CN109942717A - A kind of long-acting recombinant human follicle-stimulating hormone (FSH) and its preparation method and application - Google Patents
A kind of long-acting recombinant human follicle-stimulating hormone (FSH) and its preparation method and application Download PDFInfo
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- CN109942717A CN109942717A CN201910334484.6A CN201910334484A CN109942717A CN 109942717 A CN109942717 A CN 109942717A CN 201910334484 A CN201910334484 A CN 201910334484A CN 109942717 A CN109942717 A CN 109942717A
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Abstract
The invention proposes a kind of recombination hFSH-Fc fusion protein, the fusion protein is dimeric fusion protein, and one of single amino acid sequence is followed successively by hFSH β subunit, CTP, CTP and hFSH α subunit from N-terminal to C-terminal；Another single amino acid sequence is followed successively by CTP, hFSH α subunit, hFSH β subunit and CTP from N-terminal to C-terminal.Two CTP are connected on the coded sequence of FSH by the present invention, are avoided the region combined to receptor or bioactivity is important, are not influenced receptor binding affinity, are not had immunogenicity, can significantly be extended volume lifetime.Meanwhile the half-life period of FSH-CTP in vivo is longer, end-stage half-life period is 2-3 times of reorganization FSH-WT, and can be weekly to inject instead of injecting 7 times a day, and bioactivity is higher.
Description
Technical field
The present invention relates to biomedicine technical fields, and in particular to a kind of long-acting recombinant human follicle-stimulating hormone (FSH).
Background technique
Currently, infertility rate is up to 15% in world wide, becomes except cancer and cardiovascular and cerebrovascular disease, seriously affect
The third-largest disease of human health.China's infertility number accounts for 10% or more reproduction number of women, and its disease incidence is on obvious
The trend of liter.Human follicle-stimulating element (Human follicle-stimulating hormone, abbreviation hFSH) is that existing market is common
For treating the main ingredient of male and female infertility drug.
Human follicle-stimulating element (Human Follicle-stimulating hormone, abbreviation hFSH) is one kind by pituitary
The promoting sexual gland hormone of anterior secrets is necessary to male and female normal reproductive function.Follicular stimulating hormone and luteotropin
(LH), human chorionic gonadotropin (hCG), thyroid-stimulating hormone (TSH) collectively constitute glycoprotein hormones family.These hormones
To be formed by two subunits, α and β, α subunit be it is universal, β subunit is specific.Follicle-stimulating hormone (FSH) is used clinically for stimulating
Folliculus ovarii development progress is in vitro fertilization, to obtain more egg mother cells.In male, FSH is found to adjusting and maintains
Spermiogenesis tail process is most important.After using FSH, rear sperm ultrastrueture and locomitivity are obviously improved.Follicle-stimulating hormone it
Purifying is for clinic in the preceding urine from elderly woman.However identification FSH β and α gene enables DNA technique dynamic in lactation
Reorganization FSH is generated in object cell and is mankind's use.
Since the half-life period of FSH is relatively short, it is injected daily in the past.Therefore, it is necessary to develop long-acting heavy
Group FSH (rhFSH), to reduce administration number of times.In order to overcome this problem, other researchers describe a kind of increase rhFSH
The method of half-life period introduces the chain glycosylation site of new n- by site directed mutation.The result shows that the addition chain carbon of n-
Hydrate chain has no effect on the folding of hormone or the binding affinity with receptor, meanwhile, increase the half-life period of animal model
And in vivo bioactivity.But this strategy may change the structure of FSH, and triggering immune response in vivo.These are similar
Object is not detected in clinical studies, and immunogenicity spectrum is unclear.
Summary of the invention
In order to solve the above technical problems, the present invention provides a kind of long-acting recombinant human follicle-stimulating hormone (FSH) and preparation method thereof
And application, it is intended that a kind of long-acting recombinant human follicle-stimulating hormone (FSH) is provided, by that will include 4 O-linked oligosaccharides sites
CTP peptide be connected to the coded sequence of FSH subunit, this structure and alpha subunit co-transfection are arrived with mammalian expression vector
In Chinese hamster ovary cell (CHO), generate dimer recombinant hormone, this combine the folding to the assembling of subunit, protein, by
Body binding affinity and Bioactivity are without influence.
The present invention provides a kind of recombination hFSH-Fc fusion protein, and the fusion protein is dimeric fusion protein, wherein one
A single amino acid sequence is followed successively by hFSH β subunit, CTP, CTP and hFSH α subunit from N-terminal to C-terminal；Another single amino acid
Sequence is followed successively by CTP, hFSH α subunit, hFSH β subunit and CTP from N-terminal to C-terminal；
The amino acid sequence of the hFSH β subunit is as shown in SEQ ID NO:1；The amino acid sequence of the CTP such as SEQ
Shown in ID NO:2；The amino acid sequence of the hFSH α subunit is as shown in SEQ ID NO:3.
The present invention further protects a kind of preparation method of above-mentioned recombination hFSH-Fc fusion protein, comprising: poly- using overlapping
The mosaic gene of synthase chain reaction building CTP sequence and FSH β subunit；Mosaic gene is cloned into containing LTR/CMV promoter
In carrier for expression of eukaryon；The carrier in combination of the subunit of α containing FSH of building and FSH β subunit is transfected into Chinese hamster ovary cell
In, filter out the cell strain for stablizing expression；The FSH variant in the culture medium for carrying out the cell strain of self-stabilization expression is collected, and pure
Change obtains recombination hFSH fusion protein
As further improvement of the invention, the building of the mosaic gene includes the following steps: that S1. constructs FSH β-
CTP；S2. FSH β (CTP) 2 is constructed；The building of S3.CTP- α mosaic gene.
As further improvement of the invention, step S1's includes the following steps:
(1) using FSH β gene as the template of primer 1 and primer 2, wherein primer 1 includes the FSH β of a restriction site
5 ' terminal sequences, primer 2 include rear 4 base codes of preceding 4 base codes of CTP and 3 ' ends of FSH β sequence；
(2) template of the hCG β-CTP gene as primer 3 and primer 4 is used, wherein primer 3 is held comprising FSH β sequence 3 '
Rear 4 base codes and CTP sequence first four base code, primer 4 include CTP sequence 3 ' hold 4 base codes and a restriction site.
(3) for reacting the DNA profiling of No. 1 and No. 2, it is used as the template of primer 1 and 4, to amplify FSH β-CTP.
As further improvement of the invention, specific step is as follows by step S2:
(1) use FSH β gene as the template of primer 1 and primer 2, wherein primer 1 includes the FSH of a restriction site
5 ' terminal sequence of β, primer 2 include rear 4 base codes of preceding 4 base codes of CTP and 3 ' ends of FSH β CTP sequence；
(2) template of the hCG β-CTP gene as primer 3 and primer 4 is used, wherein primer 3 contains FSH β-CTP sequence
Rear 4 base codes at 3 ' ends and preceding 4 base codes of CTP sequence, primer 4 contain the 4 base codes and an agretope that CTP sequence 3 ' is held
Point；
(3) it is used in the DNA profiling of reaction No. 1 and No. 2, as the template of primer 1 and 4, to amplify FSH β-(CTP) 2.
As further improvement of the invention, specific step is as follows by step S3:
(1) use hCG β gene as the template of primer hCG β 1 and 2, wherein primer 1 includes the CTP of a restriction site
5 ' terminal sequences, primer 2 include alpha subunit preceding 4 base codes and CTP sequence 3 ' hold rear 4 base codes；
(2) use α gene as the template of primer 3 and primer 4, wherein rear 43 ' end groups of the primer 3 containing CTP sequence
Preceding 4 base codes of code and α sequence, primer 4 contain the 4 base codes and a restriction site that α sequence 3 ' is held；
(3) it is used in the DNA profiling of reaction No. 1 and No. 2, as the template of primer 1 and 4, is fitted into base to amplify CTP- α
Cause.
The present invention further protects a kind of pharmaceutical composition, includes pharmaceutically acceptable carrier or excipient or dilution
Agent and a effective amount of above-mentioned recombination hFSH-Fc fusion protein.
The present invention further protects above-mentioned recombination hFSH-Fc fusion protein to treat answering in infertile disease drug in preparation
With.
The present invention further protects above-mentioned recombination hFSH-Fc fusion protein preparing answering in animal reproduction field of medicament
With.
The invention has the following beneficial effects: the present invention to be connected to the CTP peptide comprising 4 O-linked oligosaccharides sites
The coded sequence of FSH subunit is thin to Chinese hamster ovary with alpha subunit co-transfection by this structure with mammalian expression vector
In born of the same parents (CHO), dimer recombinant hormone is generated.The result shows that this is combined to the assembling of subunit, the folding of protein, receptor knot
Affinity and Bioactivity are closed without influence.Two CTP are connected on the coded sequence of FSH, avoid to receptor combine or
The important region of bioactivity, does not influence receptor binding affinity, does not have immunogenicity, can significantly extend volume lifetime.Together
When, the half-life period of FSH-CTP in vivo is longer, and end-stage half-life period is 2-3 times of reorganization FSH-WT, and can be weekly to infuse
It penetrates instead of injecting 7 times a day, bioactivity is higher.
Detailed description of the invention
Fig. 1 is the schematic diagram of FSH variant (A) of the embodiment of the present invention 1 comprising HCG β carboxy terminal peptide (CTP) sequence；
Fig. 2 is the schematic diagram of FSH variant (A) of the embodiment of the present invention 2 comprising HCG β carboxy terminal peptide (CTP) sequence.
Specific embodiment
Below in conjunction with the embodiment of the present invention, the technical scheme in the embodiment of the invention is clearly and completely described,
Obviously, the embodiment described is the embodiment of part of representative of the invention, rather than whole embodiments, this field are general
Other all embodiments obtained belong to protection of the invention to logical technical staff without making creative work
Range.
A kind of recombination hFSH-Fc fusion protein, the fusion protein are dimeric fusion protein, one of monomer amino
Acid sequence is followed successively by hFSH β subunit, CTP, CTP and hFSH α subunit from N-terminal to C-terminal, such as attached drawing 1；Another single amino acid sequence
Column are followed successively by CTP, hFSH α subunit, hFSH β subunit and CTP from N-terminal to C-terminal, such as attached drawing 2.
The amino acid sequence of the hFSH β subunit is as shown in SEQ ID NO:1；The amino acid sequence of the CTP such as SEQ
Shown in ID NO:2；The amino acid sequence of the hFSH α subunit is as shown in SEQ ID NO:3
Embodiment 1
Referring to attached drawing 1, two CTP sequences are connected to the carboxyl terminal of FSH β subunit with overlapping PCR method.In LTR/
Under the action of CMV promoter, mosaic gene is sequenced, is cloned into carrier for expression of eukaryon.Describe the sequence of amino acid containing CTP
The amino acid sequence (B) of the FSH α and FSH β subunit of the modification of column.By the clone containing FSH α and the FSH β subunit of modification
Carrier in combination is transfected into CHO, the production for recombinant protein.
The preparation method is as follows:
S1. FSH β-CTP is constructed；
(1) using FSH β gene as the template of primer 1 and primer 2, wherein primer 1 includes the FSH β of a restriction site
5 ' terminal sequences, primer 2 include rear 4 base codes of preceding 4 base codes of CTP and 3 ' ends of FSH β sequence；
(2) template of the hCG β-CTP gene as primer 3 and primer 4 is used, wherein primer 3 is held comprising FSH β sequence 3 '
Rear 4 base codes and CTP sequence first four base code, primer 4 include CTP sequence 3 ' hold 4 base codes and a restriction site.
(3) for reacting the DNA profiling of No. 1 and No. 2, it is used as the template of primer 1 and 4, to amplify FSH β-CTP.
S2. FSH β (CTP) 2 is constructed；
(1) using FSH β gene as the template of primer 1 and primer 2, wherein primer 1 includes the FSH β of a restriction site
5 ' terminal sequences, primer 2 include rear 4 base codes of preceding 4 base codes of CTP and 3 ' ends of FSH β sequence；
(2) template of the hCG β-CTP gene as primer 3 and primer 4 is used, wherein primer 3 is held comprising FSH β sequence 3 '
Rear 4 base codes and CTP sequence first four base code, primer 4 include CTP sequence 3 ' hold 4 base codes and a restriction site.
(3) for reacting the DNA profiling of No. 1 and No. 2, it is used as the template of primer 1 and 4, to amplify FSH β-CTP.
The building of S3.CTP- α mosaic gene；
(1) using FSH β gene as the template of primer 1 and primer 2, wherein primer 1 includes the FSH β of a restriction site
5 ' terminal sequences, primer 2 include rear 4 base codes of preceding 4 base codes of CTP and 3 ' ends of FSH β sequence；
(2) template of the hCG β-CTP gene as primer 3 and primer 4 is used, wherein primer 3 is held comprising FSH β sequence 3 '
Rear 4 base codes and CTP sequence first four base code, primer 4 include CTP sequence 3 ' hold 4 base codes and a restriction site.
(3) for reacting the DNA profiling of No. 1 and No. 2, it is used as the template of primer 1 and 4, to amplify FSH β-CTP.
Embodiment 2
Referring to attached drawing 2, CTP sequence is connected to the N-terminal of FSH α and the c-terminus of FSH β subunit with overlapping PCR method.
Under the action of LTR/CMV promoter, mosaic gene is sequenced, is cloned into carrier for expression of eukaryon.Describe ammonia containing CTP
The amino acid sequence (B) of the FSH α and FSH β subunit of base acid sequence.By the clone of the FSH α and FSH β subunit containing modification
Carrier in combination is transfected into CHO, carries out recombinant protein production.
The preparation method is as follows:
S1. FSH β-CTP is constructed；
(1) using FSH β gene as the template of primer 1 and primer 2, wherein primer 1 includes the FSH β of a restriction site
5 ' terminal sequences, primer 2 include rear 4 base codes of preceding 4 base codes of CTP and 3 ' ends of FSH β sequence；
(2) template of the hCG β-CTP gene as primer 3 and primer 4 is used, wherein primer 3 is held comprising FSH β sequence 3 '
Rear 4 base codes and CTP sequence first four base code, primer 4 include CTP sequence 3 ' hold 4 base codes and a restriction site.
The building of S2.CTP- α mosaic gene；
(1) using FSH β gene as the template of primer 1 and primer 2, wherein primer 1 includes the FSH β of a restriction site
5 ' terminal sequences, primer 2 include rear 4 base codes of preceding 4 base codes of CTP and 3 ' ends of FSH β sequence；
(2) template of the hCG β-CTP gene as primer 3 and primer 4 is used, wherein primer 3 is held comprising FSH β sequence 3 '
Rear 4 base codes and CTP sequence first four base code, primer 4 include CTP sequence 3 ' hold 4 base codes and a restriction site.
Compared with prior art, the CTP peptide comprising 4 O-linked oligosaccharides sites is connected to FSH subunit by the present invention
Coded sequence, with mammalian expression vector by this structure and alpha subunit co-transfection to Chinese hamster ovary cell (CHO)
In, generate dimer recombinant hormone.The result shows that this is combined to the assembling of subunit, the folding of protein, receptor binding affinity
With Bioactivity without influence.Two CTP are connected on the coded sequence of FSH, are avoided to receptor combination or bioactivity
Important region does not influence receptor binding affinity, does not have immunogenicity, can significantly extend volume lifetime.Meanwhile FSH-
The half-life period of CTP in vivo is longer, and end-stage half-life period is 2-3 times of reorganization FSH-WT, and can be weekly to inject replacement
It injects 7 times a day, bioactivity is higher.
Those skilled in the art is not under conditions of departing from the spirit and scope of the present invention that claims determine, also
Various modifications can be carried out to the above content.Therefore the scope of the present invention is not limited in above explanation, but by
The range of claims determines.
Sequence table
<110>Shanghai Yan founds pharmaceutcal corporation, Ltd
<120>a kind of long-acting recombinant human follicle-stimulating hormone (FSH) and its preparation method and application
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Met Leu Thr Leu Gly Pro Pro Pro Leu Pro Cys Cys Thr Leu Ala Ile
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Cys Cys Ala Ser Cys Gly Leu Thr Ala Ile Thr Ile Ala Ile Gly Leu
20 25 30
Gly Gly Cys Ala Pro Cys Ile Ser Ile Ala Thr Thr Thr Cys Ala Gly
35 40 45
Thr Cys Thr Thr Ala Ala Leu Val Thr Leu Ala Pro Ala Ala Pro Leu
50 55 60
Ile Gly Leu Thr Cys Thr Pro Leu Gly Leu Val Thr Gly Thr Val Ala
65 70 75 80
Val Pro Gly Cys Ala His His Ala Ala Ser Leu Thr Thr Thr Pro Val
85 90 95
Ala Thr Gly Cys His Cys Gly Leu Cys Ala Ser Ala Ser Thr Ala Cys
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Thr Val Ala Gly Leu Gly Pro Ser Thr Cys Ser Pro Gly Gly Met Leu
115 120 125
Gly Ser Ser Ser Ser Leu Ala Pro Pro Pro Ser Leu Pro Ser Pro Ser
130 135 140
Ala Leu Pro Gly Pro Ser Ala Thr Pro Ile Leu Pro Gly
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<213>artificial sequence (artificial sequence)
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Leu Pro Gly Pro Ser Ala Thr Pro Ile Leu Pro Gly Met
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Ala Ala Ile Thr Ala Cys Pro Gly Cys Thr Leu Gly Gly Ala Pro Pro
35 40 45
Pro Ser Gly Pro Gly Ala Pro Ile Leu Gly Cys Met Gly Cys Cys Pro
50 55 60
Ser Ala Ala Thr Pro Thr Pro Leu Ala Ser Leu Leu Thr Met Leu Val
65 70 75 80
Gly Leu Ala Val Thr Ser Gly Ser Thr Cys Cys Val Ala Leu Ser Thr
85 90 95
Ala Ala Val Thr Val Met Gly Gly Pro Leu Val Gly Ala His Thr Ala
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Cys His Cys Ser Thr Cys Thr Thr His Leu Ser
115 120
Claims (9)
1. a kind of recombination hFSH-Fc fusion protein, which is characterized in that the fusion protein is dimeric fusion protein, wherein one
A single amino acid sequence is followed successively by hFSH β subunit, CTP, CTP and hFSH α subunit from N-terminal to C-terminal；Another single amino acid
Sequence is followed successively by CTP, hFSH α subunit, hFSH β subunit and CTP from N-terminal to C-terminal；
The amino acid sequence of the hFSH β subunit is as shown in SEQ ID NO:1；The amino acid sequence of the CTP such as SEQ ID
Shown in NO:2；The amino acid sequence of the hFSH α subunit is as shown in SEQ ID NO:3.
2. recombinating the preparation method of hFSH-Fc fusion protein described in a kind of claim 1 characterized by comprising utilize overlapping
The mosaic gene of polymerase chain reaction building CTP sequence and FSH β subunit；Mosaic gene is cloned into containing LTR/CMV promoter
Carrier for expression of eukaryon in；The carrier in combination of the subunit of α containing FSH of building and FSH β subunit is transfected into Chinese hamster ovary cell
In, filter out the cell strain for stablizing expression；The FSH variant in the culture medium for carrying out the cell strain of self-stabilization expression is collected, and pure
Change obtains recombination hFSH fusion protein.
3. a kind of preparation method for recombinating hFSH-Fc fusion protein according to claim 2, which is characterized in that described chimeric
The building of gene includes the following steps: that S1. constructs FSH β-CTP；S2. FSH β (CTP) 2 is constructed；The structure of S3.CTP- α mosaic gene
It builds.
4. a kind of preparation method for recombinating hFSH-Fc fusion protein according to claim 3, which is characterized in that step S1's
Include the following steps:
(1) using FSH β gene as the template of primer 1 and primer 2, wherein primer 1 includes that the FSH β 5 ' an of restriction site is held
Sequence, primer 2 include rear 4 base codes of preceding 4 base codes of CTP and 3 ' ends of FSH β sequence；
(2) template of the hCG β-CTP gene as primer 3 and primer 4 is used, wherein primer 3 includes rear 4 that FSH β sequence 3 ' is held
The first four base code of a base code and CTP sequence, primer 4 include the 4 base codes and a restriction site that CTP sequence 3 ' is held.
(3) for reacting the DNA profiling of No. 1 and No. 2, it is used as the template of primer 1 and 4, to amplify FSH β-CTP.
5. a kind of preparation method for recombinating hFSH-Fc fusion protein according to claim 3, which is characterized in that step
Specific step is as follows by S2:
(1) use FSH β gene as the template of primer 1 and primer 2, wherein primer 1 includes the FSH β 5 ' of a restriction site
Terminal sequence, primer 2 include rear 4 base codes of preceding 4 base codes of CTP and 3 ' ends of FSH β CTP sequence；
(2) template of the hCG β-CTP gene as primer 3 and primer 4 is used, wherein primer 3 is held containing FSH β-CTP sequence 3 '
Rear 4 base codes and CTP sequence preceding 4 base codes, primer 4 contain CTP sequence 3 ' hold 4 base codes and a restriction site；
(3) it is used in the DNA profiling of reaction No. 1 and No. 2, as the template of primer 1 and 4, to amplify FSH β-(CTP) 2.
6. a kind of preparation method for recombinating hFSH-Fc fusion protein according to claim 3, which is characterized in that step
Specific step is as follows by S3:
(1) use hCG β gene as the template of primer hCG β 1 and 2, wherein primer 1 includes the 5 ' of the CTP of a restriction site
Terminal sequence, primer 2 include preceding 4 base codes of alpha subunit and rear 4 base codes that CTP sequence 3 ' is held；
(2) use α gene as the template of primer 3 and primer 4, wherein rear 43 ' end group codes of the primer 3 containing CTP sequence and
Preceding 4 base codes of α sequence, primer 4 contain the 4 base codes and a restriction site that α sequence 3 ' is held；
(3) it is used in the DNA profiling of reaction No. 1 and No. 2, as the template of primer 1 and 4, to amplify CTP- α mosaic gene.
7. a kind of pharmaceutical composition, which is characterized in that include pharmaceutically acceptable carrier or excipient or diluent, Yi Jiyou
The recombination hFSH-Fc fusion protein described in claim 1 of effect amount.
8. recombination hFSH-Fc fusion protein described in claim 1 treats the application in infertile disease drug in preparation.
9. the recombination hFSH-Fc fusion protein of claim 1 is preparing the application in animal reproduction field of medicament.
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| CN111704676A (en) * | 2020-07-17 | 2020-09-25 | 上海延立药业有限公司 | Long-acting recombinant erythropoietin and preparation method and application thereof |
| CN112195194A (en) * | 2020-10-30 | 2021-01-08 | 北京双鹭生物技术有限公司 | Recombinant human follicle stimulating hormone and preparation method thereof |
| CN113717291A (en) * | 2021-09-17 | 2021-11-30 | 南通大学 | Ultra-long-acting stable FSH, expression recombination method thereof and assisted reproduction technology |
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Application publication date: 20190628 |