massage belly 1 minute is drawn back stoste again, and the every ml of Extract contains abdominal cavity cell more than 1,000,000 approximately, prepares the mouse peritoneal cell as required, expects blue method of exclusion counting with platform.
Two, the xenogenesis hybridoma merges technical process:
1, the cytogamy setting has related parameter: SL:653=1 * 10
8: 5 * 10
7Fusogen PEG:MW=4000, PEG configuration concentration C=50% once merges consumption=0.7ml; Culture plate: 6 96 well culture plates, every hole 0.2ml training base, the cell count after merge in every hole: be as the criterion 1.66 * 10 with SL
5/ hole; Feeder cell: BALB/C mice abdominal cavity cell, 4 * 10
4/ hole is merged the back and was just cultivated with the HAT that contains 20% foetal calf serum (selecting the training base) training base the same day.
2, the xenogenesis hybridoma merges technical process:
Carry out cytogamy by technical process shown in Fig. 1 " the xenogenesis hybridoma merges technical process ".To resist HBs positive human splenic lymphocyte (SL) and mouse plasmoma clone P
3-X
63The cell of/AG8-653 carries out cytogamy, from the 96 orifice plate hybridomas positive hole of growing, detects the positive hole of anti--HBs.Through the positive hole of antagonist hybridoma cell clone, obtain the xenogenesis hybridoma cell line of high and stable yields.
Three, the clone of the positive hole of anti--HBs hybridoma
After the fusion fused cell is added 96 orifice plates and cultivate,, have part or all of culture hole just to have the cell clone growth if merge successfully, long have the hole of hybridoma to be called the positive hole of growth, hybridoma is constantly bred, and to merging the back 12-14 days, the positive porocyte of growing can reach 1-2 * 10
4/ hole, available ELISA detected in this hole supernatant nonreactive-HBs was arranged this moment, as detected the antibody positive hole, just cell was grown, and the cell in the high hole of antibody titers is cloned.
Adopt limiting dilution assay to clone, during the clone, clone 10 cells in average every hole for the first time, 5 cells in the every hole of 2 time clonings, 2 cells in the every hole of 3 time clonings, 1 cell in the every hole of 4 time clonings, the clone of 1 cell in every hole can carry out 3-4 time repeatedly.Reach the antibody positive hole of culture plate 100%, this moment is mono-clonalization, and stable.Stablize inadequately if cultivate for some time, can clone several times the secretion anti-hepatitis B virus human monoclonal antibodies xenogenesis hybridoma cell line that just can obtain to give stable high yields irrespective of drought or water logging again repeatedly.
Four, the system of anti-hepatitis B virus human monoclonal antibodies xenogenesis hybridoma engineering cell system identifies:
1, antagonism-HBs identifies:
A, through ELISA calibrating, the xenogenesis hybridoma cell line is all secreted IgM class hMcAb, that be complementary with people μ chain is people " λ " light chain, i.e. μ (λ);
B, xenogenesis hybridoma excretory hMcAb have specificity and affinity to HBsAg (hepatitis B surface antigen(HBsAg)).
2, with other hepatitis B signs and some other viral no cross reactions.(seeing Table 1)
ELISA measures xenogenesis hybridoma hMcAb and various antigenic reaction result table 1
| Antigen | Response intensity |
| Blood source HBsAg | +????+????+ |
| Recombinant HBsAg | +????+????+ |
| ??HBeAg | -????-????- |
| ??HBxAg | -????-????- |
| Simple blister virus I-type | -????-????- |
| Simple blister virus II type | -????-????- |
| Epstein-Barr virus | -????-????- |
| Cytomegalovirus | -????-????- |
| The blister stomatitis virus | -????-????- |
| Hepatitis A virus | -?????-???- |
| The hepatitis C virus recombinant antigen | -?????-???- |
3, growth of anti-hepatitis B virus human monoclonal antibodies xenogenesis hybridoma engineering cell system and antibody secreted kinetics are identified:
The growth of xenogenesis hybridoma engineering cell system has very clear and definite positive correlation (see figure 2) with antibody-secreting.
4, the karyotyping of xenogenesis hybridoma engineering cell system:
Xenogenesis hybridoma engineering cell is the karyomit(e) that cell contains two species, and mouse chromosome (majority, telocentric) is promptly arranged, and human chromosome (minority, metacentric) is also arranged.Illustrate that the hybrid cell that heterogenous cell hybridization produces is the heterokaryotype cell.What it produced is the people IgM monomer molecule of structural integrity, so its karyomit(e) must contain people's 14,22 and X chromosome.
5, the stability of hybridoma cell line growth is identified:
The growing ability of hybridoma cell line is strong, and it is stable to go down to posterity, at the inoculum density 4 * 10 that goes down to posterity
4/ ml, cultured continuously 4 days, cell count should reach 1 * 10
6More than/the ml.
6, the xenogenesis hybridoma cell line produces the evaluation of antibody stability:
Continuous passage is cultivated, and measures its culture supernatant antibody ELISA OD value by phased manner, observes continuously more than 3～May, and it should be stable (see figure 3) that hybridoma produces antibody.
7, xenogenesis hybridoma genetic stability is identified:
When the xenogenesis hybridoma was cloned, the antibody positive clone kept 100%, and clone's time should remain on more than three months.
8, the ELISA of the anti-HBV hMcAb of culture supernatant tires 1.5 * 2
12More than.
9, engineering cell frozen, recovery is good, disposes frozen storing liquid (frozen storing liquid ratio: methyl-sulphoxide: foetal calf serum: anteserum-less substrate=1: 3: 6) by 4 * 10 as required
6/ ml suspension cell is pressed the amount packing glass ampoule of 1ml, seals rear overhang in liquid N
2Face last 2 hour, sink to liquid N again
2In frozen.Recovery in frozen 5 years is good, and viable cell is more than 70%, through the cultivation of going down to posterity, and growing ability and antibody-secreting function no change.
Claims (7)
1, a kind of construction process of secreting the xenogenesis hybridoma engineering cell system of anti-hepatitis B virus human monoclonal antibodies, it is characterized in that: this method may further comprise the steps:
(1), the preparation of anti--HBs (anti-hepatitis b surface antigen antibody) positive human splenic lymphocyte (SL);
(2), mouse plasmoma clone P
3-X
63The preparation of/Ag8-653;
(3), the preparation of feeder cell;
(4), the xenogenesis hybridoma merges technical process;
(5), the clone of antibody positive hole xenogenesis hybridoma;
(6), to anti--HBs of xenogenesis hybridoma, affinity, cross reaction, growth and secretory antibody kinetics, karyotyping, cell growth stability, antibody-secreting stability, genetic stability, frozen and system's identification and analysis of recovering.
2, according to claims 1 described method, it is characterized in that: described step (1) is anti--and the preparation of HBs positive human splenic lymphocyte (SL) is meant:
The blood chemical examination resists-the HBs positive before the spleen donor art, art intramuscular injection the last week Hepatitis B virus vaccine, through the surgical removal spleen, get the partial cortical tissue, homogenation of spleen tissue is isolated splenocyte, with RG (anteserum-less substrate) centrifuge washing 2 times, again with the RG SL that suspends, expect blue method of exclusion living cell counting with platform, it is standby to get desired number.
3, according to claims 1 described method, it is characterized in that: described step (2) mouse plasmoma clone P
3-X
63The preparation of/Ag8-653 is meant: with eugonic mouse plasmoma clone P
3-X
63/ Ag8-653 cell inoculation in RGS (training base) fully substratum, concentration 4 * 10
4Under the situation of/ml, cultivated 4 days, reach 1 * 10 at cell concn
6More than/the ml, vigor reaches 98%, the oncocyte of amount preparation on demand.
4, according to claims 1 described method, it is characterized in that: the preparation of described step (3) feeder cell is meant: draw neck to put to death BALB/C mice, with 70% alcohol-pickled 3 minutes, cut a cross sections in the middle part of abdomen, skin is drawn back to both sides, expose stomach wall as far as possible, inject 5mlRG to intraperitoneal, massage belly 1 minute with syringe, again stoste is drawn back, the every ml of Extract contains abdominal cavity cell more than 1,000,000 approximately, prepares the mouse peritoneal cell as required, expects blue method of exclusion counting with platform.
5, according to claims 1 described method, it is characterized in that: described step (4) xenogenesis hybridoma merges technical process and is meant: will resist HBs positive human splenic lymphocyte (SL) and mouse plasmoma clone P
3-X
63The cell of/AG8-653 carries out cytogamy, from the 96 orifice plate hybridomas positive hole of growing, detects the positive hole of anti--HBs, through the positive hole of antagonist hybridoma cell clone.
6, according to claims 1 described method, it is characterized in that: the clone of described step (5) antibody positive hole xenogenesis hybridoma is meant: after the fusion fused cell is added 96 orifice plates and cultivate, hybridoma is constantly bred, to merging the back 12-14 days, detect the positive hole of anti--HBs with ELISA, cell is grown, the cell of antibody titers Gao Kongzhong adopts limiting dilution assay to clone, the clone of 1 cell in every hole can carry out 3-4 time repeatedly, reach the antibody positive hole of culture plate 100%, this moment is mono-clonal China, and stable, can obtain stable yields, the secretion anti-hepatitis B virus human monoclonal antibodies xenogenesis hybridoma engineering cell system of high yield.
7, according to claims 1 described method, it is characterized in that: described step (6) is to anti--HBs, affinity, cross reaction, growth and secretory antibody kinetics, karyotyping, cell growth stability, antibody-secreting stability, the genetic stability of xenogenesis hybridoma, and frozen system's identification and analysis with recovery is meant:
A, through ELISA calibrating, the xenogenesis hybridoma is all secreted IgM class hMcAb (human monoclonal antibodies), that be complementary with people μ chain is people " λ " light chain, i.e. μ (λ);
B, xenogenesis hybridoma excretory hMcAb have specificity, affinity to hepatitis B surface antigen(HBsAg) (HBsAg);
C, with other hepatitis B signs and some other viral no cross reactions;
D, karyotyping: the xenogenesis hybridoma contains mouse chromosome and human chromosome, contains people's No. 14, No. 22 and X chromosome;
E, the growth of xenogenesis hybridoma are stablized, and it is stable to produce antibody, and inheritance stability is more than 3 months;
F, frozen and recovery is good.
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Cited By (5)
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| CN102321720A (en) * | 2011-07-28 | 2012-01-18 | 万晓春 | Method for producing pure human-derived monoclonal antibody by mixed cell culture |
| CN104152415A (en) * | 2014-08-13 | 2014-11-19 | 百泰生物药业有限公司 | Method for acquiring myeloma cell strain with high yield and stable expression of recombinant antibody and application thereof |
| CN104487090A (en) * | 2012-07-10 | 2015-04-01 | 株式会社绿十字 | An antibody composition for prevention or treatment of mutant hepatitis B virus infection |
| CN107556381A (en) * | 2017-10-12 | 2018-01-09 | 南京京达生物技术有限公司 | A kind of hepatitis B virus surface antigen detection antibody IgM and application |
| KR20180012245A (en) * | 2015-03-25 | 2018-02-05 | 아이쥐엠 바이오사이언스 인코포레이티드 | A multivalent hepatitis B virus antigen binding molecule and its use |
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2003
- 2003-09-26 CN CN 03134618 patent/CN1600856A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102321720A (en) * | 2011-07-28 | 2012-01-18 | 万晓春 | Method for producing pure human-derived monoclonal antibody by mixed cell culture |
| CN102321720B (en) * | 2011-07-28 | 2014-09-03 | 万晓春 | Method for producing pure human-derived monoclonal antibody by mixed cell culture |
| US9683029B2 (en) | 2012-07-10 | 2017-06-20 | Green Cross Corporation | Antibody composition for prevention or treatment of mutant hepatitis B virus infection |
| CN104487090A (en) * | 2012-07-10 | 2015-04-01 | 株式会社绿十字 | An antibody composition for prevention or treatment of mutant hepatitis B virus infection |
| CN104487090B (en) * | 2012-07-10 | 2017-06-16 | 株式会社绿十字 | A kind of antibody compositions hepatitis b virus infected for preventing or treating saltant type |
| CN104152415B (en) * | 2014-08-13 | 2015-09-30 | 百泰生物药业有限公司 | Obtain method and the application of the myeloma cell strain of high and stable yields expressing recombinant antibody |
| CN104152415A (en) * | 2014-08-13 | 2014-11-19 | 百泰生物药业有限公司 | Method for acquiring myeloma cell strain with high yield and stable expression of recombinant antibody and application thereof |
| KR20180012245A (en) * | 2015-03-25 | 2018-02-05 | 아이쥐엠 바이오사이언스 인코포레이티드 | A multivalent hepatitis B virus antigen binding molecule and its use |
| CN107921285A (en) * | 2015-03-25 | 2018-04-17 | Igm生物科学股份有限公司 | Multivalence hepatitis B virus antigen binding molecule and its application |
| JP2018513680A (en) * | 2015-03-25 | 2018-05-31 | アイジーエム バイオサイエンシズ エー／エス | Multivalent hepatitis B virus antigen binding molecule and use thereof |
| CN107921285B (en) * | 2015-03-25 | 2022-06-07 | Igm生物科学股份有限公司 | Multivalent hepatitis b virus antigen binding molecules and uses thereof |
| US11535664B2 (en) | 2015-03-25 | 2022-12-27 | Igm Biosciences, Inc. | Multi-valent hepatitis B virus antigen binding molecules and uses thereof |
| KR102558839B1 (en) * | 2015-03-25 | 2023-07-25 | 아이쥐엠 바이오사이언스 인코포레이티드 | Multivalent hepatitis B virus antigen-binding molecules and uses thereof |
| CN107556381A (en) * | 2017-10-12 | 2018-01-09 | 南京京达生物技术有限公司 | A kind of hepatitis B virus surface antigen detection antibody IgM and application |
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