CN108341877B - Activated blood coagulation factor V resistant monoclonal antibody and preparation method and application thereof - Google Patents
Activated blood coagulation factor V resistant monoclonal antibody and preparation method and application thereof Download PDFInfo
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- CN108341877B CN108341877B CN201710050407.9A CN201710050407A CN108341877B CN 108341877 B CN108341877 B CN 108341877B CN 201710050407 A CN201710050407 A CN 201710050407A CN 108341877 B CN108341877 B CN 108341877B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/36—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/745—Assays involving non-enzymic blood coagulation factors
- G01N2333/7456—Factor V
Abstract
The invention discloses an activated blood coagulation factor V resistant monoclonal antibody, which is characterized in that: the amino acid sequence of the light chain is shown as SEQ ID NO: 3, the amino acid sequence of the heavy chain is shown as SEQ ID NO: 4, respectively. The invention also discloses a preparation method and application of the monoclonal monomer. The monoclonal antibody of the activated blood coagulation factor V has strong binding capacity with the activated blood coagulation factor V, and can be used for detecting the activated blood coagulation factor V.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to an anti-activated blood coagulation factor V monoclonal antibody, and a preparation method and application thereof.
Background
Coagulation Factor V (FV) is a single-chain glycoprotein with a molecular weight of 333KD, and is present in plasma in a physiologically almost inactive state. Plasma FV is converted by the action of thrombin into activated coagulation factor V (FVa) having a clotting activity. FVa in plasma is an important cofactor in the coagulation process, and has a crucial regulation effect on the coagulation process, and the mechanism is shown in fig. 1. In the process of blood coagulation, FVa, FXa, calcium ions and phospholipid form a prothrombin complex together, and the activation efficiency of prothrombin can be increased by 30 ten thousand times. FVa in turn can be inactivated by cleavage of Activated Protein C (APC), thereby participating directly or indirectly in the coagulation process via the APC pathway. In conclusion, FVa is at the intersection of the procoagulant and anticoagulant pathways during coagulation and plays a critical role in maintaining the coagulation balance.
FV not only has an important role in blood coagulation balance, but also has correlation between plasma FV content and FV activity and occurrence of diseases. Research shows that in vivo FV abnormality can cause hereditary FV deficiency disease and cause hemorrhage according to different production mechanisms; or results in Activated Protein C Resistance (APCR), causing thrombosis. In addition, measurement of the activity of plasma coagulation factor V can be used as a useful index for judging the state of severe hepatitis and observing the prognosis thereof.
However, an effective method for quantitatively detecting activated FV is still lacked at present, and the development of an anti-activated FV monoclonal antibody has great significance for establishing an FVa activity detection method with strong specificity and high sensitivity so as to assist in diagnosing FV abnormal diseases. At present, no report on the preparation of monoclonal antibodies against activated FV exists.
Disclosure of Invention
The invention aims to provide an anti-activated blood coagulation factor V monoclonal antibody.
The amino acid sequence of the light chain variable region of the monoclonal antibody of the invention is shown in SEQ ID NO: 3, the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO: 4, respectively.
The invention codes the gene fragment of the monoclonal antibody, and the nucleotide sequence of the light chain variable region of the gene fragment is shown as SEQ ID NO: 1, and the nucleotide sequence of the heavy chain variable region of the polypeptide is SEQ ID NO: 2, respectively.
The recombinant vector of the invention contains the gene segment. Wherein the vector is a recombinant pcDNA3.1/ZEO (+) vector.
The transgenic cell of the present invention, which contains the aforementioned recombinant vector. Wherein the transgenic cell is a transgenic CHO-K1 cell.
The method for preparing the monoclonal antibody is characterized by comprising the following steps: the method comprises the following steps:
(1) taking the transgenic cell and culturing;
(2) and taking the supernatant of the culture solution, and purifying to obtain the culture solution.
Wherein the purification method adopts Hi Trap Protein A affinity chromatography column chromatography for purification.
The invention also provides application of the monoclonal antibody in preparing a reagent for detecting the activated blood coagulation factor V.
The activated blood coagulation factor V resistant monoclonal antibody prepared by the invention has high affinity to FVa antigen, has strong specificity when being used for separating, purifying and detecting humanized FVa, can be used as a reagent for detecting the activated blood coagulation factor V, is used for detecting the activated blood coagulation factor V, and has good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a graph showing the result of detecting phage affinity by ELISA method.
FIG. 2 is a graph showing the affinity of the resulting purified monoclonal antibody by gradient concentration by ELISA method.
Detailed Description
The following examples are further illustrative, but the present invention is not limited to these examples.
EXAMPLE 1 preparation of monoclonal antibody against activated FV according to the invention
Screening of fully human FVa single-chain antibody from phage antibody library
The fully human phage antibody library was screened using FVa recombinant protein (product of HTI corporation) as an antigen. FVa antigen was diluted to 10ug/mL with coating diluent (0.05mol/L sodium carbonate-sodium bicarbonate, pH 9.6), 100ul was added to each well of the ELISA plate, and the plate was coated overnight in a refrigerator at 4 ℃. The blocking solution was prepared by mixing PBST (PBS, 0.05% Tween 20) and 1% BSA, adding 200ul per well, and blocking for 1 hour. PBST was washed 5 times for 3min each, and a fully human Fab-based phage display library (derived from the phage display library of Shanghai Boyu Biotech) was added and incubated overnight at room temperature. Discard the plate, wash 5 times with PBST for 3min each, elute phage bound tightly to FVa antigen with eluent (50mM HCl, 500mM NaCl) for 30min, neutralize the eluent with equal volume of 1M Tris base. Coli XL-1Blue strain and helper phage were added and incubated overnight to enrich for specific phage with affinity for FVa. This screening process was repeated twice.
And (3) detecting the affinity of the phage by an ELISA method, and selecting the top 10 phage with the strongest affinity.
ELISA method: FVa antigen was diluted to 1ug/mL with coating diluent, 100ul of diluted antigen was added to each well of ELISA plate, and the plate was placed in a 4 ℃ freezer overnight. 150ul of blocking solution was added to each well, and the mixture was sealed at 37 ℃ for 40 min. 200ul of washing solution was added to each well and washed 3 times, each for 3 min. Adding the monoclonal recombinant phage to be detected, and incubating for 2h at 37 ℃. Washing with washing solution for 3 times, each for 3 min. Adding sheep anti-human-HRP (dilution ratio 1:2000) working solution, incubating at 37 deg.C for 1h, adding 200ul washing solution per well, and washing for 3 times, each time for 3 min. 100ul of the temporarily prepared TMB substrate solution was added to each reaction well, and incubated at 37 ℃ for 20 min. Adding 50ul of 2M sulfuric acid into each reaction hole, stopping the reaction, and measuring the OD value by using an enzyme-labeling instrument at the wavelength of 450 nm.
The ELISA assay results are shown in FIG. 1, and the OD of 131 samples450nmAll values were greater than 0.6, of which 57 samples had OD450nmGreater than 2; while only 61 sample ODs450nmThe value is less than 0.6, namely the 131 phage monoclonal antibodies and the FVa antigen generally have higher positive binding rate, and 57 sample antigens are strongly positive in binding; 61 samples were negative for antigen binding.
Second, construct eukaryotic expression vector
Selecting the first 10 kinds of bacteriophage with strongest affinity competition, adding primer and PCR amplification of variable region V with plasmid gene as templateLA gene; followed by human antibody VLAnd CLAmplifying an L chain gene serving as a template, and cloning the L chain gene into an LPG3 vector;
using bacteriophage monoclonal antibody DNA as template, adding primer, PCR amplifying to obtain VHGene, cloned into LPG4 vector; and adding primer by using human-derived cDNA as template to amplify CHRegion genes, cloned into the LPG4 vector.
Through screening, the nucleotide sequence (SEQ ID NO.1) of the variable region of the light chain and the nucleotide (SEQ ID NO.2) of the variable region of the heavy chain of the antibody 1C11 are expressed.
The nucleotide sequence of the light chain of the antibody (the nucleotide sequence of the variable region is SEQ ID NO.1) is taken and connected to a plasmid pcDNA3.1/ZEO (+) (product of Invitrogen company) by a double enzyme digestion mode of Hind III and EcoRI to construct a eukaryotic expression vector.
The heavy chain nucleotide sequence of the antibody (the nucleotide sequence of the variable region is SEQ ID NO.2) is taken and connected to a plasmid pcDNA3.1/ZEO (+) (product of Invitrogen company) by a double enzyme digestion mode of Hind III and EcoRI to construct a eukaryotic expression vector.
Through verification, the invention constructs a fully human eukaryotic expression vector containing a fragment shown in SEQ ID NO.1 or SEQ ID NO. 2.
The light chain nucleotide sequence consists of a sequence of SEQ ID NO.1 and a sequence of a constant region, the heavy chain nucleotide sequence consists of a sequence of SEQ ID NO.2 and a sequence of a constant region, the sequences can be directly synthesized and then added into pcDNA3.1/ZEO (+) to form a recombinant eukaryotic expression vector.
Expression and purification of antibodies
Chinese hamster ovary cells (CHO cells) accurately and less secrete endogenous proteins when expressing fully human antibodies, so the CHO cells are used as expression vectors of monoclonal antibodies in the invention.
3×105CHO-k1 cells were seeded in a tissue culture dish, and transfection was started when the cells were cultured to 85% confluency in a general DMEM medium (product of GIBCO Co.) [ method of transfection: mix 3x105CHO-K1 cells were seeded into 3.5cm tissue culture dishes and transfected when the cells reached 90% -95%, the transfection procedure was: the recombinant plasmid 10ug constructed above was transfected with Lipofectamine2000Reagent kit (Invitrogen) according to the instructions at 37 ℃ with 5% CO2After 24h incubation in the incubator, the selection medium was changed to 600ug/ml G418(Invitrogen corporation)) And 250ug/ml of a DMEM medium containing Zeocin (Invitrogen); after the continuous amplification culture, the culture broth was purified by Hi Trap Protein A affinity column (product of GE Co.) and eluted with 0.1M sodium acetate (pH 3.0) to obtain purified monoclonal antibody 1C11 of the present invention.
Through sequencing, the amino acid sequence of the variable region of the light chain of the monoclonal antibody 1C11 is shown as SEQ ID NO.3, and the amino acid sequence of the variable region of the heavy chain is shown as SEQ ID NO. 4.
The beneficial effects of the invention are illustrated by way of experimental examples as follows:
experimental example 1 measurement of antigen binding Activity of monoclonal antibody of the present invention
1. Experimental methods
The purified monoclonal antibody 1C11 prepared in example 1 was subjected to affinity detection with gradient concentration by ELISA method.
ELISA method: FVa antigen was diluted to 1ug/mL with coating diluent, 100ul of diluted antigen was added to each well of ELISA plate, and the plate was placed in a 4 ℃ freezer overnight. 150ul of blocking solution was added to each well, and the mixture was sealed at 37 ℃ for 40 min. 200ul of washing solution was added to each well and washed 3 times, each for 3 min. Adding the monoclonal recombinant phage to be detected, and incubating for 2h at 37 ℃. Washing with washing solution for 3 times, each for 3 min. Adding sheep anti-human-HRP (dilution ratio 1:2000) working solution, incubating at 37 deg.C for 1h, adding 200ul washing solution per well, and washing for 3 times, each time for 3 min. 100ul of the temporarily prepared TMB substrate solution was added to each reaction well, and incubated at 37 ℃ for 20 min. Adding 50ul of 2M sulfuric acid into each reaction hole, stopping the reaction, and measuring the OD value by using an enzyme-labeling instrument at the wavelength of 450 nm.
2. Results of the experiment
The results are shown in FIG. 2.
As can be seen from FIG. 2, the monoclonal antibody 1C11 of the present invention has very strong binding activity to the antigen of activated blood coagulation factor V (FVa), and has an EC50 value of 0.03732.
In FIG. 2, the remaining 4 antibodies, such as 2H11, were also selected using the screening method in phage antibody library, but their binding activity was significantly lower than that of the monoclonal antibody 1C11 of the present invention.
In conclusion, the activated blood coagulation factor V resisting monoclonal antibody has high affinity to human FVa antigen; in addition, the preparation method of the fully human FV-resistant monoclonal antibody is simple, can be suitable for large-scale production and has good application prospect.
SEQUENCE LISTING
<110> Wu, Jianbo
Poplar and swallow
<120> monoclonal antibody against activated blood coagulation factor V, preparation method and application thereof
<130> GY421-17P1042
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 336
<212> DNA
<213> nucleotide sequence of light chain variable region (VL)
<400> 1
gatattgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca ggcggcctcc 60
atctcctgca ggtctagtca aagcctcgta tacagtgatg gaaacaccta cttgaattgg 120
tttcagcaga ggccaggcca atctccaagg cgcctaattt ataaggtttc taaccgggac 180
tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgaattcac actgagagtc 240
agcagggtgg aggctgagga tgttggtgtt tattactgca tgcaagctac acactggcct 300
ccgacgttcg gccaagggac cagggtggaa atcaaa 336
<210> 2
<211> 351
<212> DNA
<213> nucleotide sequence of heavy chain variable region (VH)
<400> 2
caggtccagc tggtgcagtc tggagcagag gtgaaaaagc ccggggagtc tctgaagatc 60
tcctgtaagg gttctggata tagctttacc acctactgga tcgcctgggt gcgccagatg 120
cccgggaaag gcctggagtg gatggggatc atctatcctg gtgactctga taccagatac 180
agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag aaccgcctac 240
ctgcagtgga gcagcctgaa ggactcggac accgccatgt attactgtgc gagacttgat 300
gtctacggtc tggacgtctg gggccaaggg accacggtca ccgtctcctc a 351
<210> 3
<211> 112
<212> PRT
<213> amino acid sequence of light chain variable region
<400> 3
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Ala Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Arg Val
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Thr His Trp Pro Pro Thr Phe Gly Gln Gly Thr Arg Val Glu Ile Lys
100 105 110
<210> 4
<211> 117
<212> PRT
<213> amino acid sequence of heavy chain variable region (VH)
<400> 4
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr
20 25 30
Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Arg Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Asp Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Leu Asp Val Tyr Gly Leu Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
Claims (9)
1. An anti-activated coagulation factor V monoclonal antibody characterized by: the amino acid sequence of the light chain variable region is shown as SEQ ID NO: 3, the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO: 4, respectively.
2. A gene fragment encoding the monoclonal antibody of claim 1, characterized in that: the nucleotide sequence of the light chain variable region is shown as SEQ ID NO: 1, and the nucleotide sequence of the heavy chain variable region of the polypeptide is SEQ ID NO: 2, respectively.
3. A recombinant vector characterized by: it contains the gene fragment of claim 2.
4. The recombinant vector according to claim 3, wherein: the vector is a recombinant pcDNA3.1/ZEO (+) vector.
5. A transgenic cell, characterized by: comprising the recombinant vector of claim 3 or 4.
6. The transgenic cell of claim 5, characterized in that: the transgenic cells were transgenic CHO-K1 cells.
7. A method of producing the monoclonal antibody of claim 1, characterized by: the method comprises the following steps:
(1) culturing the transgenic cell of claim 5 or 6;
(2) and taking the supernatant of the culture solution, and purifying to obtain the culture solution.
8. The method of claim 7, wherein: in the step (2), the purification method adopts Hi Trap Protein A affinity chromatography column chromatography for purification.
9. Use of the monoclonal antibody of claim 1 or 2 for the preparation of a reagent for the detection of activated coagulation factor V.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0670792A (en) * | 1992-08-25 | 1994-03-15 | Tosoh Corp | Monoclonal antibody reactive with protein recognizing phosphatidyl serine |
| WO2008067056A2 (en) * | 2006-10-16 | 2008-06-05 | Novelmed Therapeutics, Inc. | Method of inhibiting coagulation with human anti-factor va antibodies and use thereof |
| CN104203980A (en) * | 2012-02-22 | 2014-12-10 | 瑞泽恩制药公司 | Anti-big-endothelin-1 (big-et-1) antibodies and uses thereof |
-
2017
- 2017-01-23 CN CN201710050407.9A patent/CN108341877B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0670792A (en) * | 1992-08-25 | 1994-03-15 | Tosoh Corp | Monoclonal antibody reactive with protein recognizing phosphatidyl serine |
| WO2008067056A2 (en) * | 2006-10-16 | 2008-06-05 | Novelmed Therapeutics, Inc. | Method of inhibiting coagulation with human anti-factor va antibodies and use thereof |
| CN104203980A (en) * | 2012-02-22 | 2014-12-10 | 瑞泽恩制药公司 | Anti-big-endothelin-1 (big-et-1) antibodies and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| 人血浆凝血因子V双抗体夹心ELISA测定;谢飞等;《上海医学检验杂志》;20020630(第3期);137-139 * |
| 人血浆凝血因子V的纯化和单克隆抗体细胞株的建立;柳胜华;《中国优秀硕士学位论文全文数据库》;20111215;全文 * |
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