CN110051830A - A kind of protease nexin II KPI protein mutant application - Google Patents
A kind of protease nexin II KPI protein mutant application Download PDFInfo
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- CN110051830A CN110051830A CN201910194270.3A CN201910194270A CN110051830A CN 110051830 A CN110051830 A CN 110051830A CN 201910194270 A CN201910194270 A CN 201910194270A CN 110051830 A CN110051830 A CN 110051830A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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Abstract
The present invention relates to a kind of protease nexin II KPI protein mutant and derivative, analog or its application for forming segment, be used to prepare treatment and acquired Hemophilia and have the hemophilia related disease of mortifier generation or the drug of illness.Present invention can apply to the preparations of hemorrhagic disease drug, especially have the haemophiliachemophiliac related drugs of mortifier, have a good application prospect.
Description
Technical field
The invention belongs to hemorrhage therapy field, in particular to a kind of protease nexin II KPI protein mutant
And its derivative, analog or its application for forming segment.
Background technique
Hemophilia A and B are the hereditary hemorrhagic diseases due to caused by blood coagulation factor VIII (FVIII) or IX (FIX) defect,
Disease incidence is 1/5000 and 1/2000 in males, shows as coagulation disorders on patient clinical, may occur in which spontaneous flesh
Meat hemotoncus and articular cavity bleeding etc..FVIII/FIX replacement therapy is currently the only effective treatment means.With biotechnology
Development, the FVIII/FIX of genetic recombination, the FVIII/FIX for having gradually replaced blood plasma or blood plasma source become replacement therapy
Primary formulation.FVIII Half-life in vivo is only less than 12 hours, and FIX also only has 24 hours or so, in order to maintain enough blood plasma
Concentration is to prevent bleeding, and patient needs to inject weekly 2~3 times, and somewhat expensive, the western countries such as U.S. in 2011 are annual according to statistics
FVIII formulations sold volume be more than 5,200,000,000 dollars, it is contemplated that 2016 can be more than 7,000,000,000 dollars.Although replacement therapy can be effectively pre-
Bleeding caused by anti-and treatment FVIII/FIX defect, but have 30% haemophiliac can generate over the course for the treatment of it is anti-
FVIII antibody, small part hemophilia B patient can also generate FIX antibody, replacement therapy caused to fail, it has to use high dose
The drug that FVIII immune induction is resistance to treated or application is including proconvertin (FVIIa) of activation etc. controls bleeding,
Medical expense is costly.It is more than 1,600,000,000 dollars to treat generation that medical insurance department, American-European countries needs ancillary cost every year
The haemophiliac of FVIII/FIX mortifier.Generation and the direct phase of dosage in FVIII preparation replacement therapy of FVIII antibody
It closes, replacement therapy is because of the high dose carried out under the bleedings emergencies such as operation, wound to children haemophiliac for the first time
When FVIII hemostatic treatment, the probability that FVIII mortifier generates is dramatically increased, and dosage is higher, and treatment time-histories is longer, and FVIII inhibits
Object is more easy to produce, and the probability that mortifier generates when dosage is higher than 35IU/Kg is less than 2.4 times of 35IU/Kg treatment group.Blood
Friendly disease bleeding performance in blood plasma FVIII or FIX activity it is related, however, patient similar in coagulation factor activity is horizontal out
Blood severity is still different.Studies have found that proposing, the genetic risk factors and hemophilia of pro-thrombotic coexist may
Improve the bleeding severity of haemophiliac.Clot strength has the quantity of fibrin ferment caused by Coagulation test related, blood coagulation
Enzyme can also convert its work for PROTEIN C under the auxiliary of the thrombomodulin on endothelial cell other than having the function of to promote to coagulate
The aPC of change form.For the latter using protein s as co-factor, catalytic pyrolysis simultaneously inactivates FVa and FVIIIa, limits the model of Coagulation test
It encloses and intensity.In addition to heredity PC lacks, labile factor (FV) Leiden mutation is because it has resistance to the cracking of aPC
Effect, is all the genetic risk factors of thrombophilia.Haemophiliac exists simultaneously FV Leiden or PC defect, bleeding
It shows slight compared with other patients.
Protease nexin II KPI be a kind of two 6,500Da of molecule peptide molecule, be protease nexin
The constituent of II albumen, is expressed in the Various Tissues of human body, such as nerve cell, blood platelet etc..protease nexin
II KPI polypeptide chain be made of 57 amino acid residues.Protease nexin II KPI albumen physiological function be specificity
Activation plasma thromboplastin antecedent mortifier.Protease nexin II KPI be all serpin suppression
Peptase is homologous in structure.Aprotinin passes through its height to fibrinolysin (Ki~1nM) and kallikrein (Ki~30~36nM)
Specific inhibitory activity is spent to inhibit fibrin degradation, while Aprotinin is also with other albumen of relatively low activity suppression
Enzyme, it is with medium inhibitory activity but compound to FVIIa/TF to FXIa (1.1uM) and activated protein C (Ki~1.1~2.6uM)
Object (Ki > 10uM), FXa (Ki > 10uM) or fibrin ferment (Ki~27~61uM) have little effect.Aprotinin is in openheart surgery
It can dramatically reduction amount of bleeding, reduce the blood transfusion needs in such operation.But Aprotinin derives from animal tissue's (mainly ox lung
It is dirty), it is possible to create the adverse reactions such as allergy are transformed by homologous protein, by protease nexin II in human body in KPI
Amino acid substitution changes its enzyme inhibition, thus the blood coagulation enhancing effect similar with Aprotinin.protease nexin II\
KPI mutant R15K/M17K and R15K/M17R inhibits the affinity of object plasma thromboplastin antecedent to be remarkably decreased its physiology, by 2nM
Increasing is 3081 and 707nM, but is reduced to 8nM or so by 200nM to the inhibitory activity of fibrinolysin, has prompted its anti-fibrinolysis activity
Enhancing.Meanwhile the inhibiting effect of aPC is also enhanced.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of protease nexin II KPI mutant (R15K/
M17K) and its derivative, analog or its application for forming segment, the R15K/M17K mutant have the work of Activated protein C resistance
Property and inhibit Fibrinolysis characteristic, can by weaken body anticoagulation, enhancing independent of plasma thromboplastin component (FIX)/
The Coagulation test of blood coagulation factor VIII (FVIII) promotes body entirety coagulation function, to correct caused by deficiency of coagulation factors
Coagulation function defect can be applied to the preparation of hemorrhagic disease drug.
The present invention provides a kind of protease nexin II KPI mutant (R15K/M17K) and derivative, analog
Or its application for forming segment, be used to prepare treatment and acquired Hemophilia and have mortifier generation hemophilia related disease or
The drug of illness.
The related disease or illness are deficiency of coagulation factors, and with coagulation factor antibody or may inhibit produce simultaneously
It is raw.
The protease nexin II KPI mutant (R15K/M17K) amino acid sequence such as SEQ ID NO:1 institute
Show.
The protease nexin II KPI mutant (R15K/M17K) merge to be formed with other fusion proteins
Protease nexin II KPI mutant (R15K/M17K) fusion protein.
The fusion protein is human albumin, 1 antitrypsin of immunoglobulin Fc, transferrins or alpha.
The present invention also provides a kind of protease nexin II KPI mutant (R15K/M17K) albumen preparation side
Method includes the following steps:
(1) by protease nexin II KPI mutant (R15K/M17K) gene be connected into carrier, obtain recombination carry
Body；
(2) above-mentioned recombinant vector is converted into host cell, obtains expression recombinant cell clone, cell can be mammal
Cell, insect cell, fungi or bacterium；
(3) the above-mentioned recombinant cell clone of continuously perfused culture or fungi bacterial fermentation in serum free medium, induction weight
The expression of group Aprotinin；
(4) isolate and purify, filter, last filling, freeze-drying, obtain expressed protease nexin II KPI mutation
Body (R15K/M17K) albumen.
Purifying in the step (4) includes just pure and mild consummate.
The present invention provide comprising protease nexin II KPI mutant (R15K/M17K) (recombination or animal tissue
Purification) drug prevent and/or treat disease, wherein the disease mainly includes hemorrhagic disease or various originals for diagnosing
The bleeding because caused by；Wherein, most probable hemorrhagic disease is hemophilia A and B, i.e., due to hereditary coagulation factors VIII or IX
Hemorrhagic disease caused by lacking, and including the hemophilia A and B that wherein there is inhibiting antibody to generate or the day after tomorrow because of mortifier
Acquired blood coagulation factor VIII or IX caused by generating lack；And other hemorrhagic diseases using bypass preparation, such as newly
Raw youngster's blood coagulation disorders；Serious liver diseases；High risk operation；Traumatic blood loss；Bone-marrow transplantation；Thrombopenia and blood are small
Plate dysfunction；Take orally anticoagulant urgent reverse；The defect of congenital factor V, VII, X and XI；Von Willebrand disease, and
Acquired von Willebrand Disease caused by vWF ELISA mortifier, and largely damages related blood loss, cerebral hemorrhage,
Dysfunction of platelet.
Beneficial effect
Protease nexin II in the present invention KPI mutant (R15K/M17K) there is the activity of Activated protein C resistance
With the characteristic for inhibiting Fibrinolysis, by inhibiting body anticoagulating active, correct because of clotting defect caused by deficiency of coagulation factors and
Bleeding performance, therefore by promoting blood solidifying independent of plasma thromboplastin component (FIX)/blood coagulation factor VIII (FVIII) mechanism
Collection promotes body entirety coagulation function, plays anastalsis, therefore can be applied to the preparation of hemorrhagic disease drug, especially right
There is the preparation of the related drugs of the Treatment of Hemophilia of mortifier, due to the transformation that it is the intrinsic albumen of human body, compared with animal-type
Protein immunization is small, highly-safe, has good treatment use prospect.
Detailed description of the invention
Fig. 1 be protease nexin II KPI mutant (R15K/M17K) inhibit activated protein C effect diagram；
Fig. 2A and B be protease nexin II KPI mutant (R15K/M17K) correct hemophilia A and have a mortifier
Blood coagulation generates the schematic diagram of defect in existing hemophilia A plasma；
Fig. 3 be protease nexin II KPI mutant (R15K/M17K) correct hemophilia A mouse dock amount of bleeding
Schematic diagram；
Fig. 4 be protease nexin II KPI mutant (R15K/M17K) promote hemophilia A blood in the micro- damage of blood vessel
Blood clotting schematic diagram in wound.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, those skilled in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Range.
Embodiment 1
Protease nexin II KPI mutant (R15K/M17K) to the inhibiting effect of PROTEIN C
In purifying protein system, by the protease nexin II of various concentration KPI mutant (R15K/M17K) with
Activated protein C reacts jointly, and by aPC specificity luminous substrate detection by protease nexin II KPI mutant
(R15K/M17K) inhibit after remaining aPC activity, the results show that with protease nexin II KPI mutant
(R15K/M17K) concentration increases, and the activity of aPC gradually decreases, protease nexin II KPI mutant (R15K/M17K)
To the inhibitory activity (IC50~1uM) (Fig. 1) with moderate of aPC.
Embodiment 2
Protease nexin II KPI mutant (R15K/M17K) correct hemophilia A, B patients blood plasma and have mortifier
Hemophilia A patients' blood plasma in fibrin ferment generate defect
Fibrin ferment generates test (thrombin generation test, TGT): it is raw to can be used for assessing fibrin ferment in blood plasma
It is a kind of whole coagulation function test of analogue body intravascular coagulation condition at ability, has reacted the summation effect of blood coagulation and anticoagulation system
It answers.Blood plasma Coagulation test is to obtain starting activator (containing tissue factor and phosphatide) is added afterwards, and fibrin ferment is generated by specificity
Fluorogenic substrate detection, is changed by FLUOROSKAN Fluorescent reader dynamic monitoring fluorescence intensity, and raw using specific fibrin ferment
At experiment software by fluorescence signal conversion digital signal, fibrin ferment formation curve is drawn.It can be with from several parameters of formation curve
Fibrin ferment generative capacity: (1) delay time (lag time) is evaluated, i.e., is taken since reaction to generating fibrin ferment
Between；(2) peak value (peak), that is, the fibrin ferment maximum generated；(3) peak time (time to peak, ttpeak), i.e., from anti-
The time required to should starting to fibrin ferment reach to peak value；(4) fibrin ferment generate potentiality (endogenous thrombin potential,
ETP), i.e., area under fibrin ferment formation curve, reaction fibrin ferment generate total amount.When the thrombus tune that solubility is added in Coagulation test
After saving plain (TM), PROTEIN C activation inhibits fibrin ferment to generate, can react influence of the anticoagulation system to whole blood coagulation.
Containing/without containing mortifier haemophilic plasmas in be added protease nexin II KPI mutant
(R15K/M17K) (30uM) starts Coagulation test TF is added, has a certain amount of fibrin ferment to generate in blood plasma, but as addition TM
After activated protein C, anticoagulation system plays a role, almost without progress fibrin ferment generation.When protease nexin II KPI mutation
After reaction system is added in body (R15K/M17K), the inhibiting effect that PROTEIN C generates fibrin ferment can be turned with Partial Inverse, remain blood
The ability that fibrin ferment generates in slurry.Compared with the effect in the haemophilic plasmas of unrestraint object (Fig. 2A), protease nexin
II this anti-PROTEIN C of KPI mutant (R15K/M17K) ability that promotes fibrin ferment to generate be not inhibited the influence (Fig. 2 B) of object.
Embodiment 3
Protease nexin II KPI mutant (R15K/M17K) improve hemophilia mouse dock bleeding phenotype
By protease nexin II KPI mutant (R15K/M17K) enter through tail vein injection 4-8 weeks hemophilia
Make in blood plasma in Mice Mice model protease nexin II KPI mutant (R15K/M17K) Cmax reach 30uM.Together
When injecting normal saline as negative control, (Cmax is that normal 100%) is positive control to blood coagulation factor VIII.Mouse fiber crops
It is to dock at 2mm, and tail is overhang and is placed in room temperature PBS buffer solution in rat-tail end diameter after liquor-saturated, timing 10min, detection examination
The concentration of hemoglobin in pipe, according to the amount of bleeding of hemoglobin content measuring and calculating docking, with the hemophilia mouse bleeding of saline treatment
Amount is control (100%) (Fig. 3).Protease nexin II KPI mutant (R15K/M17K) to substantially reduce hemophilia A small
The bleeding phenotype of mouse, lacking caused clotting defect to blood coagulation factor VIII has improvement result, when Cmax is 30uM
The anastalsis played can be similar to the haemostatic effect of 100% blood coagulation factor VIII, similar with the amount of bleeding of normal mouse.
Embodiment 4
Protease nexin II KPI mutant (R15K/M17K) promote hemophilia A blood in blood vessel micro-damage
Blood clotting
After tail vein injection fluorescent marker blood platelet, hemophilia mouse mesenteric microvessels are separated under microscope, are swashed
Light injury local vascular observes platelet aggregation.Protease nexin II KPI mutant (R15K/M17K) Cmax reach
(Cmax is that normal 100%) is similar to the ability of blood clotting, is shown very strong non-solidifying with blood coagulation factor VIII when to 30uM
The rush that blood factor VIII is relied on coagulates ability (Fig. 4).
SEQUENCE LISTING
<110>Suzhou Xin Ning biological medicine Science and Technology Ltd.
<120>a kind of application of protease nexin II KPI protein mutant
<130> 1
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 57
<212> PRT
<213>artificial sequence
<400> 1
Glu Val Cys Ser Glu Gln Ala Glu Thr Gly Pro Cys Lys Ala Lys Ile
1 5 10 15
Ser Arg Trp Tyr Phe Asp Val Thr Glu Gly Lys Cys Ala Pro Phe Phe
20 25 30
Tyr Gly Gly Cys Gly Gly Asn Arg Asn Asn Phe Asp Thr Glu Glu Tyr
35 40 45
Cys Met Ala Val Cys Gly Ser Ala Ile
50 55
Claims (5)
1. a kind of protease nexin II KPI mutant, derivative, analog or its form segment application, feature
It is: being used to prepare treatment and acquired Hemophilia and have the hemophilia related disease of mortifier generation or the drug of illness.
2. application according to claim 1, it is characterised in that: the related disease or illness are to lack with coagulation factor
Antibody or mortifier.
3. application according to claim 1, it is characterised in that: the protease nexin II KPI mutant ammonia
Base acid sequence is as shown in SEQ ID NO:1.
4. application according to claim 1, it is characterised in that: the protease nexin II KPI mutant and its
His fusion protein merge to be formed protease nexin II KPI mutant fusion protein.
5. application according to claim 3, it is characterised in that: the fusion protein be human albumin, immunoglobulin Fc,
1 antitrypsin of transferrins or alpha.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910194270.3A CN110051830A (en) | 2019-03-14 | 2019-03-14 | A kind of protease nexin II KPI protein mutant application |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910194270.3A CN110051830A (en) | 2019-03-14 | 2019-03-14 | A kind of protease nexin II KPI protein mutant application |
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| CN110051830A true CN110051830A (en) | 2019-07-26 |
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5304482A (en) * | 1989-03-06 | 1994-04-19 | The Board Of Regents Of The University Of Texas System | Serine protease mutants of the chymotrypsin superfamily resistant to inhibition by their cognate inhibitors |
| WO1996035788A2 (en) * | 1995-05-08 | 1996-11-14 | Scios, Inc. | Kunitz type protease inhibitors |
| WO1999063090A2 (en) * | 1998-06-03 | 1999-12-09 | Scios, Inc. | Protease inhibitor peptides |
| CN1882357A (en) * | 2003-11-20 | 2006-12-20 | 诺和诺德医疗保健公司 | Therapeutic use of factor XI |
| US20090004175A1 (en) * | 2004-07-16 | 2009-01-01 | Novo Nordick Health Care A/G | Methods for Optimizing Forming Vlla-Based Hemostatic Treatment |
| WO2015002611A1 (en) * | 2013-07-01 | 2015-01-08 | National University Of Singapore | Compositions and methods for inhibiting thrombogenesis |
| US20160311887A1 (en) * | 2013-12-13 | 2016-10-27 | Cambridge Enterprise Limited | Modified serpins for the treatment of bleeding disorders |
| CN109316599A (en) * | 2018-08-24 | 2019-02-12 | 上海交通大学医学院附属瑞金医院 | Application of aprotinin or mutant, derivative, analogue or constituent fragment thereof |
-
2019
- 2019-03-14 CN CN201910194270.3A patent/CN110051830A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5304482A (en) * | 1989-03-06 | 1994-04-19 | The Board Of Regents Of The University Of Texas System | Serine protease mutants of the chymotrypsin superfamily resistant to inhibition by their cognate inhibitors |
| WO1996035788A2 (en) * | 1995-05-08 | 1996-11-14 | Scios, Inc. | Kunitz type protease inhibitors |
| WO1999063090A2 (en) * | 1998-06-03 | 1999-12-09 | Scios, Inc. | Protease inhibitor peptides |
| CN1882357A (en) * | 2003-11-20 | 2006-12-20 | 诺和诺德医疗保健公司 | Therapeutic use of factor XI |
| US20090004175A1 (en) * | 2004-07-16 | 2009-01-01 | Novo Nordick Health Care A/G | Methods for Optimizing Forming Vlla-Based Hemostatic Treatment |
| WO2015002611A1 (en) * | 2013-07-01 | 2015-01-08 | National University Of Singapore | Compositions and methods for inhibiting thrombogenesis |
| US20160311887A1 (en) * | 2013-12-13 | 2016-10-27 | Cambridge Enterprise Limited | Modified serpins for the treatment of bleeding disorders |
| CN109316599A (en) * | 2018-08-24 | 2019-02-12 | 上海交通大学医学院附属瑞金医院 | Application of aprotinin or mutant, derivative, analogue or constituent fragment thereof |
Non-Patent Citations (3)
| Title |
|---|
| NAVANEETHAM,D等: ""Chain B, Crystal Structure Of The Catalytic Domain Of Coagulation Factor Xi In Complex With Kunitz Protease Inhibitor Domain Of Protease Nexin Ii"", 《NCBI PROTEIN》 * |
| NAVANEETHAM等: ""P1 and P2 " site mutations convert protease nexin-2 from a factor XIa inhibitor to a plasmin inhibitor"", 《JOURNAL OF BIOCHEMISTRY》 * |
| 贺石林等: "内在凝血途径的接触激活――抗血栓形成研究的新靶点", 《血栓与止血学》 * |
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Effective date of registration: 20200108 Address after: No. 16, qiaotouhu street, middle Qiaojing Road, Ninghai County, Ningbo City, Zhejiang Province Applicant after: Ningbo baishening Biomedical Technology Co.,Ltd. Address before: 215400 LA14, Building 11, University Science Park, No. 20 Jianxiong Road, Taicang Science and Education New Town, Suzhou City, Jiangsu Province Applicant before: Suzhou Xinning Biomedical Technology Co.,Ltd. |
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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190726 |